Abnormalities of Taste and Smell in Sjogren's Syndrome
R. I. HENKIN, M.D., N. TALAL, M.D., A. L LARSON, M.D., and C. F. T. MATTERN, M.D.,
Bethesda, Maryland
Taste and smell thresholds and forced scaling levels
were studied in 29 patients with Sjogren's syndrome
and in 10 patients with various diseases of the parotid
glands, with and without xerostomia and rhinitis sicca.
Patients with xerostomia and rhinitis sicca
due to Sjogren's syndrome or other causes had
significant decreases in taste and smell acuity.
Cyclophosphamide or X-ray treatment improved taste or
smell function if the xerostomia or rhinitis sicca
concomitantly improved. These studies suggest that
saliva and nasal mucus are important in maintaining
normal taste and smell acuity through their effects on
taste bud and olfactory epithelium function.
S J O G R E N ' S SYNDROME is defined as the symptom
complex of xerostomia, xerophthalmia, and a con-
nective tissue disorder, which is rheumatoid arthritis
in approximately half the patients ( 1 , 2 ) . A few
patients may have another associated connective tis-
sue disorder such as systemic lupus erythematosus
or scleroderma. Hypergammaglobulinemia, rheuma-
toid factor, antisalivary duct antibodies, and other
serological signs of autoimmune phenomena occur
frequently ( 2 ) . Destruction of the salivary glands by
lymphocytic infiltration leads to insufficient produc-
tion of saliva, resulting in xerostomia. A similar
process involving lacrimal and nasal mucous secret-
ing glands results in xerophthalmia and rhinitis sicca,
respectively. In some patients lymphocytic infiltration
may involve other organs such as lung or kidney
and present a histological appearance of lymphoma
or pseudolymphoma (3, 4 ) .
In this paper we describe, in detail, the clinico-
pathologic changes that occur in the oral, nasal,
and pharyngeal areas during this illness and report
• From the National Heart and Lung Institute, National Institute of
Arthritis and Metabolic Diseases, and National Institute of Allergy
and Infectious Diseases, National Institutes of Health, Bethesda, Md.
Annals of Internal Medicine 76:375-383, 1972
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the impairment in taste and olfaction that result.
Patients and Methods
PATIENTS
Twenty-nine female patients with Sjogren's syndrome
were studied at the Clinical Center, National Institutes
of Health, over a period of 4 years.
The diagnosis in each patient was made when the
clinical history and physical examination were consistent
with the disease and with the demonstration of ophthal-
mologic and oral abnormalities. Ophthalmological ab-
normalities included decreased production of tears
(measured by Schirmer's test), corneal and conjunctival
erosions (detected by rose-bengal staining), and filamen-
tary keratitis (observed on slit-lamp examination). Ab-
normalities of salivary gland function included measure-
ment of decreased parotid salivary flow rate, decreased
uptake concentration and excretion of technetium-99
(demonstrated by salivary scintigraphy (5)), an ab-
normal secretory sialogram, and the finding of lympho-
cytic infiltrates and acinar destruction on examination
of labial biopsy specimens (6).
To establish the diagnosis of' Sjogren's syndrome,
objective evidence of involvement of two of the three
major symptom areas (that is, abnormalities of eye, oral
cavity, or connective tissue) was required. Eleven of the
29 patients studied had associated rheumatoid arthritis,
2 had associated systemic lupus erythematosus, 2 had
accompanying lymphoma, and the rest had the sicca
syndrome alone. The 29 patients were examined at NIH
from 1 to 30 years after the onset of their symptoms;
the mean time after onset was 7 years.
Ten additional patients with bilateral disease of the
parotid glands were also studied. Five of these patients
had clinical complaints of oral and nasal dryness, and
the parotid salivary flow rates were decreased below
normal in each patient. However, there was insufficient
objective evidence to establish the diagnosis of Sjogren's
syndrome. One patient had excessive fat deposits in the
parotid glands (7), one had bilateral stenosis of Sten-
sen's ducts of unknown cause, and three had no obvious
explanations for their complaints. The other five patients
had normal parotid gland salivary flow rates, although
some complained of mouth dryness. Three patients had
excessive fat deposits in the parotid glands, bilaterally
(7); one had Mikulicz's syndrome; and one had parotid
disease of unknown cause.
375
 METHODS
Detection and recognition thresholds for the taste
qualities of salt, sweet, sour, and bitter were determined
for each patient, on at least one occasion, by a three-
stimulus, forced-choice drop technique, previously de-
scribed (8, 9). For salt, NaCl was used as the stimulus;
for sweet, sucrose; for sour, HC1; and for bitter, urea.
In addition, forced scaling measurements, whereby pa-
tients scaled the intensity of each taste quality over the
entire range of taste stimuli, were carried out by a
method previously described (9, 10). Measurements of
thresholds and scaling were carried out successively
in the afternoon or evening hours, at least 1 hour after
the patient had eaten or smoked. Measurements were
made by three observers, none of whom knew the
clinical status of the patients. If more than one set of
measurements was obtained, the lowest thresholds and
highest values from forced scaling data were reported.
Detection and recognition thresholds for the vapors
of pyridine in water, nitrobenzene in mineral oil, and
thiophene in mineral oil were determined for each
patient, on at least one occasion, by a three-stimulus,
forced-choice, sniff technique previously described (11,
12). Measurements of thresholds were made by one
observer immediately after the taste-testing session.
If more than one set of threshold measurements were
obtained, the lowest thresholds were reported.
Examination of the head and neck region was carried
out at the same time or shortly after taste and smell
measurements were made. In six patients biopsies of
circumvallate papillae were taken and examined by light
or electron microscopy (13) in a manner previously
described.
Results
SUBJECTIVE RESPONSES
Symptoms of Oral, Nasal, and Ophthalmologic
Dryness: Dry mouth was reported by all patients
(29 of 29), although this complaint was confirmed
by objective measurement of salivary flow rate in
only two thirds of the patients. This symptom was
particularly disturbing because it inhibited con-
versation and prompted patients to sip fluids fre-
quently so that the tongue would not stick to the
sides or roof of the mouth. Some patients sucked
hard candies instead of drinking fluids if their xero-
stomia was not too severe (14). The xerostomia
also caused patients to sip fluids during meals; if
fluids were not available, eating was either extremely'
difficult or impossible. Dry foods such as crackers,
breads, rolls, and peanut butter were avoided be-
cause they were difficult to form into a bolus and
they stuck to the mouth or teeth. Approximately
60% of the patients had this last complaint. This
often occurred without their knowledge and caused
considerable social embarrassment when pointed out
to them by friends or spouses. Six ( 2 1 % ) com-
plained that they would actually lose the position of
food in their mouth during the process of eating.
376 March 1972 • Annals of Internal Medicine • Volume 76 • Number
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Indeed, abnormalities of oral stereognosis were mea-
sured in these patients (15). Two ( 7 % ) were aware
of tongue numbness, associated with facial numbness
of 2 to 3 years' duration; these symptoms appeared
almost simultaneously with the onset of their xero-
stomia. These patients stated they felt as if their
mouths were "anesthetized." These problems, coupled
with the loss of normal salivary flow, were directly
associated with the markedly increased incidence of
dental caries observed and with the frequent loss
of dental fillings. Containers of fluids, frequently
of ingenious design to escape discovery, were kept
readily accessible in places such as purses, glove
compartments of cars, office desks, and so forth.
Not uncommonly, patients would arise each night
to drink to ease their oral dryness. Indeed, hoarseness
was a frequent complaint, particularly after speaking
or on awakening if the patient were a mouth breather
at night.
Dry mouth was generally the earliest symptom
related by the patient; it occurred 1 to 30 years
(mean, 7 years) before the patients presented at
NIH. Ninety-two percent noted the onset of dry
mouth and dry eyes simultaneously or with dry eyes
occurring later. The complaint of dry eyes preceded
the onset of xerostomia in only 8%. This symptom
also occurred in each patient (29 of 29) and was
associated with a gritty, sandy sensation on lid clo-
sure, with bilateral burning. Difficulty in reading,
sewing, or watching television for a long time was
a common complaint.
Ninety-two percent of the patients complained of
a dry nose. This symptom appeared at the same
time as the xerostomia in 4 5 % , whereas the rest
noted its appearance 1 to 5 years later. Fifty-two
percent were aware of nasal crusts, and most recog-
nized that they did not blow their noses as often
as they did before the onset of their nasal dryness.
Taste Symptoms: Fifty-two percent (15 of 29)
were subjectively aware of some loss of taste acuity
(hypogeusia) at the time they were seen at NIH.
The same percentage were aware that they were
adding more salt to their food at table or more sugar
to their fluids, or both, in order to obtain the pre-
ferred taste. The awareness of these changes occurred
either at the same time or, more usually, after the
patient's awareness of dry mouth. In no case did
subjective awareness of loss of taste acuity precede
the symptoms of xerostomia. Although this symp-
tom occurred in many patients, it did not consistently
appear in those patients whose taste thresholds were
most severely impaired.
Subjective decreases in appetite were reported
by 5 2 % . In patients with hypogeusia this was asso-
3
 dated with complaints that food tasted bland or had
no taste at all.
Smell Symptoms: Forty-five percent (13 of 29)
were subjectively aware of some loss of olfactory
acuity (hyposmia) at the time they were seen at
NIH. These patients generally also complained of
a loss of taste; only two patients who complained
of hypogeusia did not complain of hyposmia. The
latter symptom was present in those patients whose
olfactory thresholds were severely impaired.
Other Symptoms: Fifty percent noted decreases in
hearing acuity; 2 5 % noted this symptom before the
onset of their xerostomia, and it was thus probably
unrelated to the underlying changes associated with
Sjogren's syndrome. Some complained of egophonia
("like hearing in a barrel"). Fifty percent were
also aware of decreases in cerumen occurring simul-
taneously or shortly after the onset of dry mouth; Figure 1 . Photograph of tongue of patient with Sjogren's syn-
drome with xerostomia, rhinitis sicca, and rheumatoid arthri-
approximately half of these patients did not have tis of 7 years' duration. The tongue appears dry and slightly
hearing losses. This symptom was particularly furrowed. Fungiform papillae are present but decreased in num-
ber, particularly over the more anterior areas of the tongue.
troublesome since it was associated with pruritis, Circumvallate papillae are also present.
scaling, and crusting of the skin of the external audi-
tory canal. Persistent dandruff was present in ap- resulting in relatively open nasal passages. This lack
proximately 4 0 % . of moisture, when severe and prolonged, resulted
in the formation of nasal crusts and produced nasal
PHYSICAL EXAMINATION OF HEAD AND NECK
stuffiness and recurrent nasal bleeding. As a result
The buccal mucous membranes were dry and of this, some patients became mouth breathers, which
sticky. In most patients little if any saliva could be only aggravated the dryness of their oral cavity. Local
secreted from Stensen's duct by manual or tongue infections sometimes occurred with the nasal crusting
blade manipulation, or both, of the gland. The tongue and aggravated the crusting already present. Per-
was commonly dry and furrowed, redder than nor- sistence of these symptoms commonly produced an
mal, and without the normal glistening appearance atrophic appearance of the nasal mucous membranes,
(Figure 1). In 2 1 % the tongue surface was smooth with decreases in nasal gland number. At this time
and atrophic with a marked decrease or absence of patients generally had open nasal passages with nasal
filiform, fungiform, or circumvallate papillae. Ulcer- dryness; some complained of a sensation of "nasal
ations or areas of leukoplakia of the tongue or buccal blockage"; two patients had red, turgid nasal mucous
mucous membranes were not observed. membranes with squamous metaplasias of the nasal
Early in the disease nasal dryness was associated epithelium covering the turbinates. Neither synechiae,
with decreased serous fluid and a viscid mucus, adhesions, nor nasal polyps were observed.

Table 1 . Taste and Smell Thresholds in 29 Patients with Sjogren's Syndrome

Subjects Taste Smell

NaCl Sucrose HC1 Urea Pyridine Nitrobenzene Thiophene

< mmoles 1 liter > < — moles/liter •
Patients
1 8
Median* 90/120 60/60 15/30 500/500 10-710- 1
10-yp IO-^/IO- -
Range f 12-300 12-300 0.8-60 90->5K io- 4 - P /io- 4 -oo io-*-/io- 2 10- 5 -oo
12-oo 12-800 3->500 90->5K 10-3-oo
Normal volunteers
Median * 12/30 12/30 3/3 120/150 10-yio-a lO-'/lO" 3 io-yio-s
Range 3-60 3-60 0.5-6 60-150 io- 5 -io- fl 10-MO- 7 10~5-10-fl
6-60 6-60 0.8-6 90-150 10~ 2 -10- 4 10-2-10-* 1 o~ 2 -i 0- 4

* Numerator of fracton is median detection threshold; denominator of fraction is median recognition threshold.
t oosignifies inability to detect or recognize an absolute or neat substance; P signifies ability to recognize an absolute or neat substance; K
signifies a factor of 1000.

Henkin et al. • Sjogren's Syndrome 377

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OBJECTIVE MEASUREMENTS
Taste Thresholds: Table 1 shows the median de-
tection and recognition thresholds for taste and smell
in the 29 patients studied. For taste, median detection
and recognition thresholds for salt, sour, and bitter
were above the upper limit of normal, whereas those
for sweet were within normal limits. Only one pa-
tient had normal thresholds for each quality tested.
All of the other patients had elevations above the
upper limit of normal for at least two thresholds.
Thresholds elevated above normal for sour and bitter
were observed in 90%, for salt detection and recog-
nition in 76%, and for sweet detection and recogni-
tion in 38% of the patients. Six patients (21%)
had abnormalities of each of the eight thresholds mea-
sured. No patient had detection ageusia* for any taste
quality; however, one patient demonstrated recogni-
tion ageusia for salt, another for sour, and two others
for bitter.
Figure 2 compares the mean forced scaling levels
for each taste quality in the 29 patieilts with similar
measurements in 21 normal volunteers. The curves
of the patients are defined by the same single-para-
meter equation as are the normal curves (16), al-
though each curve is shifted to a higher solute con-
centration along the abscissa, demonstrating another
aspect of the hypogeusia of these patients. The re-
sponses of the patients generally did not reach 100%
despite the presentation of saturated or very con-
centrated solutions (saturated NaCI and sucrose,
0.5 N HC1, and 5 M urea). The pattern of taste re-
sponsiveness of the patients for HC1, NaCI, sucrose,
and urea is the same as that of the normal volunteers.
Taste Bud Examination: Circumvallate papillae
excised from 6 of the 29 patients were examined by
* Ageusia is operationally denned as inability to detect or recognize
a saturated solution of NaCI or sucrose, 0.5 N HC1, or 5 M urea.
378 March 1972 • Annals of Internal Medicine • Volume 76 • Number 3
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Figure 2. Mean forced scaling for
the taste of HC1, NaCI, sucrose,
and urea in 21 normal volunteers
(so//d lines) and in 29 patients
with Sjogren's syndrome (dotted
lines). Vertical bars indicate ± 1
standard error of the mean (SEM).
Concentration of solute presented
(in mM) is plotted on the abscissa;
percent subjective response is
plotted on the ordinate.
light or electron microscopy. By conventional light
microscopy, after formalin fixation, paraffin embedd-
ing, and hematoxylin-eosin staining techniques, taste
buds were not seen even though the entire papilla
was sectioned. After they were fixed in glutaralde-
hyde, embedded in epon-araldite, cut in 1-/A sections,
and stained with toluidine blue for study by light
microscopy, taste buds were observed in only one of
the six patients studied; that is, they were decreased
in number compared with similar sections taken from
papillae of normal volunteers. The taste buds from
this patient were compared, by electron microscopy,
with those of normal volunteers who had normal
taste acuity (Figure 3). The taste buds of the pa-
tient were grossly abnormal, showing disorganiza-
tion of the normal architecture of the pore area.
Neurosecretory granules were present, but they were
decreased in number. Membrane-bounded structures,
suggestive of degenerating cells or unmyelinated nerve
fibers, or both, were observed peripherally, along
with nerves that appeared histologically normal in
the basal portion of the bud. The appearance of the
Figure 3A. Electronmicrograph of distal portion of a taste bud
from a circumvallate papilla from a subject with normal taste
acuity, with the pore in the upper left portion of the figure. Type
I and type II cells (/, //) are readily distinguished. Type I cells
show numerous densely staining neurosecretory granules (G);
type II cells are characteristically vacuolated. Also observed in
the pore region is dense extracellular material (D), microvillous
projections (P), and fine extracellular vesicles (V). B. Electron-
micrograph of comparable region of a taste bud from a
circumvallate papilla from a patient with Sjogren's syndrome.
Severe disorganization of the pore area (upper left) can be ob-
served. Type I and type II cells are identifiable, but their cyto-
plasm stains more homogeneously than normal, making their
differentiation difficult. There is a relative paucity of neuro-
secretory granules in type I cells. Neither dense extracellular
material nor microvillous projections are present. Pale-staining,
membrane-bounded structures (S) containing finely granular
material are observed in areas suggestive of degenerating nerves
or cells, or both. The appearance of this bud suggests that de-
generative changes have occurred. (Both; original magnification,
X 11 000.)
 13. MATTERN CFT, DANIEL WA, HENKIN R I : The ultrastructure
of the human circumvallate papilla. I. Cilia of the papillary
crypt. Anat Rec 167:175-182, 1970
14. EHRLICH GE: Sour-ball sign of Sjogren's syndrome. JAMA
194:203, 1965
15. HENKIN RI: Manual and oral stereognosis in normal volun-
teers and in patients with various diseases, in Second
Symposium on Oral Sensation and Perception, edited by
BOSMA JF. Springfield, 111. Charles C Thomas, Publisher,
1969, pp. 357-362
16. HENKIN RI, BRADLEY D F : On the mechanism of action of
carbohydrate-active steroids on tastant detection and rec-
ognition, in Steroid Hormones and Brain Function, edited
by SAWYER CH, GORSKI R. Los Angeles, University of
California Press, 1972
17. HENKIN RI: The definition of primary and accessory areas
of olfaction as the basis for a classification of decreased
olfactory acuity, in Olfaction and Taste II, edited by HAYASKI
T. London, Pergamon Press, 1967, pp. 235-252
18. HENKIN RI, Ho YE RC, KETCHAM A A, et al: Hyposmia
following laryngectomy. Lancet 2:479-481, 1968
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19. HENKIN RI, SMITH FR: Hyposmia in acute viral hepatitis.
Lancet 1:823-826, 1971
20. HENKIN RI, BRADLEY D F : Regulation of taste acuity by
thiols and metal ions. Proc Natl Acad Sci USA 62:30-37,
1969
21. VANCE WB: Observations on the role of the salivary secre-
tions in the regulation of feed and fluid intake in the white
rat. Psychol Monogr 19:1-598, 1965
22. SHIBUYA T: Dissociation of olfactory neural response and
mucosal potential. Science 143:1338-1339, 1964
23. FENSTER IF, BUCHANAN WW, LASTER L, et al: Studies of
pancreatic function in Sjogren's syndrome. Ann Intern Med
61:498-508, 1964
24. CARDELL BS, GURLING KJ: Observations on the pathology of
Sjogren's syndrome. / Pathol Bad 68:137-146, 1954
25. DELANEY WE, BALOGH K: Carcinoma of the parotid gland
associated with benign lymphoepithelial lesion (Mikulicz's
disease) in Sjogren's syndrome. Cancer 19:853-860, 1966
26. STEINBERG AD, TALAL N : The coexistence of Sjogren's syn-
drome and systemic lupus erythematosus. Ann Intern Med
74:55-61, 1971
Henkin et al. • Sjogren's Syndrome 383
 Table 2. Taste and Smell Thresholds in Patients with Parotid Gland Disease with or Without Xerostomia and Rhinitis Sicca*

Xerostomia Rhinitis Number of NaCl Sucrose HC1 Urea Pyridine Nitrobenzene ThiopheneJ.
Sicca Patients
< mmoles /liter > — moles/liter - >
+ + 5 90/90 75/75 15/150 900/1500 10-710- 1 1 3
IO- - /! P/P
5 30/30 60/60 6/6 120/120 io- 6 3 /io- 2 io-6-3/io-8-8 io- 6 - 6 /io- 8 -
* Numerator of fraction is median detection threshold; denominator of fraction is median recognition threshold,
t P signifies ability to detect or recognize an absolute or neat substance.

patient's taste buds suggested that marked degenera-
tive changes had occurred.
Smell Thresholds: Median detection and recog-
nition thresholds for smell in the 29 patients in-
dicated that thresholds for each vapor were elevated
above normal. All patients (29 of 29) had elevated
detection and recognition thresholds for pyridine;
24 ( 8 3 % ) had elevated detection thresholds for
nitrobenzene, and 22 ( 7 6 % ) had elevated recogni-
tion thresholds. Twenty-eight patients had elevated
detection thresholds for thiophene, and 26 had ele-
vated recognition thresholds.
Table 2 compares the median detection and rec-
ognition thresholds for taste and smell in five patients
with parotid gland disorders and xerostomia and
rhinitis sicca with similar thresholds in five patients
with parotid gland disorders without xerostomia
or rhinitis sicca. Taste thresholds were elevated above
normal for all of the eight qualities in patients with
xerostomia; similarly, smell thresholds were elevated
above normal. However, taste thresholds were within
normal limits for each quality in the patients with-
out xerostomia, and smell thresholds were similarly
within normal limits for each vapor in patients with-
out rhinitis sicca.
Changes After Therapy: Four patients were treated
with cyclophosphamide (Cytoxan®) for problems
associated with their illness: pulmonary lymphoma
(Patient T.J.), pseudolymphoma of the parotid
glands (Patient F.E.), renal insufficiency secondary
to lymphoid infiltration (Patient R.G.), and active
rheumatoid arthritis (Patient H.K.). A fifth patient
(M.R.) received extensive radiotherapy to the head
and neck for pseudolymphoma of the parotid glands.
Three of these patients, T.J., F.E., and M.R., noted
subjective remissions of oral and lacrimal dryness;
salivary flow rates in all three returned to or toward
normal. Only Patient T.J. noted a remission of her
nasal dryness. Two other patients, R.G. and H.K.,
noted no subjective change in oral, lacrimal, or nasal
dryness, and there was no change in salivary flow rate
when it was measured.
Taste and smell thresholds were measured in each
patient before and after therapy with cyclophospha-
mide (Table 3 ) . No change in taste or smell thresh-
olds was noted in Patients R.G. or H.K., in whom
no change in oral or nasal dryness occurred. Of
those three patients who noted a return of saliva,
taste thresholds and olfactory thresholds returned to
normal in the patient (T.J.) who noted a remission of
her rhinitis sicca.
An attempt was made to correlate abnormalities
of taste and smell thresholds with abnormalities
observed on examination of Up biopsy specimens,

Table 3. Taste and Smell Thresholds in 5 Patients with Sjogren's Syndrome Before and After Cyclophosphamide or X-ray Treatment*

Patient Age Untreated Treatment f

NaCl Sucrose HC1 Urea Pyridine Nitrobenzene Thiophene Method Duration

yr < mmoles/liter — > < — moles/liter —

T.J. 45 12/90 60/60 15/>500 300/>5K 10-710- 2 lo-yio- 2 10-710-* CP 1 year
F.E. 59 90/90 150/150 6/6 150/300 10-75 l/oo P/P CP 9 months
M.R. 48 150/150 60/60 15/60 800/5K 10-710- 2 10-710- 1 10-7P x§
R.G. 59 150/300 150/150 15/30 500/500 10-710- 1 IO-7IO- 8 10-7P CP 2 year
H.K. 52 150/150 150/150 15/30 300/800 10-710- 1 10-71 o- 1 P/P CP 6 months
Median 150/150 150/150 15/30 300/800 10-710-1 10- 2 /10-i 10-7P Remission (3) of
xerostomia (T.J., F.E.,
M.R.)
No improvement (2) in
xerostomia or rhinitis
sicca
* Numerator of fraction is median detection threshold; denominator of fraction is median recognition threshold. 00 signifies inability to recog-
nize an absolute or neat substance; P signifies ability to detect or recognize an absolute or neat substance; K signifies a factor of 1000.
f CP — cyclophosphamide, 75 mg/day; X — X-irradiation.

380 March 1972 • Annals of Internal Medicine • Volume 76 • Number 3

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 salivary gland scintigraphy, or salivary flow rate.
An attempt was also made to correlate changes in
abnormalities of taste and smell thresholds after
treatment with changes in the same measurements.
Although no statistically significant correlations were
observed between any set of variables, patients with
the most severe hypogeusia had either absent salivary
flow or their flow was among the lowest of the pa-
tients studied.
Discussion
These studies show that with a severe depression
in saliva production there is an accompanying taste
loss. This occurred in patients with Sjogren's syn-
drome and in patients with xerostomia of other
causes. The loss of taste acuity occurred either at
the time the patients recognized the persistence of
their xerostomia or, more commonly, within 3 years
of the onset of this symptom.
The decrease in taste acuity reflected a generalized
hypogeusia and was not restricted to detection or
recognition of any quality. However, detection and
recognition thresholds for sweet were affected less
than any other taste quality. This pattern of hypo-
geusia is similar to that observed in idiopathic hypo-
geusia (9).
The lack of saliva appears to be associated with a
greatly decreased number of taste buds in circum-
vallate papillae and also with abnormalities of the
few taste buds observed. These abnormalities were
localized to the pore region and resembled the patho-
logical appearance of taste buds in patients with
idiopathic hypogeusia ( 9 ) .
Our studies also demonstrate that with a severe
depression in nasal mucous production there is an
accompanying loss of olfactory acuity. This occurred
in patients with Sjogren's syndrome and in patients
with rhinitis sicca of other causes. The loss of ol-
factory acuity uniformly followed the onset of the
rhinitis sicca; it also generally followed, in time, the
onset of the xerostomia.
The decrease in olfactory acuity reflected a gener-
alized hyposmia and was not restricted to detection
or recognition of any odor. The pattern of loss of
smell was similar to that observed in patients with
idiopathic hypogeusia (9) and to that of hyposmia
of several other causes (17-19).
Cyclophosphamide or X-ray therapy that returned
xerostomia or rhinitis sicca or both, to or toward
normal produced a return of taste or smell acuity,
or both, to or toward normal. This return occurred
even though hypogeusia and hyposmia had been
present for as long as 3 years. Return of salivary
flow to normal occurred in some patients without the
return of nasal mucous secretion to normal. Treat-
ment that was unsuccessful in correcting the xero-
stomia or rhinitis sicca also failed to restore taste or
smell acuity even though the therapy might have been
successful in treatment of other manifestations of
the disease.
These results indicate that the presence of saliva
plays a significant role in maintaining normal taste
acuity. Significant reduction of saliva appears to de-
crease the number of papillae and taste buds and to
alter the form and function of the remaining taste
buds. Vigorous treatment with fluids such as water
or saline, although difficult to perform consistently,
was ineffective in alleviating the taste loss, although
it did moisten the oral mucous membranes. Thus,
saliva appears to be important in maintaining normal
gustatory function. Increases in preference thresholds
similar to those observed in rats with hypogeusia

Table 3. (Continued)
Response t Treated
Xerostomia Rhinitis Other NaCl Sucrose HC1 Urea Pyridine Nitrobenzene Thiophene
Sicca
< mmoles/liter • < moles/liter — •

9 4
+ + 12/60 60/60 3/6 120/120 10- /10- IO-7IO-4 10-710-*
+ + 30/60 12/12 0.5/3 120/120 10"V2 10-710- 1 10-7P
+ + 60/60 30/30 3/3 120/150 10-710- 2 10-710-2 10-7P
+ 300/800 300/300 60/90 2K/2K 10-710- 1 10-710-2 P/P
1
150/300 90/90 15/60 800/1K 10-710- 1 10-710- P/P
Median 30/60 30/30 3/3 120/120

Median 225/500 150/150 30/75 IK/1500 10-710- 1 lO-i'/lO- 1 8 P/P

% + = improvement; — = no improvement.
§ = retested 2 years after therapy.

Henkln et a/. • Sjogren's Syndrome 381

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 (20) were also observed in rats in whom the ducts
of the salivary glands had been ligated (21).
Similarly, these results indicate that the production
of nasal mucus plays a significant role in maintaining
normal olfactory acuity. Significant reduction of
nasal mucus produces pathological changes in the
structures of the nasal mucous membranes and an
accompanying decrease in olfactory function. The
most likely anatomical site of this change is at the
olfactory epithelium, a structure normally covered
with mucus. In frogs, if this layer of mucus is re-
moved, significant alterations in the olfactory mucosal
response have been recorded, although the neural
response was maintained essentially intact ( 2 2 ) .
Vigorous treatment of the patients with nasal saline
douches was ineffective in alleviating the olfactory
loss, although it moistened the nasal mucous mem-
branes and decreased nasal crusting. Thus, nasal
mucus is important for maintaining normal olfactory
function.
Decreased secretion of exocrine glands is a
common feature of this syndrome. This not only
includes salivary, lacrimal, and nasal glands but
also vaginal glands ( 1 ) , tracheobronchial glands ( 1 ) ,
and the glands of the pancreas (2, 23, 2 4 ) . Indeed,
pancreatitis of a mild type has been observed in
some patients (23, 24). The patients in our study
also reported the prevalence of dandruff and de-
creases in cerumen. Dryness of the nasopharynx
can produce dysfunction of the eustachian tube,
egophonia, otitis media, and, secondarily, hearing
losses.
It is of interest that patients with Sjogren's syn-
drome rarely have been reported to develop car-
cinoma of structures within the oral cavity. Indeed,
only one case has been reported of a patient with
Sjogren's syndrome developing carcinoma in the
parotid gland ( 2 5 ) . Coupled with the generalized
dryness, it might also be expected that aphthous
stomatitis, leukoplakia, or other precancerous or
cancerous changes might occur. This does not
appear to be the case in any area so affected, even in
patients with long-standing symptoms.
The changes in taste and smell thresholds were
severest in patients with Sjogren's syndrome and
rheumatoid arthritis, intermediate in those with
sicca syndrome alone, and least severe in patients
with Sj6gren#s syndrome and systemic lupus ery-
thematosus. It has been previously observed that
patients with coexisting lupus erythematosus and
Sjogren's syndrome have less severe salivary lympho-
cytic infiltration than other patients with Sjogren's
syndrome (26).
Although it may not be apparent on casual ex-
382 March 1972 • Annals of Internal Medicine • Volume 76 • Number 3
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amination, the social and life consequences of xero-
stomia and rhinitis sicca can be extremely incapaci-
tating to the patient with this disease. The abnor-
malities of taste and smell and the associated an-
orexia and lack of ability to obtain flavor from food
add additional problems to the significant morbidity
of this illness.
Measurements of changes in taste and smell are
simple and sensitive tests that aid in the diagnosis
of this disease and measure the degree of involve-
ment of structures in the oral and nasal cavities.
In addition, these tests may be of particular useful-
ness in evaluation of patient response to several
modes of therapy.
Addendum
Since the preparation of this manuscript, one pa-
tient complaining of taste loss and one complaining of
smell loss presented themselves to the Taste and Smell
Clinic at the National Institues of Health. Sjogren's
syndrome was subsequently discovered to be the
cause of their respective taste and smell abnormalities.
ACKNOWLEDGMENTS: The authors thank Drs. Paul J.
Schecter and Robert C. Hoye, Mr. Noel Whittaker, and Mrs. C.
Franklin for their kind assistance during this study.
Received 6 July 1971; revision accepted 20 September 1971.
• Requests for reprints should be addressed to Robert I. Henkin,
M.D., Chief, Section on Neuroendocrinology, National Heart
and Lung Institute, National Institutes of Health, Bethesda, Md.
20014.
References
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3. TALAL N, BUNIM JJ: The development of malignant lym-
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Henkin et al. • Sjogren's Syndrome 383
 Geoffrey Wingfield Harris, Sc.D., M.D., D.M., F.R.S.
4 JUNE 1913 - 29 NOVEMBER 1971

Function of the Hypophysial Portal Vessels

AFTER SECTIONING the pituitary stalk in female rats, the recurrence of oestrous cycles
and a pseudopregnancy response to sterile coitus may be correlated with regeneration of
the hypophysial portal vessels. If such regeneration is.prevented by the insertion of
foreign bodies (usually paper plates) between the cut ends of the stalk, the animals re-
main anoestrus till killed (2-3 months after operation). If partial regeneration occurs,
irregular and anovular cycles may be re-established.
Regeneration of the hypophysial portal vessels after pituitary stalk section has been ob-
served to start within 1 day of operation.
These results indicate that gonadotrophic secretion by the anterior pituitary gland of
the rat is dependent on the hypothalamus and on an intact vascular pathway (portal
vessels) from the median eminence to the pars distalis, and that the cyclical nature of
oestrus activity is neural in origin.
G. W. HARRIS
Oestrous rhythm. Pseudopregnancy and
the pituitary stalk in the rat.
Journal of Physiology (London) 111:347-360, 1950

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