Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Endocrinology
Rupal Shah, AdU Shamji and Vitbika Sivabalasund.aram, chapter editors Doreen Ezeife and Nigel Tan, associate editors Steven Wong, EBM editor Dr. Alice Cheng, staff editor
Basic Anatomy Review ................... 2 Major Endocrine Organs Dyslipidemias ........................... 2 Overview of Lipid Transport Hypercholesterolemia Hypertrig lyceridem ia Combined Hyperlipidemia Dyslipidemia and the Risk for CAD Treatment of Dyslipidemias Disorders of Glucose Metabolism .......... 6 Overview of Glucose Regulation Pre-Diabetes Diabetes Mellitus (OM) Treatment of Diabetes Acute Complications Macrovascular Complications Microvascular Complications Other Complications Hypoglycemia Metabolic Syndrome Obesity .............................. FM5 Pituitary Gland ......................... 16 Pituitary Hormones Growth Hormone (GH) Prolactin (PRL) Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) Antidiuretic Hormone (ADH) Pituitary Pathology Thyroid .............................. 20 Thyroid Hormones Tests of Thyroid Function and Structure Thyrotoxicosis Graves' Disease Subacute Thyroiditis Toxic Adenoma/Toxic Multinodular Goitre Thyrotoxic Crisis(fhyroid Storm Hypothyroidism Hashimoto's Thyroiditis Myxedema Coma Sick Euthyroid Syndrome (SES) Non-Toxic Goitre Thyroid Nodules Thyroid Malignancies Adrenal Cortex ......................... 29 Adrenocorticotropin Hormone (ACTH) Adrenocortical Hormones Tests of Adrenocortical Function Hyperaldosteronism Cushing's Syndrome Congenital Adrenal Hyperplasia Hyperandrogenism Adrenocortical Insufficiency Adrenal Medulla ........................ 35 Catecholamine Metabolism Pheochromocytoma Multiple Endocrine Neoplasm (MEN) Calcium Homeostasis .. 37 Hypercalcemia Hypocalcemia Hyperphosphatemia Hypophosphatemia Hypermagnesemia Hypomagnesemia Metabolic Bone Disease ................. 43 Osteoporosis Osteomalacia and Ricketts Renal Osteodystrophy Paget's Disease of Bone Male Reproductive Endocrinology ......... 48 Androgen Regulation Tests of Testicular Function Hypogonadism and Infertility Erectile Dysfunction Gynecomastia Common Medications ................... 51 Diabetes Medications Dyslipidemia Medications Thyroid Medications Metabolic Bone Disease Medications Adrenal Medications Landmark Endocrinology Trials ........... 55 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Endocrinolo8f El
E2 Endocrinology
.....
',
ADH and oxytocin are synthesized by the hypothalamus. They are transported via neurons to the posterior pituitary and are subsequently secreted into the systemic circulation from this location.
11,
GENERAL FUNCTION OF ORGANS The Hypothalamic-Pituitary Axis Information about cortical inputs, automatic function, environmental cues (light, temp) and peripheral hormonal feedback is synthesized at the coordinating centre of the endocrine system, the hypothalamus. The hypothalamus then sends signals to the pituitary to release hormones to affect the thyroid, adrenals, gonads, growth, milk production and water balance. Anatomy +-+ Function Hypothalamic hormones: small peptides, no binding protein -+ rapid degradation High [ 1in pituitary-portal blood system Low [ 1in peripheral circulation Proximity of axis preserves the pulsatile output signals from the hypothalamic neurons. Thyroid Thyroid hormone is critical to 1) brain and somatic development in fetus and infants, 2) metabolic activity in adults, and 3) function of virtually every organ system. Adrenal Each gland, 6-Sg, has 1) a cortex with 3 layers that act like independent organs (zona glomerulosa -+ aldosterone, fasciculata -+ cortisol, reticularis -+ androgen and estrogen precursors), and 2) a medulla that acts like a sympathetic ganglion to store/synthesize adrenaline and noradrenaline. Gonads Bifunctional: sex steroid synthesis and gamete production Sex steroids controls sexuality and affect metabolic and brain functions Parathyroid Synthesize and secrete PTH, a principle regulator of ECF Ca, regulated by [Ca]. [Mg1 and 1,25(0H)2D (active metabolite ofVit-D). Pancreas Endocrine islet cells produce insulin: oppose glucose production (glycogenolysis, gluconeogenesis), increase glucose uptake into muscle, liver and fat. Glucagon, epinephrine, cortisol, and GH are counter regulatory.
Pituitary gland Anterior pituitary Growth hormone (GH) Prolactin (PRL) Thyroid-stimulating hormone (TSH) Luteinizing hormone (LH) Follicle-stimulating hormone (FSH) Adrenocorticotropic hormone (ACTH)
Dyslipidemias
Definition metabolic disorders characterized by elevations of fasting plasma cholesterol, and/or triglycerides (TG), and/or low HDL
B-100, C, E B-100, E
LDL
B-100
HDL
A-I,A-II,C,E
Endocrinology E3
EXOGENOUS PATHWAY
BIDGB- PA1IIWAY
E C.ll B-4B
Chylomicron
:_;
dilgtadw'lfi
fnla Filly Al:ids
IPE.Ptse
llC1Mitioll byApo
"lP liptQ,..,....
I
I
Figun 2.
Hypercholesterolemia
PRIMARY HYPERCHOLESTEROLEMIA
Pulygenic Hyperchalesll!ralenia
SECONDARY HYPERCHOLESTEROLEMIA
Etiology
diet
anorexia nervusa
hypothyroidism
choleabrtic liver disease (e.g. primary biliary cirrhosis) nephrotic disease monoclonal gammopathy
E4 Endocrinology
Dysllpidemias
----------------
Etiology/ Mophpialagy
Autosomal recessive deficiency of lipoproteillipase or its cofactor
Labs
Cli1icll Presentation
Treatment
Hepatosplenomegaly Decrease dietary fat 1'TG 1' Chylomicrons Splenic irhrt:t intakllto < 10% of total Moderate 1' in VLDL Anemia, pulocytopenia, calories thrombocytopenia 2_.to hypersplenism Pancrartitis Lipemia retinalis &uptive xanthomata 1'TG 1' VLDL
&uptive xanthomata Lipemia ratinalis Recummt epigastric pain Premature CAD Early adulthood develop syndrome of obesity, hyperbiglyceridsmia,
Several genetic defacts resLiting in 1' hepatic VI.DL synthesis or -J.. removal of VLDL
intakll
Abstain 1rom EtOH Fibrates or niacin
and
hypelllicemia
SECONDARY HYPERTRIGLYCERIDEMIA
Etiology
obesity/metabolic syndrome alcohol diabetes mellitus drugs (corticosteroids, estrogen, hydrochlorothiazide, retinoic acid, beta-blockers without intrinsic sympathomimetic action (ISA), anti-retroviral drugs) chronic liver failure hepatitis polyclonal and monoclonal hypergammaglobulinemia glycogen storage disease hypothyroidism hypopituitarism acromegaly
Combined Hyperlipidemia
Table 4. Primary Combined Hyperlipidemias Hyperlipidemia Familial Combined Hyperlipidemia (Frederickson Type lib) Eliologop1lllhopllysialogy Labs Clilicll Praantmion Trtllmant Xanthelasma CAD and other VBSCular dis88Se Weight reduction Demasa fat, cholesterol, and EtOH in di8l Niacin, fibrates HMG CoA reductese inhibitors Most common form of 1'TC+TG hyparlipidemia 1' VI.DL Over-population of VI.DL 1' LDL and associated 1' LDL 2!' to excess hepatic synthesis of apolipoprotein B Autosomal dominant Abnormal apolipoprotsin E 1'TC+TG 1' VI.DL 1' IDL
Tubsrou&, sruptiw, planar xanthomata Impaired glucose tolerance CAD and PVD
WBight reduction Decrease fat, cholesterol, and EtOH in diet Niacin, fibrates HMG CoA reductese inhibitors
Dyslipidemia and the Risk for CAD- - - - - - - - - - - - - - - increased LDL is a major risk factor for atherosclerosis and CAD increased HDL is associated with decreased cardiovascular disease and mortality hypertriglyceridemia is an independent risk factor for CAD in people with diabetes mellitus and in postmenopausal women
Dyslipidemias
Endocrinology E5
"-{9,
Non-ll'lditiOIIIII ...aitive Iiiii fllelorl
cigarette smoking
hypertension (sBP >140, dBP >90) obesity (BMI >27 kg!m2) family history of premature coronary artery disease clinical signs of hyperlipidemia (xanthelasma, xanthoma, arcus comeae) evidence of atherosclerosis rheumatoid arthritis, systemic lupus erythematosis, psoriasis mv infection on highly active antiretroviral therapy chronic kidney disease (estimated GFR <60 ml/min/1.73 m 2) erectile dysfunction screen children with a family history of hypercholesterolemia or chylomicronemia
1' IL-6 (interleukin 61 1' ThiF (tumour necrosis factor) 1' CRP (c-reactive pro1ein)
lldiponactin
1' hamacywte!M
....
,,
TrNimant Effllct Each 1.0 mmoVL dacraese in LDL corresponds to 20-25% rellltive risk reduction in cardiovascular di18118.
',I
For Stml Follow-Up Upid$ 111d Ii,.8\'llfV
High <0.85
Moderlle
< 1.05
Low <1.2
months or if palilnt complains Ill jiiUfldic:e. RUQ pail. dllrk urine CK at baseline and if patient complains
C-reactive protein (CRP) levels: highly sensitive acute phase reactant may be clinically useful in identifying those at a higher risk of cardiovascular disease than predicted by the global risk assessment
af
Treatment of Dyslipidemias
Approach to Treatment For clinical guideines see Clln J CanJio/ 2009; 25{1 0):567-579. estimate 10-year risk of CAD using Framingham model (see Family MelJjdne. FM6) establish treatment targets according to level of risk (see Table 6)
Tabla 6. Target LDL by Risk Group LlnlofRilk High Modarata
Law
Ta1111t LDL
Alllllllllll
lil#l.
Treatment of Hypercholestnlemil
Conumtin: 4-6 month trial unless high risk group, in
TrGibnent of Hypeltriglyceridenia
CanleMIIiva: month trial Diet Decraase fat and simple carbohydrates lncraase omaga-Jistty acids Control blood sugars Decrease alcohol intake Smoking cassation Aerobic exercise: 3().60 minutaf/day, 4-7 timer/waak Tqet body mass index {BMI) <25
l'llllcahllr
which case medical treatment shoLJd sllrt immediatEly Dis! DeCI'IIIISe fat: <30% calorias Decreese saturated 1st: <1II% calories Decreese cholesterol: <300 mQI'day lncraasefibre: Ql'day Decraase alcohol intaku Smoking cessation Aerobic exercise: 3().60 minule!/day, 4-7 times/week Weight loss: target body mass index {BMI) <25
Madical
other acclusive nrill di-. ar dillbetes IIQild 40-l!O Yllll) Ylllo ..d1111111 dlolllllniiiMI ri
VIICUiltl\llllll.
by25\ IP<O.IOOI).
blulll: Thlw of llinVIItltilligniliclndy decralledblbl nmtHiy l12.1w. 14.7, 111:1 the lnt IMIIII 1111 of llrf canliomculr IMIIII
Medical: fibrates. niacil (see Common MedicaliDns section I HMG-CaA reductase inhibitors, azatimibe, bile acid Indications: sequeslnrrt8, niacin {saa Common Mt1dicl.rlions section) Failed conservative measures TG > 10 md (885 mQI'dl) to prevent
Combined hyperlipidemia
CADpltieots.
116 EndoaiD.olotlf
1'oroDio
2011
-------MiliCII
FFA releale
Cin:UIIIIlry aymm
1$1
'
Pancn11
Gklcosarel"1' Insulin ralaua Cllbahydndls
_M_:_$_tl__PI'IIII1_at_es__lZ_D_=_Ih_illzD_I_idi-nacl_io_na_FF_A_=_Iraa_fatty_ICid_"_AG_I_=_a-tl_ucas_ida_sa_Wl_i_bito_r_ _ _ l (
I J
0
Mljar ta'QII Dr'QMS and actions of Dl'llly adminillllred an1ilyparglyclmic agams in type z dilbaCas mllitus
------------
Diagnostic Criteria impaired Wting glucose (IFG): fasting blood glucose (FBG) 6.1-6.9 mmol/L (110-125 mg/dL) impaired. glucose tolerance (IGT): 2h 75 g oral glucose tolerance test (OGTT) 7.8-11.0 mmoiJL (140-200 mg/dL)
Diagnostic Criteria any one of the following Is diagnostic presence ofclassl.c symptoms of OM (polyuria, polydipsia, polyphagia, weight loss, blurry vision, nocturia. ketonuria) PLUS random blood glucose (BG) <!:11.1 mmoUL (200 mgldL) PBG mmolJL (126 mgldL) mmoiJL (200 mgldL) 2h 75 g OGTT HbA1C (Ameriazn Dillbetes Assoda&n Guidlllines, Jan 2010)
Endocrinology E7
...,.... Elliclcy.t IMdlllilgiqnl il T,pll 111111111: 4T Trill NfJII'2009; 3&1:1736-47 lbidr: RlndDniiJd,lllllilindad trial with 3Y11B
,...._: 701 petints with typl2 dilllllll, nat an indl Cl'lbilllllldiJedilme theApy, an muilllll llllllfvmin lllld dauyMa tt.lpy. llllnlalun: Tl1ricHIIy pgndial illlllil asJIIrt, ..Uilwii:Hiily bipt.ic - anctdlily 111111 i-.Jin dllllrir. llalpywa rapllced Mh aiiiCUIIdlry inUI Ngima speciic: to IICh 11111 I therlwa pninnt
Ill. Oilier specific causes of dalletes; a. Genstic defuct& af bsta cell function {e.g. MODV- Maturity-01"1581 DiabBia& altha Yaungl or ilsulin action
b. Diseases af the exocrine pancreas: Pancrea1itis, pancrelllectllmy, cystic fibrosis, hemochromatosis ("bronze diabetes"! c. Endocrilapathies: Acramagaly, Cushing's syndrome, glucagonama, phaachi'DII'lDC'(IDma, hyperthyroidism d. Drug-ilduced: Glucocorticoids, 1hyraid hormone, beta-adrenergic agonists, thiazides, phenytoin, ciDZBpine e. Infections: Congenital rubella, CMV, coxsackie f. Genstic syndromus associBiad with diabBta&: Down's syndrome, Klinefelter's synd11111e, Turner's syndrome
hlmagilbin llgA1c. in Illes rlpilieal witutmwlftom11111tldy: 5.1\,.,lllic. 11.7\ IIIWidill. 8.5\ bull reginens There11111ignificlnt difl'nnl:ll in rnadiM HbA1 IIMIIs C
1111*
Millry Dllllllmc
pnlpOIIion ofpllilnll raach8d HbAIC <&.51 or <7.0\ in lhe biphaic- The baalllm hid leastweigllt lllin IIIII Ieist we9rt c:Wwnlnnce ilcrnH, bullighnt 1111 riiiCGIIdlry indn The UIIII1T1 hid flwest sevm llypDQiycelric MillS pll' plli8rt .,.., whiM lhe , . . hid !be rnos1 serious ldvelse ellec:ts. r.:tuial: 111111 inRIIin ragima pnMdlllhe bill! ltttlmic c:aabuiiMII 3"'11&r study; wilb blt1lr HbA1C w.ts.llld 1111 Might grin.
Epidamiolagy
Elialogy
Mare common in Caucasians Rare in Asians, Hispanics, Aboriginals, and Blacks Accounl8 for 10% of all DM
o
Mare common in Blacks, Hispanics, Aboriginals. Asials Accounts for >90% of all DM
AuiDinJOIIIe Monozygotic twin concordance is 3G-40% Associllllld with HLA class II DR3 and DR4, with aither allele prasant in up ID 95% af Type 1 DM o Certain 00 alleles also confer ariisk
o
Complex and multifllctorial Greater heritability than Type 1 DM Monal'fllotic twin concordance is 7G-90% Polygenic o Non-HLA associated
hilt in"" l DM- UIPDS 33 I.MCSt 11118; 352:137-53 Silly: lllndamilld camollld trillln.n IDIIIM'IIp
10 yllll). l'llilla: 3161 pllilnll with IIIMylllgnond Twle 2 DM 53y, 61,., men. 81hhile,l!llllll planl 6.115.0 IIIIIIVLJ. EllcUianl incUdld Clldovucullr di-.
a.- c-..
GMIIics
Pathophylialogy
Synergistic effects af genetic. irrrrame. and Impaired insulin secretion. peripheral insulin resistance environmantal factors that cause beta cell (likely due ID receptor and post receptor destruction resulting in impaired insulin secretion and eKCess hepatic glucose production AuiDinJOIIIe process is believed to be triggered by environmental factors (e.g. viruses, bovine milk protein, urea compounds! o Pancreatic cells are with lymphocytes resulting in islet cell destruction 80% of beta cell mass is destroyed before features af diabetes present
. . . . . lnllnlil81r811Jnentwith I IUranyu-11 insulin jllrgat FfG <6 IIIIIIVlJ VI. CIIMIIIilnlllr8m.t l'ltll dill IIana jlltglt FI'G
lllin ,....._ Dllletes-telllal enlpom halllfllilur8, ..... 181111faibe, aqmtian,lllilapltlly.IWIIII, dlllb !ram .....llllllad dlllb, 1111111-cue molllity. llllaltl: l'llillll11lbclted ID inl!nlive1rlllment hid krMr madiln HbA1C IMlllp<0.001l.
Nllul'll liiiDry
o...
sfJvUJ
honeymoon pariod
tim a
CIIICbiu: lnllnliva bllllld gU:ala canlnll 1lll.as micnMicullt but nat--* in Type 211A.
llialftt.relllad endpoint 12 (0.11291 llialftt.relllad dealh 10 lo.341 Akue rllOIIIlg 6(0.441 l'ltilnls IIDealld ID irm.MIIherapy hid 1111111 episodes and Grerllir wei;,ll!lin.
Alter initial presentation. honeymoon period often occurs where glycemic control can be achieved with little or no insulin 1reatment as residual cells are :;til able to produce Once th88e culls n destroyed, there is complsta deficiency
o
autDintibadi
o
o
Islet cell Ab present in up 1D 60-a!i'lli Most common islst cell Ab is against glutamic acid dacarbaxyl888 {GADI Up to 60% have Ab against
<10%
E8 Endocrinology
on.- ill'llillll zIll: AII'IANCE Trill NEIUZIXJI; 358:25&1-72 llldy: mdolrized. controlled trial l'llilra: 11,140 plliln!sMh TYJ1121J.1 11M! rilk
sli.SII'Iei1US slllllllrd gklcose controlldetlmiled
bylol:ll ldllllh fram criovuQHr cue.lllfllml MI. nonfalll sbllbl11d 11'icnMiculn11ru (aeplnpdhy, relinoplllry), 11111111: Th1 ClllqXJiill prinwy IUJ:ame- kMw in 1lle in1e111MgU:ase contro111111.1ndMdUIIy, a wa no difllr8nce in IIIIC1MSCiilr Mll'll or dciJSe morllllty, ilt1111111- illwll'incillnceof ma-ar
wml, 11MIIIIIIIri:n111111ninuril, lid I11ICI'OIIIuniluil in 11111 illtBniM glJcosl control ann. Aka1111 hO!Jiilalillliln,
llllnlill
wilh""
v.:.r
TypeZ
Age>40y Abdominal obasity/ovarwai!#lt Schimphrenia
Fatty liver
I'I'Bylllllllana:
HTN
Hyperuricemia Racl!/ethnicity (Black. Aboriginal. Hispanic, Asian-American, Pacific Islander) History of IGT or IFG Dyslipidemia
PCOS
Body Habitus Trllllmlllt Nonnal to warted Insulin
GeslalionalllM
Typically overweight with increased cenlral obesity
Acull Ca...licatian
Scr11ning
DiabBiic kstoacidO&is
Subclinical prodrome can be dstactad in first and
hospildrJb,lndsewere
irer.iw
second-degree raiBiivas of tmse with Type 1 DM by the presence of pancreatic islet allloantibodies
wm.
lYJIIZII\1.
illlpdlr incidlntl ri
Treatment of Diabetes
Glyc:emic: Targets HbAlC reflects glycemic control over 3 months and is a measure of patient's long-term diabetes control American Diabetes Association (ADA) suggests HbAlC <7.0%, whereas American Association of Clinical Endocrinologists (AACE) suggests <6.5% Canadian Diabetes Association (CDA) guidelines recommend target <7.0% there may be harm associated with strategy to target HbAlC <6.0% in certain patients with Type 2 DM (see EBM box re: ACCORD trial, E9)
TIIJII
HbAIC Fating pl1111111
o,hl
2h post
lipids
5-10 IIIIIOiit 5-I mmoll\ prandill gluca (!1().180 mgfd[J (!1().144 md/dl)
As per high ormodamla riltgroup < 130180
S11111
I I
...
HbA1C <9.1l'l'o
I I
...
HbA1C :!;9.D'll
lnilillte metfonmin
Blood
Sme
A targrtA1C of6.5'll may ba considered in some patients with type 2 diabetes but this be balanced against tha risk. of hypoglycemia.
lnitille phanmacatherapy immedillely without Wlliling for IJffect from lifustyle inblrvention1: Consider initiating metfonmin concurrently with another IIIJ&nt from a dilfurent clull; or lnitirte insulin
...
Symptomatic hyperQiycemia with mrtabolic decompensation
...
Add another agent from the list below: inhibitor Insulin secretaqogue Insulin sensitizer DPP.IV inhibitor Insulin Weight loss 1111ent (e.g. or1istat or sibutramilel
If not rt tarQet
Add another agent from a different class; or Add bedtime blllilll insulin 111 othur agunt(sl; or Intensify insulin regimen nmell' adjustmants to an,for adlltlon of amlhyPIIlllycemlc agents should be made to lltlaln 1llrget llbA1C within B11112 months
Endocrinology E9
Diet
daily carbohydrate intake 50-55% of energy. protein 15-20% of energy and fat <30% of energy intake of both saturated and polyunsaturated fats < 10% oftotal calories each limit sodium. alcohol and caffeine intake Type 1: carbohydrate counting is used to titrate insulin regimen Type 2: weight reduction
Lifestyle regular physical exercise to improve insulin sensitivity, lower lipid concentrations and control blood pressure smoking cessation Medical Treatment: Oral Antihyperglycemic Agents (Type 2 DM) initiate oral antihyperglycemic therapy within 2-3 months iflifestyle management does not result in glycemic control ifHbAlC >9.0%, initiate pharmacologic therapy immediately and consider combination oral therapy or insulin immediately see Common Medications, E51 fur details on antihyperglycemic agents Medical Treatment: Insulin (Figure 5) used fur Type 1 DM, may be used in Type 2 DM at any point in treatment routes of administration: subcutaneous injections, continuous subcutaneous insulin infusion pump, IV infusion (regular insulin only) bolus insulins: short-acting (Humulin R, Novolin Toronto), rapid-acting analogue (Apidra, Humalog, Novorapid) basal insulins: intermediate-acting (Humulin N, Novolin NPH),long-acting analogue (Lantus, Levemir) premixed insulins (%Rand %NPH) 10/90, 20/80, 30/70, 40/60, 50/50; analogues (Humalog Mix2S, Hu.malog MixSO, Novomi:x 30) estimated total daily insulin requirement: 0.5-0.7 units/kg
ffla:tatfi_..GI_ illP 2 DM: n. ACimll Trill NfJM 2008; 358:2545-51 lbldr: M.._ JllldomiNd, C411tJUiad 1rill l'lllnll: 1o,251 patients (mean age 62.2) wilh Type 2 DM. 111d Cll'dilvllailr risk flc1Drl. llllrnnlan: . . . . tlmpy llrgeting aiiJA1C laval rl laA thin 6.0'Jo or lllndlnl 111111P!' 1llgalilg 7.01D7.K. 0..-rlnorfml Ml noriml llrDkl. or dlllh flam CV CIIIIH. 11116:111t intln!M lhalpy IIIII Wlllluppad llrly (3.5"' VI. 5.6"' P8lll'lldla1D hidance rl ilcrased 1T10itllty. There WIS no dilfnlce il prim.., IIIII:Dmlfar iiiiII!Jdv IIIII. Thlrl WHisignificlnt i - in._ rnartllty, C'keUIIIII'IOIIDty. nodllll Ml, liM! all congllti8 belltfaikn in the irensive theApy PJP. There wn iiiCIIIIId IIIII rl all?jpogl'fcamic Mllll. Ill\' nonl?nogl'fcmic llrilu IIMIII Md. luid lltlnlion,ltld Wllight gain >10 ka but lower systolic ltld iludc 1m! prntiD in lha inlllllivl 1llerlpv group. There WISIII increlsed incidence rl IIIMIId ALT (>3 hiiPI* limij 111d ACE IWg Ule in the sllndllll flmpv graup. l:lli:luilll: hbmsMI lowering 1bll1py in Type 2 DM does nol in'II'M cili: M:omes 11M! IC!JJdyin-11111 rilt rillllllllllilywilh 11111111 llMnl Mllll campnd 1D llllndllll1111111!'1'. Adclilionll rasiiiiCh is rtquired to lilclm tl1ll Cllll8.
Camalil
Peak
Duration
Type 211M: D1 ACCORD Trill Nf.JM2010; 362:1575-15 .... Rtl, urllinded wilh rlflllkMrilp. . . . - : 4,733 ]lltilrGMhtype 2dillbelis, rilk 11ctors r. Clnbllcui.-ICVI sysblic
d._,
Pnndilllbal111) i1sulins
Rapid-acting insulin analogues Insulin IISpllrt (NovcRapid) Insulin lispro (Humalog) Insulin glulisine (Apidra) Short-iictilg insulins Humulin R Navolin Toronto Inhaled insulin
Bual insulils
llllrnnlan: IIIII' control Ins 1hm120 rmiig (inlllllillel 01140 ll'rilg lllllndardl.
(c:unP11
lntennediatBcting Humulin N Navolin NPH Long-ilcting basal insulin analogues Insulin detanir (l..evemir) lnaulin (Lirrtus)
1-3h
5-Bh
Upto18h
90 min
Not applicable
Pre-mind i1sulins
Premixed regular insulin - NPH Humulin 30/70 Navolin 30,170, 40,160, 50/50 Premixed insLJin analogues Biphasic insulin aspart {NavoMix 30) Insulin lispnV!ispro protamine Humalog Mix25 and MixSO
cv
A single vial or cartridge contains a fixed ratio of insulin (%of rapid acting or short-ilcting ilsulin to% of intermediate-acting insulin)
Ellldlll C...bmln lipid n.np, il TWIZ DM: tl1ll ACCDID Trill NUf21110; 362118):15&3-74
S1udy: IICT, dwblt-bhlld trill will14.7 yan II 11111111DIIawup. 5.511plllilrdlwilhlypl2dilb8tlll. . . . . . . Sllllinwilll orwillad fhtelhellpy. Mn.yo.a:.n.: MIP' Clldi-llr tcVI Mit norfml myocllllill imtiall.lllllillll staa, 01 CV-ftiUI dellll).
M:ome between 111e two anns. No dillerence il
Clncbiul: The illllilion oflinla U.rapyto slllin 1berlpr in plllienls wilh Type 211M does no1
TIICIJcalllljarCVMWI!rilk.
E10 Endocrinology
11,
DPNVInhilllbln
Regular/Toronto
Nawar antihyparglycemic agents ttlllt inhibit 1t1e degradation of endogenous incratin honnon111 tika GIP-1 Stimulate insulin ucretion. ilhibit
gluciiQCin rulaa1e from the p1111Cnllll
Bnaekfllst
Lunch
Dinner
Bed
Figure 5. Duration of Activity of Different lnsulins Insulin Regimens 1. Oral agent+ basal insulin (NPH, detem.ir, glargine) (Type 2 only) start with 10 units qhs, titrate up until FBG <7.0 mmoVL (126 mg/dL) continue metformin and/or insulin secretagogue 2. Twice daily injections with premixed insulin insulin mixture used depends on the distribution of carbohydrates in meals but usually start with30/70 estimate total daily insulin requirement then split dose into 2/3 in AM and 1/3 before supper AM bolus targets pre-lunch BG and AM basal targets pre-supper BG PM bolus targets bedtime BG and PM basal targets FBG continue metformin and discontinue secretagogue with this regimen advantages: one type ofinsulin, 2 injections disadvantages: requires rigid meal timing and carbohydrate content; limited ability to respond to increased or decreased BG (ie. serum glucose before breakfast next day) 3. Basal-Bolus therapy [multiple daily injections (MDI)] estimate total daily insulin requirement then take 20% ofthis daily dose before breakfast, lunch, and dinner using regular, aspart, glulisine or lispro (total60%) the remaining 40% is given as NPH, glargine or detemir at bedtime continue metformin and discontinue secretagogue with this regimen advantages: flexible meal timing and carbohydrate content, ability to respond to increased or decreased BG, or planned exercise disadvantages: multiple injections Table 11. Titrating Insulin Doses IIIUin Rcgillll Twice Daily/MOl Twice Daily/MOl Twice Daily
MDI
Twice Daily/MOl
R=rapid actin!l S=sllart-.:tilg inUn.l=
lncrllil58 Evenilg Itt Moming R/S Increase Moming Itt Increase Lunch R/S Increase Evening IllS
Connr.ion Chart
for pcantage HbA1C to average blood sugar control
sugar ltvel [11111oilt) Hamoglobin Al C ('II HbAIC)
::= -=-=::
12II%
10- ....... 8 6 Dptlmll -
17-
-18
Variable Insulin Dose Schedule (Sliding/Supplemental/Correction Scale) patient takes usual doses ofbasal insulin but varies doses of bolus insulin based on BG reading at time of dose use baseline bolus insulin dose when within BG target range; add or subtract units when above or below target commonly used in hospital or in perioperative management of diabetes construction of a sliding scale for a patient on anti-hyperglycemics: Correction Factor {CF) = 100/Total Daily Dose of insulin (TDD) BS <4: call MD and give 15 g carbohydrates BS between 4 to (7 + CF): no additional insulin BS between {7 + CF) to {7 + 2CF): give one unit BS between {7 + 2CF) to (7 + 3CF): give two units Insulin Pump Therapy external battery-operated device provides continuous basal dose of rapid-acting insulin analogue (aspart, glulisine or lispro) through small subcutaneous catheter at meals, patient programs pump to deliver insulin bolus provides improved quality of life and flexibility risk of DKA if pump is inadvertently disconnected Calculating Average Blood Sugar from HbA1C Average blood sugar ={HbA1C x 2) - 4
8% 7%
6%
eom-ionchartadaplldfrom Nlthan IJ.l 111L The clniclll iliormllion wkle ol a glycl)$\'llled IIIII' NfJM 1984; 310:341-6
Endocrinology Ell
Acute Complications
Table 1Z. Acute Complications af Diabetes Mellitus: Hyperglycemic Comatose States
Pltllophysiolllll'l
llilbetic lretolcidosis [DKA) o Usually occurs in Type 1DM o Insulin deficiency with 1' countaTegulatory honnones
Clinil:ll Faaturas
S1r11m
ABG
Urine
Occurs in Type 2 DM Often precipilated by sepsis, stroke, Ml, CHF, renal failure, trauma, drugs {glucocorticoids, iiTilllnosuppr8SSIII!s, phenytoin, diurstics), dialysis, recent (glucagon. cortisoL cel8cholaminBS. GH) o Can occur with lack of insulin (noncompliance, poor dosage, 1st surgery, bums presentation) or increased stress (surgery, infection, exercise) o Partial or relative insulin deficiency decreases glucose utilization in musde, fat. and o Unrestricted hepatic glucose production hyplllltfcamia osmotic liver while inducing hyperglucagonamia and hapatic glucose production diuresis -+ dahyltation and electrolyte disb.lrban:e -+ o Presence of a small amount of ilsulil pi'8VIIItl1he dewlopment of kBIDsis by Na (pseudohyponetremia) inhibiting lipolysis o Fat mobilization 1' FFA ketoacids metabolic acidosis o Dlaracterized by hyperglycemia, hyperosmolality, and dehythtion without ketosis o S8V81'8 hypellJiycemia exceeds the renal threshold for glucose end o More S8V81'8 dehycntion compared to DKA due to more gradual onset and ketone Rlllbsorption glucosuria and ketonuria 1' duration of metabolic decompansation plus impaired fluid intakB which is o Total body Kdepletion but serum Kmay be normal or elevated common in bedridden or elderly 2" to shift from ICF to ECF due to lack of insulin, 1' plasma osmolality o Volume contraction renal insufficiency 1' hyperglycemia, 1' osmolality o Total body P04 depletion shift of fluid from neurons to ECF mental obtundation and coma o Polyuria, polydipsia, polyphagia with marked fatigue, nausea, vomiting o Onset is insidious preceded by weakness, polyuria, polydipsia o Dehydration (orthostatic changas) o History of decreased fluid inlllka o LOC may be with high serum osmolality (osm >330 rrmolll.l o History of ingesting large amounts of glucose containing fluids o Abdominal pain o Dehydration (orthostatic changes) o Fruity smelling breath o LOC lethargy, confusion, comatose o Kussmaul's 185pircrtion o Kussmaul's respiration is absent unless the underlying has also caused a metabolic acidosis o 1' BG (11-55 mrnoVL, 1911-990 mQidl), Na (spurious zto o 1' BG (44.4-133.2 mmolll. BOD-2400 mQidl) for every 1' in BG by 10 mmoVL (180 mg/dl) o In mild dehydration. may have hyponatremia (spurious 2" to hyperglycemia for there is a in Nil by 3 mmoVL) every 1' in BG by 10 mmoVL (180 mlfdl) there is in Nil by 3 mmoVL) o Normal or 1' K. BUN.-t Cr. ketonemia, P04 - dehythtion progresses, may get hypematremia o 1' osmolality o Ketosis usually absent or mild starvation occurs o 1' osmolality o Metabolic acidosis with 1' AG, possible respiratory alkalosis o Metabolic acidosis absent unless underlying leads to acidosis o HS8V81'e there may be a metabolic alkalosis {e.g. lactic acidosis i1 Mil o +ve for glucose and krltonas o -w for ketonas 1here i& starvation kBIDsis o Glycosuria
o
Treatment
Pragn01ill
lrrrnediate resuscitation end emergency measures patient is o Same resuscitation and emergency measures as DKA stuporous or comatose o Rehydl'lllion: o Monitor degree of ketoacidosis with AG. not BG or serum ketone level - IV fluids: 1 lAl NS initially o Rehydration: - MIWIIII corrected serum Na - 1l,lh NS in firstZ hrs - herum Nil high or normal, switch to 0.45% NS (4-14 - after 1st ZL, 3004110 0.45% NS Nil low, maintain NS (4-14 - once BG reaches 13.9 mmol/1. (250 mg/dl)then switch to DSW - whensenm BG reaches 13.9 mmoVL (250 mg/dl) switch to DSW to maintain BG in the range of 13.9-16.6 mmol/1. (250-300 m!J'dl) o Kreplacament o Insulin therapy: - less severe Kdepletion compn to DKA - critical to resolve acidosis, not hyperglycemia K<3.3 mmol/1., hold insulin and give 40 rriqA. Kreplacement - use only regular insLJin (R) - Kis 3.3-5.4, give KCI 20-30 mE!L IV fluid - initially load 0.15 Ul kg body weight insulil R bolus - serum K mmoVL, check Kevary 2 h - maintenance 0.1 lJJ1twh ilsulil Rifusion o Saarch for precipitating Mnt - check serum hourty o Insulin therapy: o Kreplacement: - use insulin (R) - as acidosis is corrected, hypokalemia may develop - initially load 0.15llitg body weight insulin Rbolus - when K mmol/1. add KCL 30-4IMIEI\.IV fluid to blap Kin - maintenance 0.1 UJkWh insulin Rinfusion or IM the range of mE. - check serum glucose hourly o HCO,: - in general lower insulin requiement compared to DKA - if pH <7.0 or if hypotension, arrhythmia, or coma is present with a pH of < 7.1 give HCDs in 0.45% NS - do not pH > 7.1 (risk of rnetllbolic alkalosis!) - can give in case of life-threatening hyperkalemia o mamitol (for cerebral edema) o 2-5% mortality in developed countries o Overall mortality approaches 50% primarily because of the older o Serious morbidity from sepsis, respiratory complications, patient population and underlying atiology thromboerrtolic complictdions, and cerebral edema
o
Ischemia or Infarction
Infection
Average fluid loss MS Ill 3-6 l in DICA, and ll-10 Lin HONK.
E12 Endocrinology
.....
, ...-----------------,
Macrovascular Complications
increased risk of coronary artery disease (CAD), ischemic stroke, and peripheral vascular disease (PVD) secondary to accelerated atherosclerosis coronary artery disease risk ofMI is 3-5x higher in those with diabetes compared to age-matched controls CAD is the leading cause of death in Type 2 DM most patients with DM are considered as "high risk" under the risk stratification for CAD (see Dyslipidemias, E2) ischemic stroke risk of stroke is approximately 2.5x higher in those with diabetes level of glycemia is either a risk factor for stroke or a predictor of a poorer outcome in patients who suffer a stroke HbAlC level is a significant and independent predictor of the risk of stroke peripheral vascular disease manifested by intermittent claudication in lower extremities, intestinal angina, foot ulceration risk of foot gangrene is 30x higher in those with diabetes compared to age-matched controls risk oflower extremity amputation is 15x higher in those with diabetes treatment tight blood pressure control (< 130/80 mmHg) tight glycemic control tight low density lipoprotein (LDL) cholesterol control [LDL <2.0 mmoVL (77 mg/dL)] low-dose ASA in patients with CVD or increased likelihood of CV events ACE inhibitor or angiotensin receptor blocker (ARB) in high-risk patients smoking cessation
Labol'lltllry Telling: Kllone The nitropruslide 18st for ketones idmtilias acltone lll1d ac.taaclllll but
does NOT dutsct b&hydroxybutyrBIB
urinary ketones. These could be false nCJQIIIives. 2. A:l DKA is treated, BHB is converted to acstone and acutOBcelate. Serum or urinary ketones mey thererot. rise, falsely suggesting that the patient is woruning.
Bllcllfallullillc:IDrill......._ llarllltyin "1WI 2 Dll: 1111 S....Z SUir Nf.JI2008; 358:51).91 S1.dy: SilP cantra. lllllbnillld, COI"Uollld bill Pllilla: l'l1iiiD (n=I&OiwMII Typt2 [J,hlll
peqislenl mOollbcmnurill. - . - . lllndamMSignmR1D IICIIivllilllll COIMII1inl treldJrent irensilied, targeldriwn lhlrapr iMMig I corilillliDn a/ medications and fuMed beluwiour modificllion. TIJVBII incildlld I HbAIC IMiri I filling nrn IDtll challslniiMiaf <4.5 11111101"\.a luting mm triglyceride IMiri <1.7 rnmoVl.
I
Microvascular Complications
DIABETIC RETINOPATHY (see Ophthalmology. OP35)
-------------------------
&'/Sf* bbld pr&SIIDaf <l:.hrmH;. and I di151oiic blood ,_nt ri <80 1'llienll -lrOd will biJcbrl allht llliHngiDIInlil 1\'Afm blclutl of !hair micnldJ1111iuill, ntglldlla ri blood prasan, and T8C8iwd bw-dosa
sapirin u
pr-mon.
Epidemiology Type 1 DM- 25% affected at 5 years, 100% at 20 years Type 2 DM - 25% affected at diagnosis, 60% at 20 years leading cause ofblindness in North America between the ages of20-74 most important factor is disease duration
DM ___. 1- GluC1118 ___. besemant membrana thickening, ___.Altered vascular permeability, bnekdown reti1111l berriar retinal closure
1111111-: Tha prinmy and point in 1ha IDIIawiJp lrilll-llleiD Ill deldl fiam IIIII' cue. Other 8lllf1linld dllthfrom Vlriu canliovaWII MID alcoJ wMh dilb8tic: lWOpdly, nephrop111rf, and
cardi--
lei
..
P4l died,n 40 in lhe CGINall1ioMI-Ihlrapr group lhmrd rllio, o.54; 95\ comdlncl iiiiiMI(CIL 0.32111 0.19; P=0.02l. 111enivf- UIIICillld with alawer risk ri dllth from CMiovasclllar cues (bad ratio,0.43; 9!1!. 0.19 to0.94; P D.041and at Cl, D.251o 0.61; Dne patient inlhe ir0niiw-1hanpv group had piUgfUIIion 111m IIIQaiiRII ' - , with six patients in 1ha cOI"Nrionll-lhenFY P4' IP=0.04). patilnls in tha illln!M-thnpr grDlf llq.intd retinal lnilltiw risll. 0.45; 95\ Cl
D.l.lto 0.8&; P =0.02). I:GncUilnr. ....risk palieal1 with Twle 2
Microaiurysms
Macular edema
11.1, drug cautilltions and behnicu modiliclticm had IUIIJined bunafil:illllleciJ with rtlfi8CI lo11W'COIJ'IIications and 011 ratJI af dalth from IIIII' Cllll8
Rutilal traction
Retinal detachment
... ...
1' Growth factors
(VEGFI
...
Reti1111l ischemia I
Hard axudates
...
...
Vascular fllrosis
4: V"llnlous
Flolllers
Iris
hemorrhage
neovascularimtion
Neovascular glaucoma
Endocrinology E13
............ ., lilbdc . .GPIIIIr-A s,stlmllic llnilw JAAM 2007; 218:802-16 l'llpM; ll rwirN1ha btst evidence for Jllimlry llld secondlry irUMulioas in 'die 1111111Qe1!111t rJ lilbltic 1'llilqldy incUding cllbltic llliii:Wredei!IL Sludr w.ctitn: AI conlrolled trials (Rtlsl wilh more lhln 1 months Z rJ 11181Hnllyw5- incloo.d.
Clinical Features
nonproliferative asymptomatic, but if macular involvement occurs, vision may be impaired microaneurysms, hard exudates, dot and blot hemorrhages preproliferative 10-40% progress to proliferative within 1 year macular edema, cotton wool spots, venous shunts and beading, intra-retinal microvascular abnormalities (IRMA) proliferative neovascularization, fibrous scarring, vitreous hemorrhage, retinal detachment great risk for loss of vision secondary to vitreous hemorrhage (floaters) and/or retinal detachment
llt\llli COIIIIIlU critlriJ Will 1111d 1D Cllf1dud8d sbldiali. . . . . FollyoWSWdies 3 nmlysesl met the inclusion crileria. Tight !t!amic llld blaad cllltrDilldUCIIlhl iK:idiiiCIIIII'Id p!IJIIIeSSian of DR.I'IIIHIIilllllser pllolocOIQUIItiollllllb:811ha rilkof modnt8 end severe u loA by 50% il Pl1ierO Mh severe llllllp!DiillraM and prDifanliva llllilapltti. Focal llslr pllolociJIIGIIIIIian llllb:alhl rilk of madntl Willi lOll by 50 1D 70\ in Ill'S with IIWIIUir
lldarrl.
il pllienls wilh prolileriiNe retiiiGJIIIby IIIII severe "libiU bnanlilaL qiCiians rJ aids lillY be Clllllidind il eyeswitll persistert loA rJ vilion when COIMIIItionlllnll1mant
llllllicll
NP34)
diabetes-induced renal failure is the most common cause of renal failure in North America 20-40% of persons with Type 1 DM (after 5-10 years) and 4-20% with Type 2 DM have progressive nephropathy
Pathophysiology
Screening
random urine test for albumin to creatinine ratio (ACR) plus urine dipstick test for all Type 2 DM patients at diagnosis, then annually, and for postpubertal Type 1 DM patients with years duration ofDM
Clinical Features initial changes include microalbuminuria, increased GFR (up to 140%), enlarged kidneys
microalbuminuria: ACR of>2.0 mglmmol (men) or >2.8 mglmmol (women) macroalbuminuria: ACR of>20.0 mg/mmol (men) or >28.0 mg/mmol (women) progression over 15 years to cause hypertension, persistent proteinuria (macroalbuminuria), nephrotic syndrome, and renal failure elevated HbA 1C is an independent risk factor for progression to microalbuminuria
E14 Endocrinology
ar.ctlofT..-...IorSV.... rA.,._.
Dilllllic Nllraplthv: Sfstlnlic llniiW BMJ 2007; 335:87 l'llpole: To evaUII81ha afllctsoflrlllmlntsfor 111e panul dillbelic neuropathy. Slldy S.lll:lial: Randomillld conlrollld trials cornplriJrJ tD!icallv ijiplied 11111 cn1t ldmililtmed dru115 with piiiCibo illdulll wi1h painful dialic
Pathophysiology
mechanism poorly understood acute cranial nerve palsies and diabetic amyotrophy are thought to be due to ischemic infarction of involved peripheral nerve the more common motor and sensory neuropathies are thought to be related to metabolic or osmotic toxicity secondary to increased sorbitol and/ or decreased myoinositol (possible mechanisms include accumulation of advanced glycation endproducts (AGE), oxidative stress, protein kinase C, nerve growth factor deficiency) can have peripheral sensory neuropathy, motor neuropathy, or autonomic neuropathy
llldE 25 reporls COII1JII8d 1111i1:011Wislnts antidlpralllnll 194), opilidsl329), ion chlnl blocbrsl1731 N-malllyiIJ.aparla1a antaQonist 1141 {aJS), capsaicin lnd isosorllide dilitrlle SJ111Y 1221 wi1h plallo. n. oddllllios in llrms of 511\ pail l1ilef were 5.33 {95\ cndenc:e inteiYII1.77m 16.021 fortnlditiOI'IIIricOINUislnts,l.n 1211 m4.66Hor newergenemon llltiCOIMMrts, and 222415.83 tD84.7SIIorlri:yicridapra.nts. Tha oddsllliol in 111mB afwi1hd11WBis ralatBd 1nlvarsa 11V8n!SWitl11.51 {0.33 tD &.96llor 1lldilionallllllicorWsants, Z.!1811.751D 5.071 for newer glll!ration lllllicorWsants, and 2.3210.59 tD 9J9Ifortrit'jlic lllllidlpraSIIIIII.Insuflicilnt dic:ho1urnous dill were Milllble to cali:UI1B 1he odds llliolfor ion clllnnlil bklckln. c:.dtlian: AnticonQanls 11111 llllidlepleS11n!S 119 stilthl most com marly Ulld options tD IIIBTIIQIIIilbltic !*lropathy. Drel bicyti: antidaprlsllnts and baditionlllllticonwlllnts 119 betlar for short llnnpllin 11iaflhln nawtr gener*nanliconvulslnts. E\lid.e ofllle big linn llld of 011ll1llilllprlauds 1111 antii:OIIWUrti isitilllctiiQ. Furthir iludias 119 naadad on opilids, ionciMinnelbklclra
neiJTOllldrf.
Screening
128 Hz tuning fork or 10 g monofilament at diagnosis and annually in people with Type 2 DM and after 5 years duration of Type 1 DM
Clinical Features
Tabla 13. Clinical Pra1entlltian af DiabBiic Neuropathies
Peripheral SIIISCIIY Neuropilllly
Mutor Neuropllhy Less common than S!IISOIV neuropathy Delayed motor nerve conduction end 1111scle weaknew'atrophy May involve one nerve trunk {mononeuropathyl or more (rnononauritis Some of the motor neuropathies spontaneously resolve alter 6-8 wks Reversible CN palsies: Ill (ptosi!Vophthalmoplegia), VI (inability to laterally deviate eye), and VII (Bell's palsyl Diabetic amyotrophy: refers to pain, weakness, and wasting of hip ftexors or axblnsors
Aulllnomic Neuropathy
Postural hypotension, tachycardia, decreased cil'diovascLJar mponse to Valsalva maneuver Gutroparesis 111d alternating diarrhea and constipation Urinary retention end erectile dysfunction
Plreslhesias itching I, niiUI'DpCithic pain, radicular pain, numbness. decreased lllc:lile sensation
Billlllrlll and symmetric with decreased pm:eption of vibration and pairv' temperature; especially true i1 the lower extremities but may also be presiJ'II in the hands Decreased ankla rdex Symptoms may fim occur in anlnlpmunt syndromes e.g. Cllplll11111el, neuropathic ulceration of fuot
Other Complications
Dermatologic
diabetic dermopathy: atrophic brown spots commonly in pretibial region known as "shin spots': secondary to increased glycosylation of tissue proteins or vasculopathy eruptive xanthomas secondary to increased triglycerides necrobiosis lipoidica diabeticorum: rare complication characterized by thinning skin over the shins allowing visualization of subcutaneous vessels
Cataracts
subcapsular and senile cataracts secondary to glycosylated lens protein or increased sorbitol causing osmotic change and fibrosis
Infections
see Infectious Diseases, ID23
Endocrinology E15
Hypoglycemia
Etiology and Pathophysiology
hypoglycemia o=s most frequently in people: with diabc:tc:s rc:cciving insulin or certain antihyperglycemic therapies (insulin secrc:tagogues) in people without diabc:tc:s, care: must be: taken to distinguish fasting from post-prandial hypoglycemia as each invokes separate differential diagnoses
....
,..----------------. ,
iniD 1he
A short peptide
....
Rau:tinl
Fuling Hyparilsulinil11
Exogenous insulin o Sulfonylurea reaction o Autoimmune hypoglycemia (autoantibodies to ilsulin or insulin receptorl o Pentamidine o Pancreatic beta cell1umour - insulinoma
o
,,
Hypocortisolism
o
o
Alcohol use
tumours Imam error of carbohydrate metllbolism, glycogen stomge disease, gluconeogenic enzyme deficiency
.....
,.. ,
1l'ulment of Aalllllllypaglv-nlc Epiludl (IIIDad Gb:a11 <4.0 nnall'lJ In 1M Awake Pdent (e... 11111111 ..ef.4nlll) 1I Eat 15 g of cabohydnrtes ICHOJ (e.g. 3 x 5 g glucose tablets; 3 piCk8ts IU!III'dissolved in W8lll; 314 cup of juice}
2} Wait 15 minutas
+ + + +
Investigations
electrolytes, BUN/creatinine, LFrs, drugs/toxins
Treatment
for fasting hypoglycemia. must treat underlying cause: for post-prandial (reactive) hypoglycemia, frequent small feeds see Emergency Medicine. ER36 bloodwork to be drawn when patient is hypoglycemic (i.e. during hospitalized 72-hour fast): serum ketones, insulin, proinsulin, C-peptide, cortisol, and GH treatment of hypoglycemic episode in the unconscious patient or patient NPO D50W 50 mL (1 ampule) IV or 1 mg glucagon SC (if no IV available) may need ongoing glucose infusion once BG >5 mmol/L (90 mgldL)
.....
,...----------------. ,
Decreand glucagonfepilephrine raspo11111
Autonomic dysfunction
History of rap..t.d hypoglycemia or lowHbA1C
Metabolic Syndrome
defined by having three or more: risk factors (see sidebar) postulated syndrome related to insulin resistance associated with hyperglycemia. hyperinsulinemia, hypertension, central obesity, and dyslipidemia obesity aggravates extent of insulin resistance complications include atherosclerosis, CAD, MI, and stroke not to be confused with syndrome X related to angina pectoris with normal coronary arteries (Prinzmetal angina)
.....
,,
Obesity
see Family Medicine. FM5
lWril'-1
Men Ytllmn
HDL.CIM
laud,....
1M
El6 Endocrinology
Pituitary Gland
Pituitary Gland
G)
It'
The Plluituy H111111011u
Pituitary Hormones
"Go Look Far Th1 Adlnama Pla OH, Ul, FSH, TSH, ACTH, PRL + posbrior pituitary hormones: ADH and oxytocin
i
:.:
GHIH (somatostatinl
-!I r
.!I .10"11
.!i"&
Thyroid g-land
'"'! fo .c
w
r,, T4
1 1 1 1 1 1 1
ACTH GH Adrunlll cortex Liver
CRH
GnRH
i1
call& of g-onads
Ji
Breast
Somatomadins (IGFI
Androgens
Eltrogen&,
I
Gonadlll germ cells, Multiple target organs
CRH =corticlllniplin-ralauilg honnlnu; GnRH =glnlldgtrgpin-ralarlling h011111111; GHIH = hormone; GHRH =growth hormone; PIIH = hormone; lRH =thyrotropin-MasirQ hannane
Hypothalamic Control of Pituitary trophic and inhibitory factors control the release of pituitary hormones most hormones are primarily under trophic stimulation except prolactin which is primarily under inhibitory control by dopamine transection of the pituitary stalk (ie. dissociation of hypothalamus and pituitary) leads to pituitary hypersecretion of prolactin and hyposecretion of all remaining hormones Anterior Pituitary Hormones growth hormone (GH),luteinizing hormone (LH), follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), and prolactin (PRL) Posterior Pituitary (Hypothalamic) Hormones antidiuretic hormone (ADH) and oxytocin peptides synthesized in the supraoptic and paraventricular nuclei of the hypothalamus although ADH and oxytocin are produced in the hypothalamus, these hormones are stored and released from the posterior pituitary
Table 15. The Physiology and Action of Pituitary Hormones
Horm- Func:tiDn
Phyliology
o
ln.llitary Stimulus
Sacratory Stimulus
CRH Melyllpone
o
Acnt
Insulin-induced
ADH
GH
Polypeptide
Glucose challenge
o
o
IGF stilllllate5 growth of Acts ildiractly through serum Glucocorlicoids bone and cartilage feeto11 synlhesizsd in the HypathyruidiiiTI liver: IGF (samatomedins) Somatostatin
Serum GH undetectable Dop1111ine aganists for most of tha day and IGF-1 (long-loop) suppressed alter meals high in Tonically by dopamile glucose agonists o Sustained rise ckuing sleep
lnsulin-illWced hypoglycemia
ExBn:ise
GHRH
Pituitary Gland
Endocrinology E17
Polypeptide Glycopruteils
Testes:
- LH: production of testosterone (Leydig cells] - FSH: production of spermatozoa {Sertoli cals) Nonapeptide
EtOH
Suckling Dishntion of female genital tract via stretch receptors Sleep Slnlss, hypoglycamica Pregnancy, breast.feeding Midillanstrual cycle Sexual activity
TRH
TSH
Glycoprotein
Circulating thyroid hormones TRH (T;a. T,) Epileplrile Opiatas, dopamine Prostaglandins
Etiology GH secreting pituitary adenoma, carcinoid or pancreatic islet tumours secreting ectopic GHRH resulting in excess GH Pathophysiology nonnally, growth honnone is a catabolic hormone that acts to increase blood glucose levels in growth honnone excess states, secretion remains pulsatile, but there is loss of hypoglycemic stimulation, glucose suppression and the nocturnal surge proliferation ofbone, cartilage, soft tissues, organomegaly insulin resistance and IGT
Clinical Features enlargement of hands and feet, coarsening of facial features, thickening of calvarium, prognathism, thickening of skin, increased sebum production, sweating, acne, sebaceous cysts, fibromata mollusca. acanthosis nigricans, arthralgia. degenerative osteoarthritis (OA), thyromegaly, renal calculi, hypertension, cardiomyopathy, and DM Investigations glucose suppression test (OGTT) is the most specific test --+ increased GH in acromegaly insulin-like growth factor-1 (IGF-1)
Signs IIIII Symplllms of
ABCDEF
Al1hralgii/Arlhritis Blood pressure raised Carpal runnel syndrome
Diabl!as
Enlarged organs
Treatment surgery, octreotide (somatostatin analogue), growth hormone receptor antagonist, bromocriptine (dopamine agonist, acts on the pituitary gland to block the production and release ofgrowth honnone), radiation
El8 Endocrinology
Pituitary Gland
Prolactin (PRL)
....
..._---------------,
HYPERPROLACTINEMIA Etiology prolactinoma: most common pituitary adenoma (prolactin-secreting tumours may be induced by estrogens and grow during pregnancy) pituitary stalk lesions primary hypothyroidism (increased TRH) chronic renal failure resulting in decreased clearance, biliary cirrhosis medications with anti-dopaminergic properties are a common cause of high prolactin levels: antipsychotics, antidepressants, antihypertensives, anti-migraine agents (triptans/ergotamines), bowel motility agents (metoclopramide), H 2-blockers (e.g. ranitidine) Clinical Features galactorrhea (secretion ofbreast milk in men or non-lactating women), infertility, hypogonadism, amenorrhea Investigations serum PRL, TSH, liver enzyme tests, creatinine
Approach ID Nipple Dilcharp 1. Dilferentim between galiCIDIIhea !fat droplab present) versus breast
discharge !usually unilatenl, may be bloody or 5811)115) 2. If qaliu:tonhe1, determine if phy&ioi01Jil: (u.q. pragnanc:y,lac:bdion, stress) versus pathoiOIJiC 3. If abnormal bnlast diachargu. must nb out a bi"IISt malignancy
oMRI
Treatment long-acting dopamine agonist: bromocriptine, cabergoline or quinagolide (Norprolac"') surgery radiation (rare) prolactin -secreting tumours are very slow-growing and sometimes require no treatment if medication-induced, consider stopping medication if possible
DIABETES INSIPIDUS (DI) Definition disorder resulting from deficient ADH action causing passage oflarge volumes of dilute urine
Diq.-ing Wllypa ol Dl with DDAVP llelponM
Diagnostic Criteria fluid deprivation will differentiate true DI (high urine output persists, urine osmolality < plasma osmolality) from psychogenic DI (psychogenic polydipsia) response to exogenous ADH will distinguish central from nephrogenic DI Etiology and Pathophysiology central DI: insufficient ADH due to post-pituitary surgery, tumours, stalk lesion, hydrocephalus, histiocytosis, trauma, familial central DI nephrogenic DI: collecting tubules in kidneys resistant to ADH {drugs including lithium, hypercalcemia, hypokalemia, chronic renal disease, hereditary nephrogenic DI) psychogenic polydipsia must be ruled out Clinical Features passage oflarge volumes of dilute urine, polydipsia, dehydration Treatment DDAVP/vasopressin for total DI DDAVP, chlorpropamide, clofibrate, or carbamazepine for partial DI nephrogenic DI treated with solute restriction and thiazide diuretics
Pituitary Gland
Endocrinology E19
Diagnostic Criteria hyponatremia with corresponding plasma hypo-osmolality, urine sodium concentration above 40 mEq/L, urine less than maximally diluted(> 100 mOsm/kg), euvolemia (edema absent), and absence of adrenal, renal or thyroid insuffi.ciency Etiology and Pathophysiology stress (pain, nausea, post-surgical) malignancy (lung, pancreas, lymphoma) CNS disease (inflammatory, hemorrhage, tumour, Guillain-Barre syndrome) respiratory disease (TB, pneumonia, empyema) drugs (vincristine, chlorpropamide, cyclophosphamide, carbamazepine, nicotine, morphine, DDAVP, oxytocin) Treatment treat underlying cause, fluid restriction, vasopressin receptor antagonists (e.g. tolvaptan, conivaptan), and demeclocycline (antibiotic with anti-ADH properties, rarely-used)
SIADHw. c.ebnd S.ltw..tmg (CSW) CSW Clll1 oc;cur in CH85 of aubarachnoid hemontlage. Na is excreted by miiUlclioning 11111111 tubulel, mimicking findings of SIADH.
Pituitary Pathology
PITUITARY ADENOMA (see Neurosurgecy, NS13)
Clinical Features related to size and location visual field defects (usually bitemporal hemianopsia), oculomotor palsies, increased ICP skull radiograph (rarely done): "double floor" (large sella or erosion), calcification CT and MRI far more sensitive for diagnosis related to destruction of gland hypopituitarism related to increased hormone secretion PRL (galactorrhea), GH (acromegaly in adults, gigantism in children), ACI'H (Cushing's disease= Cushing's syndrome caused by a pituitary tumour) tumours secreting LH, FSH and TSH are rare
EMPTY SELLA SYNDROME
occurs when subarachnoid space extends into sella turcica, partially filling it with CSF resulting in remodeling and enlargement of sella turcica and flattening of the pituitary gland usually eupituitary may have headaches MRI may show herniation of diaphragm sellae and the presence of CSF in the sella turcica no treatment necessary
PITUITARY APOPLEXY
acute hemorrhage/infarction of pituitary tumour sudden severe headache, altered level of consciousness ocular symptoms: ophthalmoplegia with pituitary tumour likely indicates apoplexy since tumour rarely gets big enough to encroach on cranial nerves neurosurgical emergency: acute decompression of pituitary via trans-sphenoidal route
HYPOPITUITARISM
Etiology the eight "rs Invasive: generally primary tumours Infarction: e.g. Sheehan's syndrome (excessive post-partum blood loss leading to infarction of the pituitary gland) Infiltrative disease: e.g. sarcoidosis, hemochromatosis, histiocytosis Iatrogenic: following surgery or radiation Infectious: e.g. syphilis, TB Injury: severe head trauma Immunologic: autoimmune destruction Idiopathic: familial forms, congenital midline defects Clinical Features typical clinical progression in panhypopituitarism GH (most common deficiency) -+ LH/FSH -+ ACTII -+ TSH fall in GH is not clinically apparent fall in PRL is variable, but may present as decreased lactation gonadotropin insufficiency causes erectile dysfunction in men and amenorrhea or infertility in women TSH deficiency produces clinical hypothyroidism ACTII deficiency leads to adrenal insufficiency
.....
Concurmrt lldrvmd i111ufficiiiiiC'f and hypolhyroidism should betnatld wilh glucocorticoids first and lllen with tllyroid honn0111 to avoid lllirlnll crisis.
E20 EnclocrinoloBf
Pituitary Gland!Ihyroicl
1'oroDio
2011
Investignions triple bolus rest stimulates release of all anterior pituitary hormones in nonnalindividuals rapid sequence of IV infusion of insulin. gonadotropin releasing hormone (GnRH) and thyroid releasing hormone (TRH) Insulin (usual dose 0.15 units/kg of human .regular insulin)-+ bypoglycemla-+ increased GH and ACTI:I GnRH (100 J.18 IV push) -+ increased LH and PSH TRH (200 J.18 IV push over 60 sec) -+ increased TSH and PRL
Thyroid
Thyroid Hormones
Thyroid Honnone Synthesis the synthesis ofT4 (thyroxine) and T 3 (triiodothyronine) by the thyroid gland involves trapping and oxidation of iodide, iodination of thyroglobulin, and release ofT3 and T4 free T4 (0.0396) and free T 3 (0.396) .represent the hormonally active fraction of thyroid hormone& the remaining fraction is bound to thynmne binding globulin (TBG) and albumin and is
biologically inactive
T 3 is more biologically active (3-&.more potent), but T4 bas a longer half-life 8596 ofT4 is converted to T3 or revene T3 (RT3) in the periphery by deiodlna&es RT3 is metabolically inactive but produced in times of stress to decrease metabolic activity most of the plasma T3 pool is derived from the peripheral conversion ofT4
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Thyroid
Endocrinology E21
Regulation of Thyroid Function extrathyroid stimulation ofthyroid by TSH, epinephrine, prostaglandins (cAMP stimulators) T 3 negatively feeds back on anterior pituitary to inhibit TSH and on hypothalamus to inhibit TRH intrathyroid (autoregulation) increasing iodide supply inhibits iodide organification, thus decreasing T 3 and T synthesis (Wolff-Chaikoff effect) there is varying thyroid sensitivity to TSH in response to iodide availability increased ratio ofT3 to T4 in iodide deficiency increased activity of peripheralS' deiodinase in hypothyroidism increases T 3 production despite low T4 levels
Table 16. Summery of Treetments for Hyperthyroidism end Hypothyroidism
Hypertllyraidilm Hypatllyroidi1111
Tests of Thyroid Function and Structure - - - -TSH sensitive TSH (sTSH) is the best test for assessing thyroid function hyperthyroidism primary: TSH is low because of negative feedback from increased levels ofcirculatingT3 and T4 secondary: increased TSH which results in increased T3 and T4 hypothyroidism primary: increased TSH (most sensitive test) because of less negative feedback from T3 and T4 secondary: TSH is low with variable response to TRH depending on the site of the lesion (pituitary or hypothalamic) Free T3 and Free T4 total T 3 and T4 levels depend on amount ofTBG TBG increases with pregnancy, oral contraceptive (OCP) use, acute infectious hepatitis, biliary cirrhosis TBG decreases with androgens, glucocorticoids, cirrhosis, hyponatremia. phenytoin, ASA, NSAIDS, nephrotic syndrome, severe systemic illness free T3 and T4 are independent ofTBG and measure biological activity standard assessment of thyroid function measures TSH and if necessary free T4 and free T 3 Thyroid Autoantibodies thyroglobulin antibodies (TgAh), thyroid peroxidase (microsomal antibodies), TSH receptor inhibiting antibodies increased in Hashimoto's disease; normal variant in 10-20% of individuals thyroid stimulating immunoglobulin (TSI) increased in Graves' disease Plasma Thyroglobulin used to monitor residual thyroid activity post-thyroidectomy, e.g. for thyroid cancer recurrence undetectable levels may suggest cure, especially on hormone suppression normal or elevated levels may suggest persistent, recurrent, or metastatic disease, especially on stimulation Serum Calcitonin not routinely done to investigate thyroid nodules ordered if suspicion of medullary thyroid carcinoma or family history of MEN lla or llb syndromes Thyroid Imaging/Scans normal gland size 15-20 g (estimated by palpation) thyroid U/S to measure size of gland. solid vs. cystic nodule, facilitate FNAB thyroid scan (Technetium-99) differentiates between hot (functioning) and cold (non-functioning) nodules to distinguish between three major types of high-uptake hyperthyroidism Graves' disease (diffuse uptake) toxic multinodular goitre (multiple discrete areas) solid toxic adenoma (single intense area of uptake) test of structure - order ifthere is a thyroid nodule and patient is hyperthyroid
......
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1. Serum thyroid hormones (TSH, T3, 141 2. Antibodies
3. Thyroglobulin 4. Thyroid imaging/SCIIII 5. Biopsy (FNAI
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E22 Endocrinology
Thyroid
radioactive iodine uptake (RAilJ) RAIU measures the turnover of iodine by thyroid gland in vivo in areas oflow iodine intake and endemic goitre, 24 h RAIU may be as high as 60-90% in areas ofhigh iodine intake, normal24 h RAIU will be 8-30% RAIU is high in Graves' disease or toxic nodular goitre and low in subacute thyroiditis, active phase of Hashimoto's thyroiditis, and excess iodine intake (e.g. amiodarone, which has high iodine content) test of function - order if patient is hyperthyroid Thyroid Biopsy fine needle aspiration (FNA) for cytology differentiates between benign and malignant disease
Tabla 1'1. Summary of Diagnostic Tasting in Hyperthyroidism and Hypothyroidism
Hyperlhyrailhm Hypothyrailism
lnCI'IIIIsed in primary hypothyroidism Dacraasad in sacondll'{ hypothyroidism Dacraasad in primary hypDihyroidism Decreased in secondll'{ hypothyroidism No uptalra- subacute thyroiditis, antithyroid drugs, recent iodine load
TSH
Dacreased in primary hyparthyroidism Increased in secondary hyperthyroidism I11C188Sed il primll'{ hyparlhyroidism lncreesed il secondary hyperthyroidism
RAIU
Graves- increased; homogenous Multinodular Goitre - increased; heterogenous Toxic Nodule- increased in a specific area with suppression elsewhere
Altibadias
Common Etiologies
Tabla 11. Common Etiologies
GliMIS' Disease Toxic Nodular Goitre Toxic Nodule Thyroiditis Hashimota"s Congenital Iatrogenic Hypothyroid phase Ill thyroiditis
Thyrotoxicosis
Definition clinical, physiological, and biochemical findings in response to elevated thyroid hormone Epidemiology 1% of general population (4-5% of elderly women)
F:M= 5:1
RAIU
Olhar
Antibadi
Hyparthyraidilm Graves' disease Toxic Nodular Goit111 Toxic Nodule Thyroiditis McCun&-AIIright syndrome Jod Baseduw Endogenous (struma IIVilriae,IIVilrian terat011111, metastatic follicLJar carcinoma) Exogenous (drugsl Decreased Dac1118sad Dacreased Dacraased Dacreased Increased lncr8118ed lncrN&ed Increased lncrN&ed lSI Increased lnc1111sed Increased
Up to 50% of casas
DeCI'IIIIsad
At least 2111 polyostDiic fibrous dysplasia. cafe au lait spots, and autonomous endocrile hyperlunction
Decreased Decreased Iodine induced
Decreased Decreased
Increased Increased
Thyroid
Endocrinology E23
Dilonl
Exceaiva Thyruid
Pituitary thyrotrophoma Pituitary thyroid hormone receptor resistance Increased hCG
(e.g. pregnancy)
TSH
Free T41'1'3
Thyraid Antibodi
RAIU
lith
lncrsased lncrsased
Increased Increased
I11C111ased I11C111ased
DeCII!IIsed
Increased
Increased
Clinical Features
Tabla 20. Clinical Features of Thyrotoxicosis
hyperTHYROIDISM Tl1ifllor Heart me up Yawning (fltiguedl Rastlauness Oligomenorrhe!W'amenorrhea lntulenmce to heat Diarrhea lrrilllbility Swaating Muscle WB&Iing/wuight IOH
Ganalll
ClnliiiVIIICUIU
Fatigue, heat intolerance, initability, fine tremor Tachycardia, atrial fibrillation. palpitations Eldelly patients may have only cardiovascular symptoms, commoriy new onset atrial fibrillation Weight loss with increased appetite, thirst, increased frequency of bowel movements (hypenlefecation) Proximal muscle weakness, hypokalemic periodic paralysis (common in Asians) Oligomenorrhea, amenonhea. decreased fertility Fine hair, skin moist and warm, vitiligo, soft nails with onycholysis (Plummer's nails), dubbing (acropachy), palmar erythema, pretibial mxyedema
""'9}-----------------, I
MSK
Hwnltlllagy
DIICI6illied bone mas&, proximal muscle weakness Leukopenia, lymphocytDsis, splenomegaly, lymphadenopathy {occasionally in Graves' disease)
Treatment antithyroid drugs (thionamides: propylthiouracil (PTU) or methimazole (MMI)) for Graves' disease beta-blockers for symptom control radioactive iodine thyroid ablation surgery
Cllltion with Tllionamid These drugs are effective in controlling hyperthyroidism and induce pwmanant remission in 20-30'lr. of plltienll with Graves' disaue. They inhibit thyroid hormone synthesis. They may be used long-tann, although they 111'8 most oftan amployad to help patienb achiava a euthyroid state before definitive tnatmant Savaralldvarse affects have bean rarely reported, and thus use of 1hionamides is controversial. Advaraa affacts include tallltoganicity, agranulocytosis, heplllotoxicity and ANCA-positive vasculitis.
Graves' Disease
Definition syndrome characterized by hyperthyroidism with any one of the following features including di1fuse goitre, ophthalmopathy, dermopathy (need not appear together) Epidemiology most common cause of thyrotoxicosis occurs at any age with peak in 3rd and 4th decade F > M = 7:1, 1.5-2% of U.S. women familial predisposition: 15% of patients have a close family member with Graves' disease and 50% have family members with positive circulating antibodies association with HLA B8 and DR3 may be associated with other inherited autoimmune disorders (e.g. pernicious anemia. Hashimoto's disease) Etiology and Pathophysiology autoimmune disorder due to a defect in T-suppressor cells B lymphocytes produce TSI that binds the TSH receptor and stimulates the thyroid gland immune response can be triggered by pregnancy (especially postpartum), iodine excess, lithium therapy, viral or bacterial infections, glucocorticoid withdrawal cause of ophthalmopathy uncertain (can occur even when euthyroid) but may include: antibodies against extraocular muscle antigens (fibroblasts implicated) with lymphocytic infiltration glycosaminoglycan deposition dermopathy may be related to cutaneous glycosaminoglycan deposition Clinical Features di1fuse thyroid goitre thyroid bruit secondary to increased blood flow through the gland ophthalmopathy: proptosis, lid lag, lid retraction, diplopia, characteristic stare, conjunctival injection dermopathy (rare): pretibial myxedema (thickening of dermis that manifests as non-pitting edema) acropachy: clubbing and thickening of distal phalanges Investigations lowTSH increased free T 4 (and/or increased T 3) positive for TSI
1!24 Endocrinology
Thyroid
lhl
11-.11111
S,..llic
Treatment
thionamides propylthiouracil (PTU) or methimazole (MMI) inhibit thyroid hormone synthesis by inhibiting peroxidase-catalyzed reactions, thereby inhibiting organification of iodide, blocking the coupling of iodotyrosines, and inhibiting peripheral deiodination ofT4 to T3 most useful in young patients with small glands and mild disease continue treatment until remission occurs (20-40% of patients achieve spontaneous remission at 6-18 months of treatment) small goitre and recent onset are good indicators for long-term remission with medical therapy MMI contraindicated in pregnancy (teratogenic) major side effects: hepatitis and agranulocytosis minor side effects: rash, fever and arthralgias iodinated contrast agents: sodium ipodate and iapanoic acid can inhibit conversion ofT4 to T3 and are especially effective in combination with MMI symptomatic treatment with beta-blockers thyroid ablation with radioactive 1311 ifPTU or MMI trial does not produce disease remission high incidence of hypothyroidism after 1311, requiring lifelong thyroid hormone replacement contraindicated in pregnancy subtotal thyroidectomy (indicated rarely for large goitres) risks include hypoparathyroidism and vocal cord palsy ophthalmopathy prevent drying high dose prednisone in severe cases orbital radiation, surgical decompression
Efllllt111 IIMw
!RAil
l'lqiole: To assess v.ilether radioiolh1herapy cl- Gil ilassacillldMh ii1C!IIIed risk al GlidllaR1apllhr v.ritll
llllillljluiddruiiiiAlllt)cnuVBcy. Tallie etliclcy al glJCOCOiticoid prophylaxis in lbe aiOCQIIIIQ OJPIIQIIAion of ophthcllmopalby, wt. 111111 wid! RAJ. l1ldy s.lon: IW!domillld c:lllldcJd lrilli reQI!dlla al ilroiiVI or J)Ublcation 1t11us. "--Il: RAI was IIISCidlled v.ritll111 increased rist of with AID {RIIIIM Rist IHRJ 4.23, 95'.1 ccdidlnce irDMIICil: 2.o4 was no sll1isticdy ilmlsed risk IRR 1.51, 15\ Cl O.lltD 2.811. The rilt al_. GO was lllo inC!IIIId Mil RAI compllld v.ritll AID 1RR 4.35, M Cl1l811114.73l. I'I'IMDiclbla proplrjlaldJ lor AAiwas highly llfeciM in prevemng lbe paglession of 00 in plliern widl pr1-oilling Gll{RA 0.03; M Cl 0.00 1D 0.241. Till use alldjunelive AlDv.ritll RAiwasiiJIIIISCidlled Mh Illy lignliclnt bclnllt Ill thCIIXU'SII al GO. l:Gncillilllr. Alllioi:ldine lherapy lor lfflls'
GIMI' cornpllld Mh llliiiUd drugL Slaroid prophytail il banllicilllur pdlnts Mh pre-ecislilg Gmes' ....
disa1111 i11110Ci11Bd wilhallllllllllll dlfinill ii1C!IIIId risk al al
Prognosis
course involves remission and exacerbation unless gland is destroyed by radioactive iodine or surgery lifetime follow-up needed risk ofrelapse is 37%, 21%, 6%in thionamindes, radioiodine ablation, and surgerygroups, respectively
Clinical Features
thyroid gland enlargement two forms painful coe Quervain's) thyroid, ears, jaw and occiput painless ("Silent") fever and malaise may be present. especially in De Quervain's postpartum: thyrotoxicosis 2-3 months postpartum with a subsequent hypothyroid phase at 4-8 months postpartum may be mistakenly diagnosed as postpartum depression
Laboratory Investigations
elevated free T4, T3, low TSH, RAIU markedly reduced marked elevation of ESR in painful variety only as disease progresses, values consistent with hypothyroidism may appear rise in RAIU reflects gland recovery
Treatment
painful- high dose anti-inflammatories (NSAIDS), prednisone may be required for severe pain, fever, or malaise iodinated contrast agents (e.g. iopanoic acid, ipodate) to inhibit peripheral conversion ofTH toT 3 beta-adrenergic blockade is usually effective in reversing most of the hypermetabolic and cardiac symptoms in both subtypes if symptomatically hypothyroid may treat short-term with thyroxine
Thyroid
Endocrinology E25
Prognosis full recovery in most cases, but pennanent hypothyroidism in 10% of painless thyroiditis postpartum: most resolve spontaneously without need for supplementation, however may recur with subsequent pregnancies
-----------------------
Definition acute exacerbation of all of the symptoms of thyrotoxicosis presenting in a life threatening state secondary to uncontrolled hyperthyroidism - this is a MEDICAL EMERGENCY! Etiology and Pathophysiology often precipitated by infection, trauma, or surgery in a hyperthyroid patient Differential Diagnosis sepsis, pheochromocytoma, malignant hyperthermia, drug overdose Clinical Features hyperthyroidism extreme fever (hyperthermia), tachycardia, vomiting, diarrhea, vascular collapse, hepatic failure with jaundice, and confusion arrhythmia that may lead to congestive heart failure, pulmonary edema mental status changes ranging from delirium to coma Laboratory Investigations increased free T 3, T40 undetectable TSH anemia, leukocytosis, hypercalcemia, elevated LFI's Treatment principles are the same as in hyperthyroidism except use higher doses and frequencies initiate prompt therapy; do not wait for confirmation from lab propranolol (IV) for tachycardia and to decrease peripheral conversion ofT4 to T3 (watch for CHF) supportive: fluid and electrolytes, diuresis, vasopressors, cooling blanket, acetaminophen for pyrexia high dose PTU iodide (Nai, KI, Lugol's solution) to inhibit release of thyroid hormone lithium to inhibit release of thyroid hormone dexamethasone to block peripheral conversion, to lower body temperature, and to treat possible underlying autoimmune condition if extreme, plasmapheresis or dialysis to remove high circulating thyroid hormone treat precipitant Prognosis 50% mortality rate
E26 Endocrinology
Thyroid
Hypothyroidism
a,.uillllnn
.._IIIII
-----------------------------------------
fir S.bclilcll
Definition
clinical syndrome caused by cellular responses to insufficient thyroid honnone production
CIJdJtwll CIIIJbaeS'frtlle'l1007; (3l:tm411 ....,..: Ta ellec:1lci111yraid hannJoe lwpiiCIII11IIIIfw IUbc:liicll hypgtllyrgidilm. SIUy ractial: AIIMiomised cmlled 1riU
-the
Epidemiology
2-3% of general population F:M= 10:1 10-20% of women over age 50 have subclinical hypothyroidism (normal T"' TSH mildly elevated) iodine deficiency most common cause worldwide, but not in North America
hon'nont "'!!anentMIII plabo or no 11lllnWnl in lilts Mil Uc:liJicll llypolt1yroilil Milirrun dur'ltion of f11117tMJP
ci111e is!MJIIJI'ie 1llmlion 1ime IS well IS dilsluic dylfln:tion. tw, four Sludils raporl8d lldwrle eveiQ v.ith no slldisticlll'f lignificlnt llferences
batMan !J111fL c:..cu- il cmmt ACTs,IMihylaxi111
didl'lllt 11111kil 111Nivll or dec!nsed morliiiil. lli1J. on helllfi.!VId8d qulltv a1 In 111d 1'1111 c1emonstnt1 dillalunc8i bllw8lll inlnmtill PfL Some evidiiiiCI indice11s lillt lawlh)roxina ci!ipd prafilas and 11ft wrtricUII flllction.
Slaw pulse, pericardia! effusion, bradycardia, hypertension. worsening CHF + angina, hypercholesterolemia, hyparhomocyslainamia, myxedema hllllt
Gl
Weight gain
Nauralog
Paresthesia. slow speech, muscle crernps, delay in relaxation phase of deep tendon reflexes ("tllng rellexes"l. Carpal Tunnel symt'ome, increase in CK, seizures Menoll'hagia, amenonflea. impotence Pulliness of lace, periorbital edema, cool and pale, dry 111d ruui#J skin, hair liy and (lateral1/31. discolouration (clllllenemial Anemia: 111% pernicious dJe to presence at lll'liiJIIriellll cell antibodies Dacrsased axarcisa capacity, hypovantilation secondary to weak muscles, decreased pulmoiiii'V responses to hypoxia. sleap apnea due to macroglossia
GU
Dermlllllogy
eyebrows thimed
Paresthesia
Hemidlllugy
Relpiratory
Treatment
L-thyroxine (dose range: 0.05-0.2 mg PO OD) elderly patients and those with CAD: start at 0.025 mg daily and increase gradually (start low, go slow) after initiating L-thyroxine, TSH needs to be evaluated in 6 weeks; doses adjusted until TSH returns to normal reference range once maintenance dose achieved, follow-up with patient annually secondary/tertiary hypothyroidism: need to rule out and/or treat adrenal insufficiency first monitor via measurement ofTSH and also T 4
Thyroid
Endocrinology E27
Hashimoto's Thyroiditis
most common form of primary hypothyroidism in North America chronic autoimmune thyroiditis characterized by both cc:llular and humoral factors in the destruction of thyroid tissue two major forms: goitrous and atrophic; both forms share same pathophysiology but differ in the extent oflymphocytic infiltration, fibrosis, and thyroid follicular cell hyperplasia goitrous variant usually presents with a rubbery goitre and euthyroidism, then hypothyroidism becomes evident associated with fibrosis atrophic variant patients are hypothyroid from the start associated with thyroid lymphoma
Etiology and Pathophysiology defect in clone ofT-suppressors leads to cell-mediated destruction ofthyroid follicles B lymphocytes produce antibodies against thyroid components including thyroglobulin, thyroid peroxidase, TSH receptor, Nail symporter Risk Factors female gender genetic susceptibility: increased frequency in patients with Down's syndrome, Turner's syndrome, certain HLA alleles, cytotoxic T-lymphocyte-assodated protein 4 (CTLA-4) family Hx or personal Hx of other autoimmune diseases cigarette smoking high iodine intake stress and infection Investigations high TSH, low T 3, low T4 o presence of thyroid peroxidase and thyroglobulin antibodies in serum Treatment o if hypothyroid, replace with L-thyroxine (analog ofTJ
Myxedema Coma
Definition severe hypothyroidism complicated by trauma, sepsis, cold exposure, MI, inadvertent administration of hypnotics or narcotics, and other stressful events- this is a MEDICAL
EMERGENCY!
rare, but serious mortality when it occurs (up to 60%, despite therapy)
Clinical Features hypothermia, hyponatremia, hypoglycemia, hypotension, bradycardia, hypoventilation, generalized edema, unresponsiveness Investigations
Treatment aggressive treatment required ABCs - patient should be in ICU setting corticosteroids {due to the possibility of concomitant adrenal insufficiency): hydrocortisone 100mgq8h L-thyroxine 0.2-0.5 mg IV loading dose, then 0.1 mg IV OD until oral therapy tolerated supportive measures: mechanical ventilation, fluids, vasopressor drugs, passive rewarming, IV dextrose monitor for arrhythmia
E28 Endocrinology
Thyroid
Pathophysiology
the abnonnalities in SES include alterations in peripheral transport and metabolism ofthyroid hormone regulation ofTSH secretion thyroid function itself
Labs
initially decreased free T3 followed by decreased TSH and finally decreased free T4
Lcrw-T4Vlrillll:
Low free T3o normal free T4, normal TSH Proposed mechanism: inhibition of peripheralS' monodeiodination of T to T 4 3 Low free T low free T., normal or low TSH l< Low T 1iksly cl!e to inhibited T4 bindilg to serum IJUleins ll1d accelerated mlllabolic ciBIIrance 4 Poorer pi'OIJIDSiS
Treatment
treat the underlying disease; thyroid hormone replacement worsens outcomes
Non-Toxic Goitre
Definition
generalized enlargement of the thyroid gland in a euthyroid individual that does not result from inflammatory or neoplastic processes
Pathophysiology
the appearance of a goitre is more likely during adolescence, pregnancy, and lactation because of increased thyroid hormone requirements early stages: goitre is usually diffuse later stages: multinodular non- toxic goitre with nodule, cyst formation and areas of ischemia, hemorrhage, and fibrosis
Etiology
iodine deficiency or c:xcess goitrogens: brassica vegetables {turnip, cassava) drugs: iodine, lithium, para-aminosalicylic add any disorder of hormone synthesis with compensatory growth peripheral resistance to thyroid hormone
Treatment
remove goitrogens suppression with L-thyroxine (rarely done) surgery may be necessary for severe compressive symptoms
Complications
compression of neck structures causing stridor, dysphagia, pain, and hoarseness multinodular goitre may become autonomous leading to toxic multinodular goitre and hyperthyroidism
Thyroid Nodules
Definition
clearly defined discrete mass, separated from the thyroid parenchyma palpable nodules are found in approximately 4% of the population M:F= 1:4
Etiology
benign tumours (e.g. follicular adenoma) thyroid malignancy hyperplastic area in a multinodular goitre cyst: true thyroid cyst, area of cystic degeneration in a multinodular goitre
1hyroidlAdrenal Cortex
Endocrinology E29
Investigations thyroid ultrasound to determine size and characteristic (cystic versus solid) thyroid function tests thyroid scan onlyifTSH is low to determine if nodule is hot (ie. significant m1 uptake into nodule) which signifies very low malignant potential FNA for all nodules >1-1.5 em
Thyroid Malignancies
see OtolaqniWif OT37
Adrenal Cortex
Adrenocorticotropin Hormone (ACTH)
a polypeptide secreted in a pulsatile fashion from the anterior pituitary with diurnal variability (peak: 0200-0400; trough: 1800-2400} part of a prohormone (pro-opiomelanocorticotropin, POMC) which contains alpha, beta and gamma melanocyte-stimulating hormones, beta-endorphin and beta-lipotropin as well as ACTH secretion of ACfH regulated by corticotropin-releasing hormone (CRH) and arginine vasopressin stimulates growth of adrenal cortex and secretion of its hormones via cAMP stimulates release of glucocorticoids, androgens and, to a limited extent, mineralocortkoids some melanocyte stimulating activity
..V blood glucose, trauma. infection,
emo1ion. circadian rhythm
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all derived from cholesterol
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Aldosterone a mineralcorticoid, which regulates extracellular fluid (ECF) volume through Na (and CJ-) retention and K (and H+) excretion (by stimulation of distal tubule Na/K ATPase) regulated by the renin-angiotensin-aldosterone system negative feedback to juxtaglomerular apparatus (JGA) by long loop (aldosterone via volume expansion) and short loop (angiotensin ll via peripheral vasoconstriction)
Cholesterol
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1
INSIDE
DihydrotestDSterone
Figure 1Q_ Pathways of Major Steroid Synthesis in the Adrenal Gland and their Enzymes
E30 Endocrinology
Adrenal Cortn:
-.1- volume -.1- arterial preHure -.1- Na delivery to macula densa
Prostaglandins
StimuiRiion of JGA
Renin (kidney)
Angiotensinogen
l.
llimulation
Inhibition of JGA
ACE (liver)
Angiotensin
11.
Angiotensin
Aldostarone n1l1111e ---+Renal Na ratantion, Kexcnllion Arteriolar vasoconstriction Promotion of ADH release
JGA- jwdllglomiWUirr PJIIIralu& All: - angiot.nllil converting nzyme
Cortisol
Androgens sex steroids regulated by ACTH; primarily responsible fur adrenarche (growth of axillary and pubic: hair) principal adrenal androgens are dihydroepiandrosterone (DHEA), androstenedione and 11-hydro.xyandrostenedione proportion of total androgens (adrenal to gonadal) increases in old age
Diurnal variation (flllllom level less useful) Response to stimulation or suppression more informative Correlates well with secretory rates Good screaning test for adrenal hyperfunction High in primary adrenal insulficiancy Low in sacandary ll!hnal ilsulficiancy Tha main adrenal androgan
Dexamethasone (DXM) Suppression Tests (DST) gold standard to determine presence and etiology ofhypercortisolism principle: DXM suppresses pituitary ACTI:I, so plasma cortisol should be lowered by negative feedback if HPA axis were normal single dose DST: screening test DXM 1 mg given at 2300h would suppress pituitary ACI'H production in healthy individuals, so that the normal 0800h peak ofplasma cortisol would fail to develop 95% of Cushing's syndrome patients would fail to suppress <20% false positive results due to obesity, depression, alcohol. other medications confinnatory tests low dose DST: 0.5 mg DXM q6h fur 48 hours, then 24 hour urinary free cortisol (UFC) normally, UFC level would be reduced to <54 nmol/day {149 high dose DST (8 mg/day): 70-80% suppressed UFC: adrenal cortex hyperplasia due to hypersecretion of pituitary ACTII no change in UFC or serwn cortisol: adrenal cortisol-producing adenoma/carcinoma - however, 30-40% of ectopic ACTH tumours may partially suppress UFC plasma ACTH assay supplements DST for differentiation of the various etiologies of Cushing's
Adrenal Cortex
Endocrinology E31
Short Cosyntropin Stimulation Test (ACTH analogue) for diagnosing adrenal insufficiency; dexamethasone does not interfere with this assay give 250 cosyntropin IM or IV then measure serum cortisol and ACTH at baseline, and cortisol at 0, 30 and 60 minutes physiological response: increase in plasma cortisol level by >250-500 or doubling of baseline and an absolute level of >550 I!DloUL (rules out primary adrenal insufficiency) inappropriate response: inability to stimulate increased plasma cortisol
Hyperaldosteronism
Tabla 26. Hyparaldastaronism
Primary Hypal'llldoatll11111ism [PH]
Dafinitio1
------------------------------------
Etiology
Hypel18nsion reflactory to standard baatment Polyuria, polydipsia, nocturia Fatigue, weakness, paresthesia, headache; severe cases wilh tetany, intermittent paralysis Labs: low K, high Na, low Mg. abiosis, salt craving (also measure 24 hr melllnelhiles and catecholamines tDr/opheo] Normal K, low Na i1 SH (low ellectiva circulating volume leads to 1' ADH lllleasa] -1- renin, 1' aldosterone (> 15 ng/!1] Plasma aldosterone:renin ratio >20 ngfdl (nonmal n!V'dl) Confirmatory 18m: saptopril 5Upp18$$ion te&t. 24 h urile aldosterone, salt lollding test Hsuspecting adenoma: postural stirwlation test, fuosemide stiroolation test, adrenal
Diagnosis
cr
Tl'llltmllnt
Medical tx for adrenal hyperplasia -Spironolactone, amiloride Surgical ramowl for lldrenal adenoma
Cushing's Syndrome
Definition results from chronic glucocorticoid excess (endogenous or emgenous sources) Etiology ACTH-dependent (85%}- bilateral adrenal hyperplasia and hypersecretion due to: ACTH-secreting pituitary adenoma (Cushing's disease; 80% of ACffi-dependent) ectopic ACTH-secreting tumour (e.g. small cell lung carcinoma, bronchial, carcinoid, pancreatic islet cell, pheochromocytoma or medullary thyroid tumours) ACTH-independent (15%) long-term use of exogenous glucocorticoids (10 mgld for >3 weeks) primary adrenocortical tumours: adenoma and carcinoma (uncommon) bilateral adrenal nodular hyperplasia major depression and alcoholism
R32 EnclocrinoloBf
Clinical Features
1'oroDio
2011
Olllllaparusis
i ...
::1! Q
li
Normal
No Cushing's
synchme
Diatrllllis Df Cushing's
eslllbliNd
AC1ll ilci'88SIId
+
I
Measure ACTH
AC1H dacnased
adrenal
pituitary trans-sphenoidal resection, with glucocorticoid supplement peri- and post-operatively irradiation: oDly 5096 effective, with signlfica.nt risk of hypopituitarism adenoma: unilateral adrenalectomy (curative) carcinoma: palliative (frequent metastases, poor prognosis); adjunctive chemothempy often not useful
medical treatment: mitotane, ketoconazole to reduce cortisol
ectopic ACI'H tumour - usually bronchogenic cancer (paraneaplastic syndrome) chemotherapy/radiation for primary tumour agents blocldDg adrenal steroid synthesis: metyrapone or ketoconazole poor prognosis
Adrenal Cortex
Endocrinology E33
Hyperandrogenism
Definition state of having excessive secretion of adrenal androgens (DHEA, DHEA sulfate) Etiology and Pathophysiology
Table 27. Etiology of Hyperandrogenism
Conllituliaiiii/Famililll MediCitiiiiS Andragen.medilted
Onrilll
Adrenal
Congenital alhnal hyperplasia (CAH. late-onset CAH) Tumours (adenoma, carcinoma) CUshing's disease - high ACTH
Hyperprolactinemia
Clinical Features Hirsutism male pattern growth of androgen-dependent terminal body hair in women: back, chest, upper abdomen, face, linea alba
.... ' I
Vnilization masculinization: hirsutism, temporal balding, clitoral enlargement, deepening ofvoice, acne increase in musculature Defeminization loss of female secondary sex characteristics (ie. amenorrhea, .J,.o breast size, infertility) Males minimal effects on hair, muscle mass, etc. inhibition of gonadotropin secretion may cause reduction in testicular size, testicular testosterone production and spermatogenesis
Investigations increased testosterone increased LH/FSH, commonly in PCOS >2.5 DHEA-S as measure of adrenal androgen production 17-OH progesterone is elevated in CAH due to 21-0H deficiency CT/MRI of adrenals (identify tumours) Treatment discontinue causative medications oral contraceptives (e.g. cyproterone acetate - blocks androgen receptor; found in Diane 35) spironolactone - acts as peripheral androgen antagonist cosmetic therapy low dose glucocorticoid mineralocorticoid if CAH suspected surgical resection of adrenal tumour
E34 Endocrinology
Adrenal Cortn:
Adrenocortical Insufficiency
PRIMARY (ADDISON'S DISEASE)
lnfaction
lnliltmin
lmibit coritsol: ketoconazole, megestrol acetate Increase cortisol mlllabolism: rifampin, phanytuin. barbitual8s, haptlin, coumadin AdranolaukDdy&trophy Congenital adrenal hypoplasia (ill1JIIired steroidgensisl Familial glucocorticoid deficiency or resisbmce
Others
autoimmune etiology most common in developed world antibodies often directed against adrenal enzymes and 3 zones of cortex
SECONDARY ADRENOCORTICAL INSUFFICIENCY inadequate pituitary ACTH secretion multiple etiologies (see Hypopituitarism, El9}, including withdrawal of exogenous steroids that suppress pituitary ACTH production
Clinical Features Table 29. Clinical Features of Primary and Secondary Adrenal Insufficiency (All Primary AI (Addison's or Aclllll All Secandary AI
Skin IIIII mucou
Pale
I'Diaaium
Sodium Mtllbolic acidosis
Altociltld di-
neurological deficits
Altociltld sympblml
Weakness, fatigues, weight loss, hypotension, cmving, postural dizzinass, myalgia, arthralgia, Gl: nausea. vomiting, abdominal pain, dianhea High morning plasma ACTH High 2hour ulfight plasma l'l!lin
Diagnllltic test
Treatment
acute condition- can be life-threatening IVNS or D5W/NS in large volumes (2-3 L) hydrocortisone 100 mg IV q6-8h for 24h, then gradual tapering identify and correct precipitating factors maintenance hydrocortisone 15-20 mg PO qam and 5-10 mg qpm (4:00pm) Florinet- (fludrocortisone, synthetic mineralocorticoid) 0.05-0.2 mg PO daily if mineralocorticoid deficient (maintain renin between 1-3 nglml/hr) increase dose of steroids 2-3 fold for a few days during moderate-severe illness (vomiting, fever) major stress (surgery, trauma) requires 150-300 hydrocortisone IV daily divided into 3 doses medical alert bracelet and instructions for emergency hydrocortisone 1M injection
Adrenal Medulla
Endocrinology E35
Adrenal Medulla
Catecholamine Metabolism
catecholamines are synthesized from tyrosine in postganglionic sympathetic nerves and chromaffin cells of adrenal medulla predominant adrenal catecholamine = epinephrine (adrenaline) predominant peripheral catecholamine = norepinephrine (noradrenaline)
ABC Gf Adranall1111
Adrenaline activatas 181&-rvceplor$, increasing Cyclic AMP
Pheochromocytoma
Definition rare catecholamine secreting tumour derived from chromaffin cells of the sympathetic system Epidemiology most commonly a single tumour of adrenal medulla 10% extra-adrenal (95% of which are intra-abdominal), 10% multiple tumours, 10% malignant, 10% familial rare cause of hypertension (<0.2% of all hypertensives) curable if recognized and properly treated, but fatal if not Etiology and Pathophysiology most cases sporadic (80%) familial: associated with multiple endocrine neoplasia II (MEN II) (50%), von Hippel-Lindau (10-20%), paraganglioma (20%), or neurofibromatosis type 1 (NF I) (0.1-5.7%) tumours, via unknown mechanism, able to synthesize and release excessive catecholamines Clinical Features 50% suffer from paroxysmal HTN; the rest have sustained HTN classic triad: episodic "pounding" headache, palpitations/tachycardia. diaphoresis other symptoms: tremor, anxiety, chest or abdominal pain, nausea/vomiting, visual blurring, weight loss, polyuria. polydipsia other signs: orthostatic hypotension, papilledema. increased ESR. hyperglycemia. dilated cardiomyopathy symptoms may be triggered by stress, exertion, anesthesia. abdominal pressure, certain foods (especially tyramine containing foods) Investigations urine catecholamines increased catecholamine metabolites {metanephrines) and free catecholamines total metanephrine {most sensitive) >6.51!1D.ol/day (1.2 mg/day) plasma catecholamines >2000 pg/ml (11.8 mmol/L) diagnostic >950 pg/ml (5.6 mmol/L) suggestive; proceed to clonidine suppression test (rarely done) elevated plasma epinephrine unsuppressed by clonidine {central alpha-adrenergic) is diagnostic CTabdomen ifCT is negative, meta-iodo-benzoguanidine (MIBG) scintigraphy, Octreoscan, or MRl may be helpful Treatment adequate pre-operative preparation alpha-blockade for BP control- phenoxybenzamine (14-21 days pre-operative), IV phentolamine {peri-operative) beta-blockade for HR control- propranolol (initiate only after adequate alpha-blockade) metyrosine (catecholamine synthesis inhibitor)+ phenoxybenzamine or prazosin volume restoration with vigorous salt-loading surgical removal oftumour with careful pre-operative and post-operative ICU monitoring rescreen urine one month post-operatively
Episodic swemq
E36 Endocrinology
Adrenal Medulla
----------------------
neoplastic syndromes involving multiple endocrine glands tumours of neuroectodermal origin autosomal dominant inheritance with variable penetrance genetic screening for RET proto-oncogene on chromosome 10 has long-term benefit early cure and prevention of medullary thyroid cancer
Chnunosame
lmpll:llled
11
TIDUIIIIMIIVId
Pituillly
Clinicll MMifeslltions
Ant pituilllry adenoma, Dillin non-saCI'IIing but may SBCI'IIa GH md PRL
Primary hyperparathyroidism from hyperplasia Pancreatic islet cell tumours Gastrinoma (peptic ulcers) lnsulinomas (hypoglycemia) VIPomas (secretory diarrhea)
1D
(RET pruto-oncogane)
Thyroid Adrenal mellllla Parathyroid Skin Thyroid Medullary 1hyroid CIIICer (MIC) ( >911%) Pheochromocytoma (41}.511%) 1 parathyroid hyperplasia (11}.211%) Cullllaous lichen amyloidosis
2. Familial
Thyroid Ca. (a variall: of lla)
3.11b
MTC without o1hw clinical manifastations of MEN llaorllb MTC: most common more aggressive and earlier onset than MEN lla
Pheochromocytoma Mucosal neuroma, intestinal ganglioneuromas Marlanoid habitus {no aortic Chrmic constipation Megacolon
Thyroid
Adrenal mellllla
Neurons
MSK
Gl
History MENI symptoms of hyperparathyroidism, gastrinoma (abdominal pain, diarrhea, peptic ulcer disease), and insulinoma MENII family history of MEN syndromes symptoms related to medullary thyroid cancer (MTC), hyperparathyroidism, or pheochromocytoma scaly skin rash (cutaneous lichen amyloidosis in MEN IIa)
Clinical Features clinical picture depends on the endocrine organs involved and the hormones secreted MENI hyperparathyroidism - nephrolithiasis, bone abnormalities, MSK complaints generalized weakness, and alterations of mental status in severe hypercalcemia gastrinoma - upper abdominal pain due to peptic ulcers and esophagitis glucagonoma - rash, anorexia, anemia, diarrhea, glossitis pituitary tumour- headache, visual-field defects, prolactinoma (erectile dysfunction, decreased libido, amenorrhea, galactorrhea), acromegaly carcinoid syndrome - flushing, diarrhea. bronchospasm MEN II - physical signs are variable and often subtle MTC - neck mass or thyroid nodule; non-tender, anterior neck lymph nodes pheochromocytoma - elevated BP and HR
Endocrinology E37
Investigations MENI laboratory gastrinoma- elevated serum gastrin level (>200 ng/mL) after IV injection of secretin insulinoma - reduced fasting blood glucose (hypoglycemia) glucagonoma - elevated blood glucose and glucagon levels pituitary tumours - assess GH and prolactin levels hyperparathyroidism - PTH levels; bone density scan (DEXA) imaging MRI for pituitary tumours, gastrinoma, insulinoma MENII laboratory genetic screening for RET mutations in all index patients - if a mutation is identified, screen family members who are at risk calcitonin levels, urine catecltolamines, vanillylmandelic acid and metanephrine screen (pheocltromocytoma); serum Ca and PTH levels (hyperparathyroidism) pentagastrin calcium stimulation test if calcitonin level is within reference range imaging CT or MRI for imaging of the adrenal glands metaiodobenzylguanidine (MIBG) scan for pheocltromocytoma radionuclide scanning for determining the extent of metastasis octreoscan for examining the spread of MTC FNA for thyroid nodules Treatment MENI surgery is indicated for hyperparathyroidism, insulinoma, glucagonoma, pituitary tumours (trans-sphenoidal approach with external radiation when medical treatment fails) proton pump inhibitor (PPI) for acid hypersecretion in gastrinoma bromocriptine or other dopamine agonists to suppress prolactin secretion somatostatin for symptomatic carcinoid tumours MENII surgery for MEN Ila pre-operative treatment prostaglandin inhibitors to alleviate diarrhea associated with thyroid cancer alpha-blocker for at least 2 weeks for pheocltromocytoma hydration for hypercalcemia - if remains severely hypercalcemic, consider calcitonin or bisphosphonates post-operative treatment hormone replacement following total thyroidectomy and bilateral adrenalectomy calcium supplement and/or vitamin D for post-op hypoparathyroidism
Calcium Homeostasis
normal total serum Ca: 2.25-2.62 mmoVL (9.0-10.5 mg/dL) ionidfree Ca levels: 1.15-1.31 mmoVL {4.6-5.25 mg/dL) serum Ca is about 50% protein bound (mostly albumin) regulated mainly by two factors: parathyroid hormone (PTH) and vitamin D actions mainly on 3 organs: GI tract, bone, and kidney
Parathyroid Hormone (PTH) secretion increased by low serum Ca and inhibited by cltronic, low serum Mg not influenced directly by P04 (except by P04 effect on the ionic calcium levels)
E38 Endocrinology
Calcium Homeostasis
Cl'
1' Pili I
Bona
1
.
Mg [acute)
Cho!aca!ciferol
Kidnay
Ca and Mg reabsorption
+ +--------
.
I
Diat
.. Cllcilriol formation
o!PO,
1' Bone
resorption
Bone ostaoclast
Vitamin D necessary for Ca and P04 absorption from GI tract cholecalciferol formed in the skin by the action of UV light Calcitonin polypeptide secreted by thyroid C cells secretion enhanced by Ca, GI hormones, pentagastrin major actions ..V osteoclastic bone resorption (pharmacological effect) 1' renal P04 and Na clearance acute net effect: ..V serum Ca when given in pharmacologic doses Magnesium major intracellular divalent cation Ca is reabsorbed from the kidney with Mg thus Ca balance is difficult to maintain in Mg deficiency Phosphorus intracellular cation found in all tissues and necessary for most biochemical processes as well as bone formation
Tabla 31. Summary of Effacts
Nat Effect
....
,
fonn, e.g. hyperalbuminemia
dahydnnion.
UVII1I
Vit D
Decreased PO, Increased Ca Increased P04 Decreased Ca
VbmiiD
increased proiBin binding IHding tu an elsvation in serum total Ca without a rise in lhe from
....
}-----------------, total corrected serum Ca >2.62 mmol/L (10.5 mg/dL) OR ionized Ca >1.35 mmol/L (5.4 mgldL)
Approach to Hypercalcemia (Figure 15) 1. Is the patient hypercalcemic? (correct fur albumin- see sidebar) 2. Is the PTH high/normal or low? 3. If PTH is low, is phosphate high/normal or low? If phosphate is high/normal are the level of vitamin D metabolites high or low?
Hypercalcemia
Definition
For 8WfV' dacruM in albumin by 10, inCNIM in Ca bf O.Z llanip (less likely mlllignantl: Ca <2.75 mmoVL (11 lllG'dL) hthol1111ic [more likely malignant]: Ca >3.25 mmoVL (13111G'dl)
Calcium Homeostasis
Endocrinology E39
......
RilkFICID111
Apprau:h
t-----------------,
Positive FMHx
Hx of MENVIIa Hx of childhood H+N radiation Postmenopausal womBII Nonnal physical exam
Px:
- 5[1% asymptomatic (esp. with prolonged disease) - Renal neuromuscular disease, low BMD lx: sarum Ca.. PO PTH, lmagilg far renal calculi and osteoporosis Tx: surveillance V$. 5Ufll&ry
Increased PTH after prolonged secondary hyperpara1hyroidism
Tha most common CIUIB of hypBnllllcamill in h1111pibd is hyperCIIcenlll Usually occurs in the later stagn of disaBle Most commonly nan in r.nal, brlast. ovarian 111d squamo111 tumours, as well as lymphoma and multiple
myeloma
Asymptomatic Fllmlill Hypacalciurlc HvPen:alc:emia (FHH) Hypocalciuric Mutation in Ca sensing receptor Positive FMHx (autusornal gene -+ inappropria1e PTH dominan1) secretion and tubal Ca reabsorption Dlug Induced Increased set point where PTH secretion is suppressed Lithium
Mechanism: secretion of panlllryroid protein (PllirP} which mimics PTli action by preventing renal calcium excretion and lldivating osl8odast-inducad bone resorption Primary byparpambyraidism is the most common cause ol hypercalcemia in healthy outpatients.
.....
,.,J-----------------, ,
-"Pnt I
1' or
norm: phosphlllll
VitO related I
3. Ranlllllisease: tertiary 4. Drugs: calcium cartlonalll, milklllkll6 syndroma, thiazide, lilhium, 5. Familial hypocalciuric hypercalcemia
1>10% fram 1 Dr 21
hyperparathyroidism
1' Cak:idiol or
VrtD
1' Critriol
I RCC, pheochromcx:ytomal I
Low Vit DIetabolites
phaochromocytome i.lmmobilizlltion Immobilization Milk alkali syndrome {hyperc:lllcemia wilh alkalosis and renal failureI Drug&: thiazide CaCO., thaophyllina, estrogarVIamoxifan Melllstatic bone disease (e.g. breast Ca madiatad by OSIBodast Activating Factor} High bone turnover e.g. hypervilllminosis A. thyrotoxicosis, Paget's disee
Granulomatous disease e.g. lB, sarcoid, lymphome (asp. Hodgkins! which causes BXIJ'&.ranlll production of calcitriol by macrophagas in the lung and lymph nodes Excessive calcitriol intake
Gl
Constipation Anorexia Nausea Vomiting {groans) PUD pancreatitis
Renal
Rhaullllfalogicll
MSK
Weakness Bone pain
(1111111)
Psyclliliric
>3mmoVL (12llllfdi.J
fibi'BII
Polyuria Gout (Nephrogenic DIJ Pseudogout Polydipsia Chondrocalcinosis Nephrolithiasis {stones) Renalfaiua (irnM111iblel
lnc1811Sad alartnass Anxiety Depression dysfunction Organic brain syndromes >4 mmoVL (1 6mg/dl) Psyclllllil (moans)
'
Hypen:alcM'Iil crisis {usually >4 mmaVLJ: primary symp1oms ilclude oligurie/anuria and menial s1B1us changes (induding somnolence and eventually coma) -+ 1his is aMEDICAL EMERGENCY and should be 1reated immediately!
Treatment treatment depends on the Ca level and the symptoms treat acute, symptomatic hypercalcemia aggressively
E40 Endocrinology
Calcium Homeostasis
,,
300-500 ccJhr) - initial1henpy
hypervolemic
Acute Mlna..,..m of ltypen:alcllllialllypen:alcllllit: Crili 1. Vollnlllllplll1Sion (1.g. NS IV 3. Bisphosphonate- treatment of clloice 4. Corticosteroid - most useful in V"rt
Dtoxicity, glllnulollllltous dinaH,
soma maf911111Cius
Bisphosphonllles (Tx of choice) lnhl!its osteodaslic bone resotplion and promates renal excretion Df calcium Acts 111pidly but oflan tl'llnsill'll response (decreased by 0.3-0.5 mmoVL (1.2-2.0 m!fdl) beginning withi14-6 hours) Combillrlion of calcitonin and steroids may prolong reduction in calcium Tachyphylaxis may occur Indicated in malignancy-nlated hypercalcemia, IV pamidronate is most commonly used 2-4 days until full 11118ct but elf8Ct is long-lasting (2-4 W88b) MithlliTl'fCin (rarely used)- effective when patient cannot tolerate fluid load DangefliUS - hematotaxic and hepatotoxic CorticostEroids in hypervibrninosis Dand hematologic maligmn:ies Anti-tumour effects -+ decreased calcibiol production by 1he activated mononudear cells in lung and lymph node Slow ID act (S-1 0 days); need high dose
DICII. . Gl C1 Ablarption
Dialysis
Others
prostaglandin inhibitors surgical treatment ifindicated avoid immobilization
Hypocalcemia
Definition
total corrected serum Ca <2.25 mmol/L (9.0 mgldL)
Clinical Features
most characteristic symptom is tetany
Approach to Treatment
correct underlying disorder mildlasymptomatic (ionized Ca >0.8 mmol/L, 3.2 mgldL) treat by increasing dietary Ca by 1000 mglday acute/symptomatic hypocalcemia (ionized Ca <0.7 mmol/L, 2.8 mgldL) immediate treatment required IV calcium gluconate 1-2 g in 10-20 mins followed by slow infusion if necessary goal is to raise Ca to low normal range (2.0-2.1 mmol/L, 8.0-8.4 mgldL) to prevent symptoms but allow maximum stimulation of PTH if PTH recovery not expected, requires long-tenn therapy with vitamin D and calcium do not correct hypocalcemia if it is suspected to be a transient response
......
,..,
I'INitlllliu: perioral, hands end feat Chvostllk's sign: percussion of the facial nerve just anlerior to the txt.mllliiUditory meiiiUs llicits ipsilllteral spasm ol1he orbicularis oculi or orbicullris oris muscles Trou-u's sign: inflation of a blood
Layngospasm Palll8thesia
stridor)
pressure cuff above systolic pressun1 for 3 minut.s llicil1 CIIIPIII spasm end pares1hesia
Hyperreflexia Tetany Psychiabic Sx: emotional instability, anxisty and depression Chvostek's sign (tap CNVII) Trousseau's sign (carpal spasm)
CNS: lethargy, seizures, psychosis, basal calcification. Parkinson's, dystonia, hemiballisrrus, papilledema, pseudotumour cerebri CVS: prolonged QT intBMII Gl: steatorrhea ENDO: impaired insulin release SKIN: dry, scaling. alopecia, brittle and transversely fissured nails, moniliasis, abnormal dentition OCULAR: clllllracts MSK: generalized musde weakness and wasting
Calcium Homeostasis
Endocrinology E41
Primary llypapathyroidilll
Secondary llyperplrdyn)idsm PT gland IIISponds to low EC Ca. by 1' absorption and 1' bone resorption LDwMaanasium
Under normal circumstances. low Mg stimulates PTH secretion HOWIV8r, chronic low Mg is paradoxically associalld with impairlld Prn seC1'81ion Low Mg IIMIIs also impair peripheral rasponsiwnass to PTH Drugs: antineoplastic agenb (cisplatin. mithl8mycin) Alcoholism Hemoclromatosis In pregnancy, 1here is a low tDtal Ca due to hypoalbuminemia, but noi!Tiill ionimd lewI
.,..ancr
Uv.llylfunctian
"'rH
NonTIIII
;t&phate
Drelated
PsiUdahypaparathyraidism: PTH aecondary to G-protein deficiency Acute rel81se of pancralllic dec:reasas bona resorption Drugs: calcitonin, loop diuiBiics
"'C!idiol Dac11111sad Gl abaorption (intake, livar/billiary] PhenytDin Nephrotic syndrome (lose Vii D binding protein!
...
Chronic 18011 failure Vrt Ddependent rickllts type 1 (renal 1-tlph&-h\'d'oxylasa deficiency]
...
1'
...
Hyparphosphatamia
Etiology
increased intake GI intake (rectal enema, GI bleeding) IV phosphate load (K-Phos, blood transfusion) endogenous phosphate (tumour lysis syndrome, rhabdomyolysis, hemolysis) reduced renal clearance ARF/CRF hypoparathyroidism acromegaly tumour calcinosis (ability of kidney to specifically clear phosphate is defective)
Clinieal Features
non-specific, include ectopic calcification, renal osteodystrophy
Treatment
low P04 diet, phosphate binders (e.g. CaC03)
E42 Endocrinology
Calcium Homeostasis
Hypophosphatemia
Etiology
inadequate intake starvation malabsorption (diarrhea, steatorrhea) antacid use alcoholism renal losses hyperparathyroidism diuretics X-linked or AD hypophosphatemic rickets Fanconi syndrome excessive skeletal mineralization osteoblastic metastases post parathyroidectomy (referred to as 'hungry bone syndrome') P04 shift into ICF recovery from metabolic acidosis respiratory alkalosis starvation refeeding (stimulated by insulin)
Clinical Features
non-specific (CHF, coma, hypotension, weakness)
Treatment
treat underlying cause, supplement with oral P04: 2-4 g/d divided bid-qid (start at 1000 mgld to minimize diarrhea)
Hypermagnesemia
Etiology
Mg-containing antacids given to those with severe renal failure IV administration oflarge doses ofMgS04 (e.g. for pre-eclampsia; see Obstetrics, OB14)
Clinical Features
drowsiness, hyporeflexia, respiratory depression, decreased deep tendon reflexes
Treatment
discontinue Mg-containing products
Hypomagnesemia
Etiology
GI starvation malabsorption vomiting alcoholism acute pancreatitis excess renal loss 2 hyperaldosteronism due to cirrhosis and CHF hyperglycemia hypokalemia hypercalcemia diuretics
Clinical Features
seizures, paresthesia, Chvostek and 'frousseau signs
Treatment
Mg IM/IV; cellular uptake of Mg is slow, therefore repletion requires sustained correction discontinue diuretics in patients requiring diuretics, use a K-sparing diuretic to minimize rn.agnesuria magnesium deficiency can aggravate potassium depletion by increasing distal potassium secretion, often refractory to treatment with potassium replacement thus, important to check and correct magnesium levels prior to replacing potassium
Endocrinology E43
,_.I:
Primary Osteoporosis
due to post-menopausal decline in estrogen, worsens with age
Secondary Osteoporosis
gastrointestinal diseases gastrectomy malabsorption chronic liver disease bone marrow disorders multiple myeloma lymphoma leukemia endocrinopathies Cushing's syndrome hyperparathyroidism hyperthyroidism premature menopause diabetes malignancy breast cancer prostate cancer drugs corticosteroid therapy -+ second most common cause of osteoporosis individuals receiving ;?:7.5 mg of prednisone daily for over 3 months should be assessed for bone-sparing therapy mechanism: increased resorption + decreased formation phenytoin chronic heparin therapy androgen deprivation therapy aromatase inhibitors others rheumatologic disorders rheumatoid arthritis
...,_.in
IIIOCidad l'lillla 12'1. rist 11mriln il lam II .types (rill.lllioO.BB. 95\CI p=0.0004)... trials thd IIIXIflld bonl-mirlllll dnkyuanoubDna(23triak,n=41,4111.1111 trallllwlt- aaoc:iat8d will allduced 1111 bonlbe5 rf:0.54\ (U.35-D.73; p<0..0001l1t ttw hip lf1d I.1ft. (0.76-1.61\; p<O.OOD11 inila ipina. Thati1C11n rist llmriln Wli gl1lllr (24\l il trials in wflich the compiiiiC8 1111 -hillhiP<O.DOOII. The11Wnenteftecthlt1a' Mh c*ium dous 1112111 1111111 U.l'lilll dales lea 111111 1200 (O.Ml VI. 0.94; p=O.OO&I, IIIII Mh rilrrin DilJRi of BOD IU Ill" 1111R U.l'lilll dales lea 111m 800 IU ID.84 vs. 0.87; p=0.031. Canlbin: EvidlnCIIUPJIIIIts tfw Ull rf: t:llciln, or tlk:iln il cn.illlliun with Wlnil D IUJIP!mllllllion, in the pMWIIive 1n11tm1nt of peapelged 50 yen 01 okle!. For bast111111p1Utic lfflct. M IKUII11IIId milmlrn dales rf: 1200 mq ci c:ak:Un, and Ql IJ af lftllmin D(fur combinad Cllcilm ]ill vitlnin D 1Upplernenll1ion).
............ illllllapnlil
SLE
ankylosing spondylitis renal disease poor nutrition immobilization
Risk Factors
Table 35. Risk Factors for Osteoporosis
Excessive alcohol intake Exca&&ive caffuina intaks Low dietary calcium intake
Weight <57 kg Weight loss >10% of weight at age 25
SICOnduyto Mllllc:al D i Rheumatoid Artlritis Past hislory of clinical hyperthyroidism
Drugs
yn, 87\wfliiiiMh bw BMD &clilills illdudld hx of gWcor1icoid 1118, Olba! disordn ci hone, IIC1M PUD, and .a or hepatic ins*iencot ,.....: A18n*onlbl5mQ. 1011111- 20 11111- II' plallo, eiCII aoce daly. All received calcirn 500 rwl*t- .. tile 3rd 'IIIII; womun in 1111 20 mg group wnllinclyawitdlld 1D 5 lllil ...... Chll9 in BMD, I1ICIInl, 11111 hlight. lllulll: Warnm iiiii31Encnn112 gn111ps hid lignificlnt i..-- in BMD, wbiMthoel in the plll:ello IIITq) hid signiicant Women tlkilg a*"IIOI!IIe hid N118W fid.m (RRR tflr34, M Cl 161D 5181. 1111 alowur I!HIIua of haigld (p=D.0051. Thn Will liD signiliclrt difln1cM biiMeo gnlllps fur niiMIII18bnll lam, IIIMn8 .rJ.c1l, or dilainliultion IIIII. Canlbin: In posl-lllfmCIPIUSIIwnen wilb allndronall incrnsed BMD, Uld recb:edlbe riskci-VIIIIInlfrac:1ults.
-"""'*
E44 Endocrinology
......
t-----------------,
....,. ca. ,.... ........
1.l5 arM g
353 mg
..........
2\1,
a--r.bmll
b!MII
.lhcnll
S.n-
1/2 1 8111111
Sv,flln-ccdld 1 Ttlu-willllbni!ID
.... lllllllllk
M-lm
1135g
lliildben-CIIIIIII lasep-b:nlllldl
...
......
, ...-----------------,
1. Haight lou >3 em (Sn !12%1 2. Weight <51 kg 3. Kyphosis (Sp 981 4. Toolh count <20 (Sp 92%1
5. Grip strength
Clinical Features commonly asymptomatic collapsed vertebrae -+ height loss fractures commonly occur in hip, vertebrae, humerus, and wrist fragility fractures: fracture with fall from standing height Dowager's hump= collapse fracture of vertebral bodies in mid-dorsal region x-ray: vertebral compression and crush fractures, wedge fractures, "codfishing" sign (weakening of subchondral plates and expansion of intervertebral discs) pain, especially backache, associated with fractures Investigations usually normal serum Ca. P04o alkaline phosphatase also measure 25(0H)-vit D, TSH, serum and urine protein electrophoresis, celiac workup and 24 hr urinary Ca excretion to r/o secondary causes densitometry dual-energy x-ray absorpti.ometry (DEXA) - gold standard in diagnosis of osteoporosis, (quantitative CT, ultrasonography) lumbar spine and femur compared with gender and ethnicity-matched controls osteopenia: bone mineral density 1.5-2.5 SD below mean osteoporosis: >2.5 SD below mean Screening: Who should we screen7 DEXAfor: women and men :<:65 yr postmenopausal women <65 with risk factors premenopausal women or men with fragility factures of secondary causes YES on risk assessment tools: SCORE questionnaire :<:6 or ORA! :<:9 if NO reassess in 1-2 years
Endocrinology E4S
Treatment of Osteoporosis
Tabla 36. Traatmant of Ostaaparosis in Woman and Man
... , ,
.----------------.
WhomtoTreid.'?
WomBI Po&tmenapaU&al: T-score <-2.5 with no risk factors T-scora <-1.5with2:1 riskfactors Any spine or hip #
Min
UleltJI
D111111llapy Bilpho'flhandlt: of osteoclast binding SERM IIIICiin recepb' agonistic BfhK:t on bane but llllllganistic effect on uterus and br8ISI:
Parathyroid Hormone Cllcitonin {2nd line): osteoclast receptor bindilg HRT: combined estrogen + progesterone
>65 T-sC0111 <-2.5 at any sD >50 a fragility/Varlabral com1J8SSian #,OR any age with glucocorticoid 1herapy 2:3 mth OR any age with hwogonadism, AND T-score <-1.5 Diet: Bemental calcium 1000.1500 mg/day; Vlt D800 llVday Exarcisa: 3x30 min weight-bearing axercisllf/Wk Cessation of smoking. reduce caffeine intake Stop/avoid osteoporosis-inducing medications Alendronate, strontium, ranelate, risecranate, zoledronate. stidronate, pamidranate
Raloxifene: +ve: prevents osteoporotic # (Grade Ato Bevidence), improves lipid profile, decreased breast ca risk -ve: incr811Sad risk of DVTJ11E, sUuks mortality, hot ftashes, leg cramps YES fnlgiity #: 16-24 rno duration YES fnlgiity #: Calcitonin 200 IU nasally OD with Calcitriol 0.251111 BID Far most women, risks > benefits Combiled estragel\l'progestin prevents hip, vertebral, total # lnC1'88Sad risks of braast ca and cardiOVIISCUiar Mills
...........,-.y .. .....,
Ctldrn IJIIIIIIIstS)'rtllw 21D1;11l:Cil004523.
bisphaspalllt8l illlla prinllly llld sacondrf piMIIIion cl il paslnW!opllalwamen. Sludr S*:tim Womm!ICIMrG II IIIII 11111 JH' rl bi!fiiiOIFI1onltll fllr pclllmanOpluSal
llllaoporolis- 1*11181111 pllcebo or QIIICLJT8111 Dor botll. Till cUJ:anw WIS flldln ilcidiii:L . . . . l..awl ri!Mdence: tr'lft/wrM
ARR
1'PnMntioa-Hip Not ligniiclnt 1'1'reventioa- Wist Not ligniiclnt 'l' PriVIntioa Vllfllnl 451'0 RRR, R ARR
'l' Pravantioa -Hip 'l' PnMntion- Wist
IGaldl
IGI*IJ IGI*IJ
ARR
IGaldJ
Not signiiclnt Not signiiclnt Not ligniiclnt
Etiology and Pathophysiology Vitamin D Deficiency leads to secondary hyperparathyroidism and hypophosphatemia deficient uptake or absorption nutritional deficiency malabsorption: post-gastrectomy, small bowel disease (e.g. Celiac sprue), pancreatic insufficiency defective 25-hydroxylation liver disease anticonvulsant therapy loss ofvitamin D binding protein nephrotic syndrome defective 1-alpha-25 hydroxylation hypoparathyroidism renal failure Mineralization Defect abnormal matrix osteogenesis imperfecta fibrogenesis imperfecta axial osteomalacia enzyme deficiency hypophosphatasia (inadequate ALP bioactivity) presence of calcification inhibitors bisphosphonates, aluminum, high dose fluoride, anticonvulsants Phosphate Deficiency decreased intake antacids impaired renal reabsorption primary defect Wilson's syndrome, Fanconi syndrome, multiple myeloma secondary defect primary hyperparathyroidism, oncogenic osteomalacia
1'Prevention -V!lfllnl 11'ravantion -Hip 1' PnMntion Wist r PnMntion-Vllfllnl 'l'l'revention-Hip
'l' PnMntion Wist
1' PnMntion Vllfllnl 1'1'revention- Hip 1' PriVIntion Wist 'l' Prevention -V!lfllnl 'l'l'revention-Hip
'l' PriVIntion Wist
...... 15 -will
Not ligniiclnt Not signiiclnt Not signiiclnt
IGaldl
... , ,
Facton
o
for Ouantitalively and qualillllivaly na1111111 osteoid formation o Nonnll concantmion of calcium IIlii phosphate in ECF o Adaqulllll bioactivity of ALP Nonnll pH at sa of cllcificltion Absence of irllibitans of cllcification
,._..ry
E46 Endocrinology
Metabolic Bone Diseaae Table 37. Clinical Presentations of Rickuts and Osteomalacia
Ric:Uts Skeletal pain and bow legged Fracture susceptibililty Wsakn111s and hypatonia Disturbed growth Ricketic rosary (prominent costochondral junctions) Harrison's IJOOW (indentation of lower ribs) HypocalcBmia Osllamalacia Nat as dramatic Diffuse skalstal pain Bona tendamass Fractures Gait distlrbances (wadcling) Proxinal muscle weakness Hypatonia
Serum Phosphite
Decreased Decreased Decreased
Serum Cllc-.m
Decreased to normal Normal Normal
Serum AlP
Increased Decreased to normal Normal
Odler Fllllures
Decreased calcitriol Associated with hypen:hloremic metabolic acidosis
Proximal RTA
Normal
Normal
Normal
radiologic findings pseudofractures, fissures, narrow radiolucent lines - thought to be healed stress fractures or the result of erosion by arterial pulsation loss of radiologic distinctness of vertebral body trabecula, concavity of the vertebral bodies changes due to secondary hyperparathyroidism: subperiosteal resorption of the phalanges, bone cysts, resorption of the distal ends oflong bones others: bowing of tibia, coxa profundus hip deformity bone biopsy usually not necessary but considered the gold standard for diagnosis
Treatment
depends on the underlying cause vitamin D supplementation P04 supplements iflow serum P04 is present Ca supplements for isolated calcium deficiency bicarbonate if chronic acidosis
Renal Osteodystrophy
represents a mixture of four types of bone disease low tum-over osteomalacia - from acidosis and retention of toxic metabolites osteoporosis - metabolic acidosis dissolution ofbone buffers osteitis fibrosa cystica - from increased PTif osteosclerosis - from increased PTH metastatic calcification secondary to hyperphosphatemia may occur
Pathophysiology metabolic bone disease secondary to chronic renal failure combination ofhyperphosphatemia (inhibits 1,25(0H)z-vit D synthesis) and loss of renal mass (reduced !-alpha-hydroxylase)
Clinical Features
soft tissue calcifications -+ necrotic skin lesions if vessels involved osteodystrophy -+ generalized bone pain and fractures pruritus neuromuscular irritability and tetany may occur radiologic features of osteitis fibrosa cystica, osteom.alaci.a. osteosclerosis, osteoporosis
Treatment
prevention maintenance of normal serum Ca and P04 by restricting P04 intake to 1 gOD Ca supplements P04 binding agents prophylactic use of vitamin D with dose monitoring to avoid hypercalcemia and metastatic calcification
Endocrinology E47
C.,.._llfaav.lllfulilnflz.IIIIIR
Acidwilh ....... far 1'11111'1 Dis_. NfJM 2005; 353:898-tCIII lbidr:liw idar8cal, lllldomizad, !bible-bind, ICiiwly contd1d trills lcariiaed fur allltilisl. .......: 357 m.llld-whoWifl older 111M II yem af IIQillld hid fldiologiclllv can&nr.ll'lgut'l dillnu rJ bana. AI lilt 4 patieniJ llld llkllne p. . . . . levels that were mortlllln twi:e the upper imit ci !IIIIINI. llllmdan: 0..15-millll nuian ci 5 ci lliJdlanie Kid with 60 Ill rnl rilldruallflll30 P dlyJ with folkw# up 116111111lha.
-----------------------------------
Epidemiology
a common disease: 5% of the population, 10% of population >80 years old
Etiology
postulated to be related to a slow progressing viral infection of osteoclasts, possiblyparamyxovirus
Differential Diagnosis
primary bone lesions osteogenic sarcoma multiple myeloma fibrous dysplasia secondary bone lesions osteitis fibrosa cystica metastases
Prinlry D.amc IIIII ofthenpewc reiiiOI1Sii 111 six111CIIIllll, dllirlld 111011111iilllliln ci 11k1..1 plllllpbllllse levels or 1 rab:tioo Dill least 75 percllll in 1118 IDtllllkllila plllllpbiiiSe 8liC8SS. .... At lit monllis. 96.0 percllllt af patiaJis IICIMIIQ mlii!Rnie Kid bid 11banpeuti: 111pD1111 j169 II CDrflllrlld v.rilh 74.3 ,_at rJ prillniJ IICiivilg riladnmltii1Z7 ci 171, P<O.OOU. Alkllila pllospii111111M8 normdzad il 88.6 pnnt rJ pllierQ in lhe 1Diedronic Eid group lAd 57.9 PlfCIIII ol P11iantJ in 1111 riseclllate group IP<0.001].lllledlalic ICidUSDCillflld Mil I ShDrllr medilrl lima 1D I firlt 1herlpadic response 164 "19 dsys, P<O.OOI]. HigM' f1111D1118 reta1 in the Mctonic .ad PJP wm consiltlri lcnJIS dlrnDgllllllic. d i llld lnll1mllllt-lliltlfy lUbplps IIlii
Clinical Features
usually asymptomatic (routine x-ray finding or elevated alkaline phosphatase) severe bone pain (e.g. pelvis, femur, tibia} is often the presenting complaint skeletal deformities - bowed tibias, kyphosis, frequent fractures skull involvement - headaches, increased hat size, deafness increased warmth over involvt:d bones due to increased vascularity
Investigations
laboratory serum alkaline phosphatase is usually vt:ry high (unless burnt out) normal or increased serum Ca normal serum P04 increased urinary hydroxyproline (indicates resorption) imaging evaluate the extent of disease with bone scan initial lesion may be destructive and radiolucent involvt:d bones are expanded with cortical thickening and denser than normal multiple fissure fractures in long bones
wit! cllangll il alhar bane.Wrnov. mlrbrs. The unnwy- ci tile Mediell Sillly 36-illm ShortFtrm Glnnl Hllllll Survay, 1 - r a altha quaily Iiiia, nu-d from luiline It botli 1lhle ltld six -'115 in the . . . .cacid group and dillllvd from tha in IIIII rilllhnllfll graup II 1lnl months.l'llilscorn botli post-1ri11Jollow.ilp{meciln, 110 Zl ci B2 patieutl illile risemte group hid a loa rJ 1herlpadic fiSPCIA'I, 11 I ci 113 patiants iltbllmlldruaie acid group {P<0.001]. c..:lui. A1iJu1e iriwilm rJmildruaie IICid pm6.Jcllmoflmpid, mora CDIJ'IIIata.llld mort sustailed JeSPOI'jlel in l'llget's diselte 111sn does dlilv trlllnWII with rilldroolll.
Complications
local fractures osteoarthritis cranial nerve compression and palsies, e.g. deafness spinal cord compression osteosarcoma/sarcomatous change 1 to 3% indicated by marked bone pain, new lytic lesions and sudden increased alkaline phosphatase systemic hypercalcemia and nephrolithiasis high output congestive heart failure due to increased vascularity
Treatment
symptomatic therapy treat if ALP >3x normal bisphosphonates, e.g. alendronate 40 mg PO OD x 6 months OR risedronate 30 mg PO OD x 3 months OR zolendronic acid 5 mg IV per year calcitonin 50-100 U/day subcutaneous injection adequate calcium and vitamin D intake to prevt:nt development of secondaryhyperparathyroidism
E48 Endocrinology
------------------------
causes include primary (testicular failure) and secondary (hypothalamic-pituitary failure) primary hypogonadism is more common than secondary
Hypogonldatnlpic Hypaganldilm
[Secandlry
......
..,
in s8flll11 tastoatanma level
......
..
bstostJrona
Diagnosis
Sperm count LH, FSH, tastostarone hCG atimulation Testicular size and consistency (soft/firmI Karyotype
region
Endocrinology E49
Treatment testosterone replacement (improve libido, muscle mass, strength, hair growth) IM injection, transdermal testosterone patch/gel side effects: acne, fluid retention, erythrocytosis, sleep apnea (rare) contraindicated if history ofprostate cancer GnRH agonist to restore fertility administered SC in pulsatile fashion using an external pump surgery - only if testicular tissues are not functioning Causes of Male Infertility 1.primary hypogonadism 2. secondary hypogonadism 3.other causes: autoimmune disorders - spenn antibody anatomy - hypospadias, retrograde ejaculation sexual dysfunction - erectile dysfunction, premature ejaculation, infrequent coitus obstruction - vasal occlusion, vasal aplasia, vasectomy; seminal vesicle disease
DEFECTS IN ANDROGEN ACTION
... , , t-----------------,
AIIP..-b to Mllllnfllrtlily llillory
Langth of tima for 11tt1mpt to conceive Prior IUCCIIII8S With ather partners Ejac:ullrtion problem& Frequency of intercourse
Medications Alcohol and iDicit druq use Heat bath. sauna, whirlpool
Smoking
PJE
Testicular size and consistency Varicocele?
Etiology complete androgen insensitivity (testicular feminization) incomplete androgen insensitivity 5-alpha-reductase deficiency mixed gonadal dysgenesis defects in testosterone synthesis infertile male syndrome undervirilized fertile male syndrome Clinical Features depends on age of onset
lnn.liaation
S.m111 analysis x 2 (sptm1 count. morphology, motility) ScratiiVTeaticular U/S [look for
Tabla 40. Effacts of Tastastarona Daficiancy First tri-* in 1111110 klcomplete virilization of external genillllia (ambiguous genitalia) klcomplete development of Wolffian ducts to form male internal genitalia (male pseudoherrnaplrodism)
Tlinlllinaat. in 1111110
Prlpubarty Micropenis Cryptorchidism (failure of normal testicular descent) klcomplete plMtlll maturation (high pitch wice, sparse pubic+ axillary hair, absence of facial hair) Eunuchoidal body habitus (g1'8118r growth of axtramity long bones ralativa to axial bones] Poor muscle dswlopment, reduced peek bone mass Decrease in anergy, mood, and libido Fine wrDdes in comers of mouth and eyes Decrease in sexual hair, hematocrit, muscle mass. s1rength 111d bone mineral d111isty
2flJO +Ceri's Essentillso!Metlcine
Pustpublrty
Adlplld
Treatment appropriate gender assignment in the newborn hormone replacement or supplementation psychological support gonadectomy for crytochidism (due to increased risk for testicular cancer) reduction mammoplasty for gynecomastia
Erectile Dysfunction
---------------------------------------
E50 Endocrinology
....
,,.}-----------------, ,
60-90
24-65
Gynecomastia
Definition
true gynecomastia refers to benign proliferation of the glandular component of the male breast,
Epldmialagy of
lnt.w:y
resulting in the formation of a concentric, rubbery, firm mass extending from the nipple( s) pseudogynecomastia or lipomastia refers to enlargement of soft adipose tissue, especially seen in obese individuals and does not warrant further evaluation
Etiology
All 51).1
Phy8iologic puberty elderly (involutional) neonatal (maternal hormone) Pathologic endocrinopathies - primary or secondary hypogonadism, hyperthyroidism, extreme hyperprolactinemia, adrenal disease tumours - pituitary, adrenal, testicular, breast chronic diseases -liver, renal, malnutrition (with refeeding) drugs - estrogens and estrogen agonists, spironolactone, ketoconazole, cimetidine, digoxin, chemotherapy, marijuana, alcohol congenitallgenetic- Klinefelter's syndrome, androgen insensitivity other - idiopathic, familial
It'
c - "'Gyn-maatill
DOC TECH Drug Other Congenital
Endocrine CHronic dis-
Tumour
Pathophysiology
decreased androgen production + increased estrogen production increased availability of estrogen precursors for peripheral conversion to estrogen androgen receptor blockage + binding of androgen to sex hormone binding globulin (SHBG)
History
recent change in breast characteristics history oftrauma to testicles history of mumps alcohol and/or drug use
family history
sexual dysfunction
Physical Exam
signs of feminization breast must differentiate from breast cancer (unilateral, eccentric, hard/finn mass, fixed to underlying tissue) with possible skin changes (dimpling, retraction) or nipple changes (discharge, crusting) gynecomastia in contrast occurs concentrically around nipple, and is not fixed to underlying tissue genito-urinary exam stigmata of liver or thyroid disease
Investigations
laboratory - serum TSH, PRL, LH, FSH, free testosterone, estradiol, LFTs, creatinine, hCG (ifhCG is elevated, need to locate the primary tumour) CXR and CT of chesUabdomen/pelvis (to locate neoplasm) testicular U/S to rule out testicular mass MRI of hypothalamic-pituitary region
Treatment
medical correct the underlying disorder, discontinue responsible drug androgens for hypogonadism anti-estrogens - tamoxifen, clomiphene
surgical
usually required if have macromastia; gynecomastia present for> 1 year (fibrosis is unresponsive to medication); or failed medical treatment and for cosmetic purposes
Diabetes Medications
in1CIIill
II!IW
..
Suitizes periplaal1isiUIS 1D inluin -+ incraiSBI uplllb DeCRISils hepatic gU:ase Jlllll,l:tian
o.q
!iOO rrv DD1ilriiBd1D 11Dl rrv lid II'IXi1111111
lldiCIIilnl
Cmid:alials
C11111menl!
Bipnide
Glunm'
ABSOWlE:
Stirrulates iodn release 11om bela eels by wing K cllannel dature -+ depcjrriilb -+ Ca medialed iuun rellllle Use in nonabese Type 2DM
tullony\neas: glymle
J
... ...
C)
Dilbila1
Weiglitgain
Mu:ZOnWtiay
gichuide
Anvl'
GlucoNOim'
1-llmgOD
0.5-4mgtid 60-12Drrvtid
81mb'
Avan:lia1
Sllortt111 of 1hcu causes 1M Rl!lif-t- nidi, thill8ftn Mwrw piS! prandial control
Weiglitgain
rusigillillne
uplllb
piagillmne
Fracw
limhea
agUosidase ntibilor
ICI1bal8
Glucobay'
inhibiting bruill border Dipeptidyl peptidase-1'1' degllldllilo of mgenaus (IJIP.IV) inhibi!Dr antihyperglycemic ilcretin 1Mlnnanes stiiUate indn secretion, inhibit glicagan n!lease, and delay gastric emtyping
fwinajilfltnutrtilw,piiiAJ rafw1D EJ
.,j, pasljnndilllrjperglymia
Flalulelk:e Abdoniral1211!1l'l
Nasopha!y!VJitiS
..VIIlA1CO.S-1.D'Xo
I
J
e1 ...
silagiptan
JIJUiia'
URll Headache
Dyslipidemia Medications
HMGCoA llllictase inhibiiDr
m
C.U.NI111
Lese
lllchmill al AdiDn lnhilils cholestaollilsyn1hesis, "-' LDL synthesis, .,.. Ul. clelnrice, modest t Hill. inH VUl.
USNnGf-..1111
MMcor'
Prtvachal'
finlas
.V VUII..HG, rrlllled
Zoeor'
Upilil l.opid1 gmniacin
1B-BOmiday 211-BOmiday 211-BOmiday 111-40miday 5-40miday 1B-BOmiday 400 lf9'day 48-ZOOrrq'day 6DII-1200 mWdar
-.
....... .,.lirl
Clnlnid:ltilu
Sid1 Elilcll
!;'
rnoood1811py
prurinls tlivelmzymes
l'lillltintas)
HijJ&Iicdi. .
RsiiBicl lf\1leBensiMty
lnhllilnecretiorr ct hepllic VUJL via lpase !LPL) pat1rt1ay -+ dBC111sed VI.Jll dlcrrlaeed ciBIIWI:e of HDL lllsins that bind bie acils in idellilal umen and prevent aiJsD!p1irl1heleby -v Ull lnhllils cholesterol abscrptiDn It the small intestine brush bDTder
ra:mt
1' VUJL
lf\1ierumil
cholesbyamine colestipol
elriribe
12etroj8
lllllbdomyoltlis (dose >IKI ITIIJ) Gluplll t rilk ct gdl1une lormm mbined with Dtins Abnonnlll M! enzymes Pnnilus IGT
Bilucid
secJieslrwits
lb!sllln' PrMiite8
Used for tlJJL Use as adjunct with slllins orfilntes Used for 1' B
CCIIstiJD:In Nau
Ra1ulellce
Cholesterolllbsorptiorr mililol$
ld
Ph.,..
i
i
8
Thyroid Medications
in1CIIM llechmill al AdiDn llecl!llses thyroid h111111D1'11 pruductilrl by inlii!iv ioclne arrd pe!Ullidase from intmc1DJ Ntll
SIIIR: Drq Nlllla prtVI!thilllllcil (PIU)
Cnd1NI111
US Nil
t ..
II.....,
IRa
S1mt 100q PO til,
Pftvii.TlTjmcil" llpllDie'
......
Hypl!lttrjni:lism
Pregnancy, lacll1iDn
lle!Jetitis
Symptams oflrypartlr,U:iillll
Tlryroidllmlne
'Hypotbyroilsm
Recall
thymtaxi:Diis
tMiltnil'
Angine
lfype!lhennia
llanbea
... ...
&enalc lftg
CllllllNne
us Nln llllflnll
o.q
5-10q00 70 40 OD fur 6nmlls
Bisphasplnlas
alandranata
fGrrlxll
lrdCIIIianl Plwantian of poslmeTqlual asllqiorUiil TNIIment li osllopOTDis GUaJcmticcilirdJCl!d DSII!OJOOSis Paget's disease T_.llld prewntion li postrnllllpual OilaapJiulia TNIIment llld prevention li ;.r:OCOI1ic:oidinduc:ed osteopOIOSis Paget's disalse
Cllllb'lildicllia
stricbn IJacllllasia Ullllllla 1D stand ar uprijll fur >:II min lOIII) lt,1lersensitivity lfypocak:tJria H11111l inufic:imqr
J
... ...
C)
TiseDal8
AclonePI
etilranate
DidranePI
illmlnma1e
pamidronale
Aralia'
ZDielarlle
Zornell' AciiiSII1
llec:e!D
Salec:live Eflragan
llloxiane
Osteoporosis disaasa PrMntilllllld trelbn!nt li helm! pic osific:aliln llfmri!DI hip replllc:ellll!lt or spinaiCI:td iiVf TNIIment llld prevention li postrnllllpual OilaapJiulia (US onlyl Hypercalcemia of mlli]nmy Paget's disalse Osteolytic 1m 1IDslllses of iRist Osteolytic lesions of multiple Rfiekml TNIIment li osllopOTDsis Hypercalcemia of mlli]nmy T_.llld prewntion lisblnl amplications r8latad 1D cancer T_.llld prewntion li ]XIStmempual OilaapJiulia (2nd line!
I
lictltDD l'rlgnmy Active or past lislmy of 1M; PE or retinal 1lrontosis
IICJtftubes leg cramps riskoflallll
sblte,wnous
Calci1Dril
&Umin
t.lalc:in'
Clini!;lllallergy ID
I'IH
1a'pralide
Fno'
Trnlment li poslmenopauiil Wlli1WII with ostBoporosis IWMI ara Trnlment limen with prinary or l?jpogonadal IWM!ara
ol'lget's disease PrD axllmal baam or implut radim lhnpy iMmng the skllabm oBone metastases Metabole bone diseases all1111hen ostaoporosis
lhrornboilrriiolilm Rhinitis Episluis oSirusitis oNnal dlynea oOOoslatic hypolension Hypmtemia ollllilns leg cramps
!!!!
I
II>
e1
CIIIIIIIName
Indications
SideEfhc:a
Vomiting Constipation Dry mouth Hypercalcemia Headache Nausaa, vomiting Constipation
Dsteopenia
Osteoporosis Prevention Ill melllbolic bone disease
VrtaminD
BOO IU/day
Dsteopenia
Ostaoporosis Prevention Ill mBIIIbolic bone disease
Caution in patients an digDXin (risk Ill hypercalcemia may pracipilllte anhythmia) Hypercalcemia Malabsorption syndrome Decreased renal function Hypercalcemia Vrtamin Dtoxicity
l
i
i
8
50000 IU
cak:itriol {1,25{0H}z-D)
Rocllltrol1 Calcijex'
Hypoplllllhyroidism
I Adrenal Medications
lkugCI&II
Hydrocortisone Minalocorlicoid Generic DRill Name Potency {relative Activity to Cortillll) Yes Cortef Solu-Cortef 1.0 EA,Iivalont Dole{mg) 20 Duration of Action (t 1/2 in hour.)
Dosing
Ad!ll!al Crisis: 100 mg IV bolus, then 100 mg q 8hr (continuous infusion x 24-48 hr) PO once stable (50 mg q Bhr x 48 hrs, 1hen taper over 14 d) 20-30 mg PO OD (213 AM, 1/3 PM) Adrenal Crisis: 25-300 m{V'd PO/IM divided q12-24 hr Adrenal Crisis: 5-60 mg/d PO qd or divided Bill/OlD
Commentl
In high doses, mineralocorticoid side effects may emel'lle &Bit + water retantion, ECF volume axpansion. HTN, low K metabolic alkalosis) Pro-drug which is converted to active funn as hydrocortisone High doses can result in mileralocorticoid side effects (sae above) Pro-drug which is converted to active funn as prednisolone Used for undiagnosed adrenal insufficiency {won1 iltelfere with serum cortisol levels)
Yes
No No
Cortone Acetate
0.8
3.5
25 6 0.7
30
r
... ...
Endocrinology E55
DIABETES
DCCT
UICPOS EDIC
lnl!nsive blood gklcose control delayed the onset end llllllced the IJIIgression of microvascular complications (retinopathy, nephropathy and neurapathyl in Type 1 OM lnllllsiw blood gklcosa control11illces microvascular, but not macrowscular complications i1 Type 2 OM Compared with conventional therapy, intensive dabetes therapy (goal HbA1C <6.05%1 has loll!J-tenn beneficial effects on the risk of cardiovascLJar disease in patients with Type 1DM Compa11d with &lirldard thnpy, the usa of inl!nsive therapy to target nonnal HbA 1c levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events lnte115iVB gluc058 control that IOWfJRid the HbA1Cvalue to 6.5% 11duced the incidence of nephropathy but did not significantly reduce major macrovascular events, death tom cardiovascular events, or death tom any cause. Hypoglycemia was more common in the intensive control group In patients with longstanding poorly controlled Type 2 OM. intensive glucose control had no significant afflict on tha rates of major cardiovascular avants. death, or microvascular complications. AdVBISB IMIIIts, predominantly hypoglycemia. ware more common in the inl!nsive control group In patients with both Type 2 DM and coronary artery disease, no significant difference was found in 1he rates of death and major cardiovascular events in patients undergoilg 110mpt revascularization and those undergoing medical therapy or between strategies of insulin sensitillllion and insulin In at-fisk patients with Type 2 DM, intensive intervention with multiple drug combination and behaviour modification had sustained significant benaficilll affeell with respect to vascular complications and mortality. inteMntion is aitical in the menagement of Type 2 OM In patients with impaired glucose tolerance, nateglinide did not reduce progression to diabetes or risk of cardiovascular events, while vasartan only reduced progression to diab91as In patients with angina or previous Ml111d high total sinvastatin reduced: all-cause mortality, fallll and nonfatal coronary events, and need lor coronary artery bypass surgery or angioplasty In higlt-risk patients with various cholestarcl values, simvastatin 18ducad all-causa mortality, coronary deaths llld major vascular events therapy with atoMslatin 80 clinical benefit beyond atorvestlllin 10mwday in patients with stable CHD provides
ACCORD
ADVANCE
VADT
BARI-20
Steno-2
LIPIDS
4S
HPS TNT FIELD
In patients with Type 2 DM, not previously on statin tharapy, lenolibrate did not aignificantly 11duca the risk of the primary outcome of coronary ewnts. It did 11duca non-fatal myocardial infarctions and revascularizations patients with elevated high-sensnivity C-reactive prulein levels and no hypeilipidemia
Jupiter
NEJM 2008; 359:2195-207 Rosuvaslatin significantly 1111llced the incidence of major cardovascular events in
E56 Endocrinology
References
References
liZ. Etiology rl hypercalcemia. Uptodatl Online 2010; VmiDn 1D.2. www.upiOdats.CIIIII liZ. Dvarviaw of mlltlbalic bane dilllue. Upllldata Online 2:002; YatsiDn 10.2. www.up1Ddala.com ArmriCilllliabetBs AsSDI:irrtian. MaiiiQIIIlilll in llllrlts with cilbetBs (Position S1mmentJ. Dilbe11s Clre201ll; 25(S1]:S74-17. Amald A. Clllliicllian and plihDQIIIIIIil rl the 111docrine 1110pillia symmes. Uptodltl Onine 2002; V1l1lian 1D.2. www.uptodata.corn United Kingdom l'rolpel;!ive Diabltlls S1udr IUKPDS] Gmup. lrdllnlivs bload-gkrcall8 control with IIUfunylqq or iniiUiin wilh CO!NIIntionll1reltmlnt and risk of complica1ianl il pllie1lts with type 2 dillletes.l.ancet 1998; 352:837-53. llrvlwald E. lUi AS.lCuplr DL, HM1881 Slit aL Dilbltlll Mllitus in Harrison's of ln1lmal Medicile VoUml 2. New \'art: The McGrrw Hill Companies, 21101. PP 21 09-zm. Blrnlri KD. Dmvilw af1hynilltis. Uptodllle Online 2:002; Version 10.2. Canadilll Dirbatas AsSDI:illion Ciricall'rlctice liuidelines Expert Cormitllle. Canedillllilbatas AII8DCirlion 2008 clinical practice follhe p!MIItion and management of dilbe11s il Canldll. Canlldirn JoUIIIII rl Dialns 2008; 321Supplement 1]: S1.S201. Canadiln Tuk Force on Prtvantive Health Care. I'IMntion II oriiOpOIOSis arrJ OlleopOrOtic frac1ures in post-menopausal-. Canedian Medical Associ Ilion Joumel2004; Chang A. Fln1usiG. Oralantilyperglyclri: lhllllfll' fur type2 dilbllls mellitus. Canadian Medical Assacillion Joumal2005; 17212]: 213-226. lleyln CM.Intarpnrlltion of thyroid func:lian tarts. Lane at 2001; 357:61 U24. Fodor JG, Ffolil:h JJ, Gened JJG, Mcf'llarson PR. RIICGIIIIIIIIIdllions fur the ma111Q81118nl 111d lreltmant II dy$1ipidemil. Canadirn Medical AMol:iltioD Joumal2000; 16.2110]:14411447. Glllast J. Fnllil:h JJ, Fodor JG, t.ld'hlnon Pit lllcommulations tllha mllliQIIIllnt of dyslipidamia and the prawntiDn of cardiMD!r dill8111: 2003 .,_ Canadilll Medical AAocillion JOWIII2003; 169(1]:01-010. GIIIIIIJIIII FS. Glllber DG. Basic llld Clirical Endocrinology. NawYark: Mllbl BIIIIWMcGrawHill2001. pp 100163. 201272, 623-761. Hirsch 18, Plluw llS, Brullliii.L lnplliantll'lllniQIInllllafadullswith diabltaL DiabltllsCn 11115; ICitlllachi AE, U.nez GE. MurphyMB, Banet EJ etal. MII11Qe111e111rl hypergtjcemic crises inpatienbM!h diabetes. Diabetes Care 2001; 24(1]:131-152. Krnnball! HM, l.8l1en PR, Maimed S, Pllonlky, K. Willms TIDIIIIaok al EndDCrinDIIgy Ninth Edition. W.B. Ssundm Compall\', 1998. NIH ConseniiUs Pinal on Ostaaporosis l'r!Mintion, DilgliOSil end Ostaaporosis prevantion. diagnosis, IIIII lherepy-. Joumll tithe American Medical Associrrliln 2001; Orth lit EviUitionaflhe rasponseiD ACTII in adnmal insuflicillncy. Uptodatl Onine 2002; Version 1D.2. www.uptodata.corn B, a.! m; Rodbanl HW, Bonn Jr FJ et al. Pilylicilll's guide wp!MIIIion and 1r8ltmllt tl oataoporosis. Nrrtianll OsleoporiJsis Foundltio1l, 2003. Rosen HN, Aosenbllltl M. Overview of !he manag8111111! ri oslaopDAlsil inMmlll. Upllldata Online 2002; Vltsion 10.2. www.Ul)1Ddltt.com. RoRI DS. Disordeq lhlt C1U11 hypothyroidism. Uptodltll Oltna 2002; Vfton 10.2. www.uptodatll.CQI!l Ryan EA.I'regn111cy in diabetes. Medical Clinics II North Americal998; 82(2t.82J.845. Cal line R, Amillgll J. Plrilh S. PR. lllaart Proflelion Study of Mlflnll klwaring with siiiNIIIIIil in risk indivilllls: 1111ndamised placebo-wrtrolled trial Llrlcet 2002; 360: 7-22. lila Scalllline\lian Silll\Utltin SuNi111 Sludy Group. Aandomilllld 1rilll of cholesllrol bming in 4444 Pl1ilnll v.ith tonllliiY heart dis11se: 1h1 Scandinll'ian Silll\Utltin SurvMI S1udy(4S]. Llrlcat 1994; 344:1383-1389. TIIUi E.lllmie A. Ross S, l'arlles Ret al. illuin therepy Mill inun lispro: 1 rendornimd 1rial of cantiiLIJUs subcutanecu illulin illusion ver1111 multiple daily inun injactian. DillbltllsCsnl2001; 24(10]:1722-1127. Young WF. Kip lin NM. arrJ lreltment of illlllrb.Uptodatl Online 21102; V1l1lian 10.2. www.uptodlle.CQI!l