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New England ]ournal of Medicine

Established in 1812 as The NEIV ENGLAND JOURNAL OF MEDICINE AND SURGERY

VOLUN'IE 33I

\o\rE\tBER

10. 199.t

NUN,IBER

19

Original Articles
Low Serum Thyrotropin Concentrations a Risk Factor for Atrial Fibrillation in Older Persons
C.'f. SlrvIx
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Case Records of the Massachusetts General Hospital

L249

A 77-Year-Old Woman with Fever, Sweats, and Pain in the Head and Legs
\I. H.r;us l:o E."l'. HrpI-cv-\\'Hvrs

..

L293

Orrrlns

Bone Marrow Transplants from HLA-Identical Siblings as Compared with Chemo. therapy for Children with Acute Lymphoblastic Leukemia in a
Second

Editorial
a Low Subclinical Hyperthyroidism - Just or Serum Thyrotropin Concentration, 1253

Remission

....., . ..

SomethingMore?.

.......

1302

AJ. Bannur .rxo ()rnens

R.D. Urrr;rn

Accumulation of Nuclear p53 and Tumor Progression in Bladder Cancer

D. llsnrc ,c..'o OrrrEps

Sounding Board
1259

Cost-Savings For Every Dollar Spent - The Argument for Prenatal ... 1303 Care .. J. Hurrrxcrox .lxo F.A. Coxxrlr

correspondence Medicine coronary Arteriovenous Fistula on coronary .^^. iii}i::ii[l:"Jrl;;; : : : :: ::: : : :: li33 Angiography " " ' l2ti5 Acetaminophen Poisoning and Liver Function. . . 1310
Images in clinical
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Fr.Jrse

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Mineral Balance in Postmenopausal Women

Special Article
State Practice Environments and the Supply

. Treated with Potassium Bicarbonate .... Pulmonary-FunctionTesting

Risksof

Physician Assistants, Nurse Practitioners, , an Certified Nurse-Midwives . .. 1266 E.S. Sr.xscr:xsxI, S. Srrsorr. C. Brzrr.l' II.E. Srrrror.., esii F. \It'rr..rr

of

...... 1314 Cancer Therapy Meets p53 Postmortem Vififty of H..-u. Immunodeficiency Virus - Implications for the Teaching of .. . 1315 Anatomy
The Train Is Leaving the

slmeterol?.......

.... l3l4

1312 1313

Occasional Notes Station

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316

Review

Articles
-

B']' \\'IrLr'+,s

Medical Progress: Severe Adverse Cutaneous ' ) .....( tZZ Books Received /. Reactioris to Drugs '\-r' Notices / .J.C. Rorrrrr' :so R.S. S'runx

-'

Book Reviews

..

.
.

l3l7
1320 1323

. '

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^--^. T---^r^-*:-Transforming Mechanisms of Disease:

MoreontheGUsTotrial"' GrowthFactoiBirrri.ro"Fibros"is..... 1286 Information for Authors fV..n. Bororn rro \.A. \oerr
(Jwned, OCopyrighted, 1994, by the Massachusetts Medical Society anq euuPrrr5r ruDllsneq' and Owned, published,

Correction

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..

1323 1324

ithe\Iassachusetts\1edicalSocietrirrrdprirlttclinErrqIand \\'cst Pornav. .\ndovcr. SPI[) 3SF. U.K bv St. Ii.cs (ndoicr) Lrd.. \ Rcgistered as a ne\\.spapcr at the Post Olice lSS\ 0028-+793' \r ,' , -l-rl .L tt-/

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TIre Europea

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Improving survival in patients with coronary heart disease: the role of lipid management.
A special progralzrrne based on tbe Results presentaton of tbe 45 Study at a bot-line session of tbe American Heart Association meeting in Dallas on 17 Nouember 1994

22 November

23 November
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Quafity of fe, quality of care in oncology Therapeutic strategies in osteoporosis Optic nerve health
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6 December L3 December

Earlier 1994 prograrnmes available on VIIS cassette include: Euthanasia: the example ofThe Nethedands . Diagfrosis and treatment of biliary strictures . AIDS patients: emerging trends in fungal infections . The Menopause:the consequences of hormonal change . Secondary prevention of CHD in women . New guidelines for the delaying of progression of renal disease . Innovations in the treatment of schizophrenia . ESC Guidelines on the prevention of CHD in clinical practice
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Officiol iournol of rhe lnlernotionol Epidemiologicol

Ass'c"'n

lnternotionql Journol of

Epidemiology
Sex Differences in Measles Mortality: A World Revier,r,'

Editor: Peter O D Phorooh, Deporiment of Public Heolth, Universi of Liverpool, Liverpool, L K The International Journal of Epidemiology continues to be the leading journal in its field, and is essential reading for anyone who needs to keep up-to-date with the very latest developments throughout the world.
The joumal has for many years encouraged communica-

Michel Garenne.
Volume 23, nurflber 4 Forced Movements of Population and Health Hazards in Tropical

Africa. R mansell Prothero.

Myocardial lnfarction Case-Fatality Gradient in Three French Regions: 01 Acute Coronary Care. Phillipe Amouyel, Dominique Arveiler, Jean-Piere Cambou, Michle M0ntaye, Jean-Benard Ruidavets, Annie Bingham, Paul Schafler and Jaccyues-Lucien Richard.

tion among those engaged in the research, teaching and

application of epidemiology of both communicable and

he lnfluence

non-communicable disease. Research into health services and medical care is also covered, as are new methods for the analysis of data used by those who
practice social and preventative medicine.

Determinants of Stunting and Recovery from Stunting in Northwest Uganda. Venanzio Vella, Andnw Tomkins, Amandlo Borghesi, Giovanni Batlisla Migliori and Vincent Yooman 0nyem.

Volume 23, number 5 Volume 23, number

1

Stratospheric 0zone and Health. Bruce K Armslrong.

Space-Time Clustering in lnsulin-Dependent Diabetes Mellitus (IDDM) in South-East Sweden. Ull Samuelsson, Calle Johansson, John Carstensen and Johnny Ludvigsson. DNA Probes as Epidemiological Tools for Surveillance ol Plasmodium falciparum Malaria in Thailand. Bobert H Barker Jr,

Short-erm Etlects of Air Pollution on Daily Mortalily in Athens: A Time-Series Analysis. G Touloumi, S J Pocock, K l(atsouyanni and
D Trichopoulos. W-@tuil@@d.-d+3iiM+.i e6i
D

Trairal Banchongaksorn, Jeanne M Gourual, Illhnnapa Suwonkerd, Kamolwan Bimwungtlagoon, Nitaya Srittong and Dyann F Wirlh.
Volume 23, number

Modelling AIDS Reduction Strategies.

A Kault.

Drtferential Response to Early Nutrition Supplementation: Long-Term Effects on Height at Adolescence. M T Ruel, J Rivera, J-P Habicht and R Martorell.

Verbal Auiopsies Tor Adult Deaths: lssues in their Development and Validation. 0aniel Chandramohan, Gillian H Maude, Laura C Rodriques and Richard J Hayes. Childhood and Adolescent Passive Smoking and the Risk of Female Lung Cancer. Fu-Lin Wang, Edgar John Love, Ning Liu and

Mortality Following Radiation Treatment for lnfertility of Hormonal E Ron, J D Boice Jr, S Harnbuqer and M Stovall.

0rigin or Amenorrhea.

Changing Patterns in the Epidemiology and Hospilal Care o1 Peptic Ulcer. P Primalesla, M J Goldacrc and V Seagroatt.

Xu-Dong Dai. Why lnfant Very Low Birthweight Rates have Failed to Decline in the United States Vital Statistics. Samuel Sepkowitz.
Prevalence and Causes ol Visual lmpairment in ltaly.

Determinants of Excellent Health: Ditferent from the Determinants of lll-Health? J P Mackenbach, J van den Bos, I M AJoung, H van de Mheen and K Stronks.

Allredo Nicolosi, Paolo and Stelano Miglior.

Marighi, Paola Fizzardi, Alberto Osella

A Mathematical Model for the Prediction of the lmpact of HIV lnfection 0n Tuberculosis. Michael Schulzer, M P Radhamani, Stelan Grzybowski, Edwin Mak and J Mark Fitzgerald.
Volume 23, numbet 3

Differential ETTects oT Tar Content, Type of Tobacco and Use oT a Filter on Lung Cancer Risk in Male Cigarette Smokers. Simone Benhamou, Ellen Benhamou, Ariane Auquier and Roberl Flamant.
Diarrhoea - Defining the Episode. Saul S Mottis, Simon N Cousens, Claudio F Lanala and Betty R Xilkwood.

l^. ; Please send me subscriplion details and rr free sample copy I of the lnternational Journal of Epidemic,logy. I I (Ee4t2) I I I I I etease return to: Journals Marketing Depl,, O:dord University press, Walton Street, Oxford OX2 6DP, UK. Tel: (O) A65 56767 I . Fax: +44 (O) 865 267773. ln N. America, +44 please return to: Journals I Marketing Dept., Oxford University press, 2001 Evans Road, Cary, I NC 27513, USA. Iel: 919 677 0977 Fax: gtg 677 1714

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The New England

Jolrrnal of Medicine
@Copyright. 1994, by the Massachusetts Medical Society

\iolume

331

\OVE\IBER

10. 199+

\umber l9

LOW SERUM THYROTROPIN CONCENTRATIONS AS A RISK FACTOR FOR ATRIAL FIBRILLATION IN OLDER PERSONS
Ct-.c,nr

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\{.D.. Axoxlrv Gr:,I-lrn., \I.D.. Prrrr-rp A. \\rolr. \I.D., Ar-saR.rJ. Brlexcar<, NI.A.. Ennol B.rrrr. Pn.D.. P..rrrrr.r B.lcH.rrrc:H, 8.A., Pr,rE'n \\'.F. \\'rr-sox, \I.D.. Elrr.r-rr.|. BrxJ.l,urx. I,I.D.. exo Rer.pn B. D'--\cosrrro. Pn.D.
Low serum thyrotropin concen-

Abstract Background.

trations are a sensitive indicator of hyperthyroidism but

can also occur in persons who have no clinical manifesta-

tions of the disorder. We studied whether low serum thyrotropin concentrations in clinically euthyroid older persons are a risk factor for subsequent atrial fibrillation. Methods. We studied 2007 persons (814 men and 1193 women) 60 years of age or older who did not have atrial fibrillation in order to determine the frequency of this arrhythmia during a 1O-year follow-up period. The subjects were classiied according to their serum thyrotropin concentrations: those with low values (<0.1 mU

per liter; 61 subjects); those with slightly low values

(>0.1 to 0.4 mU per liter; 187 subjects);those with normal values (>0.4 to 5.0 mU per liter; 1576 subjects);
and those with high values (>5.0 mU per liter; 183 subjects).

Results. During the 1O-year follow-up period, atrial fibrillation occurred in 13 persons with low initial values for serum thyrotropin, 23 with slightly low values, 133 with

among those with normal values (P : 0.005). After adjustment for other known risk factors, the relative risk of atrial fibrillation in elderly subjects with low serum thyrotropin concentrations, as compared with those with normal concentrations, was 3.1 (95 percent confidence interval, 1.7 to 5.5; P<0.001). The 1O-year incidence of atrial fibrillation in the groups with slightly low and high serum thyrotropin values was not significantly different from that in the group with normal values. Conclusions. Among people 60 years of age or older, a low serum thyrotropin concentration is associated with a threefold higher risk that atrial fibrillation will develop in the subsequent decade. (N Engl J Med 1994;331:1249-52.)

those with low values and 10 per 1000 person-years

normal values, and 23 with high values. The cumulative incidence of atrial fibrillation at 10 years was 28 percent among the subjects with low serum thyrotropin values (<0.1 mU per liter), as compared with 11 percent among those with normal values; the age-adjusted incidence of atrial fibrillation was 28 per 1000 person-years among

roidism. ,\mong older people. in u'hom atrial fibrillation is common.r-r hvpertht,roidism is relatitelv Llncommon, hou'ever.'''; Thus. although hl'perthvroidism is a risk factor lor atrial fibriliation, most oldcr people tvith atrial fibrillation do not have h,vperthvroidism.s!' Subclinical h,vperthvroidism. defined as a lou, serum thvrotropin concentration in an asvmptomatic p"..on r,vith normal
hr perthr

l_\ of

ATRIAL fibrillation

is a well-knorvn manilestation

serum thr.roid hormor-re concentrations. is more common amons older persons than overt hvperthyroid-

ism. For example, altcr patients taking thr-roid hormone havc been excluded, Iow serum thl,rotropin
concentrations have been lound in 0.9 to 1.9 percent of
From thc Medical and Medical Research Seruices. Boston Vcterans Affairs Medical Center. Boston (C.T.S.. A.G.. 8.8., P.B.): the Section oT Prevenrive Medicine and Epidemiology-. Evans Memorial Depanment of Clinical Research (P.A.W.). and thc Departments of Neurology (P.A.W.). l\'lathematics (A.J.B.. R.B.D.), and Medicine (C.T.S.. E.J.B.). Boston University, Boston; and thc Framingham Heart Study. Framingham. Mass. (P.A.W.. P.W.F.W.). Address reprint requests to Dr. Sawin at the Boston Veterans Altirs Medical Center. 150 S. Huntington Ave.. Boston. MA 02130. Supponed in pan b) the N{etlical Research Service. Depanment of Veterans Affairs: bl grants from the National lnstitute of Neurological Disorders and Srroke (2-R0l-NS'17950-12). the National Heart. Lung. and Blood Institute (R0l-HL.l042l-04). and Boots Pharmaceuticals: and b1' a contracl (NOl-HC38038) with the National Heart. Lung. and Blood Institute.

older pcrsons, Iu' ol r,r,hom rvere judged to have clinical irvperthr,roidism. ro- 5 \\'hether people rvith subclinical hr.perthvroidism have an increased risk of atrial fibrillation is unknorvn. Because atrial fibrillatiorr is an independent risk factor frrr stroke and can dccrease cardiac output, it is important to identifv anv factors that preclispose paticnts to have tiris arrhythmia. To assess this risk u.e examined prospectivelv the incidence of atrial fibrillation in relation to serum thvrotropin concentrations over l0 vears among older people (more than 60 vears ol age) r,vho rvere participating in the Framinsham Heart
I

Studv.

Mrrrroos
studied all the members of the original cohort ol the Framingham Heart Studr rrho rvere 60 r'ears ol'aee or oldcr at thc time ol' the l5th biennial exanrination in 1978 through 1980. 'flrose

\\'c

nho h:rd atrial Iibrillation ar rhar rirne or had a historv of

the

:rrrhvthmia uere excludccl. :rs \!ere t\\'o subjects krund to hivc clinical hvpt'rthvroidism at tliat cxamination. Subject,. rvho did not return lbr anv follorr'-up esaminations altcr the l5th L'xarninJti()n \\ crr: also excluded. \\'e revieuecl the records of thc remainine 2007 pcrsons (Bl4 mcn ancl Il93 nomcn) to dcternriue uhether thev rvere takinq a thvroid hornrone prcpararion ar the rime of the lith esanrinatiorr and to idenril\ atrial fiLrrillation occurring during the nest I0 lears. The 60 subjects rith a histon ol lrr perthvroidism beforc the

250

THE,

\E,\\' E\GL:\\D JoUR\,\L OF \IEDIC]I\E

\or'. Rrsur-rs

10. 1994

I 5th examination and the I I 5 subjects rlho rlcre taking a thr roid hormone preparation at that time nere includecl.'l'hosc rvith a histon' ol hvperthvroidism had been treated uith surgeri' (21) subjects), antithvroid druss (15 subjects). radioiodine (13 subjects), or iodine (ir sulr.jccts): had not bcen treated (l sutrject)l or thcir treatmcnt \\'ils unknortn (3 subjccts). total of l()*B ol the men and women stuclied at the l5th examination returned lbr the 2Oth examination: 6+8 persons had dicd in the interim. and the other 3l I had rcturned f<rr onc or more of the intcrvening exarminations. Serum sample s u cre collccted during the l 5th examination and stored at -20'(1. Serum thvrotropin cr,ncentrations rrere mt'asurecl in 1990 and l99l uith ;r chemoluminescence assav (London l)iagnostics. Eden Prairic. \linn.: this assav is norl madc br' \ichols Institutc Diagnostics, San.Juan Capistrarlo. Clalif.): the sensitiritr of the assav rvas 0.005 mU per liter, and the interassav coefcicnt o1' variation *as 5 perccnt at I mU pcr liter and I I pcrcent at 0.0,1 mU per liter. Srrum thvrotropin conccntrations liad been measurcd in l98l through 1983 u,ith an older radioimmunoassar-.r'i'fhe nrcan of' the serum thvrotropin concentrations that u'ere greater than 5 mU per liter and less th;in or equal to l0 mU per liter uas 6.8 mU pcr liter rvhen measured bv the older assav and 6.7 mU per liter bv the newer zrssa).; lor valucs abovc 1 0 rnU per lite r, the meirns rqerc I 7.9 mU per liter and 16.8 mU per liter. respectivelv.'l'he correlation coe{licient of the t\\'o assat's lor values above 5 mU per liter rvas 0.91. These results inclicate the stabilitv of serum thvrotrupin cuncentrations mcasured in lrozen serum samples. Iror the neu er assar', the normal range ol'serum thyrotropin values in vounger adults lvas from >0.4 to 5.0 mU per liter. Serum thvroxine concentrations \rcre nleasured in I98l through l9B3 b,v radioimmunoassav (Diagnostic l)roducts. Los Aneeles): thc normal range ras -1.7 to 12.0 pg per deciliter (60 to 15-l nmol per liter). Sixtr,-fir'c persons (52 rvomen and l3 men) tere takins estrogen at (he time ol the I5th examinationl amclng thosc takins estrogen rvho had normal serum thyrotropin tuncentrations and rlere not taking a thyroid hormone preparation. the mean serum thvroxine concentration rvas 7.6 pg per deciliter (98 nmol per liter). indicatine that the estrogen therapv had little ellcct on the serum thvroxine concentration. r\ll assavs rvere done singly, sasspl those on samples rvith values outside the normal rangc. rlhich rere reassaved in du-

lncidence ol Atrial Fibrillation

During the 1O-vear follorv-up period, atrial fibrillation developed in 192 pcrsons. The overall age-adjusted rate was l2 per 1000 person-vcars ('fable 1).
lnitial Serum Thyrotropin Concentrations and lncidence of Atrial Fibrillation

Among tl.re subjects \r.ith lo$' serum thvrotropin concentrations (<0.1 mU per liter) in 1978 through 1980, the cumulative incidence ol atrial fibrillation after l0 vears was 28 percent (Fig. i)l the comparable rates in the other groups \\'ere l6 percent in the eroup with slightlv lon,serum thvrotropin values, I I percent in the group \r'ith normal values, and l5 percent in the group with high values. The age-adjusted rate of atrial fibrillation in the group lr'ith lo\r' serum thvrotropin concentrations was significantlv higher than that in the group with normal concentrations (P : 0.005) ('I'able l). There was a nonsignificant trend in the same direction for the slightll'-lou'-serum-thvrotropin and hieh-scrum-th) rotropin sroups. \Vhen the results \,vere adjusted for age and sex and for the presence of other knou,'n risk lactors ibr atrial fibrillation, including smokins. diabetes mellitus, hvpertension, left ventricular hypertrophv, myocardial infarction, congestive heart failure, and cardiac murmur, the relative risk of new atrial fibrillation in those in the lor'-serum-thvrotropin group \{as 3.1 (95 percent conlidence interval, 1.7 to 5.5), significantl,v di ferent (P<0.001) from that in the normal-serum-th)'-

plicate. rere divided irrto lour qroups a(cording to their serum thvrotropin values: those *ith values S0.l mU per liter (lo* r'alues): those rvith values )0. I to 0..1 mU pe r liter

In our analvscs. the subjects

rotropin group (Table 2). Aftcr adjustments. the subjects rvho had slightl,v lou' serum thvrotropin concentrations also had a somelvhat higher risk than those n,ith normal concentrations (reiative risk, 1.6; P:0.05). Excluding the subjects receivins thvroid hormone therapv at thc i5th examination had onlv a limited e{Iect on the relative risk in anv of the groups with abnormal scrum th1'rotropin concentrations (Table 2). Furthermore, the exclusion of those u'ho had had hyperthvroidism had no cllect rvhen the lowserum-thvrotropin group \as compared rvith the normal-serum-thyrotropin group (relatir.'e risk. 2.4; 95 percent confidence interval. 1.3 to 4.8: P : 0.007).
Relation of Serum Thyroxine to Serum Thyrotropin

(stightlv lorl values): those n'ith valucs )0.{ to 5.0 mL per liter (normal values): and those with valucs >5.0 mU pcr liter (hiqh

values). fhese categories rere based on the normal ranqe :rnd the likelihood that a serum thvrotropin valuc of 0. I rnU per liter or less is indicative ol'hvperthvroidism. \\'ith this thrrotropin assa\,. most patients rrith clinicallv evident htperthvroidism had serum thvrotropin concentrations l;clorv 0.05 mL per liter :rnd nonc had ir con(enlratiun aborc U.l rrrt per lit, r.l; Atrial fibrillation s'as diasnosed bv electrocardiosraphv pcrformed at the biennial cxaminations and during anv inrervening hospitalizations during the l0 r'ears of fbllorr-up. altcr revierv of the records bv tno cardiologists; the date of onset rvas considered to be the date of thc first electrocardiographic documentation ol atrial fibrillation. 'l'he incidence of'atrial fibrillation during the lO-r'ear lollou-up period. adjusted bv the direct method lbr the age distribution ol'the lull cohort at the l5th biennial examinarirn. rlas calculated for each uroup accordins to the Kaplan-\Ieicr techr.rique.ls Proportional-hazards analvsisrl'rr,as used to test the association of' the serum th1'rotropin groups rlith the iucidence of atrial fibrillation after adjustment for age. A multivariate model uas also computed to control Ir other knoun risk factors lor atrial fibrillation rhar \r'erc present at the I5rh examination (smoking, diabetes mellitus. hvpertension. left ventricular hlpertrophr'. mvocardial inl:rrction, conscstive heart failure. and hcart murmur). The rcsults are expressed as rates per 1000 person-\,ears of lollou-up or as relative risks. uith 95 perccnt conlidence inten'als, lor the group in question. rvith thc uroup lith normal serum thvrotropin conccntrations as the relerence group.2" Calculations rlere perlornred lor all subjects toqether and also aftcr the exclusion of those takins thvroid hormone prcparations at the l5th examination and those t'ith a histon'of'hvperthvroidism before l97B through l9B0. .\ll P values :rre b:rsed on a two-tailed
analvsis.

and Subsequent Atrial Fibrillation

concentration was rvithin the normal ranqe in 21. There u.as no relation betrveen the serum tht'roxine concentration altd the subsequent occurrencc of atrial fibrillation in the stud,v group as a u'hole (P:0.71 rn'ith adjustment lbr age : P : 0.60 with acljustmenr for age and risk factors). After adjustment for the serum thvroxine concentration. the relative risk of' atrial fi-

Subjects in the lor,r'-serum-thvrotropin group had a significantl,v higher mean (tSD) serum thvroxine concentration (8.9-t2.4,ug per deciliter [1 l5+31 nmol per literl) than those in the normal-serum-thvrotropin group (7.311.7 ttg per deciliter 194122 nmol per litcrl; P : 0.001) at the I5th examination. Amons the 25 persons in the lorv-serum-th\irotropin group who \vere not taking thvroid hormonc, the serum tht roxine

Vol.

lllll No. l1)

Lo\\.SERUII THYROTROPI\ AND ATRIAL FIBRILLATIo\

I\

oLDER PERSONS

251

brillation in thc subjects in thc lou'-serum-tl-rvrotropin group was 3.0 (95 percent confider-rce intcrval, 1.7 to 5.5: P<0.0{Jl).
Clinical Hyperthyroidism and Thyroid Hormone Treatment in Subiects in Whom Atrial Fibrillation Developed

30
c o 'E (g
TL

25

s20
E15 b10
oCC o E
G)

,\mong the l3 persons in thc lol'-serum-thyrotropin group \{'ho had atrial llbrillation during the 10-,vear follorv-up period. onlr'2 had clinical hvperthvroidism during the same period. In onl,v one of tl.rem, rvho had a recurrencc ol Graves' hy'perthyroidism that had previouslv been successfully treated, did the hyperthyroidism appear at the same time as atrial fibrillation. This person rvas also the onh' I of the 13 rvho had a serum thvroxine concentration above I0 trrg pcr deciliter (129 nmol per liter) at the l5th cxamination; hcr serum thvroxine concentration at this time lvas I4.4 pg per decilitcr (185 nmol per liter) . Thc other person u'ho later had hypcrthvroidism had a serum th1'roxine concentration of 10.0 pg per dccilitcr (129 nmol per liter) at the 15th examination. In fbur other subjects, tu.o in the lou,-serum-thvrotropin eroup and onc each in the slightly-low- and normal-serum-thvrotropin
Table
1

0 C
Years

Figure 1. Cumulative lncidence ot Atrial Fibrillation among Subjects 60 Years of Age or Older, According to Serum Thyrotropin Values at Base Line. Low serum thyrotropin values were defined as <0.1 mU per liter; slightly low values, >0. 1 1o 0.4 mU per liter; normal, >0.4 to 5.0 mU per liter; and high, >5.0 mU per liter.

46 were takins thyroid hormone at the time of the 15th examination. No further data on serum thyrotropin concentrations were available lor l0 of the 46. Among the remaining 36 subjects, l9 had serum

Serum Thyrotropin Concentrations in 1978 through 1980

RarF oF AF

and lncidence of Atrial Fibrillation (AF) in the Next l0 Years.

SERU\I

THrRorRoPlN No. ar

S[x

-o.

VALUE

Rrsx

(!l/F)

slrH AF l3
23

(PER

lX)

PERSoN-YEARS)* P Val-uEi

thyrotropin concentrations of 0.1 mU per liter or Iower on at least one subsequent occasion and 6 others had concentrations of 0.2 mU per liter or lower at least once; I9 also had at least one subsequent serum thyrotropin concentration within the normal
range.

Low (<0.1 mu/liter) 61 8/51 Slightly low (>0.1 r 187 84/103 0.4 mU/litcr) 1576 680/896 Nomal (>0.4 to
5.0 mu/liter) High (>5.0 mu/liter)

)c

0.005 0.1 I

l6

133

lt
l5
t2 0.08

DrscussroN

183 42tl4l
2W1 814/1193

23

All

subjects

192

*The age-adjusled incidence per 1000 [E6o.-veaA of fbllow-up. iFor the comptison wilh the rate in the group sith the nomal serum thyrotropin values.

groups, h1'perthvroidism developed after the l5th ex-

amination. but thev did not have atrial fibrillation during tlie follou-up period. Overall, onh' 2 ol the 192 subjects rvho had atrial

The sensitive assays for serum thyrotropin2l now available make it possible to distinguish normal from subnormal values and to identi desrees of suppression of thvrotropin secretion. Persons with low serum concentrations of thyrotropin but no clinical manifestations of hyperthvroidism can be lollowed for the manifestations (such as atrial fibrillation) that are usuallv associated with overt hyperthyroidism. In our stud,v we found that a low serum thyrotropin concentration (<0.1 mU per liter) in persons

fibrillation also had spontaneous h1'perthvroidism; 60 1,ears of age or older was an independent risk factor both ol them had lou' serum thl,rotropin concenlor atrial fibrillation. trations at the 15th examination. l-our of the 57 subjects rvho beTable 2. Serum Thyrotropin Concentrations in '1978 through 1980 and Relative Risk ol gan taking thvroid hormone durAtrial Fibrillation, with and without the Exclusion of Subjects Beceiving Thyroid ir.rg the follou,-up period also had Hormone Therapy.* atrial fibrillation, 3 of uhom u'ere ExcLUDrNc SuBJEcrs among the 28 subjects in the highSERLNl THYRoTRoPT\ Rr( Et!rNc TH\ RolD ,{r.r SLBTE( HoRMoNE serum-thvrotropin group u'ho beREI.A] IVE RELATI! gan taking thvroid therapv during \O, T 5E\ NO, T S[\
rs

RISK

this peririd.

RISK

RrsK

(\1 F)

(957 CI)*

P VAI,L!

RI5K

(M F)

(95% CI)*

P VAI-UE

Low Serum Thyrotropin Concentrations in Subjects without Atrial Fibrillation

Low (<0. I mU/liter)

Slightly lou, (>0.1 to

Fortv-six subjects in tl're lowserum-thvrotroPin groull did not

mu/litcr) Nomal (>0..+ to 5.0

0..+

61 8/5.3 3.1 <0.001 25 5/20 3.8 (l.7-5.s) (1.7-8.3) 187 8,1/103 1.6 0.05 168 80i88 t.6 il .0-2.5) 0.0_2.5) 1576 680i896 1.0 1530 6741856 t.0
I8l 4).it1t
rO

<0.001
0.04

havc either atriai fibrillation or o\.ert hvpcrthvroidism during the lollou'-up period. 'Ihirtr ol' the

mU/liter) High (>5.0 mu/liter)

q-1 lr

1..1

0.

12

169 40/129 L6
(t.0-2.4)
th)-

0.06

*Adjulted br other risk tialors for atflal fibrillaircn l\e the Rc\uli\ section) Thc subjects with norm!l serum ralues *crc the refercnce rroup. CI denotes c()nfidence interval.

rotropin

2t2

l'HE \E\\'E\GL.\\D IOUR\.{t. OF \IEl)I(llNE

\or'. RErrnrNcBs

10. 1991

In previous studies the prevalence of atrial fibrillation at the time of the diagnosis of o\-ert h)'perth\'roidism ranged lrom 2 to 30 percent2r-5' the Preva-

Kanncl WB. Abbott RD. Savage DD. N{cNamara PM. Epidemiologic tatures oi chronic atrial fibrillation: the Framingham Study. N Engl J Med
1982:306:1018-22.

jects r.t'ith subclinical hyperthyroidism during two years of follow-up, as compared with none of 35 with normal serum thyrotropin concentrations.?7 In another studl'. there rvas an increased risk of unspccified ischemic heart disease in hospitalized paticnts rl'ho had been taking thvroxine. but this risk u'as not relatecl to tl-re serum th\-rotropin concentration and rvas significant or-rlr, lor patients vounger than 65 r'ears of age.29 Our finding that a lou' se rum tht rotropin colr-

lence is higher among patients more than 60 I'ears ol age than amoug vounger patients.J3-l8 Ferv stuclics, hou'ever. har,'e examined the relation betu'een lou'serum thvrotropin concentrations and the subsequent deveiopment of atrial fibrillation. In one stud_v, based on serum samples obtained lrom a central reference laboratory', atrial fibrillation developed in 3 of 32 sub-

Wolf PA. Kannel WB. McGee DL. Mceks SL. Bhaucha NE, McNamara
PM. Duration of atnal librillation and imminence o[ stroke: the Framingham Study. Stroke 198-1:1.1:66.1-7. a review of course and Petersen P. Godtfredscn J. Atrial flbrillation prognosis. Acta N'[ed Scand 198,1:2t6:5-9. Wolf PA. Abbon RD. Kannel WB. Atrial fibnllation: a major contributor to stroke in the elderly: thc Framingham Study. Arch Intem Mcd 1987;147:
l

56 I -'1.

Furszyfer J. Kurland LT. McConahey WM. Elveback LR. Graves' disease in Olmstead County, Minnesota, 1935 through 1967. Mayo Clin Proc I 970:45:636-44. Phillips DI. Barker DJ. Rees Smith B. Didcote S, Morgan D. The geographical distribution of thyrotoxicosis in Enqland according to the presence or absence of TS H-reccptor antibodies. Clin Endocrinol (Oxf ) I 985:23:1837

Lundgren E. Borup Christenscn S. Dccreusing incitlenc!'ofth)'rotoxic\i\ in an endenric goitre inJantl area of Srveden. CIin Endocrinol (Oxf) 1990:33:
I3.3-tt.

centration u-as a risk lctor lor atrial fibrillation u'as based on ciata from a large. unselected. communitt'based populatior.r ol older pcrsons lollorved for up to
10 r'ears.

9
IO

The mean serum thvroxine concentration rr,as higher among the subjects r,r,ith low serum thYrotropin concentrations than among those rvith normal serum thvrotropin concentrations. although in mosl the values n,ere u'ithin the normal range. 'Ihere lvas no relation between the serum thvroxine concentration and the an observalater development of atrial fibrillation - variation in tion that is probablv related to the large serum thvroxine concentrations in the seneral popu-

il. ll
r3

Fagcrberg B. Lindstedt G. Stromblad SO. et al. Thyrotoxic atrial fibrillation: an undcrdiagnoscd or overdiagnosed condition? Clin Chem 1990;36: 620-1. Siebers N'[J. Drinka PJ. Vergauu'en C. H1'perth;"roidism as a causc of atrial librillation in long-term care. Arch [ntem Mcd 1992:152:2063-4. E-egensen R. Petersen K. Lundberg P-A. Nystrom E. Lindstedt G. Screening for thyroid disease in a primar-"- care unit with a thyroid stimulating hormone assal' uith a low detection limit. BIt'lJ l98tt:297:1586-92. Bagchi N, Broun TR. Parish RF. Thlroid d1'sfunction in adults over age 55 vears: a sturll in an urban US communitl. Arch Intern Med I990:150:
785-7 . Parle JV. Frankll n JA. Cross KW. Jones SC. Sheppard MC. Prevalcnce and

l.l

follou'up of abnormal th)rotrophin (TSH) concentrations in the elderly- in the United Kingdom. Clin Enclocrinol tOxf ) l99l:-l-1:77-83. Sauin CT. Gcller A. Kaplan MI\l. Bacharach P. Wilson PW. Hershman JN'I. Lou, serum thlrtxrpin (th)roid-stimulating hormone) in older persons uirhout hlpcrthlroidism. Arch lntcm \'Ied l99l:151:16-5-8. Sundbeck G. Jagcnburg R. Johansson P-\'t. Etlcn S. Lindstedt G. Clinical si-cnilicance of lou serum thyrotropin conccntration bl chemiluninometric assav in 85,1ear-old uomen and mcn. Arch Intem Mcd l99l:l5l:5.1956.

lation and to the variation in cardiac sensitivitv to

thvroxine.

l5
t6

Approximatelv l0 to l5 percent of patients u'ith overt hvperthl-roidism r'r'ho have atrial fibrillation have an arterial embolic event.:r(r"ii Hence. the identificatioll ol risk factors lor atrial fibrillation is important.
that is. subA lou' serum thvrotropir.r concentratiorl - l:e one such clinical h1'perthl'roidism appears to - not increase much, if at factor. l'hvroid secretion need

Friedman D. Reed RL. l\looradian AD. The prevalence of ovemedication with levoth,r-roxine in ambulatory elderly patients. Age 1992;15:9-13. Pekrl AE. Hershman JM. Parlo* AF. A sensitive and precise radioimmunoassal tbr human thy'roid-stimulating bomrone. J Clin Endocrinol Metab
I

975:4 t:676-84.

t7

t8

lg

all. for atrial fibriliation to occur. Onlv tu'o ol the subjects in this studv t'ho had lon,serum thvrotropin concentrations and subsequentlv had arial fibrillation
also had overt hvperthvroidism during tire follou'-up period. Exclusion from the anah'sis of those rvith a

:l

Ross DS. Daniels GH. Gouveia D. The use and limitations of a chemiluminescent thyrotropin assay as a single thyroid tunction test in an out-patient endocrinc' clinic. J Clin Endocrinol Mctab 1990:71:764-9. Kaplan EL. Meier P. r-onparametric estirnation fiom incomplete obsen'ations. J Am Star Assoc l95tJ:53:.157-81. Cor DR. Regression models and life-tables. J R Stat Soc [B] t972;3.1:187220. {iscellaneous topics. ln: Kalbfleisch JD. Prentice RL. The statisticl analvsis of failure time data. New York: John Wilei'. 1980:199-201. Weeks I. Stur,sess M. Siddle K. Jones NlK. Woodhcad JS. A high scnsiti\it\ imnrunochemilurinometric assav for human thvrotrophin. Clin Endo-

historl' of hvpertln,roidism or those taking thvroid hormonc at the l5th examination had little effct on the results. Overall, u'hen atrial frbrillation occurs. there is onlv rarelt' either concurrent or subsequent o\rert hvperthvroidism; it is more commonll' associated rvith subclinical hvperthl'roidism. which can occur either spontaneouslv or in association with thvroid
hormone therapv. Older persons rvith lorv serum concentrations ol thvrotropin should be follou'ed for the development ol overt hvpcrthvroidism and atrial fibrillation.'r: \\'hether antith\.roid treatment can prevent atrial fibrillation

crinol (Oxf ) 198-1:10:.1ti9-9-5. White PD. Aub JC. The clectrocardiogram in thyroid diseasc. Arch lntem Mcrt l9l8:22:766-9. Sandler G. Wilson GM. The nature and prognosis of hean disease in thyrotoxicosis: a revieu of l-50 patienrs treated sith rrrI. Q J Nled 1959:52:3,1769. Peterscn P. Hansen lNl. Strokc in thyrotoxicosis uith atrial Ilbrillation. Stroke 1988:19:15-8. 25. Nordyke RA. Gilben FI Jr. Harada AS. Graves' disease: inlluence ofagc on clinical Iindings. Arch Intem Med 1988:148:626-31. 26. Daly JG. Greenuood R\{. Himsuonh RL. Th1'rotoxic atrial fibrillation.

BMJ
27. 28.

1982:285:157.1.

Tenerz
patients

A.

Forberg R. Jansson R. Is r more active attitude wamanted nith subclinical thyrotoxicosis'l J Infem Med 1990:228:229-33.

in

in such persons is not knor,r'n. Among those t'ho are receiving thvroid hormone and have iolr'- serum tht'rotropin concentratiorls. the risk of arial fibrillation can be lessened bv avoiding excessivell'high doses.

Tibaldi JM. Barzel US. Albin J. Surks M. Th1'rotoxicosis in the very old. Am I Med 1986:81:619-21. 29. Leese GP. Jung RT. Guthrie C. Waugh N. Browning MC. N{orbiditl in paticnts on r.-th1 mrine: a comparison of rhose with a nonnal TSH to those uith a suppressed TSH. CIin Entlocrinol (Oxl) I992:17:500-3. 30. Sraffurth JS. Gibberd MC. Ng Tang Fui S. Arterial embolism in thyroroxicosis uith atrial librillation. BMJ 1977;2:688-910. Presti CF. Hart RG. Thyrotoxicosis. atrial fibrillation, and embolism. revisitcd. Arn Hean J lt)89:l l7:q7o-7 32. Singer DE. Ranrlornized trials of warfrin tbr atrial fibrillation. N Engl J Med l99l:317;l-15t-3.

ll.

Vol,

33l \o.

l!)

tsO\E }I,\RRO\T TR.\NSPLAN'IS VERSUS CHE\IO'THERAPY FOR C]HILDRE,\ \\'ITH .{i,I,

253

BONE MARROW TRANSPLANTS FROM HLA-IDENTICAL SIBLINGS AS COMPARED WITH CHEMOTHERAPY FOR CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA IN A SECOND REMISSION
,\. Joux Benrr:,rr,

\I.D.. N'Ienv \L HonowIrz, II.D., Bna H. PoLrocx, Pn.D., Nlr,r-Jrr Zuexc, PH.D., Nlonuurn NI. Bonrrx, N[.D.,* GroncE R. BucHaNax, N'I.D., Br<uca NI. Cenrrrre, N{.D., Juorrn Ocns. N{.D.. JoHx Gn,c,HeM-PoLE, ,{.D., Purlrp A. Ror'r,r-rxcs, }I.8., B.S.. Arrxrp A. Rrlrrr. Pu.D.. Jon:'r P. KreIN, PH.D., Joxsru.lx J. SursrEn, Pu.D., K.q,rni-rex A. Sosocrxsrr, M.S., arv RoeEnr Pnrr,n Gar-r,, \I.D., Pu.D.
tation in the transplant recipient. A total of 255 matched pairs were studied. Results. The mean (*SE) probability of a relapse at five years was signilicantly lower among the transplant recipients than among the chemotherapy recipients (45+4 percent vs. 8013 percent, P<0.001). At five years the probability of leukemia-free survival was higher after transplantation than after chemotherapy (4013 percent vs. 17+3 percent, P<0.001). The relative benefit of transplantation as compared with chemotherapy was similar in children with prognostic factors indicating a high or low risk of relapse (the duration of the first remission, age, leukocyte count at the time of the diagnosis, and phenotype of the leukemic cells). Conclusions. For children with acute lymphoblastic leukemia in a second remission, bone marrow transplants

Abstract Background. lt is unclear how best to treat

children with acute lymphoblastic leukemia who are in a
second remission after a bone marrow relapse. For those with HLA-identical siblings, the question of whether to perform a bone marrow transplantation or to continue chemotherapy has not been answered. Methods. We compared the results of treatment with marrow transplants from HlA-identical siblings in 376 children, as reported to the lnternational Bone Marrow Transplant Registry, with the results of chemotherapy in 540 children treated by the Pediatric Oncology Group.

A preliminary analysis identified variables associated with treatment failure in both groups. We selected cohorls by matching these variables. A possible bias associ-

ated with differences in the interval between remission and treatment was controlled for by choosing matched pairs in which the duration of the second remission in the chemotherapy recipient was at least as long as the time between the second remission and transplan-

from HLA-identical siblings result in fewer relapses and longer leukemia-free survival than does chemotherapy. (N Engl J Med 1994;331:1253-8.)

1--IURREN-I resimens of intensive chemotherapy \-,,{ produce rcmissions in almost all children with acute lvmphoblastic leukemia. Additional treatment u'ith consolidation and maintenance chemotherapv
cures up to 70 percent of these children, but in about 25 percent of them the disease recurs in the bone marrorv.l-:l \Iost of these children have a second remission u,ith chemotherapl,', but the choice of subse-

quent treatment is conroversial. One approach is more chemotherapv. In large pubiished studies, chemotherapv resulted in leukemia-free survival at five vears in B to 76 percent ofpatients but generaily in 10
From rhc National Hean. Lung. and Blood lnstitute. Bethesda, Md. (A.J.B.): the lntemational Bone Manow Transplant Registr)'. Health Policy lnstitute (NI.M.H., M.-J.2.. M.M.B., P.A.R.. K.A.S.). and the Departments of Pediatrics (B.M.C.)and Biostatistics (J.P.K.). Medicai College of Wisconsin, Milwau-

to 20 percent.+-rr The main determinant of the outcome of chemotherapy is the duration of the first remission: a child with a brief first remission fares worse than one rvith a long first remission. Other variables reported to predict the outcome of chemotherapy are age, the leukocyte count at the time of the diagnosis, and the phenotvpe of the leukemic cells. Resistance to chemotherapy is the main cause ol treatment failure. Bone marrow transplantation from an HLA-identical sibling is an alternative treatment for children in a second remission.r2-r6 Transplantation has resulted in ieukemia-free survival at fi\'e years in 22 to 64 percent of patients in large series.rT-2+ The duration of the first remission is also a primarv determinant of the outcome of bone marrow transplantation.re-2r Unlike the results 'n'ith chemotherap_v, treatmentrelated mortalin' and resistant leukemic cells contribute equalll' to the lailure ol treatment rvith bone marrow allogralts.
\\rhether a child r,vith acute lvmphoblastic leukemia

kee: the Pediatric Oncology Group Statistical Office (8.H.P., J.J.S.) and the College ot lledrcine. Universitl'of Florida (J.G.-P.). Gaincsville; the University of Texas Southwestem Medical Center. Dallas (G.R.B.): St. Jude's Children's Hospital. Memphis. Tenn. (J.O.); Case westem Reserve University School of \{edicine. Cleveland (A.A.R.): anrl Salick Health Care. Los Angeles (R.P.G.). Address reprint rcquests to Dr. Horowitz at the Intemational Bonc Manow Transplant Registr). Medical College of Wisconsin. 8701 W. Waterton Plank Rd., Ntilwaukee. Wl 53226. Supported by grants (POl-CA-40053, Ul0-CA-29139. CA-33625, CA-29281, CA-32053. CA-31566. and CA-30969) from thc Ntional Cancer lnstitute. the Narronal Hean. Lung. and Blood Institutc. und the ){ational lnstitutc of Allergy and Infectious Diseases and bl grants from the Alpha Therapeutic Corporation. Armour Pharmaceutical Company. Lynde and Harry Bradley Foundation. Bristol-N'1]ers. Buroughs Wellcome Companl. Charles E. Culpeper Foundation. Elcanor Nallor Dana Charitable Trust. Eppley' Foundation for Research. Hoechst Rousscl Phamaceuticals. Immunex Corporation. Kettering Family Foundation, Robert J. and Helen C. Kleberg Foundation. Eli Lilly and Company Founclation, Nada and Herben P. Mahler Charities, Marion Menell Dow, Ambrore Moncll Foundation. Samucl Robcrts Noble Foundation, Ortho Biotech Corporation, John Oster Famill' Foundation. Jane and Lloyd Pettit Foundation. RGK Foundation. Roerig Dir ision of Pfizer Pharmaceuticals. Sandoz Research Instirute. Stackncr Famill Foundation. Star Foundation. Joan and Jack Stein Charities. Suiss Cancer Lcaguc. and W)clh-Ayerst Rescarch
"Deccased.

in a second remission n.ho has an HlA-identical sibling should receive chemotherapy or a bone marrolv transplant is a matter ol intense debate.l5 16'21 2r To our knolvledge, no randomized trials have addressed this
question. because the relativel,v lolv incidence of acute

lymphoblastic leukemia and the limited number o{' HLA-matched donors make accrual of patients di{ficult. even for multicenter cooperative eroups.26 Other
reports comparing chemotl.rerapv and transplantation are either inconclusive or contradiclo.u.l:r.22.25-2u {r, u previous comparison of data from the International

Bone \'Iarrorv 'Iransplant Registrv (IBMTR) and

data from trials rvith chemotherapv, we suggested that bone marrorv transplantation in patients in a second

l 254

THE

\E\\'

E,NGLA\D.JOI,,iR\AL OF \tEDICI\T]

\or'.

10. I991

remission after a bone marrow relapse resulted in a higher probabilitv of leukemia-free survival in children with a short first remission (<18 months) but not in those rvith a long first remission.2e Hor,r'ever, prognostic and treatment information that mieht have accounted for the dillerence !as not available for the patients receiving chemotherapv. In this studv rve performed a matched-pair analvsis to compare the results of treatment with bone marrow transplants from HLA-identical siblings in 255 children, as reported to the IBNITR, with the results of chemotherapy in 255 similar children enrolled in trials conducted by the Pediatric Oncologv Group.

Table 'l . Variables Signiticantly Associated with Treatment Failure (Relapse or Death) among Children with Acute Lymphoblastic Leukemia in a Second Remission Receiving either Continued Chemotherapy or Bone Marrow Transplants from

HLA-ldentical Siblings. *

VARIABLE

CHEIIoTHERAPY (N = 5.10) RELATIIE RISX P VTL|E

TR{\SPI-ANTAnoN (N = 376)

REr-IIIE RISX

\'I

Age >10 yr T-cell phenotype lukocyte count at diagnosis

<50.000rmm1

r-S NS 0,9: 1.58

t.00+
NS 0.002

l.5l 2.16

0.003

<0.001

50.001- 100.000/mmr > t00.000immr Duration of nrst remission (mo)

MrrHos
Patients Treated with Transplantation The ItsIITR collects data (iom over 250 transplantation centers worldu idc rhar report informatiou on consecutive patients receir inq allogeneic or identical-tu'in bone marrou' ransplants. Participants account for about trvo thirds of all actite transplantation teams.l" The registn'. rrhich includes information on ,10 to 50 percent ol all allogeneic bone marrorv transplantations since 1970. is the lareest data base lor transplantations in patients rlith acute l1'mphoblastic leukemia. !-or this studv. the cohort of transplant recipients rtas drawn from a population of patients 18 l ears of aee or vounger u,ho received transplants from HI-A-identical siblinss between 19U3 and 1991, while ther.uere in a second remission after a bone marro\{' relapse. Children uith an isolated extramedullan, relapsc. Ivmphoma rrith a leukemic transformation, or Dortn's svndrome uere excluded. The selection o[ candidates for transplantation varied according to the policies of the transplantation teams. \Iost transplantations u'ere performed in children rithout serious concurrent illnesses. The interval betlveen the second remission and transplantation varied from I to 222 neeks (median. I0). For this paticnt population, the results of transplantation reported to the IB\ITR are similar to those reported bv most centers.l:lI Patients Treated with Chemotherapy

<18
18.01-36

>36

1.88 <0.001 2.01 2.85 <0.00t 1.42 I.00+ L00+

<0.001
0.05

*Sex and the yeil of the diagnosis were not signi,icanrl! associated with th. risk of trea(menr tilure. NS denotes not significant (P>0. I ). iRefercce group.

the IB\ITR cohort included onlv children rrho *ere in remission

long enough to rcceive a transplant, uhereas the Pediatric Oncolopr'Group cohort included all children er.rrolled in the group's stuclies rrho had a second remission. Thc transplantation grclup there-

fore ercluded children u'ho died earll or had an earh secoud relapse. 1'his could have introduced a bias favorinq transplantation.3z lll \\'e used the l'ollorving statistical methods to address these issues. First, using a Cox proportional-hazards regression.r+ re identified

patient- and disease-related variables associated uith treatment failure (relapse or death) in each group. 'fhe variables \\'e tested in the model were age. sex. thc leukocvte count at the tirnc of the
diagnosis. the phenotl'pe. the vear of the diagnosis, and the duration of the first remission. \\'e then sclected pairs of chemotherapr' and transplant recipients by' matching members liom tlte trlo cohorts for all variables associated u'ith the outcome o[ either therapr' (P<0.1).'fhese variables *ere the age at the time of thc second remission (0 to 2. 3 to 10. or I I to l8 r'ears), the leukocvte count at the time of the diagnosis (<50.000, 50.001 to 100.000. or >100.000 cells per cubic millimeter). the T-cell phenotlpe (r'es or no). and the duration of the lirst remission (rvithin six months). II'more than one patient in the chemotherapv group rras eligible for matchins rvith a patient in the transplantation eroup. rve selected the chemotherapv recipient rith a first remission closest in duration to thar of the transplant recipient. In addition. the chemotherapv recipient in each pair was selected liom among the children uith a second remission at least as lons as the interval benveen the second remission and transplantation lbr the transplant recipient. \\e identified 255 pairs uho met these criteria. -I'he primarv end points rve analvzed uere the duration of survival uithout a relapse of leukemia (leukemia-free surr-ival). the time to treatment-relaled mortalitr'(death in continuous complete remission), and the time to a relapse. The probabilities of leukemiafree survival. treatment-related mortalitv. and relapse rverc calculated *'ith Kaplan-\leier methods and compared bv paired log-rank test.si For thc analvses of leukernia-free survival. treatment rras considered to have lailed at the time of' a relapse at any site or at the time of de:rth lrom an1'cause: data on patients n,ho rvere alive and in continuous complete remission rvere censored onh' at the time of the Iast follorr-up visit. For analvses of treatment-related mortalitv. failure sas defined as death during a continuous complete remission: data ltere censored at the time of a relapse or. among patients uith continuous remissions, ar the time of the Iast lollorv-up visit. For anall'ses ol relapse. failure was defined as the recurrence ol acute lvmphoblasric leukemia at anv site: data ryere censored at the time of a death or the last follrrv-up visit during a continuous remission. \\'e used a Cox proportional-hazards regression model to test {br inreractions between treatment and age. sexr the leukocvte count at

The Pediatric Oncologl' Group is a multicenrer clinical-trials

eroup including over 80 institutions in the Unitcd States. Canada, and Europe. 'fhe cohort of patients lvith acute lvmphoblastic leukemia who were treated with chemotherapv tras dral n from a population of patients rvho ltere l8 vears of age or vounqer and had had a second remission after treatment ficr a first bonc marro\r relapse. Thev rere treated betu'een April l9B3 and IIav l99l in studr'8303. 8304,8710, or 8862. f)etails of the treatments are reported elseu'herell3r and are also available from the group's statistical center. Study 8303 excluded patients who had a relapse more than six months after maintenance chemotherapy had been discontinued (late rclapse). Studr' 830,] included onlv patients \irh a late relapse. Studv B7l0 included patients u'ith either an earlv or a lare relapse but escluded those rvith T-cell acute lvmphoblastic leukemia or Dorvn's svndrome. Stud_v 8862 included parienrs u,ith 'f-cell acute lvmphoblastic leukemia or T-cell non-Hodgkin's lvmphoma but excluded those x-ith Dorvn's svndrome. The patients trith T-cell nonHodgkin's l,vmphoma uere excluded from this anall.sis. The results of these trials are tt'pical of the published results of'studies in the Lnited States and other countries in n,hich children rith acute lymphoblastic leukemia are treated after a first bone marrolr. relapse. l'3

Statistical Analysis
The initial studv group consisted of 376 children in the IB\tTR
cohort and in thc Pediatric Oncology Group cohort. Two potenbias ltere considered in comparing these groups. First. patient- and disease-related variables associated rvith the outcome of chemotherapv nright have influcnced the selection of patients for bone marroll transplantation. This could have resulted in an imbalance in prognostic factors betueen the groups. Second,
5.10

tial

sources

of

Vol.

331 No. 19

BONE }IARRO\\.TRANSPI,:\\.IS VERSUS CHE\IOI.HERAPY FOR CHILDREN \VITH ,\LL

255

the time of the diagnosis, the leukcmia-cell phenonpe. and the duration of the first remission.

o
1.0

Rnsurrs
Characteristics of the Patients

a = ar o)
ta

0.8 0.6 o.4

Table I shorvs the variables associated with treatment failure in the unmatched groups of children r.r,ith acute lymphoblastic leukemia in a second remission
u,ho received either chemotherapy

or bone marrow

_3
o
-o (g 0-

o =

transplants. Among the 540 patients who received

chemotherapv, an increasecl risk of treatment failure was associated with a leukocyte count )100,000 per cubic millimeter at the time of the diagnosis and by a first remission that n'as (36 months long. Among the
Table 2. Characteristics of the Matched Chemotherapy and
Transplantation Cohorts.x
CHEMOTHERAPY TRANSPLANTATION

0,
o.o

12 24 36 48
192 113 87 187 105 72 65 50

60

Months after Treatnr ent

Transplantation 376 Chemotherapy 540
48
35

38 24

CHRACTERIsnc

(N = 255)
(%,)

(N = 25s)

no. Male sex Age at diagnosis

Median
Range

163 (64)

r63 (6+) 7.0

yr 6.0 0.4-18.1

Figure 1. Actuarial Probability of Leukemia-free Survival in Unmatched Cohorts of Children Receiving Chemotherapy or Undergoing Transplantation. The numbers below the tigure indicate the nurnbers of children at risk.

0.5- 18.4
r6 (6) 163 (6.+) 76 (30)
1983
1971

Age group at diagnosis

0-2 yr 3- l0 yr

no. (7c)

ll-18

yr

l6 (6) 163 (64) 76 (30)

l

Yeu of diagnosist
Median
Range

983

r975- 1990

T-cell phenotype
Yes

no. (7r)

-t989
(8)

2l

(8)

2l

For the 255 matched pairs from the tv,'o cohorts, the probability of leukemia-free survivai at five vears was significantly higher after transplantration than after chemotherapl' (40-+- 3 percent vs. l7t3 percent, P<0.001). \,loreover, the risk of a relapse n'as signitcantly lower after transplantation than aft,er chemotherapy (+5'r+ percent vs. B0i3 percent, P<0.001) (Fig. 2 and 3 and Table 3). The probabilit.', of treatment-related death within five vears was l4t4 per-

No
Leukocyte count at diagnosis Median
Range

234 (92)

)?A rO)r
9000

per mmr 10.000

0-600.000 no. (lcl

214 (84) 24 (9) t7 (7)
25

r000-456,000
214 (84) 24 (9)

Leukocyte count at diagnosis

<50,0)/mml
50.001- 100,000/mnrr

>100,)0rmml
Duration of first remission
Median
Range

t7 <

(71

mo 26

cent with chemotherapy and 27 !3 percent 'with bone marro\r' transplantation (P<0.001 ). Table 3 shorvs the probabilities of leul:emia-free survival and relapse in subgroupsr of children ac-

<l-105
no. (%)

l-

104

cording to the prognostic factors listed

in Table

1.

Duration of first remission

<18 mo
18.01-36 mo

9l

(36)

89 (35)

>36 mo Weeks from second remission to transplantation Median

Ran-{e
*Because

88 (35) 76 (30)

90 (3s) 76 (30r,

= U)
t0
<

t-

I40

o o
(U

0.8 0.6 0.4 o.z o.o

of rounding. not all percenlages total

100.

iP :

0.9 by paired t-tesl.

0) Y

376 children u'ho received marro\\, transplants, an in-

_9

and a first remission lasting (36 months. 1'able 2 shows the characteristics of the matched cohorts. which were very similar.
Outcome

creased risk of treatment failure was associated with an age ) l0 vears, the presence of a T-cell phenotype,

b o(U

12 24

36 ,48 60
,47

72

Months after Treatment

Transplantation

Fisure I shows the actuarial probabilities of leukemia-free survi\.al in the unmatched transplantation and chemotherapy cohorts. The mean (aSE) probability of leukemia-free survival at frve vears was 3613 percent in the transplantation group and 16+2 percent in the chemotherapy group (P<0.001).

Chemotherapy

255 133 81 60 255 105 58 39

37
19

28
15

29

Figure 2. Actuarial Probability of Leukemia-free Survival in

Matched Cohorts of Children Receiving Chenlotherapy or Undergoing Transplantation. The numbers below the figure indicate lhe numbers ot

children at risk.

256

.fHE NEW ENGLANDJOURNAL OF \IEDICINE regression model fitted

\or'.

10,

1994

A Cox prop()rtional-hazards

u'ith first-ord er interaction variable s did not show significant interactions between the treatment and anv of
the proenost: c variables studied that is, the relatir.e benefit of tnansplantation as compared rvith chemotherapl' rvas similar in all groups. The probability of Ieukemia-free survival at fi\,e years lvas higher after transplantat,ron than after chemotherapy both in children whose l'irst remission had lasted 36 months or less (35X4 percrrnt vs. l0-r3 percent for 179 pairs) (Fig. 4A) and in those u'ith a first remission that exceeded 36 months (:t3!7 percent vs. 32 16 percent) (f ig. aB) . Comparisons of pairs of children with a first remission

Table 3. Probabilities of Relapse and Leukemia-free Survival Five Years after Chemotherapy or Bone Marrow lransplantation.
No. oF PArRs
LEtrxEMt^-rREE

RELAPSE

SuRvrval

CHEMO- TRANSPLAN. CHEMO- TRANSPLAN. ]HERPY TATION THERAPY TTION nkan ( =SE) Percet

All

patients

255
179 76

8013 45:t4
781:4

l7+3
t2!4 t4 l3+4
19

40+3 4414

Age (yr)

<10 >10
Sex

86a5 79+1
83

4315 51!'7
49

I8a3

30r6
31

Male
Femalc Leukocyte count at diagnosis

r63 92

t5

l: 5 3716

.!:4

46*6
39t:4 5l rr 17 32*10

longer than 48 months (36 pairs) or lonser than 60 months (lB pairs) vielded results that rvere similar to those for chiLldren with a first remission that excecded
36 months.

DrscussroN

< 100.0l/rnmr 238 > 100.0001mmr 11 T-cell phenotype 2t Yes No Duration of first re
mission (mo)

80+-1

9l

j6

37:!

45+4 13

l7

!3 916

8618 80* 3

50r:12 44!4 63*6 39+7 30a7

lt+7 17 .L3 l1:t4 7+3 32*6

41!4
29+5

Our stuc.y provides evidence that treatment with

bone marrolv transplants lrom HLA-identical siblings results in a statistically greater likelihood of leukemialree sun,ivzrl at five years than does chemotherapy in

<18
r8.01--36

>36

91 88 76

83i4
91

14

4l+6
53+7

66!6

children u'rth a bone marrorv relapse after a second remission of acute lymphoblastic leukemia. The reason lor this diflerence was the lower risk of relapse after transplantation, which outweighed the higher risk of trc:atment-related mortality associated lvith this treatm ent. The outcome after transplantation was superior to the outcome aftcr chemot]rerapy in subgroups of <:hildren with lavorable or unfavorable prognostic lactrrrs (duration ol first remission, < 36 months or )36 monthsl leukocvte count at the time of the diagnosis, < 100,000 per cubic millimeter or > I 00,000 per cubic rnillimet er; age, { I0 years or } I 0 vears; and phenotvpr:, T-cell or non-T-cell acute lymphoblastic leukemia). Since the numbers of matched pairs that
'1.0

could be evaluated in some of these subgroups were small (21 pairs with'I'-cell acute lvmphoblastic leukemia and 17 with leukocyte counts over 100,000 per cubic millimeter), the relative benefits of chemotherapy and transplantation remain uncertain in patients

with these characteristics. This study indicates that leukemia-free survival is longer after transplantation than after chemotherapi, but does not completel,v answer the question of the best treatment strategy for children with acute lvmphoblastic leukemia in a second remission. Our analysis does not consider a third option: to reserve transplantation lor children who have a second relapse after receiving chemotherapy for their first relapse. Horvever, the poor outcome of chemotherapy in

3
o_

o.a 0.6 o.4

6 tr

(!

children rvhose first remission lasts lor 36 months or less (lcukemia-free survival at five years, ( l0 percent) is an argument for early transplantation if an HLAidentical sibling is available. For chilclren whose first remissir>n is longer than 36 months and in whom
chemotherapy results ir.r a better outcome (leukemiafree survivai, about 30 percent). it mav be reasonable

E
(

to deler transplantation until a subsequent

occurs. Because there are

relapse

LL

o ^^ -! u,z
0.0

no randomized trials comparing chemotherapy and transplantation, we used a

matched-pair design to control both for known prognostic lactors in childhood acute lymphoblastic leuke-

0122436486072
Months after Treatment

ransplanlation 255
Chemotherapy 255

'133 105

81

58

60 39

47 29

37 19

28
15

mia and for a time-to-treatment bias. Although the two cohorts were matchcd lor these factors, there may have been unknown factors that differed between the cohorts. Consequentlv, our flndings should be interpreted cautiously. Our conclusions applv only to the chemotherapy and transplantation resimens used for the patients rve studied and only to the transplantation ol grafts

Figure 3. Actuarial Probability of a Relapse in Matched Cohorts ol Children Rec.eiving Chemotherapy or Undergoing Transplantation. The numbers b,elow the tigure indicaie the numbers of

children at risk.

lrom HlA-identical siblings. Other

chemotherapy

Vol.

lllll No. 19
o
= a o 0)
(!

BO\E }I.-\RRO\\'TR\SPLANTS

VERSUS CHE}IOTHE,RAPY I'OR

(]HILDRE\ \\'ITH ALL

t%1

0.8 0.6 0.4

-Y

E c)
=

Champlin R. Gale RP. Acute lymphoblastic leukemia: recent advanccs in biology and therapy. Blood 1989:73:2051-66. Rivera G. Murphy SB. Aur RJ. Vcrzosa MS. Dahl GV, Mauer AM. Recurrent childhood lymphocytic leukcmia: clinical and cytokinetic studies of cytosine arabinoside and methotrexate for maintenancc of second hematoIogic remission. Cancer I978:42:2521-8. Ekert H. Ellis MW. Waters KD. Matthews RN. Poor outlook fbr childhood acute lymphoblastic leukacmia with relapse. Med J Aust 1979.2:2246.

_9
(d

0, -o

o.o

24 36 48
85 53

60

72

Months after Treatment

Transplantation
179

Chemotherapy
(s

179

46 22

37 16

32 14

24
10

18 7

t0

lt
1.0

= a o o)
(U

0.8 0.6 0.4

Remission >36 mo

T2

l3

E (l)
=

_9

15.

o.z
l6
t7

oo 0Transplantation
76

12 24 36 48
48
at

60
13 9

72
18.

Months after reatment

35
Jo

23

Chemotherapy 76

tJ

15 15

Chessells JM, Combleet M. Combination chemotherapy tbr bone marrow relapse in childhood lynlphoblastic leukaemia (ALL). Med Pcdiatr Oncol I 979:6:359-65. Kimbali JC, Herson J. Sullivan MP. Favorablc response to maintenance therapy of second or subsequent remissions in childhood acute lvmphocytic Ieukcmia. Cancer 1980:.15: 1093-7. Amadori S. Spiriti MA. Mebni G. Pacilli L. Papa G. Mandelli F. Combination chemothcrupy tbr marrou' relapse in childrcn and adolesccnts with acute lymphocytic leukaernia. Scand J Haenratol l98l;26:292-6. Baum E. Nachman J. Ramsay N. et al. Prolonged second remissions in childhood acute lymphocltic leukemia: a report from the Childrens Canccr Study Group. Med Pediatr Oncol 1983:l l:l-7. Hcnze C. Fenglcr R. Hartmann R. ct al. Six-year cxperiencc with a comprchensive approach to thc treatment of recunent childhood acute lvmphobiastic leukcmia (ALL-REZ BFM 85): a relapse study of the BFM group. Blood 199]t:78:1t66-72. Sadowitz PD. Smith SD. Shuster J. Wharam MD. Buchanan GR. Rivera GK. Treatment of late bone manow relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study. Blood 1993:ttl:6029. Ramsay NK. Kersey JH. lndications fbr bone manow transplantation in acute lynrphoblastic leukemia. Blood 1990:75:815-8. Brett AJ. Bone mmow transplantation for acute lymphoblastic leukaemia. In: Treleavan J, Barett AJ. eds. Bone marow transplantation in practice. Edinburgh, Scotland: Churchill Livingstone. 1992:33-41. Sanders JE. Thomas ED. Buckncr CD. Done]- K. Manou, transplantation tbr children with acute lymphoblastic leukcmia in second remission. Blood 1987:10:324-6. Chessells JM. Rogers DW. Lciper AD, et al. Bone-mmow transplantation has a limited role in prolonging second mmow remission in childhood lymphoblastic leukaemia. Lancct 1986:l: 1239-41. Pinkel D. Allogeneic bone mmow transplantation in children with acute leukemia: a practice whose time has gone. Leukemia 1989:3:212-4. Coccia PF, Strandjord SE. Warkentin PI, et al. High-dose cytosine arabinoside and fractionated total-body inadiation: an improved preparative regimen for bone marow transplantation of children with acute lymphoblastic leukemia in second remission. Blood 1988:71:888-93. Banen AJ. Horowitz MM. Gale RP. et al. Marow transplantation fbr acute

10 8
19

lymphoblastic leukemia: factors aftcting relapse and survival. Blood

1989:74:862-7 I .
and prevention of relapse of acute lymphoblastic leukaemia after bone manow transplantation. Br J Hac-

Bmett AJ, Joshi R, Kendra JR. et al. Prediction

Figure 4. Actuarial Probability of Leukemia-free Survival in

Matched Cohorts of Children Receiving Chemotherapy or Undergoing Transplantation, According to the Duralion of the First Remission.

The numbers below the figure indicate the numbers ol children at risk.

and transplantation regimens and autografts or transplants lrom donors other than HlA-identical siblings u'ere not considered and may have dillerent outcomes. However, the methods used for this study can

readily be applied to comparisons of these other

approaches.
This article is dedicatecl to tht' memon of Dr. \'Iortimer \{. Bortin. rho diedJulr'25. I99+. Dr. Bortin uas a pioneer o1'bone marro\\' transplzrntatiolr, participatillg in olre of' the first successfirl transplantations in humans. He helped fbund the International Bone \Iarron Transplant Registrr in 1970 and sen ed as its scientil: it director lur o\cr lft rerrs.

matol 1986:64:179-86. Herzig RH, Bortin MM. Bffiett AJ. et al. Bone-marow transplantation in high-risk acute lymphoblastic leukaemia in first and second remission. Lancet 1987:l:786-9. 21. Brochstein JA. Keman NA, Groshcn S, et al. Allogeneic bone mmow transplantation after hyperfiactionated total-body irradiation and cyclophosphamide in children with acute leukemia. N Engl J Med 1987:317:t61824. 22. Dopfer R, Henze G, Bender-Gotze C, et al. Allogeneic bone marow transplantation for childhood acute lymphoblastic leukemia in second remission after intensive primary and relapse therapy according to the BFM- and CoAll--protocols: results of the German Cooperative Study. Blood l99l; 78:2780-4. Wingard JR, Piantadosi S. Santos GW. et al. Allogeneic bone mmow 23 transplantation for patients with high-risk acute Iymphoblastic leukemia. J Clin Oncol 1990;8:820-30. Poynton CH. Bamett AJ. Bone manou transplantation in childhood lymphoblastic leukaemia. Lancet 1986;2:395-6. 25 Johnson FL. Thomas ED. Clark BS. Chard RL. Hartmann JR. Storb R. A compison of manow transplantation with chcmotherapy for children with acute lymphoblastic leukemia in second or subsequent remission. N Engl J
z0
26 27
198 I :305:846-5 I . Darbyshire PJ. Pinkerton CR. Stevcns RF. Oakhill A. Treatment of acute Iymphoblastic leukaemia after relapse. Lancet 1990;335:733. Buchanan GR. Boyett J. Rivera GK. Comparison of bone manow transplantation and intensive chemotherapy for children uith acute lymphoblastic leukemia in second manow remission: a Pediatric Oncology Group (pOG)

Med

RErrnnNcrs
l. 2.
Rircra GK. Raimondi SC, Hancock ML. et al. lmproved outcome in childhood acute limphoblastic leukacmia with reinforced early treatment and rottional cunbination chemothcrapy. Lancet 1991:337:61-6. ChessellsJN{. Treatmentofchildhoodacute llmphoblastic leukaemia: present issues and future prospects. Blood Rev 1992:6:193-203.

study. Bk)od l9tl6:68:Suppl I :2 I 9a. abstracr. Hanis R. Feig S. Coccia P. et al. ALL in second renrission a CCSG srudy - [n: Gale RP. ol maintenance chemotherapy vs ntamow transplantation, Champlin R. eds. Pro_srcss in bonc marow transplantation. Ne York: Alan R. Liss. I987:91-5.

258

fHE \E\\' E\Gr.,\\D.JC)L R\.\L OF \rEt)lcI\E,

Butturini A. Rivera GK. Bortin MM. Gale RP. Which tretment for childhood acute iymphoblastic leukaemia in second remissionl Lancet 1987:l:
425-32.

\or'.

10. 199{

Begg CB. McGlave PB. Bennen JM, Cassileth PA. Oken MM. A critical comparison of allogeneic bone manou transplantation and conventional chemotherapl as treatment fbr acute nonlymphocytic leukemia. J Clin On-

MM. Bortin MNt. The role of regisiries in evaluating the results of bone manow transplantation. ln: Treleavan J. Banctt AJ. eds. Bone manow transplantation in practicc. F-dinburph. Scotland: Churchill l-ivinsstone.
Horow itz 1992:367 -77
.

col

198,1:2:369-78.

l3 l4
35

ll

Buchanan GR, Rivera GK. Bo1'ett JM. Chauvenet AR. Crist WM. Vietti TJ. Reinduction therp) in 297 children sith acute lvmphoblastic leukemia in first bone manou'rclapse: a Pediatric Oncolo-ey Group Study. Blood I 988:72: I 286-92.

Horowitz MM. Messerer D. Hoclzer D. et al. Chemotherapy compared with bone marow transplantation fbr atlults with acute lymphoblastic leukemia in lirst remission. Ann lntern N{ed l99l:l t5:13-8. Cox DR. Regression models and Iifc-tablcs. J R Stat Soc [B| 1972:34:187220. Andersen PK. Borgan O. Gill RD. Keiding N. Statistical models bascd on counting processes. Neu' York: Springer-Verlag. 1993:386-8.

Yol. 331

\o.

l!)

\(:CL \IUL.-\TIO\ OF \UCILE'\R p53 \D TL\IOR PROGRESSIO\

I\

BLDDER

C:.\\CER

l2i9

ACCUMULATION OF NUCLEAR p53 AND TUMOR PROGRESSION IN BLADDER CANCER

Drvro Esnro. \I.D., Doxar-o Enrelrex, \I.D.. Suses GnosHEN. PH.D., Jonx A. Fna,Ert.rx. \LD.. Jonx P. Srrrx. \'I.D., Su-Cnru CsEx. \I.S., PErr,n \\:. Nrcnor-s. N[.D., Doxer.o G. Srrxrnn, \1.D., Pr,rr,n A. JoxEs, Pu.D., ,A.No RrcHero.]. Corr,, NI.D.

Abstract Background. We have previously

demon-

strated a strong association between nuclear accumulation of p53 protein, as determined by immunohistochemical analysis, and mutations in the p53 gene. The purpose of this study was to determine the relation between nuclear accumulation of p53 and tumor progression in transitional-cell carcinoma of the bladder.

that had no detectable nuclear p53 reactivity at five years were 7, 12, and 11 percent, respectively, as compared with 62, 56, and 80 percent, respectively, for tumors that had p53 immunoreactivity. Similar results were obtained when the presence or absence of p53 in the nuclei of the tumor cells was studied in relation to overall survival. ln a
multivariable analysis stratified according to grade, pathological stage, and lymph-node status, nuclear p53 status was an independent predictor (and in cancer confined to the bladder, the only independent predictor) of recurrence

Methods. Histologic specimens

of transitional-cell car-

cinoma of the bladder (stages Pa, noninvasive disease, to P4, disease with direct extension into adjacent organs or structures) trom 243 patients who were treated by radical cystectomy were examined for the immunohistochemical detection of p53 protein. Nuclear p53 reactivity was then analyzed in relation to time to recurrence and overall survival. Results, The detection of nuclear p53 was signif icantly associated with an increased risk of recurrence of bladder cancer (P<0.001) and with decreased overall survival (P<0.001). ln patients with cancer confined to the bladder, the rates of recurrence for stage Pl, P2, and P3a tumors

and overall survival (P<0.001). Conclusions. ln patients with transitional-cell carcinoma confined to the bladder, an accumulation of p53 in the
tumor-cell nuclei detected by immunohistochemical methods predicts a significantly increased risk of recurrence

and death, independently of tumor grade, stage,

and

lymph-node status. Patients with transitional-cell carcinoma confined to the bladder that demonstrates nuclear p53 reactivity should be considered for protocols of adjuvant treatment. (N EnglJ Med 1994;331:1259-64.) cle invasion.rt) Surgical treatment is curative in a substantial proportion of such patients, but in a large number incurable metastatic disease appears after surgcr)'. Adjuvant therapl' (including chemotherapr. and radiation therap-v) is under investigation in this setting, and sholvs encouraging results.rr'r2 It ma1' thus be important to distinguish patients for rvhom

U'IATIO)iS of.the p53 gene are the most common genetic defect in human tumors.l The p53 gene functions as a tumor-suppressor gene and more specificallr,' as a cell-ct'cle regulator.2 Levels of p53 protein increase in response to damage to DNA, arresting the cell c,vcle and allou,ing time lor the repair

of D\A. \'lutations o[ the p53 gene occur in a high pcrcentage of invasive transitional-ccll carcinomas of the bladder3 and appcar to be an earlv event in the formation o1'carcinoma in situ.+ They are much less frequent in noninvasive papillarv tumors.-'o \Iutations of the p53 gene and nuclear accumulation of p53 protein are associated rvith the srade and stage ol bladder canceri and mav be important in the multistep progression of bladder cancer.T'!''I'he immunohistochemical detection ol the protein, u,irich exploits the difference in iile span betrveen mutated and rvild-tvpe p53. has been shorvn to correlate strongll' u.ith mutations of the p53 gene in bladder cancer.' The primarr. lactors used in determining the clinical treatment of patients u'ith earlr'-stage bladder cancer are the depth of tumor invasion, the tumor grade, and the presence or absence of lvmpl'r-node metastases. Radical cvstectom)' is a eenerally accepted treatment

surgery alone is adequate and who can avoid the morbidity and expense of adjuvant therapv from patients

who might benefit from both surgerv and additional

treatment.

for patients rvith invasive cancer con{ined to the bladder, particularlv lhen there is evidence of mus-

tor in predicting the clinical behavior ol bladder cancer. Previous work has suggested that alterations of p53 can predict disease progression in superficially inr.asive bladder cancer.l'l Horvever, a studv of patients rvith bladder cancer u,ho received a varietv of treatments suggested that nuclear accumulation of p53 is not a predictor of disease progression that is independent of clinical stage and the rate of proliferation of the tumor cells.t+ We demonstrate, in 243 patients rvith bladder cancer treated br. radical cvstectom,v, that nuclear accumulation of p53 identifies transitional-cell carcinomas with a propensitl' for progression that is independent of tumor grade and
stage.

In the present studv rve sought to determine rvhether a nuclear accumulation of p53 is an important fac-

From thc Departments of Urologl'(D. Esrig. D. Elmajian. J.A.F., J.P.S.. D.G.S.. P.A.J, ), Preventive Medicine (S.G., S,-C.C. ), and Pathology (P.W.N. , R.J.C.), University of Southern California School of Medicine and Kenneth Nonis Jr. Comprehensivc Cancer Center. Los Anseles. Address reprint requerts to Dr. Cote at the Depannrcnt of Pathlog)'. University of Southem Calitbmia School ol- Medicine. Kenncth r'.oris Jr. Cancer Center, l.l4l Eastlakc Ave.. Los Angeles. CA 90033. Supponed in part by grants (R35 CA,19758 and P30 CA1,1089) from the National Crncer lnstitute, b) the American Foundation for Urologic DiseaseNational Kidney Foundation Fellowship. and by the Firestein-Genz Cancer Research Fund.

MBrrroos
Population of Patients
\\'e studied 2.[3 patients rlho undcrenr radical cr.stectontr.. pelvic-lvmph-node dissection. and urinarv divcrsiorr irt the Kennetlr \orrisJr. Comprehcnsite Cancer Center. To assess the association bet$'een nuclear accumulation ol p53 and clinic;rl outconrc. rr e iucluded all patients rvith transitional-cell carcinoma treatecl br radicill c)stectomv fiom April l9B3 through June lgBT lirr uhom fbllon-up data and tumor samples lrom the cvstectomv specimens

l 260

THE NEW ENGLANDJOURNAL OF MEDICINE

Nov. 10, 1994

(preserved in archival parafn-embedded tissue blocks) were available. An additional 33 patients who underwent cystectomy bet\4r'een July 1987 and December l9BB were studied in order to increase the number of patients with cancer confined to the bladder. The study also included 53 patients described previously whose tumors under-

v/ent both molecular and immunohistochemical analysis for p53.s Thus, ol the entire group of 243 patients, 190 had not previously been evaluated for nuclear accumulation of p53. Patients with pure adenocarcinoma, squamous-cell carcinoma, or small-cell carcinoma of the bladder were excluded. The median age of all patients was 63 years (range,49 to B3); 77 percent were men, and 23 percent were
women.

Cllnical and Pathological Evaluation

The indications for radical cystectomy included invasion of muscle or prostate stroma by the tumor; high-grade, superficially invasive tumors associated with carcinoma in situ; carcinoma in situ refractory to intravesical chemotherapy or immunotherapy; and recurrent multifocal disease alter conservative therapy. None of the patients received pelvic irradiation or systemic chemotherapy before surgery. All the specimens included in this study were transitional-cell carcinomasl a minority demonstrated glandular or squa-

tumors \/ere classified as stage Pa (noninvasive papillary tumors), I I as stage Pis (carcinoma in situ), 50 as stage Pl (superficial invasion),32 as stage P2 (supercial invasion into muscularis propria), 35 as stage P3a (deep invasion into muscularis propria),68 as stage P3b (invasion into perivesicular fat), and 42 as stage P4 (direct extension into adjacent organs or structures). Sixty-six Patients were found on pathological examination to have metastatic disease in the pelvic lymph nodes. None of the patients had distant metastatic disease at the time of cystectomy. Forty-one patients received systemic chemotherapy after surgery, either cisplatin, cyclophosphamide, and doxorubicin or methotrexate, vinblastine, doxorubicin, and cisplatin. The median follow-up for the 243 patients was 6.0 years, with Bl percent having at least 3 years of follow-up. The patients were seen at three-month intervals during the first postoperative year, every four months during the second year, and every year thereafter. Follow-up consisted of a biochemical profile, chest radiography, and physical examination. A computed tomographic scan or bone scan was performed to confirm suspected recurrences of disease. Data on recurrences of transitional-cell carcinoma and causes of death were obtained from office and hospital records.

mous differentiation. The histologic grading was performed according to the method of Bergkvist et al.,rs and the pathological
staging \^/as done according to the tumor-node-metastasis classification.lG All tumors were reevaluated for histologic grade by two of the investigators. Among the 243 tumors, 11 were classified histologically as grade 2, 157 as grade 3, and 75 as grade 4. Five

Monoclonal Antibodies and lmmunohistochemical Analysis

Five-micrometer sections of archival formalin-fixed, parafEnembedded tissue were placed on slides coated with poly-lJysine (Sigma, St. Louis). The immunohistochemical procedure was performed as described elsewhere.5 In briet after deparalfinization and blocking of endogenous peroxidase, the antipS3 mouse monoclonal

Figure 1. lmmunohistochemical Detection ol ps3

tt:"il$#

Xffiflj,J lriional-Cell

Carcinomas of the Bladder with the Anti-psg

No detectable nuclear staining is seen in Panel A, only a few cells (1 to g percent) with nuclear reactivity are seen in Panel B, heterogeneous nuclear reactivity is seen in 10 lo 49 percent of tumor cells in Panel C, and intense homogeneous nuclear reactivity is seen in 50 to 100 percent of tumor cells in Panel D (all panels x 105). Tumors with 0 to g percent nuclear staining were considered p53negative, whereas tumors with 10 to 100 percent nuclear staining were considered ps3-positive.

\:ol. 331

\o. I9

ACICIU\IULATION OF )iLCLEAR p53 AND TU\IOR PROGRL,SSION

I\

BLADDER

CA\CER

I26l

Table 1. Association of p53 lmmunoreactivity with Grade and

Pathological Stage of Bladder Cancer and Presence or Absence of Lymph-Node Meiastases in "lg0 Patients Not Previously Tested for p53 Alterations.
No. oF
VARIBI-E

sionlt u'ere usecl to evalu:rte the association of p53 accumulation nitli l;mph-node st.ttus. pathological stage of the priman tumor.
and histologic grade. Kaplan-\Ieier plotsls and the loe-rank testll' l'cre used to evaluate the association of these three standard clinical prognostic variables, as rvell as the expression of' p53. rrith the time to recurrence and u'ith sun-ival. Greenu'ood's I'ormularq ras used to estimate thc standard errors of the Kaplan-\Ieier estimates of the probabilitv of survilal or recurrence. To determine rvhether an accumulation of p53 prolided prognostic inlormation betond that provided bv the three standard clinical variables. a stratified loirank test uas used. ll P values reported are nro-sided. The statistical analvses rrere performed for the entire cohort of 2.13 patients and rsere perficrmed separatch lor the 190 patients nor previouslv tcsted for accumulation of p53.

PaTrENrs

NUCLEAR p53 NECAI I\

REAcflvlTt!
TSITIVE

V{LU[

number lpercent)

Gradet
2
3

4 Stage Metastases absent Pa or Pis

9 122 59 15 39 29 20 36 9 42

79 33

7(78) (65) (56)

2(22)
43 (35) 26 (411
0.20+

Rnsurrs (tt0) 30 (77) (66) l9 1l(55) 2l (58) 7(78) 19 (45)

12

PI
P2 P3a P3b P4

3 (20) 9 (23)

l0 (34) 9(45)
t5 (42)

2(22)
23 (55)
0.0031

Metastases present

xNegatie indicates that less than l0 percenr of tunror cell nuclei demonstrated p53 immuno reaclivil). nd positive lhat I0 percent or morc of tumor-cell nuclei demonstrted p53

immnoreactisit)

iAccording to the method of Bergkvi5l ls iDerived tiom Peason's chi-square test for a tso-b!{wo table comparing grade 2 nd
tumors with grade 4 tumors.
N'letastases refers

l'

Pathological staging was performed according to the tumor-node-metastasis sysrcm.l6 to lymph-nodc metastases identilied during the pathological ealuation.

Of the 190 bladder tumors not previouslv examined for accumulation of p53. I 12 had no nuclear reactivity and 7 had a ferv locallv positive tumor nuclei but less than l0 percent. These ll9 tumors were considered p53-negative. In 54 of the remaining 7l tumors, p53 protein was detected in l0 to 49 percent of tumor-cell nuclei. and in 17 tumors p53 was seen in 50 to 100 percent of tumor-cell nuclei. These 7l bladder cancers 'rvere considered p53-positive. In all 2+3 patients, 142 tumors were classified as p53-negative and 101 as p53positive.
Association of p53 Nuclear Reactivity with Tumor Grade, Pathological Stage, and Lymph-Node Status

lBased on the likelihood-ratio tesr for logistic regression.li

antibod)' PAblB0l (IgGl class. l:10 dilution, Bioqencx, Sarr Ramon, Calif.) uas incubated overnight rr.ith tissue at .1"C. P.\blB0l
recosnizes the p53 protein at a dcnaturation-resistant epitope corresponding to amino acids 32 through 79. l'issues \\'ere thcn incubated uith a biotinllatcd horse antimouse secondarv antibodr'(\rector Labs, Burlingame, Calil). and reactivitv ras visualized rrith an avidin-biotin-immunoperoxidase svstem (\'ector) using diaminobenzidine (0.03 percent) as the clrromosen and hematoxvlin as the counterstain. Samples of bladder c:rrcinoma rlith knorvn p53 muta-

Analysis of the 190 tumors not previously tested for

p53 revealed that nuclear p53 was identified more frequently in grade 4 tumors than in grade 2 or 3 tumors)

but this association !!'as not statisticallv significant (P:0.20) (Table l). Bvcontrast, thepresenceof nuclear p53 was significanti)' associated rvith pathological stase (p : 0.003); 32 percent ol the patients with negative lvmph nodes, as compared with 55 percent of the patients u'ith positive lymph nodes, had nuclear accumulation of p53 (P : 0.008). In patients with no evidence of lymph-node metastases, the presence of nuclear p53 lvas associated with greater depth of invasion; 22 percent of the patients with superficial disease (stage Pa, Pis, or Pl), as compared with 38 percent of the patients with disease invasive of muscle (staees P2

tions and documented accumulations ol'p53 protein bv inrmunohistochemical analrsis lere used as positive controls. Normal urothelium and nonepithelial cells (hmphootes, stromirl cells, and endothelial cells), used as internal neqativc controls. demonstratcd no immunoreactivitr'. Onlv nuclear localization of immunoreactir'itv lvas evaluated. 'I'he extent of nuclear reactit'itt rtas classified in four catccories: no nuclear reactivitvi a leiv focallr positive nuclei ( I to 9 percent of tumor cells): heterogeneous nuclear reactivit\' ( I 0 to 49 percent of tumor cells): and intense homogeneous nuclear reactivit) (50 to 100 percent of tumor cells) (l:ie. 1). C)nh'samples demonstrating ar least I 0 percent nuclcar reactivitv rvere considered to be p53-positive (to have an alteration in p53). \\'e based this criterion on our demonstration ol' a slrong correlation of mu tarions in the p53 gene rvith the accumulation of p53 protein in l0 percent or more of the tumor-cell nuclei.r The immunohistochemical analr'sis was performed rithout knorledee ol the tumor stase or the results ol clinical follorr-up.

through
(P

P4) , had nuclear p53 in the tumor cells 0.044) . Similar results were obtained for the en-

tire cohort of 243 patients.

Association ol p53 lmmunoreactivity with Recurrence and Overall Survival

Statistical Analysis
Survir.al was calculated lrom cvstectomv to the clate ol death or the date of thc last follorv-up (either a clinical r,isit or a discussion rvith the patient's referring phr,sician)l deaths duc to anv cause were considered to represent treatment lilures. 'fime to recurrence s,as

In the group of 190 patients not previously tested for p53 alterations, nuclear accumulation of p53 was significantll' associated with an increased probability
of tumor recurrence (P<0.001) and a decreased probability of survival (P<0.001). Identical resuks were obtained for the entire cohort of 243 parients; Figures 2 and 3 sholv curves for recurrence and survival for all
patients.

calculated lrom cvstectomY to the date of thc first documented clinical recurrence or the last folkr.up: data r:n patients rho died free ol disease beltlre anv recurrence u'ere censored at the time of death. One patient u'as knorvn to have clied of disease, but the date of recurrence was unkno\\n and therelore a datc nriduav berueen the last clinic visit;rnd the date of'dcath $'as used. For the purpose of the statistical analvsis. nuclear accumulations of'p53 rvere classifred as either positive (accumulation in I0 percent or morc uf tumor cells) or neqatirc.
Contingencv tables. Pearson's chi-square test. aud loeistic regrrs-

Among the patients u,ith no evidence ol lvmphnode involvement, nuclear accumulation of p53 lvas sienificantly associated with recurrence in those with disease confined to the bladder (srage Pi, P2. or P3a). Horvever, this association \r'as not statistically sienificant amons the patients with extravesical extension of

262

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\E\\' E,\GLA\D.JOUR\AT,

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10. 1994

o)

'

'E.
tro o G

tumor (stage P3b or P4) ('fable 2). The five-r'ear recurrence rates for patients r.vith stage Pl. P2. and P3a tumors that rvere p53-negative rvere 7. 12. and I I percent, respectivelr-. In contrast, the fir.'e-l-ear recurrence rates were 62, 56, and B0 percent for stage Pl. P2, and
P3a tumors that n'ere p53-positir-e (Table 2).

E(r (!
_o

*
o

9O

In

all

subgroups of tumors confined to the bladder, the recurrence rates at five vears for pS3-negative and p53pS3-positive (n = 101)

o-

positive tumors di{Iered significantlv. Signi{icant di ferences in estimated fir'e-\'ear survival rates \1'ere also

0 1 2 3 4 5 6 7 8 9
Years since Cystectomy

found among patients with tumors conlined to the bladder (except stage P3a tumors) (Table 2). Identi10

Figure 2. Probability of Bemaining Relapse-free in 243 Patients with Bladder Cancer and either ps3-Positive or ps3-Negative Tumors. ldentical results were obtained for the subgroup of 190 patients not previously lested for p53 alterations. Each tick mark represents a patient who had not had a recurrence of disease at the time of the last follow-up.

c')

.=

a
o
.= -o (
_o

f,

cal results rvere obtained ficr the entire cohort ol 243 patients. Figures 4 and 5 shon' the Kaplan-\Ieier curves for recurrence and survival in all 243 patients, stratified according to the depth of tumor invasion. In a multivariable anah'sis stratified according to grade, patholoeical stage, and presence or absence of lymph-node metastases nuclear p53 status u,as an independent predictor of the recurrence ol bladder cancer and of o'n'erall survival (P<0.001). \\'hen patients rvith ivmph-node-negative cancers confined to the bladder were stratified accordine to p53 status, pathological stage (i.e., depth of inr,asion) lvas not an independent predictor of either recurrence (P = 0.62) or survival (P : 0.23). Forty-one of the 243 patients received postoperarive adjuvant svstemic chemotherapr'. \Vhen these patients were removed from the analysis. the presence of nuclear p53 remained highlv associated rvith recurrence and death. 'Ihis anah'sis demonstrates the predictive value of nuclear p53 reactir,'itv in a cohort of

o-

patients uniformlv treated rvith radical cvsrectomy and pelvic-lvmph-node dissection but no adjuvant

0 1 2 3 4 5 6 7 I
Years since Cystectomy

10

therapy.

DrscussroN

\\'e found that the immunohistochemical detection Figure 3. Probability of Survival in Patients with Bladder Cancer of p53 protein in the nuclei of tumor cells can proand either ps3-Positive or ps3-Negative Tumors. vide prognostic information in patients with bladder Each tick mark represents a patient who was alive at the time of the last follow-up. cancer. In patients u'ith transitional-cell carcinoma of the bladder treated bv cvstectomv, the nuclear accum;l;tion of Table 2. Estimated Rates of Recurrence and survival at Five years in 1g0 patients with Bladder Cancer, According to p53 Status of Tumors and Pathological Stage.* p53 correlated rvith a significantlv
No. oF
CRoLp AND

SrAoE

PT|ENTS

RECURRENCE Relrs or SunvrrlL p53p53P ps3p53P NEGA'IIVE rcSITIVE VALUE NECATIVE rcITtVE VAI.UE
RAIES oF

Lymph nodes negative

Confined to bladder
Pa or

increased risk of recurrence and decreased overall survival. The link betlveen nuclear p53 and prognosis rvas independent ol tumor grade, pathologicai stage. and l"'mph-node status.'fhe strongest association

Pl P2 P3a
P3b
P:t

Pis

15

39 29 20 36
o

Not conlined to bladder

Lymph nodes

positive

42

33*27 0.48 75!13 *27 7+5 62+17 0.002 9315 78a l.l l2+8 56* t7 0.007 79+ l0 30* l5 Il+ll 80* 17 0.01 I 6.1a l5 22!14 591 ll 73*t2 0.23 52+11 27+l 43+t9 100 0.20 57t19 0 69* 12 9l t6 0.054 32:t I I l3+7
18+12
6'7

0.'73
0.00.1

betueen p53 immunoreactivitv in tumor-cell nuclei and tumor progression lvas observed when the disease rr.as confined to the bladder. 'Ihe presence ol nuclear p53 was stronglv associated n,ith an increased risk of recurrence among patients rlith Pl. P2. or P3a disease and with decreased overall survival amons those u,ith Pl or P2 disease. It rtas the onlv independent predic-

0.023

0.20 0.18 0.12 0.19

*Rates of recurcnce and sun i\'{l &c based on Kaplan- Meier esiimaresril plus-minus values e estimates of the standard crror. calculaled u ith Greenwood s lbmula.l9 Tumors considered lo bc p5-l-negative had less than l0 percent of tumor-cell nuclei demonsralrng p53 immunoreactivity. and those considered to be p53-positive had l0 percent or nx)re of tumor-cell

nuclei demonstratrn!

f5l

immunoreactrvl.

Vol. 331

\o.

19

,\CCU\ILL.\'I'IO\ ()F \tICLEAR

p5l)

,\\D'tU\lOR

PROGRI'ISSIO\

I\

BL.\DDER CANCIER

l2i:l

pS3-negative (n = 34)

ps3-positive (n =

'1

1)

0)

;a
(

1.00
p53-negative (n = 20)
P = 0.018

P
c =
C

0.75

nohistochemical methocls. A long-lived mutated p53 protein, in contrast. is usuallr" detectable by such techniques. \\'e have previouslv demonstrated a significant association ol p53 mutati;r'rs *'ith the immunohistochemical detection of p53 protein in tumor-cell nuclei.:' Immunohistochemical techniques identied most cases ir-r u'hich thc cells ]rad mutated p53 genes. but 15 to 20 percent of tumors 'rvith demonstrable mutatiolls of the p53 gene were ncgative bv immunohistochemical analvsis.r \Ioreovcr. a substantial proportion of tumors rvith nuclear accumulation ol p53 lacked evider.rce of p53 gene mutation. Alterations that rer.rder the p53 protein clctectable bv immunohistochemical analr-sis mav not require a mutatiorl in the p53 gcne. For example. celh-rlar oncoselle products that bind to and inactivate n'ild-tvpe p53 protein, such as ,IDNI2,rr mzrv prolong the half-lile ol'p53, allowing it to accumulate in the nucleus. Although this phenonlenon has not been shou'n directlv, recent studies indicate th.rt cells that overexpress NIf)NI2 can also
overexprcss p53 protein in thc absence of a p53 gene mutation.r: N{oreover. the level of u'ilcl-tvpe p53 protein can incrcase in response to D\A damage.::r Thus, increases in the ler.el ol the p53 protein and mutation of the p53 sene occur together in most cases but can be separate events. Although u,e have shorvn that the presence of p53 alterations as detected bv immunohistochcmical methods is clinicallr- rele'u'ant, it mav also be important to assess mutations of the p53 gene

F
c) (r

o.so

o
(

o.2s

.=

o.oo

directlv as a prognostic indicator in bladder cancer. 'lhe most important fincling of this studv is that in patients u'ith transitional-cell carcinoma confined to

of lvmph-node

the bladdcr (stages P1, P2. and P3a). and no evidence

metastases. p53 nuclear reactivit)-

iclentifies tumors rvith a tendencv to progress. In these

cases. the detection
0.s0

ol

nuclear p53 is more stronglv

o.25

pS3-positive (n = 12)

0.00

6 7

10

Years since Cystectomy

Figure 4. Probability of Remaining Relapse{ree According to
Pathological Stage in Patients with Organ-Confined Bladder Cancer but No Regional Lymph-Node Metastases. All patients with P1, P2, or P3a dlsease from the entire cohort of 243 patients were included in this analysis. ldentical results were obtained tor the patients with P1, P2, or P3a disease in the subgroup of 190 patients not previously tested for p53 alterations.

tor o[ disease proeression in a multivariable comparison of p53 status, pathologicai stagc. and histologic
gracle.

associated lvith tumor recurrence and decreased survival than is the depth ol invasion or histoloeic grade. Patients u'ith p53-negative tumors had relativell. lou, rates of recurrence. r.vhereas metastases developed in the majoritt' of patients rvith p53-positive tumors, regardless of depth ol invasion. Although depth ol invasion is clcarlv associated n'ith the proeression of disease in patients rvith bladder cancer, this ma1' reflect the proportion of tumors in each stage that have p53 alterations. This studv mav in{luence the selectir-rn ol patients for ad.juvant treatment of blaclder cancer. r'r'hich currenth'ciepends on the depth of tumor invasion and the detection of regional ivmph-node metastases. The results of t\\'o recent studies are encouraging," '' but the role ol ad.jur.ant chemotherapv after c)'stectom)', particularlv in patients rvith disease con{rnecl to the bladder. remains unresoh'ed. Patients rvith p53-negative

tumors confined to the bladder havc a lou. rate of

disease prouression (even lvhen there is deep muscle

The product of mutated p53 gene t:an be a nletabolicallv stable protein rvith a lons half-lif.ri' In contrast, rvild-npe p53 has a short htrll'-lit. orih'6 to 30 minutes, and thus it dot's lrot scncrally accrrmulate in high enough levcls to be clctected l>r' standard immu-

inr,asion) and mav not recluire adjuvant treatment after radical cvstectom\,. In c()ntrrISt, paticnts \\'ith
p53-positir.,e cancer conhned to the bladder (including those rtith onh. superficiallv invasive tumors) have a poor prognosis. 'fhev mav bencfit lrom adjuvant trear-

l 26+

THE NE\\' ENGI,A\D JOURNAL OF \IEDICJINE

1.00

Nor'. 10. 199{

cvstectom-v and mav therelrrre benefit from adjuvant

0.75

treatment. Thus, the immunohistochemical detection of p53 mav identif,v patients u'ith cancer confined to the bladder rvho could benefit lrom radical surgerv
ar.rd adjuvant therap\'. Furthermore, the absence

of

0.s0

detectabie p53 mav be an indication for conser\iative tl.rerapv. er,en in the presence of localll' advanced
disease.
ps3-positive (n = 11)

0.25

\\'e are in<lebted to f)rs. Garl Licskovskr and Stuart Bovd Ibr providing sonrc of the paticnts included in this studr'. and to I)rs. Ron \atale and Cllive 'far lor for tht'ir critical rer,ieit of
this rvork.

0.00

RrprnnNcrs
l.
1.00

2. 3.
.1.

c
.=
f

(,)

0.75

a
o
.= 0.50

5. 6.

o (

o o

o.25

7.
0.00

M. Sidranskl'D. Voqelstein B, Hanis CC. p53 Mutations in human cancers. Sciencc l99l:253:.19-53. Lane DP. Cancer: p53, guardian of the -senome. Nature 1992:358:15-6. Sidransky D. Von Eschenbach A. Tsai YC. et al. Idcntification of p53 gcne mutations in bladder cancers and urine samples. Science l99l:252:7069. Spruck CH Ill. Ohneseit PF. Gonzalez-Zulueta M, et al. Two molecular pathwa]-s ) transitional cell carcinoma of the bladder. Cancer Rcs 1994: 54:784-8. Esrig D. Spruck CH llt. Nichols PW. et al. p53 Nuclear protein accumulation conclates with mutations in the p5l gene. tumor,erade. and stage in bladder canccr. Am J Pathol 1993:143:1389-97. Sarkis AS. Zhang Z. Cordon-Cardo C. et al. p53 Nuclear overexpression and disease progression in Ta bladder carcinoma. Int J Oncol 1993:3:35560. Sidransky- D. Messing E. Molecular gcnetics and biochemical mechanisms in bladder cancer; oncogenes. tumor suppressor genes. and growth factors.
Hollstein

Urol

Cf

in North Am 199219:629-39.

1.00

0.75

pS3-negative (n = 14)

II
12

0.50
l3

Cordon-Cardo C, Wartinger D. Petrylak D. et al. Altered expression of retinoblastoma gene product: prognostic indicator in bladder cancer. J Natl Cancer Inst 1992:ti4: I25l-6. Logothctis CJ, Xu HJ. Ro JY. et al. Altcred expression of retinoblastoma protcin and known prognostic variables in localll,advanced bladder cancer. J Natl Cancer In 1992;84:1256-61. Skinner DG. Mangement of invasive bladder cancer: a meticulous pelvic node dissection can make a diffrence. J Urol 1982:128:34-6. Skinner DG, Daniels JR. Russell CA, et al. The role of adjuvant chemotherapy followin-e cystectomy for invasive bladder cancer: a prospective comparative trial. J Uro! t99l:145:,:159-67. Stijckle M. Meyenburg W. We llek S. et al. Advanced bladder cancer (stages pT3b, pT4a. pNl and pN2): improved survival after radical cystectomy and 3 adjuvant cyclcs of chemotherapy: resu lts of a controlled prospective study. J Urol 1992:t48:302-7. Sarkis AS. Dalbagni G. Cordon-Cardo C. et al. Nuclear overexpression of

0.25

ps3-positive (n = 12)

14. 15.

p53 protcin in transitional cell bladder carcinoma: a marker for disease progression. J Natl Cancer lnst 1993:85:53-9. Lipponen PK. Over-expression of p53 nuclear oncoprotein in transitional-

0.o0

012345678910
Years since Cystectomy

cell bladder cancer and its prognostic value. Int J Cancer I993:53:365-70. Bcrgkvist A, Ljungqvist A. Moberger G. Classificalion of bladder tumours based on the cellular pattern. Acta Chir Scand 1965:130:371-8. 16. Hermanek P. Sobin LH. eds. TNM classilication of malignant tumors. 4th ed. New York: Springer-Verlag. 1987:133-4. t7. Fienberg SE. The analysis of cross-classified categorical data. Cambridge.
Mass.:
18.

Figure 5. Probability of Survival According to Pathological Stage in Patients with Organ-Confined Bladder Cancer but No Regional Lymph-Node Metastases.

MIT

Press. 1977:9-86.

ment. This studv and the studv bv Sarkis et al.r:r are also relevant to the controversial issue of surgical treatment of superficially invasive bladder cancer. Patients with superliciallv invasive p53-positive tumors Iiave a high rate of disease progression and mav therefore benefit from earlv radical c),stectomv. N{oreover, our study indicates that patients rvith p53-positive tumors are at high risk of progression dcspite radical

Kaplan EL. Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958:53:457-81. 19. N'liller RG Jr. Suruival analysis. New York: John Wiley. l98l:44-102. 20. Finlay CA, Hinds PW, Tan TH. Eliyahu D, Oren M. Levine MJ. Actirating mutations for transformation by p53 produce a gene protJuct that foms an hsc70-p53 complex with an altered half-life. Mol Cell Biol 1988:8:531-9. 21 Oliner JD, Kinzler KW. Meltzer PS. George DL. Vogelstein B. Amplification of a gene encoding a p53-associated protein in human strcomas. Nature I 992:358:80-3. Cordon-Cardo C. Latres E, Drobjnak M. et al. Molecular abnormalities of mdrn2 and p53 genes in adult soti tissue sarcomas. Cancer Res 1994:.54:7949. Kastan MB, Onyekwere O. Sidransky D. Vogelstein B, Craig RW. Panicipation of p53 protein in the cellular response to DNA damage. Cancer Res

22

23

l99l:51:6304-l I.

\irl. ll3l \o.

l9

III.\GE]S

I\

CLI\ IC],\L IIEDI(JI\E

l 265

Images in Clinical Medicine

Kru En<;r.r, M.D.,
Eorr<>n

Coronarl Arteriouenous F'istula on Coronary Angiograph2

A large coronary arteriovenous fistula can be seen originating in the left coronary artery, coursing over the lateral and posterior walls of the left ventricle, and eventually emptying into the right atrium. The solid arrow indicates the origin of the fistula (not well visualized), and the open arrow indicates a normal-sized left anterior descending coronary artery, which is of much smaller caliber than the greatly dilated fistula. Patients with such fistulas often have loud continuous cardiac murmurs and may have congestive heart {ailure, myocardial ischemia (due to a coronary-artery "steal" phenomenon), and pulmonary hypertension. Coronary arteriovenous listulas typically arise as congenital anomalies. With obliteration of the fistula by suturing, the prognosis is usually excellenl.

KENrcnr Fuyrse,

II.D.
77030

University of Texas Health Science Center at Houston

Houston,

TX

\\trnnEs Suenlrax, \I.D.

Beth Israel Medical Center

)Jen'York.

\Y

10003

THE

\E\\' E\Gr..\\D.IOUR\'\1. Or \IEDIC:l-\E

\or .

1t).

l9!t{

SPECIAL ARTICLE
STATE PRACTICE ENVIRONMENTS AND THE SUPPLY OF PHYSICIAN ASSISTANTS, NURSE

PRACTITIONERS, AND CERTIFIED NURSE-MIDWIVES

Eou'eno S. Sprsorxsrr, lvl.P.H., Srr,pHaxIr, SeNsol,r, trI.P.H., NI.P.P., Canol BezclL, \{.D., N[.P.H., Nlanr-,q, E. Seluox, Sc.D., R.N., axn Frlznc;cn Nlurr-ex, M.D.

Abstract Background.

Most proposals to increase access to primary care in the United States emphasize increasing the proporlion of generalist physicians. Another approach is to increase the number of physician assistants, nurse practitioners, and certilied nurse-midwives. Methods. We analyzed variations in the regulation of

nurse practilioners, physician assistants, and certified nurse-midwives in all 50 states and the District of Columbia. Using a 100-point scoring system, we assigned numerical values to specific characteristics of the practice environment in each state for each group of practitioners, awarding a maximum of 20 points for legal status, 40
points for reimbursement for services, and 40 points for the authority to write prescriptions. We calculated coefficients for the correlation of summary measures of these values within states with estimates of the supply of practitioners per 100,000 population. Results. There was wide variation among states in
both practice-environment scores and practitioner-to-population ratios for allthree groups of practitioners. We found

positive correlations within states between the supply of physician assistants, nurse practitloners, and certified nurse-midwives and the practice-environment score for the state (Spearman rank-correlation coefficients, 0.63 lP<0.0011,0.41 [P 0.003], and 0.51 [P<0.001], respectively). Positive associations were also found in the states between the supply of generalist physicians and the supply of physician assistants (r 0.54, P<0.001) and nurse practitioners (r = 0.35, P 0.014). Nevertheless, in the

17 states with the greatest shortages of primary care phy-

sicians, favorable practice-environment scores were still

associated with higher practitioner-to-population ratios for physician assistants (r = 0.68, P 0.003), nurse practitioners (r 0.54, P 0.026), and certified nurse-midwives (r:0.42, P = 0.09). Conclusions. State regulation of physician assistants, nurse practitioners, and certified nurse-midwives varies

widely. Favorable practice environments are strongly associated with a larger supply of these practitioners. (N EnglJ Med 1994;331:1266-71.)
terpret laboratory tests, establish and carrv out treatment plans, suture wounds, and provide preventive health services. Each profession is about 25 r'ears old

\ 7[OS'I proposals to increase access to primarr' IVI care in the United States emphasize increasing
the proportion of generalist phl,sicians.r-i Another approach is to increase the number of other practitioners specificallv, physician assistants, nurse practitioners, and certified nurse-midwives.'t!'Within their areas of competerrcv, and lvith appropriate training and supervision. these practitioners may pror.ide medical care similar in qualit,v to that of phvsiciar-rs and at less

cost.r''ri' 'fhese practitioners ma_v be especiallv valuable in areas rvhere there are shortages of primary care phvsicians. Yet state legislation and regulation mav discourage or prevent them from seeking emplol'ment, even rvhen jobs would otherwise be ar.ailable. To understand the relation betweerr statcs' practicc environments and the suppl,v of these practitioners, ll'e analyzed variation in the regulation of nurse practitioners. physician assistants, and certified nursemidwives in all 50 states and the District of Columbia (n,hich, for the purposes ol this analvsis. rve considered a state). Although the education, Iicensure. and reeulation of nurse practitioners and physician assistants diffr. manv have similar job descriptions.r'j 'fhe1, diaenose illness, perform physical examinations, order and in-

in the United States. Phl.sician assistants are saiaried emplovees nho bv law must work under the supervision of a ph,vsician. Of the 22,300 phl.sician assistants practicing in 1992, 44 percent rvorked in primarv care specialties. and another B percent lvere in emergenc). medicine. The majoritv were educated in trvo-year training prosrams. About 34 percent of phvsician assistants rvorked in rural areas.l7 In some states, nurse practitioners can establish independent practices and be reimbursed directlv for their services. Because the states have no common definition of nurse practitioners. estimates of their number varv widelv. 1-hrough 1992. about 42.600 emploved registered llurses had receir,ed lormal training as nurse practitioners bevond their professional education as nursesrs: estimatcs of the number practicing as rlurse practitioners ransed lrom 21,900re to 27,200.2" 'lhe majoritv were educatcd in certificate prosrams a'"'erasins about one vear in length; 4 of everl' l0 l'rad rnaster's degrees. About three quarters rvere in primarr, care. Eighteerl percent of nurse practitioners lvorked outside metropolitan areas in 1992.re Certified nurse-midwives are registered nurses u'ith advanced education in the pror,ision of prenatal, perinatal, postpartum, neu'born, and routine gvnecologic care. About fJl pcrcent hacl master's degrees in
1991.'rr Sincc 1971. national certification as a nurse-

From the Bureau of Health Professions. Health Resources and Services Administration, Depanment of Health and Human Services. Rockville. Md. Address reprint requests to Mr. Sekscenski at the Bureau of Health Prolessions. Health Resources and Services Administration. Rm. 8-47. 560O Parklawn Dr.. Rockville. MD 20857. The vieus cxpressed in this article are srictly those ofthc authors. No ofhcial endorsement b! the Department ol Health and Human Services or any of its components is intended or should be infened.

nridrvifc has rccluired eraduation ll'om an accredited program lbr nurse-midr,vifelv and the passine of an

Vol. 331

\o. l9

PR-\C]-|IC]E

E\VIRO\\{ENTS.\ND THE

SUPPLY OF NO}iPHYSICIAN PR.\CTII'IO\ERS

1267

examination administered by the American Collegc of \urse-Nlidu'ir-es. In 1992, 43 states recosnized certified nurse-midwives in their statutes or regulations.22 About half of all states allou'ed direct reimbursement ltir the services of a certified nurse-midwife. In 1992, betn een 3500 and 4300 certified nurse-midwit,es u'ere eligible to practice in private offices, community health centers, free-standing birthing centers, and other health care settinss2'r (and unpublished data) . Certified nurse-midwives attended 4.1 percent of all delir,eries in the United States in l99l.i+ Betu-een 1l and 22 perccnt practiced in rural areas.l32*

of

state h'ere obtained lrom various sources (Table 2). The estimates 27,200 practicing nurse practitioners and '1300 certified nursemidrvives u'ere the onll available estimates that providecl statespecific figures. The estimates of the number of phvsician assist-

ants do not include federal emplolees. The supph of sencralist phvsicians was cstimated as the total number of nonfederirl allopathic phvsicians activeh'involved in patient care u'ho designated themselves as being in eeneral practice. lamilv practice, general internal medicine, or general pediatrics in the 1992 Area Resource File.rs Practice-environment scores and estimates of the supplv of practitioners u'ere calculated independentll'. Data from the
Bureau of the Census on state populations in 1992 were obtained from the nrerican \ledical ssociation.'j'r Estimates ol' the percentage ol each state's population that was Iiving in areas designated as having a shortage of primarv care u'ere obtained lrom the Bureau of Primar.v Health Care of the Department of Health and Human
Service s.'ll

Mr:rHoos
Practicc environnrents in the states u'ere assesscd bv rerierring journal articles and lcgislation and bv consultinq rvith researchers. legal scholars. anrl 1;rolessional organizations. In all jurisdictions. infbrrn:rtion las sorrght aborrt conditions in lgg2. Spccilic criteria are shoun in 'I'able l. A 100-point scoring svstem \\'as corlstructed for each group; a maximum ol-20 points rras allocated if practitioners had legal status as professionals. '10 points i[ rcimbursement lor their srrvices rvas requircd. and.l0 points il thcv had the authoritv to \lrite prescriptions. \Irrrc leigltt uas gir-en to the second and third categories becausc the simple recognition ol prolessional iclentitv cntailcd in the confrring o['lce:rl status alonc uas consiclered less important; houevcr. rvhen equ:ll rveiqht rvas given to each o{'the three rnajur catesories. the results did not change substantiallr'. Points rrere allocated llithin cach categorv and then totaled..\ score of 100 represcntecl the most lavorable enVironmcnt. and a score of 0 the least favorablc. The assessnrent *as perlormed consistenth lirr all the states in a given discipline. but the actual criteria lbr the disciplincs varied bccause ol' prolcssional and resulatorv di{Ierences. Thus, comparison of scort's benveen states is more appropriate rvithin a discipline than between disciplincs. Thc practice environments Ir phvsician assistants \iere quantified primarilv on tlle basis ol' inlormation lrom the American Academv of Phvsician Assistants!; and other published studies.tr'26 'fhe practice environrnents lr nursc practitioncrs rrere quantificd on the basis of inlbrmation lrom published studies.rili The practice ertvironnrcnts [or certified nurse-midu ives were quantified

Becausc the practice-erl'ironment scores \\'e developed had non-normal distributions. the\' \r'ere analt zed lvith nonparametric methods. States rere ranked according to their practice-enrironment scores and the number of practitioners per 100.000 population (practitioner-to-population ratios). Rank-correlation coe{Hcients n'ere derivrd lbr pairs of individual practitioner-topopulation ratios and practice-en\ ironment scores. according to the method of Spearman.32 \\'e calculated partial correlation coe{cients that compared the supplv of nonphr.sician practitioners rvith that ol generalist phlsicians. rvith control lbr the state population.3s AII P values are based on t\r'o-tailed tests.

Rrsurrs There was lvide variation in both state practiceenvironment scores and practitioner-to-population ratios for all the groups of practitioners (Table 2, Fig. I ). For phvsician assistants, the practice-en\rironment scores ranged from a high of 100 in the state of Washington to 0 in N{ississippi. Twenty states had scores of 90 or higher; l4 had scores below 50. Practitioner-tofrom a high of 24.6 phvsician population ratios "'aried assistants per 100,000 population in Maine to a lo!r,of 0.2 in Mississippi. Twenty-one states had I0 or more phvsician assistants lor every 100,000 people, whereas 13 states had 5 or fewer. Practice-environment scores lor nurse practitioners ranged lrom 100 in Oregon to l4 in Ohio and Illinois. Twelve states scored 86 or abol'e; l9 had scores belo$' 50. The ratios of the number ol nurse practitioners

on the basis ol information f-rom tlie .\merican Ciollege of \ urse\{idrvives2328 and a survev bl the Ollice of the Inspector General of' the Department of' Health and Human Services.lr Supplemental information on all threc groups ol practitioners *as obtained from the 1993 annual report of the Phvsician Parment Revierv
Commission.+

Estimates

of the supph of nonphr.sician practitioners in

each

Table 1. Scoring System Used to Quanti the Practice Environment in States in Regard to Physician Assistants, Nurse Practitioners, and Certified Nurse-Midwives.
ScoRrNc CArEcoRt PHYsrctAN AssrsrNTs
NURsE PRAcTlrloNERs
CERTTFTI:D

NriRsF-MrDwrvFs

Legal status
(20 points)

Rcimburscment (40 poinrs)

Authority to
prcscribe (.+0 points)

License recognition. 5 points: scope of practice regulations, 0-5 points more: practice under physician's indirect superuision. additional 0 l0 points. Mandated payment. 30 points: paymcnt for services under indirect superuision, l0 points more unless payment was less than that paid to physician. then percentage mlti' plied by I0, for 0-10 points. Any authority to write prescriptions. 20 points:0-20 more points based on absence of specilic restrictions. (Limited auth0ritl'to order medications in inpatient settings. 0- l0 poinrs.)

Licensc or title recognition. 6 points: scope of practice defined by board of nursing alone. 7 more points: no required superuision by physician, another 7 points. Mandated palment. 20 points: :ervices covered. another 0- 10 points; percentge of physician fees paid by Medicaid (times l0). 0 l0 points more.

License or title recognition, 10 points; regulation by board of nursing alone, additional l0 points.

Mandated payment, 20 points: types

of matemity. perinatal, or familyplanning services covered. additional 0-20 points.

Continuum of points bascd on level of independence: no authority. 0 points: full authority without physician oversight. 40 points.

Three categories: no authority. 0 points; limited or restricted authrity. 20 poinrs: tull authority. 40 points.

268

THE NE\\- E\GL.\\D JOUR)iAL Ot- \lEDICINE

\or'.

10.

199,1

to members of the population also varied w-idel1,, lrom 37.2 per 100,000 in the District of Columbia to 2.7 per 100,000 in Nebraska. Trventv-six states had ratios of more than 10, including 10 above 20. In contrast, five states had ratios of 5 or fewer.
Table 2. Practitioner-to-Population Ratios and Practice-Environment Scores for Physician Assistants, Nurse Practitioners, and Certified Nurse-Midwives According to State, 1992,*
CERTIFIED STATE

PHYsrcrAN NURSE PRACT! NURSEAssrsrANTSi uorrnsi lrIrD\\1\ ES RATIO SCORE RTIO SCORE RATIO SCORE
2.7 20.8 8.9
1.2 5.1

Alabama Alaska

Arizona
Arkansas

Califomia
Colorado Connecticut Delaware District of Columbia

I 1.0
15.3

Florida
Georgia Hawaii Itlaho

7.7 5.9 8.2

9.0 4.6
5.1
2.1

Illinois
Indiana

39 90 99 54 58 80 87 55 92 48 59 38 89 59
5t

6.3 30.5 23.3 28.9

12.9 16.2 20. l

20.4 37.3

t4.9
7.8

9.4 8.r
'1.O

lowa
Kansas

9.3

I0.6
6.2 2.2 24.6

Kentucky Louisiana Maine Maryland

Massachusetts

l3.9
8.9
10.4

Michigan
Minnesota

7.t
0.2
2.0
13.0

Mississippi Missouri
Montana Nebraska Nevada New Hampshire

6.2

t2.7
2.3
10.4

Neu'Jersey New Mexico New York North Carolina North Dakota

Ohio Oklahoma Oregon Pennsylvania Rhode Island South Carolina South Dakota
Tennessee

t2 t5

l8
4

5.0
s.3
I 1.5 10.5 2.1
r

9.5 5.1

Texas Utah

4.8
9.1 12.7

Vemont
Virginia
Washington West Virginia Wisconsin

4.6 I r.4

l0
t2 t2

Wyoming
Mean Median Standard deviation

I
8.9 5.3

99 8,3 87 1.4 42 6.0 31 3.8 94 21.5 49 I 1.8 83 18.3 .1.5 89 83 9.7 4.8 0 39 9.6 98 16.0 93 2.7 98 8.2 95 22.9 31 5.0 91 17.0 98 ll.7 92 7.? 87 t2.3 51 7.8 46 7.1 99 21.3 86 10.8 93 19.7 37 9.1 94 l0.l 42 7.2 '77 6.5 93 10.7 86 t7.3 42 15.,1 r00 2t.4 96 7.7 95 1.5 97 l 1.0 72.8 t2.7 86.0 10.1 25.3 7.4

1.4

33 93 86 48 30 59 58 60 53 68 32 27 46 14 34 73 52 78 20 12 93 68 45 68 72 63 98 46 73 95 65 62 93 43 98 t4 40 r00 66 50 4t 65 27 42 91 68 38 90 89 67 94 60.2 62.0 23.E

0.9 6.4 2.8 0.4 t.7 3.2 3.2 2.t 4.7 2.3 2.7 1.8 0.1t 1.4 0.4 0.s 0.,1 1.4 0.4 2.6 3.r 3.5 t.3 2.3 1.1 0.5 t.2 0.1 0.8 4.0 2.1 4.6 2.3 t.2 l.l 0.9 0.5 4. l 1.5 2.5 2.6 l.l 0.9 t.0 3.2 5.1 r.3 2.8 1.2 1.0 0.7 2.O t.4 1.4

32 84

76
35 80

50 93 60 60 98

't0

12 54
31

25 55

68 68
37

90 69
51

70
100

Practice-enr,ironment scores for certified nursemidwives ranged from 100 in Nlinnesota to 25 in Indiana. Six states had scores of 90 or higher; 13 had scores of 50 or less. The number of certified nursemidu,ives per 100,000 population was low in all the states, ranging from a high of 6.4 in Alaska to a low of 0.1 in Nebraska. Six states had practitioner-to-population ratios of 4 or above, and 14 had fe"r'er than I certified nurse-midwife per 100,000 population. \\'ith a felv exceptions, states that had favorable practice-environment scores for one group ol practitioners also had favorable scores for the other tlvo groups. States r,vith more favorable practice-environment scores were clustered in the West and Northwest: several states r,r,,ith less lavorable scores were in the Southeast. Among states ll,ith generally unfavorable practice environments, the lack o[ authority to write prescriptions rvas an important contributor to lou, scores for all eroups. For example, 16 of the l7 states with the lowest practice-environment scores lor physician assistants prohibited these practitioners from writing prescriptions, as did l1 of thc 17 states rvith the lowest scores lor certified nurse-midu'ivcs and 9 of the l7 rvith the lowest scores for nurse practitioners. Reimbursement n,as an important factor in the practice-environment scores lor nurse practitioners, but it was somelvhat less important for physician assistants, who, as salaried employees, are not reimbursed directly for their services, and for certified nurse-midr,vives. Of the

l7

states r,r,ith the least

59
21

98 50 30 70 54
18

lavorable practice environments for nurse practitioners, 4 had a score of 0 on the reimbursement scale, and none scored higher than 20 out o1'a possibie 40
points.
Correlations among Groups of Practitioners

67 90
55

We found significant positil'e correlations for all

three groups of practitioners betneen favorable state

60 54 80 34 84 59 70 56 54
73 51

47 70 47 62 80 62.1

practice-environment scores and higher practitionerto-population ratios (Table 3). Positive associations n'ere also found in the states betrveen the supply of physician assistants and the practice-environment score of nurse practitioners and between the suppiv of nurse practitioners and the practice-environment score of physician assistants (Table 3). This suggests that in most instances a greater suppl,v of practitioners in one group \as not associated rvith barriers to practice for the other. \Ve examined the

60,0
19.2

*Practitioneuo-population ratios for crch group ofpractitioners are based on estimates of rhe total suppl.v of pnctitioners per 100.0m population in each state.
+Estimates of the supply ofpracticing nonfederal physician assistnts were obtained from the American Academ)- of Ph!sician Assistants.lT with extrapolations for nonmemtrers. Federal erployees ilc not include<i.

possibilitv that the supph' of physician assistants, nurse practitioners, and certified nurse-midwives in a particular state depends on educational opportunities for these practitioners. \\''e analvzed the supply of each group of practitioners in relation to the number of accredited schools in the states in
1992. The results \\'ere inconclusive (data not shorvn).

iEstimates of the suppl) of practicing nurse practitioners were obtained from the studl_ b) Morgan.lo Estimates of the supply of praclcing ce(illcd nurse-midsives wcre calculated b)'lhe Dir ision ofNursing.,f lhe Bureau of Health Professions on the ba\is ofdah liom the American College of Nurse-Midrr rres.:l

Although several states rvith schools had a higherthan-average suppll' of practitioners of the discipline in question, no overall correlation was found between the state-specific supply of practitioners and the number of accredited schools for any group.

Vol.

3lll \o. I9

PR'\C1'ICE EN\rIRO\\'{E\TS AND THE SUPPLY OF NO\PHYSIIIIA\ PRACI'IITIO\ERS

269

c o
(u

= oo o-

r = 0.626

To examinc the potential effect of competition betrveen phr-sicians and either phvsician assistants or nurse practitioners, we comparcd the supph' ol each
group of practitioners u'ith that of seneralist phvsicians in the state. (Ccrtified nurse-midwi\res were excluded from this analvsis because of their relatively small numbers; federallr, emplo,ved ph'n'sicians u,ere also excluded.) \\'e found sisnificant positive relations betu'een the supph' ol each group of practitioners and the suppiv of allopathic generalist phvsiin graduate medical training excluded) after controlling for state population (Table 4) . In most states, a sreater number of phvsician assistants and nurse practitioners did not appear to be associated \vith a lesser supplv of generalist phvsi-

o o oo o
o
(u

P<0.001

15

aa

'
t.

ttt
i.

-o

o o

aata'.
.(U

aa

.. '

cians (rvith residents

.9
_c

o
0+
0

IL

'10 20 30 40 50 60 70 80 90
Practice-Envi ronment Score

100

.E

(!

= o(L

o O

=0.412 P<0.003

o o o
.F
(.)

\Ve found a positive correlation in the states betlveen the supplv of phvsician assistants and the number of resident phvsicians in graduate medical training, suggesting that a disproportionate number of phvsician assistants mav be emploved in teaching hospitals (Table 4). No comparable relation l'as apparent behveen the supplv of nurse practitioners and the number of resident phvsicians in tl.re
states.

cians.

a <l) c o
(d

Some studies suggest that competition

15
10
attt o' ' '

betr,veen

phr,'sicians and nonphvsicians has triggereci the crelr

IL

o
f z

q)

0 0

10 20 30 40 50 60 70

B0

90

ation of barriers to practice lor nonphr-sician practitioners in some states.li 3+ \\'e therefore compared the suppl,v of generalist phvsicians in the states rvith the practice-environment scores for nurse practitioners and physician assistants. No associations were lound
100

beveen the practice-environment scores

Practice-Environment Score

group of practitioners and the supplv of generalist or excluded from the anaivsis.
Areas with Shortages of Primary Care Physicians

for either

phvsicians. u,hether resident phvsicians n'ere included

c o
(!

= o _
(L

o o o o o
o o

r = 0.505

P<0.001

An adequate suppll' of phvsician assistants, nurse practitioners. and certified nurse-midu'ives mav be particularlv important in areas lacking sulHcient numbers of primarv care phvsicians. \Ve repeated some of
our analyses for the I 7 states rvith the hiehest proportions of people living in areas desisnated as having a shortage of primary care in 1992 (Table 3). These proportions ranged lrom I l.6 percent of people in

p =
q)
U)

.t

North Carolina to 25.0 percent in \orth Dakota.

z ro
0)

j.'.' '
10 20 30 40 50
60

Three quarters ol these areas u'ith priman' care shortages rere rural. Nonphl'sician practitioners are not counted in the lormula used b1'the federal so\iernment

.E L

()

0)

80 90

to characterize these areas.3r

100

In the l7

states^ lavorable practice-en\.ironmenr

Practice-Environment Score

scores for phl,sician assistants and nurse practitioners

Figure 'l . Correlation of the Praclitioner-to-Population Ratio with

the Practice-Environment Score for Three Groups of Practitioners in Each of the 50 States and the District of Columbia, 1992. The numbers of practicing, nonfederally employed physician assistants (Panel A), nurse practitioners (Panel B), and licensed, certified nurse-midwives (Panel C) per 100,000 population are shown, with Spearman rank-correlation coetficients and P values for the correlations.

were associated rvith practitioner-to-population ratios significantlv above the national average (Table 3). For certified nurse-midlvives there was a similar trend (P : 0.09).'fhe nine states with practice-environmenr scores ol 90 or hieher for phvsician assistants had an averase ratio of 13.4 phr.sician assisrants per i00,000 people. as compared rvith LB in the states n'ith scores of 40 or less. The four states rvith practice-environ-

1270

]'HE

\E\\' E\GL,\ND.JOUR\AL

OF \IEDICTI)iE

\or'.

10.

199-l

ment scores of 90 or higher for nursc practitioners had an average of 17.5 nurse practitioners per 100,000 people, as compared with 6.4 in the five states rvith scores of 40 or less. For certified nurse-midu'ives, the ratios were 1.2 per 100,000 for the two states with scores of 90 or higher. and 0.8 per 100,000 for the four states with scores of 40 or less.

Table 4. Partial Conelation Coefficients and P Values lor the Comparison of Estimates of the Supply of Physician Assistants and Nurse Practitioners with That of Generalist Physicians and Residents in the 50 States and the District of Columbia, with Control for State Population, 1992.*
No\RlstDENT
GRouPs CoUPARED

(;ENERAI-rsr PH\\t(r\\s= r PvaruE

ALL Ar LoPTHtc Rst-

DE\r PH\st(l\\(i

PVALUE

DrscussroN

Favorable state practice environments for phvsician assistants, nursc practitioners, and certified nurse-midwives were strongl-y associated with a greater supplv of these practitioners. States r,r,ith less favorable practice environments had ferver such practitioners for everv 100,000 people. In general. practice environments rvithin a statc rvere consistentlv favor-

Physicians and physician Physicians and nurse

assistnts

0.539 <0.001

0.583

<0.001
NS

practitioners 0.3.17 0.014 -0.033

*First-order panial corelation coefficienls wilh population held constant a denotcs not signifi canlilncludcs all allopathic physicians in general practice. lamil) praclicc. general intemal medicine. or general petiiatrics. excluding federal enrployees, accordig to lhe Bureau of Health Professions.:9

ilncludcs all allopathic re\idents and fellows in all spccialties Association of American Medical Colleges.lr)

in 199f.

according to the

jor factor in

able or unlavorable for all thr-ee groups. Inabilitv or limited ability to write prescriptions was a malorvering practice-en\-ironment
scores

Our findings do not support the hvpothesis that

larger suppll,' of gene raiist phvsicians in a state is asso-

for ail three groups. Reimbursement issues n'ere important in lorvering the scores for nurse practitioners, but thev u'cre ol iesser importance tor ph,vsician assistants and certified nurse-midlvives.
Table 3. Rank-Correlation Coefficients and P Values lor Practitioner-to-Population Ralios and Practice-Environment Scores for All States and for the 17 Stales with the Largest Proportions of People Living in Areas with a Shortage of Primary Care
Physicians. *

ciated r,r,ith a Iess Ivorable practicc en"'ironment for nonphvsician practitioners. Indeed, rve lound that the supplies ol' generalist ph1'sicians. phl'sician assistants. and nurse practitioners rvithin states were positivelv associated. Horvever, states u,ith documented shortages of primarv care phr.sicians that had environments favorablc to ph1'sician assistants and nurse practitioners had more such practitioners than the na-

tional average.
Factors other than those rve identified affect the practice environment lor nonphvsicians at the state Ievel. For example, acceptance as professionals bv phvsicians (including the extension of hospital admitting privileges and professional collaboration), inclusion in the terms of private and corporate health insurance policies, ability to obtain malpractice insurance, and acceptance bv the public are probablv important determinants of the supplv ol practitioners at
the communitr,, regional, and state lcvels. Ir.r addition, because our analysis applied to onl,v one short period, u'e could not determine u,hether the greater supplv of

ALr
MEASLRES CovPARED

STrES

AND

D,C,

SiloRTcE AREAs

(N = 5l)
COEFFI.

(N
coEFft-

17)

CIENI

P VALUE

CIENT

P vALUE

Ratios and scores within group

Physician assistants Nurse practitioners Certilicd nurse-midwives

0.626 0.505

0.412

<0.001
0.003

<0.001

0.68I 0.518 0.424

0.513 0.623 0.493 0.142
0.2

0.003

0.026 0.090

First-practitioner ratio and secondpractitioner scorei

Physician assistants and nurse practitioners Physician assistants and cenilied nurse-midwivcs Nurse practitioners and ph;-sician
assistants

0.452
0.502

0.001

0.035 0.008 0.044

<0.001
0.002 0.002 0. I l0

0..+16

Nurse practitioners and cenified nurse-midwives Certified nurse-midwives and physician assistants

0.411 0.226

0,076
0.398

l9

First-practitioner score and secondprctitioner scorei

Physician assistants and nurse practitioners Nurse practitioners and ccrtified

0.570

<0.001 0.010
0.002

0.593

0.0r2
0.036

nonphvsician practitioners preceded the removal of barriers to practice! or the rcverse. Our stud1. demonstrates that regulation bv the states of phvsician assistants. nurse practitioners, and certified nurse-midn,ives varies u'idelr.. Thcse findings mav help state legislators and regulators reduce specific barriers to practice and thus make these practitioners more available to paticnts.

nurse-midwiles
Physician assistants and certilied nurse-midwives

0.3s7 0..132

r2 0.602
0.5

RrrnnnNcrs
t.
2.
3.

0.011

ll The I 7 srart'. u irh the highest lere!'ntag\ of p.ople residing in such rr'r\ ere Nonh Dakota (25.0 percentt. Mississippi (24.3). South Dakota (22..1), New I'lerico (21.9). Idaho (19.6). W)oming 119.5). Louisiana (19.1). Wcsl Virginia (19.1). South Carolina (18.,1). Alabama ( 16.8). Ala\ka ( i.1 0). \'lontana ( l3 5). Arkansat ( 13.5). Oeorsia (13.5). the Districr of Columbia {D.C.) (12-0). Illinois (l 1.9). and No(h Carolina ( I 1.6).
Car.-

*Spearman rank-conelation cfhcients are shos n. Shonage arcas were determined on the basis of the percentaSe of each state's population that was Iiving in areas with a designated shona3e ol healrh professionals in Septenrber l 992. according to thc Bureau of PrimaN Health

4.
5

ilndicate\ tht the ralio ibr rhc lirsr gr()up lisred i\ compared u ith lhe score for the second
sroup.

Budetti PP. Achicving a unifom tderal priman care policy: opponunities presented b1' national health reform. JAMA 1993:269:49ti-501. Kindig DA, Culticc JM. Mullan F. The clusive generalist physician: can we reach a 507r goal? JAMA 1993:270:1069-73. Rivo ML, Satcher D. Improving access to health care throu-uh ph1'sician workforce retbrm: directions for the 2 I st century. JAMA I 993;270: I 074-8. Annual repon to Congress I993. washington. D.C.: Physician Payment Review Commission, 1993. Starfield B. Primary care: concept, evaluation, and policy. New York: Oxford University Press. 1992. Josiah Macy, Jr., Foundation. Report of the Josiah Macy. Jr.. Foundation: for July l, 1991 through Junc 30, t992. New Yorkr The Foundation.
t992. Mundin-qer MO. Advanccd-practice nursing cians? N Engl J Med 1994:330:21 l-4.

ilndicates that rhc ..ore lbr the first group li\tcd is comparecl s ilh lhe score for the rccond
group

good medicine Iilr physi-

Vol. 331 No.

19

PRACTICE E\\'IRON\,IEN]'S

A\D'I'HE

SUPPLY OF NONPHYSICI,\\ PRACI'ITIONE,RS

t2i

The National Health Scrvice Corps White Paper: proposed strategies fbr fulfilling primary care professional needs: pan II: nurse practitioners. physician assistants. and certilied nurse-midwivcs. Rockville. Md.: National Health Service Corps. 1991. Primary cae workforce 2000: federal health policl'strategies submittcd to Hillary Rodham Clinton and the Presidcnt's Task Force on National Health Reform. Washington, D.C.: Pew Health Professions Commission, 1993. 10. Brown SA, Grimes DE. Nursc practitioners and certified nurse-midwives: a meta-analysis of studies on nurse primary cre roles. Washington. D.C.: American Nurses, 1993. ll Schaft GE, Cawley J. The physician assistants in a changing health care environment. Rockville. Md.: Aspen Publications, 1987. t2 Clawson DK, Osteryeis M. eds. The roles of physicin assistants and nurse practitioners in primary care. Washington. D.C.: Association of Academic Health Centers. 1993. 13. Scupholme A, DeJoseph J, Strobino DM, Paine LL. Nurse-midwifery cue to vulnerble populations: phase l: demographic characteristics of the National CNM Sample. J Nurse Midwifery 1992;37:341-8.
14.
15. 16.

20.

17

t8

l9

Nichols LM. Estimating costs of underusing advanccd practicc nurses. Nurs Econ 1992:10:343-51. Safriet BJ. Health care dollars and regulatory sense: thc role of advanced practice nursing. Yale J Reg 19929:417-87. Fowkcs V. Meeting the needs of the underserved: thc roles oi physicran assistants and nurse practitioners. In: Clawson DK. Osterweis M, eds. The roles of physician assistants and nurse practitioners in primy care. Washington. D.C.: Association of Acadcmic Health Centers. 1993:69-8;1. General census data on physician assistants. Alexandria, Va.: American Academy of Physician Assistants. 1993. Bureau of Health Protssions. 1992 Sample suruey of registered nurses. Rockville. Md.: Depanment of Health and Human Seruices. 1993. Idem. Suruey of cenified nurse practitioners and clinical nursc specialists: December 1992. Rockville, Md.: Department of Health and Human Serv-

21. Ofllce of the lnspector Gcneral. A survey o[ certilied nurse-midwires. Washington. D.C.: Dcpartment of Health and Human Sen,ices. 1992. 22. Barickman C. Bidgood-Wilson M. Ackerly S. Nurse-midwifery today: a lcgislative update. J Nurse Midwifry 199237:207. 23. National Commission on Nurse-Midwifery Education. Education of nursemidwives: a strategy for achieving afTordable. high-quality maternity care. Washington. D.C.: American College of Nurse-Midwives, 1993. National Center tbr Health Statistics. Advance repon of flnal natality staristics, 1991. Mon Vital Stat Rep 1993;42(3):Suppl:l-48. 25. Gara N. Physician assistant state laws and regulations. 6th ed. Alexandria. Va.: American Academy of Physician Assistants. 1993. 26. Willis J. Baniers to physician assistant practice in primary care and rural medically underserved settings. J Am Acad Physician Assist 1993:6:418-22. 27. Pearson LJ. 1992-93 update: how each state stands on legislative issues affecting advanced nursing practice. Nurse Pract 1993;18(l):23-38. 28. Nurse-midwifery today: a handbook of state legislation. Washington, D.C.: American College of Nurse-Midwives. Political and Economic Affairs Committee- 1992. 29. Bureau of Health Prolssions. Area resource lile. Rockville. Md.: Department of Hcalth and Human Seruices. September 1993. 30. Roback C, Randolph L. Seidman B. Physician charactcristics and distribution in the U.S.: 1993 edition. Chicago: American Medical Assocration.
1993.

Morgan wA. Using State Board of Nursing data to estimate the number of nurse practitioners in thc United States. Nursc Pract 1993:lE(2):65-7.1.

ices.1994.

Bureau of Primary Health Care. Health professions shortage areas. Washington, D.C.: Department of Health and Human Services. 1993. 32. Gibbons JD. Nonparametric methods for quantitative analysis. New York: Holt. Rinehan & Winston. 1976. 33. Klcinbaum DG. Kupper LL. Applied regression analysis aml other multivariablc methods. North Scituate, Mass.: Duxbury Press. 197E. 34. Ginzberg E. Ostow M. Physician supply strategy: the case of the South. Health Aff (Millwood) 1992:l l(2):193-7. 31.

THE \L,\\' E\GL.\\D.JOLR\.\L

OI \IEDICTI\E

\or'. l(). 1994

REVIEW ARTICLES
'fable MEDICAL PROGRESS

presents the kcr' clinical features

ol the re-

actions u'c shall discuss.

RBcocNrrroN Drug eruptions are most often morbilliform or exanthematous (Fig. 1).i ? Thev usuallv fade in a ferv da1's but nla\' lr'orscn. In rare instances in which no alternative therapy is available, a drug may be contin-

SEVERE ADVERSE CUTANEOUS REACTIONS TO DRUGS Jr,ex Crauoe Rotlnet', II.D., A\D RoBERT S. Srens. \I.D.

ued in spite o{' a morbilliform eruption. Unfortunatelv, a morbilliform eruption is often the initial presentation of more serious reactions including toxic

.\

/t LTHOU(iH the ratc o{'acute severe advcrse cuta-

,r"orrs reactions to medications is lou'. these reactions can aflct anvone rvho takcs medications and can rcsult in death or disabilin'.r Even a small number of cases associated rvith a particular drug mal' alter the recommendations lor its use.z-l Prompt differentiation of severe adversc cutaneous reactions Irom less serious skin disorders mav be difficult. Rapicl recognition of sevcre reactions is cssential. Prompt rvithdra',val of the

oflending drus is often the most important action to minimize morbiditv. Adr,erse cutaneous reactior-rs to drugs are frequent. affecting 2 to 3 pcrcent of hospitalized patients.i \Ianv commonlv used drugs l'rave reaction rates above I percent.j Fortunatelr'. most adverse cutaneous reactions are no1 severe. and [rt, are ltal. Complications o[ drug thcrapv are the most common tvpe of adverse event ill hospitalized paticnts. accounting for I9 percent o[ such events." Cutaneous or allergic reactions to druss are responsible for approximatelr' 3 percent of all disabline injurics during hospitalization.'; The reported percentage of cutaneous drug reactior.ls that pht'sicians diagnose as potentiallv serious varies greatlv but is probablv about 2 percent.TB \\te estimate that about I ol everv 1000 hospitalized patients has a serious cutancous drug reaction. Each vear thousands ol- outpatients have cutaneous reactions that mav rcsult in substantial morbidin. or death unless promptll, recognized and treated. Not all serious adverse reactions to drugs lvith a prominent cutaneous component develop rapidlv. For cxample. the distinctive cutancous chanses of eosinophilia-mvalgia svndrome ciruse great morbiditv but usuallv occur alter prolonged exposure.l' In this article, '"r'e shall emphasize the clinical recosnition, epidemiologv. pathophvsiologv. ar.rd treatmer-rt of acute. serious cutancous adverse reactiorls.

cpidermal necrolvsis, hvpersensitivitv svndrome, and 2 lists clinical features that should alert the ph1'sician that a reaction is serious. \\'hen a drug reaction is suspected, the presencc ol urticaria. blisters, mucosal involvement. facial edema. ulcers, palpable or extensive purpura, fever, or lvmphadenopathv almost ahvavs necessitates discontinuation of the drug. Several algorithms have been proposed lor the assessment of adr.erse drug reactions,l0-r''l but none have pror,'ed to be both sensitive and specific. The follorving criteria and 'Iables I and 3 provide euidelines for formulating a diflerential diagnosis. First, alternative causes should be excluded. especiallv inlections, since manv inlectious illnesses are difficult to distinguish clinicallv from the adverse effects of drugs used to treat infections. Second, the interval between the introduction o[ a drus and the onset of a reaction should be examined. f hird. anv imprclvement after drug u.ithdrawal should be noted. Fourth, the phvsician should determine rvhether similar reactions have been associated with the same compound. Fifth, any reaction on readministration ol the drug should be noted, A skin biopsv is often critical for an accurate diagnosis. but biopsv does not help in establishing rvhether the disease is drug-induced. In vivo tests include readministration of the drue (rechallenge) and skin tests. Reactions after rechallenge mav be worse. Rechallenge should not be performed after a serious reaction. Skin tests and in vitro tests (such as the radioallersosorbent test) help diaenose IgE-mediated type I hypersensitivitv reactions, especially to penicillin.r3 In other t),pes of eruptions, skin testing has lorv sensitivit,v and specificitv.rtln vitro testing ol cellular proli erativc responses to drugs is usually' not helpful.15 Although still investigational, in vitro studies of enhanced toxic effects of drugs or drug metabolites on cells mav someday aid in the diagnosis and understanding of the pathogenesis of some tvpes ol reac-

serum sickness. 'Iable

tions.
From the Depanmcnt of Dematology. Henri Mondor Hospital. University of Paris Xll. Creteii. France (J.C.R.). and Beth lsrael Hospital. Hanud Medical School. Boston (R.S.S. ). Addrcss reprinl rcquests to Dr. Stem at the Department of Dematologr. Bcth Israel Hospital. 330 Brookline Ave.. Bosron. MA 02215. Supportcd in pan b! a grant from TNSERIV1 (9O-O812).

l6'17

SrrvnNs-JoHNsoN SvNnolrn aN Toxrc

Eprornuer Nrcnorvsrs
Stevens-Johnson svndrome and toxic epidermal necrolvsis are two relatcd mucocutaneous disordcrs rvith

Vol.33l No. 19

MEDICAL PROGRESS
Table 1. Clinical Features of Selected Severe Cutaneous Reactions Often lnduced by Drugs.

t273

DrGNosts

Mucos^L LEsloNs

TvBc^L SKrN LEsloNs

FREQUENT

sloNs

^ND

SyMmoMs

PERCENT

PERcaNr

DRUG-INDUCED FATAL

Stevens-Johnsonsyndrome Erosionsusually
at

>2

sites

Toxic epidemal

necrolysis

Erosions usually

Small blisters on dusky purpuric macules or atypical argets, rarc areas of confluence, de tachment of <107o of body-surface ea Individual lesions like those seen in SievensJohnson syndrome, confl uent erythema, outer layer of epidemis sepates readily from basal layer with lateral pressure,t ltrge sheets of necrotic epidemis, total detachment of >30% of body-surface area Severe exanthematous rash (may

10-3070 of cases involve

fever,

50 >80

<5
30

at >2 sites

lesions of the respiratory tract* md gastrointestinal tmct Nerly all cas involve fever, "acute skin failure,"*t leukopenia, lesions of the respiratory tract* and gastrointestinal tract

Hypersensitivitysyndrome

Infrequenl

purpuric), exfoliative

become dematitis legs;

urticilia

Small-vessel

vasculitis

Infrequent

Palpable purpura, most often on the nodules; ulcerations;

urticaria

30-507o of cases involve fever, lymphadenopathy, hepatitis,* nephritis,* crditis,* eosinophilia, atypical lymphocytes 30-507o of cases involve the
gstrointestinal tract,* neu-

>90

ritis, fever, glomeruloSerum sickness or reactions rcsembling serum

sickness

Absent

Morbilliform lesions, sometimes with

nephritis* Fever, arthralgias

<5

Anticoagulant-induced necrcsis Angioedema

Infrequent

Erythema then purpura and necrosis, espe-

Pain in affected

reas cardio-

cially of fatty
Often involved

areas

Urticaria or swelling of central part of face

Respiratory distress,. vascular collapse*

100 >50

>10

l-6

*Pontial ca of death. fSystemic conrequenccs of widespread injury to the skin, as seen with thcmal bums.

iNikolsky's sign.
The flgure refers to the percenlage among hospitalid patients; a much smaller percentage

of all cases

drug-induced.

high rates of morbidity and morraliry (Table l).t'ts'ts Although the nosology and specific diagnostic criteria for these disorders remain controversial, we believe certain clinical features help define these conditions2o (Tables

and 3).

Clinica! Features

ln

with febrile erosive stomatitis, severe ocular involvement, and a disseminated cutaneous eruption of discrete dark-red macules, sometimes with a necrotic center. This became known as Stevens-Johnson syndrome.2l In 1956, Lyell introduced the term "toxic epidermal necrolysis" to describe patients with extensive loss of epidermis due to necrosis that leaves the skin surface looking scalded.22 In severe cases, Stevens-Johnson syndrome can include extensive areas of epidermal necrolysis. In most cases of toxic epi dermal necrolysis, the discrete red macules typically seen with Stevens-Johnson syndrome occur around larger necrolytic areas. The similarities between the histopathological findings and the drugs responsible suggest that these two conditions are part of a single spectrum.ta'te'23'24 The term Stevens-Johnson syndrome is also frequently used as a synonym for erythe-

1922, Stevens and Johnson described children

benign course.25 Patients with widely distributed purpuric macules and blisters (Fig. 3) and prominent involvement of the trunk and face (Fig. a) are likely to have Stevens-Johnson syndrome, which is usually drug-induced. Patients may present with a clinical picture of Stevens-Johnson syndrome that evolves to one of toxic epidermal necrolysis within a few days. Fever and influenza-like symptoms unexplained by infectious ill-

ma multiforme major, resulting in confusion. In our opini<ln, the two are different conditions that are usu-

ally clinically distinguishable.20 Patients with erythema multiforme major have typical target lesions, predominantly on the extremities (Fig. 2). Erythema
multiforme major usually occurs after infections, especially herpes simplex and mycoplasma, and has a

Figure 1. A Morbillilorm Drug Eruption with Numerous Erhematous Macules and Papules That Vary in Size and Are Symmetrically Distributed.

Most lesions are faint, but some may be slightly inliltrated and resemble urticaria. This exanthematous eruption often starts on the trunk, as in this patient. lt may also begin on areas subjected to pressure. The rash may become confluent.

127

'rHE NEW ENGLAND JOI-IRNAL

Table 2. Clinical and Laboratory Findings That Should Alert Clinicians That a Druglnduced Cutaneous Eruption May Be Serious.
Clinical findings
Cutaneous Confluent erythema Facial edema or central facial involvement Skin pain Palpable purpura Skin necrosis Blisters or epidemal detachment Positive Nikolsky's sign* Mucous-membrane erosions

OF.

\{EDICINE

Nov. 10. l9!)4

lesions are usuallv poorly defined macules rvith darker purpuric centers that coalesce (Fig. 5).

Although precise diagnostic boundaries between the two disorders have not been established, cases with Iimited areas of epidermal detachment are usually labeled Stevens-Johnson syndrome and those with
extensive detachment toxic epidermal necrolysis. We classi' cases with detachment of less than l0 percent ol the epidermis as Stevens-Johnson syndrome and those with more than 30 percent as toxic epidermal necrolysis.20 In cases with detachment of l0 to 30 percent of the epidermis we consider the two syndromes to overlap.2o In toxic epidermal necrolysis,

Urticaria Swelling of tongue

General

High fever (temperature >40"C) Enlarged lymph nodes Arthraigias or arthritis Shonness of breath, whcezing. hypotension

sheet-like loss of epidermis and raised flaccid blisters, rvhich spread rt'ith pressure, often occur, and Nikolsk,v's sign (i.e., dislodgment of epidermis by lateral pressure) is positive on ervthematous areas.

Labortory results
Eosinophil count ) 1000/mml Lymphocytosis with atypical lymphocytes Abnomal results on liver-function tests
+The outer layer of the epidemis basal layer with lateral pressure.

With trauma, full-thickness epidermal

(Fig. 7).

detachment

(Fig. 6) yields exposed, red, sometimes oozing dermis. In other areas, pale necrotic epidermis may remain

spuates readily from the

of these two conditions by one to three days. Burning and pain occur. Initiallv, these eruptions are symmetrically distributed on the face and upper trunk, areas that usually remain the most severely allcted.!'r The rash spreads rapidly and is usuallv maximal within four days, sometimes within hours. The initial skin
ness often precede the mucocutaneous lesions

Al:out 90 percent o[ patients with each disorder have mucosal lesions, including painful erosions and crusts on anv surface (Fig. B).r'r Impaired alimentation, photophobia, and painful micturition often result. The epithelium of the trachea, bronchi, or gastrointestinal tract may be involved.2o-2t Often overlooked, these lesions may cause substantial morbidity. About 85 percent of patients have conjunctival lesions.rs'2s'30 These range from hyperemia to extensive pseudomembrane lormation.2e-:rr Synechiae between eyelids

Table 3. Factors to Consider in Diagnosing Severe Cutaneous Adverse Reactions and Their Causes.
Tvprcar lNrelver rrou

DIAcNosts
Stevens-Johnson drome

DRucs lt osr OmEN

RESTNSIBLE

BEcrNNrNc o DRUG THRAPY To ONsET oF REcrtoN

ALTERNATTvE CAUSES

NoT RELt To DRUos

ED

HELPFUL TESTS

syn-

l-3

wk

Postinfectious erythema multiforme major (especially in the case of

Skin biopsy with immunofluorescence testing

Toxic epidermal crclysis Hypersensitivity

nesyn-

* Anticonvulsants, sulfonamides. allopurinol

infection with herpes simplex or mycoplasma)

t-3

wk
Cutaneous lymphoma

Skin biopsy with immunofluorescence testing

drome
Drug-induced

2-6 wk

vasre-

Intravenous proantibiotics

I-3
8-

wk

Infection, rheumatic diseases, lymphomas

culitis
Serum sickness or scrum
14 days

lnfection

Skin biopsy. blood count, eosinophil count, liverfunction tests Antinuclear antibodies. rheumatoid faclor C-3 and C4 complement

actionsresembling teins,p-lactam

sickncss

Anticoagulant-induced Warfarin
necrosis Heparin

3-5

days

Disseminated intravascultr coagulopathy. septicemia lnsect stings, foods

Protein C defrciency Platelet count Specific IgE antibodies for penicillin allergy

Angidema

Penicillin, cephalosporins, contrast medium. glafe-

5- I 0 days A few minutes

to a few houni

nine,i drugs used in

anesthesia

Nonsteroidal antiinflammatory drugs

-7

days

ACE inhibitors
*See Table .1 for a conrplete list. iSee Table 5 for a complete list.

<4 wk

iGlafenine is no lonfer mekered.

).11.1)!( : \1.

l,li(

)( ;

tti.\\

;;.,:.

\i.{1. {-+l
.

Figure 2. Typical Target Les ons of Erythema Multiforrne Major. This case was classifled as erylhema multiforme major because of associated mucous-membrane lesions. These tarqel lesions include three zones: an erythematous or dusky small cntrai pap-

Figure 3. Dusky or Purpuric Macules Typrcal of Stevens-Johnson Syndrome. These lesions may develop an overlying blister. They do not have

ule that may blister. a raised edematous middle ring. and an

erylhematous outer ring.

the three zones of typical target lesions (shown in Fig.2) and generally are irregularly shaped and vary rn size.

ancl corrjun<'tivir olicn oct rrr'. Kerirtitis :rrrd r.orrrt'al erosions arc l('ss l)'eqtrt'rrt. Ircver is usllallv lriqhr.r in trixic t PiclcrrnlLl rrt'crolvsis (icntpcnrtrrrt.. )38"(11 thlrn in Stt'r'cns-Joirrrson svnrlrr,rrrc. lrrrrl astlrcrriir, skin pairr. :irrd anrii'tv aIe olit'rr ('\tr('nt(,. 'l'ht' cor-rrltlic'irtions ol loric t:piclt'rrnlrl nt't lolvsis arrrl t rlcnsivc tlrcrr-nal [rurns lrre -rinrilirr'. 'f lrt. sr vt.ritr is prol;orrior)ill l() the extt'rrt ol skin rrtt'r'osis. -\lrLssir,. trans('pidcrrnal Iluicl losst's (l'i to I litt'r's clailv in atlrrlts
n itlr lrall thcir lrorlr -srrrl'ucc irrca i1l\ ()l\'(,(l
ass()(
1 o cLrr rvith iatecl elt't'ttolvtc inilrirllrnct-.1" 1'r't'rt'nal :rz()t(.rni.r is cornnror-t. Bat tt'rilrl colorriziitir,n ril' the skin lln(l (lc-

,"
i,

cl'(':ls('(l intrnrrrrc rt'sporrsivt'nrss irrtlr.usc

Iroorl ol s('psis.

tlrt' likr.ii-

tFigure 4. Widespread Lesions Characteristic of Stevens-Johnson syndrome.

The lesions are most heavily concentrated on the trunk and proximal extremities. The darker areas are sites of epidermal necrosis.

-\ hr pt'rclrtrrlrolic stirtt'. s()nictillls \\ itl) irrlribition ol in:ulirr s(,.r'('ti()n or irrsulin lcsist.rrrt t . ir c()rrrnr()n. Ditlirst intelstitilrl pnr'rinrorritis. r'hiclr nr.r. It'ltri to thc irrlrrlt rcspinrtolr (iistr( ss sr rrrlronrt,. sorrrr'1inrc's rlcvelop,s.

l,r t'rt i1 t]rt' tlilrqrtosis o1'Slcle tts .Jolrnsotr 5\'nrlr'()ln(' cpiclt'r rn:rl nt r:r't.,lr sis is c lirrir':illr t,r'irlt.rrt. l skirr biopsr' ht'l1rs conlirnr tlrt' cliaqnrrsis. tlrus rrsrrirllr, cxcludinq tullorrs clist'iist's n()t r('lat('(l to clrug thclapr. I',arlr on. tht't't' is lirll-thit ktress cltirlcn-n:rl lrr.( r'()si-s irn(l (l('ta( irm( rrt. \r itlr irn rrtrlt sliqhrlr lrltcrt'ci un(lcr'lr irrq cit't mis l l iq-. 6t. 1'ltt' trst' ol' ft'ozt,n st.c tions lrllon,s ir ral)i(l clilrq-nosis. Irnnr rrnoflrror('s( ('nc(' strrclit's orrlr' lrt'JP t'rcltrclc otirt'r'llrllotrs rli-scast's. .\ntrnia arrtl lr nipltr,1;t'rrirr nlt- li t'r1rrcnt. lrtrt cosinol-llrili;r is l'lrrr.. \ r.rr1r'olrcrri:t sllqg(,sts a por)f llloqnr,sis. : 'l'lrc rt,qrouth ol epidclnris mar'llcqin uiti-,iri ilavs bLrt rrsualh ttrkt's :rlrout tlrltc u'r'cks. iltt'tr pic:rl l,,,,,lilr o1' tlrc }rospit:riizlrtior-r.l .\r,.as sub jcct t() l)rasslrr(. un(l 1tt'r'iolilicial ar('lts ofi('n hr'aI Iast. ()r'trlar seclrrr'lirr. .r1lr't ulrout 35 pcrct'rtt ot lrutients ulro sun,irc torit:

or torir

.' ':..

.'*:l*S8

cpirlCrnral nt't |olt si-. :tnrl e sn]ltllt't l)crcciltirq( ()f tir,st' u iti'r St,'r't'ns-.Johnsorr s\ rldroln('.li -\ Siii,glcn-

Figure 5. Purpuric Macules Typical ot Stevens-Johnson Syndrome.

The macules may coalesce 1o torm blisters.

1276

THE NEW ENGLANDJOURNAL OF IVIEDICINE

Nov. 10,

1994

like sicca syndrome with a deficiency of mucin in tears, inturned eyelashes, proliferation of squamous metaplasia, and neovascularization of conjunctiva and cornea, symblepharon, punctate keratitis, and
corneal scarring may develop.30 Persistent photophobia, burning eyes, visual impairment, and even blindness may result. Other possible sequelae include scarring, irregular pigmentation, eruptive nevi, persistent erosions of the mucous membranes, phimosis, vaginal synechiae, and abnormal regrowth of nails.rB
Differential Diagnosis

Skin disorders involving desquamation, exfoliation,

or blistering are sometimes misdiagnosed as StevensJohnson syndrome or toxic epidermal necrolysis. Ex-

foliative dermatitis is characterized by generalized

Figure 7. Necrolysis of Skin in Toxic Epidermal Necrolysis. Varying degrees of erythema are seen. The wrinkled areas repre' sent full-thickness necrosis of the epidermis. This dead skin will be lost, resulting in superficial skin ulcers.

Figure 8. Ulcerations and Erythema of the Oral Mucous Membranes and Lips Caused by Toxic Epidermal Necrolysis.
These findings can also be seen with erythema multiforme major, Stevens-Johnson syndrome, and primary bullous diseases such as pemphigus vulgaris.

erythema and scaling (Fig. 9).3+ When the scales separate in large sheets, especially on the palms and soles,

desquamation may be clinically confused with fullthickness epidermal detachment (Fig. l0). In infants, staphylococcal scalded skin syndrome

may resemble toxic epidermal necrolysis. Specific

staphylococcal exotoxins cause extensive subcorneal separation of the stratum corneum (Fig. 6 and I l).35 Acute exanthematous pustulosis is drug-induced and resembles pustular psoriasis.36 The subcorneal aseptic pustules are usually distinctive and may coalesce to produce extensive superficial exfoliation (Fig. l2). The mucous membranes are infrequently involved. Subcorneal skin separation (Fig. 6) and the absence of necrosis in both conditions facilitate their pathological and clinical diagnosis. Paraneoplastic pemphigus of acute onset may be confused with toxic epidermal necrolysis.3T Direct im-

Figure 6. Cross Section of Epidermis and Upper Dermis of Normal Human Skin. The number 1 denotes stratum corneum, 2 stratum granulosum, 3 stratum spinosum, 4 basal cells, and 5 dermis. ln toxic epidermal necrolysis, the necrosis of cells from the basal layer and stratum spinosum results in detachment ol the epidermis lrom the dermis. Exfoliative dermatitis is characterized by increased thickness of the stratum corneum. ln staphylococcal scalded skin syndrome and exanthematous pustulosis, detachment occurs between the stratum granulosum and the stratum corneum or within the stratum granulosum (hematoxylin and eosin, x400).

Vol. 331 No. l9

MEDICAL PROGRESS

1277

about 50 percent of cases) probably reflects the common confusion between this syndrome (Fig. 3 and 4) and erythema multiforme major (Fig. 2). Drug-induced Stevens-Johnson syndrome and

toxic epidermal necrolysis typically begin one to three weeks after the initiation of therapy but occur
more rapidly with rechallenge.rB More than 100 different compounds have been implicated in both syndromes.3,
I

B'

te'33 3a'4o,42'43

Table 4 lists frequently impli-

cated drugs. For all drugs, the reported reaction rates are relatively low. The drugs with the highest estimat-

ed incidence include co-trimoxazole (trimethoprimsulfamethoxazole; I to 3 reactions per 100,000 us-

a long-acting combination of sulfadoxine and pyrimethamine (Fansidar-R; l0 reactions per

ers),3'3e'a0

100,000 users),4'23'aa and carbamazepine (14 reactions

per 100,000 users).45 These estimates, which

were based on retrospective series or spontaneous reports, may substantially underestimate the true incidence.

Patients often have underlying diseases. A role for infection as a cofactor has been postulated, but there is little supporting evidence.a3 Conditions that alter immunologic function, including systemic lupus erythematosus, may increase risk.a6 The HLA phenotype Bl2 is associated with a threefold increase in risk.aT Toxic epidermal necrolysis has been described in an animal model of cutaneous acute graft-versushost disease (GVHD).48 Toxic epidermal necrolysis has developed in humans a few weeks after bone

Figure 9. Exfoliative Dermatitis.

marrow transplantation.4e'so In transplant recipients cutaneous necrolysis is most often related to acute GVHD, but in some cases it is drug-induced.50,sr Ocular lesions are rare in acute GVHD and frequent

There is widespread, scaling, brawny erythema and desquamation.

in drug-induced toxic epidermal necrolysis.ts'50'5r

Whether drug-induced or related to acute GVHD, epidermal necrolysis after bone marrow transplantation suggests a very poor prognosis.4e-sl

munofluorescence microscopy can be used to distinguish these disorders. Thermal burns, phototoxic reactions, and pressure blisters occurring in comatose patients may resemble toxic epidermal necrolysis, even on pathological analysis. The pattern of the blisters and the clinical history facilitate proper diagnosis. Epidemiologic Features

Although infrequent, toxic epidermal necrolysis and Stevens-Johnson syndrome occur in all ages, all races, and both sexes, with an incidence ranging from 0.4 to 1.2 and 1.2 to 6 per million person-years, respectively. t,3,ls,:a-'r Most cases

of toxic epidermal necrolysis are druginduced. Fewer than 5 percent of patients report no drug use.3'le A strong association with specific medications is observed in about 80 percent of the cases. Other occasional reported causes include chemicals, mycoplasma pneumonia, viral infections, and immunizatlon.+t'a2 That there is a less frequent clear-cut reIation of drugs to Stevens-Johnson syndrome (in

the Upper Epidermis in a Patient with a Severe Morbillilorm

Eruption.

Figure '10. Superficial Blisters of the Feet Consisting of Sheets ol

This kind of desquamation, especially on the palms and soles, should not be conlused wilh the true full-thickness necrosis of toxic epidermal necrolysis and Stevens-Johnson syndrome.

THE NEW ENGLANDJOURNAL OF MEDICINE

Nov. 10,1994

Patients with the acquired immunodeficiency syndrome have a higher incidence of many drug-induced skin rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, with a combined incidence of I per 1000 person-years.s2-ss Sulfonamides are the most frequently implicated agent. The risk of reactions to sulfonamides is l0 to 100 times higher among persons infected with the human immunodeficiency virus (HIV) than among other persons. This high risk reflects more frequent drug use and greater susceptibility.5a'55

Pathophysiology

Patients with Stevens-Johnson syndrome or toxic epidermal necrolysis induced by sulfonamides or anticonvulsant agents often have an alteration in the detoxification of reactive drug metabolites.56's7 T'he recurrence of Stevens-Johnson syndrome and toxic epidermal necrolysis within 48 hours of rechallenge (although the initial reaction occurs about 14 days after treatment is begun) argues against a di-

Figure '12. Acute Exanthematous Pustulosis. Small pustules are seen on erythematous skin. Gonfluent pustules may produce superficial erosions and sometimes blisters.

rect toxic effect and is more consistent with immunologic mechanisms.rs

suggests

The immunopathologic pattern of early lesions a cell-mediated cytotoxic reaction against epidermal cells.ss-6r The epidermis is infiltrated by
activated lymphocytes, mainly CD8 cells, and macro-

phages.s-6r An immune reaction against drug-reactive metabolites produced in excess may be responsible.

infiltrating cells are present in only modit is unlikely that these cells are the principal cause of epidermal necrosis. Cytokines, released by activated mononuclear cells and keratinocytes, may contribute to local cell death, fever, and
Because

erate numbers,

malaise.
Prognosls and Treatment

Mortality rates are below 5 percent for StevensJohnson syndrome but about 30 percent for toxic epidermal necrolysis.rs'le Sepsis is the principal cause of death. More extensive epidermal detachment, increased age, increased blood urea nitrogen concentrations, and visceral involvement indicate a poorer prognosis. The prognosis does not appear to be affected by the type and dose of the responsible drug or the presence of HIV infection. The physician is responsible for the early recognition of the reaction, the withdrawal of all potentially responsible drugs, and the initiation of intravenous-fluid replacement. Although some drugs are clearly more often responsible than others (Table 4), all drugs, especially those introduced within one month of the reaction, should be considered suspect. Patients with widespread skin involvement should be transferred to an intensive care unit or burn

Figure 11. Staphylococcal Scalded Skin Syndrome. The patient has pical periorilicial efihema and crusting, aS well as superiicial peeling and erosions of the upper epidermis with indistinct underlying erythema. The clinical picture is similar to that seen with a superticial thermal
scalding.

unit. During transfer, pain control, fluid replacement, aseptic handling, and avoidance of any adhesive material are important. The main principles of therapy are the same as for thermal burns, including aggressive fluid replacement, nutritional support, and antibacterial treatment.62,63

\/ol.

3:ll \o.

19

NIEDICAI, PROGRESS

279

Table 4. Drugs Associated with StevensJohnson Syndrome and Toxic Epidermal Necrolysis.
DRUCS

Mosr

DRUcs ALso
ASSoCIATED

FRteutNr I-Y AssmlATED*

Sulldoxine Sulfadiazine Sulfasalazine Co-trimoxazole Hydantoins Carbamazepine Barbilurates

Cephalosporins Fluoroquinolones Vancomycin Rrfampin Ethambutol Fenbufen Tenoxicam

Benoxaprofeni
Phenylbutazone

Tiaprofenic acid Diclolenac

Sulindac Ibuprofen Ketoprofen Naproxen

Isoxicami
Piroxicam Chlomezanone

I, 2, and 3). Perhaps because of its relatively late onset, slow evolution, and clinical similarity to many infectious illnesses, the diagnosis of hypersensitivity syndrome may be delayed. The aromatic antiepileptic agents (phenytoin, carbamazepine, and phenobarbital) with an estimated - patients and perincidence of I reaction per 5000 haps a higher rate among black patienl5 2nd strl- of hyperfonamides are the most frequent causes sensitivity syndrome.56'57'7r-76 Other drugs, especially allopurinol, gold salts, dapsone, and sorbinil, are also associated with the syndrome.TT-80 Hypersensitivity syndrome may be di{ficult to distinguish from serum sickness or drug-induced vasculitis. Laboratory findings often help distinguish these clinicall,v similar conditions from each other and from infectious diseases
malities (Tables (Table 2). The hypersensitivity syndrome t,vpicallv develops two to six weeks after a drug is first used, later than
most other serious skin reactions (Table 3). With antiepileptic drugs, fever and rash are the most frequent presenting symptoms (in B7 percent of cases). Lt'mphadenopathy (in about 75 percent) is frequent and usually due to benign lymphoid h,vperplasia.ri Atvpical lymphoid hyperplasia and pseudolymphoma occasionally occur.sr Some ol these cases resolve with withdrawal of the drug, but in some cases lymphoma eventually develops.B2 Hepatitis (51 percent); interstitial nephritis (l I percent); hematologic abnormalities, especially eosinophilia (30 percent); and mononucleosis-like atypical lymphocvtosis are also common.l' Involvement of the heart, lung, thyroid, and brain is less frequent.rT'83 Severe cases of hepatitis may be lifethreatening.Br A genetically determined inability to detoxify the

Allopurinol Amithiozone Aminopenicillins

Thiabenduole

+Together these drugs account for approximatcly two thirds of the cases attributed to drugs in lage series in France, Gemany. and the Uni(ed States. l l 19 ll ll

iThis drug is no longer

markete<.l.

Many interventions meant to halt the progression have been tried, each in a few patients. A positive result, usually defined as one that halts the spread of necrolysis, has typically been noted after several previous "ineffective" treatments. However, in untreated patients, the average duration of progression is less than four days. Therefore, the results ol these uncontrolled studies cannot be interpreted. Short courses of corticosteroids early in the disease have been advocated,Ga but their e{fectiveness has never been demonstrated in controlled trials. Toxic epidermal necrolysis can develop in patients who are receiving hish-dose corti-

of toxic epidermal necrolysis

costeroids.3'65 Retrospective studies demonstrate no

benefit ol corticosteroids or higher rates of morbidity and mortality in corticosteroid-treated patients.66-68 We recommend against their use. Case reports claiming that plasmapheresis, cyclosporine, cyclophosphamide, and monoclonal antibodies directed against cytokines are helpful should be resarded with skepticism.
s9,6e.70

toxic arene oxide metabolic products of anticonvulsant agents has been observed in patients with the hypersensitivity syndrome, but the syndrome also occurs in patients without this abnormality.rT85 Cells from the parents of affected patients have a degree of in vitro sensitivity to these toxic metabolites that is intermediate between that of a{fected patients and that of controls.rT Positive tests have been noted in multiple family members.s6 Cross-sensitivity between
the various aromatic antiepileptic drugs is well documented, making it dilficult to select alternative anticonvulsant therapy.BT'88 Rashes of all types are reported with carbamazepine or phenytoin therapy.T3Be Most o[ these rashes are morbilliform (Fig. l) and will abate even if

Because these disorders progress so rapidly, many

lully before the patients are hospitalized, thus limiting the practical value of such treatments. Therefore, therapies that reduce morbidity associated with skin loss or accelerate regrowth of the
cases have evolved

skin are the most promising.

ff yprnsrNsr:rrvrry SyNonoun
A variety of hypersensitivity responses are responsible for most cutaneous reactions to drugs. The term "hypersensitivity syndrome" refers to a specific severe

idiosyncratic reaction. The syndrome typically includes skin rash and fever, often with hepatitis, arthralgias, l,vmphadenopathy, or hematologic abnor-

the drug is continued. Unfortunately, the hypersensitivity syndrome often initially presents as a morbilliform eruption indistinguishable from less serious reactions (Fig. 1). The reaction may become indurated and infiltrated (Fig. l3). Any cutaneous reaction associated with aromatic anticonvulsant agents that includes facial swelling, exfoliative dermatitis (Fig. 9), fever, lymphadenopathy, eosinophilia, arthritis, hepatitis, or bullous or purpuric skin lesions

Vol. 331

\o.

l9

X,{[,DICAI. PROGRESS

1279

Table 4. Drugs Associated with StevensJohnson Syndrome and Toxic Epidermal Necrolysis.
DRUGs

malities (Tables

It{osr

DRrr(is At so

I_REquri\TLY

Ass(rATLr)'

Ass6tATED

Sultadoxine Sulfdiazine Sulfasalazine Co-trimoxazole Hydantoins Carbamazepine Barbiturates Benoxaprofenf Phenylbutazone

Cephalosporins Fluoroquinolones Vancomycin

Rifampin
Ethambutol Fenbufen Tenoxicam

Tiaprofenic acid
Diclofenac Sulindac Ibuprofen Ketoprolen Naproxen Thiabendazole

Isoxicami
Piroxicam Chlomezanone

l, 2, and 3). Perhaps because of its relatively late onset, slow evolution, and clinical similarity to many infectious illnesses, the diagnosis of hypersensitivity syndrome may be delayed. The aromatic antiepileptic agents (phenytoin, carwith an estimated bamazepine, and phenobarbital) - patients and perincidence of I reaction per 5000 haps a higher rate among black patients and sul- of hyperfonamides are the most lrequent causes sensitivity syndrome.s6'i7'7r-76 Other drugs, especially allopurinol, gold salts, dapsone, and sorbinil, are also associated with the syndrome.TT-80 Hypersensitivity syndrome may be difficult to distinguish lrom serum sickness or drug-induced vasculitis. Laboratory findings often help distinguish these clinicalll' similar conditions lrom each other and lrom infectious diseases
(Table 2). The hypersensitivity svndrome tvpically develops two to six weeks alter a drug is first used, later than most other serious skin reactions (Table 3). With anti-

Allopurinol Amithiozone Aminopenicillins

*Togcther these drugs account for approximately two thirds of the cases attributed to drugs in large series in France. Gemany, and the United state(.l.l'le'll 4l

This drug is no lonqer marketed.

Many interventions nleant to halt the progression

of toxic epidermal necrolysis have been tried,

each

in a few patients. A positive result, usually defined as one that halts the spread of necrolysis, has typically been noted after several previous "ineffective" treatments. However, in untreated patients, the average duration of progression is less than four days. Therefore, the results of these uncontrolled studies cannot be interpreted. Short courses of corticosteroids early in the disease have been advocated,Ga but their effectiveness has never been demonstrated in controlled trials. Toxic epidermal necrolysis can develop in patients who are receiving high-dose corticosteroids.3'6'" Retrospective studies demonstrate no

epileptic drugs, fever and rash are the most frequent presenting symptoms (in B7 percent ol cases). l,ymphadenopathy (in about 75 percent) is lrequent and usuall,v due to benign lymphoid hvperplasia.lT Atypical lymphoid hyperplasia and pseudolymphoma occasionally occur.sr Some of these cases resolve with withdrawal of the drug, but in some cases lymphoma eventually develops.B2 Hepatitis (51 percent); interstitial nephritis ( I I percent); hematologic abnormalities, especially eosinophilia (30 percent); and mononucleosis-like atypical lymphocytosis are also common.rT Involvement of the heart, Iung, thyroid, and brain is less frequent.ri'83 Severe cases of hepatitis may be lifethreatening.B+

benefit of corticosteroids or higher rates ol morbidity and mortality in corticosteroid-treated patients.66-68 We recommend against their use. Case reports claiming that plasmapheresis, cyclosporine, cyclophosphamide, and monoclonal antibodies directed against cytokines are helpful should be regarded with skepticism.se,6s.70

toxic arene oxide metabolic products ol anticonvulsant agents has been observed in patients with the hypersensitivity syndrome, but the syndrome also occurs in patients without this abnormality.ri'B' Cells from the parents of ailected patients have a desree of in vitro sensitivity to these toxic metabolites that is intermediate between that of affected patients and that of controls.rT Positive tests have been noted in multiple family members.BG Cross-sensitivity between
the various aromatic antiepileptic drugs is well documented, making it di{ficult to select alternative anticonvulsant therapy.B''B* Rashes o[ all types are reported with carbamazepine or phenytoin therapy.T3'Bs lvlost of these rashes are morbillilbrm (Fig. l) and will abate even il

A genetically determined inability to detoxi

the

Because these disorders progress so rapidly, many cases have evolved fully belore the patients are hospitalized, thus limiting the practical value of such treatments. Therefore, therapies that reduce morbidity associated with skin loss or accelerate regrowth of the

skin are the most promising.

HyprnsrNsITrvrrY SyNnotr.r
A variety of hypersensitivity responses are responsible for most cutaneous reactions to drugs. The term "hypersensitivity syndrome" refers to a specific severe idiosyncratic reaction. The syndrome typically includes skin rash and fever, often with hepatitis, arthralgias, lymphadenopathy, or hematologic abnor-

the drug is continued. Unfortunately, the hypersensitivity syndrome often initially presents as a morbilliform eruption indistinguishable from less serious reactions (Fig. l). The reaction may become indurated and infiltrated (Fig. l3). Any cutaneous reaction associated with aromatic anticonvulsant agents that includes facial swelling, exfoliative dermatitis (Fig. 9), fever, lymphadenopathy, eosinophilia, ar-

thritis, hepatitis, or bullous or purpuric skin lesions

280

THE NETV ENGLANDJOURNAL OF NTEDICI\E

Nov. 10, 1994

proved.s8 Alternative proposed mechanisms include direct drug toxicity against vessel walls, autoantibodies reacting with endothelial cells, and cell-mediated cytotoxic reactions against vessels.e3'es-l0r
Clinical Presentation

Figure 13. lnfiltrative Papules Coalescing inlo Plaques. These papules are pical of the more advanced eruptions seen in the hypersensitivity syndrome associated with aromatic antiepileptic drugs. The histologic appearance of these induraled conlluent papules and plaques is often similar to that of early stages of cutaneous T-cell lymphoma.

Serum sickness has distinctive skin findings. Typically, erythema first occurs on the sides of the fingers, toes, and hands, before a more widespread eruption that is most often morbilliform (in two thirds of patients), sometimes with urticaria,es-ei lJrticaria is seldom seen alone. About half the cases of serum sickness have visceral involvement. Rash, fever, constitutional symptoms, arthralgia, and arthritis are the most frequent clinical findings.ss'e6 The clinical hallmark of cutaneous vasculitis is palpable purpuric papules, classically located on the lower extremities, although any site may be involved (Fig.
l4).e3'r02'103 Hemorrhagic blisters, urticaria, ulcers, nodules, Raynaud's disease, and digital necrosis may also occur. The same vasculitic process may also affect the kidney, liver, gastrointestinal tract, or neryous

or begins more than two weeks after therapy is initiated is especially worrisome.

system and can be life-threatening. Histologically,

small dermal vessels exhibit fibrinoid necrosis, infiltration by polymorphonuclear leukocytes, and nuclear
dust.lo3 The results of direct immunofluorescence are

Sulfonamide-induced hypersensitivity syndrome and that induced by antiepileptic agents are clinically indistinguishable.16'57 Slow N-acetylation of sulfonamide and increased susceptibility of patients' Ieukocytes in vitro to toxic hydroxylamine metabolites are associated with greater susceptibility, but only a small percentage of people who acetylate sulfonamides slowly have reactions to these drugs.t6,sz,so Recovery is usually total, but rash and hepatitis may persist for weeks. Treatment with corticosteroids has been widely advocated, but controlled studies are lacking.er We have observed dramatic improvements
in symptoms and laboratory measurements in patients given systemic corticosteroids (>0.5 mg per kilogram of body weight). Relapses of rash and hepatitis may occur as corticosteroids are tapered. Transient hypothyroidism may also develop.s2

often positive, with deposits of IgM and C3 complement on capillary walls.ro3 In serum sickness, serum C3 and C4 complement levels are markedly decreased.e6 Serum sickness begins B to l4 days after the initial exposure to a foreign protein. Other kinds of drug-induced vasculitis typically develop 7 to 2l days after a new drug is begun, but the interval can be longer.ee When otherwise unexplained palpable purpura develops in a patient, any drug the patient is taking, especially those inroduced within the preceding two months, should be considered suspect. Withdrawing the drug usually leads to rapid resolution. Systemic corticosteroids may benefit
some patients. Diflerential Diagnosls

Vescur,rrrs aND SERUM Srcxxess Vasculitis characterized by inflammation and necrosis of blood-vessel walls has many causes.s3 Druginduced vasculitis typically involves small vessels and is a subtype of hypersensitivity vasculitis,sa which also includes cutaneous leukocytoclastic vasculitis and se-

Drug-induced hypersensitivity vasculitis may be difficult to distinguish from other types of vasculitis.
Schnlein-Henoch purpura usually occurs in younger patients, with characteristic large purpuric cutaneous lesions, often on the buttocks. Renal and gastroin-

testinal involvement

In 1905, von Pirquet and Schick described serum sickness in children treated with horse serum containing diphtheria antitoxin.es More recently, serum sickness has been noted in patients treated with horse antithymocyte globulins or human diploid-cell rabies vaccine.es'e7 Serum sickness is a type III hypersensitivity reaction mediated by the deposition of immune complexes in small vessels, activation of complement, and recruitment of granulocytes. Drug-induced vasculitis is believed to result from antibodies directed against drug-related haptens, but this has not been

rum

sickness.sa

in

is common. IgA is

deposited

vessels.roa Cryoglobulinemia-associated vasculitis

has a chronic or recurrent course. Polyarteritis nodosa and Wegener's granulomatosis sometimes begin as a palpable purpura.to5 Most patients with Wegener's granulomatosis have autoantibodies to neutrophil cytoplasmic antigens,106 a feature that is usually absent in drug-induced vasculitis. Infection and colla-

gen vascular disorders can also induce vasculitis.e3 Excluding infection as a cause is often the greatest challenge. Drugs cause about l0 percent of cases

of acute cutaneous vasculitis. 102,103 Only a small fraction of drug reactions take the

Vol. 331 No.

19

MEDICAL PROGRESS

crosis (Fig. l5), with hemorrhagic blisters or necrotic scars, frequently in areas with large quantities ol adipose tissue, including the breasts, hips, and buttocks.

Acral involvement is infrequent. People with hereditary deficiency of protein C,

natural anticoagulant protein, are at highest risk, even if they are heterozygotes and thus have no history of recurrent thrombosis.lls-122 In these persons, warfarin greatly depresses protein C levels before decreasing other vitamin K-dependent coagulation factors, inducing a transient hypercoagulable state and throm-

bus formation.rls Rapid recognition of painful, red

plaques in fatty areas is the key to diagnosis. Therapy includes discontinuing warfarin, administerine vitamin K to reverse the effect of warfarin, giving heparin as an anticoagulant, and administering mono-

clonal antibody-purified protein

concentrate.r23

Necrotic tissues may require surgical dbridement

and grafting. If not rapidly treated, this condition may be fatal. It develops in I in 10,000 patients receiving warfarin, a prevalence that is about 2 percent of the estimated prevalence of protein C deficiency.lls,l2a Since most persons with protein C deficiency tolerate warfarin, other factors must play a part. Protein S or antithrombin III deficiency also confers an increased
risk.r25

Figure 14. Drug-lnduced Vasculitis Presenting as Palpable Purpuric Papules and Plaques, Occasionally with Overlying Small Blisters, Especially on the Lower Extremities.

Heparin can also cause thrombosis and necrosis in the skin and other organs.r26 The mechanisms of heparin-induced and warfarin-induced necrosis are almost certainly different. Heparin can induce vessel thrombosis with fibrin thrombi at injection sites and distant skin sites and in other organs.l2T'r2B Localized reactions at injection sites are frequent, but devastating widespread reactions are not. Heparin-induced platelet aggregation may be responsible for widespread reactions. These lesions need to be dilferentiated from other cutaneous reactions to heparin at injection sites, which are most likely immunologic.l26'r27 Neither proTable 5. Agents Most Otten Associated with Vasculitis, Serum Sickness, and Reactions Resembling Serum Sickness.
Vasculitis Allopurinol Penicillin Aminopenicillins
Sulfonamides Thiazides Pyrazolones Hydantoins

form of vasculitis.Ts Propylthiouracil may induce a clinically distinctive vasculitis initially involving the face and ear lobes, with erythema and later purpura.r07,r08 Antinuclear antibodies and antineutrophil
cytoplasmic antibodies may be produced.roe,rr0 Table 5 lists drugs that are often implicated in causing vasculitis. Recently reported drugs associated with vasculitis include the retinoids and quinolones and agents used in immunotherapy.t I t-t ts Reactions resembling serum sickness (rash, fever, and arthralgias) occur in about I of 2000 children given celaclor and have also been reported with minocycline, penicillins, propranolol, streptokinase, and other drugs.r14-ll8 Since reduced concentrations of serum complement are not generally noted, most such cases probably do not represent rue serum sickness.

Propylthiouracil Raynaud's disease or digital necrosis

Beta-blockers Ergot alkaloids

ANrrconcureNr-INoucr SxrN Nncnosrs

A rare and devastating effect of warfarin therapy is skin necrosis, a consequence of occlusive thrombi in vessels of the skin and subcutaneous tissue.lls Typically, warfarin-induced skin necrosis begins three to five days after therapy is initiated. The use of higher initial doses, obesity, and female sex appear to increase the risk.r20 Red, painful plaques evolve to ne-

Bleomycin Serum sickness

Serum preparations Vaccines

Reactions resembling serum sickness

Beta-blockers Streptokinase p-Lactam antibiotics

282

THE

\E\\' E\GL\D

JOUR);AL OF \TEDICI\E

\ov. I0.

199.1

a rate that is probably new users of ACE inhibitors higher than that associated- with penicillins.r3i The risk is highest during the first three weeks of therapy.137 These reactions ma-v be due to the inhibition of kinin metabolism.l3s Hemodialysis'o,ith high-flux dialysis membranes, which may increase the production of bradvkinin, greatlv increases the risk of anaphviactoid reactions associated with ACE inhibitors.l3e-r+l Reactions occur in up to 35 percent of patients treated

in this manner.l+1
CoNcr-usroNs

q.",
Figure 1 5. Warfarin-lnduced Necrosis.

ln this woman, painful erythema and induration of the breasts

were followed by necrosis of these tatty areas.

Adverse reactions to drugs most often affect the skin, but onlv a small fraction are life-threatening or lead to disabling sequelae. Because of the low frequency of such severe reactions (usually less than I reaction per 5000 exposed patients), they are unlikely to be detected in premarketing clinical trials. Only if clinicians recognize and report severe reactions to regulatory authorities and manufacturers can ne'' drugs associated rvith a high risk of such reactions be identified, relabeled, or r,','ithdrawn from the market.
r42.143

tein C nor protein S piavs a part. ln heparin-induced necrosis, levels of fibrinogen and fibrin-split products are usualll' normal. but platelet counts are often depressed.r26 Evidence of primar,v vasculitis is iacking. Heparin-induced thrombocytopenia and thrombosis mav be an immune-complex disorder.rrlr In addition to discontinuation of the drug, treatment rvith lvarfarin or antiplatelet drugs is useful.126

For many severe cutaneous reactions to drugs, including toxic epidermai necrolvsis, Stevens-Johnson
syndrome, vasculitis, and serum sickness, medical in-

tervention is limited to the earlv recognition of the symptoms and the withdrawal of the offending drug. Even for other reactions that mav benefit from therapy, early recognition of the symptoms and prompt
rvithdrau'al ol suspect drugs are usuallv the most important steps. Therefore, clinicians should carefully evaluate the signs and svmptoms of all adverse cutaneous reactions thought to be due to drugs and immediately discontinue all drugs that are not essential, especialll'when the signs or svmptoms associated with more severe reactions are present (Table 2). After recover)', patients should be advised to avoid the drug thought to be responsible for the reaction and all chemically related compounds. Patients with toxic epidermal necrolysis and hypersensitivitl, svndrome should alert their first-degree relatives to their ele',,ated risk of such reactions to the same drugs.

ANcrororua
Immediate-hypersensitivitv reactions can produce angioedema or anaphvlaxis. The mechanism and treatment of IgE-mediated immediate-hvpersensitirity reactions inciuding anaphylaxis, which are most often induced bv insect stings and food, have been reviewed recentlv.l30'lrlr Many drug-induced cases of angioedema are nor mediated b,v IgE. \\'e shail briefly discuss newer drugs that cause angioedema or anaphylaxis. Antibiotics (especiallv the penicillins), anesthetics, and radiocontrast aeents are the most common causes of serious IgE-mediated. drug-induced immediate ht'persensitivity.r:o'tst Ansioedema occurs in about I per I0,000 courses of penicillin and leads to death in I to 5 per 100.000 courses. In persons receiving longa range of cutaneous findings from simple urticaria to

RrrrnnNcr,s
l.
Chan HL. Stern RS, Arndt KA. et al. The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidemal necrolysis: a population-based study with panicular reference to reactions caused by drugs among otpatients. Arch Demratol 1990:126:43-7 . Cone KA. Spielberg TE. Adverse drug reaction processing in the United States and its dependence on physician reporting: zomepirac (Zomax) as a case in point. Ann Emerg Med 1988:17:1,15-9. Roujeau JC, Guillaume JC, Febre JP. Penso D. Flechet ML, Gine JP. Toxic epidemal necrolysis (Lyell syndrome): incidence and drug etiology in France. 1981-1985. Arch Dermatol 1990 12637-42. Miller KD, Lobel HO, Satriale RF. Kuritsky JN, Stem R, Campbell CC. Severe cutaneous reactions among American trvelers sing pyrirrethamine-sulfadoxine (Fansidar) for malaria prophylaxis. Am J Trop Med Hyg 1986:35:45 1 -8. Bigby M, Jick S. Jick H, Amdt K. Drug-induced cutaneous reactions: a report from the Boston Collaborative Drug Surueillance Program on 15,438 consecutive inpatients. 1975 to 1982. JAMA 1986;256:3358-63. Leape LL, Brennan TA, Laird N, et al. The nature of adverse events in hospitalized patients: results of the Harvard Medical Practice Study ll. N Engl J Med 1991t324:37'1-84.

term penicillin prophvlaxis for rheumatic fever. the risk of angioedema persists during treatment.r32
Other frequently used drugs, including angiotensin-

2. 3. 4.

converting-enzvme (ACE) inhibitors, nonsteroidal antiinflammatory drugs, radiocontrast agents, opiates, and curare, cause angioedema that is not IgEmediated. ACE inhibitors induce the majority of cases of ansioedema that lead to hospitalization.l33'l3r The observed incidence of drug-related angioedema has increased in parallel w'ith the increased use of ACE inhibitors, especiallv ionger-acting ACE inhibitors.13r-136

5. 6.

Angioedema occurs

in 2 to l0 per 10,000

Vol. 331 No. li)

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ME,DICAL PROGRESS

283

Alanko K. Stubb S. Kauppinen K. Cutaneous drug reactions: clinical types and causative agents: a nve-year suruey of in-patients (1981-1985). Acta Dem Venereol (Stockh) 1989:69:223-6. 6. lves TJ. Bentz EJ. Gwyther Rt. Dematologic adverse drug reactions in a family medicine setling. Arch Fam Med 1992;1:241-5. 9. Varga J, Vitto J. Jimenez SA. The cause and pathogenesis of the eosinophilia-myalgia syndrome. Ann Intem Med 1992;ll6:140-7. 10. Kramer MS. Leventhal JM, Hutchinson TA, Feinstein AR. An algorithm tbr the operational assessment of adverse drug reactions. L Background, description, and instructions for use. JAMA 1979:242:623-32. ll Tumer WM. The Fmd and Drug Administration algorithm: special workshop regulatory. Drug InfJ 1984:18:259-66. t2 Louik- C. Lacouture PG. Mitchcll AA. ct al. A study of adverse reaction algorithms in a drug suneillance program. Clin Phmacol Ther 1985;38:
183-7.

39.

40. 41.
42.

43.
,14.

Naldi L, Lati F. Marchesi I, Cainelli T. Incidence of toxic epidemal necrolysis in Italy. Arch Dermatol 1990; I 26: I 103-4. Strom BL. Cmon JL. Halpem AC, et al. A population-bed study of Stevens-Johnson syndrome: incidence and antecedenl drug exposures. Arch Dematol l99l : I 27:831-8. House RA, Jakubovic H, Wong L. Holness DL. Work-related toxic epidermal necrolysis? J Occup Med 199234:135-9. Nethcrco JR, Choi BC. Erythema multiforme (Stevens-Johnson syndrome) chart review of 123 hospitalized patients. Dematologica 1985:l7l:383-96. Stem RS, Chan HL. Usefulness of case repon litemture in detemining drugs responsible for toxic epidemal necrolysis. J Am Acad Dermatol
1989;21:317-22. Hellgren U, Rombo L, Berg B, Cillson J, Wilholm BE. Adverse reactions to sulphadoxine-pyrimethamine in Swedish travellers: implications for prophylaxis. BMJ 1981 ;295:365-6. Askmark H, Wiholm B-8. Epidemiology of adversc reactions to crbamzepine as seen in a spontneous reporting system. Acta Neurol Scand

l3 t4 l5

LM. Skin test lbr diagnosis of penicillin allergy cunent status. Ann Allergy 1987l,59:16'7-10. Bruynzeel D. van Ketel W. Skin tests in the diagnosis of maculo-papular drug eruptions. Scmin Dematol 1987l.6:l19-24. Shea NH. Diagnosing cutaneous adverse reactions to drugs. Arch DemaRessler C, Mendelson

45.

1990:81:l3l-40.

l6
t7 t8

20

2t

I990:126:94-7. Rieder MJ. Uetrecht J. Shear NH. Cannon M. Miller M, Spielberg SP. Diagnosis of sulfonamide hypersensitivity reactions by in-vitro "rechallenge" with hydroxylamine metabolites. Ann lntem Med l989ll l0:286-9. Shear NH. Spielbcrg SP. Anticonvulsant hypereensitivity syndrome: in vitro assessment of risk. J CIin Invest 1988;82:1826-32. Revuz J, Penso D. Roujeau JC. et al. Toxic epidermal necrolysis: clinical findings and prognosis factors in 87 patients. Arch Demtatol 1987l.123: I 160-5. Schpf E. Sthmer A, Rzany B. Victor N, Zentgraf R. Kapp JF. Toxic epidemal necrolysis and Stevens-Johnson syndrome: an epidemiologic study from West Gemany. Arch Dermatol l99l:127:839-42. Bastuji-Garin S, Rzany B. Stem RS, Shear NH, Naldi L. Roujeau JC. Clinical classifrcation of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome. and crythema multifome. Arch Dermatol 1993;,129:92-6. Stevens AM. Johnson FC. A new cruptive tver associated with stomatitis

tol

46. 47. 48.

49.

Burge SM. Dawber RPR. Stevens-Johnson syndrome and toxic epidemal necrolysis in a patient with systemic lupus erythematosus. J Am Acad Dermatol 1985;13:665-6. Roujeau JC, Huynh Tn-, Bracq C, Guillaume JC, Revuz J, Touraine R. Genetic susceptibility to toxic epidemal necrolysis. Arch Dermarol

50.
5 I

1987;t23:l l7l-3. Billingham RE, Streilein JW. Toxic epidemal necrolysis and homologous disease in hamsters. Arch Dematol 1968:98:528-39. Peck GL, Elias PM, Graw RG Jr. Graft-versus-host reaction and toxic epidermal necrolysis. Lancet 1972;2:l l5l-3. Villada G, Roujeau JC. Cordonnier C, et al. Toxic epidemal necrolysis after bone mmow transplantation: study of nine cases. J Am Acad Derma-

tol

and ophthalmia: report

1922.24:526-33. 22.
23.

of two

cases

in childrcn. Am J Dis

52. 53. 54. 55.

Child

Lyell A. Toxic epidemal necrolysis: an eruption resembling scalding of tbe skin. Br J Dematol 1956:6ll:355-61. Bergoend H. Lffler A. Amu R, Maleville J. Ractions cutanes surue-

1990:23:870-5. McDonald BJ, Singer JW, Bianco JA. Toxic epidermal necrolysis possibly linked to aztreonam in bone marow transplant patients. Ann Phmacother 1992:26:34-5. Cmpman SA, Johnson RA, Platt R, Stern RS. Cutaneous disease and drug reactions in HIV infection. N Engl J Med 1993t328:1670-4. Porteous DM. BergerTC. Severe cutaneous drug reactions (Stevens-Johnson syndrome and toxic epidemal necrolysis) in humm immunodeficiency

nues au cours de la prophylaxie de masse de la mningite cbro-spinale par un sulfamide long-retard ( propos de 997 cas). Ann Dermarol Syphiligr (Ptris) 1968;95:481 -90. 24 Ruiz-Maldonado R. Acute disseminated epidermal necrosis types l, 2, and 3: study of sixty cases. J Am Acd Dcmatol 1985;13:623-35. 25 Huff JC. Weston WL, Tonnesen MG. Erythema multiforme: a critical review of characteristics. diagnostic criteria, and causes. I Am Acad Dermatol 1983:8:763-75. 26. Roupe C. Ahlmen M, Fagerberg B. Suurkula M. Toxic epidemal necrolysis with extensive mucosal erosions of the gastrointestinal and respiratory tracts. Int Arch Allergy Appl lmmunol 1986180:145-51. 27 Timsit JF, Mion C. Rouyer N, [ Gulluche Y, Cusin H. Bronchopulmonary distress associated with toxic epidermal necrolysis. Intensive Care Med 1992:18:42-4. 28. Chosidow O. Delchier J-C. Chaumette MT. et al. Intestinal involyemenr in drug-induced toxic epidermal necrolysis. Lancet l99l :337:928. 29. Wilkins J, Morison L, White CR Jr. Oculutaneous manifestations of the erythema multiforme/Stevens-Johnson/toxic epidermal necrolysis spec-

virus infection. Arch Dematol l99l :127 t1 4O-1. Saiag P. Caumes E. Chosidow O, Revuz J, Roujeau JC. Drug-induced toxic epidermal necrolysis (Lyell syndrome) in patients infected with the human immunodeficiency virus. J Am Acad Dematol 1992,26:567-74. Rzany B, Mockenhaupt M, Stocker U, Hamouda O. Schopf E. Incidence of Stevens-Johnson syndrome and toxic epidermal necrolysis in patients with the acquired immunodeficiency syndrome in Germany. Arch Derma1993;129:1059. Spielberg SP, Gordon GB. Blake DA, Goldstein DA. Herlong HF. Predisposition to phenytoin hepatotoxicity assessed in vitro. N Engl J Med l98l'.305:722-7 . Shear NH, Spielberg SP. Grant DIr{, Tang BK, Kalow W. Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann lntem Med 1986:105:179-84. Merot Y. Gravallese E, Guillen FJ, Murphy GF. Lymphocyte subsets and Langerhans' cells in toxic epidemal necrolysis: report of a case. Arch Dermatol 1986: I 22:455-8. Heng MC, Allen SG. Efficacy of cyclophosphamide in toxic epidemal necrolysis: clinical and pathophysiologic aspects. J Am Acad Dematol

tol

56. 57. 58. 59. 60.

trum. Dermatol Clin 1992; l0:571-82.

30 Binaghi M. Kosos M, Saiag P. Roujeau JC, Coscas G. Atteinte oculaire au cours du syndrome de Lyell: incidence. volution, pronostic. Ophtalmolo-

gie l9E8;2:l2t-2.
Prendiville JS. Hebert AA. Greenwald MJ. Esterly NB. Management of Stevens-Johnson syndrome and toxic epidemal necrolysis in children. J Pediatr 1989:l l5:881-7. 32. Westly ED. Wechsler HL. Toxic epidermal necrolysis: granulocytic leukopenia as a prognostic indicator. Arch Dematol 1984;12O:721-6. 33. Jordan MH, Lewis MS, Jeng JG, Rces JM. Tretment of toxic epidemal necrolysis by bum units: another market or another threat'l J Bum Cile Rehabil l99l ;12:579-81. 34. Marks J. Ervthroderma and its management. Clin Exp Dermatol 198217: 4t5-22. 35. Melish ME. Glasgow LA. The staphylcal scalded-skin syndrome: development of an extrnrimental model. N Engl J Mcd 1970;282:l I l4-9. 16. Roujeau JC. Bioulac-Sage P, Bourseau C, et al. Acute generalized exanthematous pustulosis: analysis of 63 cases. Arch Dermatol 199|.127:
I

3l

61. 62. 63. 64.

l99l:25:778-86. Villada G. Roujeau JC, Clerici T, Bourgault I, Revuz J. lmmunopathology of toxic epidermal necrolysis: keratinocytes, HLA-DR expression, Langerhans cells, and mononucler cells: an immunopathologic study of five cases. Arch Dematol 1992;128:50-3. Coneia O, Delgado L. Ramos JP, Resende C, Toninha JA. Cutaneous T-cell recruitment in toxic epidemal necrolysis: funher evidence of CD8+ lymphocyte involvement. Arch Dematol 1993;129:466-8. Heimbach DM, Engrav LH. Min JA, Hamar TJ. Grube BJ. Toxic epidemal necrolysis: a step forwrd in treatment. JAMA 1987;257:21715. [Enatum, JAMA 1987;258:1894.] Demling RH. Bums. N Engl J Med 1985;313:1389-98. Sheretz EF. Jegasothy BV. Lazms GS. Phenyroin hypersensitivity reaction presenting with toxic epidermal necrolysis and severe hepatitis: repon ofa patient treated with corticosteroid "pulse therapy." J Am Acad Derma-

rol 1985:12:178-81.

65.
66. 67.

Rzany B, Schmitt H, Schpf E. Toxic epidermal necrolysis in patients receiving gluconicosteroids. AcIa Dem Venereol (Stockh) l99l:71:
t7 t-2.

333-8.

31

Mutasim DF, Pelc NJ, Anhalt GJ. Paraneoplastic pemphigus. Dematol Clin l993lll:473-81.
Boniger LE. Strandberg l, Westerholm B. Drug-induced febrile mucocutaneous syndrome with a survey of the literature. Acta Med Scand
I

38.

975:198:229-33.

Kim PS, Goldfrb lW, Gaistbrd JC, Slater H. Stevens-Johnson syndrome and toxic epidemal necrolysis: a pathophysiologic review with recommendations for a treatment protocol, J Burn Cre Rehabil 1983;4:91-100. Halebian PH. Corder VJ. Madden MR, Finklestein JL. Shires GT. Improved bum center survival of patients with toxic epidemal necrolysis managed without conicosteroids. Ann Surg 1986:204:503- I 2.

I 281

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Weston WL. Oranje AP, Rasmussen JE. et al. Corticosteroids for erythema mltifome? Pediatr Dermatol 1989:6:229-50. 69 Kamanabroo D, Schmitz-Landgraf W, Czmetzki BM. Plasmapheresis in severe drug-induced toxic epidemal necrolysis. Arch Dermatol 1985:l2l: I 548-9. 70. Renfro L, Grant-Kels JM, Daman LA. Drug-induced toxic epidemal necrolysis treated with cyclosporin. Int J Dematol 198928:441-4. 1t. Pelekanos J, Camfreld P, Camfield C, Gordon K. Allergic rash due to antiepileptic drugs: clinical features and mnagement. Epilepsia l99l;32: 554-9. 72. Pellock JM. Carbamazepine side effects in children and adults. Epilepsia 1987;28:Suppl 3:S64-S70. 73. Rapp RP, Norton JA, Young B, Tibbs PA. Cutaneous reactions in headinjured patients receiving phcnytoin for seizure prophylaxis. Neurosurgery 1983:13:272-5. Temkin NR, Dikmen SS, Wilensky AJ. Keihm J, Chabal S. Winn HR. A randomized. double-blind study of phenytoin for the prevention of posttraumatic seizures. N Engl J Med 1990l'323:497-502. 15. Hmda F. Phenytoin hypersensitivity: 38 cases. Neurology 1979129:14805. 76. Livingston S, Villamater C, Sakata Y. Pauli LL. Use of crbamazepine in epilepsy: results in 87 patients. JAMA 1967:200:2M-8. 11 Lupton GP, Odom RB. The allopunnol hypersensilivrty syndrome. J Am Acad Dermatol 1979:.l :365-7 4. 78. Sene H, Sany J, Rosenberg F. Les effets secondaires de la chrysothrapie. Ann Med Inteme (Paris) 1916l,127:552-9. 79. Tomecki KJ, Catalano CJ. Dapsone hypersensitivity: the sulfone syndrome revisited. Arch Dematol 1981:l l7:38-9. 80. Spielberg SP. Shear NH, Cannon NI. Hutson NJ, Gunderson K. In-vitro assessment of a hypersensitivity syndrome associated with sorbinil. Ann
68
81

99. Dubost JJ, Souteyrand P, Sauvezie B. Drug-induced vasculitides. Baillieres Clin Rheumatol 1991:5:l l9-38. 100. Brasile L, Kremer JM, Clarke JL, Cerilli J. Identification of an autoantibody to vascular endothelial cell-specific antigens in patients with systemic vasculitis. Am J Med 1989:87:74-80. Falk RI. Jennette JC. Antineutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med
I

988:3 I 8:165 I -7.

to2. Ekenstam EAF, Callen JP. Cutaneous leukocytoclastic vasculitis: clinical

and laboratory features of 82 patients seen in private practice. Arch Dermatol 1984:120:.184-9. Sanchez NP, Van Hale HM. Su WP. Clinical and histopathologic spectrum

103.

of necrotizing vasculitis: repon of findings in

1985: l2 I :220-4.
104

l0l

cases. Arch Dermatol

105. 106. 107.

Van Hale HM, Gibson LE, Schroeter AL. Henh-Schonlein vasculitis: direct immunofluorescence study of uninvolved skin. J Am Acad Dematol 1986: I 5:665-70. Hoffman GS. Ken GS, Leavitt RY. et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intem Med 1992;l t6:488-98. D'Cruz D. Hughes G. Systemic vasculitis: new tests, new treatments. BMJ 1992:3M:269-70.

Intem Med l99l:1 l4:720-4. Rijlaarsdam U, Scheffer E. Meijer CJ, Kruyswijk MR, Willemze R. Mycosis fungoides-like lesions associated with phenytoin and carbamazepine therapy. J Am Acad Dermtol 199l|.24:216-20. Rosenthal CJ. Noguera CA, Coppola A, Kapelner SN. Pseudolymphoma with mycosis fungoides manifestations, hyperesponsiveness to diphenylhydantoin. and Iymphocyte disregulation. Cancer 1982;49:230514.

83

84. 85.

Ray-Chaudhuri K, Pye IF, Boggild M. Hypersensitivity to carbamazepine presenting with a leukemoid reaction, eosinophilia, erythroderma, and renal failure. Neurology 1989:39:436-8. Parker WA, Shearer CA. Phenytoin hepatotoxicity: a case report and re-

\ryemer MC, Romaldini JH, Bromberg N, Wemer RS, Farah CS. Advene effects related to thionamide drugs and their dose regimen. Am J Med Sci 1989:297:216-9. 108. Carrasco MD, Riera C, Clotet B, Grifol M, Foz M. Cutaneous vasculitis associated with propylthiouracil therapy. Arch Intem Med 19871,147:1677 . 109. Horton RC, Shepprd MC, Emery P. Prophylthiouracil-induced systemic lupus ervthematosus. Lancet 1989:2:568. I10. Dolman KM, Gans RO, Vervaat TJ, et al. Vasculitis and antineutrophil cytoplasmic autoantibodies associated with propylthiouracil therapy. Lancet 1993:342:651-2. Dwyer JM, Kenicer K. Thompson BT, et al. Vasculitis and retinoids. Lancet 1989:2:494-6. I12. Huminer D, Cohen JD, Majadla R, Dux S. Hypersensitivity vasculitis due to ofloxacin. BMJ 1989:299:303. I r3. Taylor RJ. Hypersensitivity vasculitis occuning in a patient receiving immunotherapy. J Allergy Clin Immunol l99l;87:889-90. I 14. Heckbert SR. Stryker WS. Coltin K, Manson JE, Platt R. Serum sickness in children after antibiotic exposure: estimates of occurence and morbidity in a health maintenance organization population. Am J Epidemiol 1990;

lll.

t32:336-42.
I 15.

86.

view. Neurology 1979;.29:17 5-8. Maguire JH, Wenrell G, Rane A. Apparently nomal phenytoin metabolism in a patient with phenytoin-induced rash and lymphadenopathy. Br J Clin Phamacol 1987 :24:554-1. Gennis MA. Vemuri R, Bums EA, Hill JV, Miller MA, Spielberg SP. Familial occunence of hypersensitivity to phenytoin. Am J Med l99l;91:
63 I

I 16.

lt7.

87 88

-4. Beran RG. Cross-reactive skin eruption with both carbamazepine and ox-

crbazepine. Epilepsia 1993;34: 163-5.

Pirmohamed M. Graham A, Roberts P. et al. Crbamazepine-hyperrensiassessment of clinical and in vitro chemical cross-reactivity with phenytoin and oxcilbazepine. Br J Clin Phmacol l99l:'32:74-9. 89. Wilson JT, Hojer B, Tomson G. Rane A, Sjoqvist F. High incidence of a concentration-dependent skin reaction in children treated with phenyloin. BMJ 1978:l:1583-6. 90 Rieder MJ, Shear NH, Kanee A, Tang BK. Spielberg SP. Prominence of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions. Clin Phmacol Ther l99l:49:13-7. 9t Murphy JM, Mashman J, Miller JD, Bell JB. Suppression of carbamazepine-induced rash with prednisone. Neurology l99l :41 : 144-5. 92 Gupta A, Eggo MC. Uetrecht JP. et al. Drug-induced hypothyroidism: the thyroid as a ttrget organ in hypersensitivity reactions to anticonvulsants and sulfonamides. Clin Phrmacol Ther 1992:51:56-67. 93 Fauci AS. Haynes B. Katz P. The spectrum of vasculitis: clinical, pathologic. immunologic and therpeutic considerations. Ann lntem Med 1978;

il8
I 19. 120.

tivity:

Platt R, Dreis MW, Kennedy DL. Kuritsky JN. Serum sickness-like reactions to amoxicillin, cefaclor. cephalexin, and trimethoprim-sulfamethoxazole. J Infect Dis 1988:158:474-7. Yen MC, Piszczek JE, Mintzer DL. Serum sickness-like syndrome associated with propranolol therapy. Postgrad Med 1983:74:291-4. Puyana J, Urena V, Quirce S. Femandez-Rivas M, Cuevas M. Fmj J. Serum sickness-like syndrome assiated with minocycline therapy. Allergy 1990;45:313-5. Noel J, Rosenbaum LH, Gangadharan V, Stewart J, Galens G. Serum sicknessJike illness and leukocytoclastic vasculitis following intracoronary arterial streptokinase. Am Hean J 1987;l l3:395-7. Bauer KA. Coumarin-induced skin necrosis. Arch Dermatol 1993',129:

766-8.
Comp PC. Coumrin-induced skin necrosis: incidence, mechanisms, management and avoidance. Drug Safety 1993;8:128-35. Teepe RG, Brkmans AW, Vermeer BJ, Nienhuis AM, Loeliger EA. Recunent coumarin-induced skin necrosis in a patient with an acquired functional protein C deficiency. Arch Dematol 19861122:1408-12. Vigano D'Angelo S. Comp PC, Esmon CT. D'Angelo A. Relationship between protein C antigen and anticoagulant activity during oral anticoagulation and in selected disease states. J Clin Invest 1986',77:416-

Izt.
122

25.
123

95.

89;600-76. Calabrese LH. Michel BA. Bloch DA, et al. The American College of Rheumatology 1990 criteria for th classification of hypersensitivity vasculilis. Arthritis Rheum 1990:33: I 108-13. von Pirquet C. Schick B. Serum sickness. Baltimore: Williams & Wilkins,
195 1.

t24.
125.

t26.
127. 128.

96. Biebry

L, Yancey KB. Young NS, Frank MM, Lawley TJ. Cutneous manifestations of serum sickness in patients receiving ntithymocyte globulin, J Am Acad Dcrmatol 1985:13:41 l-7. 97. Wanington RJ, Martens CJ, Rubin M, Rutherford WJ, Aoki FY. Immunologic studies in subjects with a serum sickness-like illness after immunization with human diploid cell rabies vaccine. J Allergy Clin lmmunol
987:79:605- I 0. Wintroub BU. Stern R. Cutaneous drug reactions: pathogenesis and clinical classif,cation. J Am Acad Dermatol 1985:13:167-79.
I

t29.
I

Schramm W. Spannagl IVI, Bauer KA, et al. Treatment of coumrininduced skin necrosis with a monoclonal antibody purilied protein C concentrate. Arch Dermatol 1993l.129:7 53-6. Miletich J. Sheman L, Broze G Jr. Absence of thrombosis in subjects with heterozygous protein C deliciency. N Engl J Med 1981l,317:991-6. Grimaudo V. Gueissaz F, Hauen J, Sanai A, Kruithof EK, Bachmann F. Necrosis of skin induced by coumarin in a patient deficient in protein S. BMJ 1989:298:233-4. MacLean JA. Moscicki R, Bloch KJ. Adverse reactions to heparin. Ann Allergy 1990;65:254-9. Tuneu A, Moreno A. de Moragas JM. Cutaneous reactions secondary to heparin injections. J Am Acad Dematol 1985l.12:1072-7. Kelly RA, Gelfand JA. Pincus SH. Cutaneous necrosis caused by systemically administered heparin. JAIIIA I 98 I ;246: I 582-3. Kelton JG. Sheridan D, Santos A, et al. Hepin-induced thrombocytopenia: laboratory studies. Blood I 988;72:925-30.

98

30.

Bochner BS, Lichtenstein LM. Anaphylaxis. N Engl J Med 19911324:

I

785-90.

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l3l
t32

Horan RF, Schneider LC, Sheffer AL. Allergic skin disorders and mastocytosis. JAMA 1992:268 :2858-68. Intemational Rheumatic Fever Study Group. Allergic rcactions to longterm benzathine penicillin prophylaxis for rheumatic fever. tancet 1991; 337:1308-10.

138.

t33.

Megerian CA, Amold JE, Berger M. Angioedema: 5 yeus' experience, with a review of the disorder's presntation and treatment. Laryngoscope
1992:lO2:256-60. Hedner T, Sarnuelsson O, Lunde H, Lindholm L, Andren L, Witrclm BE. Angieoedema in rclation to treatment with angiotensin converting enzyme inhibitors. BMI 1992:304:941 -6. Thompson T, Frable MA. Drug-induced, life-thrcatening mgioedema rcvisited. Laryngoscope 1993;103:10-2.

134

135. 136,
137
.

MW, deSho RD. Studies of the mechanism of angiotensinconverting enzyme (ACE) inhibitor-associated mgioedema: the effect of an ACE inhibitor on cutaneous responses to bmdykinin, codeine, and histamine. J Allergy Clin Immunol 1990;85:856-8. 139. Verresen L, Waer M, Vanrenterghem Y, Michielsen P. Angiotensin-converting-enzyme inhibitors and anaphylactoid reactions to high-flux membrane dialysis. Lancet 1990;336: I 360-2. 1). Pames EL, Shapiro WB. Anaghy\actoid reactions in hemodirlysis patients eated wftfr me AN9 diIyr. Kidney Int t99I;4O:l l4E-52. 14l. Brunet P, Jaber K, Berland Y, Bz M. Anaphylactoid reactions during hemodialysis and hemofiltration: role of sociating AN69 membrane and mgiotensin l-converting enzyme inhibiton. Am J Kidney Dis 1992;19:
444-7. Kessler DA. Introducing MEDy'atch: a new approach to rcporting medication and device adverse effects and product problems. JAMA 1993; 269:2765-8. 143. Moorc N, Biour M, Paux G, et al. Adverse drug reaction monitoring: doing it the French way. Lancet 1985;2:1056-8. 142

Bielory L, I,ee SS, Holland CL, Jaker M. I-ong-acting ACE inhibitorinduced mgidem. Allergy Pr 1992;,13:85-7. Slater EE, Menill DD, Guess HA, et al. Clinical profrle of angioedema associated with angiotensin converting-enzyme inhibion. JAMA 1988;
260:967-70.

Massachusetts Medical Society

Registry on Continuing Medical Education

To obtain information on continuing medical education courses in the New England area, call between 9:00 a.m. and 12:00 noon, Monday through Friday, (617) 893-4610 or in Massachusetts 1-800-322-2303, ext. 1342.

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MECHANISMS OF DISEASE
FneNxr.rx

H. Ers'rrrN, M.D., Editor

TRANSFORMING GROWTH FACTOR P IN TISSUE FIBROSIS

WayNr A. Bonnn, NI.D.,
aNo NaNcy A. Nonrr,. Pn.D.

f)ROGRESSIVE fibrosis in the kidney, liver, lung, heart, bone marrow, and skin is both a major cause of suffering and death and an important contributor to the cost of health care. All of this is likely to change in the future. Advances in cell and cytokine

I.

remodeling, whether planned (as in embrvogenesis and development) or unplanned (as in carcinogenesis and tissue repair after injurl ).-'' TGF-B is a prototvpical. multifunctional cvtokine that u'as isolated from platelets and characterizedjust over l0 years aeo.i The name is derived from the observation that TGF-B stimulates normal cells to grow in soft asar as though thev had been virally transformed. In mammals the cvtokine has three isoforms, TGF-pl, 2, and 3, rvhose biologic properties are nearIy identical. 'lhe TGF-Bl gene is up-regulated in response to tissue injury, and TGF-Bl is the isoform most implicated in fibrosis. In this review the generic term'|GF-B is used in discussins properties that are probably shared bv ail three isoformsl the specific isoform is mentioned. however. i{-it has becn identified or
used in a particular studv. TGf-p1. svnthesized as a 391-amino-acid precursor molecule, is proteolvticallv cleaved to vield peptide

biology have brought a new understanding of the molecular events underlying tissue fibrosis. It is becoming clear that fibrogenesis is not a unique pathologic process but is due to excesses in the same biologic events involved in normal tissue repair.r A central event in tissue repair is the release of cytokines in response to injury. Several lines of evidence point to transforming grorvth factor B (TGF-B) as a key cytokine that initiates and terminates tissue repair and whose sustained production underlies the development of tissue fibrosis.2 'Ihis review will explore the biology of tissue repair and the properties and actions of 1'GF-B that make it such a potent fibrogenic molecule. Understanding the actions of TGF-p in fibrosis could lead to the development ol clinically
useful antifibrotic asents.

a ll2-amino-acid subunit. Active TGF-Bl is a 25-kd dimeric protein composed of tu'o subunits linked by a disulfide bond. TGF-Bl is secreted in an inactive (latent) form that requires activation before it can exert a biologic eflect. The latent form of TGF-Bl is a high-molecular-n'eight complex in which TGF-Bi is noncovalentlv bound to another
fragments and
dimeric peptide, the latenct'-associated peptide, which precursor. Latent TGF-Bl is sl.ored at the cell surface and in the extracellular matrix and is converted to active TGF-BI at these sites bv an unknown mechanism.B

is formed from cleavage lragments of the TGF-BI

CyroxrNrs rN Trssur IN;unv Tissue is made up of organized groups of cells attached to an extracellular matrix and surrounded by a network of blood vessels. Tissue homeostasis is maintained b1' coordinating cell growth and prolileration with the production and turnover of the extracellular matrix. Cells achieve this coordination by constant signaling to themseives (autocrine activity) and each other (paracrine activity) by means of polypeptides called cytokines (also known as growth factors).3 Cytokines difler from conventional hormones in that they act locall.v, not at a distant site. Ihe action of a cytokine can be positive or negative, depending on the influence of other cvtokines and the physioiogic state

TGF-B binds to at least three membrane proreins, referred to as receptor tvpes I. II, and III, that exist on virtuallv all cells. The tvpe I and tvpe II receptors are transmembrane serine-threonine kinases that interact with one another and facilitate each other's signaling.!)The tvpe III receptor, also called betaglycan, is a membrane-anchored proteoelycan that lias no signaling structure but acts to present TGF-B to the other receptors.r0 The effects of TGF-B on the svnthesis and deposition of extracellular matrix are mediated by the type I receptor. The effects on cell grorvth and prolileration are mediated by the type II receptor. The regulation of TGF'-Bl secretion and action involves complex post-transcriptional events, including messenger RNA (mRNA) stabilization, the assembly and activation

of the latent 'IGl'-pl

complex. and the

of the target cell and the surrounding extracellular matrix. This variability of cytokine action provides
ceils and tissues with a range of potential responses to any stimulus.a Cytokines regulate all aspects of tissue
From the Division of Ncphrology. University of Utah School of Medicine, N. Medical Dr.. Salt Lake City, UT 84132, where reprint requests should
addressed to

50
be

Dr. Border.

Suppo(ed by a grant (DK 43609) from the National Institute of Diabetes and Digestive and Kidney Diseases.

modulation of receptor expression.r I Other cytokines involved rvith TGF-Bl in tissue remodeling alter injurv are platelet-derived growth factor, basic fibroblast grolvth factor, tumor necrosis factor, and interleukin-l.r Each cvtokine has distinctive, synergistic roles in tissue repair. as recent studies involving in vivo gene transfection. gene disruption ("knockout"), and the administration of cytokines have sho\&,n.1!-l:r The dominant eflect of plateletderived grolvth factor is to stimulate cell prolileration and migration; fibrobiast grorvth factor induces the

Vol.

331 No. 19

lv{ECHANIS\,IS OF DISEASII

t2Bl

formation of ner,v blood vessels (angiogenesis); and tumor necrosis factor and interleukin-l promote inflammation, cell migration, and proliferation. TGF-Bl is unique in its widespread actions that enhance the deposition ol extraceliular matrix. It also acts as a potent regulator of repair, coordinating or suppressing the actions of other cytokines.7,l6

resident cells to produce more of itself. This autoinduction amplifies the bioiogic effects of TGF-B I at the injur,v site and mav have a central role in chronic
fibrosis.2r'

Bror,ocrc AcrroNs or TGF-B rN Trssun Rrparn The healing of a dermal rvound, a paradiem lor tissue repair in general, is a coordinated sequence of
biologic events beginning rvith plateiet-induced hemostasis, foilowed by an influx of inflammatory cells and fibroblasts, the formation of nell' extracellular matrix and blood vessels (granulation tissue), and the proliferation of cells to reconstitute the tissue.r TGF-BI plays an important part in each of these events, lvhich can largely be reproduced in normal tissue by the administration of TGF-B1.to'r; Platelets contain high concentrations of TGF-Bl and platelet-derived grorvth lactor that are released into the tissue at the site of injury. Inactive (latent) TGF-Bl, bound locallv to the extracellular matrix, can aiso be activated after injurv. In femtomolar concentrations TGF-Bi is strongly chemotactic for neutrophils, T cells, monocytes, and fibroblasts.r6'18'le \tloving to the site of the injury, these cells become activated as they encounter higher (picomolar) concentrations of TGF-B1. NIonocytes begin secreting fibroblast gro\\'th factor, tumor necrosis factor, and interleukin-1, and fibroblasts increase their synthesis of extracellular-matrix proteins.l6 TGF-Bl also induces both infiltrating cells and

At phl.siologic concentrations, TGF-B1 regulates platelet-derived growth factor (in smooth-muscle cells and fibroblasts), fibroblast growth factor (in endotheIial cells). and tumor necrosis factor and interleukin-1 (in monocvtes) b1'stimulating or inhibiting their production or modulating their actions to both synchronize and control the repair process.2''22 TGF-Bl also inhibits the functioning of T cells and B cells and their production ol tumor necrosis factor and interleukinl.!:rNeonatal mice in which the TGt'-Pl gene has been inactivated live lor several weeks, until the maternal supply of TGF-Bl is gone, and then die ol a svstemic autoimmune-like disease in which tissue concentrations of tumor necrosis factor and interleukin-l are
markedlv elevated.l3
r+

TGF-Bl also modulates the cy-

totoxicity of macrophages by suppressing the production of superoxide and nitric oxide.r6'2+

Whereas TGF-Bl can function as either an agonist or an antagonist o{'cel} prolileration and inflamma-

tion, it consistentlv and potently acts on cells to induce the deposition of extracellular matrix.T The accumulation of matrix in tissues is the chief pathologic feature of fibrotic diseases. Extracellular matrix is a dvnamic superstructure o{' selaggregating macromolecules, including fibronectin, collagens, and proteoglycans, to which cells attach bv means of surface receptors called integrins.2i The matrix surrounding cells is continuall,v degraded by proteases. Figure I illustrates how

Actions of TGF-B

I I I I I

l\4atrix proteins

Proteases

Protease inhibitors

lntegrins

GF-p

Figure 1. Actions of TGF-B in the Healing of lnjured Tissue. Platelets release TGF-B at the site of tissue injury. To repair the damage, TGF-B then induces the deposition of extracellular matrix by simultaneously stimulating the production of new matrix proteins (fibronectin, collagens, and proteoglycans), blocking matrix degradation by decreasing the synthesis of proteases and increasing the synthesis of protease inhibitors, and modulating the expression of cellsurface integrins in a manner that enhances cell-matrix interaction and matrix assembly. TGF-B also induces its own production by cells, thus amplifying its biologic effects.

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TGF-Bl causes the deposition of exrracellular matrix by simultaneoush' stimulating cells to increase severalfold the synthesis ol most matrix proteins, decrease the production of matrix-degrading proteases, increase the production of inhibitors of these proteases. and modulate the expression of integrins in a manner that increases cellular adhesion to the matrix. These comprehensive effects on the extracellular matrix reflect the diverse biologic properties ol TGF-BI and
mav also be part of a negative-feedback loop that normally regulates the expression of TGF-B.26 TGF-B binds to proteoglycans in the matrix or near the cell surface, and such binding may act as a signal to termiis

Table 1. TGF-p in Animal Models of Fibrotic Disorders and in Human Fibrotic Disorders.
ORGAN AND DTSoRDER* REFERENcE

Animal models
Kidney Acute ATS glomerulonephritis Okuda et al.3r Chronic ATS glomerulonephritis Yamamoto et al.r4 Anti-GBM elomerulonephritis Coimbra et al.15 Habu-venomglomerulonephritis BarnesandAbboudr6 Acute and chronic puromycin- Jones et a1.37
induced nephrosis

Diabetic nephropathy

HIV nephropathy
Ureteral obstruction

Angiotensin-induced nephropathy

Yamamoto et al.rE Kopp et al.3e Kaneto el al.$ Kagami et al.ar Czaja et al.a2 Czaja et al.r:

nate the production of TGF-B after tissue repair

complete. ENrreNcuvrBNT oF

Liver
Schistosomiasis Carbon tetrachloride-induced hepatic fibrosis Lung Bleomycin-induced fi brosis

l{ouNo HrnrrNc nv TGF-B l'ibrosis represents a pathologic excess of the normal process of tissue repair. Excessive or sustained production of TGF-B I is a key molecular mediator of tissue fibrosis. The topical application of TGF-B accelerates wound healing.5'r6 In rats, topical or limited intravenous administration of recombinant TGF-Bl
normalizes r,r,ound healing that is impaired by age or In humans, TGF-82 has been used to repair retinal holes. TGF-B therefore has great promise as a therapy lor poorly healing wounds.2B However, the fibrogenic potential of TGF-B is revealed with repeated injections of higher doses. Two weeks of intravenous injections of TGF-Bl produced serious systemic effects in rats, including marked fibrosis in the kidneys and liver and at the injection site.2e Severe cachexia and generalized tissue fibrosis developed in mice given TGF-pl intraperironeallv for
glucocorticoids.2T

Westergren-Thoreson et al..$ Khalil et al.{ Spom and Roberts,2E Tenell et al.:e

Skin

Nomal and impaired wound

hcaling Arteries Vascular restenosis Central nervous system

Wolf et al.;5
Logan et al.6
Brandes et

Scming after injury

Other

Acute and chronic arthritis

Radiation-induced fibrosis Granulomas Postoperative adhesions

al.ll
al.a7

Brcellos-Hoff et
Appleton et al.a8 Williams et al.ae

Human disease Kidney

Glomerulonephritis Diabetic nephropathy Allograft rejection HIV nephropathy

Yoshioka et al.50 Yamamoto et a1.38

Shihab et al.5l

Border el al.s2 Castilla et al..5r Nagy

et al.5o Anscher et al.rr Anscher et al.,3l Broekelmann et al.5s
Deguchi56

Liver Cinhosis
Veno-occlusive disease Lung ldiopathic fibrosis

l0

davs.ro

The clinical counterpart of these results may be the rapid onset of liver and lung fibrosis in patients with
advanced breast cancer who receive high-dose chemo-

therapy in preparation for autologous bone marrow transplantation. In one study, more than 90 percent of the patients whose plasma TGF-B concentrations were 2 SD or more above the normal mean ( l0 ng per

Autoimmune fibrosis
Skin Systemic

sclerosis Keloids Hypenrophic burn scm

syndrome

milliliter) had liver or lung fibrosis.3r The source of the elevated plasma TGF-B concenrations in these patients is unknown. Measuring TGF-B is expensive and technically cumbersome with existing bioassays, but a newly reported bioassav promises to be more sensitive

Eosinophilia-myalgia Aneries
Vascular restenosis Central neryous system lntraocular fibrosis Other Rheumatoid anhritis Nasal polyposis

Kulozik et a1.57 Peltonen et a1.58 Ghahary et al.5e Vuga et al.m

Nikol et al.6r
Connor et
a1.62

Lafyatis et al.6l
Ohno et al.8

and specific.32

TGF-p rN FrsRorrc Drsrasrs lists the animal models and human disorders in rvhich TGF-B has been implicated in the pathogenesis of fibrosis. The involvement of TGF-B in Table

*ATS denoles antith_vmvte serum. GBM glomerula basemenr membrne. and HIV human immunodeliciencv virur

kidney, liver, and lung disease has been the most thoroughly investigated.
Kldney

the kidney make

The intricate architecture and frltratine function of it particularly vulnerable to the con-

of fibrosis. A model of acute glomerulonephritis in rats has provided a unique opportunitv to stud,v the role of TGF-Bl in fibrogenesis, because glomeruli can be rapidly isolated and studied in vitro throughout the course of disease.33 In these rats a single injection of an antithymocyte serum injures glomerular mesangial cells. Extracellular matrix accumulates in the nephritic glomeruli, reaching a peak level in 14 days, after which the glomeruli
sequences

\rol. 331

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\IECHANISMS OF DISEASE

289

return to normal. The temporal pattern o TGF-BI gene expression and the actions ol TGF-BI on the extracellular matrix mirror the pattern of accumulation and removal of the pathologic matrix. For example, nephritic giomeruli contain man), times more TGF-BI mRNA than normal glomeruli, synthesize more TGF-BI protein, and produce much more fibronectin and proteoglycans.:r3 The plasmin protease system) which is thought to have an important role in marix degradation. is strikingly suppressed owing to a decrease in plasminogen activator and a substantial increase in the synthesis of plasminogen activator inhibitor type 1.65 Simultaneously, the synthesis and expression of integrin receptors for fibronectin and collagen increase.oG Platelet-derived
growth factor and fibroblast growth factor also mediate some biologic events, especially cell proliferation, 'I'hree lines o1' evidence point to a causal relation betw'een elevated production of TGF-Bl and the accumulation of extracellular matrix in the model of glomerulonephritis. First, the in r.'ivo events that underlie increased production the accumulation of matrix - inhibition of protease of extracellular-matrix proteins,
have all activity, and increased integrin expression been reproduced by incubation of normal glomeruli or mesangial cells as well as nonrenal cells with TGF-p1.33 65 66 Second, injecting nephritic rats with an antiserum capable of neutralizing TGF-BI or with a proteoglycan that binds TGF-Bl prevented the increased production of matrix proteins by the glomer-

mRNA and TGF-Bl in their glomeruli.38 The stimulus

that triggers the expression of TGF-BI in diabetes may be hyperglycemia or an increase in the activity of the renin-angiotensin system in renal tissue. In humans, good control of blood glucose with insulin and the administration of an angiotensin-convertingenzyme inhibitor retard the development of diabetic nephropathy. In diabetic rats, insulin treatment reduced the increase in the amounts of glomerular TGF-Bl mRNA and the extracellular-matrix proteins known to be induced by TGF-BI.38 In cultured rat
mesangial cells, both increased glucose and increased angiotensin II concentrations induced the production of TGF-BI, which then stimulated the synthesis of fibronectin, collagens, and proteoglycans.ai,T0 The administration of angiotensin II to rats leads to elevated

amounts of glomerular TGF-BI mRNA and type I

collagen mRNA in one week.ar The relevance of these studies to human glomerular diseases has recently been demonstrated. In kidneybiopsy specimens from patients with mesangial prolif-

in these rats.67

uli and blocked the accumulation of matrix.68'6s Third, in r.'ivo transfection of the 7GF-B1 gene into normal rat kidneys led to increased production of TGF-B1 in glomeruli and the rapid development of glomerulosclerosis.r2 Identical transfection of the gene for plateIet-derived growth factor markedly stimulated the proliferation of glomerular cells, with an associated slight increase in extracellular matrix. The dillerences in the biologic activities of TGF-Bl and plateletderived growth factor, revealed in the gene-transfection experiments, are similar to earlier findings in which these cvtokines were delivered in vivo by osmot-

erative glomerulonephritis, a disease histologically similar to the model of glomerulonephritis described above, glomerular immunostaining for TGF-Bl was intense, and the intensity correlated closely with the amount of mesangial matrix.5o In the glomeruli of humans with diabetic nephropathy. TGF-Bl protein and matrix proteins induced by TGF-BI were increased, as they were in the glomeruli of diabetic rats.38 Glomeruli from patients with renal diseases in which fibrosis does not occur and from patients with no renal diseases were negative for TGF-Bl. Recently, elevated amounts of TGF-BI protein were found in fibrotic kidneys from patients with human immunodeficiency virus-associated nephropathy and patients with chronic allograft rejection.sr'52
Liver

mRNA for type I collagen, the predominant matrix component in injured liver, is increased in cultured rat hepatocytes incubated with TGF-Bl.a2 In liver-biopsy specimens from patients with chronic liver disease, the amount of TGF-BI mRNA correlated closely with that of type I collagen mRNA.s3 TGF-Bl mRNA concentrations in the liver are mirrored by serum concentrations of peptide fragments of type III collagen and the histologic activitv of the liver disease. In biopsy specimens from patients with chronic liver disease, TGF-Bl protein was detected by immunostaining in areas of fibrosis, but not in areas of inactive disease or in normal liver.5a As previously discussed, elevated
plasma TGF-B concentrations are highly predictive of the development of hepatic fibrosis (veno-occlusive disease) in the recipients of bone marrotv transplants.3r

ic minipumps.r5
An exciting leature of the glornerulonephritis model is the recent discovery that animals receir,'ing a second

injection of the antiserum have persistent elevations of glomerular TGF-Bl mRNA and TGF-Bl itself.3a Myofibroblast-like cells appear in the tubulointerstitium of the kidnev and strongly express TGF-Bl. The persistent production of T'GF-Bl in the kidney leads within weeks to glomerulosclerosis and tubulointerstitial fibrosis, a picture closely resembling the histologic
findings in humans with chronic glomerulonephritis.
Elevated concentrations of I'GF-Bl may also be imin the pathogenesis of glomerulosclerosis in diabetic nephropathy. Rats made diabetic with streptozocin, a drus that causes insulin deficiency, had

portant

progressively increasing concentrations

of

TGF-Bl

In two models of hepatic fibrogenesis, one induced by the administration of carbon tetrachloride and the other by infection with schistosoma, increased concentrations of TGF-Bl mRNA and TGF-p1 in perisinu-

Vol. 331

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MECHANISMS OF DISEASE

289

return to normal. The temporal pattern o1 TGF-PI gene expression and the actions of TGF-BI on the extracellular matrix mirror the pattern ol accumulation and removal of the pathologic matrix. For example, nephritic glomeruli contain many times more TGF-BI mRNA than normal glomeruli, synthesize more TGF-BI protein, and produce much more fibronectin and proteoglycans.33 The plasmin protease system, rvhich is thought to have an important role in matrix degradation, is strikingly suppressed ou'ing to a decrease in plasminogen activator and a substantial increase in the synthesis of plasminogen activator inhibitor type l.r Simultaneously, the synthesis and expression of integrin receptors for fibronectin and collagen increase.66 Platelet-derived growth factor and fibroblast growth factor also mediate some biologic events, especially cell proliferation,

mRNA and TGF-Bl in their glomeruli.38 The stimulus that triggers the exprcssion ol TGF-Bl in diabetes may be hyperglycemia or an increase in the activity of the renin-angiotensin system in renal tissue. In humans, good control of blood glucose w'ith insulin and the administration of an angiotensin-convertingenzyme inhibitor retard the development of diabetic

nephropathy. In diabetic rats, insulin treatment reduced the increase in the amounts of glomerular TGF-Bl mRNA and the extracellular-matrix proteins known to be induced by TGF-B1.38 In cultured rat
mesangial cells, both increased glucose and increased angiotensin II concentrations induced the production of TGF-BI, which then stimulated the synthesis of bronectin, collagens, and proteoglycans.ar'70 The administration of angiotensin II to rats ieads to elevated

amounts

of glomerular TGF-BI mRNA and type I

in these rats.67 Three lines o1' evidence point to a causal relation betw'een elevated production of TGF-Bl and the accumulation of extracellular matrix in the model of glomerulonephritis. First, the in vivo events that underlie increased production the accumulation of matrix - inhibition of protease of extracellular-matrix proteins, have all activity, and increased integrin expression - glomeruli been reproduced by incubation of normal or mesangial cells as well as nonrenal cells with TGF-p1.33'65'66 Second, injecting nephritic rats with an antiserum capable of neutralizing TGF-BI or with a proteoglycan that binds TGF-Bl prevented the increased production of matrix proteins by the glomeruli and blocked the accumulation of matrix.68'6s Third, in vivo transfection of the TGF-BI gene into normal rat kidneys led to increased production of TGF-Bl in glomeruli and the rapid development of glomerulosclerosis.r2 Identical transfection of the gene for plate-

erative glomerulonephritis, a disease histologically similar to the model of glomerulonephritis described above, glomerular immunostaining for TGF-Bl was intense, and the intensity correlated closely with the amount of mesangial matrix.5o In the glomeruli of
humans with diabetic nephropathy, TGF-Bl protein and matrix proteins induced by TGF-BI were increased, as they were in the glomeruli of diabetic rats.38 Glomeruli from patients with renal diseases in which fibrosis does not occur and from patients with

collagen mRNA in one week.al The relevance of these studies to human glomerular diseases has recently been demonstrated. In kidneybiopsy specimens from patients with mesangial proli

TGF-BI. Recently, elevated amounts of TGF-Bl protein were found in fibrotic kidneys from patients with human immunodeficiency virus-associated nephropathy and patients
no renal diseases were negative for

with chronic allograft rejection.5l,52

Liver

let-derived growth factor markedly stimulated the proliferation of glomerular cells, with an associated slight increase in extracellular matrix. The differences in the biologic activities of TGF-BI and plateletderived growth factor, revealed in the gene-transfection experiments, are similar to earlier findings in
which these cvtokines were delivered in vivo by osmot-

mRNA for type I collagen, the predominant matrix component in injured liver, is increased in cultured rat hepatocytes incubated with TGF-Bl.a2 In liver-biopsy specimens from patients with chronic liver disease, the amount of TGF-BI mRNA correlated closely with that of type I collagen mRNA.s3 TGF-Bl mRNA concentrations in the liver are mirrored by serum concentrations of peptide fragments of type III collagen and the histologic activity of the liver disease. In biopsy specimens from patients with chronic liver disease, TGF-pl protein was detected by immunostaining in areas of fibrosis, but not in areas of inactive disease or in normal liver.5a As previously discussed, elevated
plasma TGF-B concentrations are highly predictive of the development of hepatic fibrosis (veno-occlusive disease) in the recipients of bone marrow transplants.3r

ic minipumps.r5
An exciting feature of the glornerulonephritis model is the recent discovery that animals receiving a second injection of the antiserum have persistent elevations

of glomerular TGF-B1 mRNA and TGF-Bl itself.3+ Myofibroblast-like cells appear in the tubulointerstitium of the kidney and stronely express TGF-B1. The persistent production of TGF-Bl in the kidney leads within weeks to glomerulosclerosis and rubulointerstitial fibrosis, a picture closely resembling the histologic findings in humans with chronic glomerulonephritis. Elevated concentrations of 1'GF-Bl may also be important in the pathogenesis of glomerulosclerosis in diabetic nephropathy. Rats made diabetic with streptozocin, a drug that causes insulin deficiency, had progressively increasing concentrations of TGF-Bl

In two models of hepatic fibrogenesis, one induced by the administration f carbon tetrachloride and the other by infection with schistosoma, increased concentrations of TGF-BI mRNA and TGF-Bl in perisinu-

290

HE NE\\' ENGL-{-\-D JOURN.{L OF \IEDICINE

a

\or'.

J0.

1994

soidal cells paralleled the increased expression of

collagen sene and increased collagen svnthesis.+2
Lung

10 times more'fGF-Bl mRNA than similar cells obtained from normal subjects or patients with asthma.56 Fibrotic Disorders of Other Organs

In rats u.ith pulmonary fibrosis induced b.v the administration of bieomvcin. total lung'|GF-Bl content \.vas several times higher than in normai rats. 'Ihe increased production ol TGF-Bl preceded the synthesis of collagens, fibronectin, and proteoglvcans.l:' The principal cellular source of TGF-Bl lvas alveolar mac-

'IGf--Bl and collagen are increased in tissue sections from patients with svstemic sclerosis.-'7 keloids,58 and hypertrophic scars from burns.5lr TGF-Bi has been implicated in the frbrosis associated rvith eosinophilia.6" Increased amounts of TGI--Bl are also found in the arteries of rats at the sites ol balloon angioplasty and in vascular lesions associated lvith restenosis in

rophages, in which increased production of TGF-B1 couid not be suppressed by high-dose corticosteroid treatment, a possible explanation for the ineffectiveness

humat)s,'*:il

ol this treatment in patients rvith idiopathic pul-

In humans w'ith idiopathic pulmonary fibrosis, TGF-Bl is increased in alveolar walls at the sites at
which extracellular matrix has accumulated.ri Bronchoalveolar cells obtained by lavage from patients with autoimmune diseases and lung fibrosis contained
lnjury

monary fibrosis.a+

OvrnpnooucrroN or TGF-B rN Frsnosrs In both animals and humans, acute. limited irlury is accompanied br only a transient increase in TGFBl, and fibrosis does not occur. \\'ith repeated injury, the increase in TGF-Bl production is sustained. leading to the progressir.'e deposition of extracellular matrix and tissue brosis.'ra The manner in rvhich TGFHealed Tissue

!.-..
_

Protease inhibitor Collagens

t
-/'/'Proteogt'cans
...,1

lq

I
a
Fibronectin

Repair

Protease

Repeated lnjury?

'd*tr

{5

--;_-

Fibrotic Tissue

"ry
Repair
Figure 2. Overproduction of TGF-P in Fibrogenesis. ln normal tissue repair, the production of TGF-p and extracellular matrix is terminated by unknown mechanisms as the damaged tissue. heals. ln patients with chronic disease, repeated tissue injury, a de{ect in TGF-B regulation, or both lead to the continuous production oi TGF-B and extracellular matrix, resulting in tissue fibrosis.

Vol. 331 No.

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\IEC:HANIS\,{S OF DISEASE

l29l

Bl production is normally terminated is unknown. Repeated injurv. with continued autoinduction of TGI'Bl, overrides the normal termination signals. creating a chronic, vicious circle of TGF-Bl overproduction, as shorvn in l'igure 2.
TGF-B ANracoNrsrs As ANTrFrBRorrc AcrNrs Injecting an antiserum capable of neutralizing the activitv of TGF-Bl inhibited its action in the kidner',';8 skin,Tr lung.72 brain,nt; joint,73 and arterial lvall.+5 In each case excessive amounts of extracellular matrix were not deposited, and tissue repair was normal. In nephritic rats, the injection of the antiserum dramaticallv reduced the synthesis ol matrix proteins and the dcposition of plasminogen activator inhibitor t1'pe I in
the glomeruli and blocked the accumulation of mesan-

offers a target for the development of new therapeutic agents for the many frbrotic conditions associated with

the overproduction of TGF-B.

\\'e are indcbted to Drs. \Iarkus Ketteler and Douglas Brees lor their usefl comments on the manuscript, and to \Ir. Bruce Goudelock lor preparinq the fisures.

RrrrneNcrs
l.
2. 3. 4. 5. 6.

gial matrix. The collagcn content of dermal rvounds

treated with anti-TGF-Bl rvas substantially reduced, but their tensile strength u'as normal and scar formation w-as minimal. Anti-TGF-Bl reduced fibrous scar tissue and inflammation at the site of brain injur1,.

lM, Snydeman R. eds. lnflammation: basic principles nd clinical conelates. 2nd ed. New York: Raven Press, 1992:809-19. Border WA, Ruoslahti E. Transfoming growth factor-B in disease: the dark side of tissue repair. J Clin lnvest 1992;90:l-7. l0 yean later, Ann Intern Spom MB. Roberts AB. Autocrine secretion Med I992:l l7:408-14. Nathan C, Spom M. Cytokines in context. J Cell Biol 199lll 13:981-6. Roberts AB. Spom MB. Physiological actions and clinical applications of transfoming growth factor-B (TGF-B). Growth Factors 1993:8:l-9. Idem. Diflerenlial expression of the TGF-B isofoms in embryogenesis suggests specific roles in developing and adult tissues. Mol Reprod Dev
Davidson JM. Wound repair. In: Gallin JI, Goldstein
I

992:32:9 I -8.

7.

lden. The transforming growth factors-B. In: Spom MB, Roberts AB, eds. Peptide growth factors and their receptors. Vol. 95 of Handbook

of experimental pharmacology. New York: Springer-Verlag,

8.

In arthritic joints, anti-TGl'-Bl decreased inflammation and bone and synovial destruction. Finally, in rats with carotid-arter,v injurv, the injection of antiTGF-Bl suppressed the accumulation o1'matrix that underlies the development of intimal hvperplasia and restenosis. These consistent therapeutic successcs make clear the enormous clinical potential associated with decreasing the action of TGF-Bl in vivo.
CoNcrusroNs
As the complexities of TGF-B regulation are unraveled, a number of possible therapeutic approaches for decreasing the action of the cvtokine have arisen that may be more suitable than antibodies for use in humans.25 For example, soluble TGF-B tvpe III receptors inhibit the binding of TGF-B to its membrane receptors and block its action; soluble type I and II receptors, rvhich have higher affinities lor TGF-B, may be even more potent in blocking its action.!'r0 Similarl,v, the latenc-v-associated peptide that is released

9.

10.

ll.
t2.

1990:41972. Flaumenhaft R, Abe M. Mignatti P, Rifkin DB. Basic fibroblast growth factor-induced activtion of latent transfoming growth factor B in endothelial cells: regulation of plasminogen activator activity. J Cell Biol 1992; I l8:901-9. Ebner R, Chen R-H, Lawler S, Zioncheck T, Derynck R. Detemination of type I receptor specificity by the type II receptors for TGF-p or activin. Sciencc 1993:262:90O-2. Lopez-Casillas F, Payne HM, Andres JL, Massague J. Betaglycan can act as a dual modulator of TGF-B access to signaling receptors: mapping of ligand binding and GAG attachment sites. J Cell Biol 1994:124:557-68. Kim S-J, Puk K, Koeller D. et al. Post-transcriptional regulation of the human transforming growth factor-pl gene. J Biol Chem1992.267:137027.

Isaka Y, Fujiwra Y. Ueda N, Kaneda Y, Kamada T. Imai E. Glomerulosclerosis induced by in vivo transfection of transfoming growth fctor-B or plateletderived growth factor gene into the rat kidney. J Clin Invest 199392:2597 -6Ol . 13. Kulkami AB, Huh C-G, Becker D, et al. Transfoming growth factor pr null mutation in mice causes excessive inflammatory response and edy death. Pr Natl Acad Sci U S A 1993:90:770-4. 14. Shull MM. Omsby I, Kier AB, et al. Targeted disruption of the mouse transfoming growth factor-pl gene results in multifocal inflammatory disease. Nature 1992:359:693-9.
15.

Ogawa

Y, Ksander GA, Pratt BM, et al. Differences in the biological

16.

in the process of TGF-B

activation mav

be
t7

used to inhibit the action of TGF-B. Several members of the superfamilv of retinoid-steroid receptors mav act as post-transcriptional regulators ficr gcnes of different isoforms of 'tGF-p.? Manipulation of this regulation may lead to decreased production of TGFp. Using TGF'-B antisense oligonucleotides is another possibilitv. A low dietary intake of protein decreased the expression of TGF-Bl in rats rl,ith acute glomerulonephritis.Tr This {inding mav help explain the beneficial ellect of lowlprotein diets in patients rvith various kidney diseases. Finally, some proteoglycans bind TGF-B.26 The injection of one of these proteoglvcans into nephritic rats \\,as as elfective as the injection
o1'

activities of transfoming growth factor-p and platelet-derived growth factor in riyo. Growth Factors l99l;5:57-68. Roberts AB, Joyce ME, Bolander ME, Spom MB, Transforming growth factor-beta (TGF-): a multifunctional effector of both soft and hard tissue regeneration. In: Westemark B, Betsholtz C, Hkfelt B, eds. Growth factors in health and disease: basic and clinical aspects. Amsterdam: Excerpta

Medica.1990:89-101. Roberts AB, Spom MB, Assoian RK, et al. Translbming growth factor type B: rapid induction of fibrosis and angiogenesis in yiyo and stimulation of collagen tbmation in \'ro. Pr Natl Acad Sci U S A 1986:83:4t6771. t8. Wahl SM, Hunt DA. Wakefield LM. et al. Transforming growth factor type B induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci U S A 1987:84:5788-92. l9 Postlethwaite AE, Keski-Oja J. Moses HL. Kang AH. Stimulation of the chemotactic migration of human libroblasts by transfoming growth factor B. J Exp Med 1987:165:251-6. 20 Kim S-J, Angel P, Lafyatis R. et al. Autoinduction oftransforming growth factor Bl is mediated by the AP-l complex. Mol Cell Biot 1990;10:14927.

2l

anti-TGF-Bl in inhibiting glomerular accumulation of matrix.6s Whetirer any of these approaches will yield an efctive antifibrotic drug is unknown. Nevertheless, un-

22

derstanding that TGI--B is a key Ictor in fibrogenesis

Battegay EJ, Raines EVy', Seifert RA, Bowen-Pope DF, Ross R. TGF-B induces biomodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop. Cell 1990:63:515-24. Pepper MS, Belin D. Montesano R. Orci L, Vassalli J-D. Transfoming growth tctor-beta I modulates basic frbroblast growth factor-induced proteolytic and angiogenic propenies of endothelial cells in vitro. J Cell Biol 1990:l 1 l:743-55. Brandes ME, Allen JB. Ogawa Y, Wahl SM. Transfoming growth factor pl suppresses acute and chronic anhritis in experimental animals. J Clin Invest 1991;87:l l0E-13.

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Vodovotz Y, Bogdan C, Paik J, Xie Q-W, Nathan C. Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor p. J Exp Med 1993;178:605-13. 25. Ruoslahti E. Integrins. J Clin Invest l99ll87:l-5. 26. Ruoslahti E, Yamaguchi Y. Proteoglycans as modulatoB of growth factor activiries. cell 1991 :64:867-9. 27. Beck LS, DeGuzman L. Lee WP. Xu Y, Siegel MW, Amento EP. One systemic administration of transfoming growth factor-B I reverses age- or glucoconicoid-impaired wound healing. J Clin Invest 19931'92:2841-9. 28 Sporn MB, Roberts AB. A major advance in the use of growth factors ro enhance wound healing. J Clin Invest 19931'92:2565-6. 29 Tenell TG, Working PK, Chow CP, Green JD. Pathology of recombinant human transfoming growth factor-Bl in rats and rabbits. Int Rev Exp Pathol
30,

Williams RS, Rossi AM, Chegini N, Schultz G. Effect of lransforming

growth factor p on postoperative adhesion fomration and intact Peritoneum. J Surg Res 1992;52:65-70. Yoshioka K. Takemura T. Murakami K. et al. Transfoming growth factorB protein and mRNA in glomeruli in normal and diseased human kidneys. Lab Invest 1993:68:154-63. Shihab F, Yamamoto T. Nast C. et al. Acute and chronic allograft rejecrion in the human kidney corelate with the expression ofTGF-B and extracellular matrix proteins. J Am Soc Nephrol 1993i4:671. abstract. Border W. Yamamoto T. Noble N, Gold L, Nast C, Cohen A. HlV-associated nephropathy is linked to TGF-B and matrix protein expression in human kidney. J Am Soc Nephrol 1993;4:675. abstract. Castilla A, Prieto J, Fausto N. Transfoming growth factors 1 and a in chronic liver disease: effects of interferon alfa therapy. N Engl J Med

50.

5l

52

53.

ll

199334:43-61. Zugmaier G. Paik S, Wilding G, et al. Transforming growth factor Bl induces cachexia and systemic fibrosis without an antitumor effect in nude mice. Cancer Res l99l:51:3590-4. Anscher MS, Peters WP, Reisenbichler H, Petros WP, Jirtle RL, Transforming growth factor B as a predictor of liver and lung fibrosis after autologous bone marrow iransplantation for advanced breast cancer. N Engl J Med
1993:328:1592-8. Abe M, Harpel JG, Merz CN, Nunes I. Loskutoff DJ, Rifkin DB. An assay for transforming growth factor-B using cells ansfected with a plasminogen

I99l:324:933-40.
54. 55. Nagy P, SchaffZ, Lapis K. Immunohistochemical detection oftransforming growth factor-Bl in fibrotic Iiver diseases. Hepatology l99l:'14:269-73. Broekelmann TJ. Limper AH, Colby TV, McDonald JA. Transfoming growth factor Br is present at sites of extracellular matrix gene expression in human pulmonary'librosis. Proc Natl Acad Sci U S A 199l:88:6642-6. Deguchi Y, Spontneous increase of transforming growth factor B production by bronchoalveolar mononucletr cells of patients with systemic autoimmune diseases affecting the lung. Ann Rheum Dis 1992:'51:362-5. Kulozik M, Hogg A, Lankat-Buttgereit B, Krieg T. Co-localization of transforming growth factor B2 with a I (l) procollagen mRNA in tissue sections of patients with systemic sclerosis. J Clin lnvest 199O86:917-22. Peltonen J, Hsiao LL, Jaakkola S, et al. Activation of collagen gene expression in keloids: co-localization of type I and VI collagen and transforming Srowth factor-Bl mRNA. J lnvest Dematol l99l;97:2.10-8. Ghahary A, Shen YJ, Scon PG, Gong Y, Tredget EE. Enhanced expression of mRNA for transforming growth tctor-p, type I and type III procollagen in human post-bum hypertrophic scar tissues. J Lab Clin Med 1993:122: 465-73. Varga J, Uitto J, Jimenez SA. The cause and pathogenesis of the eosinophilia-myalgia syndrome. Ann Intem Med 1992:l l6:140-7. Nikol S, Isner JM, Pickering JG, Kearney M. Leclerc G. Weir L. Expression of transforming growth factor-p I is increased in human vascular restenosis lesions. J Clin Invest 1992:,90:1582-92. Connor TB Jr, Roberts AB. Sporn MB, et al. Corelation of fibrosis and Iransfoming growth factor-p type 2 levels in the eye. J Clin Invest 1989;83:

56

32

activator inhibitor33

promoter-luciferase construct. Anal Biochem 1994;

57.

216:276-84. Okuda S. Languino LR, Ruoslahti E, Border WA. Elevated expression of transforming growth factor-B and proteoglycn production in experimental glomerulonephritis: possible role in expansion ofthe mesangial extracellular

58

34

matrix. J Clin Invest 1990;86:453-62. [Eratum. J Clin Invest 1990186: 2t7s.l Ymamoto T, Noble NA. Miller DE, Border WA. Sustained expression of TGF-pl underlies development of progressive kidney fibrosis. Kidney Int
1994:45:916-27. Coimbra T, Wiggins R. Noh JW. Menitt S, Phan SH. Transfoming growth factor-B production in anti-glonrerultr basement membrane disease in the rabbit. Am J Pathol l99l:138:223-34. Bames JL. Abboud HE. Temporal expression of autocrine growth factors conesponds to morphological features of mesangial proliferation in Habu snake venom-induced glomerulonephritis. Am J Pathol 1993;143:136676. Jones CL, Buch S, Post M, Mcculloch L. Liu E, Eddy AA. Pathogenesis of interstitial f,brosis in chronic purine aminonucleoside nephrosis. Kidney Int

59

35

60.
61.

36

62

37

t66t-6.
63

l99l:40:1020-3
38

l.
64

39

40

4l

Yamamoto T, Nakamura T, Noble NA. Ruoslahti E, Border WA. Expression of transforming growth factor is elevated in human and experimental diabetic nephropathy. Proc Natl Acad Sci U S A 1993:90:1814-8. Kopp JB. Klotman ME. Adler SH, et al. Progressive glomerulosclerosis and enhanced renal accumulation of basement membrane components in mice transgenic for human immunodeficiency virus type I genes. Proc Natl Acad Sci U S A 1992:89:1577-8t. Kaneto H, Monissey J. Klahr S. Increased expression of TGF-BI mRNA in the obstructed kidney of rats with unilateral ureteral ligation. Kidney lnt 1993.44:313-21. Kagami S, Border WA. Miller DE. Noble NA. Angiotensin II stimulates extracellular matrix protein synthesis through induclion of lransfoming growth factor-p expression in rat glomerular mesangial cells. J Clin Invest

Lafyatis R, Thompson NL, Remmers EF. et al, Translbrming growth factorp production by synovial tissues from rheumatoid patients and streptococcal cell wall arthritic rats: sttrdies on secretion by synovial fibroblast-like cells and immunohistologic localization. J Immunol 19891143:1 142-8. Ohno I, la RG. Flanders KC, et al. Eosinophils in chronically inflamed human upper airuay tissues express transforming growth factor Bl gene (TFGpl). J CIin lnvest 1992:89:1662-8.

65.

Tommka S. Border WA, Mrshall BC, Noble NA. Glomerular matrix

accumulation is linked to inhibition of the plasmin protease system. Kidney lnt 1992:,42:1462-9. Kagami S, Border WA, Ruoslahti E, Noble NA. Coordinated expression of Bl integrins and transfoming growth factor-p-induced matrix proteins in glomerulonephritis. Lab lnvest t993;69:68-76. Floege J, Eng E, Young BA, et al. lnfusion of platelet-derived growth factor or basic libroblast growth factor induces selective glomerular mesangial cell proliferation and matrix accumulation in rats. J Clin lnvest 1993:92:295262. Border WA, Okuda S, Languino LR, Spom MB, Ruoslahti E. Suppression

67

199493:2431-7.
42 Czaja MJ, WeinerFR, Flanders KC, et al. In vitro and in vivo association of ransfoming growth factor-pl with hepatic librosis. J Cell Biol 1989;108: 2471 -82. Westergren-Thorsson G. Hemns J, Smstrand B, Oldberg . Heinegrd D, Malmstrm A. Altered expression of small proteoglycans, collagen, and transfoming growth factor-Bl in developing bleomycin-induced pulmonuy fibrosis in rats. J Clin lnvest 1993:92:632-7. Khalil N, Whitman C, Zuo L, Danielpour D, Greenberg A. Regulation of alveolar macrophage transfoming growth factor-B secretion by corticosteroids in bleomycin-induced pulmonuy inflmmation in the rat. J Clin Invest 1993t92:1812-8. Wolf YG, Rasmussen LM, Ruoslahti E. Antibodies against transfoming growth factor-Bl suppress intimal hyperplasia in a rat model. J Clin Invest 1994:93:1172-8. Logan A, Berry M. Gotzalez AM, Frautschy SA, Spom MB, Baird A. Eflcts of transfoming growth factor Bl on sca production in the injured central nervous system of the rat. Eur J Neurosci 1994;6:355-63. Barcellos-Hoff MH, Derynck R. Tsang ML-S, Weatherbee JA. Transfoming growth factor-B activation in ifiadiated murine mammary gland. J Clin lnvest 1994;93:892-9. Appleton I, Tomlinson A, Colville-Nash PR, Willoughby DA. Temporal and spatial immunolalization of cytokines in murine chronic granulomatous tissue: implications for their role in tissue development and repair processes. Lab Invest 1993169:405-14. 68

43

experimental glomerulonephritis by antiserum against transfoming growth factor Bl. Nature 1990:346:371-4. 69, Border WA. Noble NA. Yamamoto T, et al. Natural inhibitor of transfoming growth factor-B protects against scaning in experimental kidney disease.

of

45

Nature 1992:360:361-4. 70. Ziyadeh FN, Sharma K, Ericksen M, Wolf G. Stimulation of collagen gene expression and protein synthesis in murine mesangial cells by high glucose is mediated by autocrine activation of transforming growth factor-p. J Clin Invest 1994:93:536-42. 7t. Shah M, Foreman DM, Ferguson M\vV. Control of scaring in adult wounds by neutralising antibody to transforming growth factor B. Lancet 1992;
339:213-4.

46

73

Giri SN, Hyde DM, Hollinger MA, Effect of antibody to transforming growth factor p on bleomycin induced accumulation of lung collagen in mice. Thorax 1993:48:959-66. Vr'ahl SM, Allen JB, Costa GL, Wong HL, Dasch JR. Reversal of acute and chronic synovial inflammation by anti-transfoming growth factor p. J Exp
Med 1993:177:225-30. Okuda S, Nakamura T, Yamamoto T, Ruoslahti E. Border WA. Dietary
protein restriction rapidly reduces transfoming growth factor Bl expression in experimental glomerulonephritis. Proc Natl Acad Sci U S A l99l;88:

48.

9765-9.

\rol.

3l'|l \o.

19

CASE RECORDS

OF]'HE \IASS.ACHUSETTS GE\ER,\L HOSPITAI,

293

CASE RECORDS
OF THE

the chest and both ankles and feet n'ere normal. A computed tomographic (C'l') scan of the abdomen
and pelvis showed no abnormalitv except a small cyst

MASSACHUSETTS GENERAL HOSPITAL

**0"

:'.:Ti::::::l
.f

*':*.'

"'

at the upper pole of the left kidne,v. The patient's customary medications were discontinued. The temperature rose to 40'C on the second hospital dav. Marked srvelling of the scalp der.eloped, with tender lumps in the temporal and occipital areas bilateralll,. Ampicillin was given by vein for two days, then ceftriaxone was substituted and continued for one lveek. On the fifth hospital day prednisone (60 mg dailv) lvas begun, and the dose rvas later reduced to 40 mg daily for a total course of l0 davs. Fever rvith the
temperature as high as 3B.5oC persisted during the

Roeanr E. Scur-lr'. Nl.D., Editor

EucrxE

administration of prednisone, and pain persisted in

the head and lorver lees, althoueh the patient was able to rvalk rvith the aid of a stationar)' rvalker. The scalp swelling and tender lumps resolved during treatment with prednisone, and the patient's appetite improved. On the l Tth hospital da1' she was transferred to this

\I,ux, trI.f)..

,lssorlale Editor
,{ssoczale

Wrt-rtelt F. NIcNrEr-v. \,I.D..

Editor

Berrv U. \lc\art-v.

Assistant Editor

CASE 40-1994

hospital. wooded area. She had had a dry' cough for many years. She had not smoked tobacco for more than 30 years and ingested little alcohol. Nlammograms obtained nine months earlier were normal. Her medications at the time of the transfer to this hospital were prednisone (40 mg dailv) and meperidine (75 mg everv three hours as required). There was no history ol visual problems, claudication of the jaw, lymphadenopath,v, dvsphagia, cough, sputum, wheezing, hemoptysis, dvspnea, abdominal pain, nausea, r.omit-

The patient was widorved and lived alone in

PnrsrNrarroN oF

CASE

A 77-vear-old rvoman was admitted to the hospital because of pain in the head and legs. fever, and
sweats.

The patient had been r'vell until four lveeks earlier, ivhen she began to experience pain in the neck that extended over the lon er third of the left side of the head and lelt mandible. The next morning she had an acute onset of "burning" in the lorver legs, as il thev rvere "on fire." That night she changed her nightgolvn se',.eral times because of sr.l,eats. After several days of such symptoms the patient consulted a dentist; radiographs w'ere reported to sho'w'a dental abscess, and cephalexin vr,as prescribed, rvithout improvement in the pain. ThreeTveeks before admission the patient's physician prescribed indomcthacin, rvithout improvement. Sixteen da;'s before admission she entered another hospital. She had a history ol hypertension of'more than l0 years' duration, which was manased with spironolactone-hvdrochlorothiazide; she also used lovastatin because of hvperlipidemia. She had lost 1.5 kg in weight during the preceding rveek. The temperature !\ras 37.3"C. the pulse rvas 104, and the respirations rvere 20. The blood pressure was 145175 mm Hg. Phvsical examination rvas negative; no rash, l1'mphadenopathy, or temporal-arterv tenderness rvas detected. The blood chemical findings were normal. Th1'roid-function tests; tests lor antinuclear antibodies, rheumatoid factor, hepatitis A antibody, hepatitis B surface antigen and antibodr', hepatitis B core antibodl', and hepatitis C antibody; and a serologic test for Borrelia burgdorri were negati\.e. The results of other laboratory studies are shorvn in Table L Six blood cultures u'ere sterile. A cardiac ultrasonographic examination !as negative. Radiographs o[

ing, diarrhea, dvsuria, drug allergies, swelling of the extremities, rash, recent or previous arthritis, Ra,vnaud's phenomenon, tral'el, exposure to farm or wild animals. risk factors for infection u'ith the human immunodeficiencv virus (HI\r), exposure to tuberculosis, recent insect bites, or ingestion of unusual or unpasteurized foods. The temperature lvas 3B.3oC, the pulse rvas 96, and the respirations were 22. The blood pressure lvas 140/80 mm Hg. Ph,vsical examination lvas negative. No rash, cutaneous signs of sepsis or vasculitis, or lymphadenopathy was found. The head and neck w-ere normal; no scalp or temporal-artery tenderness or lumps were detected. The lungs, heart. breasts, and abdomen were normal. No articular abnormalitv or muscle tenderTable 1. Laboratory Values at the Other Hospital.
VARIBLI VALUE

Hemoglobin (8/dl) Erythrocyte sedimentation rate (mrdhr) White-cell count (per mmr)
Platelet count (per mmr) Alkaline phosphatase Aspanate aminotransferase 7-Glutamyltransferase

t2.6

l2l,

then 94

29,700-42.700

up to 970.000
Increased

lncreased lncreased

129-1

THE \E\\- E\GLA\D.JOL R\AI, OF }IEDICI\E

Table 2. Hematologic Values on Admission.
V{RIABLE VALUE

\ov.

10. 199{

Hematocrit (7o)
Mean corpuscular volume (pmr)

3t .7 92 90 22.500
78

Erythryte sedimentation rate (mtrhr) White-cell count (per mmr) Differential count (7c)
Neutrophils Lymphocytes Monocytes Eosinophils Platelet count (per mm3)

results of serum immunoelectrophoresis and agarosegel electrophoresis were normal. Prednisone and meperidine lvere discontinued, and acetaminophen \!-as given. The patient continued to have intermittent pain in the lower legs but was able to rvalk n-ith a stationarv walker. The temperature rose dailv to the ranse of 38.9 to 39.1"C. The blood

pressure did not exceed 140/80 mm Hg. Repeated

6
9
7

680.000

phvsical examinations were unchanged. Blood cultures $'ere sterile except that one flask grew a coasulase-negatx,e Staphllococcus aureus; a urine culture
vielded moderate enterococci. A urinalvsis was negative; the sediment contained I red cell and 4 white cells per high-porver field. On the sixth hospital day microscopical examination of a biops-v specimen from the left temporal arterv sho$,ed intimal fibrosis and Ibcal medial calcification. n,ithout evidence of arteriTable 4. Results of LiverFunction Tests.
Hosprral DAY
SERUM

ness rvas found. Neurologic examination las grossly negative. The urine \4'as normal except that the sediment contained B white cells and moderate numbers of bacteria per high-pou,er field. 'fhe hematologic and

blood chemical findings are presented in Tables 2 and 3. Radiographs of the chest, paranasal sinuses, and mandibles lvere normal. Skin tests with tuberculin (purified protein derivative IPPD], 5 TU) and candida antigen were negative; a test with mumps antigen \{,as positive. Tests for antineutrophil cvtoplasmic antibodies, hepatitis A antibodv, hepatitis B surface antigen and antibod)., and hepatitis C antibodr.u'ere nesative. Nlicroscopical examination of an aspirated specimen of bone marrow showed normal cellularity with relative mveloid hvperplasia; iron stores were abundant; no malignant-tumor cells were seen. The
Table 3. Blood Chemical Values on Admission.*
VARIABLL

ASPARTATE Sr:ruu ArlNtlt

ALKAT-rNE

AMINoTRANSFERASE AMINOTRANSFERASE PHOSPHATASE

BILIRUBIN*

Ulliter
I 3

ngltll
146 130
159

90
28
.15

293
149

0.3 0.7
0.5

6
8 9
12

87

50 40
53

19 60
'74

144
128

r5r

0.4

*To conveft values for bilirubin lo micromoles per liter. multiplt'. by 17.1.

tis: a single small adventitial inflammatorv infiltrate that contained numerous eosinophils $'as considered
nonspecific. On the seventh hospital day indomethacin (25 mg three times dail,v) was begun, but the temperature continued to rise on most days to 39.1"C, and on tu'o davs it reached 39.6"C. An ultrasonographic examination of the abdomen showed a normal liver and a mild

Urea nitrogen Creatinine Protein (g/dl)

Nomal Nomal
5.6

Albumin Globulin Glucose (mg/dl) Calcium (mg/dl)

Phosphorus

t.7
3.9
187

7.7

Nomal
9

Iron (pgldl) Iron-binding cpacity (pgldl) Bilirubin

Sodium (mmolrliter) Potassium (mmol/liter)

t31
Normal r37

Chloride (mmol/liter) Cubon dioxide (mmol/liter) Magnesium (mmol/liter)

Aspnate aminotransferase (U/liler)

r00

3t.9
0.65 90 293

Alanine aminotransferase (U/liter) Creatine kinase (U/liter) Alkaline phosphatase (U/liter)

1l
146

xTo conven values for glucose to millimoles per liter. multipl! l: ro convefr values for calcium to millimoles per liter. mulliply by 0.250; to conven values for iron and iron-binding capacil) to micromoles per liter. mlliply bl- 0.1791: and to conven values for magnesium lo milliequivlents per liter. divide
bt" 0.0555

right hvdronephrosis. A consultant in neuromuscular disorders lound that the patient rvas alert and fullv oriented, lvith fluent speech and a normal mental status. A mild head-nodding tremor \,r'as present. Cranial-nerve functions \,r'ere intact. N{otor po\Ier r,vas 5/5 in all major muscle sroups; extension and eversion of the toes \,r,ere graded 4*/5, with decreased tone. Sensation was reduced distal to the midpalms and knees. Coordination was normal. The gait was narrou,-based, with an equivocal Romberg sign. The tendon reflexes lvere *+ except that the anklejerks rvere * bilateralll,; the plantar responses u'ere flexor. Nerve-conduction studies and electromvographic examination were performed. NIotor-nerve conduction was normal bilateraliy; no conduction block was observed. The sural-nerve action potentials were unobtainable bilaterallv, and the right ulnar sensorynerve action potential was of low amplitude. The

by 0.5.

Vol. 331 No. l9

C.{SE RECORDS OFTHE \{ASSACHUSEI'TS GENERAL HOSPI'I'AL

were observed; coronary arterial and mitrai annular calcifications were present. A diagnostic procedure r,l'as performed.

DrrrpnBNtteL DrAcNosrs

DR. Mrcnerl Havps*: This

77-year-old woman

had an acute onset ofjaw and neck pain and burning sensations in the lower extremities, with episodes of diaphoresis. She r,r'as initiallv treated lbr a dental abscess. Examination revealed tachycardia and the development of scalp swelling, subcutaneous nodules, and findings consistent with a peripheral neuropathv.

The pertinent laboratory findings included very elevated white-cell counts, a verv high sedimentation rate, and abnormal results of liver-function tests, and a temporal-arterv biopsy revealed only a small focus

of eosinophilic infiltration in the adventitia. May we review the nerve-conduction and electromyographic studies, Dr. Cros? Dn. Drorr,n P. Cnos: Iotor and sensory-nerve conduction studies were performed in the upper and lower extremities. The amplitude of the compound motor responses was low in the distribution of both peroneal nerves (recorded from the extensor digitorum brevis muscie) and normal in the distribution of the tibial nerves. Conduction velocities were normal, and no evidence of conduction biock was found. Sural sensory-nerve action potentials were undetectable bilater-

ally; the ulnar sensory-nerve action potentials were of low amplitude bilaterally. The F responses \^r'ere slightlv delaved in the tibial distribution bilaterally, and the soleus H reflex was also slightly delayed on both sides. Needle electrom,vographic studies rn'ere
B

negative in the thigh and lower muscles. Spontaneous activitv (fibrillations and positive sharp waves) was
seen in both plantar muscles. Blink-reflex studies were

Figure 1. CT Scan of the Chest through the Upper (Panel A) and Lower (Panel B) Lungs, Demonstrating Bilateral Multifocal Ground-Glass Opacities Involving All Lobes.

negative bilaterally. These studies disclosed evidence of a generalized sensorimotor axonal poiyneuropathy. Dn. Heves: Dr. Shepard, may we see the radiologic findings?

tibial F responses and H reflex lvere prolonged bilaterally. Needle electroml'ographic examination disclosed spontaneous activity in the flexor hallucis brevis muscles on each side. The overall pattern was consistent with a generalized axonal sensorimotor polyneuropathy. 1-he white-cell count graduallv declined to 15,200 on the I lth hospital dav; repeated differential counts showed 0 to 4 percent eosinophils. Nlultiple liver-function tests revealed a trend toward improvement in the aspartate aminotransferase and alanine aminotransferase levels (Table 4) . On the l3th hospital day the patient coughed more frequently and produced a small amount of clear sputum. A CT scan of the chest (Fig. l), performed rvithout the intravenous administration of contrast material, demonstrated bilateral multifocal patchv and ground-glass opacities in all lobes; atelectasis and pleural thickenine were observed at both lung bases; no abnormal lymph nodes

Dn. Jo-Axxr O. Snrpano: The x-ray films of the A CT scan of the chest (Fig. 1), with high-resolution imaging, disclosed a diffuse parenchymal pulmonary abnormality consisting of multiple patchy and ground-glass opacities in a nonsegmental distribution throughout all lobes, probably reflecting an air-space process. Dx.. Hevrs: Although the clinical picture and the
chest were normal. results of the electrodiagnostic studies were consistent

with a peripheral neuropathy, the onset of the disorder lvas not typical of an axonal polyneuropathy.
which generally presents more insidiously. The sudden onset and the nature and severity of this patient's pain are consistent with nerve ischemia or infarction.
*Staff physician. Division of Neurology, Department of Medicine, St. Elizabeth's Hospitali assistant Professor of neurology, Tufts University School of
Medicine.

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10. 1994

multiple nerves are involved in this manner, the of mononeuritis multiplex is usually entertained.r The clinical and electrophysiologic hallmark of that disorder is the involvement of multiple nerves, with other nerves totally una{Iected. If the involvement is widespread, the disorder becomes indistindiagnosis guishable from a generalized polyneuropathy. CIearly, the findings on electrophysiologic studies in a considerable proportion of cases of neuropathy caused by a microvascular occlusive process are consistent with a generalized axonal sensorimotor polyneuropathy. The

If

and limbs and are not associated with angioedema, which was present in this case. For these reasons a
diagnosis of sarcoidosis is unlikely. Another disorder that was initially appealing in this

clinical history must be eiven great weight

in

these

cases. Ischemic neuropathies present suddenll' with pain and severe disability. There is often pain at the site of the nerve infarct,2 which is constant and burning. The pain, unlike that associated n,ith a typical axonal process, is not preceded by paresthesias or by a gradual ascending sensory loss. The common causes of generalized polyneuropathy, such as uremia,

"itamin 8,, deficiency, hypothyroidism, and toxins, can be readily ruled out in this case, since other clinical and laboratory features do not support any ol these

diagnoses.

The differential diagnosis o[ painful neuropathy of sudden onset includes diabetes, sarcoidosis, and vasculitis.
Diabetes can cause ischemic nerve lesions as well
a generalized polyneuropathy,3 sometimes
as

with a high

sedimentation rate.t The single blood glucose level reported in this case was elevated at lB7 mg per deciliter (10.4 mmol per liter). but rve are not told whether the specimen was obtained while the patient was fasting or during the administration of high-dose corticosteroids. However, other features of the case. especially the skin lesions and high eosinophil count, are not Sarcoidosis is a chronic multisystem disease in which noncaseating granulomas in various organs are associated with derangement of the normal tissue structure.5'6 The findings are protean and may include mild eosinophilia, an elevated sedimentation rate, peripheral neuropathy or mononeuropathy multiplex,T and lung involvement affecting the alveoli, small bronchi, small blood vessels, and occasionally the large vessels. In the so-called acute form of the disease constitutional signs, such as fever, anorexia, and weight loss, may be seen.5'6'B We are not told whether the angiotensin-converting ezyme level was determined; it is elevated in approximatel,v two thirds of cases,6,s but a normal level does not rule out the diagnosis. Several features of this case, hor.r'ever, are unlike those of sarcoidosis. Hilar lymphadenopathy, which is seen in up to 90 percent of cases of sarcoidosis, was absent in this case. The sedimentation rate, r,r'hich ma,v be elevated in sarcoidosis, is not as high as that seen repeatedly in this case. Hypergammaglobulinemia is common in patients with sarcoidosis but was absent in this patient. Also, although subcutaneous nodules are observed in sarcoidosis, they usually involve the trunk
associated lvith diabetes.

is the hypereosinophilic syndrome,r0'12 w'hich is characterized by peripheral eosinophilia and eosinophilic infiltration of various organs. The disease presents in several forms, often r,r'ith lung involvement and angioedema. Peripheral neuropathy is seen in 6 to 14 percent of the casesr3ra; it is not caused by eosinophil infiltration or vasculitis but results from abnormalities seen in nerve-biopsy specimens that are postulated to be secondar,v to injury to the blood-nerve barrier, with a consequent increase in endoneuralfluid pressure.r+ Dystrophic changes in Schwann cells and dissolution of myelin and axonal damage u'ith wallerian degeneration are seen. Toxins released by eosinophils have been postulated to be the cause. Fever, weight loss, and malaise are also observed with this disease, as they rvere in the patient under discussion. However, this patient did not have the hypereosinophilic syndrome. Cardiac involvement, which is prominent in the hypereosinophilic syndrome,r0 was absent in this case. Moreover, the diagnosis rests on prolonged peripheral hypereosinophilia and an increased number of eosinophilic promyelocytes evident on bone marro\^r' biopsy, and neither feature was present in this case. Did the patient have some form of vasculitis? Vasculitis is a major consideration in the diferential diagnosis of ischemic neuropathy15-r7 or any neuropathy associated with a very elevated sedimentation rate. NIany classifications of vasculitis have been suggested. The simplest ones classify vasculitis according to the size of the vessels involved.rs-20 The large-vessel arteritis group includes'fakayasu's arteritis and temporal arteritis. Takal''asu's arteritis,2l which causes symptoms related to the aortic arch and the carotid and renal arteries, is easily ruled out in this case. Although the high sedimentation rate and anemia and possibly the jar.r'pain led to a temporal-arter-v biopsy, temporal arteritis, with the typical symptoms
case

oculomotor-nerve palsies, clearly does not explain most of this patient's s)'mptoms. Horvever. temporal arteritis has been reported to occur simultaneousl,v with other vasculitic syndromes.22'23 Hypersensitivity vasculitis encompasses a heterogeneous group of disorders that presumably result from a h,vpersensitivity reaction to endogenous or exogenous antigens.re The vasculitis mav a{fect any organ system, but the skin is usually the most severely afected; other organ systems are generally much less markedly affected than they'are in cases of necrotizing vasculitis. Immune-complex deposition is believed to be the inciting mechanism. The antigenic trigger may be exogenous, as in Henoch-Schnlein purpura, serum sickness, mixed cryoglobulinemia. and drug-induced vasculitis, and the disease is occasionally postinfec-

of

headache,

jaw claudication, visual

changes, and

Vol. 331

\o.

19

CASE RECORDS OF

]'HE \IASSACHUSETTS GENER.{L HOSPIT.{L

tious. None of these causes are relevant in this case. Hypersensitivity vasculitis can also be caused by an
endogenous trigger,2a as with systemic lupus erythematosus, rheumatoid arthritis, and Sjgren's syndrome and more rarely with other collagen-vascular diseases. The absence of the classic clinical findings of

systemic Iupus erythematosus, rheumatoid arthritis, and Sjgren's syndrome and the negative tests for antinuclear antibodies and rheumatoid lactor make these diagnoses improbable. This form of vasculitis can also be part of a paraneoplastic syndrome,rT but there is nothing in the case record to suggest a malignant tumor. Necrotizing vasculitis includes Wegener's granulomatosis, lymphomatoid granulomatosis, polyarteritis nodosa, the Churg-Strauss syndrome, and the polyarteritis overlap syndromes. In lymphomatoid eranulomatosis various organ systems are invaded by angiocentric polymorphonuclear inflammatory infiltrates that also contain lymphocytes. histiocvtes, plasma cells, and atypical lymphoreticular cells. Vascular occlusion and necrosis of tissue occur.2+'25 The lungs, kidneys, skin, and central and peripheral nervous system may all be involved. The histologic and clinical features of the disease are

infiltrates, as seen in this patient's temporal-arterybiopsy specimen, mav be found even in the absence of peripheral eosinophilia.32 The Chure-Strauss syndrome has also been called "allergic granulomatosis and angiitis" because of the histologic finding of necrotic eosinophilic exudates with a proliferation ol epithelioid and giant cells, but these sranulomas are
frequentl,v not found, even at autopsy. A recent set of

criteria proposed for the diagnosis of the ChurgStrauss syndrome33 emphasizes that the syndrome is distinguished from polyarteritis nodosa on clinical
rather than histologic grounds, including the presence of asthma, a very high peripheral eosinophil count, and a documented history of allergy other than asthma or drug sensitivitv. The findings in this case do not fulfill these criteria. Polyarteritis nodosa is the diagnosis that I favor. It invoh,es small and medium-sized arteries in multiple organ systems, including the kidneys, muscles, bow-

el, liver, and skin.3{'35 The lungs are generally less involved than in the Churg-Strauss syndrome, although some studies indicate that they are affected in
up to 25 percent of cases. Because of the Iung involvement in the case, an argument might be made for classiing the illness as the polyarteritis overlap syndrome. This term. when used to describe cases of overlap between polyarteritis nodosa and the ChurgStrauss syndrome,36 has generally been resen'ed for cases with a combination of symptoms that are peculiar to each disease, such as a case in which the patient has severe asthma and bowel infarction.

similar to those of a malignant lvmphoreticular neoplasm, and a fatal lymphoma develops in many patients. However, the lung lesions are often cavitating, peripheral neuropathy occurs in only about 7 percent of the cases,26 and leukopenia and anergy to skin testing are usually seen. Neuropathy is a central lature of this case, no cavitating lung lesions were seen, and there was neither anergv nor leukopenia. For these reasons the diagnosis of lymphomatoid granulomatosis is unlikely. The first subtype of necrotizing vasculitis to be recognized as a distinct entity was Wegener's granulomatosis,27 an illness characterized by a granulomatous vasculitis. It can affect virtually any organ system and is often accompanied by fever. malaise, anemia, a high

sedimentation rate, and mild eosinophilia.2'1'28 Involvement of the peripheral or central nervous system
and the skin is common.2s'30 However, the disease usually presents with severe upper respiratory tract manifestations, including rhinorrhea and purulent nasal discharge often complicated by mucosal ulceration or septal perforation. In addition, the absence o[ eye and kidney involvement and the negative test for antineutrophil cytoplasmic antibodies, although not sufficient to rule out the diagnosis, make it improbable. The second subtype to emerge as separable from polyarteritis nodosa is the Churg-Strauss syndrome,3r which is characterized by fever, a high sedimentation rate, and peripheral eosinophilia. The peripheral nervous system is frequently involved. Skin involvement is more frequent in the Churg-Strauss syndrome than in polyarteritis nodosa, especially in the form of tender nodular lesions that may be found in the limbs and scalp, as in this case.32 Extravascular eosinophilic

In over hall the cases of polyarteritis nodosa the peripheral nervous system is a site of vasculitis in the form of either mononeuritis multiplex or symmetric sensorimotor polyneuropathr,. The vasculitis involves epineurial arterioles 50 to 300 ;r,m in diameter, causing a characteristic central fascicular pattern of nervefiber damage.'ri The generalized symptoms of polyarteritis nodosa include fever, malaise, and m,valgia, and the laboratory findings include a high white-cell count and an elevated sedimentation rate. A positive hepatitis B surface antigen or antibody titer is seen in 30 to 50 percent of cases but is rarely, if ever, found in patients with pulmonary involvement.sB The vasculitis results in aneurvsmal dilatations and beading and occlusions of the medium-sized arteries, and in cases with atypical symptoms or equivocal biopsy findings the diagnosis is aided bv arteriographic examination, which shows aneurysms of the renal, hepatic, and visceral vasculature.:i5

The diagnosis of polyarteritis nodosa is made by biopsy. In this case the lung was the most clearlv and most prominently affected organ. The ground-glass appearance on the CT scan suggests an alveolitis or possibly microgranulomas3s; in this case it suggests a generalized alveolitis. A lung biopsy could have been performed, but I would have favored a sural-nerve biopsy or a nerve and muscle biopsy as a less morbid procedure. The diagnostic yield of a nerve biopsv is

298

THE NE\\' ENGLND JOURNAL OF \{EDICINTI

a

Nor'. 10. 199-i

lairlv high and is improved with rhe addition of

muscle biopsy'.lu A biopsy' of an electroph.vsiologically abnormal nervc is believed bv some obsen'ers to be more likely to shorv evidence of vasculitis.+r I u'ould have expected the biopsv to show perivascular and

transmural inflammatory-cell infiltration and patchy. asymmetric nerve-fiber loss within the nerve fascicles. Making the diagnosis of polyarteritis nodosa is very important to the patient, since the disease may respond u,ell to immunosuppression. In one study the five-year survival rate for patients receivins a resimen includins prednisone and cvclophosphamide rvas 90 percent, as compared n'ith a fir.e-vear survival rate of l3 percent in untreated patients.si Dr. E. Tessl Hpor.ry-lVnyrr: Dr. Cros. rviil r.ou tell us u'hat the clinical diagnosis rvas before the diagnostic procedure? Dn. Cnos: Our reasoning v!'as verv similar to that of Dr. Haves. \\'e thought that the patient had a vasculitic neuropathy, probably caused by polvarteritis
nodosa.

CrrNrclr DrecNosrs
Polyarteritis nodosa, with sensorimotor axonal neuropathv.

Dn. Mrcrrerr, Heyrs's DracNosrs

Polyarteritis nodosa.

Parrror,ocrcar DrscussloN

Dn. HEor-sv-WnvrE,: The diaenostic procedure consisted of a muscle biopsy and a sural-nerl'e biopsv. The muscle fibers varied greatly in size, rvith grouping of small fibers and many hypertrophied fibers findings consistent with neurosenic atrophy (Fig. 2). The fiber-type grouping indicates that reinnervation had occurred. In addition, necrosis of fibers and intersti-

Figure 2. Muscle-Biopsy Specimen (x120). Groups of small angulated Jibers and hypertrophied fibers with central nuclei are present. A tew deeply stained necrotic fibers and interstitial fibrosis are also visible.

tial fibrosis w'ere present, susgestins ischemia superimposed on a chronic neuropathr'. 1'he histoeram of muscle-fiber size u,as broader than normal, w'ith an excess of both small and larse iibers (Fig. 3). In contrast to the usual bell-shaped curve. this cur\re is prob-

Type 1, 59%
Mean size. 45.0;rm

fype 2, 41o/o
Mean size, 38.6 pm

N=163

N=112

S20
o
-o
IE
0)

8ro
U)

ut
q)

*io F

310

10 20 30 40 50 60 70
Fiber Size (pm)

B0

90 100>100

10 20 30 40 50 60 70 B0 90 100>100
Fiber Size (ptm)

Figure 3. Histograms of Type 1 and Type 2 Fibers in the Muscle-Biopsy Specimen. Both histograms are broad and shifted to the left. The number oT type 1 fibers is increased. The mean size of the type 2 fibers is reduced.

\'bl. 331 No. 19

CST] RECORDS

O} HE \I,\SSCHUSI]]'TS GENER.\I, HOSPIl"\L

299

,.s-.

**., ..1*, 1 ;iliifi **= U., ; Cffi*"

':.
r*"

"

,{r* }

{.}>.''*. _ **{;:Ji -'-* tt --

;*., * - .'"t" * .

. t-'

,'*-;

Ot

in the medium-sized mvelinated fibers. In retrospect, the inflammatory cells in thc temporai-artery-biopsv specimen may have bcen a manifestation of the polr'arteritis nodosa. Dr<. Ar-laN H. Ropprn: f)r. Havcs, do you believe
o[ generalized axonal ncuropathv is simmononeuropathies lvhen there is no clinical and electrophysiologic evidence of a single nerve being preferentiaily or completell' aflcted, or should we accept the existence of-a related syndrome ol polyneuropathy that is due to

that this

t1.pe

plv the summation of multiple

- ^ ',1

-rl--1.,;:',+t :-r-q -: .-.,. -'.--r "l; l,t t*i.*

:*

-L--.

:ji1l Ei.f,i*rr'i: ;r'i.i*r;H = ;;;rt

Figure 4. Sural-Nerve-Biopsy Specimen (x220). There is fibrinoid necrosis ol the vessel wall, with an adjacenl
inf

many fascicular infarcts rather than to cumulative mononeuropathies? It is the summation of these incomplete nen'e lesions that is likelv to resemble a generalized sensorimotor poll'neuropatht'.

lammatory

inf

iltrate.

Dn. Heyns: The rvidespread small-vessel chanses with vasculitis may result in lolr,-grade ischemia o\:er a length of nerve or mav cause microinfarcts ol the nerve that ciinicaily resemble an axonal neuropathy rather than the larser nerve infarct that lve generaliv associate with mononeuritis multiplex. Dn. Htnrry-Wunrt,: 'fhe changes in the sural nerve in this patient consisted ol multiple areas of degeneration of individual fibers, not a total loss of fibers within a single area. Dn. DaNrpL L. jvlr,xras: The patient rvas discharged eight days after the biopsv, uith a regimen of prednisone (60 mg per dav) and cvclophosphamide
seen

(100 mg per day).

ANarolrrcar Dra,cNosrs
Pojarteri tis nodosa, with neuropathl.

.i

.,

,. -t',.
'- - '! j

'

, ,, .. i,'. , f ,.". ., I
-:' ,*'--,' i - r, -:1_.' _ .

. :l.s_ ..;

AorNpuu Dn. Cnos: \\rithin three days after discharge the fever and slvelling had almost completely resolved. Three months thereafter the dose of prednisone was tapered over a period of eight months. 'fhe dose of
cvclophosphamide was reduced one month later to 50 mg per day. One vear alter discharge the patient rvas receiving this dose of c1'clophosphamide as maintenance therapy. She is asymptomatic except for persistent acral dysesthesias of her exfemities, and she performs her household tasks '"vithout anv di{cultv.

Figure 5. Sural-Nerve-Biopsy Specimen (x90). An epineurial vessel, with surrounding fibrosis and mild inflammatory-cell inTiltration, is shown.

RrrrnrNcrs
1. 2. 3. 4. 5. 6. 7. 8. 9.
Chang RW, Bell CL, Hallet M. Clinical characteristics and prognosis of vasculitic mononeuropathy multiplex. Arch Neurol 1984;41:618-21. Anatomical classification of PNS disorders. ln: Schaumburg HH, Spencer PS, Thomas PK. Disorders of peripheral nerues. Philadelphia: F.A. Davis. 1983:7 -23. Metabolic neuropathy: diabetes. In: Schaumbur-q HH, Spencer PS, Thomas PK. Disorders ofperipheral nerues. Philadelphia: F.A. Davis. 1983:41-55. Ganda OP. Markedly increased erythrocyte sedimentation rate. hyperfibrinogenemia, and peripheral vascul disease in diabetic patients: association with clinical implications. Am J Med 1988;85:584-5. Siltzbach LE. James DG, Neville E, et al. Course and prognosis ofsrcoidosis around the world. Am J Med 1974.51:847-52. Poole GW. The diagnosis of sarcoidosis. BMJ 1982:285:321-2. Stern BJ. Krumholz A. Johns C. Scott P. Nissim J. Sarcoidosis and its neurological manifestations. Arch Neurol 1985:42:909-17. Fanburg BL. Sarcoidosis and other granulomatous diseases of the lung. New

ably biphasic, particularly for the type 2 fibers. The mean fiber sizes were only slightly smalier than
normal. The fat surrounding the sural nerve contained a medium-sized vessei with fibrinoid necrosis in its wall (Fig. 4) and an adjacent inflammatorv-cell infiitrate. In the epineurial connective tissue there was another vessel with extensive adventitial fibrosis (Fig.

5), which is consistent with polyarteritis

nodosa.

Teased nerve-fiber preparations showed multiple myelin ovoids, and the 1-pr,m epon-embedded sections

contained axonal sprouts indicating wallerian degeneration of the nerve fibers, with most ol the fiber loss

York: Marcel Dekker. 1983.

Rohrbach MS. DeRemee RA. Pulmonary sarcoidosis and serum angioten-

sin-convening enzyme. Mayo Clin Proc 1982',57:64-6.

l 300

'IHE

)i'Etr\: ENGLAND JOURNAL OF' I.'IEDIC INE

Nov. 10. 1994

l0

Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore) 197 5:54:l-27. il Fauci AS, Harley JB, Roberts WC, Fenans VJ. Gralnick HR. Bjomson BH. The idiopathic hypereosinophilic syndrome: clinical. pathophysiologic, and therapeutic consideralions. Ann Intem Mred 198297 :'7 8-92. t2. Enright T, Chua S, Lim DT. Pulmonary eosinophilic syndromes. Ann AllerlJ. 1989;'62:277-83. Wichman A, Buchthal F. Pezeshkpour GH, Fauci AS. Peripheral neuropathy in hypereosinophilic syndrome. Neurology 1985135: I 140-5. Monaco S, Lucci B, Laperchia N, et al. Polyneuropathy in hypereosinophilic syndrome. Neurology 1988;38:494-6. Said G. Lecroix-Ciaudo C, Fujimura H, BIas C, Faux N. The peripheral neuropaahy of necrotizing arteritis. Ann n-eurol 1988t23:461-5. Dyck PJ, Benstead TJ. Conn DL. Stevens JC, Windebank AJ, Low PA. Nonsystemic vasculitic neuropathy. Brain 1987;l l0:843-53. Hawke SH. Davies L, Pamphlett R. Guo YP, Pollard lD, Mctod JG. Vasculitic neuropathy: a clinical and parhological study. Brain l99l;114:

27

28

Wegener F. Uber eine eigenartige rhinogene Granlomatose mit besonderer Beteiligung des Arteriensystems und der Nieren. Beitr Pathol Anat 1939; 102:36-68. Wanen J. Pitchenik AE, Saldana MJ. Granulomatous vasculitides of the lung: a clinicopathologic approach to diagnosis and treatment. South Med J
1989182:481-91.

gy

t4.
15. 16.

t7.

2175-n.
18.

Leavitt RY, Fauci AS. Pulmonary vasculitis. Am Rev Respir Dis

19861

134:149-66. r9. Scott DG. Classification and tretment of systemic vasculitis. Br J Rheumatol 1988:27:251-3. 20. Fulmer JD. Kaltreider HB. The pulmonary vasculitides. Chest 1982;82:615Shelhamer JH, Volkman DJ, Parillo JE, Lawley TJ. Johnston MR, Fauci AS. Takayasu's arteritis and its therapy. Ann lntem Med 1985:103:l2l-6. 22. Amato MBP, Barbas CSV, Delmonte VC, Carvalho CRR. Concunent Churg-Strauss syndrome and temporal arteritis in a young patient with pulmonary nodules. Am Rev Respir Dis 1989:139:1539-42. 23. Frayha RA, Abu-Haider F. Polyrteritis nodosa masquerading as temporal arteritis. J Rheumatol 19791.6:76-9. 24. Nadeau SE. Collagen vascular disease: vasculitis. systemic lupus erythematosus nd rheumatoid arthritis. Semin Neurol 1985:5:324-43. 25. Fauci AS. Haynes BF, Costa J, Katz P, Wolff SM. Lymphomatoid granulomatosis: prospective clinical nd therapeutic experience over l0 years. N Engl J Med 1982;306:68-74. 26 Ktzenstein AL, Carington CB, Liebow AA. Lymphomatoid granulomatosis: a clinicopathologic study of 152 cases. Cancer 19191;43:36O-73.

2t.

Finkelman R, Munsat T, Mandell H, Adelman L, Logigian E. Neuromuscular manifestations of Wegener's granulomatosis: cse report. Neurology 1993143:6 t 7-8. 30. Drachman DA. Neurological complications of Wegener's granulomatosis. Arch Neurol 1963:8:145-55. 31. Churg J, Strauss L. Allergic granulomatosis, allergic angiitis, and periarteritis nodosa. Am J Pathol 195l'.27:277-301. 32. Lanham JG, Elkon KB, Pusey CD, Hughes GR. Systemic vasculitis with asthma and eosinophilia: a clinical approach to the Churg-Strauss syndrome. Medicine (Baltimore) I984;63:65-81. 33. Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology I 990 criteria for the classification of Churg- Strauss syndrome (allergic gmnulomatosis and angiitis). Arthritis Rheum 1990;33:1094-100. J+ Guillevin L, Du LTH, Godeau P. Jis P, \Vechsler B. Clinical findings and prognosis of polyarteritis nodosa and Churg-Strauss angiitis: a study in I 65 patients. Br J Rheumatol 198827:258-64. 35 Lightfmt RW Jr, Michel BA, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodos. Anhritis Rheum I 990:33: 1088-93. 36. tJavitt RY, Fauci AS. Polymgiitis overlap syndrome: classifrcation and prospective clinical experience. Am J Med 1986;81:79-85. 37. Kissel JT, Mendell JR. Vasculitic neuropathy. Neurol Clin 1992l,10:76181. 38. Stokes LT. Turner-Warwick M. Lungs and connective tissue disorders. In: Munay JF. Nadel JA, eds. Textbook ofrespiratory medicine. Vol. 2. Philadelphia: W.B. Saunders, 1988: 1479. 39. Chiles C. Putman CE. Techniques for interpreting pulmonary opacities in the ICU. J Crit Illness 1994:9:198-206. 40. Panegyres PK, Blumberg PC, Leong AS, Boume AJ. Vasculilis ofperipheral nerue and skeletal muscle: clinicopathological conelation and immunopathic mechanisms. J Neurol Sci 1990;100:193-202. Wees SJ, Sunwoo IN, Oh SJ. Sural nerve biopsy in systemic necrotizing vasculitis. Am J Med l98ll'11:525-32.

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Vol. 331 -\o.

19

THE t(E!V DNGI-A.NDJOURNAL OF IIEDICTNE

l3() I

The New England Journal of Medicine

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t 30!

THE

\L\\' ENGI,A\D.JOUR\AI- O[ I{EDI(;I.\E

-\or'. 10. I99-1

SUBCLINICAL HYPERTHYROIDISM _ JUST A LOW SERUM THYROTROPIN CONCENTRATION, OR SOMETHING MOREP

rum th)'rotropin that are sensitive cnough to distinguish betn'een normal and lou' concentrations, thc
measurement of serum th1'rotropin has becomc tht: singlc best tcst of thyroid function. The reason is that an increase in the serum thyroxinc (T,) or triiodothyronine (T,,) concentration sufficient to cause clinically'apparent hyperthyroidism inhibits thvrotropin sccretion substantialll; just as a decrease in the serum thi'r'oid hormone concentration sufficient to cause hy'pothvroidism increases it. Serum th1'rotropin concentrations are usuallt' undctectable in patients rt'ith overt h1'perthl'roidism' Thev ma1'be detectable but lon'in patients r'r'ith thvrotropin dcficicnc,v caused by hypothalamic or pituitary disease and in patients with nonthyroidal illness. Patients in thcse tr,vo groups can bc identified b1' the clinical context, historli and physical examination and b1'thcir lou' or lorv-n<lrmal serum T, and 'f, c<lncentrations. Hon' evcr, lo\^' serum th1'rotropin concentrations are ntost commonly encountercd in patients rvho havc [u'or no clinical manifestations of hy'perthy'oidism and normal a disorder callecl serum T, and T, concentrations

Str-cn the introduction 10 1'cars ago o1'assavs I'or sc-

thyroidism.'Evrence that the an\thmia r.,,ith antith,vroicl therapv in these patients is sparse' Among patients rvith ovcrt hvperthvroidism, ho\t'ever, atrial fibrillation clis;rppcars in 60 percent rithin four months after thc initiation o[ antithvroid therapl'.6 Other carcliovascular effects of subclinical h1'perthl'roidism

is rt:vcrsirrlc

subclinical hyperthvroidism. What are the frcquencl,, natural history; and risks o[' subclinical h,vpcrthyroidism? Somc ans\vcrs to tht:se qucstions are provided by Sau'in et al. in this issue of the Journal.t Among 2007 clinically cuthy'roid persons
60 vcars of age or older n'ho rlere examined in
Framingham, \{assachusetts, Ii'on.r l97tl through l9t}0,

including l15 u'ho \r'ere recciving thvroid hrrmone therapy; l2 percent had subclinical h1,perth1'roidism. In sever;rl other sun'evs o[' oldcr l]ersons, thc frequenc,v avcraged about .[ percent2-r (it is lorver among younger persons). The variation can be explainecl largely b1, differcnces in what was considered a lou, serum thtrotropin concentration, in the frequenc,v <ll' nontoxic goiter in the rcgion -rf'the studl; and in u'hether patients rcceiving thyroid hormone therapli in u'hom the
Irequency- of subclinical h1'perthl'roidism is substantial,

u,erc included.

In an1, clinicallv cuthl'roid person found to havc a lolv serum th1'rotropin concentration, serum free 'I'r should be measurcd. A normal value, albeit usuallv
above average , conlirms the prescnce of subclinical h1perthyroidism. Stricth's1>caking, the serum T,, crlncentration should also be normal in these persons, but that mcasurenlcnt is not important ftrr decisions about managemcnt. What is important is asscssment ol'the possibilitl,that the person has pr<-rblems that mipht be attributcd to cxcess th1'roid honnonc. Orrc o[ these problems is atrial fibrillation, ir uellknou,n mani{station of' hvperthvroidism, especially in the t'lclcll1,. Arnor.rg patients rvith atrial fibrillation ancl no cardiovascular clisease, a lu'har.'e subclinical hlpcr-

include increases in the pulse rate and lhe frcquencl of atrial prematurc contractions and incrcascs in left ventricular mass and contractilitl.; Anothcr potential problem is accelcrated bone loss, causccl bv increased bonc resorption. The mineral densitv of' the sltine , femur, and other bonv sitcs is decreased to a variable degree in postmenopausal lvomen n'ith subclinical hi' perth,vroidism, but not in men or \'()Llnger \\'omen.lr Horvever, in I ltlO patients receiving thrloicl hormone, the rate of hospitalizatior.r for lracture (and also for ischemic heart diseasc) during follou'-up u'as similar among those u'ith lou' zrnd those uith nortnal serum thyrotropin crrcentrations.r) Patients rvith subclinical hyperthl'roidism can also have muscle rve:akness, neuropsychological clyslunction, or other clinical manifstations of hvperthl'roidism in elderll' patients.ro In other \\rords, the process might not alu'a1's bc subclinical. lVhat is the risk r[ atrial brillation or ol' the subsequent development ol'overt hy'perthl'roiclism in patients u,ith subclinical h1'perthvroidism?'fhe studl bv Sartin ct al. addresses thesc risks ancl is uniquc for its large sizc and long f<lllon.up.l Among thc 2(X)7 subjccts, r'vho rverc ftrllou'ed for up to l0 vears, atrial Iibrillatirln dcvcloped in 192 (10 percent). As t:omparecl u'ith the group rvith normal serum thvrotropin ('onccntrations, the risk o{'atrial Iibrillation rvas 3.1 timcs higher in the group u,ith lou' serum thvrotropin conccntrations and 1.6 times higher in thc group u'ith slightlv lorv concentrations. Onl;'2 of these 192 persons also hacl clinicalll' evident hy'perth,vroidism, although more ma1'have had elcvated senrm T, or'f , concentrations. Three persons in the trvo lorr'-serut-n-th1'rotropin groups and one in the normal-senrm-thvrotropin group subsequently had hy'perthr-roiclism but not atrial librillation. Lou'serum thyrotropin concentrations tnav be transient as n'ell as largch'innocent. h.r thc studv b1'Sau'in et al., 19 o1'36 persons in the lorv-serum-thvrotropin group had norrnal scrum thvrotropin values at some later time. Among 66 patients n'ith subclinical hvperthy'roidism in a British general practice rcstudied one year later, 26 (39 pcrcent) still had lou'serum th;'rotropin conccntratiotrs (one had rlr,crt hvperthvroidism) and ,t0 (61 perccnt) had norrnal concentratiotrs.r In another studv ol 53 euthl'roicl paticnts at a primarv care center in Su'edcn u'ho had lovn'scrum thvrotropin concentrations, 27 (5 I pcrcent) had normal values t\1'o to three l'ceks lzrter.r Iu short, thc onll clefincd risk of subclinical h1'perthvroidism is atrial fibrillation. Subclinical h1.perth1'roiclism olen clisappears, ancl progression

lo ovcrl

h1

Thc natural history' ol' subclinical l.rvpcrthvroidism is rthich, in turn, variable because it has several causcs - causc is th1'roid alfect managemcrnt.'lhc rnost c()mmon

llert h1'roidisnt is uttt otrrmott.

Vol. 331

\o.

19

]DlTORIAI

303

hormone therapl'. Treatment is simplc: rr:ducc the dose, unlt'ss the patient h:rs thvroid carcinoma ancl the risk of recurrence is det:med greatel- than the risk of
subr:linical h1'pcrthvroiclisn.r. Therc is probablv no nccd to rccluce the dose in a patient n'hose serum thlrotropin concentration is onlr, slightlr, kr', irccause there ma1' be somc fluctuation betrveen claih'doses, becausc the risks ol slightlv lorv values in othcrrisc healthl' paticnts are lon, and because frequetrt rnanipulations o{'the dosage complicate therap,v ancl increase its cost. C)ther in-rportant causcs of pcrsistent subclinical h1perth).roidisnr are n-rultinodular goiter, solitarl' thl.roid aclenoma, ancl subclinical Graves' discase, clefinr:cl as persistent protluction ol'small arnounts of' thvroid-stimulating antibodics. Uttlbrtutratchl Sarvin ct zrl. do not

thyroirl lLnction, more people with this condition n'ill be identified. If thc patient alreadv has atrial fibrillation, other atrial arrhythmias, other cardiac disorders, or accelerated bone loss, to nhich small degrees of thyroid hormonc exct: ss might contribute, antithyroid
therap,v should be scriously considered. For the remain-

dcr ol patients, no intervention should be undertaken uuless subclinical h1-perthyroidism persists for several months. Er''en iI' the patient's serum thyrotropin concentration rcmains lolv, balancing the risks of the dis-

of antithl'roid therapy leads me to thc conclusion that careful follou'up rather tl.ran intencntion is thc most prudcnt policy..
ease against the problems

RoerRr D. Urrcrn, \{.D.

pror.ide inlirrmatirn about the frcqucncv of goiter in their subjects. Autonomouslv lunctioning thvroid tissuc
tr,pe ma1' slou'I1' cnlarge, cause h1'perthr-roidism, or both. u'ith time. Each of thesc disordcrs could be managed b1' thc arlministration of radioiodine, but large dt-rses are olten neeclcd bt:cause thc fractional thyroirl uptake is normal. 'fhis tl.rcrapv might be appropriate Ibr a patient nith othcr risk Ictors fbr atrial fibrillation or for lorv bone densitv anrl fi'ar:ture, but it is a drastic interr,ention lbr a siler.rt biochernical abnormalin'. Thc same considerations applv to therapl'rvith an antith,vroid clrug, u'hicl-r cntails thc addition:rl risk of side e{fects and thc probable need {br long-term, sometimcs cven lifelong, treatment. As noted abl'e, subclinical hvpcrthvroidism mav be transient, caused by painless (silent) thvroiclitis or a norlthvroidal illness, u,hich nccd not be sevt:re. The increased risk ol' atrial hbrillation and possibl,v
<lf any'

RrrrnrNcrs
l. 2.
Sawin CT, Geller A, Wolf PA. et al. Low serum thyrotropin concentrations as a risk l'actor for atrial librillation in older persons. N Engl J Il1ed 1994: 331:1249-52. Eggertsen R, Petersen K. Lundberg P-A, Nystrom E. Lindstedt G. Screening for thyroid disease in a primary care unit wrth a thyroid stimulating hormone assay with a low detection limit. BMJ 1988;297:1586-92. 3. Sundbeck C. Jagenburg R, Johansson P-M, Eden S, Lindstedt G. Clinical signihcance of low serum thyrotropin concentration by chemiluminometric assay in 85-year-old women and men. Arch Intern Med l99t;l5l:549-56. .1. Parle JV. Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follorv-up of abnormal thyrotropin (TSH) concentrations in the elderly in the

United Kingdom. Clin Endooinol (Oxf) l99l;34:77-83.

5. 6. 7. 8. 9. I0.

Woeber KA. Thyrotoxicosis and the heart. N Engl J Med 1992327:94-8. Nakazau'a HK, Sakurai K. Hamada N, Momotani N, Ito K. Management of atrial fibrillation in thc post-thyrotoxic state. Am J Med 1982172:903-6. Biondi B, Fazio S. Carella C. et al. Cardiac ef'fects of long tem thyrotropinsuppressive therapy wirh levothyroxine. J Clin Endocrinol Metab 1993;77:
33.1-8. Faber J, Galbe AM. Changes in bone mass during prolonged subclinical hy-

perlhyroidism due to L thyroxine treatment: a meta-analysis. Eur J Endo-

crinol 1994:130:350-6.
Lecse GP. Jung RT. Guthrie C, Waugh N, Browning MCK. Morbidity in patients on L-thyroxine: a comparison of those u'ith a nomal TSH to those with a suppressed TSH. Clin Endocrinol (Oxf) 1992i37:500-3. Stdt DJ, Mcl-ellun AR, Finlayson J. Chu P, Alexander WD. Elderly patients with suppressed serum TSH but normal liee thyroid hormone levels usually have mild thyroid overactivity and are at increased risk of developing overt h1'perthyroidism. Q J Med l99l:78:77-84.

other problems means that subclinical hvperthvroidamounts to more than.iust a lorv scrum th1'rotropin concentration. And as mcasurcments o[- serum thyrotropin become mrlre u'idelv used as the initial test of
isr-n

SOUNDING BOARD
FOR EVERY DOLLAR SPENT _ THE COST. SAYINGS ARGUMENT FOR PRENATAL CARE
Puut Ic spending lbr prenatal care in the United States has becn justiiicd in rcr:t:nt 1'ears prir.narilv bv the cost-savings argument. Prenatal c:rre, it is argr-red, can prevent tl'rc costs ancl mcdical complications associated lr,ith lou'birth rreight; it is public hcalth spending^ that pa1's lbr itsclf. 'fhis proposition seems in-

$2.57'or
f<,rrm

$3.311'J)

o[ arguments

rvill be saved. Yet this is the common usccl to justify- public spending on

prenatal care.

tuitir,ch' rcasonable and stlpports a popular public policr'. \Iorcovcr, the finclings of thc boclv ol rescarch ue consider here havc givcn this asscrtion consiclerablc

That lr.omcn should seek regular medical care during normal, healthy pregnancies u'as rst rvidcly recommended at the bcginning ol'this centur,l-.rr In the United States, social reformcrs and nurses introduced the {lrst organized programs o{' prenatal care, which led to impressive reductions in nconatal and maternal lrortalit\'.r; The cost effcctiveness of prenatal care was assumcd lrom thc start. A l9l3 article in the Boston Iedical and Smgical Journal stated, for example, "The
cost of

'rveight atrd remarkablc precision. !-erv other claims in meclicinc or in public hcalth can bt: cncapsulated into the statement th:rt Ir evcn. $1.00 spenl, tl.70r (or

$ I .16/paticnt suggests its economic feasibilit.v at this nominal cost."7 In the latc l9tl0s, researchers attempted to measure the rcturn in savings that could be expectcd from expenditures for prenatal care' f'heir published conclu-

30+

]'HE NEIV ENGL\ND.JOURNAI, OF \IEDICINE

Table

\ov.

10,

199.1

siotrs were quoted uncriticall,v in both the scientific literature and the popular press and lvere instrumental in shaping government debate on the expansion ol N{edicaid coverage lor pregnant u,omen.sThe public's lscination with numbcrs carried this process along, and the cost-savings argument has become commonplace rvhenever prcnatal care, preventive health care, or rcform o{'health care financing is mentioned. A critical look at the evidence lor the claim that the cost of pror,'iding prenatal care is offset by savings in the cost of postnatal care reveals a far more complicated picture. Serious flarvs in research methods undercut the r.'aliditl'of the studies of'cost savings resulting from

I.

Methodologic Shortcomings of 11 Studies of the Cost Savings Due to Prenatal Care.+

Problems in estimating the effectiveness of prenatal care in reducing the incidence of low birth weight Noncomparable controlsr e-r5 Unsupported assumptionsrr r: r7 Problems in cstimating the cost of providing adequate prenatal care Underestimation of the cost of comprehensive prenatal cuelj I2 r7 Underestimation of the cost of overcoming nonfinancial barriers to access to prenatal carer'ie17 Problems in estimating savings in the cost of postnatal care Inaccurate detemination of costs of postnatal carer r'e ri !5 Oversimplification of the relation between changes in the frequency of low birth weight ancl actual cost savingsr-r'e'r I ri r6

prenatal care.

.":'r1,:,:Ti ;i::,,i:::

I studies Bdh Korcnbrot i and Lennie et

Tnr Booy

oF RESEARcH

6 percent in the treatment group.r0 The estimates in

the studies based on calculations rere more conservative. For example, in the Institute of N,Iedicine stud); the cost-savings estimate \\'as based on a reduction in the percentage of babies u'ith low birth u'eight from 11.5 to 9.0 perccnt. In estimating the elfectiveness of prenatal care in reducing the frequency ol lorv birth u'eight, all l2 articles \r'ere allected by one of tw'o llaws.
Noncomparable Controls

To identify studies on the economic elfects of prenatal care, rve revielved articles in refereed.journals and government documents from 1975 through 1993. Over 100 studies on the efctiveness and economics of pre-

natal care rvere identified. Only 12 specically addressed the issues of cost and cost savings. Four o{' the articlesl'e-ll tvere based on three natural
experiments (both Korenbrotr and Lennie et al.l)rvere based on the Obstetrical Access Project). In each experiment, the "treatment" groups received comprehensive prenatal care; the controls received either no prenatal care or routine care. Four studiesl2-li rvere cross-sectional analvses ol eroups ol patients. Each of these eight articles used an empirical studv clesign that is, each rncasured or estimatt:d thc rates of lon' birth u'eight and costs lor actual populations. The remaining four article s2:r'r6 r7 used synthetic or hypotht'tical calculations of cost savings. In three of these,2:l'r7 the authors began u'ith the assumption that providing improved prenatal cre to specified groups ol'women would reduce the proportion o1'babies rvith lou, birth rveight. The costs saved as a result ol this assumed decre ase in the percentage of babie s u,ith lolv birth n'eight n'ere used to calculate net savings. The other studyr6 askecl the question in reverse: Ho'rv much of a reduction in the proportion of babies rvith lorv birth u,eight rvould be needed to cover the cost of improved prenatal care

Self-selection bias rvas a problem in all four crosssectional r1r.li"r.t2-t5 Random assignment to studv groups, rvhich rvould entail u'ithholding adequate prenatal care from some prcgnant women, rvas not possible . In realitli the women themselves chose their study groups. This is problematic because, as the Institute of trIedicine report asserts, women r.vho choose to obtain prenatal care, or choose to obtain earh'prenatal care, are likell' to be diflrent from those rvho do not receive adequate prenatal care in fundamental 1\'ays that may influence the outcome of the pregnancy and that cannot be controlled statisticalll,.3 Il the tr,vo groups differ lvith respect to factors other tl'ran their use of prenatal care, factors that might be associated rvith adverse outcomes, such as income, living conditions, stress, health-

related behavior, and maternal health status, then it

rvould be inappropriate to attribute cliflerences in outcome solely to diflrences in prenatal care. In the other cmpirical studies,r'!r-rr the studl' groups may not in fact have been comparable r,vith respect to income,l'e substance abuse ,lr' maternal age,l0 citizenship,l0 and moti-

for lou-income u,omen? In each of these articles, u,e identified methodologic problems (Table l) that could have resulted in the overestimation ol'the cost savings due to improved prenatal care. These problems are discussed in more detail
belou'.

Pnost,eMs rN

ESTTMATTNG THE

ErrrcrrvnNBss

OF PRENATAL CARE IN REDUCING THE INCI. DENCE

Or LOW Brnrn \{rrCUr

vation and ability to seek timely care.l0'11 In trvo articles,l'e historical controls r,l'erc used over a period when rates of low birth rveight were declining. One studyll u'as flarved b1'a common bias in obsen,ational research on prenatal care; an association betw-een low birth weight and fcwer prenatal care visits may be found simpl-v because preterm delivery itself curtails the number of prenatal visits.
Unsupported Assumptions
tions2'3'16'17 rvas

The apparent (or assumed) elfectiveness of prenatal care in reducing the frequency o[ lou'birth rveight varied enormously among the studies. Itr general, the empirical studies claimed the greatest reductions; one study found the proportion of low-birth-u,eight babies to be 21 percent in the control group, as compared rvith

Each of the four studies using h,vpothetical calculabased on the assumption that providing adequate prenatal care'"vould result in a decrease in

\'('1. :i.i I

\o. l!l

sot'\l)l\(;

IJ().\RI)

the 1r'e<lrrcnr:\'of low birth rrt'ight. ()nlv tl.rt' r'eports ltr' thc Instilute of \[crlic'incr an([ the ()llice ot"fcchnologv ,\sscssrrrt ntl'' expli<'itlv t onsiclerecl tht' t'r'itlcncc fbr thc ellt'ctiveness ol l)rcnlrtal cat'c. l'he ilillhols of' both the sc r-cports couclurlccl that thc reieht ol'thr cviclence

supl;oltecl thc elli'ctiveucss o1' prenatlrl care. Recetrt

stu<lics. lronevcr-. have nrt bccn irble to rlcnxrnstrate the
ef

t.urtul t:lrrc.
n

ft.ctivetrcss ot' prcnatal calc, t'spt'cialh' routine ltlt'in I'cclrrcing the inciclcnr:c o[' lor birth

cxpt'nsive) than routirrr' prenirtal calc lil'nonrcn at lorr' 1'lr[.]r':' Nevcltheless, threc o1' thc lirul strrrlics trsins lnpothctical calculatiotrsl i l" atrcl all thc closs-srr'tiottaI slurliesll Il \\'cl'c basccl on thc assunrpti()n tltirl lotrtint: pt'ettat;rl care \\1)ul(l bc cllttivt'enough to pt'ocluct'lhc assume(l rlccl-casc in the fi't'cprcncr. rl- lorr birth \\.cight in the talgt:t groul)s. -l'hus. these sttrclies nt:n h:u'c unclercstin.raiccl il',c ti'rr" r'ost rrl plovi<[inq cllet iire l)rena-

titl

'at'r'.

t'ight.l'-ll Asirle lionr tliis clLralitativc assurrptit)li. thcse Iur'

stuclies u'ere alsr bascrl on cluantitatilr' cstinrates ol'the

Underestimation of the Cost of Overcoming Nonrinancial Barriers to Access to Prenatal Care

nlagnilude ol' thc tcrltrclion in the li'erluencr' <-rf kr' birth u't'i--.ht. Tht:sc cstir.natcs art: clitital to thc ck'terrninatiorl riI cost savillgs. 1-he Institrrtc ol' \Icclicint'
sttrclr"i u as basccl ott tltc suLgcon eerrclal's objt'ctivt', cs-

Ilnsuring that lou-inconrc \\onlcn lett'ivt' plenatal cart' recltrires lror'(- th:ut sinrplr paving- rlre bill lr tl-ris
c'rlt' .l'l-l! Othcl l;allit'r's thal rnust bc o\'(f

l(onr(

irrcltrcle

tablishecl

rveieht ovetall ancl a nurxinrul)r r.rt(' ol !) pelccnt irr high-risk subpoltul:rlirns" lrv 1990. l'his sturh l)rcselrts tto clirlencc as to rlrelhcl thl' surg('on gcneral's goal coul(1. in Iact. bc achicvctl ll.thc kincl ol-prt'rralal crrrt: nr':riIablc Ii' the ('osts use([ in thc calctrlittion. Auotltt'r sttrclr'l stt'atilit'tl uortten accorrlitrg to crlur.ation zrnc[ cltosc the propol'tiorr of'lorr-l;ilth-\\'eits^ht babics boln to \\onlcn rho harl lc('cive(l acleclr-rate llrcnittal care as th(' olltcolne variabk'. l'his stuch uas baserl on thc assunrlttion that the use rl'prt'natal cur'c \\'l1s the onh ftrctor lhal ex1>lainccl di11r't'nct's in tlre inciclcnce o{- lou'-birthrcieht babies bctrr'('n groul)s o['uon.rt'r.r uith sin-rilar' lcvcls ol- edttcalion. ISLrt it is likclr. that. cvt'n rithin groulls delinec[ bv ctlttcation lcvel. nonrcu u'lro t'cct'ivc inarlecluate prenatal ( rll'c nl:rv hzrve a ]righel trnclcllr.ing risk ol' ach'crse outconrL:s ol prcgnarrcv thun \\'()nr('n

in

1980.

ol l "5 l)cr(cnt rat('ol klu,birth-

thc scarcitr.ol healtlr carc llloviclt'rs nilling trr 1>r'ovidt: l)r('nirtal cale to krrr'-iucr.>nrt- \\'olll(.ll! thc lat'k ol' trltusl)('tiltion atrcl chikl i'alt' lirl sucli n-orrrcn. <[ilhcrtics uith cnr-ollnrcnt rerluilcl'llents l'crr' ptrblic ploulalns. the c rrlt ural insensit ivil v ol' ltro9..rartrs. lack ot nrot ivatiorr on thc part of'rr-onren. au([ the l:elic[' that 1;r't.natul calc is not inrpoltant. Tht'sc nonfinancial ballicls alc clill]cult t() overcolnc. ;rntl cflirlts to clo so rrrav ltt' erpensirc. \onc of thc sturlie s n c t'xnrnint:cl c,rnsiricr'. cl thc cost <-rl'
arklrt'ssing thcsc r.rou[]nant ial balricls.

PRosmNrs rN

ESTTMATTNG SAvTNGS

rN THE Cosr

OF POSTNATAL CARE

uho rcceive a(lequatc ('arc. 'fhe othel sturlv in tlris groupl; cliliclccl lor-birthreicht inlants into sis categol'ies. f'lrt' atrthor assunrecl that intensive plenatal sun'eillanct' lulc[ inter'\enti()ll uorrlrl be efft'ctive t:noush to cause 20 pelcrr-rt o[' thc inlirr-rts in each clrtcgor\- to be shifit'cl to the ncxt hight:r birth-neight czrtcB()r\'. -\o.justifir:ation lirr this assunrl)tiorr. or fbr the choice ol'tlre 20 pcrcent lisule. uas giu'n.

llstitnates o[' trst savitrgs alit'r- tleliven ut'rc also highll variirblc. ritluing- [r'onr $3]7rr to S13.6 l(itper' -fl'rc pr.actical clilficultics ol acculult.lv cstil)regnanc\'. nrirting the cosl of' treatinc thc ''avclast"' lon-bilthueight inlnt ancl cxcessive sinrpli{itittion in c'alcul:rtine thc estimates nrnv hart lecl to an urcrcslinration of
cost savings.
lnaccurate Determination of Costs of Postnatal Care

The Institutc ol' IIctlicirrc ; and Olct' ol''li'chrroloer'

Asse ssntetrt

bast'cl lrospitalizatic)n an(l lates ol' r.nortalit\ anrl nrolbic[in'

l'' sturlit's t't:liecl on t'laltolalt' r'alculations on stale ot' turtiotial cstitnates oI t'harccs lor'

Pnorrtus

rN ESTTMATING THE Cosr or PnovrotNc Aorquarr Pnexaral C,lRe

alrlong lou-birth-u'eiqht inl'ants. This inIirrnralion is tlillicult to cletenniur' pt't'cisclr'. 'l'he costs ol l)ostnatal cart' lor tht' coutlol gr()rU) \\-cre un:rr-ailal;lc lirr one ol
the tl'rlee n:rtural ('\l)crirnentslr'; onlr- otrc o[- thc lhrt'c ust:cl lata ft'onr actual hospital bills.l" I-hc noncolnl)aI'ablc stuclv groups in all the cmpilical strrclics cast clorrlrt ou tlre clainr that rlifli'rences in c'osts lt'llect sarings attl-ilrtrtal)lc to l)r('natal cart'.
Oversimplification of the Relation between Changes in the Frequency of Low Birth Weight and Actual Cost Savings

l'hc estimatecl costs o['ltrenatal care varie(l cor-rsicler-ablv auror.rs sttrrlit's. rauging il'orn $lllJ0r"r7 to $1.0-l2rI I)er pregnarlcr: In arlclitirn to the inrplccision anrl potential inaccuracv ol' (l-resc cstinr:rtes. tu'o other problcnrs allctcd cstinrates rl'thc cost ol provirling l)renatal carc to lon-incotric \\'omcn at high risk of having krrr'-llilt lr-rr ei ght lralrit's.
Underestimation ol the Cost ol Comprehensive
Prenatal Care

l)ata fi'onr thc sirnulation lx' Schrvzrrtzr;

thc

n-ragnitr-rcle

ol' the

suege st that s;u'ir.rss clcpcnc[s heavilr. on

Thcre is an enrcrgillg conscrlsr-ls that clli'ctivc l)rer)atal care lor rlomeu irt liigh risk ol haling lor-birthneigl'rt l;:rbir:s. thr.rsc rnost likelv to bc the targets o[' lttrltlic Proqr:tnrs. Irt'crls to be n.rr'c intt,rrsivc (anrl rlorc

uhetlter pretratal care is ellcctive in plt'r,cnting birth rvciehts at the upper or thc kr'er cnrl ol'the kr-bir-thrvcight clistribution. Recluctions in the pt'rccntage ol'in[)rnts n ith mo(lcriltelv lor birtl'r u'cigl'rt (1500 to 2191) u) hale ;r large inllucncc oll thc overall l)('l'('('llt:rg(' ol-lou.-

TFIE

\t-\\. E\Gr..\-\]) l ou R-\.\L oF -\ I Fl,D I C: I-\ H

cl}cts

\oi'.

10.

l9!)l

bir.th-rveight babies but a smaller elict on costs. Reclucing the proportion of infants u'ith r,en, lorv birth ut'ight (undcl 1500 g) has a much grcater cllct on costs. In Ict, in the projections ltv Schrvartz, alntost halt (12 percent) of the estin-rated savings u'as attriltutable to changes in birth-u'cight catcgorl' among the vclr-lon'-birth-u'eisht inlants, .iust 1.6 ltcrccrrt o[ all inlnts and I7 percent o[' infants rveighing less than 2500 e. Bv con-rparison, inlants born u,eigl'ring 2000 to

ol rccent expansior.rs ol public lirnclins for prenirtal carell lrr t:onlirm that pr-eventing adversc pclinatal outcomcs rrill bc ncither sinrple nor cheap. l{ieorous cvicleuce ancl a l;road nnah'sis alc inrltortant, not onlv tbr the selling of'this policl but also {Lrr the acccptance ol' luturc public health initiatives. Because tlte cost-savings argunrent has dor-rinatcd thc discussiorr, publich' Iirnded preu:rtal care rlav be abancloned il it tr-rrns out not to pal lol itscll. I1' tht: prr4>rltion ol babies u'ith lou' birth ueiglit ancl rlit: costs ol their care do not actuall)'decrease, those responsible Ibr these programs, and for {uture programs that protnise to serve n1o[e\; mar' fincl themselves u.ithoLrt sru)l)ort.

2{99 g accountecl lor 0 pelcent of kr'-birth-rreight in-

onll-24 percent ol'the projected cost savings. Without a more exact picture of the eflect of prenatal care on the distribution ol birth u'eiehts, savings canfar.rts but

tlot be accuratell predictccl. In aclclition, problerrrs relatcd to social clisadvallt:rge, substance abuse, ancl urcdical clisorders in nen'borns ancl mothcLs ale clisplopoltionatcll'associalec[ u ith lou birth n eight. T]rus, the increased costs of caring Iirr lorr-birth-rreight inlnts rna\- not clisirppear simplv as a rcsult of recitrcing the fi-r'cluencv of lorv birth rveight. IupLrcarroNs FoR FUNDTNG oF PnnNnrar Cenr Pnocnaus Saldell has arguerl that it u':rs in largc part thc costsavinss argument lirr prenatal carc thiit cunvirrcccl policl rrakers, lcgisl:rtors. and taxpavers to Iirncl prcnatal care pr.oerams.s Dcspite thcir limitations, thc studics re har.e discussed u'ele instnrmcutal in pron-rotinu this policl, sincc thcl'ploviclecl pre cise numerical values for projectcd savitrgs, expressecl clorln to thc

('(lLrate prenatal cu.c arc not thc issue. It is halcl t<-r in'rasine a 1'ct1'('at ll'onr tlic enlichlened legislation tl.rat hclps lou'-incolle rlolren reccir-c r.cconrmcndccl nredi-

lhc valuc :urd inrportancc ol'enstrring

act:ess 1o acl-

cal care dulinq thcir

1;reer-rancies.

that rvith bt'ttcr clata. thc cost savings duc to bettcr pretratal care coulcl be convincinglv clenronstratecl. \er.crtltelcss, on the basis of t:xistins studics, it u'oulcl be inapprol;riate, il'not irnpossiltle, to atterlll)t such au es-

It is evt:n l,rossiblc

tillate.
Four steps should bc taken in ltroruotine ancl stuclring prenatal care in the luture. Iilst, uc sl-ror-rlcl be rttort' circunrspect ancl less paltisan in interpret- stuclies. rcing ancl citilrg the conclusior-rs o1' scientific garciless of theil provcuance . Sccorrcl, u'c shoulcl n-rakc cven' ellirrt to cva[ratc tht' costs ancl benefits ol' r-neclical carc bc(orc it bccorlcs established in the protssion's or the pul;lic's n-rincl as the stanclarcl of carc. Ihis is as true Ii' potentiallv u-ictcspreacl ltrevcntivc ltlrrgranrs. srrch :rs prenatal cilre, as it is lbl a ncu- ch-ug or
rureclical tcchnolosr. It mav bc tor-r late to ntcasure adecluatclv tl'rc oveliill cost savings associated rvith prenatal czirc, but there arc oplloltLurities to sturlv specific coml)on('nls of' ltrenatal cirrc pr'osl)('ctir-elr'. Fbr cxar-np[e. t'csearch shoultl cxamine rrhcther dillrcnt n'roclcls anrl lcr.els o{'cale mav lte optirtral fol clilfcrcnt groul]s ol'u'clmeli. Third, u-e shoulrl lecoe'r-rizc that nreasuling the costs and bcnclits ol' anv trczrtment is neithcr siml;lc nor straiehtftrru'iircl. It is u'rr.possiblt' that prcnatal cart' is bcnelicial in less easih' r'ncasulecl \\'avs fol exan'rPle,

penrn'1'ol evcrr.clollar sl)cnt. The evidcncc tl'rat plenatal cale pavs {-or itsell is simph. not strong enoush to nrelit the virlr-ral certaintr. rith rvl.rich this clzrint has becu cspr.rr-rsccl. 1'here is considcrable risk in basing healtl'r irrogranrs zrnd public health polio'orr inlirrmation that is t-nore optir.nistic than scienti{it:, for scvcral
citsolts. 'L.hc stuclv rcports van in the clegrec to tvhich the authot-s acknorr,ledgc the uncertaintit:s inherent in their research; Itou't:r'cr, enrphatic ancl overlv precise conclusions havc olten obscurcd the limitations of the rlata. Preciselv becausc these studies have been trsecl to supf

port lar'-reaching rncdical and public health polio, their shortcor.r'rir.r{s, and the completc disregarcl Ibr
those shortcomings, slrou]d bc of particular conc-e ln. l.hesc alticlcs irnplicitlv alguc that there is a simplr nrerlical remeclr' filr problems that are probablv nraniIstations of cleepll' rooteci sor:ial and cconomic lactors. In lar-gc part because of their assumed authoritr; it has beelt comnronltlace. but misleading. to hold up ltrenatal ('arc especialh, tl-re relativelv inexpcnsive sen ice s - to u'omen at lou'risk 15 116 solution to tht: provickrd

bv proclucing hcalthiel and happiel prcenancies ancl

prorrititine bettel relationships rvith health care providct's. Thcse, in turn, lnav cncourag'e better ltalcnting, r-r-rore completc childhood imnrunization, ancl inrprovtments in other hcalth-related behavior. In this reeald, the comtncnt bv Enkin an<l Chalnrers on the value o1'

ltroblenrs o{'chilclrcn bom in povert\'. The currcnt pul)ltot lto\\' receive it, overestin.rates thc ber.refits ol prcnatal care, and contributes to the r.r.rcclicalization ol'complex soc:ial problems. Stuclics that hzrve er,aluatecl the

preniltal carc is apt: "trlanv thinss that lcallv count

lic perception of prenatal care oversirnpli{ies the dil'Iictrlties ol dclivering prcnatal care to \\'onren u,ho clo

cannot be counted."i1 Finalh. re shoulcl corrsi<ler nl'rcthcr cost saritrqs is tlie appropriatc criterion ltv uhich to .judgc prcnatal carc programs. It is ter.r.rpting to assllme that in orcler lbr thcse pl'ograms to be valtrable, thev re:rll1' shoulcl save morc than the\ cost. \'ct $ herr $ e rccluirc prenatal

\k)1.

33

I \o. l9

SOU\DINC BOARI) ti

307

and other prcvcntive health carc, to pai'f'or itself, \\'e lrav be inadvcrtentlv denving valuable bcncfits to societr'. lt mav be better to ask not "Hor much does this salc?" but, rathcr, "Hou' much is this u'orth?"
care ,
Group Health Cooperative Seattle. WA 981 l2

Nlorales WJ. Vaughn BJ. Diebel ND. The cost of no prenatal care. J Fla \{ed Assoc 1985:72:852-5l+. Schramm Yr'F. Weighing costs and benefits o[ adequate prenatal care tbr 12.023 births in Missouri's Nledicaid program. 1988. Public Health Rep I 99:: I 07:6-17-52. Wilson t5 AL. Munson DP. Schubot DB. Leonardson G. Stevens DC. Does prenatal care decrease the incidence and cost of neonatal intensive care admissions l Am J Perinatol 1992:9:28 1 -4. 16. Oftice of Technology Assessment. Healthy children: investing in the tture. Washington. D.C.: Govemment Printing Office. 1988. (OTA-H-31-5.) t7. Schwartz RM. What price prematurityl Fum Plann Perspect l989l2l:1701.
18, 19.

J,rsl:

Huvn\cro\, \[.]).
\{.D., \I.P.H.

University of Washington School of Public Health and Community Medicine Scattle. WA 98195

FRI:ol.Rrcx A. Cosxr,r.L,

Hall MH. Chng PK. MacCillivray I. ls routine antcnatal care uorthwhilel

Lancet l98O:2:78-80. Peoples MD. Grimson RC. Daughtry GL. Evaluation of the eflects of thc North Carolina Improvecl Pregnancy Outcome Project: implications lbr state-level decision-makin-c. Am J Public Health 1984:7.1:5.19-5.1. Strobino DM. Chase GA, Kim YJ. Crawley BE. Salim JH. Baruffi G. The impuct of the Mississippi Improled Child Health Project on prenatal cue anrJ lou' birthueight. Am J Public Herlth l9E6:76(3):27+-8. Piper JM. Ray WA. Criflin MR. Ell'ects of Medicaid eligibiliti' expanrion on prenatal care and pregnancy outcome in Tennessee. JAMA 1990:26.{:221923.

Acldress reprint requcsts to [)r. f]onnell at thc f)epartnrcnt ol' Hcalth Services. SC-117. Unilersitr of \\hshington. Scattle. \VA 9t r95. Supportcd iu part bv a grarrt (\IC.J !)0{3) fionr the \Iaternal Chilcl Hcalth Bureau of the Health Rcsourccs ancl Scrvices dministration.

20

RnreRrNcrs
L
2.
Korenbrot CC. Risk rtduction in pregnancies of low-income women: conlprehensive prenatal care through the OB Access Project. IMobius 198-1:-l(3):
34-.11.

2l

Guyer B. Medicaid and prenatal care: nccessar)'but not sutcient. JAMA

13.
I 990:26-l:126.1 5. Buescher PA. Smith C. Holliday JL. Levine RH. Source of prenatal care and infanl birth weight: the case of a Nonh Carolina county. Am J Obstet Gynecol 1987:156:20-1- I0. Sokol RJ. \4bolf RB. Rosen MG. Weingarden K. Risk. anteparlum care. and outcolne: jmpact of a rnatemity and intiint care project. Obstet Gynecol | 980:56: I 50-6. Oakley A. Rajan L. Grant A. Social support and pregnanc) outcome. Br J Obstet Gynaecol 1990;97: 155-62. Currl' MA. ed. Access to prenatal care: key to preventing los binhweight. Kansas City: Arnerican Nurses' Association. 1987. Poland ML. Ager JW. Olson JM. Bariers to receiling udequate prenatal care. Am J Obstet Gynecol 1987:157:297--303. Sr Clair PA. Smeriglio VL. Alexander CS. Connell FA. Niebyl JR. Situational and linancial bruriers to prenatal care in a sanrple of lou.income. innercity women. Public Health Rep 1990:105126.{-7. Lazarus ES. Falling through the cracks: contradictions and barriers to carc in a prenatal clinic. Med Anthropol 199Ol.12:369-87. Haas JS. Udvarhelyi IS. Monis CN. Epstein AM, The ettect of providing health coverage to poor uninsured pregnant women in Massachusetts. JAMA I 993:269:E7-9 I . Etlctiveness and satisfaction in antcnatal care. ln: Enkin M. Chalmers l. eds. Eilctiveness and satisfction in antenatal care. Clinics in dcvelopmental medicine nos. 8l/82. London: Spastics lnternational Mcdical Publications. 1982:266-90.

3.

Corsky RD- Colby JP Jr. The cost el'fectiveness of prenatal care in reducing low birth weight in New Hampshire. Health Serv Res 1989;24:583-98. Institute of Medicine. Preventing low binhweight. Washington, D.C.: National Academy Press, 1985.

2.1

.1. Leavitt fW. Brought to bed: childbearing in America. 1750 to I950. New

5. 6. 7. 8. 9.
10.
I

12.

York: Oxtord University Press. 1986. Wertz RW. Wenz DC. Lying-in: a history of childbinh in America. Expanded ed. New Haven. Conn.: Yale Unirersitl Press. l9lJ9. Thompson JE. Wulsh LV. Merkatz lR. The history of prenatal care: cultural. social and medical contexts. ln: Merkatz lR. Thompson JE. eds. Neu perspectives on prenatal care. New York: Elsevier. 1990:9-30. Huntington JL. Relation of the hospilal to the hygiene of pregnancy. Boston Med Surg J l9l3;169:763-5. Sardell A. Child health polic.v in the U.S.: the paradox o[ consensus. J Health Polit Policy Lau' 1990:15:27 I-30.1. Lennie JA. Klun JR. Hausner T. Low-binh-weight rate reduced by the Obstetrical Access Project. Health Care Financ Rev 1987:tt(-l):83-6. Moore TR, Origel W. Key TC. Resnik R. The perinatal and economic impacr of prenatal care in a lou-socioeconomic population. Am J Obstet Gynecol I 9tl6: I 54:29-33. Leppert PC. Namerow PB, Cost averted by providing comprehensive prenatal care to teenagers. J Nurse Midwilry l9tl5:30:285-9. Lereno KJ, Cunningham FC. Roark ML. Nelson SD. Williarns ML. Prenatal care and the low binh weight infant. Obstet Gynecol 1985:66:599-605.

25.

26.
21. 28.

29,
30,

3t

308

THE

\E\\'L\GLA\D.lOUlt\i.
l. 2. 3.

OI:

]IEI)ICII\D

\ov.

10,

l99l

CORRESPONDENCE

Saper CB. Breder CD. The neurologic basis offever, N Engl J Med 199'113-30r
I ti80-6. Saper CB. Autonornic disorders and thcir nranagenlent. In: Wi'ngaarden JB. Srith LH Jr. Bennett JC. cds. Cecil texttrttok of ntedicine. l9th ed. Philadelphia: W.B. Saundcrs. 1991:2091-8. Simon HB. Hlperthermiu. N Engl J Med !993:-329:"183-7. Coodman EL. Knochel JP Heat stroke and other fbrms of hypertherrnia. In: Mackosiak PA. ed. Fever: basic ntechanisms and managemcnt. Neu'York: Raven Press. 1991:267-87. MacKenzie MA. Hermus AR. \\irllersheinr HC. et al. Poikilothermir in mun: pathophlsiologl and clinical implications. \'ledicine (Baltimore) 1991:70: 257-68.

.1.

5.

THE NEUROLOGIC BASIS OF FEVER

'lb
the

liditor: Saper ancl Bredcr provide a comprchensive

rclieu'ol'the neurologic basis of Irtr (June 30 issuc).r Thcrmc'egulation invo]r'cs a complt'x intcraction of autononric,
cndocrinc. and behavioral responses sovcrnecl largelv bv the I'rvpothalamus. Darlage in thc preoptic region, uhich lunctirrs as a thermostiit ancl contains mct'hanisms lbr hcat <lissipation, nlal cause hcat intolclance or thermostatic clvslirnctin, ancl ,r f".'.. rcsponsc uill occur.l ' Lesic,n.; of the posterior hvpothalamus or brain stenl rra\- clestt'ov the pathu'a1-s {rr autonomic and behaviural thcrmoregulation. rith consequcnt hr'potherrnia or poikilothertnr'.r Thc authors do not clearll'dillr'entiate bcnteen lr'er ancl non-pvrogen-induccd hr-pclthermia. F-cvcr is a regulatecl clt-valiun ir) thc preoptic lcmP( r'alur'( srl l){)iilt in l.esl)ollse l() ( irculating pr-rogenic cvtokines. In cor.rtlast, in hrpcrthernria there is no rcsettirlg of thc set 1>oirrt or'1rrroqenic lesponse; instead, the thermoreglllatorv mechanisrns are ovenlhehrred bv excessive heat ploduction, heat storage, or impaired heat dissipation.'r' r CIinicallr, the dillerentiatiou bclrteen [r'er anrl hrperthermia is oftcn cli{Tcult and depencls largeh on a meticulous histolv taking, but it is pivotal fbr the managemcnt ol elevated core temperatule.3 + Hvperthclmia can easilv bc mistakcn for (intermittent) lever and licc versa. particularh' in paticrrts rritlr poikil,,rhrlrn\ ol lrcatstt,rkr'.;

To the Editor: The revit:r bv Sapel ancl Bredel is cxcellent. but their l:rst tlo sentcr)ces nrake placticing pecliatric ncurologists shuclcler. The in.rplication that ne\r rnedications to prevent rreuronal daDiage iD stlokc nrav bc especiallY inrportant in treating chilch'en u'ith lblile seizures isnorcs one o1'thc basic lcts about Iblile seiztrres that rte have leartrccl lronr the \ational Collabolative Pcrinatal Ploject.r I lt has been rrcll established that sirnple l'cbrilt' seizurcs causc no lleur-ologic morbiclitv in chilclrcn. Such seizurt's ltave no ellcct on intclligence later in lile and alc not associated l'ith r-nolbiditv or r.nortalitr'. Bv iniplving in their closing scnterc('s that ncuronal protection for hr'perthcn.nia rnar-lle important in tt'cating cl-rilclrcn u'ith lbrile seizures, the authors ignole tl-ris impoltant fct. ltrr rt'ars pediatric neut'okrgists have bectr trving to clispel this r-nvth about the cllects of lbrilc seizurcs in childrcn.

J,rrres \V. \Vrn:r-Ess, ]I.D. Universitr- oi'Texas

Houston.

]'X

77030

\lt:clical School. Houslorr

l. 2. 3.

Nelson KB. Ellenberg JH. Prognosis in children u'ith febnle seizures. Pediatrics 1978:61:710-7. Ellcnberg JH. Nelson KB. Febrile seizures and Iater intellectual perfbrmance. Arch Neurol i 978:35: I 7-2 l. Hirtz DG. Nelson KB. The natural history ol febrile seizures. Annu Rel Med
198.1:3,1:451-7 I . best medicine for tbrile seizures. N Engl J Med 1992:327:

,1. Freeman JN{. The

I 161-3.

6500 HB \ijmt:gen. the Netherlands

\I.\cKH\zrl, \I.D. Glnr..rcu l".F.II. Prc'r'r*s, \I.D. Au R.\I.\I. Henrrr s. \I.D. L ttiri lsitr Hospital \ijnregt rr
-\Lrnn-s A.

'lb the Etlitor:

Brecler stale

In their .*r, revierr, Drs. Saper ancl that "r'cn high bodv tcrnperatures (abovc {{J"C)

Instructions for Letters to the Editor

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available).

Letters should not duplicate similar material being submitted or published elservhere, and they should not contain abbreviations. Financial associations or other possible conflicts of interest should always be disclosed. Submission of a letter constitutes permission for the Massachusetts Medical Society, its licensees, and its assignees to use it it the Journal's various editions (print, data base, and optical disk), in anthologies, revisions, and any other form or medium. Letters referring to a recent../ournal article must be received within four weeks of the article's publication. To expedite receipt of such letters, we encourage authors outside the United States to communicate by fax (617.739.9864 or 617-734-4457),
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\,'ol.

33L\o.

19

CORRESPO\DE\CE

309

can clearlv injure both the central nervous s.vstcm and other bod1,s1stems." This has not been proved. About 20 percent ol' children sccn in the emcrgencl' roorn have temperatures over -l0oC,r but the,v usuallv havc a full recover\.. Il there is morbiditv or mortalitl', it is due to the underlving disease. The associated fi'r,er mat, in lact be protcctive. Fcr.er, commonlr.clue to viral infection, mav induce ibrile scizures in 3 percent ol susceptible children. Temperatures above 40oC at the onsct are reported to be associated n'ith a decreased incidence ol' lebrile seizures.l In one studv lever above 40oC in children rvith nrcningitis clid not indicate a poor prognosis, but all thc children presenting u'ith hypothcrmia died.l With lver, unlike hyperthermia, bodv temperature is rvell regulated b1'a h1'pothalamic set point that balances heat production and heat loss eflectivelv so that the temperature does not excecd an upper limit ol'-12"C. Within this upper range, -[0 to 42oC, thcre is no evidence that thc lr'er is injrrrious to
tissue.

Although it has been difficult to establish a critical thermal thresholcl (defined as the tempcraturc abovc rvhich tissue darnage occurs) in humans, a temperature above -l2oC is like11' to inducc such damage.+ Houever, temperatures that high are usuallv due to hvpcrthcrrnia, u'hich is not regulated centralll'. Ternperatures ;lbove -12"C are uncommon,5 eind complications and mortalifi'lirom temperatures abor,e -12"C are more closel'r related to the severitr,ol'the underlling disease than to the level of the temperatr-rre.
Sidcup, Kcnt DAl4 6LT, A.S. Er-R.rosr, \LR.C.P. Queen \Iar1"s Hospital

belorv). Establishing an arbitrar,v temperature threshold mar' be lcss important than understanding thc pathophvsiobgy ol brain injurt; rvhich mav occur at r.arious bodv tcmperatures depending on the physiologic state of'thc patient. l'inallr; Whelcss and El-Radhi makc the important point that simple lebrile seizures (i.e., single, brief, nonlocal convulsions) in children are nearly alu'ays associated rvith a goocl prognosis and thereforc do not rcquire treatment. The evidence supporting this vierv is quite strong, but unfortunately not all Ibrile seizures are simple. 'fhc prognosis is much n'orse for patients n'ith repeated or prolonged seizures associated nith lever, since alebrile seizures later devclop in l0 to 20 percent of these patients.r'b It is still unclear uhethcr the lever lorvers the threshold lirr a preexisting (but prer.'ious11, clinicall,v silent) seizurc disorder or u,hether the prolonged or rcpeated seizures are themselves injurious to the brain. Holr. ever, recent advances in understanding the pathogenesis o[ partial complex scizures suggcst that prolonged exposure ol neurons to high levels of excitator)'amino acids during seizures may cause cellular damage.' The tendeno lor h,vperthermia to depolarize excitable tissue mav cxacerbate this process, rvhich is the basis lor our suggestion that neuropro-

tective agents aimecl at blocking :V-methyl-o-aspartate rcceptors ma1' find a place in the treatment of lebrile seizurcs. This treatmeut lr'ould, of course, apply onl,v to complex lbrile seizurcs. Simpie Ibrile scizures are bv definition briel and not repcated, and hencc are finishcd by the time the diagnosis is marle.
Cr.n'r-oRD

B. S,\I,ER, \,I.D., PH.D.

Beth Israel Hospital

United Kingdom 1.

Boston,

\IA

02215

2. 3. .{. 5.

El-Radhi AS. Carroll J. Fever in paediatric practice. London: Blackwell Scientific.1994:23. El-Radhi AS. Banajeh S. Effccts of fevcr on recutrence rate of ttbrile convulsions. Arch Dis Child 1989;64:869-10. Wong VK. Hitchcock W. N{ason WH. Meningococcal intctions in children: a review of 100 cases. Pediatr lntct Dis J 1989:8:224-7. Bynum GD, Pandolf KB. Schuette WH. et al. Induced hypenhemia in sedated humans and the concept of critical thermal maximum. Am J Physiol I 978; 235:R228-R236. Sirnon HB. Hyperthermia. N Engl J Med 1993;329:.183-7.

CrtnisropunR D. Bnr:ln, NI.D., Ps.D. Chicago, IL 60637 Universin of Chicago l. 2. 3. 4. 5. 6. 7.

Simon HB. Hyperthermia. N Engl J Med 1993;329:.183-7. Yi PN. Cellulu ion content changes during and after hyperthermia. Biochem Biophvs Res Commun 197 9 :9 | :17 7 -82. Yatvin MB, Cramp WA. Role of cellular membranes in hyperthemia: some obseruations and theories reviewed. Int J Hyperthermia 1993:9:165-85. Laszlo A. Davidson T, Hu A, Landry J. Bedford J. Putalive deteminants of the cellular response to hyperthermia. Int J Radiat Biol 1993:63:569-81. Verity CM. Ross EM. Golding J. Outcome of childhood status epilepticus and lengthy febrile convulsions: findings of national cohort study. BMJ 1993;307: 225-8. Annegers JF. Hauser WA. Shirts SB, Kurland LL Factors prognostic of unprovoked seizures after febrile convulsions. N Engl J Med 1987;316:4938.

The authols rcph':

To tlte Editor: NlacKenzie and colleagucs note the importance ol'distinguishing lr'er lrom h1'pcrthermia. trVe deliberatell'did not focus on hyperthermia in our article, sincc it uas covered in detail b1'Sirnon in a recent revieu,in the Journal.l We agree uith the points made b1'\IacKenzic et al. concerning the phvsiologic distinction bctrt,een lr.er and hyperthermia and the importance of- considering thc clinical sctting in dilli:rentiatins bctrvecn the two at the bedside. Becausc lever and hvperthermia mav occur simultaneouslr. it is als'a1.s important to look lbr infectious causes ol lever in patients rvith elevated bod)' tempcraturcs, even if there is an explanation

Sloviter RS. The functional organization of the hippocampal dentate gyrus and its relevance to the pathogetresis of temporal lobe epilepsy. Ann Neurol
1

994:35:640-54.

RISK OF RECURRENCE OF BIRTH DEFECTS

To tlte Editor: Lie et al. (July 7 issuc)r report that i{'a woman's first child had a birth delect, the risk ol'her second child's being affected u'as increased, but that this excess risk in the second child l,as lou'er il'thc u'oman moved alter the birth ol her first child than if she staycd in the same place. They attribute this differcnce to cnvironmrnt. There are a number of other explanations lbr this result. First, u'omen u'ho move to another municipality are likely to dillr in a numbcr of s'avs from those nho do not move, w-ith regard to other factors related to the risk of a birth dclct, such as socioeconomic status. Differences in this and other variables ma1'explain at least some of the dilference attributcd bv Lie et al. to environment. Second, the ascertainment ol some birth delccts mav vary considerablyl Thc authors maintain that the mother o{'an infant u'ith a birth delct is not likelv to overlook a similar defect in a subsequent inlnt. This

lor l-r'n'perthermia.
Thc issue of'cstablishing a threshold Ibr thermal lissue injur1. in humans, raised br. El-Radhi, remains controversial. An elcvated bodv temperature has graded t:llects on a varietr,ol' cellular processes ranging Iiom the s)'nthcsis o['nucleic acids and protcins to changes in membrane lluiditv and intraccllular ion conccntrations.2-r Long-term damage. at lcast to the nervolrs s)stcm, is likell'to bc associatecl \\'ith the release ol' excitator)'amino acids due to neuronal depolarization. This proccss mav be cxacerbated b1'h1,poxia (e .g., in pneumonia), ischemia (c.g., r'hen an elevated temperature precipitates a cardiac al'rl1\lhmia), or prolonged or repeated seizures (see

l'Ht. \F.\\ t:\GLA\t)JOt R\.\L ()t \IEDI(:l\t

is Iikclv t() bc tl'ue, horrcver. orrlr. li'a major birth rlelct. Recoqllition of the mole numcrous ntinor birth dcfccts lrr rnothets oL mt'c'lical persor.rncl is likeh to bt- mort- raliablc. as is r'(-porlillg o1'thern, aud rninor clcli'cts ltlobabh contribute into1-

\or'.

10. l!)9-l

Dr. Hughes-Davie s asks u,hether the patterns o[.recurrencc

ol birth clelrcts miqht be cluc to the concentration ol ter:rtogens in spccific gcographic zrrcas. J.he seneral tcrrdencr-irr
Nonrav has becn to movL- fion lulal to ulban arcas, and
solrc' t\-pes ol dclcts r.nav be dctcctecl bettel in urban :rlcas. prcvalence ol dclcts in the seconcl inlnts of'liunilies rrhose Iirst inlants had no delct and rrho thcn movccl. Houever.. this nruld not cxplain thc decreased risk of'rccrrrrcnce aurong {irn-rilics rho tnovr-cl alter having a hrst inlant rith a dt'l't:ct. \\i: cloubt that dillrences in thc risk of reculrence ivith nioving are rclatecl to dilli'rent background ratcs ol'clelcts, because thc backgrouncl tates clo not varl greatlv in clillrent art:zrs o1'the coulltr\:1 It seems more likeh'that lrnilics rrhose first inlirnts had a clefct have sor.ne susccptibilitl to teratosens in their imrnccliate envir.onmcnt (thc houst:holcl. thc neic-hbor.hoocl,

'fhus. ecogl althic dilli'rcnccs iu the recognitiorr anc[ rcpoltinq ol'such clclcts coukl ac('ount lbl thc. authors' observatiorrs. fhe lorrel risk olclelcts in thc secontl chilcl o['a rromau s.ho hacl chaneed ht'r citv of rcsiclenct sincc thc birth ol'her first chilcl roulcl exemplil\'resrcssion to thc nrean. Also. it is not clear rht:ther the anah'sis incluclccl delects detectecl bv postnlortcnr t'rauritration. II'it rtid. thcn ccouraphic I'ar-irrtion ir.r the fre<lrrencv of autolrsics coukl also t'ontriltute to tlie repot'ted trend.

portantll to sorne

thc categories anallzed bl l-ic ct

al.

'fhis mav have contributed to thc slightlr higher

All tht:sc issues shoulcl be adch'essed btl'ore thc aurhors' staterrcnt tltitt "cnvilotrntctrt pl:rvs a strorlg J)ul't in lcpcated
rlelcts" can be accepted. Unir clsin' ol' (lalilbrniir, Berkelcr, School ol' Public Health

thc u'orkplace. and so lbrth) and that this crrvilorrnrtrnr

is

Lnrryl B. Iloor, \I.D.

chaugccl bv r.noving.

Berkelcr. (:-\ 9+720

1. Lie

RT. Wilcor AJ. Skjtenen R. A population-based stud]' of rhe risk of rccurrence of birth defcts. N Ensl J N,ted 199.1:33 I : 1,.1-

\-502 I Bcrgen, \oru'av

Rt'seat'ch

TLt lhr Editor: Lir: ancl his collcagues linc[ that a rnothcr's chaucc ol-havins a second babv uith a birth detct is hah-ed i{'sht' tnovcs to alx)thel' toln alitr thc bilth of her first babr'. I1. as thcl suggest. tl-ris is due to r1r1 cscrape li'onr tcratoeens,

Tlianele Park. NC 27709

Rolr- Trt1l, Lrr,. Prr.I). \lcclical Birtli Reqistn' ol \r'tar Alr.r:r J. \\rrL{:clr, \1.D.. Prr.D.
Ror.r' Sxl.rnvr\. Plr.I). \Icclical Birth Registlr'

National Institute of Envilonmcntal Health Sciences

-\-502 I Br:rgen, \oru'al

ol'\or.l'av

lathcr thal) to sonr(' ch:rractct'istit of ruoltilitr, sLrch as incomr, therc should be arr opposite clJct rht:n nrothcrs ol- normal
cl'rilclrcn movc into atr altctecl arca. ()1'such nrothels. 316 per

l.

Medical Birth Regisry of Norway. Annual report 1990. Bergen. Norua),: University of Bergen. I 99 I .

100.000 (3 l0 ol' 89.:r8ll) hacl an abnolrnal second chilcl. as cotnparcd u'ith 235 pel 100,000 (15{ o1' 192.990) ol those uo stavecl put. It l ould be interesting to knorl u hether this cllcct is coulirrncil bv topoelaphic iinalr.sis.

ACETAMINOPHEN POISONING AND LIVER FUNCTION

To lhe Editor:'Ilie suggcstion bv C)heung et al. (Junc 30 issue)l that an acetaminophcn overclosc itr ern alcoholic shotrlcl be treatcrl u'ith acetvlclstcine regardless o[' thc scrLlln acctaminc4rl'ren concentration is unkrundecl an(l coutrar\- to thc availablc cvidencc. The litelatulc includes lell ovt.r 10.000 cascs ol'acetarninr4;hcn olerdosc.l r ancl the ar.ctuuulatcrl expcrietice l'c'lcluicle must involvc rrell ovcr 100,000 c:.rscs. Despite this extt'nsirt crpcrienct', \\'e al-(, unu\\'are ol anv othet bona fide cxamplt:s ol tht: plrcrror.rrenon descrilled br' ()heung and colleagues. u'ho reported a cast'of fatal acetaminophcninclucecl hcpatic firilure irr an alcolrolic paticnt despite zr "nonI()\ic" set unr ar'ctantittolrltrn (()il( r.llltillioll. One must first question 1hc acculacv ol'the histon- in this ctrse, l)articularh'$'ith |egarcl to tl'rc time ol'insestioll o{'acctanlillol)herl arrcl the possibilin'ol'repeatccl ingestion. It is inconceivablc that the insrcrstion of 2j g of acctanrinophcrr loulcl rcsuh in a crrcentraticrn ol-onlv l2{ pg pt'r milliliter Iirur hours alter ingestion, suggestine that either thc amourrt or thc time is inaccura(c. Such an clror is lirrthel suggestcd bv the occun'encc o{'severe hepatic lailule u'ith an undeteclablc serunr acctaminophen concelltlation iithin 50 hc>urs al'tcr ingestion. In patients l ith such lirlminant toxic elicts, tht: metabolism ol ace tarninophen quicklv becomcs neuliuiblc, resr-rlting in the pclsistenct-- o1' kx le vels of circulatine ac( tamir)-

fordingbrirlgc. lJarnpshile SP6 2EJ,

flnitccl Kingclrn-r

1..H. IIur.;r rrs-D.s'rns. F.R.C.P. Blt'ar.nore \Iitrsh

'fhe autlxrrs replr':

To lht Editor: f)r. I'Iook rzriscs tuo points irbout alternativ' intcrplctatior.rs o['our' <lala. I'hc first is that firrni]ies rho nrove rrar bc a sclcctcd erorrp. f'his is no doubt trtrc. \\t sought to clcal lith this 1>r'ol:lern iu tlre aralvsis l>r'making the cornparisorr n ithiu thc grltrp ol lantilies rvho hacl ntoved tliat is, - moved l;rnrilit:s rlrose first inlants had no clclct and lho then

rltrc the lt-lrencc groult lcrl thc lmilies rltrse first iulnts
hacl a clefi'ct zrucl

uho thcn nrovccl. His scconcl con<:cnr is pcr'-

haps mort' sclious. He asks rlhethel clillrenccs in the ascertaiumclrt r{'clcli.cts rnight account lor tlrc observcd trcnds. In ellct. coukl thc lalc o1'ascertainr.ncnl ol'a birtlt clelct in a sccrrcl inliurt sinrilal to rhe rrc in thc fir'st ir-rlant be 50 pcrccnt lolcl irr u cli[Irent hospital? Althorrgh therc is considerable unclct'uscertrlilunent r>f clclects ovcrall. rte clcl not lhink the di{-lt-rerrccs in the r';r1cs of asccrtaiumcnt coulcl bc tl'ris l:rrge. cspecialh firr lamilies rrho al'cadl had an allctecl inlnt. \\t- crplorcd this prol;lcnr I;r- r"rnorins llrrnr the ar.rah sis chrbftrot. the nrost comm(r clclct and ort: iith notol-ioush' poor asceltainrnent. If as(ertainnrerrt bias crrtributed to thc rcsults. the ellct shoulcl be cspci:iallr.strong Ii.club{iiot anr[ l'euku lbr tht'r'est. Lr Iact. ue liruud the opposite. Althoueh utrknou n biascs nrar be afIcting our results. l e uncl no er. irlerrcc that incornpletc ascertirinnreut is a conlriltrrtine firctor'.
f

ophen.

Remalkablt' caises clo occut', horrcver. an(l consider:rtion must also be given to the implications ol'this case il the inlbrnrati(r providecl is corrcct. \\t: agree that both stuclit-s in aniu-rals atrcl l-el)orts oI long-telm irrg^estion ol' a<etarninophen sugsesl that alcoholics arc at ir.rcle:rsed risk firr heprtotrxit cflcts ol'the clrug. \\'hr. then. ..rre such ellcts not rcported

Vol.

l:i.:i

I \o.

I9

(]ORRESP()\DE,\C]L

ISlt

-flre

licrlrrentlv in alcoholics with iicetarninopherr ovcrckrscs.rl ol'ir conscrtativc nor.noglam (25 pclcr:nt lorrel than the original clata-basecl vcrsion)l anrl liberal closes ol'acrtrlcvsteitrt' (11330 nrg pcl kiloulirrn ol botlv rrcight over i-L thlceclai- pelirlrl) are likcll r\plilnirtions and appeal to ovel'c()lnc an\ disa(hantage associatc(l rrith alcoholism ol'other condin.rot'e

ust:

7'o tlte llditor: Chr:ung et al. dcscribe their crperiencc lith a 25-r'car<rlcl \\'oInall rho hacl consllm(]d 25 g ol aeetanritr-

tions.

Lorg-tc|rr use ol alcoh()l appears to be relevant to the cliscussion of' the rnana{enlcrlt ol' long-tt:rrrr overingestion of :rceturninoplror. Erpcricnce sugge sts that ulcoholir:s, patients rccciving thcr':rp1' llrat causcs tlrc irrrluctiorr ol cr tochlor-nr: inlnts rr'it]r Icbrilc ilhrcsscsr are at substantiallv higher risk lor licpatotoxic eflcts. Such ellects are cssentiallv ullhear'(l o['in patients rithout these risk Ictrrs. Givcn tht' high plcvalenct' ol both alcohol abrrse ancl acrrte a( etanliilol)llen ovcr'(lo:jc. ltlr\ ( hangc irr tlcllttl]e nt lecon'rrlrcn(laliolls rotrlrl havr a sul)stalltiul c[li'ct. Palticulalh rrith the cur'r'eIit rmphnsis otr cost c11i:ctivcness.:r chiurg,: in trt;.rtrncrlt Ie(on)r1cn(lations on the basis ol this ol alrv olhcl |enlal'kal)l(' tuse l'rltrlrl be u l;ig stcp blckrr:rrcl.
P--150 cnzvmes.l anc[

ophen il a suicide attempt but u'as not treatecl l ith acetvlclsteirrc bccatrse she rvas not coltsidered to ltc a risk orr thc l>asis ol' the acctaminophen treatulcnt nolrogram. fulmin:rnt hepatic lailure subsequentlv developed, alrd she clied. 'I-hc lcas()n, the authors conclude, is that shc had consumed Iarge anlounts ol'cthanol lbr a long period. Long-terrn usc of ethanol \r'as thought tr> have altered the m(:tabolism ol'acetamin-

^\I.\Rl'r

\ .f . S-rrrr.xs'r'r-r-r, r\I. l). Drrtrt- R. [)ot'r;r-.rs. \1.D. \Iou.*rro R. D.'.r, \I.D.

Poltlancl. OR 9720 1

Olcgon Hcalth Scienccs Univelsitr-

Cheung L. Pons RG. Nlever KC. Acetanrinophen trcatnlent trorlrogralr. ;r.- Engl J N'led l99l:-1-3():1907 8. f. Rurnack BH. Peterson RC- Koch GG. Amrra lA. Acetrminophen orerdose: 662 cases rr ith evaluation of oral rcetvlc\ steine treatncnl. Arch lntern Med l9Ul:l-11:380 5. -. Snrilkstein MJ. Knapp GL. Kulig KW. Run)ack llH. Eflicacl' of oral N-acetvlcysteine in the treatmcnt of ucetunrinophen orerdose: anulysis of the National Multiccnter Studi ( 1976 lo I985). N Engl J Nleti lt)EE:319:1557-62. -1. Bray CP Harrison P\'1. O Gradl'J(i. Tredger JNl. Willianrs R. Long-terrrl anticonrulsant therapy \\orsels outc(nre in paracctamol induced tulrninant hepatic fuilurc. Hunr Erp Toricol 1992:l l:265-70. 5. Henretig FN{. Selbst S\,I. Fonest C. ct al. Repeutc-d acetanrinophen orerdosing: causing heparrxicitS in childrcn. Cliu Pediatr 1989:18:525-8.

l.

Tit tlrc Editor: I lln suLc I rr'ill rrot bt' thc onlv lJlitish lraclel uho fels nrovt'cl to lcplv to tlrc lcttct'lrr Cheulrg ct al. The

ar:ctanrinr4rlren tr('atnrent ]lomogranr is inclcccl ricleh' ust:cl ;rs a guiclt-linc 1r' 1r't'atmenl irr paticnts u ith acctanrinoplrerr oleldost's.r hert- as irr tlrc L'nitr-cl States. Horrever, in this countr\, il not in tlrt Unitcrl States, it is alreatly *ide11'r'etognizetl that cthanol, as \rell as nranr otlrcl hepatic cr tochlonral enzvnre-inclucing rlruqs, n)aY Cor)foun(l t[ris aPproach. lb| this l'e:tsorl, it is consiclerecl loutirre l)rrlctice to hah'e thc level at rlhich tleatnrt'nt is corrsiclelr'(1. as prol)osccl in thc curr'('nt isrjrre of tlr(' IJriti.h -\'ational hiuulatt'.) If Cihcung et al. h:rcl takt'n this into account, the ac(:tanlinophett lcvt:l o1' I2{ pg per r)lilliliter irt lirut'hout s (rrhich is lcss than 2(X) p.s per ulilliliter-. thc cutolT pr-rint in thc nomogram, l)ut nlolc than 100 g.g per nrilliliter'. hall thc cLrtolf point) \rould lraYc clictatccl tl'catnient ith acctvlcrst(:ine, n(]t nont|eatnlcnt. A dcclinc that bcciLrne irlcr,ocablt'lnight []a!e been plevetrtcd. As Cihcung ct al. pt-rint out. tlicre shoulcl be a Ior threshold Ir tleatnrcnt rr ith acetvlcr stcinr. sincc tlrc hazar([s ol'su(h treatnicnt ale ncgligible.r

ophcn sullicientlv to invalidale the plt:clictile valtrc ol' tl.re acctatnitiophcn treatmcnt n()nlogranr fi)r' deterrnitling hep:rtotoxicitl,. 1'hus, thc authors conclude that a carelul historv of alcohol usc should be taken lbr er-erv paticnt \ith an acetanlinophen overdosc. There arc several serious problems u'ith the arrlhors' ltlesr.lpl)ositions irnd conclusions in this cast'. Filst. 25 g ol lcctallrinopllcn (u'hich is rnoLe than six tinres tht: ntasiural lt:c(nmt:ndccl rlailv closc) is clcarlv in tht: toxit: r'alrgc.l Sc(olr(l! although thc acetarriinophell tl'c,rtmellt nonrogranr is ust:lirl lot'populatiorr studirs. it shotrld ne\cr llt: uscd t() n'ithholcl :r benign ancl potcntiallv lil-csaving trcalmcnt in thc c:rse ol'a knon'n ovt:r'close. Thircl, the rnagnitude bv u,hich alcohol cr.rhances the toxic ellcts o1'acetarninophen has nriver bccn estal;lished iu humans. 'fhc indtrction ol- o lochrotnc P-+50 2lrl cllzymc acti\,it)'by alcohol is onlv trvolbld r thleelirld ancl LetLlrns to normal *'ithin fir'e da1,s,J suggestins that lecent alcohol r-rse is rnore inlportallt than long-tclm use. Irurthemor(-. tlre rc<iuction in serum glutatl-rionc levt'ls in alcolxrlics is orrlr' nroclcst,:j and thc rcduction in hepatic glutathionc lcr-els <ltrr'ine ethanol consurnption. u,hcn controllt:d Ibl lirsting. has rrot been dernonstratecl ilr humans. l-inalh, ot]rer fctors that nrav incleasc the toric cfk'cts ol acctamillol)hen. such as a gL-nctic 1>t'cdisposition or lsting,+ rnav be evcn nlore inrl:ortarrt than a liistorr' rf alcohol consumptirn. Thus, the casc b)- C)hcrrng et al. pr-ovides an argument fi.lr the treatntcnt ol'l)atie llts u ith acetatninophen ovcrcloses rcgardless <>l thc sclunr lcetanrinophen le\'('l l-lut lails to plovc that the toric ellcts of a(:('tantitiophett are increased bv alcohol collsumpti(r. I uoulcl suggcst the lollouing appr<>ach. 'I'r't:at cven acr'tanrinophetr ovcrdose (>4 g 1>cl dcciliter) rvith acetllcvstinc. Use the acct:rminophcn trcrrtn)rlt llonlogram to inlirrrl the p:rtient ol' frnih that in largc populations an acetaurinr4rhcrr lertl similar to thztt in the patient usuallr- results in he1;atic: tosic ellccts or miuimal toxic efIcts, dcpending on the l(\'cl.

D,sl
Pittsburgh, PA 15213

Cl.

\'\'rrlLc:orrr, Il.D.. PH.D. Universitl ol l'ittsbulgl'r

School ol lleclit:ine

Prescon LF. Roscoe P. Wright N. Brou'n SS. Plasma-paracetamol half-lit and hepatic necrosis in patients with paracetamol orerdosage. Lancet 1971:l: 5 I 9-22. 2. Perrot N. Nalpas B. Yang CS. Bcaune PII. Motlulation of cytochronre P-150 isozl'rnes in hunran liver. by ethanol and drug intake. Eur J Clin Inrest 1989: I 9:519-55. 3. Lauterburg BH. Velez ME. Glutathione deficiency in alcoholics: risk tacrr firr paracetamol hepatotoxicity. Gut I 988129: I I 53-7. -1. Whitcomb DC. Block GD. Enhancecl susceptibilitl'to acetanlinophcn h!'patotoxicit)': the ellct\ of tasting and ethanol use. JAMA (in press).

l.

Fiilkirk FKI 5QE.

Unite<l

Kins(lonr

A\I)RL\\' D.s rt,. lI.B.. Clu.ts. Falkilk an<l Distlict Roval Intrnrarv

L l.

Runack BH. Peterson RC. Koch (iG. Anrara lA. Acetarljnophen oveLdosc: 662 cases Iith eralurtion of oral ucetYlcysteine treatment. Arch Intcrn Med

l98l:l1l:180-5.
British National Formulary. Nu.27. N,larch

199-1. London: British Medical Associatinn. 199.1:20- l. .1. Miller LF Rumack BH. Clinical satty of high oral doses of acetylcysteine. Semin Oncol I98.1: l0:Suppl I :76-tt5.

The authors replr': 'lb tfu Editor: \\ihitcornb, r:iting Plcscott et al.,r states that ittgcstion ol'25 g ol acetarninophen clearh llls in the rarrqe associatccl rrith l'rcpatotoxic ef]cts. Horlever, i.rn :rbsrlutt: rt:lation bcr.ecn all ingestcd clrrse ol' acctaminopht:n ancl thc I)lasma level or degree o1'hepatoto.xicitl has uot bcttt clt:at'lr t'stablished in hunrans. Accoldins to the acetanrinophen tlcut-

t3r:

]'Hti \L\\- E \GLA\D.JOUR\.\L OF .\lLl)lC: l-\li

\or'. 10. l!X) l

(in nricroelanrs pcr nrillilitcr') tras not iu thc loxic range; the l)lasma levcl, ttot the total itrgcstt--d anrount. is comrnorrlv uscrl zrs a guiclt' to ltrt'clict toxicitr'. \\thitconrb also st:rtcs that thc inclr.rction of'cr-tochromc P-{50 enzr-nrr: activitv is onlv niildhittctcascd bv alcohol and rcturns to norrnal rvithin {ivc clavs, suggcsting that reccnt alcohol use is moLc irnport:rnt than long-term use. Houeveq the induction of crtochrome P-450 cnzvnlc activitv br,alcohol can ranse {iom t$r- or tlireelcrlcl to six- r.rl sevcr-rlbld ltccausr: ol lzugc variations in gt-netic anrl cnr,irournt:ntal firctorsl it t'etulns to nrtrnlil lithin firr: clavs onlr afiel abstilcnce.j C.lontinuctl rllrilv usr: rrr:rv not allor a l'ctul'n to normal c|tochrome P-{50 enzvme activit\,. Although the reduction o{'glutathione levcls in alcoholics rnav be onlv modest, a modest dccline mav be sulficienl to increase thc toxic t:lct:ts, if'toxic at:cumulation of at'etarninophen rnetabolitcs frrrthcr cleplctcs glutathionc stores. Srrrilkstein et al. suggest that the conrbination cll hcpatotoric eficts uith a rrontoric zrcctarninopheu plasnra lcr.el that ur: clescliberi irl a long-tcrnr :rlcohol trser is "re rnark:rl:le" in that a silnilal case has not bccu rt:1:ortcd in stuclics invoh'ing over It)0,(X)0 cases. Ho\r'cver, nrost studies har,e nnt becrn specificallv designccl to erplorr thc outcome in such paticnts. Firr cx:u-r'rple. arnolg thc studies citcc[ ]tv Smilkstein et a[., onh' 5 ol' thc 662 cases in the stuclv leprtrrd bv Rumack ct al. invohed trontoxic acetalnirxll)hen levcls altd a histor'\' of' long-tcrnr al-

nlellt l)onrogriirll.r olrr l)aticnt's plasna acctaninophen le\el

MINERAL BALANCE IN POSTMENOPAUSAL

WOMEN TREATED \{ITH POTASSIUM BICARBONATE
7b tht, Editor: St'bastian aucl collcagues (Jture 2,i issur)r le-

p('t that the aclr-r'rinistralion ol' 1tc-rtassiuur lticalltonatc lerluced uet acicl ancl calciurr crcretirr arrcl hacl bencficizrl ellccts on measures ol bont- tutnover in pr,rstnterropausal \\'onlen. l'lrcl sugecst that the "krng-tentr aclnrirristlatiotr of 1:otassium bir:arbonatc r.nar thelclble be t:llctile in ltrelcnting anrl tr('iltir)g l)ostnteltol)arlls:rl ostcc4tolosis." It is r;trcstionablc uhcthcr thc lesults ol this stuclr ar(. I'clrvanl to thc tast

cohol use l'ithout short-tcrm alcohol ingcstiou (rrhich alorrc: has becn suguestecl to bc protectir.e against thc hcpatuto\i(' ellccts ol acetaminophen).: Iurthclmore. in the \ational \Iulticentt'r Studv lcpolted br Smilkstcin ct al..r patir:nts rr it[.r a historv of alcohol trse l\'cre unilirrrrilr,clistribr"rtecl arriong thc sturlv groups itr otdcr to dccrcase conliruncling variables. r\lcohol rrse \\'as not cvaluatcrl :rs al inrlcpcnclcnt risk Tact<lr. An accuratc historv inrlicatine thc :rmount and time ol- irrgcstion is critical I'or plcdictinu lrt--patotoric elcts. Lr our prticnl, the rmsc't of'srlrptoms and the elcvation in thc livcr-enzvrne levcls colrcl:rtccl rvith thc exl:ected clinical stirgcs of' acr:tarninophen toxicitr', suB-gcsting that thc time of insestiort ras
acc ur'zttc.'

Darie points out tirat hahing the acetamiuoplten level at rhich treatnrcnt is consiclered is routine practicc ir paticuts u'ith an alteration in cvtochromirl enzvrnc incluction. Wc art: not a\\'are of'such a routine practicc in the Unitccl States, but this approach shoulcl be consiclcred. \Ve agrce rlith \\'hitcomb thal a 1;otentiallv lifsaviug aucl bcnisn therapv should not l:e rrithhckl solclv on the basis of thc :rcet:rnrinol;hen levr:1. The case ol our paticnt demorlstl'ates that rcliancc on thc acctantinrDlten trcattent rrontogram as a guidc to thctapv can havc firtal collse(luenc(:s. \\t do not aeree uith Snrilkstein et al. that a leconsidct'ation of cun'ent trcatment rcconrnrendatiorts uoulcl bc "a big stcp backl'arcl."
Lrs.r Clrrr:urr;.

majoritv ol uomcn. The proti:in cont(:nt ol' the u,omen's clailv cliet (96 g per' 60 kg of bodl'u eight) u as cousidcrablv higher than that cousunred l)\'nrost \\'onrcn. Accorcling- to (lilta collecterl b\ thc \utiolal Clcltt'r' fi'IIealth St;rtistics iu the fir'st -\ational Htalth ancl \utliti<r E-runriuatiorr Suln:v (l!)76 thtrtglt l9i3t)).r thc nrcan ploteirr intiikc o1' \\1)lner) .lit to (i I r-eals o1- agt' in th,: [,niterl States uas 5i s pcl clav an(l t]lc !)0th ancl 95th Pclt--crttile valtrcs nelt'90 ancl I()7 g per'<lar'. r't's1rt'ctirt'h'.'flrus. litlt lcss than l0 pcrtcnt of tlrc Postnrcnr4rilrsal rolt](]tt itt thc Unitetl Statcs consunring thc lalgc uluount of plote iu qir t'rr irr the stuch'l>i-St'bastian ct al.. thc gcnelalizabilitv ol theil finclings is opcn to qucstion. Rais.ing- thc (lictar\ pr.tltt'iu intake is known to irrcrt'lsr uIitt:rt v cnlcirrm rxt Lction lrnrl rolscn (alciunr l;:rLurt e.' Fbl cranrple, in atr analvsis ol'l6 publishccl stutlies invohinq- l5l aclults. Kcrstr'ttel attcl Allctt+ culculatccl tlrat irr pels,,rrs rlrtirrg less than 200 g ol'protcin dailr, thc lclation benle,'rr l)rotrin intake arlrl urinan t:alt--iutn cxctctiou uas littr':u', srrch that Ibr cach 50-s increment in tlailr prot('in intake an ('\.tril 60 nlsol'raltiurn las ercrctecl in tht'utine. Thus. iI tltc usual clietan protein inllke ol the urnen stucliccl ltv Scbastian ct al. u'as sinrilal to the U.S.,rvelage lirr this age glorrp; tht' rnean (+Sl)) r'ecluction in ulinarv calciulrl crcretion rel)ortr-([ (-6++ l9 Ins per clar'pcr (r0 kg) dtrrirre supplt'rrrentation rrith polassium bicarlxrnatt upplorinr:rtes tlrc irrclcasc in <:al<itrur excLction intluccrl lrv tlre consunll)lior] ol- llre crcrss l)r'()tcirr clulitre the str.rclr'. 1'hercfirrr:, potassiurrr ltic:irbonatc strpplenrentati()lr nrrl\ have k:ss clfit acl in thc nrajoritr o1- postnrcnopausal \\'onren. nho ]rave lorrel plotein irrtakcs an<[ errclogenous zrcid kracls thzrn thc \\onrell in the strrclr'. Until a stu(l\-ol'uonrt.n sirrn srraller ar)rounts of ploteirr is conclucterl. the srr*=aestit)n lhtLt alkiLli suppler-rlentatioll lte trserl 1o prt\1'nt ()r tlcut olitcol)or'()si\ ill l)r,\llltIll(,1).llrs.ll \\(,nr( n is l)rcilrirtllr'('.
Boston. -\IA 021 I I

Rtr:u.ru J. \\'rxru, Pu.D. Tirfis l,'rrivclsitr

\[.]).
\'1.D.

Krrru C. Xlr:r'rx.
\Iaclison.

\\iI

53792

Univcrsitv of' \\Iisconsin Clinical Science (ientcr

L 2. 3.

Prescott LF, Roscoe P. Wright N. Brown SS. Plasma-paracetamol halt:lit and hepatic necrosis in patient\ ith paracettunol oterdosage. Lancet l97l:1: 5 r 9-22. Rurlack BH. Petcrson RC. Koch GG. Amara IA. Acetaminophen overdose: 662 cases with evaluation of oral acetylcvsteine treatment. Arch Inrern Med

Sebastian A. Harris ST. Ottawal, JH. Todcl KM, Nlorris RC Jr. I:rprored mineral balance rnd skeletal nretabolisnr in poslnrcnopausal uomen treatc'd qith potassiunt bicarbonate. N Engl J Med 199,1:-l-i0:1776-81. 2. National Center tbr Hcalth Statistics. Canoll -VD. Abraham S. l)resser CM. Dietarf intake source dara: United States. 1976-80. Vital und health statistics. Serics I l. No.23l. Wrshington. D.C.: Governnrent Printing Omce. I98-l:l+. (DHHS publication no. (PHSl E3-l6El.) -3. Allen LH. \[bod RJ. Calciurn and phosphorus. In: Shi]s \'l. Olson JA. Shike M. eds. Modern nutrilion in hcalth and disease. Sth ed. Vol. l. Philadelphiu: Lea & Fcbiger. 199..1: I-17. -1. Kerstctter JE. Allen LH. Dietarl, prolein increascs urinarv calciuu. J Nutr
I

989: | 20: I 3.1-6.

l98l:l.ll:38(I5.
Perrot N, Nalpas B, Yang CS, Beaune PH. Modulation of cytochromc P-150 isozy'nes in hunran lirer. b1' ethanol antl drug inttrke. Eur J Clin Invest 1989:
I

9:5.19-55.

Thc :ruthors rtplr':

7b the Editor: l)r'. \\irocl is skeptital that yrotassiutn bicurbonate rill halt' a long-tcllr l;errelicial ellct orr bone rnuss beclrtrsc tltu rlir:talv intirke ol g;rotcitt in lhe lrrtnen rlc sttrcliecl \\'as at thc high crrrl r-rl'tht nonrral lansc lirr licc-living sr,rl;-

-1. Srniikstein MJ, Knapp GL. Kulig KW. Rumack BH. Eflicacy of oral N-acetylcysteine in thc treatment ol acetaminophen overdose: analysis of the National Multicenter Study (1976 to I985). N Engl J Med 1988:319:1-557-62. 5. Lintlcn CH. Rurnack BH. Acctaminophen overdose. Enrcrg Med Clin Nrth

Am

198-1:2:103-

l9

\i,1.

ll.l

( t(

)Rl{

t.tsPo\t)ll\(:E
narv calciunr ercretion clccrr:asecl lrr about one thir(1. 'Ihe nrean l;ast'-litrc ert'rctiou of net urci<l (37 rltrcl ptl clur) ancl
c:Llcium (122 mg [:].1 nrnlrl] pcl clar) rtas about lrirlf th:rt o1' tlre l)ostnrenoparrserl rrrrntcn in otrr stuclr. .\tcolclinglr. .rrbstantiallv lorr'cl rlietan intakcs ol' l)l'otcin than tlxrsr ol tht' \\'om('n irr oru strrclv rroulcl not prt,r'lucle lr ltcrrefit ial tl'fer:t o1' potassiutn bitarl;onutt on borrc. il' thc hr ltocirlciLrlic t.[]r t otpotassiurl bit'arltorr:r{c 1;crsists cltrlirrg kruq-telnr lLrlnrirrist

jects.'fl-rc clailr intake of l)lot('ir] \ras !)6 g l)el'60 kg ot'bochrvt ighr (62 l)er'(.cllt allimul an(l 138 pt:rct'trt rr'gctablt ltrotcitr). irith ll llercenl o1 llir totrrl Plotcin intlrkt cor.nine liorn ltlotein-errrichecl blcur[ lirrnrrrlatt'rl rrccotrlinq to thc r'('cil](' of' Lrrtz.i Clle alh. lol er irrtzrkts of ploteitr rrotrlcl genclatt' lou er' anlour)1s ol aticl. 'l'hc cak irrnr-rrlrsting- lrnrl lront-rllrstinq cf1cts o1' 1r'oteitr-clt'rirtcl ut icl. lrorr t'r'rt. clo not abltrl;tlv cornmencr'alt the Iriqlr cntl ol thc Irorrrt;rl Innq'r'ol proteitt int:rke. R:rtht'r'. tlrc rttagttiturL' ol ll pct'cult irrt ia itrchrt e<l bl rlietalrplotcin irrtake. likt thc inriclertce o1'hip liactrrlc rrncl tlrc rlet Lr';rst' irr lront' rnincral rlensitr. is :r < ontinrrorrs lunctit.rrr o1'the .ulount ol Plotcirt ingcstccl olct':r br',,iLtl lalrgr ol intake l llcc-livirrq subjccls.r-r-\s Il':trttr' pLrts it. "'l'lrt' [calciulic] el'li'r't crtcrr<l-r.r(l'oss th( lirll larrge ot'plotein inlakes. li'orn rlcllcient to sulli'i1.1ulcl is rrot firtutrl olll\ \\'itlI'erct'ss'l)lotcin intakt."r l,r'err lith intakt's ol pt'ott'iu in thc rni<lcllc ol thc nolnlrl rlrrig(. \\'()nler) rlr ut lisk lirt :r ncgatirt tlrlcirnn l;alarrcel thc rleqlec tlr'pcrrcls on srrclr furlors as talcirrm iutakr'. ('stlogen stiLlrrs. :rrrtl llrt sorrrte ol clictarr ptott'itt (atritnal or
rr.geIrrblt ). Pol:rssirrrn bicrrllroturtr is ir ll()t.nl lrr.poclLlcirrric .rg.nt. ,'rcrr uhen plottiu intake is not high. Spccilic:Llh. \\e strr(li('(l sir noltn:ll utt'tr t'atinq:r rrlrolt'-tirocl rliet cont:rinirtu 113 g ol plott'in pt't' clitr plr' (i0 ku (unpublishr'rl cluta). 'l'lrt v tcceivccl 90 to 100 nrlrx)l ()l potassiunr bicar'lron:lte l).r'([e\'li'r'ight dars itltcl a bast'-lint'perio(l ol-t'iqht dais (ltie. 1). \\'ithin l8 horrr-s afit'r' tlrl initralion ol potassirrttr l;ic:u'lrorr:rt,. LrliBefore KHCO3 During After KHCO3

rati()r1.

r'r'rrorY
R.
San I:t:urcisc o. (1.\ 9 l

flt

nt

l+ll

St:s.rs'r r.rr. \l.I). r: .\Ionrrs. .]R.. \1.D. L triri r.itr ,l (.;rlilolrri:r. S;rrr ft.urtirt,r

l. 2.

Lutz J. Calciun balance and acid-base \tatus ol romen as rlelcd by in crcased protein intake and hr sotlium bicarbtmate ingestit. An J Clin Nut:
I

98.1:i9:28 I -8.

Helnel' RP Protein intakc anrl thc calciunt ec(ntonl\. J Am Diet Arsoc I99l: 9l: I 259-60. -1. .{belou BJ. lloltbrd TR. [nsogna KI.. Cross-cultural associatiorr hr'tuc'cn dietarv animal protein and hip trrcture: t hl pnthcsis. Calcil Tissue Int 1992:50: I -l-t. -1. Hu J-F. Zhao X H. Paryir B. Cantpbell TC. Dir'tary intakes rrrd urinarr ercrctiorl of cleiur)l and acids: I cross-scctionul stud\ ot \\omcn in (lhinr. rn J Clin Nutr l99l:58:398-.106.

5. llu I

F. Zhao X-H. Jia J-8. Parpia [3. Carnpbc-ll TC. Dietarl calciunr antl hone

tlcnsitr arong nrirlclle accd ancl elderll uomcn in Chinr. Art J Clin Nutr
l99l:-58:l I 9-27.

PULMONARY-FUNCTION TESTING
KHC03

o
^a

tU

x
=o)

vi

,'Y @

>(
Y\ LO)^

t5

il'
-40 -60

il
l1

knotrr agettts ol lutrg injulr, such as asbrslos or cliisocrallatos) arc at higlrcl risk of lunc clisrascl scrcerling an<1 nrcritoring alc rrlprolrriatc lirr'lhem." Thc reli:rcrrccs citt cl rlo not zlppr'al t() sul)port scrcerring ancl <lo not ollr'or rcir'lo <lata thal roLrlcl .jLrstil-v spiromctric st lecttins ol'all snrokcls.2 Tlie stanctalcl reii'renccs lirr thc eliLlrration anrl rer'orrrnlr:lcl:rtiott of'sctt'ertitrg 1;roccclut'cs Iirl the gerrer:rl ltoprrlation or' subpoptrlatiotts are the positi,,n l)ill)( r\ ()n \(rcrninq issue(l l thc Clanaclian Tltsk l:orcc on the Perioclic Ilcalth E-xitrnilualion. the L.S. Prt'r'entivt Sclviccs f usk ltrrcc. ancl tht Atlt't'ican Clollee(- of Phvsiciirns. \one rcconlmencl tlrc rrsc ol' sl)iromctr\ lirl screcnine ant po1;trlation or strbpopulation. Lr acltlition. .r rt-c('llt leyiol ol-screctrirtg ptocr'<lulcs bv Sox cli<l not rrrcnlion sprironrctrr rrs a possible scrt'cnirrg proceclule for'
;

ltr (iliqro's lclierv ol ltulrnonlrlr-lirncti(,n t('srine (.Julr'7 issue).1I l'as sutprist'cl l>r'tlrc stiitcnltnt. "Sonr(' strbetorrps ('.o.. cirtirlr:tte sntokt-r's ancl pcoplc erltoserl to
7b tlte l-ditor:

sruokcrs.l

; P
(u

_c

1 3 5 7 I11131517192123
Day
Figure 1. Effect of Oral Administration of Potassium Bicarbonate (KHCO3) on Urinary Calcium Excretion in Normal Men Eating a Whole-Food Diet Containing an Amount of Protein in the Middle of the Normal Range (48 g of Protein/Day/60 kg). The bars indicate the daily mean change in excretion relative to that before the administration of KHCO., and the thin vertical lines above the bars indicate the standard errors. To convert values for calcium to millimoles per day per 60 kg, divide by 40.

Thert'are at lcast tl\'o qurstions tlrat lrart'to be lnsut'r't-rl belirrc spirorn{rtr'\' can bt' cottsiclcrecl a rotrtirre sclc( linlt' t( st Ior sr.nokers. l-irst. uill the rlcnronstration ol an ircccltlatetl cleclirre in lrrng lirncliou in the l0 to l5 pclccut ol'srnokrrs rlestinecl lo Iravt irir'flor obstrrrt:tion t'esult in a hisl]o'ratc ol' stnokirrg t:cssation thirn thzrt associrrtcd irith thc strorle recomnlcn(lation to quit sn.urking that cvcl'\' l)hYSician shoultl nrake to evt'rv srnokcr.'Scconcl. rill the "nornral" ratc ol'(l('clint'in lung lunctiorr in tht'r't-rnaining [35 to !)0 pt't'cerrt ol' stnokcrs provicle a llrcasr.lle of rcasstrrarrcc irncl rlett act li'onr the plnsician's abiliti to irrlltrcr.rcc srnokcrs to cluit? Sincc
thesc clut-stir-rns havc lrt to lte alsr'r'ecl l;r'ttpploll'iiit(' stu(lies, it is l)l'cnrature to l'r'('ournlen(l sc reening ol srnokers l'itli
.ipit ornt't Lr'.

Austin.

'l'X 7lt70l

Wtrst'or
SoLrtlr

\\i.rtt'tr.

ll.D.. \l.P.H.

.\ustirr I l,'rrltlr I )ist r it t

L l.

Crapo RO. Pulnonarl -funclion testing. N Engl J NIed 199+:l-l I ::-5--iU. Amcrican Thomcic .Socien. TasL Group on .Screcning lbr Adull Rr'spiratory' Disease. Screening ibr adult respiratory discase. Am Ro'Rcspir Dis 198-l:
I

l8:76|t-7.1.

r3 t+

TItE

\t-\\' E\GL-{\D.JOUR\.\L

OF

}IIrl)I(;I\E

\or.

lt). Ml-l

3.

HirnkinsonJL.Pulmonarvfunctiontestinginthescreeningofuorkers:guidelines for instrumentation. performance. and inlerpretation. J Occup Med

I

986:28: I 08 I -92.
199,1:330:

,1. Sox HC Jr. Preventive health services in adults. N Ensl J Med

1589-95.

Dr. Crapo replies:

To lhe

Editor:

I apprcciate I)r. \\alr's

comrnents and basi-

as corrlparccl $ith voungcl paticnts. Accordilg to l9!]l clata lrorn tl'rc -\alional Clentcl Ir' Hc:rlth Statistics, thc asthrnulclated dt:zrth rate pcr l(X).000 p;rtients is [30 pcrcerrt liighel amorrg peoplc s'ho aLc 0o to 7l lears olrl than irnrotrg thosc rho alc 5ll to 6{ r-r'ars olcl an<l three tinrt:s the ratc alllonethosc J5 to 5-l vcars olcl. With t.he adclition ol- salmctcrol to a thcrirpeutic lugintcrr. patients shorrl<l be instructe(l to usc thtil shc't-acling. inltalecl

calh'agrc('rith thcnr. It uas rrot rnr intcr.rt to imlth'that all srnokers shruld bc scleenecl l'ith spilou-rctn'. I{, honever, I)r. \\iarr's re{t't'ctx:es to tlre position papcrs on scrccninq bv thc (lanaclian Task lbrcc and thc American Collegc ol Phvsicians ar(' triken to mean that there arc no indications Ibr usinc
spir'ometrv to screen ar)\'gl'oul) of-smokcrs, I disacree. \h'position on screenins coir-rciclcs rrith that rif'the Amcrican Tlror':rcit:

B,-adrorrrqic-l'eccpt()r :rgonist firr tht' rclicl'ol aculc bronchospzrsm. Salnretcrol is inclicatt'<l lil' Iong-te rm rnainttnllce 1r'eatnrcnt aud prcv'ntion ol l>ronchospasrn in 1)atielrts \\'itl') zrsthnla rtho arc l2 r'eals ol'ase or oklel ancl lccpile legular'
trcat.ment rith inhalecl. short-actineB,-agr.rists. It is ntrt inlor the I eliel-ol thc acrrte svrnl)tor)rs ol'astlinra. as csplicitlv statcrl in both the plo<lutt inli'rnaticr ancl thc inslfr.lctions Iirr use ltv I)atier)ts. \\'hcn usccl :rs rt'conrtrtentlr'<1. saln.reterol ollrs patit'nts sevt-r'al unique bencfits, ancl onsoing u'orlclrvi<le monitolins ol'its s;r[tr cLrcs rrot in<licatc an irrct'eltsctl t isk .rttr,,ttrg .lrl,'t lr plrtit trlr.
clicated

Socirn.r rlhich states, irr part. "Apparcntlv healthr, high

lisk patients slxrulcl bc considcred for spilomctt'ic tpstinu ir\ l)alt ol llicir lt'gul:rr eramination." As examples, thcv inclrr<lc
ht'm'r' smokers arrd people rvith occupuriiotral cxposurc to tlre

inhalation ol- hazalcrus subst:urces. Salt Lzrkt-

(lit\. Ll-f 8+l+3

RouriR.'r'

O. Cn.rpo, \1.D.
LI)S Hospital
Rcscarch Tlianglc Palk,

K.rrrrlrr:r A. Rrr:r-rnu. \I.I). J. Rrr:tr.rno'l'r rorrpsrr. Pn.rnrr.l).

J.urrs ts.D. P,rr,ru.r. I[.]).

(ilaxo

l.

Anrerican Thoracic Society. Task Group on Screening lbr Adult Respirarry Disease. Screcning fin adult respirak)ry disease. Am Ro, Respir Dis 1983:
I

\Cl

277()9

l.

28:761,l-7-1.

Jenkins MM. Price K. Pounsfbrd JC. ct al. Satet)'anrl efficacy of salmeterttl in elderll'patients uith asthnra. Am Rer Respil Dis 1992:l-15:Suppl:A65. abstract.

RISKS OF SALMETEROL?

Daue CN. Cheesman MG. Pounclstirrtl JC. Salntctcrol is an ellective bronchodilator in elderly pllients. Eur Respir J 1992:5:Suppl l5:20-lS-205S. rbstract.

[o

the

]rditor: I have a large gerizrtric-intemal mcdicine

practicc. I havt- cnthusiasticalll'adopted tht: use ol thr: salutt'It'rol inhurlcr (trrice ir clar) fur-ml patients as a \\'av to irnptove conrpli:rnct-. In the past thlec rnonths, tro eklerh pxtients u ith rnocleratcll' sevele aslhma have hacl f iital respiratorr ar'r('sts at honre. Botli ucre lourrcl holding their inlralcrs. Both h;trl bccn tolcl that ther-shoulcl expect a delav oI a half-lxrtrr' to an hour in the onsct ol- thc action of salmetclol and that tht'1'could use thoir l)revious inhalcr (albutcrol) lirr emcrgetrcies, but thcv did not do so. I bclieve that alth<>ugh tht' occurrenct: ol thesc t\\1) c.lses nrav be er t'oincidencc, the use of salmetcrol mav pose an incteasccl risk amolrg the eiclerlll I suggest cauti(t in thc usc of tliis tlrug until the l:ood ancl l)r'ug Administrzrtion irrvcstigates this matter. Ph'mouth.

Stark ID. Luce P Inhaled salmeterol in c'lderlr patients s'irh rerersible airu'ays obstruction. Eur Respir J I 99 I :-l:Suppl i -l:-j-31S. abstract. Castle W. Fuller R, Hall .[. Palmer J. Screrent natirwide surreillance study: comparison of salmeterol uith salbutamol in asthnratic patienls \\,h requlre regular bronchodilator treatrrent. B\,lJ I 991:106: I 0-l-l 7. National Arthma Education Progran. Expert Panrl reporr guidclines ti the diagnosis and management ol asthnra. Bethescla. Mtl.: National Institutes of Health. August 1991. lNIH publication no. 9l-30-12.)

CANCER THERAPY MEETS p53

To the Edilor: Kinzlel ancl \'irgelsteirr (.fuh 7 issuc)r eloquenth' cliscuss thc clinical inrplicatirrs ol' basit r(,searclt olr thc p53 tumor'-supplcssor scne. In kev st;rlements. thev srrBgcst that p53 tnutatiotrs mav provide a gclr('tic bzrsis lbl cL'ug rcsisl:rnce anc[ thirt the lelation betleerr pil3 nrut:ttions anrl thelapeutic responsc shoulcl bc rtrifierl. hr lrt t. thc fi<.lcl rnoves lapiclh-aheacl, and a pl3-rlcpencle nt cross-r'('sistare e t(, ionizing racliation ancl chcnlotll('r'il[)('utic agcnts can nor lle cousidcrerl a rell-cstablished ltht'rromcnon. It uccurs not orrlv as lt result o[' p53-rlependcnt apoptosis n]o(lulaling t r trrtorir'itr'.1 but also becarrsc oI p53-clt'perrdent g('ne an)])lificalionir p53-clepcnclenl e-rplc'ssiorr ol- thc nrrrltirlnre-r'esistance gent' l.lIDR I ).1 ltt<l pj3<lt prrrrk rrl t rll prrrliIi'r'rrtiorr.-''-

\tA

F'r-,rrr N. lir\K[r.s'rEr\*. \I.l).

02360
I

l0 Long Pond

Rd.

Glaxo, the nranulactureL of salmeterol, rcplies:

To the Editor: It is dillcult to comnrent on f)r. Finkclstein's cases as pr'csented, l:ecause hc provides fi'rr details. Since sallleterol rst bccat'ne availablc, in 19!10, hol'ever. ovcr I I ntil-

f'lrerc is also stronq evirlt'uce that

p5l3-clcpellclent cross-

liorr palit-nt-months ol' e\pcricnce havr bcen accumrrlatccl rrorklrtidc. Salmt'tt:rol l'as shonl to be rell tok'r'ated ancl t'f'Iective

in

177 r:klt'rlv patients

l'ith asthrna (mean

age,

)70

x'at's) unrler conlr.)llcd conclitions in zr total ol ninc Glaxosponsored clinical trials.r-:l In addition, lalge, doublc-blinct.
randomizo(l surveillance studv conducte<l in thc United King-

rlotn inrolverl over' 25,0[X) patients. alrproxirnatelr' -1000 of tr'ltotn u'ere over 65 r'cars ol age.r No cviclence ol'a c[r'ugrelated incrcasc in the risk ol' molbirlitr' rr mortalitv iu lrrv
age group, includiug the elderlr'. r,r.as uotecl. 'l-he irrrl>ort:urcc ol'eclucation Ir p:rtir.nts rilli asthm:t cantuot bc ovcrcmphasized.' llducation is particulallr irlportant lirr t:lderll'patients,:r group uith a creatcr potclttial for pr'rl>-

rr-sistallce is indeed clinicalh lt'lt-r'ant. irr lh:rt :rl;rron'nal p513 ncgativeh'afli'cts thc I)r()gnosis ol u-raur tllnrol's. Since the app('nrancc in tl'rc .Journtlof thc levier article on pirl3 in l9!t3.r'" aclclitior-ral dirtu lr:ue bccn publishecl orr thc pleclictir-e rolc ol' p5l3 mrrtatior.rs an(l lh(' abnolrrral rspr-ession ol pjll protriu irr a varictv of tur.r.rors. 'l'hus, p5li-clepenrlcnt closs-r't'sistuncr' is a t:onrplex l)hcnomrrt()n u'ith it clcar clinical iml;ot'tance.

CrH-+03
I

I Blsel, Su'itzerlanc[

H. Pr.rr:n Rr tz. \I.D.

Bast'l Lniversiti Hospital
199-1:

Kinzler KW. Vreelstein B. Cancer therap)' nreet\ p53. r'. Engl .l NIed
3.11

lenrs in cornpliance and a highct-risk ol'clcatli li.onr aslhma.

l.

:19-50. Lo$e SW. Ruley.HE. Jacks T. Housnran DE. ps.3-Dependent apoplosi\ nrodulates the c)totoxicit), ol lnticancer agents. CelI |993.71.t)51-67.

\-ol. :l3l -\o. l9 3.

Yin

CORI{ESPO.\DT].\CIE

I3l:r

Y Tainskl N{4. Bischoll FZ. Strong LC. Wahl GM. Wild-type p53 re-

c;cle control and inhibits genc amplification in cells rvith mutant p53 alleles. Cell 1992:70:937--18. .1. Chin K-V. Ueda K. Pastan I. Cottesman MM. Modulation of activit)' of the promoter of the humun MDR] gene h1' Rirs and p53. Science 1992:2-55:-159stores cell 62.

Despite a thorough search ol thc litcrature. \rc coulcl not fintl clata on thc (lisilllctant propcl'ties ol' fluicls cor'r'unonlv
used to cnrbalm c(r'pscs. The ernbiilnriug- tluid use(l

in aniltog*h

nrr' dcpartmcnts c(ltains firativcs. clisinlctants.

ccrol.

5. 6. 7.

Hanis CC. Hollstein M. Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 1993:329;1318-27. Clinical implications of thc p53 tlrmor-supprcssor gene. N Engl J Mcd 199'1:
330:86.1--5. Bourhis J. Bosq J. Wilson GD. et Jl. Corelation bet$'een p53 gen( c\pre\sion and tumor-cell proliferation in oropharyngeal cancer. Int J Cancer 199,1:57:

and salts dissohecl in latcr. Thc most fi'cquentlv usecl Iiratives and clisinlictiLnts are ethanol) fi'nr.rlin, anrl Jrherurl. Lr suspension tests, 251 pcl'cent ethanol ;rncl 0.5 pcrccnt f<rrnnlclehr-de rvere sholtt to be ef-fective against HI\r.r IIoucvcr. it is not clear lhetht'r tltcsc concentriltions are also r:Ictive in
cadavers, firr several rcasons. First. in suspension tcsts. cell{i-ee vinrs is tcstccl, l'hereas in hurnans. HfV- is also bczrlizccl rrithin cells. Seconrl. the concentr'.ltir.ln o1'thc c()llll)onellts of enrbalming fluicl rlt:creascs as the\-dilluse thloughout tht: huntan bod): 1hild, scveral classes ol' pl'ochrcts inclutling phenolit: agents al'e partialh' ol complctelr. inactivatcd bi' the I)resencc of prott:inr':: this sensitivitv t<> organic load sirggr.'sts that the elficicncv o['the clisinlectants will be much louel in c;rcl;n'ers tharr in in vitro tests. On tl're othcl hauct, the combinati<.rn ol firatives an(l (lisinlectants in en'rbalmirrg Iluicl coulcl bt: nrore eflctile in inactivating HIV than cach agenl alone. Ncvcrthclcss, the 1>otential hazard poscd bv enrbalmed col'pscs to mcmbers ol- alrat()nr\' clepartments necrls itlestigation. u'ith l)articular enpliasis on the lensth of tirnc it takes to inactitatt: IIIV in all parts ol cmbalned hurnan bodics, including the bones (since HI\,'mar be spread bl acrosolsr).

{58-62.

POSTMORTEM VIABILITY OF HUMAN IMMUNODEFICIENCY VIRUS IMPLICATIONS - ANATOMY FOR THE TEACHING OF
7b the Editor:

I rant to drar r'our attention to thc viabilitr'

cadavers and

ol the htrman immunodellcicnc\'\'irus (HIV) in

thc implicirtiorrs o[-the presence o{'live

III\r during

cmbalm-

ing proccclures in arlatorn)' clepartments ancl during the dissection ol' cnrbalmed cadavers b1' students. It is thc policr- of'anatom\'(lcpartments to kr:cp thc period bctrrcen the death ol'a patieut and thc cmbahning of the bodv as short as possiblc to minimizc degeneration. Rcccnt findings inclicatc that HIV irr zi paticnt lho dit-d of'AIDS is still inlcctious at the timc of the bodr's arri\.al at the anatom) departmcnt ((-18 hours post mortcm). Inlectiorrs HIV has been

rcportccl in the pleural lluicl, pericardial fluid, irnd blood of such patitrnts aiter storage at 2oC for up to 16.5 da1,s post mortem.r Viable Hr!' ras also rccovered lrom bone liagments, brain, bone marros, splccn, and lvniph nodes fi'om a patient rvith AIDS at autops). six clavs alter deathj Recentll; an occupatiorlal HIV in{ction in a nursc l"ho \\:as pricked bt,a rreedle that had becn used on a drug addict \r'as Ieportcd:l; at the time of thc injurr, the sourcc patient \ras negativc lor zrnti-HN'antiboclies blrt positi\.c t'ol p24 HfV antigen. This (:ase ol lransmission cluring tl're "lindorr period" ol HIV infction sLrggcsts tl-rat the bodics of p;rtients *'ho havc died ol'AII)S are potcntial carriers of inlectious virus, as are other bodies arri\-ing in dcl:artments ol'anatomr'. Therefore, univcrsal precautions should alt'avs be lollorvccl in embalming rooms o{ allalomv clcpitrtnlents.

Dttx Dn Cr.rl-rrun,
ts-1090 Brussels. Bclgiurn

Pu.D. Vri jc- Univcrsiteit Brussel

l. 2. 3. J. 5.

Douceron H. Deforgcs L. Gherardi R. Sobel A. Chariot P Long-lasting postmortem viability of human immunodeficieno' r irus: a potential risk in lbrensic medicine practice. Forensic Sci Int 1993:60:61-6. Nyberg M. Suni J. Haltia M. lsolation of human immunode ticicncl r irus (HIV) at autopsy one to six days postmortem. Am J Clin Pathol 1990:9.1:'1225.

Ippolito G. Puro Y De Carli G. Itlian Study Group on Occupationll Risk of HIV lnfection- The risk of occupational hunran immunodeficiener rirus infection in hcalth care s orkers. Arch Intern Med I 993: l -53: l,l5 I -8. Sattar SA- Springthorpe VS. Suriral and disinfectant inactilation of the human irnmunodeticicncy rirus: a critical revies. Rer Infct Dis l99t:l-1:-1307.

Scully C. Samaranal'akc L. Martin M. HIV; answers to comnron quc\rrons on transmission. disinfection and antisepsis in clinical dentistry. Br Dent J 1993: 175:1'7 5-9.

r3l6

THL

\L\\' E,\GL-{\DJOUR\AL OF \IEDI(lI\E

\ov.

10. 199{

OCCASIONAL NOTES
THE TRAIN IS LEAVING THE STATION

Ir is 7 a.m. I am sitting in a heroically proportionecl lecture hall try,ing to lbcus mv e\:es. On a table in front ol me, slightll' blurred, sits rvhat n'as advertised as a continental breakfast: lukervarm colle in a styrofoarr-r cup and a Danish, n'hich is "continental" onlf in thc sense that it may be a leftover from D-day'. I am recovering from a bad night on call. Several assaults bv telephone designed to make me "aware " of a problem at a nursing home reduced the architecture of' my sleep to rubble. RE\{Jess, m), mind \\'anders. I catch m1'self thinking about a girl I dated in medical
school. " I he train is leaving the station." This phrase shoots

that of the anuouncement, \'ears ago at a concert in Las Vegas: "EIvis has entcred the building." Disoriented, a young internist in lront ol' me leaps to his feet, spilling his lukerarm crifle. He shoots me a panicked look, but I cannot reassure him about this train. I fincl mvself r'r,ondcring, Has Elvis been sighted on this train? Am I likelt,to bun-rp into a brokenhcarted Ann-llargret on the platform?
There must be othcr trains
1r'e could board. \\'l'rat

past me like a cannonball across mv bou,. Although grogg),, I am an,are that I have heard it before. About five minutes before. A speaker in the lront ol the room

it at regular inten'als, possibll' as sort of mantra. A consultant from California is haranguing (in
has been repeating

a
a

about the Peace'frain, the Love Train, the Soul'l-rain, the \Iidnight Train to Georgia. or the one that lell off the bridge over the River Kr.r,ai? We'r.e got to be careful rhich train rve hop aboard. Recall lbr a minute The Little Engine That Could. It chugged along say'ing, "I think I can, I think I can." The problem Ior n're is that at this point in m1'career I not unno longer think I can. In fact, I knou.I can't - precerless I fill out endless rclerral forn'rs and obtain tification {rom a clerk u.ith an eighth-grade education. NIoreor.er, thc little engine pulled a circus train. At my' age, do I reallr'\\'ant to share a compartmcnt rvith a giraife?

soft, Ne'rv Age rvay) the hospital's medical staff. Assembled in all our giorv at this earlv hour, becpers honking nonstop, rve resemble nothing so much as a lost flock

Rcmember that train bearing a\\.ay a mournful Humphrev Bogart, the platlorm at the Gare de L1'on
l,acant of an1'sign ol Ingrid Bergr.nan? It could be a sad trip if I boarded the urong train. "Think like a businessr.nan." The consultant is urging us to jump on the PHO train. Nlissins it rvill mean

of rvild

geese.

But u'e're not lost. \\'e'r,e attr:nded meetings like this

in the past. Battle-scarred

veterans

of the \{anaged

Care Wars, many of us have alread,v been captured and capitated, branded and corralled. lVe'r'e been H\'IO'd, IPA'd, PPO'd. We have seen our goocl names printed in slick brochures and touted among the populace. We make a grim-looking audience.

exposing rnv patients (he refers to them as "market share") to risk. Ilarauding bands of Hl{O clerks n.ill su,eep dou'n at night from the parched hills and carrl' oll great numbers ol' mv patients. I u'ill be lelt alone,
destitute.

"Life is change." Another phrasc zings past

me.

lVhere does this guv get his material? The Californian

is urging us to take advantage ol a ne rv concept itr managed care: the physiciar.r hospital organization, or PHO. His tone is urgent. There's not much time left. We ma1' be able to ensure our financial viabilitv in the Iuture if \'r'e are not averse to selling our practices to this nerv PHO entit1,, lvhose dissipated representative sits blandlv on staJe looking somer'vhat like MickJagger on

The situation seems desperate, the landscape charged u'ith danger. Can this PHO protect me? Would it be better simpll-to l.rire armed guards (equipped n'ith automatic \\'eapons protected bv the National Riile Association) to l'atch over mv patients? And u-hcre is l,Iarshall Dillon nou'that I need him? He's dou'n at the depot, *'aving goodbl'e to \Iiss Kittr', n'ho has had the goocl sense to board the train that I nor,r'fel certain I
should be on. Run and jump, I tell m,vsclf, run and.jump! "The train is leaving the station. Think like a businessman." OK, I r.r,ill. Hand me one of those golden parachutes 1'ou businessmcn get. I'm readv to jump. Give me a push. With m,v luck I'll float dou,n right onto thc lVhite Housc grounds, be taken prisoner immediatelr, b1' Socks and

Iithium.

Am I read,v lor this? The idea that the Nlanaged Care Express mav leavc me behind is beginning to \{,orry me. Can w'e find out a iittle more about this trainl Where is it eoing? lVho is the enginecr? Are sleeping accommodations available or rvill $,e ride in
cattle cars? Is there a club car, a snack bar n{rere I can get a hot cup of coffee?

Hillary; and paraded in ignominl.belre the running

dogs of the press corps. "The horrorl The l.rorrorl" Slr,eat soaks my bron'. Am I au'ake or asleep? I find m1'sell'running down the platform at the Gare de L1'on.

an1'place

IIy mind is drifting. I imagine mvself seated on a tiny train. A little girl in pigtails rvalks dorvn the aisle
shaking a box of candr.. But instead of thc larniliar chorus "Good 'n'Plentl; Good 'n'Plent1" I hcar "single paver, single pa),er." I crane mv head out thc u'indou' to get a glimpse of the engineer. Sure enough, it's Cho.1Choo Charlie. Is this the right train lor n.re? "The train is leaving the station." Each time l're sa1's this it sounds morc like a thrcat. The phrase clearlv has a galvanizing eflect on the audience, much like

A train is pulling au'ar'. \I1' girllriend from mcdical

school (she u,as alu'a)'s smartcr than I u,as) is alreadv on board, leaning out a rindou' atrd observitrg mr' progrcss rvith clinical detachmcnt. "Life is change." I must get on that train. I race to\l'ard her, gasping for breath, arthritic knees about to gile out, nrv vision blur'-

ring. Chest pains course up mv neck and dortn I.ut'lelt

arm as I near tl.re caboose. Surnmoning mv last nlotor nellror-r, I fling myscll' f'orrard.

\:ol. 3lJl .\o.

1!)

ts(X)K R}]\IIE\VS

Crusade

Remembcr the scene in Itdiana.fones ond thc Last in u'hich tl-rat beautilul bloncle \zrzi temptress

of anothcr man. Evcn lrom this clistance, I

recoqr-rize

lor the Hoh' Grail but it just clLrcles her grasp? That's uhat hi,rppens to me. I lall hcarih'to thc tearclives

his silhoucttc: it's Eh is. I arvaken alonc, mv hcad resting Llncomfortabl)- on the rock-hard Danish. Thc lecture hall is emptr,. The
speaker eviclenth' has ridtlen o1' ir.rto the sunsct. 'Ihe train, thc tr.Ianagecl Care Express. has left.

{br the last time to rrtv departing girlliiencl. I see her turn slorvlr. li-om the liuclon'ancl melt into the embracc

soakcd platform. Crun-iplcd and bruist:cl,

I iook up and u.ave goodbl'e

PO. Box 30ti Concordville. PA 19-l3l

BuRro-r J. Wrrlr.rrrs,

II.D.

BOOK REVIEWS
Psycnra.rnrc Eprorurorocy:
CONCEPTS AND METHODS ASSESSMENT

rcll unde rstood eve n bv the lv not br societv in general.

re

st ol mcclicine, iincl certain-

(ThcJohns Hopkins Series in Psrchiatn' atrcl Neuroscit'trce.) ,clited br-Juan E. Ilczzich. \Iigucl R.Jorgt:. and Ihsan \[. Salkrun'r. 6I2 pp. Baltirnolc,Johns Hopkins Univcrsin' Press, 1991. $6r. ISBN 0-U01u-+615-3.
Arncricans t:njov big nou:ls, biogt'aphics. and textbooks.

\or thev havc a big book on psichiatric cpirlemiologr.

The

titkr rnav reprcscnt a limitation. since rith the prescnt tendencv lor psvchiatrv to cuclclle up to the nculosciences it lould

bc nrore au nanl to spt:irk of neur-orpiclctrrioklgr'. Pclhaps this is a selling point. 'l'his is zr bie book. but is it reallv a book at all? It is a collection r>l publishecl picces, u ith conlnrntarics ar-rd shol't slrmm:rries ol'other articlcs. It is not the proceeclir-rgs

psvchiatrists because it irrvolves lhat thcv do clinically'r.rit large. The rcsult has bccn a bettcr description ancl classifrcation of svmpton.rs, svncL'omes, and clisolders. This in itself' shoultl lead to tnore eflective ancl efllcient trcatment. This book, therelbt'c, dcserves to be rrcll receir.ed as a tributc t<; all thc l'ork clcvotecl to rnt-thodologr'. The obr ious cavcat, hou.cver'. is that the unarare rill lind the detail tcclious ancl the expcrt ri1l knon it alrcadr-. Finallr; n'hoer,cr attends that course in Pittsburgh lould gain lrom the inclusion ol' rnorc on the historv o[' thc topic and lcss discussiorr of irtclividrrlrl qucstiotrnaitcs. Tolonto, ()N

Epiderniologv has bcen a popular scientilic pursuit ol'

\I5T

\I.R.

E.r.s'r'n'o()D. N{.D.

1RB, Carracla

Clarkc Institutc o[ Pslchiatrr'

of a confrcncc.

r.rr

a Frstschrili. or thc- invited vit'us

of cxperts on a fixecl topic. The book is unusual, bccause all thc nratcrial hzrs bcc-r'r successlulh pcer-revicu'ccl ancl pr-rblishccl elserhcrc. So lhelc docs that leavt- tlte revicler? Gircn that I arn cited. along l'itli liiends ancl collcagues, lhat can I.justiliablv sar'? -fhe eclitors state that thc dcveloptnenl ol the book "started iith the plt'paration of a course on assessmcnt itt psrchiatric epidcmiologl at the Graduate School ol Public Health ol' the Univcrsitv of'Pittsl:rrlel-r." Fint-, but al u'hat Ievcl. and Ibl teachcrs attcl studctrts alike.'Arc these articlcs prcparation for lectures aucl scminars. or aIe theY backgrotrnd reading? Thev arc lull ol detail anrl trnlikelv to hold thc l>cginner's attcntion. 'l.hosc u lto clo psvchiatric epicle rniologr', such as the peoplc \rho atterld thc biennial r:onlrence ol' thc \\irlld Psvchiatric Associatiou, Ior esample. u'ill recognize namcs ancl substance. But thev are an in-gt'oup. not tht: ridcr rorld. f'hev r-nav cvr:n cluestion thc choice of matclial, sincc tl'rc al'ticlcs arc lrniliar brrt llot neccssirrilv
c

BrNcn Eerruc: NAtunn,

TREATMENT E,dited
99ri-0.

ASSESSMENT, AND

bl Clrristophr:r G. Failburn ancl G. Tercncc \Yilson. {19 pp. Neu York, Guilfbrd Pless, 1993. $+0. ISB\ 0-89862Research r)e\r-s on nutrition. cating- bchavior, and bodl' u'cight is t:urrcntlv cpluring headlincs in the nrcclical literatnrc ancl the popr,rlar press. 'I-his multiauthored book prt-rvidcs a timelr; conprehensivc olervier ol currcnt rescarch on bulimia n('rvosa! I'or lrhich binut: rating is a sine qua non, and explorcs the rolc of' binge catirtg in anorcria n,'n'osa and
obc sitr'.

In thcir'prefce. the eclitors state, "Some books scem contrived: ft us this book seemed lilmost :r necessilr'." Thc probehaviolal :rnd mcclical svmptoms associated l'ith bulimia ncrvosa ancl anoresia ncrvosa. In Ict. this hcuristic theme u'r-rrks notal:lr, l'cll, lith a fi'n t-xceptions.'Ihe book is methoclicallv organizecl itrto majol sections covering clinical charactcristics, cpiclcrniologv and etiokrel; and cvaluation and treatment a stlucllrr(' that contributes to its readabilitv and acccssibilitv as a relcreuce 'rvork. The introcluction iittempts to clefine bingc cating prisinglr- cor.nplex task and includes a lscinating historical overviol ol- the mcdical litcrature on binge ealing. For n-rnspecialists hoping {-or an update on psvchiatric nosokrgv lbr thc eating disorders, this book proviclcs a cogent euidc to the lcrurth t-clition of' the Diagnostic ond Slati.tical -llanual oJ' .\[ental Disorderr (DSNI-IV), rect'ntlv publishcd bl the Amcrican Psvchiatric Association (Washington, D.C., 199-l). It also includcs an oveLlicrr' of nerll clelelopccl recommcndations Ibr the subclassification of paticnts uith l:ulima ncrvosa accolcling to rlhether thct-engegc in recurrcnt purqing;, ancl of
spectivc reacler mal incleecl roncler wht:tlre r a book rhose focus is bingc eating can accurateh' portra)' thc complex

lassic.

So, apart fr'oni the stuclents in Pittsburgh, rho rrill leacl ancl benelit fi'om this book? It's hald to sa1, especiallrsince thc book conccntrates or1 assessmcnt, concepts. and nreth<lcls r.atheI than finclings. It carlllot conrparc. loI exCatchnrcnt Area

anrple, t;ith Ps-ythiatric Di.orders in .lncrica: 7'he Epidemiologic ,\tudl' (Let: N. Robins arrd Darrcl A. Rcgicr,

cds. \er York: Frcc Pless, 199l). u'hich recountcd the

Epiclcmioloeic Catchmt'nt Area studies instigatcd bv Rosalvnn C,'arter. For martr', that book, sholittg that melrtal illness was uiclesprcacl ancl mort' conrmon than manv other lcll-knoun discases. rras a rcvelartion. It ras creitilg stul1. leading to grcater public alareness and improvecl

trcatnlenl. Ol:r'iouslr'. though, l ithout thc in'rprovec[ reliabilitv and vaIiditv me:rsurL'nrents of' pslchiatric phenomen.r ()\'er thc p:ist lrr clt-cadcs, the Epiclcnriologic Catchment Arca stu(lies l'oulrl not have comc about. \Icasuring thcsr phenomcna has bcen a success stor1, 1;r'obablv nr,rt

TIIE,

,\E\\' L-\Gr.A\l)JOL R\-\L OF ,\IEDI(:I\E

\r.

10.

199.1

l).lticnts \\-itll .rnorcxia ncr\'osa accordins to \\'hethel' thcv eng.r1', itt r'( r u|l ( nt I>irrqc eatirrq ,rr ptrrqirrg. :\s nolecl in this book. thcre has lrectt less e\tcl]silc rr'search on thc prclalent:e and role ol binge eating in ol;csitr. Rellccting thc neecl ['rrr aclclitional inlcrrmation in this ;rlca. thc DS\I-IV inclrrcles rcsearch critt:ria hrr' "bingc-eatins clisolclcr" irr an appcnclir. In this contt-xt. thc psvchosocial Iactols. neclicul collscqLlences. and treatlnent of obesitv itself arr' l:rrgch lrovonc[ tht' scope of'Bingt Eating. \\'ith a lirlrnat rcllectirrg scholalli: cletailed rcvicrrs of tht' Lesclrrch litt'ratlrlc, tlrt: book rcflccts points ol'r'icrv that alc eclcctic ancl inclusive. A consiclelatiou ol'thc causc of thc bchalior', lirl t'ranrple. cliscusses dcvelr4rmcntal, psicholoeiczrl, an<.1 psvchobiolrgic nie chanisnrs. Inclilidual cltapters o11 trcalmcnt cliscuss plurrmacologit' interventions. short-telrrl psr-choIosical :ipploachcs, ant[ pslcho<lrnanric l)svchotherapr: Clinical approaches ftl' the tretmcnt ol' patients rr-ith rell'actolr' illncss, such as hospitalization, iLLc less lcll covelccl, rr:flecting a lcss estensivt- r'esczit'ch litt'ratttre itr thcsc are:rs. Thc chaptels t'cflect the cxpcrtis(' and individtrirl points o{' vicrr'o1'thc contlibutors. lho are active inlcstigators iu the fit'ld. Thc bibliog^raphv in cach chaptcr is conrprchetrsive ancl up to datc. and the index is notablr-cor.upletc. Rcaders iuvohr:d in clinical teaching nrav llote thc relative paucit\'of illusllative casc prcsclrtations. Thc conchrclinp sectiou, h<xler. cr. contilins an extcnsirr:lv lt:searchecl intcrvicrr qucstionnairt Ibl thc stanclarrlized asscssn.rent o['paticnts l ith cating clisor'dets aurl a tlctailecl outline clesct ibing a cognitive-bchavioral trcatmer)t ap1;roar:h lirr bulimia rler\'osa. IIr sutturarr'. this is a user'-f iendh. colrpre]lcnsivc surnmarv o1' thc current r"escirrch litcraturc on l;ulimia ntn't.rsa ancl lclatcd eating disorclers. Gcneralists u ill fincl this lxrok a valuable rcli'rence. Fol clinicians alcl resc:rlchers lho l'ork regularh' lith l)aticnts lho have eating clisorders, this slioulrl
l)r'()\'e a ielcomc hanrlbook.

D.rrr
Boston.

C.

lIA

0221i

Beth Israel Hospital

Jtur-tsor. \I.I).

is a sct o['svnrptor.ns clcrivcd fi'otn sociocultural al)d persol]al psvchokrgical cxpericnces [i-rr rrhich n-rcdical advice is sought anrl a diagnosis is rnaclc. \\ rmcn givcn this ncl tliagttosis nra\- l)e t'asicr to treat (h:ru the maloritr'ol'uomcn l'ho have svmptolns c()usistcnt lith prenrenstrual sr,nclrornc but rrho do not meet the strict cliagnostic critt:ria. \Iost lorncn being secn lor prer-nenstrual svuclrome have a complicatecl and inconsistcnt patteln of s\-mptonrs. Plemenstrual svndrome rud premenstlual d1'spholic clisolclt't catr be clistinguishccl bv esarnining the clailv recorcls a \\onliur has kcpt of'her r.nenstmal crclcs. On thc bursis o[' l'ristolr' :rlonr. manr' \\'{)nlen associatt lters, rnel, lanrilial, antl l ork prol:lenrs ritlt the onset ol their r.nenscs. 'l'hc svnrptotns neecl to I)c takel) scrioush ancl mav rcfleci a prolorrncl lil rlistLrrbante. 'fhev rnav also t'equit'c extcncled evaluatiot.t. \\bnrerr uho repot't havitrg pt'ctnt:nstrual svndrome but clo not n'rcct tht' strit t clitcria lor prencnstrual clvsphoric disoldcr irle particularh- likcli to have another psvchiatric disorcler. such as dvsthvmic clisolcler. grhobia, obsessive-cornpulsive clisorclct, or alcohol- or substitttcc-abuse disr.rrder. Thcr- can bc l'ell scn'ecl bv lelrral to :r psr-chiatlist lol' trcatmcnt of thcir prir.narv psvchiatric problcr-ns. A trcncl torrarcl pt'oqrcssire rrc.rlscning of' problems ovct scveLal urcnsttual cvclts in ptospc( tivc lecoLcls can be a plcclrrsor of a nrajol mental clisorcler and anothel rcason lbr a psvchiatlic refcrrarl. 'fhelc havc bct'u llr.rmcl'ons tl'catlllcnts lcrr premcnstt'ual svnclrome , an(l the bettcr stuclies itre t-ell sLlnlniu'izrd in thc clrirlrtcr it Prtntanslruol D-ysphorias bv Rilcla-'liar zrnd colleagues. 'l.he clTctiveness ol tr-eatmt'nts li.rl thosc rrho mect the criteri:r lor prunenstrual clisphoric rlisorclcr raiscs irlter'r:sting qLrestions about tl'ris cliagnosis. A placebo resp(,lsc is frecprcnt anrl substantial. 1'hough a horr.nonallr' corrclatccl clisorcler. pl-cmenstlual svnrlLorne is not consistenth'hclpcd bv trea(ment rlith prorestcronc. Ovulation supprcssors such as clanazol mavlork llut havc exccssivc sidc ef-lccts: the cxtrcme of oopliorectomv has been usecl. Psvchotherapics have not becn lcll stucliecl but ckr r.rot apl)eal' espccialh plomising as tht: onlr- Itrnn ol' trcatment. \Ianr- sor.r.ratic treatlnents (such as

PRnvExsTRuAL DYSPHORIAS: MYTHS AND REALITIES Eclitcrl br. .Judith H. Gold :intl Salli K. Sevcritlr. 262 pp. \\lLshington, D.C., Arnerican Psvchiatric Prcss, 1991. 532.

rsB\

0-rJB0+B-666-X.

'l.his rcsorrrce book l;rings us up to datc ou the Ihcts about prcrnenstrual dvsphoria lhilc sholiug hou thesc lat'ts are enrl;eclcled in a sociot'ultural contcst that is Ii'aught u-ith psvchological r-ncanir.rg and r.nvthokrgv and tnuch itr trt'ccl o1'cotrtinuecl studv ancl clalifi catiott. Pret.t-tcttstrual clvsphoric clisor'der. or plcme nstrual dr-sphoria, is the curLenth acccptecl tet'm Ii a controvelsial ctrclition related to premelrstrllal svttdrornc and late-lutcal-pl'rase cllsphoric clisordcr that has been aclcled to the Iur-th eclition ol' the Diagno.ttic and 'Stati.titl .l I u rr ttal of .l Icttttr I Di,ordtr,. 'Ib nrcct thc tliagnostic criteria lirr prer.nenstrual d1'sphoric clisolclrr'. a \\'onrarl necds to dcmonstrate! l:r' kccping daili lecorcls ol- trro nrenstrual c)clc':j, that dLu'ing thc last rcck ol tht' luteal phase in most mcrlstl'ual cr-cles, slr has at lcast fi\'e phr sical or t'rnoticr:rl s\nl)toms that m:rrkedlv iutcrlelc l'ith htr lork anc.l social life. Ol thc fir'r:, onc n-rust bc associatccl iit]r a moocl disorcler'. such as severe allective labilitt, inctcasr(l :urger or irritabi]itr. ol clcplession. Thcse srlrptoms nrust be present prcmenstruallr' (in the lutcal phirsc), l;r.rt abscnt in the u'cek altel thc onsct o1- mLuscs (the follicular' phasc): thcv cannot bc ahals prescnt, r)or can thcv rcflect exaccrbations ol other conclitions. Prcrnenstmal dvsphoric clisorclct'lack' a l;iologic rnarker'. its cause is utrknorln. and its nzrtur:rl histon- irnd cpidemiologr- have lrt to l;e clesct'ibecl. It

thosc invohir.rs alprazolan, bromocriptine, buspinrc, light thefap), melolazonc. naltre\one, ancl spilonolactonc) al'c supcrior to placcbo rhen aclministcrecl cvclicalh. Ol 1>articular' interest is u'lx- alprazolar.n rrorks. aucl rln' clcpenclencc and ckrst escitlation do not seem to occur lhcn it is givcn in a clailr' dost' ol'0.25 to {.0 mg <rlv in the slrnptomati( phase. This book is particularlr'apptopriatc l'or avnccologists, primar'\- cafc phr-sicians rr ho scc man\' \\'omtn rlith pt'cmenstrual problcrns. ancl psvcliiatlists. It is au oxcelleut resoulcc hrll o1' carchrllr- clocumcnted and current str-rclies. \\'ith its balanct'cl prcsentzrtion ol- contrortrsic's, tl'ris book goes lal to conrbat the stign'r:r that has bcen associatcrl l'ith plcnrcrtstt-ual svnclLor.r'rc.
Boston. -\IA 02115

RrennrlJ. Arrcr.. \1.D., \I.P.H. Han'ar-d Ilcdical School

SELF

A Sruprr, Tnnonv oF THE

$25.

Bv Davicl \V. \Iann. 176 pp. Ncrr \irrk.

\\i\\i. Norton,

199-1.

rSB\

{t-39'.3-70t72-7.

-\Ieclicinc is lal rnore than arr cmpirical :lctivit\', ancl pl'x'sicians are not merc technocrats. 'I-he underlring philosophies of hor lre rcgarcl natur-e ancl oursclves cletcrmine the verv challictrr ol' meclicint:. 'flrus, tlre vast cli{Ircnces bctucett n-reclicincs il China ancl the \\'est mav b(i traced to thcir dilIr'ing vicrr-s of the l-orld. Ouc ol'tlic quandat'icrs itr \Vcstet'n thotrght and \\'estcrn meclicinc is the Cliirtcsian ntiud-boclv dualitr-. \iarious plrikrsol>hical lcsponses to this problem havc given lise to clillrcnt psvchologies rl' tl-re self . In me<licine,

Yol.

ll:ll \o.

l!)

BOOK RE\/IE\\-:i

l3l!l

111;11 it mearrs to be an in- evervthing liom pslcl-riatt'ic has implicatiotrs fol dividual pra('tice to doctor-paticnt relationships. Thcolirs ol' thc self

our understarrcling ol' selllxrocl

thcir diliderl subjt'ct-prcrlicatc status to a uniou, r'et this is uhat is rcquirecl. Ilann's sell'is lost in a grnmnrat'\'et to l)e
ar-ticulated. Hr still relrs to the psr-chiatric patient as a sul).jcct. :r multitlinrt'nsion:rl cntitv that he c:rnnot aclequatelv rlcscribe. His rlt'scription lltcrs becatrse in nl' opinion hc is sinrplv and ironicallv still lockecl into a pre-Ht-gcliarr psvchologr. \Iann, uho persists in regarding the st'll'as alr entit\. onh' vaguelr- pcrccives tl'rc phikrsophical conunclnrnr. It'rve seek a ucl psv'hologr. it is unlikelv to ernerst' li'or.t.t the version clescribed in this book. A psvcliologv basecl on a reflr:sivc lirn<liorr trrust dcvck4r .l gl'.tnrr.nilr- that pl;rces ortrsclvt:s itr out'lorlcl, ncither as strbjects nol olr.jects, but ils ilrteqratcd "sul).i(:ct-lcss verl)s" o['e\periencc. This is the proicct bt'gun l' \\'illianr.Jamt-s, an(l onc that lenrains itrcornplete. -lir so situatt' the sclf is l rnost ambitious philosophical task. perhayrs inrpossil>le. ][anv are hailinq the cnd ol 1;hilosopln, not bt'causr the t'l:rssic yrroblcn.rs hzlt' been soh'ecl. bul bccause thrrt-- is grruirrg atrxit-tv that phikrsophical analvsis cannot rcsohe strch isstrt's as the scll. \cvertht'lcss. ert'tt llarecl. dclivative clorts such as \Iarrn's lemincl us that thc ploblt'rn renrains ancl sce ks l'csponses.

therclbrc allct nrattcrs rrrll bcrrrrl t'sotclit'

discrrssiorrs

anrong [)hilosoPhers. TIrc thesis o|-'1 ,Sinple Thcort'rtl tht,5'r'f is that (lrr self'has

cztt lt Ir;lt ir pcrsonal histc'r. ancl aul at\\.trcness ol'ottt' emboclirncnt. But rhat is "rclation"? \Iatttr has iticor'prrr:rtctl a donrinant 20lh-ct-ntrlr\ l)hilosoi)lrical torrct'nr t'ith thc so-callrcl sel[-othcr lclatiou thitt incluclcs not onlv our rt-l:ttionship rrith oth('r l)elsons iul(l our envilor-rr.nent (both social ancl natural) brrt also our rclationship uith orrrsclu:s. llann r.rses tho tctnl "reflcsivitr" to itrclir.atc sell'-alutrttt'ss, a psrrhrkrgical <lirnt'usiou in rhich \r'c rccognizc thul lhcrc is a scll. Bv lctrsing otr sclf-cortsciousrtess, l'hich is the ittnt--rmost ltart ol'ottr iclcntin. llann builds :r psrchologr tliat rrses sell-iclerrti{ication as i.r nlcilns ol'opetring- our psvcltt'. Bv t'splicith isolating the reflr'sive compol)ent ol out cor.tst iottsttcss. IIanrr hopes to develop nt'u categories of psrt'hiatrit th'sliurctintt atrtl it.nprovt' olu trnrlcrstanrling^ ol nolrnirl bchavior. 'l'hcrc is thc gerni oI a porrcrfirl lrslchologv in thc rel]crivc scll. l;ut I clo not belicle \lann lurs rlevelopcd the potcntial of its intrigtring nlrrativt. polet'. I regalcl his thesis as:r preltrclt' ol perhaps zur allusion to a rich intt'llct'tual historv thzrt uill revt'al u highh' nuanccrl aucl cornplt'x thcorr'. Illlher than ol-lr a rlt'tailcd (riti(lur. I lill onh indicate thc origins of
g^t'nclal

tlrrt'c clir.nensions: tirrrt-, bodr' (spacr'. loosch'r'it'rrtd). lation. 'l-hc iirst trl'o cutt'gories arr' st'lllerplallitt()t\

:rn<[

rt'\\-e

Ar.rRe L 'Lrunr:x.
Boston.

ll.D.

\lA

022l5

Boston Univ'rsitr

Coron Arlas oF
0-72 I 6-+663-8.

CLTNTCAL

Evrnvorocv

ll:rnn's ploposirl ancl tlie

rlirt'ction in rr.hich he

ancl

tsr'Keith L. \Ioore. T.V.\. Pcrsaud. iinrl Kohei Shiota. 2J2 p1;., illustrutc<1. Phil:rcielphia, \\iB. Saunders, 199-1. SB9. ISts\
This is an easilv rcad book that makes clnbr\1)log\-cas\ to I think it is geared n)ol'c t() llre sencrirl public than to tht rneclical profssion. fhc book cleals uith the cmbnrrlogic processt's lcading to congenital abnormalities.'I'ht:re :lle rore illustrations than te\t. and the illustrations arc beuutifirlll prest'ntcd and st'll annotate(I, :r misturt' o[' diagrarns, ltaI trltrasonogrlms. anrl photouraplrs. \Ianl arcas arc onh skctchilr' <liscusscc[. Frlr exarnple, thcrc is no nrcntion ol' hcpiltic and pant:reatic :rbnormalitics. rvhcrcas alrnormalitics ol- thc car and erc are describc<l in great dctail. The chapter on the cardiovas('ulal'slstem in lirct covcrs onlr thc hcart, lith verv little discussion of'the vascular svstenr. ltrr instancc, therc is no clescription of'aortic c[eveloprnent apart li'om a bricl'rliscussiot-r of thc aortic al'ch('s. 'l'here is also no nrention o['tltc rvork bvJapartese rcscarchers
rrnclerst:rncl. IIorrever,

olhcrs ol'sirrrilat' thotrght utav be hcacle<I. That tlris purticular borrk sccms to lllc iIIr ina<lt'cluatc liruttclittion lor a ncrl psr. chologv basc<1 on rcflerivitv harrlh' torrtlernns tht' gcneritl

ctlirlt.
-'l ,\inllr Theo of tht,5r'll originatt:s iu a complex histon'of' the philosr4rhr-o{- personzrl identitr: Hegt'l ancl his Mth-centtr-

sensc ol'i<lcntitr'. Kiclkesaalcl \\'r-ot(' thart the sell'is "u reiation rhich rclates itscll'to its oun sell. ;Ln<[ in rclating itsclf'to its orlrr sell'rt'latcs itsell to anothcr."'l'ltis tk'linitiort nas expancled ll'20th-ccntrrn phcnonrt'nologists. rr ho lcrcrrsccl ort hou rclations clcfinecl. ol' iruthenticiitecl. thc sell. Ancl latt'r thcorists. oltcn lelr'rcd to ils l)ostnro(lcrnists. clt'constructcd the self as conrplctt'lv clepcndent on a particulut' crtltnral anrl histolical
dc

n'lirllorvcrs chunqerl tlx'srll'fl'orn att cntitv lo ir l)r-ocess. Thcir vicu las that tlrt's<'l{'tteith,'r is givcn Itol ettrt'rscs in sor.nc firral lorrn lrtrt cun be crnstilutcd orth in t'clalion to its llcthrl th:rt is the cxtt'r'iol rvorlcl ol sonrc irrrrcr' objcct

sign.

lLutn's thesis is a :onlirst'cl rnixttrt't. of these tso viels. Otr tht' one hand seenringll ultau.arc ol tlte rich histon' ol' his
central iclc:r in philosopln: hc alfirnrs that "the st'll'i' cluintt'sscntiall\ rt'flcxivr." \'et. on the othe r hall(t, he fils to clrau'thc lirnrlanrcntal lesson li'n.r.r that chalactr:r'ization: thc scll- as an cntit\ clissoh'es. \Iann corrt.cth' pcl ceilcs th:rt therc is a ploblem. nit h hc charactcrizcs as tht' st'lf 's indctcrn-rinacr'. This hc fincls to be a nirtlrral conscqucncc ol Heisenbcrg s unccrtaintl principle. in rhich. in quar.rturn mt:chanics. the sirnrrltan('ous clctcrmination ol'both th(' rnonrr:ntum anc[ thc positiou of'a l).rrticlr is ir.upossible. Horr'. or Iirr that r.r.lilltcr', \\'h\'. rclations lbunrl in elcrncntarl parti('lc pllsics rescnrblc hurnan rclationships is uever cxplainc<I. I tkr not bclicvt'tliat thc: prol-llem ol- defining the sclf'can bt' explzrinctl l;r'tht' metaphvsics ol'quarks. \lost Conler-nporar\ Phikrsophe|s regarrl thc sclf Problcnt :rs onc ol'scvcr:rl lrprs ot'imbroglios itrtpost:cl ltv thc linritatiorrs ol'our lzrneu:rge . ()nc viel . irr kt't'pirrg u ith llarrn's ou n orit:nt;rlion, is tl-rat tl-rc self is nritlrt'r'srrbjcct nor obirct but rcflexivitr' (in philosophital tt'rnrs. a dialt'ctic). Onlv vt'rbs captrrtt'such action. antl uc rkr uot lr'arlilv collal;sc rtlbs Iiotn

on snrall-bouel atrcsia in [tal lambs. an abnormalitv causecl l' tlrc lilrrrc ol' crrrraliz:ttiott. Hacl this l;ook gonc into nrolc cletail, it loulcl have been a usrfirl :rdclition lo the librarics o['pcdiatricians, petliatlic sut'geons, racliologists, and ol;stelrit:al ultrasono{raphcrs.

Blackler. \Iancht:stcr Cl-rnot.lrl \I. Dltc. C:tt.\I. Ultiversitv ol \Ianchcster \l9 2AA, Unitecl Kingdonr

Drsrasns oF THE BnoNcutorrs

Editt'cl lrr- Garr R. F,plcr. { } } pp., illustrirtccl. Prt'ss. 199 1. S105. IsiB-\ 0-7{Jl7-0123-6.

\el

York, Rirven

Iixcept rvhcn caused bv noxious gascs or lirrnes, bronchiolar' clist'ases havc krg bccn viese<l as diseascs ol- childhoocl thut arc caused rnainlv br-microbes. Rccentlr. bronchiolar diseuses have bcen recognized as clinicallv inrport:rnl clist'ases allicting all agc gr'(]r.rps. Onh' in tht' past clccatle lrarr' the clinical and pathological latures ol rnanv ol- thcse diseascs bccn charactcrizcd su[ficientlr'[rn'trs to bcgin to undcrstand tlrt:n.r iu ati orclcrlr' Iaslrion. Ttr mv kuol'letlge, this tcxtbook olJers the orrlv tholough cliscussion of'diseases ol thc bronchiolcs. In

llil

|H

[ \]r\\' L,\(;l.A\l).JoL

R\AL OF -\ II;DICI \ Il

\or'.

10.

l!)11

the plcf:rcc. f)r'. I)1;lel states thal he clcsigncd tlrc book to bc a cornpreltcnsivc rcfcrt'nce lirl the clinit:al ancl pathological [atttrcs ol lrtrnrirtr bronchiollrr discrLses as \\'e cul'fenth un(lel: startcl therrr. I brlielt' hc actornplislrec[ this task quitc uell.
\,'atiorrs chal)tels hatc great sti'cngths arncl sot.rrc l'eakncsses, but I r-iei thc book as it l-eltome urldition to ntv libralr:
Divae.c o[

tfu

l]rutnthiola

is a multiaulll'erl \\1)l'k and

is

stvles. Somt'chaptt.rs ale crccllcnt. Othcrs are l)oring. al)(l therc is corrsidt'rabk. ovet'lap an(l rel)ctition. IIou,evcr', nrost cliaptcrs irre lt.ll tllittcn, utrcl thc

t]roclolt'ulitlcn in nrrrltiplc

nrarrr illrrstrations ancl tabk's ale trsualh clt:ar. Dr'. Ilpler's

t-hoict' of contril;utors is velv goocl.

'l'hc nr'\t t\\() sr-t:tious consiclcr lrloncliiolar rliseascs Iilst .rs "rrir\rav t[iscllrlers" irr)cl th('n as "inlerstitial cliscases." Fronr a lxrthogettctic slancllloint. I roulcl crrsiclcl all ftirms to br brotrchiollrl anc[ rrrost {irlnrs to bc tapablt' of carrsinr.l interstitial rliseasc. rlepcnding on tlic severitv ol the injurr: thc chronicitr ol'tlrc injulr. antl thc abilitr-rl- 1hc hrng tr lcpail itsr'H. 'fhis clivision al)l)ciu's artifir'ial but is pcllraps usecl to sepaes.

l'ht'organiz:rliotr ol-the book is unusual. It is divirlecl into lour scctiorrs. rith thc filst clt'rrrterl to:u)iltollt\: l)atltolog\; l'('s('at'(.h. anrl a clinical classiication ol- thc llont'hiolal cliseas-

chiolitis) bLrt is larg-rlr rlcvotccl tr.r a cliscussit.rtt ol'the icliopathic zrncl knorlr) caus('s ol' bronchiolitis obliterans ot'gellizing 'l'hc lbru'th and final scction clcals l'ith blonchi1)ucutrtonizr. olar clisease in chilrh'or. Sevcral chirpters alr: srrpcrb. (ihapte r [i. bv Finklcstein and (losio. is e-xccllent. It bcautilLrlll inteslates rk'scriPtions ol 1-lathokrsr. l)athosellesis, arrr[ clinicirl cliscase. Sirnilarlr. Izinti's succ:irr< t chal)tcr olr a slol)a1 r'icu' ol' icliopatliic blonchiolitis ol)litcrilns olq:urizing pneunroniu is esccllt:nt. II I had to select otrc r:huptel ls outstanclitrg. it rrould be thc otre l;r Ciorclier, l'evrol. ancl Loilt:. lhich Iircuscs on blonchiolitis oblitelans oLgzurizing plrcrrrnonia as a nro(lel o(' inflantrnatolr' (airuarJ Itrng rlist'asc. This chaptcl is a svrrth.sis.l rctent cllitu on lrrng injun ancl lellair that portrivs the eu'rrts n'sulting in clirrical
cl i

ncakest chapters are on ilnaging. ()ticn thelc appeals to be conlusi.rtr about rvhethcr 1he autlx.rl is cliscussing ltront'hiolitis oblitt'r'ans orts-ilnizing pneunronia or l;r'onchiolitis oblitelans. \lani illustlatirrs art' soo(l an(l rlill prov' usclirl,

scase.

-l'he

Itol'evt't

ganizine Pneunrouia. '|he sr:<oncl scr:tion inclrrckrs rlescriptions ol- srnoker"s lrronchioIitis. nlineral-dust llonchiolitis. clillirsc prrrrlrronclriolitis, :rncl the sl)c('tnrrlr of icliopathic ancl knourr ciurscs ol bronchiolitis oblitcrans, 'l'hc thircl section
cliscrrsses lt-spir:r(orv bronchiolitis (a lblrr-r o1' srrrokcr's bron-

rate bt'ortchiolitis obliter':rns Ironr lrronchiolitis oblitelans or.

I rccomnrcntl tliis book to all clinicians aucl clinical scientists rrith an iutelcst in ltrns cliscascs. lt is not likr-:lv to be helplirl to st-ttr-ralists or busic rt:scalcht'r-s. It is a book that bcgins to ill-rrninirte \hal littlr: le knou aborrt cliscases o1'the
l:t onchiolcs.

.f.rr:r D. IrrL.\rnR, \Lf).

Birmirrgham, AL 3529I
LLrivclsitr- ol' Alabanra at Birrriing-ham

BOOKS RECEIVED
'Ihr rutipt ll lhtt lruils it atliuottlttl:lrtl. ttrl tlti' li:ling nust fu tgartltd a' ruffi.itl ,1ilt fot lht nurlt.fi oJ llu tndn: llaoJ;t lltat oppttt ta b( of pattitult ittilt'tt ;,ill h ntitt,rrl n' rut lttrntil:. I/a'Jotrrrrrl t' nul ltttllith utttliLilt.d ni ir;,r. llto-rttDtr rr. 5t.lt:rr
r:

Glycobiology: A practical approach. (The Practical Approach Series.) Edited by

M. Fukuda and A. Kobta. 401 pp. New York, Oxtord Universrty Press, 1994. $68 (cloth): S47 (paper). ISBN 0-19-963372-X (cloth): 0-19-963371-1 (paper). The Liver: Biology and pathobiology. Edited by lruin M. Arias, with five others. '1628 pp., illustrated. New York, Raven Press, 1994. $265. ISBN 0-78'17-0133-3. Medical Virology. Fourth edition. By David O. White and Frank J. Fenner.603 pp., illustrated. San Diego, Calif.. Academic Press. '1994. 95. ISBN 0-12-746642-8. Molecular Genetics oT Haemostasis and lts lnherited Disorders. (Oxford Monograph on l\redical Genetics. No. 25.) By Edward G.D. Tuddenham and David N. Cooper 585 pp. NewYork, Oxtord University Press. 1994. $145. ISBN 0-19-2616617.

Alzheimer Disease, Down Syndrome, and Their Relationship. Edited by J.[i\. Berg,
H. Karlinsky, and A.J. Holland. 297 pp. New York, Oxford University Press.
1

993. $85.

Molecular lmaging in Neuroscience: A practical approach. (The Practical Approach

Series.) Edited by N.A. Sharif. 245 pp.. illuslrated. New York. Oxlord University Press. 1994. S38. tSBN 0-19-963380-0. Molecular Methods lor Microbial ldentitication and Typing. By K.J. Towner nd A. Cockyne. 202 pp. New York. Chapman & Hall, 1 994. $44.50. ISBN 0-41 2-49390-

lsBN 0-1 9-262382-6. Bacterial Pathogenesis: A molecular approach. By Abigail A. Salyers and Dixie D. Whitt. 418 pp.. illuslrated. Washjngton. D.C., ASN, Press, 1994. $44.95. ISBN
1

-5558'1 -070-5.

Blood, Blood Products and HlV. Second edition. Edited by R. Madhok, C.D. Forbes. and B.L. Evatt. 276 pp. New York, Chapman & Hall. '1994. $74.95. ISBN 0-412-40400Bloom and Fawcett: A Textbook of Histology. Twelfth edition. By Don W. Fawcett. 964 pp.. illustrated. New York. Chapman & Hall, 1 994. $89. ISBN 0-412-04691-1 . Cells and Cylokines in Lung lntlammation. (Annals of the New York Academy of Sciences. Vol.725.) Edited by Michel Chignard, [,4arina Pretolani. Patricia Renesto,
nd B. Boris Vargaftig. 380 pp., illuskated. New York, New York Academy of Sciences, 1994. S110. tSBN 0-89766-855-3. Cellular, Biochemical, nd Molecular Aspects oI Reperrusion lniury. (Annals of the New York Academy of Sciences. Vol. 723.) Edited by Dipak K. Das. 506 pp., illustrted. New York. New York Academy ot Sciences, '1994. $135. ISBN 0-89766-8820.

New Findings in HSV-lnduced Retinitis in the Von Szily Mod1. By Manfred Zierhut. 95 pp., illustrated. Boston, Butlemodh-Heinemann. 1994. S49.95. ISBN 9-07043006-r. Pathogenic and Clinical Microbiology: A laboratory manual. By Sharon S. Bowland, Sherril Ross Walsh, Louise D. Teel, and Amy M. Carnahan. 389 pp., illustrated. Boston, Little. Brown. 1994. S25.95. ISBN 0-316-76049-8.

Physiochemical Hydrodynamics; An introduclion. Second edition. By Fionald F.

Probstein.400 pp., illustrated. New York, John Wiley. 1994. $69.95, ISBN 0-47'101011-1.

The Pituitary Gland. (Comprehensive Endocrinology.) Second edition. Edited by Hiroo

lmura. 520 pp., illustrated. New York, Fiaven Press,
1

994.

$1

40. ISBN 0-781 7-0207-0.

Plasmids: A practical approch. (The Practical Approach Series.) Second edition.

Edited by K.G. Ha'dy. 252 pp.. illustrated. New York. Oxford University Press, 1 994. s33. tsBN 0-'1 9-963444-0. Principles oI Benal Physiology. Third edition. By Christopher J. Lole. 200 pp. New York. Chapman & Hall. 1994. S24.50. ISBN 0-412-55520-4. Receptor Autoradiography: Principles and practice. Edited by John Wharton and Julia Nil. Polak.335 pp., illustrated. New York, Oxford University Press, 1994. S59.95. lsBN 0-'1 9-262209-9. Sherris Medical Microbiology: An introduction to infectious diseases. Third edi-

A Color Atlas oI Urine Microscopy. (Chpmn & Hall N.4edical Atlas Series. No. 13.) By D.F. Birch, K.F. Fairley, G.J. Becker, and P Kincaid-Smith. 1 48 pp., illustrated. New York. Chapman & Hall, 1994. 5125. ISBN 0-412-47950-8. Developmental Biology. Founh edition. By Scott F. Gilbert.894 pp., illustrated. Sunderland, I\.4ass., Sinauer. 1994. $57.95. ISBN 0-87893-249-6. Devlopmental Biology: A guide for experimental study. By Mry S. Tylet. 172 pp.
Sunderlnd, Mss.. Sinuer, 1994. S18.95. ISBN 0-87893-834-6. DNA Topology. (ln Focus.) By Andrew D. Bates and Anthony Maxwell. 114 pp., illustrated. New York. Oxford University Press. 1994. S15.95, ISBN 0-19-963349-5. The Endocrine Pancreas, lnsulin Action, and Diabetes. (Endocrine Reviews Monographs I2l.) Edited by Louis E. UndeNood.216 pp., illustrated. Bethesda, Md.. Endocrine Society Press, 1994. $55. ISBN 1-A79225-14-X.

tion. Edited by Kenneth J. Byan. 890 pp., illustrated. Norulk, Conn., Appleton & Lnge. 1994. S49.95. ISBN 0-8385-8541-8. Stroke in Children and Young Adults. Edited by Jose Biller. with Katherine D. Mathews and Betsy B. Love. 259 pp.. illustrated. Boston, Butterworth-Heinemann,
1

The Functional Gastrointeslinal Disorders: Diagnosis, pathophysiology, and

treatment

994. S69.95. tSBN 0-7506-9203-0.

- a multinationel consensus. Edited by Douglas A. Drossman. with Joel E. Richter, Nicholas J. Talley, W. Grant Thompson. Enrico Corazziari, and William E.
Whitehead.370 pp.. illuskated. Boston, Little. Brown. 1994. S87.50. ISBN 0-31619342.9.

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Allergies A-2. By Myron A. Lipkowitz and Tova Navarra. 352 pp. New York, Facts On
File. 1994. S40. ISBN 0-8160-2824-9.

Gas Chromatography: A practical approach. (The Practical Approach Series.) Edited by PJ. Bugh.426 pp.. illustrated. NewYork, Oxford University Press, 1994. $47. tsBN 0-1 9-963271 -5.

The Complete Guide to Prevenling Cancer: How you can reduce your risks. By Elizbeth Wheln. 385 pp. Amherst. N.Y, Prometheus Books,'1994, $26.95. ISBN
0-87975-890-2.