E

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

Toronto Notes 2011

Endocrinolo8f El

E2 Endocrinology
.....

Basic Anatomy Review/Dyslipidemias

Toronto Notes 2011

',

Basic Anatomy Review

Major Endocrine Organs
Hypothalamus Corticotropin-RH (CRH) Gonadotropin-RH (GnRH) Thyrotropin-RH (TRH) Growth hormone-RH (GHRH) Antidiuretic hormone (ADH) Oxytocin Note: RH = releasing hormone Thyroid gland Triiodothyronine (T3 ) Thyroxine (T,)

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)

Adrenal gland Cortex: aldosterone, cortisol. androgens Medulla:

Parathyroid glands Parathyroid hormone (PTH) Pancreas Insulin, glucagon

Figure 1. Endocrine System

Dyslipidemias
Definition metabolic disorders characterized by elevations of fasting plasma cholesterol, and/or triglycerides (TG), and/or low HDL

Overview of Lipid Transport

lipoproteins are spherical complexes that consist of a lipid core surrounded by a shell of water-soluble proteins and phospholipids lipoproteins transport lipids within the body apolipoproteins serve as enzyme co-factors and stabilize the lipoprotein micelle Table 1. Lipoproteins
Lipoprotein Exogenous pathway Chylomicron Endogenous Pathway VLDL IDL B-48, C, E, A-1, A-11, A-IV Transports dietary TG from gut to adipose tissue and muscle Transports hepatic synthesized TG from liver to adipose tissue and muscle Product of hydrolysis of VLDL by lipoprotein lipase resulting in depletion ofTG core Enriched in cholesterol esters Formed by further removal of residual TG from IDL core by hepatic lipase resulting in greater enriched particles with cholesterol esters Transports cholesterol from liver to peripheral tissues (gonads, adrenals) Transports cholesterol from peripheral tissues to liver Acts as a reservoir for apolipoproteins Apolipoproteins Function

B-100, C, E B-100, E

LDL

B-100

HDL

A-I,A-II,C,E

'IbroDlo Nota 2011

Endocrinology E3

EXOGENOUS PATHWAY

BIDGB- PA1IIWAY

E C.ll B-4B

Chylomicron

:_;
dilgtadw'lfi
fnla Filly Al:ids

IPE.Ptse

Mpoae TIIIUIIIld Muac:le

llC1Mitioll byApo

"lP liptQ,..,....

I
I

Figun 2.

alii! E'lld111Janoua BiDQIIItlatic Upid

Hypercholesterolemia
PRIMARY HYPERCHOLESTEROLEMIA

Tlllla 2. Tha Pri..ary llyparchalllltaralamias

Tn11dn11n Familial Hyparchala&t11rana (Fredlridcscln Typallll)
1/!iOO in US 1' UJL Tm.Jus Xllnthomlltolis Hatarozygotal: improvement Autlls111111l cklminn Mill 1' TC (achles, patella!; 111d axl&nlar of l.lll Mill lbll combilalian high pnlnlnce ta'ldn af hand) of HMG CoA lllilctasa Defect ilthe llDil11lll Arcus com!B! iHJitors, niDI. or ble acid UJL recaptor an cell xanthelaama 8&q.l81111ntl o Heterazygotas: 11111111ura Hamorygotal: ptrtial control manmnaa CAD. SIR. risk af Ml ilman Mill pclllc:aVlll shlnt or by aga30 Llll apharais il HlllllllYIIDII!S: ITIIIIifest CAD with riacil; large lilse end ather YIICuler dileeee llorvaabllil is modallly Billy il clildhaad ll1d can be 8llilctive faml( <20 y) I Wl1nlllld
o o

Pulygenic Hyperchalesll!ralenia

MDII: common hw mid ilhlliled dafactl il dlalaateral matabali&m

1' TC 1' Ull

AsymptllniiQ: umil vascu!. cisease develops ND antharnab

o

HMG CoA lllb:tase

Dillurs, bie acid a&q.181111nt, niacin

SECONDARY HYPERCHOLESTEROLEMIA

Etiology
diet
anorexia nervusa

hypothyroidism
choleabrtic liver disease (e.g. primary biliary cirrhosis) nephrotic disease monoclonal gammopathy

drugs (cyclosporlll. d!uretia, carbamazeplne)

E4 Endocrinology

Dysllpidemias

Toronto Notes 2011

Hypertriglyceridemia (Elevated TG)

PRIMARY HYPERTRIGLYCERIDEMIA
Table 3. The Primary Hyperlriglyceridemias Hypertriglyl:eridemia Flrnilial Lipoprotein Lipase deficiency (Frederickson Type I)

----------------

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,

Flrnilial Hypertriglyceridamia (Frederickson Type IV)

Several genetic defacts resLiting in 1' hepatic VI.DL synthesis or -J.. removal of VLDL

Decrease dietary fat

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

Dysb8lalipopruteinemia (Frederickson Type Ill)

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

Toronto Notes 2011 Screening

Dyslipidemias

Endocrinology E5

screen men over age 40, women over age 50 or postmenopausal

if following risk factors present, screen at any age:
diabetes

"-{9,
Non-ll'lditiOIIIII ...aitive Iiiii fllelorl

1' Apa-B (apalipoprotain Bl

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

Small dense LDL 1' fibrinogen

1-PAI-1

Apa A-1 (apalipoprot8il A- H

1' IL-6 (interleukin 61 1' ThiF (tumour necrosis factor) 1' CRP (c-reactive pro1ein)
lldiponactin

1' hamacywte!M

Factors Affecting Risk Assessment

metabolic syndrome apolipoprotein B (apoB): each atherogenic particle [VLDL, IDL, LDL and lipoprotein(a)] contains one molecule of apoB serum [apoB] reflects the total number of particles and may be useful in assessing cardiovascular risk and adequacy of treatment in high risk patients and those with metabolic syndrome

....

,,

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

Table 5. Optimal Target Levels of Apolipoprotein B by Risk Group

Tqst apoB lavals !ttl

High <0.85

Moderlle

< 1.05

Low <1.2

'Risk Slrllification by fi'Wngham Risk Scot&. See Famj!v Ml!icjnL FM7

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

of myalgia lliC statin if CK > 1Ox upper nonnll

af

lllllliwl14*ftawWg il CAD: m 11Uf21105; 352{14):1425-35

S1udy: r.uDnbl, nrulomiliCI. trill l'liGI medBi follllrtiJp rl4.9 yen. 1'11i11D: 10.001 plliadl with CADII'Id LDI.C <14. IDvlnlill: 80mgversus 10 mg lflrmlatil ddf. ... --=llellhtrom CAD, r.'j, l:lldiiC liTE. antmkl. blulll: Aplirmy IMirt OCIUI8d in 8.7'11 Dlthe pllilnts irnive tha111lY. cDfllPII'Ci'ID 10.91 rl plliertnceivin; stl!lllilrd theApv (AA
0J8,p<0.001).

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

111-yaar Rilk of CAD 10-19% <111%

Ta1111t LDL

(mg/dL) <78 llllfdL <136.5mQI'dl <195mQI'dl

Targlt TCIHDL <4 <5 <6

Alllllllllll

lTIIItJiy.lncidence rl pelliltJd lrnllrillle Wllligllar in thu intnivltllalpy gruup

<2.0 <3.5 <5.0

apoB <0.80 gA. apoB <0.80 WL

11.2hnus 0.2\ p<O.OOU.

Concbila: lntnile 5ll1in lhinP't' il l'liallawlr 11111 of CAD -m than llltldlld u-p,, bli 11110 of lrnllrillllll e.tion.

lil#l.

Table 7. Treatment of Hypercholesterolemia and Hypertriglyceridemia

Annltllil tiiAiww CAD Iiiii-lllllllllt

lR6t 2002; 360:7-22 S1udy: lllndamilld. ddll-illnd. plallot:anlraled trilllmedilm 111111. ...... 20,536 J)ltilrts l'liGI ca-v 3.5mnaUL

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

IDvlnlill: Sirwlltii4D ar fAICibO. lllil Clall:ana: MOI1IIty, IIIII or nan-111111

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

Concbila: TrlltmantMh llinVIstllil impRMd

IUrviVIIIIIld f:lldiavuc:ullr lllil:amal iJ higl!-rilk

CADpltieots.

116 EndoaiD.olotlf

Dilo!dera of Glucose Metabolism

1'oroDio

2011

Disorders of Glucose Metabolism

Overview of Glucose Regulation
linr
AlipDII

-------MiliCII

FFA releale
Cin:UIIIIlry aymm

1$1

'

"1'Gb:DI& 11---FFA _ _...J "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

f"IJIFI 3. AlltihyplfllyclllliC Ageits

Pre-Diabetes (Impaired Glucose Tolerance/ Impaired Fasting Glucose)

1-596 per year go on to develop diabetes mellitus 50-8096 revert to normal glucose tolerance weight loss may Improve glucose tolerance Increased risk of developing macrovascular complications lifestyle modifications decrease progression to DM by 5196

------------

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)

Diabetes Mellitus (DM)

Definition syndrome ofdisordered metabolism and inappropriate hyperglycemia secondary to an a.baohm:l relative deficiency of insulin, or a reductlon In biologic:al effecUvenese of insulin. or both

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)

Toronto Notes 2011

Disorders of Glucose Metabolism

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

Etiology and Pathophysiology

Tabla B. Etiologic Clalification of Diabetll Mallitus
I. Type 1dillbutea {immune-mediated beta cull desbuction, usually l1111ding 1D absolute deficiancyl II. Type 2 dilbeles {ranges from predominantly insulin resistance with ralativa insulin deficiancy to apredominantly insulin sacnrtary defact mistance 210 bBia cell dysfunction!

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

IY. Gllbdioall Diallatas Mellitus

Tabla 9. Comparison of Typa 1 and Typa Z Diahatll Mallitus

Type 1 Usually < 30 years af age Typa Z Usually >40 years af age o Increasing incidence in pediatric popule1ion '1!' to
o

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

11-. ratinopedly,llld ottws.

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

eel dalact cell cellaikllll dacompalllllion

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

Early an, glucose tolerance nmaim1 nonnal despite

insulin resisbrlce as beta cells with increased insulin production As resistance and cornpall8atory hyperinsulilism continue, the beta cells are unable to maillain the hyperinsulinemic state which in glucose intolerance and diabetes
0

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

Diaorders of Glucose Metabolism

Toronto Notes 2011

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

Teble 9. Comperison of Type 1 end Type 2 Diebstas Mellitus (continued)

Type 1
Risk r.ctars
Persanal histcry of ather autoimmLroe diseases

TypeZ
Age>40y Abdominal obasity/ovarwai!#lt Schimphrenia

ilcklding Graves", myasthenia gravis,

autoimmune thyroid disease, celiac disease and pernicious anemia

Fatty liver

First-degree ralativa with DM

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

Ulestyle modification Oral antihyperltr'cemic agents

Insulin therapy Hyparo&molar norbtotic (HONK) hyperglycaric rtcrte Screen individuals with risk factors (sea abova)

Acull Ca...licatian
Scr11ning

DiabBiic kstoacidO&is
Subclinical prodrome can be dstactad in first and

hospildrJb,lndsewere

irer.iw

CCIIbd arm. Clnrillilnl: lnt8nlil'8 gUcole COI'Uol Clll

second-degree raiBiivas of tmse with Type 1 DM by the presence of pancreatic islet allloantibodies

wm.
lYJIIZII\1.

illlpdlr incidlntl ri

hypaglrclmic - - M'ltl in pltients witll

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)

Canlllliln Diabetes Guiclaliles ZOOI

TIIJII
HbAIC Fating pl1111111

o,hl

[ Clinical assessment and initiation of nutrition therapy and physical activity J

4-7 mmoi/L Hi mmoi/L (72-126mgfd[J

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

...

Initiate insulin metfonmin

If not 111: tarQet

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

MlpledfrumCIIIJ ll8beles 2008; 32(.

Figure 4. Approech to Treltment of Hyperglycemia in Type 2 DM

Toronto Notes 2011

Disorders of Glucose Metabolism

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.

Hilda Ill. . . laad

Camalil

Tabla , D. AYIIilabla Insulin Farmulatians

lnsuln Type [trade nama) Dnsat

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.

10-15min 10-15min 10-15min 30 min 10-20min

1-1.5 h 1-2h 1-1.5 h 2-3h 2h

J-5 h h 3-5 h 6.5h 6h

l'riniiJ DID-. MlljofCV

IIIIIIIIIIIITjOCI!dial inlldon, nodllll . . . or

(c:unP11

a....: Mlln lllrm. rimllicllin 1111 ,_, flr

in1an1Mtlmy Wl53.4 (95\ Cl, 3.4-3.51Z.I Z.l-2.2) flr ltlndltd thlapv-. Thill wa 1 signiiCI!It inCII!Ise in sllious ICNerse events il 11111 inllnlivl1lllllmlllt 11111 (3.3\ VI. 1.m p= especillly bnidyca Ill anvnil {0.5\\'1. 0.13%, p=0.0211111 hypurklllllil (0.4' -vs. D.04'- p=0.01]. Tllere WISIIO signlicllll lifnlce in plinuy in111e1wv lllJdv IIIIlS, Clllklllll mmllity. Thii'IWISIIigriCIId lllllcti1111 in lillY IIUa (O.m.lr w. 0.53\fyr, p-=0.01) ltld nonfml stroka incidlncll (o.mtyr "VI. 0.471t p=0.03)in the irensiw 1berlpy .,.,, .-..........: .._..siw BP lawllilgiD lasdllll 120 11111Hgvmus140 mrnHg in pllienls wilh Type 2DM ltld CV lilt factors doe$11011'81b:1 mljor Mil risk Telllctioo mile ewniJ.

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

Up to 24 h (glargine 24 h, detemir 16-24h)

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

a111'111Cri11 irillt1ion, allllakl, ar d-CIII

mcmly
studyanns.

Clncbiul: The illllilion oflinla U.rapyto slllin 1berlpr in plllienls wilh Type 211M does no1
TIICIJcalllljarCVMWI!rilk.

E10 Endocrinology

Diaorders of Glucose Metabolism

Toronto Notes 2011

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

end delay gastric emptying

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

Moming BloadGiuca.e lncrBil&ed

Lunch BloodGiu1:011 Increased

Dilner Blood Gluc:ase

Bedtille Bload Glui*IB

klcreased Increased Increased

Acting, L=LIQJ-tetn.J

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

Toronto Notes 2011

Disorders of Glucose Metabolism

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

Hyperglycemic llypemmol Nonkelotic State (HONK)

o

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

The & l's I'Nalpildng DICA:

llllrogenic (glucocorticoids) In!Dxiclllion Insulin missed Intra-abdominal process

Ischemia or Infarction

Infection

[e.g. panc1881itis, cholecyslitis)

Average fluid loss MS Ill 3-6 l in DICA, and ll-10 Lin HONK.

E12 Endocrinology
.....

Diaorders of Glucose Metabolism

Toronto Notes 2011

, ...-----------------,

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

(BHBI. the kalona most frequently in exc:en. This hQ two clinical

consaquii!Cas: 1. Be WillY of 1 patient with 1 clinical

picture of DKA but negative serum or

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--

Loss of capillary pMicytas,

lei

..

retinopdly. 1111u11r. TMnly-w plliRI in 111a inllnlivt-

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

Retinal hemorrhage (dot and blot)

RCIIinal vascular leakage

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

Figure 6. Pathophysiology of Diabetic Retinopllthy

... ...
1' Growth factors
(VEGFI

...

Reti1111l ischemia I

Hard axudates

...

Nerve fibre layer infarcts (cotton wool spots), venous

...

Vascular fllrosis

4: V"llnlous
Flolllers

changes {shunts and beading),

capillary non-perfusion

Iris

hemorrhage

neovascularimtion
Neovascular glaucoma

Toronto Notes 2011

Disorders of Glucose Metabolism

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

Treatment and Prevention

tight glycemic control (delays onset, decreases progression) ifhypertension is present, treat aggressively panretinallaser photocoagulation for treatment of neovascularization vitrectomy annual follow-up visits with an eye specialist (optometrist or ophthalmologist); examination through dilated pupils whether symptomatic or not (immediate referral after diagnosis of Type 2 DM; 5 years after diagnosis of Type 1 DM) interval for follow-up should be tailored to severity of retinopathy

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

las fliled. There is insufticient evidence for lhe

llllllicll

DIABETIC NEPHROPATHY (see Epidemiology

NP34)

i111NIIdialls. 111llllimailr lndathtlll gruwlh facm on1ha iK:idenca prograuiln rJ DR.

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

,._man rJ DR. fm.lltinlllnd facallltinll._

pllolocOIQUIItiollllllb:Bi1ha rilkof viulloA il pltilnls wilh -.. DR llld miCU'- adlml, il currrif indicilllll avidance 1D niCIIIII!llllld I'1IUlinll 11111 rl adler11111m111111.

I'.IIDilll: Til# llld blood priSSUII 1be comel1lone in 1be pinlry

Pathophysiology

thiclcening of capillary basement membrane and glomerular mesangium resulting in

glomerulosclerosis and renal insufficiency diffuse glomerulosclerosis is more common than nodular intercapillary glomerulosclerosis (Kimmelstiel-Wilson lesions)

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

Treatment and Prevention

tight glycemic control tight blood pressure control (<130/80 mmHg) with ACEI or ARB numerous studies have shown that even in the absence of glycemic control. ACEls or ARBs reduce the level of albuminuria and reduce the rate of progression of renal disease in normotensive and hypertensive patients with Type 1 or Type 2 DM Type 1 DM if normotensive or hypertensive and patient has micro albuminuria or macroalbuminuria inhibitors 1st line; ARBs 2nd line Type 2 DM -+ if normotensive or hypertensive and patient has micro albuminuria or macroalbuminuria--+ ACE inhibitors or ARBs if creatinine clearance (CrCl) >60 ml/min; ARB ifCrCl ml/min consider use of non-dihydropyridine calctum channel blocker (e.g. diltiazem) in those unable to tolerate both ACE inhibitors and ARBs limit use ofnephrotoxic drugs and dyes protein restriction (controversial) renal failure may necessitate hemodialysis and renal transplant

E14 Endocrinology
ar.ctlofT..-...IorSV.... rA.,._.

Disorders of Glucose Metabolism

Toronto Notes 2011

DIABETIC NEUROPATHY (see Neurololn) N30) Epidemiology

approximately 50% of patients within 10 years of onset of Type 1 DM and Type 2 DM

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

Treatment and Management

tight glycemic control fur neuropathic pain syndromes: tricyclic antidepressants (e.g. amitriptyline), pregabalin, anti-epileptics (e.g. carbamazepine, gabapentin), and capsaicin foot care education Jobst fitted stocking and tilting ofhead ofbed may decrease symptoms oforthostatic hypotension treat gastroparesis with domperidone and/or metoclopramide (dopamine antagonists), erythromycin (stimulates motilin receptors) medical, mechanical and surgical treatment for erectile dysfunction (see U31)

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

Bone and Joint Disease

juvenile cheiroarthropathy: chronic stiffness of hand caused by contracture of skin over joints secondary to glycosylated collagen and other connective tissue proteins Dupuytren's contracture bone demineralization: bone density 10-20% below normal frozen shoulder

Cataracts
subcapsular and senile cataracts secondary to glycosylated lens protein or increased sorbitol causing osmotic change and fibrosis

Infections
see Infectious Diseases, ID23

Toronto Notes 2011

Diardera of Glucose Metabollsm/Obesity

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

circulation when proinsulin is a-d

1o insulin.

A short peptide

Tabla , 4. Common Causal of Hypoglycamia

....
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

,,

Wrthaut llyparillulinism o Severe hepatic dysfunction o Ctnrlic renal insufficiency

o

u.. C-pepdde Llnll t1l Diltinguisb

Alimentay Functional pancreatogenous hypoglycemic syndrome o Occult diabetes Leucine sensitivity Heredibry fructose inllllerance o Galactosemia o Newborn infant of diabetic mother
o

btltwwn Exllglna aNI Endapn-

Hypocortisolism

o
o

Alcohol use
tumours Imam error of carbohydrate metllbolism, glycogen stomge disease, gluconeogenic enzyme deficiency

So- of ltyperinsulinllllil Increased = endogenous DecraiiSIId or nolllllll = BXDgenous

.....

,.. ,

Clinical Features Whipple's triad

1. serum glucose <2.5 mmol/L (45 mgldL) in males and <2.2 mmol/L (40 mgldL) in females 2. neuroglycopenic symptoms or adrenergic symptoms (autonomic response) 3. relief provided by administration of glucose adrenergic symptoms (typically o = first; caused by autonomic nervous system activity) palpitations, sweating, anxiety, tremor, tachycardia neuroglycopcnic symptoms (caused by decreased activity of CNS) dizziness, headache, clouding of vision, mental dullness, fatigue, confusion, seizures, coma

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

+ + + +

3) Retest Blood Glucose (BG}

4) Rllpllllllllps1.J until BG >5 mmoVL
5} Eat next 1Ch8duled meal. Rn8Xt meal is > 1hour WRf, eat snack including 15 g ofCHO lllld prolllin.

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

Hypoglrl:emia Uuwa,._: (Type 1 DM > > > Type Z DM}

-ratv hypoglycemic levals are reached ea..-:

o
o
o

Patient remains asymptomatic

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)

.....

,,

F.-... of M8tabolie Synd._. (lntllmationai Diu.... Fedlmion, ZUOS] Mdunilll Obllilr

Men Wlmell

Obesity
see Family Medicine. FM5

Wlisl circtmllnince an 137 ilchlll Wlisl an 131.5 indiiS)

lWril'-1
Men Ytllmn

HDL.CIM

laud,....
1M

El6 Endocrinology

Pituitary Gland

Toronto Notes 2011

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

MLitiple target organs

Somatomadins (IGFI

Androgens

Eltrogen&,

I
Gonadlll germ cells, Multiple target organs

Figure 1. Hypcrthalamo-Pituitary Hormonal Axes

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

Stimulates IJliWih of an-.&1 cortex. and seC1'81ion of honnones

Polypeptide Dexamethasone o Pulsatile llld diurnal variation Cortisol

(peaks at 02:!XHI4:00; lowest at 18:00-24:00)

-.1- serum osmolality Oclllpeptide Osmoreceptors in hypathalamus detect serum osmolality o Conlnlcllld plasma voiLIIIB dell!cted by b1111receptors is a more potent stimulus 1han osmolality
o

Insulin-induced

Fever, pain, str8ss

Hypovolemia or -.1- effectiw circulatory volume 1' serum DSITiolality Stress, pail, fever, panmeoplllstic o Lung or brain pathology

ADH

AcU at nmal collecting

ducts to cause insertion of channels and increases water 111absorplion tlunby cancentnJting urine

GH

Needed for linear growth

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

REM sleep Arginile, donidine, propnr1olol, Ldopa

o

GHRH

Toronto Notes 2011

Pituitary Gland

Endocrinology E17

Table 15. Tho Physiology and Action of Pituitary Hormones (continued)

Harmone Func:lian lMSH gonads via cAMP Physiology lnibillny Stimulus S.crlllny Estrogen Pulsatile GnRH Ov!ry: Prog811bmle - LH: production of (similar alpha Testostl!rone androgens (thecal cells) subunit TSH and Hlibin which are converted 1D hCG) Continuous (i.e. non-pulsatile) 8Sb'Ogans (granulosa cells); SeCI'8bld in pulsatile GnRH infusion induces luteinimtion in fashion follicles - FSH: growth of g111oolosa cells in ovarian folide; conttols IIS1rogan formation

Polypeptide Glycopruteils

Testes:

- LH: production of testosterone (Leydig cells] - FSH: production of spermatozoa {Sertoli cals) Nonapeptide

Oxytacin Causes uterine contlllction Breast milk secretion

EtOH

Suckling Dishntion of female genital tract via stretch receptors Sleep Slnlss, hypoglycamica Pregnancy, breast.feeding Midillanstrual cycle Sexual activity

Prollctil Promotes milk production

lrnbits GnRH seCI'IIIion

Polypeptide Episodic sacration

TRH

Drugs: psychD1ropics, antihyparblnsives, dopemina antagonisls, opiates, high dose estrogen

TSH

growth of thyroid and seCI'IIIion of Ta and T, via cAMP

Glycoprotein

Circulating thyroid hormones TRH (T;a. T,) Epileplrile Opiatas, dopamine Prostaglandins

Growth Hormone (GH)

GH DEFICIENCY cause of short stature in children (see Pediatrics, P35) controversial significance in adults GH EXCESS gigantism excess GH secretion before epiphyseal fusion acromegaly excess GH secretion in adults (after epiphyseal fusion)

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

Fiald defect {visuall

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

Toronto Notes 2011

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

Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH)

HYPOGONADOTROPISM Clinical Features hypogonadism, amenorrhea, erectile dysfunction (ED),loss ofbody hair, fine skin, testicular atrophy, failure of pubertal development Treatment Pergonal (combined FSH/LH hormone therapy), hCG, or GnRH analogue if fertility desired symptomatic treatment with estrogen/testosterone HYPERGONADOTROPISM 2 hypersecretion in gonadal failure

Antidiuretic Hormone (ADH)

----------------------------------------

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

Concentrated urine = Cenlnll No llfflct = hphrOIJnic

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

Toronto Notes 2011

Pituitary Gland

Endocrinology E19

SYNDROME OF INAPPROPRIATE ADH SECRETION (SIADH)

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

.....

Important !Wicilncin to I'ICDQnizl n: 1. Adrvnal illlllfficiam:y 2. Hypolhyroidism

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
C.cell

Foilicular cell

\
TG+t+HP,

DIY DIT T,

DIT MIT

V coulllilciV
T,

anzru T,
T,

.......,..,__,

Blood vessel
Colloid

T, -1Jiado11ryronlne; T, -11ryrQD!t (tllnlado11ryrcnn)

DIT- diDdotyrQP!e;

MIT -I!VIdcdotyroP-e;

TG

F"re 8. lbyraid Harmane Synthai1

Toronto Notes 2011

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

Propylthio118cil Methimazole Bet&-blockars Ablll1ion with Radioactiva Iodine Surgical Resection

L-thyroxine (dosing diffaent Uo1hynmine (T3}

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
......

,.----------------. "
.

Tbyraid Al-llllnt
1. Serum thyroid hormones (TSH, T3, 141 2. Antibodies
3. Thyroglobulin 4. Thyroid imaging/SCIIII 5. Biopsy (FNAI

0. ta Pllillt 11M I llainl .IAM41&!15;m:B1l-17 CI!EaldiQIDiilw. baed on af 1111nl pron'inlncl. and pllplbity 111111 1f1nid glirld. MOIIprilwyttlldia cld IIIIIIIJOII 1111speclicsfltf1nid llll1illlion taclllilua. and thftm'lna MiliCI uiiii1D 1qlp0111ll1 111peririy rf: nv one ll1ilhod.

The corrtined cl I slulies dellillhe 1CaJ11CY cl1ba clinii:IIIIXII11i1111ian far 1111 ]Jllllftll of goibe {using RlMid or IUIDpsy u 1111 gold Sllndlnl for complliiGn): SensiiMty 7DI{&rJ..7:11I SpiCilicity aa fiK-115\I UH 3.8 {131o4.5) Ul0.371a331o DAOI The corrtined fl 4lluli81 dlllil1ba pradii:M utilityaf gndas afilymid gllndwuiQI't
6-20Q 21l-4Da

Wlii!!
>40a

.......
1'111111'111

1-2x

Ill+ 0.15 u

IHCI (0.10-11..211

(1.1-lOI

>2x

25.11

(2.t-1751

E22 Endocrinology

Thyroid

Toronto Notes 2011

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

Graves - Thyroid stilllllating lg (TSII

Hashimoto's -Antithyroid peroxidase (TPOI

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

Etiology and Pathophysiology

Tabla 19. Differential Diagnosis of Thyrotoxicosis
Disorder TSH fnla TJTi
Th)'l'llid

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

In classical subacute thyroiditis, ESR incr8118ed

At least 2111 polyostDiic fibrous dysplasia. cafe au lait spots, and autonomous endocrile hyperlunction
Decreased Decreased Iodine induced

Decreased Decreased

Increased Increased

Extralllyruidal Sources of Thynlid Hannane

Toronto Notes 2011

Tabla 19. Differential Diagnosis of Thyrotoxicosis (continued)

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

It' Signs lllld Sympblms of

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

Toronto Notes 2011

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

Subacute Thyroiditis (Thyrotoxic Phase)

Definition
acute inflammatory disorder ofthe thyroid gland characterized by an initial thyrotoxic state followed by hypothyroidism, eventually followed by euthyroidism in most cases two subtypes: painful and painless

Etiology and Pathophysiology

acute inflammation of the thyroid gland characterized by giant cells and lymphocytes disruption of thyroid follicles by inflammatory process results in the release of stored hormone rather than excessive production of new thyroid hormone painful= viral (usually preceded by URTI), De Quervain's (granulomatous thyroiditis) painless= postpartum, auto-immune, lymphocytic occurs in 5-10% of postpartum. mothers and is symptomatic in 1/3 of patients

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

Toronto Notes 2011

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

Toxic Adenoma/Toxic Multinodular Goitre

Etiology and Pathophysiology autonomous thyroid hormone production from a functioning adenoma that is hypersecreting T3 and T4 may be singular (toxic adenoma) or multiple (toxic multinodular goitre [Plummer's disease]) Clinical Features goitre with adenomatous changes tachycardia, heart failure, arrhythmia, weight loss, nervousness, weakness, tremor, and sweats atrial fibrillation is a common presentation in the elderly seen most frequently in elderly people, often with presentation of atrial fibrillation Investigations low TSH, high T 3 and T4 (with a larger increase in T 3) thyroid scan with increased uptake in nodule(s), and suppression of the remainder of the gland Treatment initiate therapy with PTU or MMI to attain euthyroid state in order to avoid radiation thyroiditis, use high dose radioactive iodine to ablate tissue over weeks propranolol often necessary for symptomatic treatment prior to definitive therapy surgery may also be used as 1ot line treatment

Thyrotoxic Crisis/Thyroid Storm

-----------------------

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

Toronto Notes 2011

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

._.No !rill astessed ICIJdbJiscut.l mar111ty or mortillly. SMn lllJcill Mknd

JIIJod ll1d qUIIty cilewilh no llllilticdy liQMiC8111 in'fJANmlri. One sbJdy ftwed I cogritMI fll1ctian. Six llilliasiiiiiUIId 1111111
lpids, 1hlrl - - lor rdlction il1111111 pai'IINtlltS folawing IM!hymxina raplcamant. Some ediocW:Igraphic 11111 lewulllyloxile lepiacement 111111171', l*e III0CIIdill

was 0111 month.

Etiology and Pathophysiology

primary hypothyroidism (90%) inadequate thyroid hormone production secondary to intrinsic thyroid defect iatrogenic: post-ablative (131I or surgical thyroidectomy) autoimmune: Hashimoto's thyroiditis, chronic thyroiditis, idiopathic, burnt out Graves' hypothyroid phase of subacute thyroiditis drugs: goitrogens (iodine), PTU, MMI, lithium infiltrative disease {progressive systemic sclerosis, amyloid) iodine deficiency congenital (114000 births) neoplasia secondary hypothyroidism: pituitary hypothyroidism insufficiency of pituitary TSH tertiary hypothyroidism: hypothalamic hypothyroidism decreased TRH from hypothalamus (rare) peripheral tissue resistance to thyroid hormone (Refetoff syndrome)

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.

Tabla 21. lntarprllbltion of Serum TSH and FraaT4 in Hypothyroidism

S.umTSH

Overt PriDIIlry Hypothyroidism

Subclinical PrilliiiY Hypothyroidism Secondary Hypothyroidism

lncrsased lncrsased Decreased or mrt appropriatay elevated

Decreased Nonnal Decreased

Clinical Features Table 22. Clinical Features of Hypothyroidism

Fatigue, cold intoiBilllce, slowing of mml111d phylical plrio1111111ca, hoarnn888, macroglossia
Sign lllllymptom of HriiDihYraidilllll

Slaw pulse, pericardia! effusion, bradycardia, hypertension. worsening CHF + angina, hypercholesterolemia, hyparhomocyslainamia, myxedema hllllt

HIS FIRM CAP Hypoventilation

lntol1111nc1 to cold Slow HR Fllligue Impotence Renal impairment M111011'11qia/8111111onhu. CIJn51iplllion Anemia

Gl

Weight gain

poor appetite, constipation

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

CONGENITAL HYPOTHYROIDISM see Pediatrics, P30

Toronto Notes 2011

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

decreased free T3 and T4, increased TSH, decreased glucose

check ACTH and cortisol for evidence of adrenal insufficiency

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

Sick Euthyroid Syndrome (SES)

Definition changes in circulating thyroid hormones amongst patients with serious illness, trauma, or stress not due to intrinsic thyroid or pituitary disease

E28 Endocrinology

Thyroid

Toronto Notes 2011

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

Etiology T1ble 23. Etiology af SES

Types of SES
Features

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

Toronto Notes 2011

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

CNS<IIII---------,
Hypothalamus <1111- - ,

... ...

:
:

CRH

11
11H

Pituillry <1111--

Epinephrine

! ;e
:e,- ,
: :

VP

!:
e

:::___:

CD!IIsol

Adrenocortical Hormones
all derived from cholesterol
mineralocorticoids (aldosterone) from zona glomerulosa glucocorticoids (cortisol) from zona fasciculata androgens (DHEA, androstenedione) from zona reticularis

Adrenal gland --'

Figure 9. Regulation of CRH-AC111-Adrenal Gland Axis

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

!
1

0
0

...
17-0H-pregnenolone

G)

6)
0

G)

17-hydroxyl-

..._

3-jl-delrydrtll,jenose
21-hydroxylose 11-hydroxylose

, ...----------------.
GlamuiDu

LIJII'I of the Adrlllll Cortu

"'"_f_,
Aldo&!Brone Minplocorticoids {zDna glumerulua)

16)
Cortilul Glucocorticoids {zDna

. 1
Emdiul

DHEA-S

17-jl-clehydrl)genose
(!)
G) (!}
7
Aroma111e 1S.Irydroxytua

OUTSIDE

*Most common enzyme defect

1
INSIDE

Faciculm produce. c.m.ol

llticuluis produc111 su lltaraids

DihydrotestDSterone

Sex Slllroids {wna micularis)

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

Toronto Notes 2011

1'volume 1' arterial preHure Dopamine Renal Na ratantion

Prostaglandins

StimuiRiion of JGA
Renin (kidney)

Angiotensinogen

l.

llimulation

Inhibition of JGA
ACE (liver)

Angiotensin

11.

Angiotensin

(with negative feedback to inhibit JGA)

Aldostarone n1l1111e ---+Renal Na ratantion, Kexcnllion Arteriolar vasoconstriction Promotion of ADH release
JGA- jwdllglomiWUirr PJIIIralu& All: - angiot.nllil converting nzyme

Figura 11. Ranin-Angiotanlin-Aidostarona Axil, (see NelilirololliJ

Cortisol

Table 24. Physiological Effects of Glucocorticoids

Inhibitory Eflecls Stil!lllate hepatic glucose production (gluconeogenesis) Increase insulin resislalce il peripheral tissues Increase protein calabolism Stil!lllate leukocytosis lymphopenia Increase cardiac output, vascular tone + Na retention Increase PTH release, urine calcium excretion Inhibit bone formation; stimulate bone resorption Inhibit fibroblasts, causing colagen and connective tissue loss Suppress inflammation; illlJiir cell-mediated immunity Inhibit growth hormone axis Inhibit reproductive axis Inhibit vitamin 0:, and imibit calcium uptake

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

Tests of Adrenocortical Function

Table 25. Marbrs of Adrenocortical Function Plasma cortisol
24 hour urinary free cortisol

Serum morning ACTH Serum DHEA-S

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

Toronto Notes 2011

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

------------------------------------

Secondary Hyparaldllllll11111ism [SH]

High aldosterone in response to activation of RAAS Renill1li1Jducing tumour (rare] Renal artery stenosis (renDVBSCUiar hypertension) CHF. cinhosis. neplvutic syndrome Diuraticllaxativa abuse Hartter's syndrome

Diastolic hypert!nsion without edema

Aldostenm81Jroducing adrenal adenoma (Com's syndrome) (75%) Bilateral adrenal hyperplasia (25%) -Idiopathic - Glucocorticoilkemadiable aldosteronism Adrenal carcinoma (1%] Adrenal enzyme defect/deficiency -11fl-HSD type II -11fl-hydroxylil58 -17a-ttydroxylase

Etiology

Common Clinical Felllures

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

1' renin, 1' aldosterone

Aldosterone: renin 0 ngfdl

cr

Tl'llltmllnt

Medical tx for adrenal hyperplasia -Spironolactone, amiloride Surgical ramowl for lldrenal adenoma

Treat undenying cause

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

Thil arms and lags

i ...
::1! Q

li

Clinitalleabns suspicious for hyparcortisolism

Normal

No Cushing's
synchme

24 hall' urilarv free cortiecl

Low clos1 DST to CGIIfirm dillgnoei8

Diatrllllis Df Cushing's
eslllbliNd

AC1ll ilci'88SIId

MRI piluiay, inf1rior pelluPI-.u. sampling with CRF Slinullltion t1ISt

+
I
Measure ACTH

AC1H dacnased

CT adnmal, cdrmatury high-don DST

11 HJ118rcartisollm: Algorithm for Diagalllil

Treatment

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

Toronto Notes 2011

Adrenal Cortex

Endocrinology E33

Congenital Adrenal Hyperplasia

see Pediatrics. P32

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

Famiy history, predisposing ethlic backQround

Premature adrenarche Anabolic steroids, ACTH, androgens, progestational agents

PCOS (see Gvneco!ogv. GY23) Ovarian hyperthecosis

Theca eel tumours
Pregnancy: placental sulfatase/110matase deficiency

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

T- Conditiona that do NOT llep...-.nt True Hir.utiun 1. Androgen-indipllndent hair

(u.g.lllllllllahllirl

2. Drug-induced hyp811richosis (e.g. phenytoin, diazoldde, cyclosporine, minoxidil)

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:

Toronto Notes 2011

Adrenocortical Insufficiency
PRIMARY (ADDISON'S DISEASE)

Etiology Tabla 28. Etiology of Primary Adranocorticallnsufficiancy

AIIIDimiiWII (71J.811%I
Isolated alhnal insufficiency autoirrmune syndrume type I &II TB (7-ZO%IImost common in developing world I Fungal: histoplasmosis, paracoccidioidomycosis HIV;CMV Syphilis African trypanosomiasis Metastatic cancer (lung>stomach>esophagus>colon>breast); inlJhoma Sarcoidosis, amyloidosis, hemochromatosis Bilateral alhnal hemoll'hage Sepsis (meningococcal, Coagulopathy in adults or Waterhouse-Friderichsen syndrome in children Thronto&is, embolism, adranal infarction
Drugs

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

Dark (palmar crease, axtensor surface!

High Low Present
Prinary hypothyroidism, type 1 diabetes, vitiligo,

Pale

I'Diaaium
Sodium Mtllbolic acidosis

Normal Normal or Low

Absent Central hypogonadism or hypothyroidism, growth honnone deficiency, diabetes insipidus. haadachas, visual NO hyperpigmll'llltion NO craving Glless common Low morning plasma ACTH Low 2hour ulfight plasma renin

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

Adaldfnlm: SalmrL R.JWA 21M;294:24812488.

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

Toronto Notes 2011

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

Classic TriM Gf PHbchrDmocytDma Palpitations H81ld11Cha

E36 Endocrinology

Adrenal Medulla

Toronto Notes 2011

Multiple Endocrine Neoplasm (MEN)

----------------------

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

T1ble 38. MEN Clusificltion

Type MENI
MEN 1- W...mBr'l Syndrom1 Affldl 111131'11

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)

Wenn11r'1 SyndromB (P'fGM gena)

Pituitary
l'llllllhyroid l'llncrtlllll

Parathyroid Entero-pmcreatic endocrine

MEN II 3 Distinct Syndl'lllllel

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

1. lla Sipple's SJndromB

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

Toronto Notes 2011

Adrenal MedullaJCalclwn Homeostaaia

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'

Toronto Notes 2011

IN light I

1' Pili I
Bona

1' Osteoclast activity 1' Resorption

.. Rel81lSe of Cl and P04

1
.

Mg [acute)

Cho!aca!ciferol

Kidnay

Ca and Mg reabsorption

+ +--------

25 [DH) vit D(liver]

.
I

Diat

PO,axcrlllon in urine and renal tub!Jar reabsorption

.. Cllcilriol formation

24, 25 [OH,] vit D (inert!

o!PO,

1' Bone
resorption

Bone ostaoclast

1' Gl Ca and P04

absorption

Kidnay Cl and PO, axcration

1' Cland HP04 ra!81lSa

Nat Effect

1' ECF Ca, 1fd D

ECF phosphate

Figura 14. Parathyroid Hormone IPTHI Regulation

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

Paraflrwroid Honnona (Pill)

....

,
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

....

Correctlld Ca {mmoK.) = musurad Ca + 0.02 {40- umln)

}-----------------, 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)

Toronto Notes 2011

Calcium Homeostasis

Endocrinology E39

Increased Ca with Higlt,/Nonnal PTH

EtiDIDtw
Plinary Hyp.puathvraidml (#1 cause of hypercalcemia in outpatienbi) Solitary AdB!Iorna 81% Hyperplasia 15% Carcinoma 4% MEN I and lla Tertiary Hwlerparalllyreidism

......

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

Renal failure Previous renal1nmsplant

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

lx: nonnaVmildly elevated PTH, low urinary Ca. nonnai25-0H Vll D

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.

lx: increased serum Ca wi1h hypocalciuria

.....

,.,J-----------------, ,

Increased Ca with Low PTH

-"Pnt I
1' or

Olfwantill af fiVpan:illcamill 1.1'11mary byparpambyroldlllm 2. MlligMncy: hematologic. humDrll. llblmiiUtHIHIII

norm: phosphlllll
VitO related I

phoiiphate trr to 1- PTHrPI Humollll mediation (lung C.,

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

Hypervilllminosil ll: excessive intab of D or its

1' Critriol

I RCC, pheochromcx:ytomal I
Low Vit DIetabolites

theophylline, villlmin AID intoxication

6. GIWlulomatous disease: sarcoidosis,

1B 7.Thyroid disease: 1hyrotmcicosis B. Adrenal disease: adrenal insufficiency,

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

Figura 15. Differential Diagnosis of Hypercalcemia

Clinical Features symptoms depend on the absolute Ca value and the rate of its rise (may be asymptomatic)

Table 32. Symptoms of Hypercalcemia

Cardiovascul
Hypertension Anhythmia Short QT Deposition of Ca on vfies, coronary artaies, myocardial

Gl
Constipation Anorexia Nausea Vomiting {groans) PUD pancreatitis

Renal

Rhaullllfalogicll

MSK
Weakness Bone pain
(1111111)

Psyclliliric
>3mmoVL (12llllfdi.J

Nauralogic HypD1onia Hyporallaxia Myupalhy Paresis

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)

Witch Out Far: Volume daplation viii diuresis Antlythmills

'

Tha &ymptoms and signs of hypercalcemia induda:

-....... - fl8rehlllliHiuld mans, and abdaminal groans"

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

Toronto Notes 2011

Teble 33. Treatment of Acute Hypercelcemia/Hypercalcemic Crisis

......

,,
300-500 ccJhr) - initial1henpy

Inc:- Urinary C1 Exaati111

Dininilh B1111 Rlurpli111

Isotonic salile (4-5 L) :!: loop diuretic (e.g. furosemide) but

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,

2. C.lcitoni1-1ninsient, pllrtial 18SJ10rlli8

5. same diUI'IIIil + loop diuretic (for volume overload) - temporary

me8SU111

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

EDTA or IV phosphate (rarely used) Oral phosphate in chronic hypercelcamia

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

Differential Diagnosis of Tetany

metabolic alkalosis (with hyperventilation) hypokalemia hypomagnesemia

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

......

,..,

Table 34. Clinical Features of Hypocalcemia

Acullllypocalcellia Delirium Chnmic Hypocalcemia

Sign and Syntplams of Acute

llypot:lllcemla

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

Approach to Hypocalcemia (Figure 16)

l.ls the patient hypocalcemic (correct for albumin)? 2. ls the PTH high or low? 3. IfPTH is high, is phosphate low or normal?

Toronto Notes 2011

Calcium Homeostasis

Endocrinology E41

Decreased Ca with Low P1H

latluganic llypapmthyraid1111 l'ost-lhyroidectomy, 131 I ablation. post surgical correction of prim.-y hyperparathyroidism hypoparathyroidism: DiGeorge syndrame, polyglard!llr' auiDinmune disease (acquired hypopnthyroidism :!: acnnal ilsufficiency :!: gonlldal faillre hyplllhyroidism and rarely hypopituitarism. diabetes ilsipidus, Type I DM) lnfiltnrtiw disiiiiSIIS of parathyroid gland HIV Risk flctors R811111 failu111: low vit Dsynthesis Low dietary Ca Gl malabstrption Bisphosphonate use Approach lx: incl8a&lld Prn, nonnaVdeCI8il$11d serum Ca; renal function (Cr), Vlt ll/Ca sufficiency (25-<lH Vlt D. urin.-y Ca); Gl w/u if high suspicion

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

Decraased Ca with High P1H (Secondary Hyperparathyroidism)

"'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'

HaradiatJy Vii Dresistant type II (receptor defect]

...

Figure 16. Etiology and Clinical Approach to Hypoc:alcamia

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

Toronto Notes 2011

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

Toronto Notes 2011

Metabolic Bone Disease

Endocrinology E43

Metabolic Bone Disease

Osteoporosis
Definition
a condition characterized by decreased bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to bone fracture
ETIOLOGY AND PATHOPHYSIOLOGY
1111 D!CIIc:i.-n or CllcUn il c.llilllilnwilh villnU DSuPIII-IIIIIIilltD PrMrt l'rll:llm - .... 1.111 ill'laplllpd 50 pill IIIII

Lmt:st 2007; 370:&57-66 To dabmnn wllllillr ..,pamentltion

l'lilll tlk:iln II' clllci1111 in c:lriinllion l'lillllftllmil D llduces frlcllns rf: al types 11111 pen:enllge dlange of bn-ll'inml dllllkyfrom basllh. S1udy ln:liln: lllndorriled 1Ms IIIII recruiled JliOPIIIQid 50 yt1111 or oklal.
lllulll: .. trills IIIII JIIIOIIed fllc1ure 15 111 outcoma(171rilll, lnlltmlnt-

,_.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

Nfi.IM11115; 333:1437-43 S1ully: lllndomizld, blinded, pilcaho-CIIIbdld iill 13 f'l!folklw-upl.

poslilllnDJlllllll-(1111111 &4

SLE
ankylosing spondylitis renal disease poor nutrition immobilization

Risk Factors
Table 35. Risk Factors for Osteoporosis

Major Rilk Faclara

Age >65 ye1n Vertebral compression tacture flllgility fracture after age 40 Family history of osblaporotic frllcli.n (especially IMIIImal hip frllctural Propensity to faI (general lraity, poor balance. decreased visual acuityI Osteopenia apparent on x-ray film

Minar Rillk Factln

Smoking

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.

-"""'*

SICOndlrytD Madical Dil Malabsorption syndrome Primary hyperparathyroidism

Drugs Systemic glucocorticoid therapy >3 months duration

Chronic anticonvulsant therapy Chronic haperin therapy

Hannallll Defi:iiiiCY Eariy menopause (before age 451 Hypogonadism

E44 Endocrinology

Metabolic Bone Diseaae

Wall-Occiput Telll: fur Thoracic Fracture

Toronto Notes 2011

......

t-----------------,
....,. ca. ,.... ........
1.l5 arM g
353 mg

..........
2\1,
a--r.bmll

Calcium Contllnt in Co11mon Fooll

a-- Bri:l Oildillt a--CIItlge,.cnmd,

87mg 1.J!i!rMg 1.J!iii1Mg 26!1mg Q!mg 13mg 151 mg 315mg 321lmg

b!MII

Ml-111'\W, 3tlp'45 nt Ml-wlm.2'4 1\liin

1l5g
Milt, ... ...,... llinllilll

.lhcnll

S.n-

Bllll-ccdld Sllines, 11111111115

1/2 1 8111111

Sv,flln-ccdld 1 Ttlu-willllbni!ID
.... lllllllllk

Ill 200 mg llmg 153 mg 1111mg 1J!img 1Jlmg 2Smg 50mg

M-lm

1135g

lliildben-CIIIIIII lasep-b:nlllldl

...

38mg 2JOmg 11111dlllw'l80g 52mg

10

Figura 17. Physical Examinlllion last

163mg llllimg 189mg 111r1.

......

, ...-----------------,

Clinlcll 11.- of FI'ICtlnl or

O.Oporelil

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

6. Ann1J111n-height difference >5 em

(Sp76%l

7. Wall-occiput distanCI >D em

(Sp67%1 8. Rib-pelvis distance S2 fingw lnlldth (Sn68%1

Toronto Notes 2011

Metabolic Bone Disease

Endocrinology E4S

Treatment of Osteoporosis
Tabla 36. Traatmant of Ostaaparosis in Woman and Man

... , ,

Bisphosphonates are considnd

.----------------.

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

first-line treatment in women with ISIIIIblilhed ouoporolis.

Al...nlllltw ... rm.y lllls.:.Hiy

....naplllllw... Ctldrn tJ1111111st S)'rtRill' zooa; l1l:C0001155

Elillllllllt. till prmy IIIII .--., , _ . . lfllllljllrOiic frldlnl in

Ctldrn tJIIIIIIIst S)'rt llw 2lDI;j1):CIXXl3371i.

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

,_..., llllljllrOiic frldlnl in

...........,-.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

,.,_ To ISsesslbe ellic:lt.y r111ne

111d Wll fllr 5'I'll IRcb8 incidlncl lllllction.

Alldlllllll (1 Dn9'd)

1' PnMntioa-Vllfllnl 451'0 RRR,

ARR

Osteomalacia and Rickets

rickets - osteopenia with disordered calcification leading to higher proportion of osteoid
(unmineralized) tissue prior to epiphyseal closure (in childhood) orteomalacla - osteopenia with disordered calcification leading to higher proportion of osteoid (unmineralized) tissue after epiphyseal closure (in adulthood)

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

531'0 RRR, 11 ARR 5!WO RRR,

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

47\ RRR, SOX. ARR ISilvlr)

No benEfit Nablnafit

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

39\ RRR, SOX. ARR 26\ RRR, 11 ARR

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

Toronto Notes 2011

Investigations Table 38. Laboratory Findings in Osteomalacia and Rickets

Dilarder
V"rt Ddeficiency
Hypophosphrtemia

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

Conditions associllllld with abnormal mlllrix formation

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

Toronto Notes 2011

Metabolic Bone Disease

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.

Paget's Disease of Bone

Definition

-----------------------------------

a metabolic disease characterized by c:xcessivt: bone destruction and repair

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

strong familial incidence

Pathophysiology initiated by increased osteoclastic activity leading to increased bone resorption; osteoblastic
activity increases in response to produce new bone that is structurally abnormal and fragile

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

Male Reproductive Endocrinology

Toronto Notes 2011

Male Reproductive Endocrinology

Androgen Regulation
both positive and negative feedback may occur by androgens directly or after conversion to estrogen testosterone (from the Leydig cell) primarily involved in negative feedback on LH, whereas inhlbin (from the Sertoli cell) suppresses FSH secretion

Tests of Testicular Function

Figure 18. Hypothalamo-PituitllryGonadaiAxis
testicular size (lower limit = 4 em x 2.5 em) LH, FSH, testosterone human chorionic gonadotropin (hCG) stimulation test assesses ability of Leydig cell to respond to gonadotropin semen analysis semen volume, sperm count, morphology and motility testicular biopsy indicated in the context of normal FSH and azoospermia/oligospermia

Hypogonadism and Infertility

deficiency in gametogenesis or testosterone production
Etiology

------------------------

causes include primary (testicular failure) and secondary (hypothalamic-pituitary failure) primary hypogonadism is more common than secondary

Table 39. Classification and Features of Hypogonadism

Hype111onldalrapic Hypaao1a.di1111 [Primary llypoganlllismJ Definition

Hypogonldatnlpic Hypaganldilm
[Secandlry

......

..,
in s8flll11 tastoatanma level

1' Ui and FSH.'T' FSH:Ui ratio

testosterone and sperm count
Congenital: Chromosomal defects Noon111] Cryptorchidism Male BiliriEnll anonchia [vanishing testicle syndrome) Myollllic dystrophy Mutation of FSH or LH receptor gene Varicocele Disorden of androgen synthesis Germ cell defects Sertoli cell oriy syndrome Leydig cell apla&iillfailura lnlectiorv' Inflammation On:Mis - lB,Iymphoma, llllmps, leprosy Genol tract infection Physical factcrs Trauma. heal iradiation, testiculartmion Drugs Marijuana. alcohol, chemotherapy, kstocDiliiZOis, glucocorticoid Autoillmlne Oronic systemic diseases [AIDS) Idiopathic

Prilllil'f bsticular faiura

axis failure HH + FSH testosterone and sperm count

Congenol o Kallman's syndrome o Prader-Willi syndrome Abnormal subunit of LH or FSH Infection o meningitis Endocrine Adranel androgen excess Cushing's syndrome o Hypo or hyperthyroidism o disease (tumour, hyperprolactinemia. hypopituitarism] Drugs o Alcohol, marijuane, spironolactone, ketoconazole, GnRH agonists, androgen' estrDgiiiL"progestin use, chronic IWCOtic use Chronic illness o Cilhosis, cllnnic renal faiure, AIDS o Sarcoidosis, Langerhan's cell histiocytosis hemochromatosis Critical illness o Surgery, Ml, head trauma ldiopalhic Sperm count L.H, FSH, 1aslosla'one Prolactin levels MRI of

Two Diltinct FKtures af Primary

Hypagonadilm 1. The decreese in spann count is affecll!d to a greater extent 1han 1he

2. Lila!ly to be associated with

gynai:OIII8Iilia

......

..

Two Feltunle of SecondeJy

Hypogonadism 1. A5saciated wi1h an equivalent in 1perm count and l8fUI11 2. Len lilaJiyto ba aAOCilltad wilh gynecomastia

bstostJrona

Diagnosis

Sperm count LH, FSH, tastostarone hCG atimulation Testicular size and consistency (soft/firmI Karyotype

region

Toronto Notes 2011

Male Reproductive Endocrinology

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

Partner 1tatus re: infertility

l'r8v Surg, Med Hx, S1D Hx Hx orchitis? Cryptorchidism? Hxtwlic axpo1111re?

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?

Pilllitary disease? Thyroid disea111?

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

varicocele} Bloodwork: 111. FSH. Tem5terone,

Prolactin, TFTs, DNA fng!MntBtion of &penn. Karyotype. Y chrornolome deletion
TNitllllnt No specific therapy for majority of
CUS&

Trut splcific causn

Consider: intrauterine insemination, IVF, lhnpautic donor insemination, testicular aspiration of sperm, adoption

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

Male Reproductive Endocrinology

Toronto Notes 2011

....

,,.}-----------------, ,
60-90
24-65

Gynecomastia
Definition
true gynecomastia refers to benign proliferation of the glandular component of the male breast,

Epldmialagy of

Oocmen1111 Ill Gv-amatill

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

Gellric Dlug Nn Canida._

me1lomii

o.q
!iOO rrv DD1ilriiBd1D 11Dl rrv lid II'IXi1111111

lldiCIIilnl

Cmid:alials

Side Ellecll Gl upset (abda ciacllrnfllf,

Lactic acidosis Ancnxia

C11111menl!

Bipnide

Glunm'

ln'fiU'Ias both futiv 1111 pJ5Ipmllil Madnla 1o IIMir&livelllysflmian

Also..Vm MDdenle dyslunclill ABSOWlE: MDdenle 1o SIMire live! dysflmian RB.ATM: Ad;.t a. in patiBots with dysflllctian (and awid glyburile in these patieatsl Avoid gly!uide il the INTERACnDNS: Do nat combine Mil anon-dcnyUrea 01 prep131dal insulin ABSOWlE: Sewn liver dysfunclill SevnTnl dy!functar INTERACnDNS: Da nat combine Mil anon-dcnyUrea 01 preprlldal insulin ABSOWlE: Sevin In dysfunclill NYIIA > dass II CHF INTERACnDNS: Do nat combine Mil iniUiil ABSOWTE: Wlammi!Dry bowel disease Sevin In dysfuncta. ABSDUJTE: Type 111A llA RB.ATM: Adjist cae in petienls with kDiey dysflmian

U..U in obae Type 2

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

flicrallase1 Glynase PreTab1

2.5-5.0 nWtlay titmed tll>5mgbid

Weiglitgain

Mu:ZOnWtiay

gichuide

40-1&Drrvbid lJ.120 lTV OD

gimelliile non-sulfllrlmu: repaglinide I'DIIIinide

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

..V HbA1C 1.0-1.5% IDr and O.S-1.!/Iifor

lnsuli sensitizln (thillalidinedilnel

Sensitizes periphefal1issues 1D inluin

-+ incraiSBI

rusigillillne

2-llmgOD 15-45 rrv DO

uplllb

Decreases ffl\ n!lease from adjme BindsiDnudlereceptor

piagillmne

Fracw
limhea

Pulrm111ryBdena CHF Anemia Weiglitgain

agUosidase ntibilor

..V carlJa!TflhteGI abllllption by

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

25mg0Dtitratad tll100mgtid 100 mg OD

.,j, pasljnndilllrjperglymia

Flalulelk:e Abdoniral1211!1l'l
Nasopha!y!VJitiS

..VIIlA1CO.S-1.D'Xo

I
J
e1 ...

silagiptan

JIJUiia'

..V HbA1C 0.5-1.D'Xo

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.

G.ric inl Nln

USNnGf-..1111

a1DMsta1iJ f'IMslltin IIMISI!tin prmstllin

fOSIMSIIIil

MMcor'

Prtvachal'

finlas

UpreguliD[!Iop!UIBin lipa111 +ApoA1.

modest t HDL Nile in

.V VUII..HG, rrlllled

sirMsta1in baibllll fadibrate gemfilllozil

nicatilicacid

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

' Active Mr diiiiiiB P!11isbn h ML ALT

prurinls tlivelmzymes
l'lillltintas)

Used for t TG. hyperchyi:Knamia

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

0.5-lfday 1-3 glday

Used for 1'

1' VUJL

Hepatic dysfurctiorr Active P\JD Overt DM

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

2-24 Wday 5-30 ll'dar 10mWday

Used for tlJJL Use as adjunct with slllins orfilntes Used for 1' B

Compllla lillry Dllslnl:liln Pl!gnancy, lactation TG>:Dll111tdl Girdilydillllle!

lf\1leBensiMty

CCIIstiJD:In Nau
Ra1ulellce

Cholesterolllbsorptiorr mililol$

ld

Hepatic dysfurctiorr Donlmbinel'lilbfiln111s cr bile acichtsils

Ph.,..

i
i
8

SiJ.Jilis Abdomilllll pail Diant. ArdntJja

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

Also intern with CCIMniDnli

T41oTl

than adjuslacCOidiljf Thyroid sbrm: sblrt 200ll0 PO qid, then adjusl

S1mt 520 11'41 PO OD, than adjuslacCO!d'Dif 0.05-2.01111tday. ilet:lerlypMis sblrt It 0.1125 mWdar

Hypenmitivity Rellli8: liJ'IIIIiliUa, Mr disease

SiiiiEII'actl Nuea.wmilirG !lash , !Wg-im:ed hepds AwallhyiDsis

methimllmle !MMI) IIMIIIr,Toxine 14hyale Syulhroid' levollroid1

levalyl.

Pregnancy, lacll1iDn

lle!Jetitis
Symptams oflrypartlr,U:iillll

Tlryroidllmlne

'Hypotbyroilsm

Recall

thymtaxi:Diis

tMiltnil'

Angine
lfype!lhennia

llanbea

lnsonliia TralllDTS Muscle Wlllness

... ...

Metabolic Bone Disease Medications

in1CIIill
llidlllilm" Aciln

&enalc lftg

CllllllNne

us Nln llllflnll

o.q
5-10q00 70 40 OD fur 6nmlls

Bisphasplnlas

Wiibits asl8ocllsl mediated bona morpliCII

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

Sidellln GI MSKpain Headache

Osmieaasisofthej&W

J
... ...
C)

TiseDal8

AclonePI

5mgOD 35 mgooceW&Bklt 150 q CIICe :11 mwODfur2 nm11s 5-10 q/lg0Dx611Dl!hs

etilranate

DidranePI

illmlnma1e
pamidronale

Aralia'

2.5 mg 00 or ISO q rn:e IV

ZDielarlle

Zornell' AciiiSII1

5mg IV once yeq

IV

llec:e!D

Salec:live Eflragan

Dacreues rasorplirl ci hone lhrough binding 1D es1nQ!n receplln

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

Wiibits asl8ocllsl mediated hone morpliCII

&Umin

t.lalc:in'

Ona ifRY 1200 lJ) par day, allnlting

T_.lipomanopauiil asllqlorulil, tlln 5years

]XIStmempiiiSe

Clini!;lllallergy ID

I'IH

oStii1JIIIesnewbone fonnation by plifarantia stindation at DIIBoblastic activityiMI'osll!oclastic activity

1a'pralide

Fno'

201111SCOD X1824 months

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

Metabolic Bone Disease Medications (continued)

lkugCI&II
Calcium Mechlnilm of Action Inhibits P1H secretion

Generic D11111 Nme

CIIIIIIIName

US Name flf dffnnt)

Doling 1500 IIIWdav {including diet) Divide il3 doses

Indications

CIIIIIRildicati Caution renal stones

SideEfhc:a
Vomiting Constipation Dry mouth Hypercalcemia Headache Nausaa, vomiting Constipation

Dsteopenia
Osteoporosis Prevention Ill melllbolic bone disease

VrtaminD

Regulation Ill calciLIIl and phosphata homaostasis

cholecaldfercl {vitaminll3) argocalcnerol {vitaminll2) Ostaoforte'

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

Osteoporosis in patients with liver

dyslunction. reh'aelllry ricksts, hypopnthyroidism

cak:itriol {1,25{0H}z-D)

Rocllltrol1 Calcijex'

SWt 0.251!Wday Trlnlt8 up by 0.25 I!Wdey at 4-8 week intervals to

0.5-1 I!Wday

Hypocalcemia and ostaodyslrophy in patient8 with chronic renal failure

ondiaysis

SWt 0.251!Wday Trtrate up by 0.251!Wdey at 2-4 week intervals to 0.5-2 I!Wday

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)

Cortisone aceblle Prednisone Dexamathasone

Yes
No No

Cortone Acetate

0.8
3.5

25 6 0.7

oral= 8 IM=18+ 16-36 36-54

Deltasane LicJiid Pr8d

Decadron AK-Dex Dexone

30

Adrenal Crisis: 4 mg IV; repeat q2-6 hr necessary

r
... ...

Toronto Notes 2011

Landmark Endocrinology Trials

Endocrinology E55

Landmark Endocrinology Trials

Trill
lllfii'IIICI

DIABETES
DCCT
UICPOS EDIC

NEJM 1993; 329:977-86

I.JJncst , 998; 352:837-53

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

NEJM ZOOS; 353:2644-53 NEJM 2008; 358:2560-72 NEJM 2008; 358:2545-59

ACCORD

ADVANCE

VADT

NEJM 2009; 360:1 11

BARI-20

NEJM 2009; 360:2503-1 5

Steno-2

NEJM 2008; 358:580-91

NAVIGATOR NEJM 2010; 362:1

LIPIDS

4S
HPS TNT FIELD

Lancet 1994; 344:1383-89

Lancet 2002; 360:7-22

NEJM 2005; 352:1425-35

lancet 2005; 366:1849-61

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

Toronto Notes 2011

References
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