Endocrinology Toronto Notes 2023 PDF

E2 Endocrinology Toronto Notes 2023 Acronyms A1c AAA Ab ABCA1 ACEI ACR ADH AG ApoA1 ApoB ApoC 2 ApoE4 ARB ARR AVP BG BMD CAH CHO CK CKD CMV CNS CrCI CVD DDAVP hemoglobin Ate abdominal aortic aneurysm antibodies ATP-binding cassette transporter A1 angiotensin converting enzyme inhibitor albumin- crea...

E2 Endocrinology Toronto Notes 2023 Acronyms A1c AAA Ab ABCA1 ACEI ACR ADH AG ApoA1 ApoB ApoC 2 ApoE4 ARB ARR AVP BG BMD CAH CHO CK CKD CMV CNS CrCI CVD DDAVP hemoglobin Ate abdominal aortic aneurysm antibodies ATP-binding cassette transporter A1 angiotensin converting enzyme inhibitor albumin- creatinine ratio antidiuretic hormone anion gap alipoprotein A1 apolipoprotein B alipoprotein C2 alipoprotein E4 angiotensin receptor blockers absolute risk reduction arginine vasopressin blood glucose bone mineral density congenital adrenal hyperplasia carbohydrates creatine kinase chronic kidney disease cytomegalovirus central nervous system creatinine clearance cardiovascular disease desmopressin (1- deamino 8 - D-arginine vasopressin) dehydroepiandrosterone diabetes insipidus diabetic ketoacidosis dexamethasone deep vein thrombosis extracellular fluid extracellular fluid volume free fatty acids fine needle aspiration fasting plasma glucose glomerular filtration rate growth hormone releasing hormone GLP-1 glucagon- like peptidel GnRH gonadotropin releasing hormone Hb hemoglobin human chorionic gonadotropin hCG high density lipoprotein HDL hyperosmolar hyperglycemic HHS state human leukocyte antigen HLA HMG -CoA 3 -hydroxy- 3 -methylglutaryl coenzyme A hypothalamic pituitary adrenal HPA Hs-CRP highly -sensitive C-reactive protein homovanillic acid HVA ICF intracellular fluid DHEA Dl DKA OXM DVT ECF ECFV FFA FNA FPG GFR GHRH - IDL IFG IGF 2 IGT JGA LCAT LDL LDL- C LDL-R LP LP(a) LPL MEN MMI MTC NS OGTT PA PAD PCOS PCSK9 POMC PRL PTH PTHrP intermediate density lipoprotein PTU impaired fasting glucose RAAS insulin-like growth factor 2 impaired glucose tolerance RAI RAIU juxtaglomerular apparatus lecithin-cholesterol RANKL acyltransferase RH low density lipoprotein low density lipoproteinRRR SA cholesterol low density lipoprotein receptor SGLT2i lipoprotein inhibitor SHBG lipoprotein (a) lipoprotein lipase T3 multiple endocrine neoplasia T4 TBG methimazole medullary thyroid cancer TC TG normal saline TgAb oral glucose tolerance test primary aldosteronism TPOAb peripheral arterial disease polycystic ovary syndrome TRAb Proprotein convertase subtilisin/ TSI kexin type 9 pro- opiomelanocorticotropin VIDl prolactin VMA WC parathyroid hormone parathyroid hormone-related protein propylthiouracil renin-angiotensin- aldosterone system radioactive iodine radioactive iodine uptake receptor activator of nuclear releasing hormone factor- xB ligand relative risk reduction secondary aldosteronism sodium/glucose cotransporter-2 - sex hormone binding globulin triiodothyronine thyroxine thyroid- binding globulin total cholesterol triglycerides thyroglobulin antibodies anti -thyroid peroxidase antibodies TSH receptor antibodies thyroid stimulating immunoglobulin very low density lipoprotein vanillylmandelic acid waist circumference Basic Anatomy Review Major Endocrine Organs HYPOTHALAMUS Corticotropin- RH ICRHI Gonadotropin-RH ( GnRH ) Thyrotropin- RH ( TRH ) Growth hormone -RH (GHRH) Antidiuretic hormone ( ADH)* Oxytocin* THYROID GLAND Triiodothyronine (T3I Thyroxine (T4) PITUITARY GLAND Anterior pituitary Growth hormone ( GHI Prolactin ( PRL) Thyroid- stimulating hormone (TSH) Luteinizing hormone ILH) Follicle- stimulating hormone ( FSH) Adrenocorticotropic hormone ( ACTH) Posterior pituitary Antidiuretic hormone ( ADH)* Oxytocin* ADRENALGLAND Cortex Aldosterone Cortisol Androgens Medulla Catecholamines TESTES Testosterone ’ADH and oxytocin are produced in the hypothalamus and stored in the posterior pituitary gland PARATHYROID GLANDS Parathyroid hormone ( PTH ) PANCREAS Insulin Glucagon Somatostatin OVARIES Estrogen Progesterone © Stefania Spano 2012 Figure 1. Endocrine system + Activate Windows Go to Settings to activate Windo E3 Endocrinology Toronto Notes 2023 Dyslipidemias Definition metabolic disorders characterized by elevations of fasting plasma LDL- C and/ or TG, and/ or low HDLcholesterol Overview of Lipid Transport lipoproteins are spherical complexes that consist of a lipid core surrounded by a shell of water-soluble cholesterol , apolipoproteins, and phospholipids lipoproteins transport lipids within the body apolipoproteins serve as enzyme cofactors , promote clearance of the particle by interacting with cellular receptors, and stabilize the lipoprotein micelle Table 1. Lipoproteins Lipoprotein Function Chylomicron Transports dietary TG from gut loadipose tissue and muscle VIOL Transports hepatic synthesized TG from liver to adipose tissue and muscle IDL Product of hydrolysis of TG in VLDLby lipoproteinlipase resulting in depletion of TG core Enriched in cholesterol esters LDL Cholesterol rich atherogenic particles Formed by further removal of residual TG from I0L core by hepatic lipase HDL Transports cholesterol from peripheral tissues to liver Acts as a reservoir for apolipoproteins EXOGENOUS PATHWAY CW ENDOGENOUS PATHWAY CM = Dietary TGs Cholesterol Cholesterol absorption [ inhibitors h I HMG-CoA - — N Dietary cholesterol W LIVER B - 100 Endogenous cholesterol % - apoE \ f - TG E I \ _ f ^ ^ ^ N ^ LP Lipase* degradesTG I Hepatic Lipase C- ll ^^ ^ - 48 E ,, , ** * TRemnant Free Fatty Acids i Adipose Tissue and Muscle Fibrate I LPLipase* 4 degrades TG Figure 2. Exogenous and endogenous biosynthetic lipid pathways Primary Dyslipidemias (rare) — B-IDO B -1! E T'DL jVLDL EXTRAHEPATIC TISSUES Cholesterol = a MACROPHAGE | + * I I i Adipose Tissue and Muscle I @ EARLY ATHEROSCLEROSIS AI^AII HDL PLASMA ^ Free Fatty Acids m FOAM CELL I TOLIVER l B BCAPILLARY BB B BCAPILLARY BB Fibrate I -I- I.1 Endocytosis through Remnant Receptor B-48 Chylomicron 1 * Statin Statin JU Niacin C-ll subendothelial space of arterial bloodvessels Endocytosis through LDL Receptor A A Acetyl- CoA Bile acid | sequestrants (resins) ~ X "T 1 SMALL BOWELv 3 Oxidized LDLoccurs in Bile Acids Dietary LCAT IIDL gives phospholipids and TG to HDLand receives cholesterol esters from HDL) ICholesterol Triglyceride - * LP Lipase requires activation by Apo C ll Definition caused by a genetic defect in lipid metabolism LJ + Activate Windows Go to Settings to activate Wii El Endocrinology Toronto Notes 2023 Table 2. Primary Dyslipidemias Condition Main Lab Abnormality Mechanism Familial Hypercholesterolemia t Total cholesterol Familial Combined Hyperlipidemia Polygenic Familial Hypercholesterolemia Hereditary Chylomicronemia Familial lipoprotein lipase deficiency (e.g. Familial Hypertriglyceridemia /type IV familial dyslipidemia) ApoC2 deficiency » LOL cholesterol t ApoB t TGs. Clinical Features.. Treatment Genetic defect in LDLR (most common) PCSK 9 orApoB An autosomal dominant condition that can be homorygous or heterozygous Impacts liver 's ability lo clear LDL from the circulation Tendinous xanthomatosis ( achilles patellar and extensor tendons of hand ) Arcus cornealis Xanthelasmata Heterozygotes: premature CAD 50% risk of Ml in men by age 30 Homocygotes: manifest CAD and other vascular disease early in childhood which can be fatal (in < 20 y/o) Maximally tolerated Stalin as initial drug therapy, addition of second drug leietimibe and / or PCSK 9 inhibitor) as second line, third line for homocygotes is portacaval shunt or LDL aplieresis: potential liver transplant Refer to lipid specialist in drug-resistant hypercholesterolemia Increased production of ApoB -100 containing lipoproteins from the liver Premature coronary heart disease, xanthelasma, and obesity Statins as initial drug therapy Addition of ecetimibe and/or PCSK 9 inhibitor if LDLIowering is not achieved. May consider fib rate if elevated TG.. t LDL t LDL Mild defects in multiple genes responsible for IDLmelabolism: LDL- R. ApoB ApoE 4 Higher risk of cardiovascular disease similar Statins as first line to familial hypercholesterolemia for patients Use ecetimibe, bile acid sequeslranls PCSK 9 older than 40 inhibitor, or nicotinic acid as alternatives (if not tolerated ) or in addition t TG from excess Lipoprotein lipase deficiency: prevents proper digestion and storage of fats leading to massive accumulation of triglyceride rich chylomicron particles ApoCz deficiency: prevents activation of lipoprotein lipase leading to massive accumulation of triglyceride rich chylomicron particles Presents at infancy (LPL), adolescence to adulthood ( ApoCr) Abdominal complaints (pain, hepatosplenomegaly pancreatitis) Lipemia retinalis Eruptive xanthomata <. chylomicron particles.. 10-15% of calories from fat Supplement with essential fatty acids, fat soluble vitamins Plasmapheresis may help individuals with ApoCx mutation Familial Hypoalphalipoproteinemia * HDL cholesterol Autosomal dominant inheritance of a mutation in the A 8 CA1or the ApoAr gene Premature atherosclerosis Cerebrovascular disease Reduce the risk of atherosclerosis with lifestyle changes, management of concomitant hypercholesterolemia, hypertriglyceridemia, and metabolic syndrome if present Tangier Disease * HDLcholesterol Autosomal recessive inheritance of mutations in the ABCA1 gene Impaired HDL-mediated cholesterol efflux from macrophages and impaired intracellular lipid trafficking Mild hypertriglyceridemia Neuropathy Enlarged, orange- coloured tonsils Premature atherosclerosis Splenomegaly Hepatomegaly Corneal clouding T 2DM Reduce the risk of atherosclerosis with lifestyle changes, management of concomitant hypercholesterolemia, hypertriglyceridemia, and metabolic syndrome if present Secondary Dyslipidemias Definition caused by acquired medical conditions or lifestyle factors that affect lipid metabolism Table 3. Etiology of Secondary Dyslipidemias Hypercholesterolemia Low HDL Hypertriglyceridemia Endocrine: hypothyroidism (small dense LDL with T 2DM and obesity, with normal LDL level) Endocrine: obesity/metabolic syndrome. DM Endocrine: obesity/metabolic syndrome, DM Drugs: p -blockers. anabolic steroids Renal: nephrotic syndrome, CKD Other: acute infections, inflammatory conditions Immunologic: monoclonal gammopalhy Hepatic: cholestatic liver disease ( e.g. primary biliary cirrhosis) Nutritional: anorexia nervosa Drugs: cyclosporin , carbamazepine, steroids Lifestyle: smoking, obesity Renal: nephrotic syndrome. CKD Drugs: corticosteroids, estrogen, hydrochlorothiazide, retinoic acid, P-blockers without intrinsic sympathomimetic action (ISA) , anti- retroviral drugs, atypical antipsychotics, oral contraceptive pills Lifestyle: alcohol, high carbohydrate /high fat diet Other: pregnancy Dyslipidemia and the Risk for Coronary Artery Disease increased LDL is a major risk factor for atherosclerosis and CAD increased HDL is associated with decreased CVD and mortality moderate hypertriglyceridemia (triglyceride level 2.3-9 mmol/ L ) is an independent risk factor for CAD, especially in people with DM and in post - menopausal women Screening Familial Hypercholesterolemia and Cardiovascular Risk Calculators Risk calculators such as Framingham and SCORE do not apply to patients with familial hypercholesterolemia Consider all adults with familial hypercholesterolemia as “high-risk" Treatment Effect Each 1.0 mmol/ L decrease in LDL corresponds to approximately 20-25% relative risk reduction in cardiovascular disease Statins lower LDL by about 30-40% Ezetimibe lowers LDL by about 18% PCSK9 inhibitors lowers LDL by about 50% 6% Rule If the dose of a statin is doubled, there is approximately a 6% increase in the LDL lowering efficacy rn L J screen men and women > 40 yr or post -menopausal women if the following risk factors are present, screen at any age: DM + current cigarette smoking or COPD H 'l N ( sBP >140, dBP >90 ), hypertensive diseases of pregnancy obesity ( BM 1 > 30 kg / m ) ' Activate Windows Go to Settings to activate Windows. E5 Endocrinology Toronto Notes 2023 family history of premature CVD or dyslipidemia clinical signs of hyperlipidemia ( xanthelasma , xanthoma, arcus cornealis) clinical or radiological evidence of AAA clinical evidence of atherosclerosis inflammatory disease ( rheumatoid arthritis, SLE , psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disease) HIV infection on highly active antiretroviral therapy ( HAART ) CKD (estimated GPR < 60 mL / min /1.73 m -) erectile dysfunction high - risk ethnicity: South Asian , Indigenous peoples screen children with a family history of hypercholesterolemia or chylomicronemia components of screening: history and physical examination , lipid panel ( total cholesterol, LDL C, HDL cholesterol, TG ), - For Statin Follow Up Liver enzymes and lipid profile: liver enzymes measured at the beginning of treatment, then once after therapy initiated. Lipids (once stabilized) measured annually. Order both if patient complains of jaundice, right upper quadrant pain, dark urine CK at baseline and if patient complains of myalgia Discontinue statin if CK >10x upper limit of normal or patient has persistent myalgia 1 - - non-HOL cholesterol, B( > , eGFR optional: urine ACR, ApoB 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 I.p( a ) levels may help stratify those at intermediate risk , but is not recommended for routine measurement (only measured once in a patient's lifetime ) coronary artery calcium (CAC ) may help stratify those at intermediate risk CRP levels highly sensitive acute phase reactant ( non -specific) may be clinically useful to identify those at a higher risk of CVD than predicted by the global risk assessment CVD Risk Assessment Framingham Risk Score ( IRS): I 0 yr risk of major CVD event. Calculated based on gender, age, total cholesterol, HDL - cholesterol, sBRand smoking ( >20%: high - risk; 10 - 19%: moderate risk ; < 10%: low risk ) Reynolds Risk Score: 10 yr risk of major CVD event. Calculated based on age, sBP, total cholesterol, HDL- cholesterol, high sensitivity CRP, family history of Ml - Treatment of Dyslipidemias Approach to Treatment Primary Prevention Low - Risk Intermediate - Risk High- Risk FRS < 10% FRS 10- 19 9% and LDL C> 3 5 mmol/ L or Non HDL C >$ 2 mmol/ L or ApoB > 1.2 g/ Lor Mon>50 and women > 60 with one additional risk factor low HDL C IFCThigh WC. smoker. HTN or with presence of other risk modifiers: hsCRP > 2.0 mg/ L, CAC > 0 AU. family history of premature CAD , Lp ( a) > 50 mg/ dL (100 nmol/L) FRS >20% _ , i H Discuss hoalth behavioural modifications 4 Monitor. - - See Landmark Endocrinology Trials far more informal!on on the JUPITER trial. It details the effects of statm treatment on cardiovascular events m patients with elevated high -sensitivity CRP levels. ^. ^ ?VS,>m2oli/n,utLn?[, ,f 52,80f SiMindcS» ^ HDL YES YES Discuss add - on therapy with patient: Evaluate reduction in CVD risk vs. cost/access and side effects r ~i "- J / NO Rosponsoto statin Rx Response to add on lipid lowering Rx Health behaviour changes - Initiate Statin Treatment nun -* - _ NO Honllh Behaviour Modifications: Smoking cessation Diet : it is recommended all individuals adopt a healthy dietary pattern Exercise : itisrecommended adults accumulate at least 150 mirx/ wk of moderate vigorous intensity aerobic physical activity -. — Statin thorapy not recommondod for most low risk individuals, oxcoptions includo: a. LDL C >5.0 mmol/L lor ApoB >J 45 g /L or non HDL C >4 2 mmol/ L) or b. FRS is 5 9.9% with LDL C >3.5 mmol/ L (or non HDL C > 4.2 mmol/ Lor ApoB >J.05 g /L), particularly with other C V risk modifiers le. g. FHx , Lpla ) 50 mg/ dL |or 100 nmol/ U or CAC >0 AU ) as the proportional benefitfrom statin therapy may be similar to other treated groups 2021 Canadian Cardiovascular Society Guidelines on the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult Can J Cardiol 2021:S0828 282X ( 21)00165 3 Patients with clinical atherosclerosis AAA, LDL C £5.0 mmoLL , and most with diabetes or CKD should be started on statin therapy Lipid/ llpoprotein screening Is recommended in patients >40 yr or at any age for those at increased risk Non- HOL cholesterol or Apo8 are preferred to LDL-C as lipid parameters for screening in patients with TG >1.5 mmol/L LP(a ) should be measured once in a person's lifetime as part of initial lipkl screening to assess cardiovascular risk Lipid -lowering therapy should be intensified with ezetimibe and/or PCSK9 inhibitors in patients with LDL C remaining >1.8 mmol / L (or non HDL cholesterol >2.4 mmol /L or ApoB 20.7 g/l) on a maximally tolerated statin dose YES ADD ON Ezotiinibo as 1st line (BAS as alternative ) + Figure 3a. Treatment approach for primary prevention patients (without a statin indicated conditiont) Adapted from 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult Canadian Cardiovascular Society.. Activate Windows Goto Settingsto activate Windows, E6 Endocrinology Toronto Notes 2023 I Statin Indicated Conditions _ Most potients with diabotos: Ago £t0 Ago >30 & 0Mx> 15 yrdurotion Microvasculor disoasu LDL > 5.0 mmol/ L orApoB >1.4Sg/Loi non - HDL C i 5.8 mmol/L Familial hypoicholostorolomio or gonotic dyslipidomio _ Most patients with diabotos: >50 and oG FR 3 mg/mmol Ago Atherosclerotic Cardiovascular Disoaso: Myocardial infarction, ocuto coronary syndromos Stable angina, documented coronary artery disoaso by ongiography Stroke, TIA, document carotid disoaso Peripheral arterial disease, claudication and/or ABI 3.0 cm or previous aneurysm surgery Rcvicw/Discuss health behavioural modifications I Initiate Statin Treatment If LDL- C £.5 mmol/ L (or < 50% reduction) orApoB 20.85 g / Lor non HDL C 23 2 mmol/L NO J ft If LO L C. 2 0 mmol/L or ApoB >^ 0.80 g/Lor non HDL C 2.6 mmol/ L on ^ statin dose maximally tolerated YES YES Discuss add - on therapy with patient Evaluoto reduction in CVD risk vs. cost/access and sido offocts ADD ON E / otimibo or PCSK 9 inhibitor u. If LDLC >J.8 mmol/ Lor ApoB 21.70 g/L or non H DLC >2.4 mmol /Lon maximally tolerated statin dose YES Discuss intensification of therapy with patient ADD ON i Ezotimibcas 1st lino IBAS as alternative add onto othor diugs ) INTENSIFICATION Refer to Figure Treatment Intensification Approach foi Potients with ASCVO Monitor t Rosponso to statin Rx Response to add on liprd lowering Rx * Health behaviour modifications un NO Figure 3b. Treatment approach for patients with a statin indicated condition Adopted horn 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipldemia lor the Prevention of Cardiovascular Disease in the Adult. Canadian Cardiovascular Society. I Patients with Atherosclerotic Cardiovascular Disease If LDLC >1.8 mmol/ Lor ApoB.2).70 g /Lor if non HDL C >2.4 mmol/ L LDL C 1.8 2.2 mmol/ Lor ApoB 0.70 0.80 g/ Lor non HD L C 2.4 2.9 mmol/ L LDLC > 2.2 mmol/ Lor ApoB >0.80 g/ L or non HDL C > 2.9 mmol /Lor high PCSK 9i benefit patient Consider Consider PCSK 9 inhibitor ezotnmbo EzotimiboiPCSK9 inhibitor If TG >1.5 to 5.6 mmol/ L A Consider Icosapent ethyl 2000 mg BID Figure 3c. Treatment intensification approach for patients with atherosclerotic cardiovascular disease (ASCVD) Adapted horn 2021 Canadian Cardiovascular Society Guidelines lor the Management of Dyslipldemia lor the Prevention ol Cardiovascular Olscose In the Adult Canadian Cardiovascular Society.. ri LJ + Activate Windows Go to Settings to activate Wind 1 1.. ' E7 Endocrinology Toronto Notes 2023 Disorders of Glucose Metabolism Overview of Glucose Regulation s \ gi lls of the pancreas stimulated to roloaso insulininto the blood S Insulin stream ( Body colls take up more glucose / A - Liver takes up excess glucose and stones it as glycogen Increase in blood glucose levels Blood Glucose Level Decrease in blood glucoso levels Liver breaks down glycogen stores and Reduction of Cardiovascular Events with Icosapent Ethyl Intervention Trill - REDUCE IT - HLIU 2019;580:11 22 Study Mjtticenter nnUonned, double -blind, bacebo co tio led trial with S yr ot follow - up. Population: 81)9 patients with established CUD or with diabetes and other risk lac tors, who hadbeen relenting statin therapy arid who had a fasting ID revet of 135 - 459 ragfdLard a LDL level of 41-100 mgidL Intervention: Randomly assigned to receive 2 gof icosapent ethyl BID or placebo. Primary Outcome: Composite ol cardiovascular death, nonlatal HI. nonlatal stroke, coronary revascolariiation or unstable angina. Desalts 4 pnmatyendpoint event occurred in t).2% ot the patients in the icosapent ethyl groupiom pared to 22\ of the patients In the placebo group (HR 0.7 S. 95% Ct 0.68-0.83, P 0.001). The rates of additional ‘ ischemic eod points were significantly lower in the icosapent ethyl groupthan in the place hogroup. induing the rate of cardiovascular death.A larger percentage of patients in the icosapent ethyl group than in the place bn group ware hospitaliied for atrial fibrii’ation or flutter (P* 0.004|and serious bleeding occur led in 2.1% of the patients in the icosapent ethyl group as compared to 2.1% in the placebo group (P 0.06) Conclusions Among patients with elevated 16 levels despite statin therapy, the risk of cardiovascular events wassigrufrcanlly lower in the group who received 2 gof icosapent ethyl BIO compared to those whoreceived placebo. See trralfor more details, outlining spec die emb oi nts -. - rclcascsglucosc into the blood Glucagon stimulated to release glucagon into the blood a culls - Figure 4. Blood glucose regulation Pre- Diabetes ( Impaired Glucose Tolerance/Impaired Fasting Glucose) and results. 1-5% per yr go on to develop DM 50 -80% revert to normal glucose tolerance weight loss may improve glucose tolerance (5 10% of body weight ) - increased risk of developing niacrovascular complications lifestyle modifications decrease progression to DM by 58% Diagnostic Criteria (Diabetes Canada 2018 Guidelines) (any of the following) ll - G: I PG 6.1-6.9 mmol / L 1GT: 2 h 75 g OGTT 7.8-11.0 mmol / L Ale: 6.0- 6.4% Diabetes Mellitus Definition DM is a heterogeneous metabolic disorder characterized by the presence of hyperglycemia chronic hyperglycemia of diabetes is associated with relatively specific long term microvascular complications affecting the eyes, kidneys, and nerves, as well as an increased risk for macrovascular complications such as CVD, stroke, and peripheral vascular disease. Diabetes also increases the risk of - See Landmark Endocrinology Trials foe more information on the 4 T trial It details the efficacy of complex insulin regimen for patients with T 2DM.. heart failure Diagnostic Criteria (as per Diabetes Canada 2018 Clinical Practice Guidelines) any one of the following is diagnostic: Table 4. Diagnosis of Diabetes FPGs7.0 mmoDl Fasting - no caloric intake lor at least 8 h or A1c »6.5% (in adults) Hot lor diagnosis ol suspected MOM.children, adolescents, or pregnant women or 2 hPG in a 75 g OGTT >11.1 mmol/L or Random PG »11.1 mmol/ L Random any lime of the day without regard to the interval since last meal -. in the presence of hyperglycemia symptoms ( polyuria , polydipsia , polyphagia , weight loss, blurry vision ) , a confirmatory test is not required in the absence of hyperglycemia symptoms , a repeat confirmatory test ( IPti , A Ic, 2 hP(i in a 75 g OGTT ) on another day is required for diagnosis of diabetes See Landmark Endocrinology Trials for more information on the UKPDS trial. It compares the safety and efficacy of intensive blood - glucose control with sulphonylurea or insulin vs. conventional treatment on the risk of complications in T 20M. 1 LJ See Landmark Endocrinology Trials for more information on the DCCT trial. It details the use of intensive insulin injection therapy for the treatment of T1DM in patients with no cardiovascular history or severe diabetic complications. + Activate Windows Go to Settings to activate Windows: E8 Endocrinology Toronto Notes 2023 Etiology and Pathophysiology Table 5. Etiologic Classification of Diabetes Mellitus. Diabetes Canada 2018 Clinical Practice Guidelines I T1DM immune - med ated or idiopathic cell destruction, usually leading to absolute insulin deficiency (includes latent autoimmune diabetes in adults ( LADA)) ^ target. III.Other Specific Causes of DM II T2DM occurs when the pancreas does not produce enough insulin or when the body does not effectively use the insulin that is produced < Fasting plasma glucose a. Genetic defects of 8 cell function (e.g.Maturity - Onset Oiabetes of the Young (MOOY; also known as monogenic diabetes)) or insulin action b. Diseases of the exocrine pancreas: Pancreatitis, pancreatectomy, neoplasia,cystic fibrosis,hemochromatosis Tbronre diabetes") c. Endocrinopathies: Acromegaly Cushing's syndrome, glucagonoma.pheochromocytoma hyperthyroidism d. Drug-induced: Glucocorticoids, thyroid hormone 8 - adrenerg.c agonists, thiazides,phenytoin. antipsychotics e. Infections: Congenital rubella CMV coxsackie f. Genetic syndromes associated with DM: Down's syndrome Klinefelter 's syndrome, turner's syndrome. 1.0% (most adults) 4-7 mmolI A1c 5-10 mmol/L 5-8 mmoLl if not meeting target A1c and can be safely 2h post-prandial glucose. achieved..... Lipids LDL 40 yr of age Increasing incidence in paediatric population 2" to obesity Epidemiology traditionally more common in European populations less common m Asian. Hispanic.Indigenous, and Black populabons Accounts for 5-10% of all DM More common in Black. Hispanic. Indigenous, and Asian populations Accounts for >90% of all DM Etiology Autoimmune or idiopathic Complex and multifactorial Genetics Monozygotic twin concordance ts 30-40% Associated with HLA class IIDR3 and DR 4. with either allele present in up to 95% of T1DM Certain DO alleles also confer a risk Monozygotic twin concordance is 70- 90% Pathophysiology Synergistic effects of genetic,immune,and environmental factors that cause 3 cell destruction resulting in impaired insulin secretion Autoimmune process is believed to be triggered by environmental factors (e.g.viruses, bovine milk protein,urea compounds) Pancreatic cells are infiltrated with lymphocytes resulting m islet cell destruction 80% of 8 cell mass is destroyed before features of DM present Natural History Greater herilability than T1DM Polygenic Kon-HLA associated Impairment of insulin secretion, excess glucose production by the liver, insulin resistance in fat and muscle, impaired renal handling of glucose|SGLT2i). impaired incretin activity ( decreased insulin production, excess glucagon production, enhanced carbohydrate absorption in the gut and increased appetite from the hypothalamus) insulin resistance glucose ^ (3 cell function. - t ''v /AiAA - '' insulin I honeymoon period time N. ' v * insulin I I (S coll 0 cell defect glucose (3 cell failure decompensation. After initial presentation, honeymoon period often occurs where gtycemic control can be achieved with little or no insulin treatment as residual cells are still able to produce insulin Once these cells are destroyed, there is complete insulin deficiency Early on glucose tolerance remains normal despite insulin resistance as 8 cells compensate with increased insulin production As insulin resistance and compensatory hyperinsulinemia continue, the 8 cells are unable to maintain the hyper insulinemic state whichresults in glucose intolerance and DM Circulating Autoantibodies Islet cell Ab present in up to 60 - 85% Most common islet cell Ab is against glutamic acid decarboxylase|GA 0) Up to 60% have Ab against insulin i SGLTO '. QrtuQlrfloiin" * ISGLT2i) —_ SGLT2J , Acarbosc Sylfonylurcas Mcglitinidcs s- i Q Highestlevelofevidence ( GradeA.. " Dm sitagliptm, linagiiplm, alogliptm |t 2? — - SGLT2i' O S 2 SGLT2T -s | § * benefit'. canagliflozm. dapagliflozm. J empagliflozin : CVmonadtv RISK of HF - GLP1 RA Weight loss GLPI RA dulaglutide exenatide ER liraglutide. lixisenatide semaglutide SGL2T 1.E CV safety, but NO proven cardiorenal PROVEN Risk factors HF ] I * Study: Multi -centre, double- blind KUcompairq liragtutide to placebo control: 9340 patients (drug n 4668 placebo n 46!2| median obserratam 3.8 ft. Outcome:Death from cardiovascular causes, nonfatal Ml. or nonfatal stroke. Resalts: Both groups concurrently received the standard treatment for I20M Ihe lirag jt de group had significantly louver rates of death from cardiovascular causes than control|4.7V vs. 6 %: P“0.00 ?|.Ihe drug group also had lower all-cause mortality |8.2% and 9.6 V R'0.02). Bales ol nonfatal Ml. nonfatal stroke, and kospitaIllation lor heart la Bure were not signhcantly lower In Ihe litagliditfe group. Conclusion: Adding hraglutide to standard treatment lor pabants with 12DM radoced death from cardiovascular cause and all -cause mortality when compared to placebo -. T f ADD or SUBSTITUTE AHA with demonstrated cardiorenal benefits CKO analogue) has any effect on cardovascular risk in patients with T 2 DM whenadded to standard care. Adjust or advance therapy * ASCVD, CKO or HF OR age >60 with 2 CV risk factors ASCVD Liraglutidc andCardioviscularOutcomes in 12 DM NEJU 2016; 375:311 322 Rugose lo investigate whether liraglutidc (a ClP-1 Insulin Hypoglycemia ( GiadeBj (CradaCorD) Initiate only if eGFR >30 ml/min/1.73m‘' saxagliptin IDPP4H Thiarotidinediones Weight gain rixed dose combinations may be considered to reduce burden Changes in clinical status may necessitate adjustment of glycemic targets and/or depresciibing Tobacco uso; dyslipcdomio luso of lip< d modifying thorapy or o documented untreated low density lipoprote n ILDLI > 34 mmoVL or high density lipoprotein chalastorol IHDL 0 cl.Ominol/lfor mon and < 1.3 inmoVLfoc womon or triglyceridos > 2.3 mmolU; or hypertension ( use of blood pressure drug or untreated systolic blood pressure ISBPI >140 mmHg or diastolic blood pressure |0 BP| >95 rnmHg) All antihyperglycemic agents ( AHAs) have grade A evidence for effectiveness to reduce blood glucose levels Consider degree of hyperglycemia, costs and coverage, renal function, comorbidity, side effect profile and potential for pregnancy ~ In CV outcome trials performed in people with atherosclerotic cardiovascular disease IASCVDI chronic kidney disease ( CKO ), heart failure ( HF) or at high cardiovascular ( CV) risk ' Vortis ( CV outcome trial for ortuglifloMi) presented at Americon Oiabetes Association ( ADA ) Juno 2020 showed noninferiority for major adverse CV events ( MACE ). Manuscript not published at time of writing A 1C - glycated hemoglobin; DPP 4i - dipeptidyl peptidase 4 inhibitors; eGFR estimated glomerular filtration rate; GLP1 RA - glucagon like peptide 1 receptor agonists; exenatide ER = exenatide extended release HHF - hospitalization for heart failure SGLT2i - sodium - glucose cotransporter 2 inhibitors. ".. ^ _. Figure 9. Treatment approach for patients living with diabetes Microvascular Complications Diabetic Retinopathy (see Ophthalmology, OP34 for a more detailed description ) Epidemiology diabetic retinopathy is the most common cause of incident blindness in people of working age among individuals with T 1 DM , limb amputation and vision loss due to diabetic retinopathy are independent predictors of early death Clinical Features macular edema: diffuse or focal vascular leakage at the macula non - proliferative ( microaneurysms , intraretinal hemorrhage, vascular tortuosity, vascular malformation ) and proliferative (abnormal vessel growth ) retinal capillary closure r t L j Treatment and Prevention tight glycemic control ( delays onset, decreases progression ), tight lipid control, manage HTN, smoking cessation ophthalmologic il treatments available ( see Ophthalmolcmv, OP35 for more details ) annual follow up visits with an optometrist or ophthalmologist to examine whether symptomatic or not through dilated pupils ( immediate referral after diagnosis of T2 DM; 5 yr after diagnosis of 'TlDM for those >15 yr) interval for follow up should be tailored to severity of retinopathy -. + Activate Windows Go to Settings to activate Windows, Toronto Notes 2023 El 6 Endocrinology Diabetic Nephropathy ( see Nephrology, NP33 for a more detailed description ) Epidemiology DM -induced renal failure is the most common cause of renal failure in North America 20 10",, of persons with T1 DM ( after 5 10 yr ) and 4 20% with T2 DM have progressive nephropathy. - - - Screening serum creatinine for eGFR, random urine ACR ACR is used as albuminuria is considered the earliest clinical sign of diabetic nephropathy ( microalbuminuria ); diagnosis requires persistent elevated urinary albumin ( 2 out of 3 urinary samples required over 3 mo) 24 h urine collection for protein / albumin is the gold standard but is difficult to perform, inconvenient, and often incorrect; random urine albumin is insufficient as albumin levels vary with urine concentration begin screening annually at diagnosis for all T 2 DM, and > 5 yr after diagnosis of T 1 DM for postpubertal patients Treatment and Prevention appropriate glycemic control appropriate BP control ( 5 yr after diagnosis of IT DM for post- 3 CO I pubertal patients Clinical Features Peripheral Sensory Neuropathy Motor Neuropathy Autonomic Neuropathy Paresthesias ( tingling , itching ), neuropathic pain , radicular pain , numbness, decreased tactile sensation Bilateral and symmetric with decreased perception ol vibration and pam ' tempcrature; especially hue in Ihe lower evlremilics but may also be present In Ihe hands Decreased ankle reflex Distal predominant as the longest nerves are affected first Classic stocking glove distribution May result in neuropathic ulceration ol loot Less common than sensory neuropathy end occurs later in the disease process Delayed motor nerve conduction and muscle Postural hypotension , tachycardia , decreased cardiovascular response to valsalva maneuver Gastroparesis and alternating diarrhea and - constipation weaknesslatrophy May involve one nerve trunk ( mononeuropalhy) Urinary retention and erectile dyslunclion 0 m 0It ( mononeur tis multiplex ) Some ol the motor neuropathies spontaneously resolve after 6- 8 wk Reversible CN palsies: III (ptosis/ ophthalmoplegia , pupil sparing ). VI (inability to laterally deviate eye), and VII ( Bell 's palsy ) Diabetic amyotrophy i.e. Bruns Garland Syndrome: refers to pain , weakness, and wasting ol hip flexors or extensors , s Figure 10. Monofilament testing for diabetic neuropathy Table 12. Clinical Features of Diabetic Neuropathies - V o , Treatment and Management tight glycemic control for neuropathic pain syndromes: tricyclic antidepressants ( e.g. amitriptyline ), pregabalin , duloxetine, anticonvulsants (e.g. carbamazepine, gabapentin ), and capsaicin foot care education |obst’ fitted stocking and tilting of head of bed may decrease symptoms of orthostatic hypotension treat gastroparesis with dietary modification , domperidone and /or metodopramide (dopamine antagonists), erythromycin ( motllln receptor agonist ) medical, mechanical, and surgical treatment for erectile dysfunction (see Urology, U 33) Pharmacologic Interventions for Painful Diabetic Neuropathy: An Umbrella Systematic Review a ad Comparative Effectiveness Network Meta Analysis Ann Intern Med 2011;141:639 - 49 Purpose: focompare the efficatiesof rarionsoral and topical anatges.esfor diabetic neuropathy. Study Selection: RCIs that assessed pharmacologic treatments lor pa nful diabetic peripheral neuropathy in adults Results: 65 RCIs , r , a eg 12632 patents were included. Ibelolluwng pharmacological agents demonstrated superiority over placebo for short-term pain control: seroton :n and norep inepbrine reuptake inhibitors (SNRIs) lstandaidired mean difference (SMD) 1.36; 95% credible interval (Cil) |1.77 to 0.9S1I, topkalcaps4ii , r (SMD, 0.91; Crl ( MS to -0.0811, tricyclic ante] epressants|ICAs|( SMD. -0.78; Crl|-1.24 to -0.33]), and anticonvulsants (SMD, -0.67:Crl [-0.97 to -0.37]). Spedfe agents included: carbamaiep , e (SMD -1.57; Crl [-2.83 to 0.31[|, renlalaiine (SMD 1.53: Crl ( 2.41 to -0.6511 dularetmelSMO. 1.33: Crl 1182 to 0 86 )). arid amitriptyline (SMD. -0.72: Crl ( 1.35 tn -0.08'J. Conclusion: SNSIs. topical capsaicin. TCAs and anticonvulsants are effective in short-term nanagementdf painful diabetic neuropathy, but their relative cflicacy compared to each other is unknown...-.- -.. LJ. - + Activate Windows Go to Settings to activate Windows. E17 Endocrinology Toronto Notes 2023 Other Complications Dermatologic diabetic dermopathy: atrophic brown spots commonly in pretibia! region ( “ tibia spots") secondary to increased glvcosylation 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 Other Players in Glucose Homeostasis These hormones act to increase: Blood glucose levels Glucagon Epinephrine Cortisol Growth hormone 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 increased fracture risk in both T 1 DM and T2 DM due to decreased bone quality adhesive capsulitis (“ frozen shoulder") - C Peptide A short peptide released into the circulation when proinsulin is cleaved to insulin Cataracts subcapsular and senile cataracts secondary to glycosylated lens protein or increased sorbitol causing osmotic change and fibrosis - Use of C pcptide Levels to Distinguish between Exogenous and Endogenous Infections Source of Hypetmsulinemia Increased endogenous Decreased or normal = exogenous see Infectious Diseases. Diabetic Foot Infections. ID 14 Hypoglycemia Etiology and Pathophysiology hypoglycemia occurs most frequently in people with DM receiving insulin or certain anti hyperglycemic therapies ( insulin secretagogues ) in people without DM, care must be taken to distinguish hypoglycemia that occurs in critically ill or medicated patients from hypoglycemia that presents in individuals who are seemingly well each invokes a separate DDx the timing of hypoglycemia may also provide a clue to the diagnosis (e.g. individuals with an insulinoma typically have fasting hypoglycemia whereas those with non insulinoma pancreatogenous hypoglycemia experience predominantly postprandial hypoglycemia ) must be distinguished from pseudohypoglycemia , defined as situations in which either BG >3.9 mmol/ L with clinical signs of hypoglycemia (e.g. fatigue, headache, visual disturbances, or lightheadedness) or BG 1 h away, eat snack including 15 g of carbohydrate and protein - © Hypoglycemia Unawareness (T1DM »> T2DM ) Patient remains asymptomatic until severe hypoglycemic levels are reached Often occurs after repeated episodes of hypoglycemia as the patient develops blunted/ minimal autonomic response Causes: Decreased glucagon /epinephrine response History of repeated hypoglycemia or low A1c Autonomic neuropathy May not be safe for patient to d rive Suggest that patient obtain a Medic Alert " bracelet if at risk for hypoglycemia, especially with hypoglycemia unawareness and consider use of advanced monitoring systems (continuous glucose monitor, flash glucose monitor) - © Refer to Diabetes Canada 2018 guidelines for advice around diabetes and driving T LJ + Activate Windows Go to Settings to activate Windows. E 18 Endocrinology Toronto Notes 2023 when the cause of hypoglycemia is not evident, screen for oral hypoglycemic agents ( ideally all available sulfonylureas and glinides) and measure plasma glucose, insulin, proinsulin, C -peptide, - b hydroxybutyrate, and insulin Ab during a spontaneous hypoglycemic episode or a supervised fast of up to 72 h If hypoglycemia occurs only in the postprandial state, evaluate the patient first with a mixed meal test correct hypoglycemia with injection of 1.0 mg glucagon IV with measurement of plasma glucose response. This will distinguish endogenous and exogenous hyperinsulinism from other causes of hypoglycemia. Treatment for tumoural hypoglycemia , definitive treatment requires resection of the tumour. If that is not possible certain medications can be helpful such as diazoxide for patients with insulinoma for non insulinoma pancreatogenous hypoglycemia and post bariatric bypass hypoglycemia, dietary changes including reducing the amount of carbohydrate intake and small frequent meals may be helpful. For patients who do not respond to nutritional modification or have severe symptoms, acarbose can be utilized see Emergency Medicine, ER 34 treatment of hypoglycemic episode in the unconscious patient or patient NPO D50 W 50 mL ( 1 ampule ) IV in 1 3 min or 1 mg glucagon SC or 1 M ( if no IV access is available ) may need ongoing glucose infusion once B(i > 5 mmol/ L - - - Metabolic Syndrome postulated syndrome related to insulin resistance associated with hyperglycemia, hyperinsulinemia, HT' N , central obesity, and dyslipidemia obesity aggravates extent of insulin resistance complications include DM , atherosclerosis, CAD, Ml , and stroke women with PCOS are at increased risk for developing insulin resistance, hyperlipidemia, and metabolic syndrome not to be confused with syndrome X related to angina pectoris with normal coronary arteries (Prinzmetal angina ) Obesity $ Features of Metabolic Syndrome | - 3 measures to make a Dx ) - see family Medicine. 1 M 9 Measure Men. Pituitary Gland - Mediterranean. >90 cm >80 cm Asian (35 indies) Japanese 31.5 Inches) South ( Central America >1.7 mmol/ L (150 mgfdL ) TO level Somatostatin Dopamine I CRH GHRH l I I ACTH Prolactin 1 I H Adrenal SI — ' GnRH FSH GH IH of gonads Male I Androgens | Breast Multiple target organs Figure 11. Hypothalamic-pituitary hormonal axes - HDL C level «1.0 mmol/L ( 40 mg/dl) Blood Pressure fasting Glucose Level ;130 /8SmmHg - 100 mg/dl) > 1. Female Estrogens progesterone j o < Dt ug treatment for any elevated marker is an alternate indicator Endocrine cells Liver Somatomedins (IGF-1 ). - cortex Cortisol sas iS. Saharan Africa Pituitary Hormones If It Women Abdominal Obesity (derated Waist Circumference) >102 cm >88 cm Canada USA (40 inches) (35 inches) >80 cm Europid. Middle >94 cm Eastern , Sub (37 Indies) (31.5 inches) i Gonadal germ cells, Multiple target organs Anterior Pituitary Hormones FLAT PIG FSH LH r LJ ACTH TSH PPL GH + Activate Windows Go to Settings toactivateWindows. i Ely Toronto Notes 2023 Endocrinology Hypothalamic Control of Pituitary trophic and inhibitory factors control the release of pituitary hormones most hormones are primarily under trophic stimulation except FRL, which is primarily under inhibitory control by dopamine. CiH and TSH are stimulated by GHRH and TRH respectively while inhibition by somatostatin is less important for control transection of the pituitary stalk ( i.e. dissociation of hypothalamus and pituitary ) leads to pituitary hypersecretion of PRL and hyposecretion of all remaining hormones Anterior Pituitary Hormones FSH , LH , ACTH , TSH , CiH , PRL these hormones are produced , stored , and released from the anterior pituitary but regulated by hormones produced by the hypothalamus Posterior Pituitary ( Hypothalamic ) Hormones 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 in and released from the posterior pituitary Table 14. The Physiology and Action of Pituitary Hormones Physiology Hormone Function IH / FSH Polypeptide Stimulate gonads via cAMP Ovary: Glycoproteins (same asubunit as TSH and hCG) Secreted in pulsatile fashion LH: production o( androgens ( thecal cells) which are converted to estrogens (granulosa cells): induces luteinization in follicles FSH: growth ol granulosa cells in ovarian follicle: controls estrogen production lestes: LH: production ol testosterone (leydig cells) FSH: production ol spermatocoa (Sertoli cells) Inhibitory Stimulus Secretory Stimulus Estrogen Progesterone Testosterone Pulsatile GnRH (low frequency pulsation fSH release, high frequency pulsation LH release) Inhibin Continuous ( i.e. non pul satile) GnRH infusion - - ACTH Stimulates growth of adrenal cortex and secretion of its hormones via cAMP Polypeptide Circadian rhythm ( highest in the morning, lowest at midnight ) Dexamethasone. cortisol, and other glucocorticoids TSH Stimulates growth ol thyroid and secretion ol 14 andT 3 viacAMP Glycoprotein Note: hCG can activate the TSH receptor and therefore have thyroid stimulating activity thyroid hormones (14 and 13) and analogues, dopamine, somatostatin cytokines, high dose glucocorticoids Promotes mi Ik productionand breast tissue Polypeptide Episodic secretion Dopamine (only pituitary hormone under tonic inhibition of secretion ) PRL development - - Corticotropin Releasing Hormone Melyrapone hypoglycemia Vasopressin fever, pain , stress. Inhibits gonadotropin secretion TRH AVP a adrenergicagonist Sleep Stress, hypoglycemia Pregnancy, breastfeeding Mid menstrual cycle Sexual activity TRH ( primary hypothyroidism ) Drugs: anlipsycholics tricyclic -.. antidepressants, metoclopramldc domperidone verapamil, methyldopa , opioids, high dose estrogen. Has direct effects on peripheral target cells Needed (or linear growth and also has metabolic effects to increase serum glucose Stimulates secretion of IGF -1 by the livec a potent growth and differentiation factor Polypeptide Acts indirectly through IGF -1|somatomedin -C) synthesized in the liver and has direct effects Serum GH undetectable lor most of the day and suppressed alter meals high in glucose Sustained rise during sleep Glucose challenge Glucocorticoids Somatostatin Dopamine D 2 receptor agonists in some GH secreting tumours IGF 1 llong loop) GHRH Insulin induced hypoglycemia Ghrelin Exercise REM sleep Arginine, donidinc propranolol L dopa Sex hormones Dopamine agonists in normal individuals ADH Acts at renal collecting ducts on V 2 receptors to cause insertion of aquaporin channels and increases water reabsorption thereby concentrating urine Octapeptide Secreted by posterior pituitary Osmoreceptors in hypothalamus detect serum osmolality Contracted plasma volume detected by baroreceptors is a more potent stimulus than i osmolality a serum osmolality Hypovolemia or a effective circulatory volume t serum osmolality Stress , pain , fever, system CNS disorders Oxytocin Causes uterine contraction Breast milk secretion Nonapeplide Secreted by posterior pituitary EtOH Suckling Distention ol female genital tract during labour via stretch receptors GH. - - - -..- + Activate Windows Go to Settings to activate Windows. Toronto Notes 202J E 20 Endocrinology Growth Hormone GH Deficiency cause of short stature in children (see Paediatrics. P13) adults exhibit increased fat and decreased lean body mass, decreased bone mineral density, and fatigue diagnosis made with low serum l (il;- l levels in individuals with deficiencies in three or more pituitary axes, or by failure to increase GH with a provocative test (see above under GH secretory stimulus ); insulin tolerance test to induce hypoglycemia is the gold standard dynamic test Tx: GH replacement is not always indicated after max linear height and peak bone mass is reached; consider in an adult patient with childhood onset irreversible GH deficiency (some children who are diagnosed with idiopathic GH deficiency will have normal GH responses when tested as adults and do not require GH treatment). GH replacement can also be provided to patients with adult onset GH deficiency who do not have an active malignancy and prefer treatment after a discussion about its potential benefits, adverse effects, and cost GH Excess Etiology GH secreting pituitary adenoma, neuroendocrine tumours secreting ectopic GH or GHRH (very rare) Pathophysiology normally GH is a catabolic hormone that acts to increase blood glucose levels in GH excess states, secretion remains pulsatile but there is loss of hypoglycemic stimulation , glucose suppression , and the nocturnal surge proliferation of bone, cartilage, soft tissues, organomegaly insulin resistance and 1GT Clinical Features leads to gigantism in children ( before epiphyseal fusion ) leads to acromegaly in adults (after epiphyseal fusion ) dermatologic (thickening of skin , increased sebum production , sweating, acne, sebaceous cysts ), musculoskeletal (enlargement of hands and feet, coarsening of facial features, thickening of calvarium , prognathism, carpal tunnel syndrome, osteoarthritis), cardiometabolic ( HTN, DM , acanthosis nigricans, cardiomyopathy ), sleep apnea, sexual ( low libido ) Risks Associated with GH Excess Cardiac disease (e.g.. cardiomyopathy, valvulopathy arrhythmias, CAD) in 1/3 ol patients. Two fold increase in mortality in acromegaly due to acromegaly associated complications such as HTN, diabetes, CVD, and cerebrovascular disease HTN in 1/3 of patients Increased risk of cancer ( particularly colon cancer ) - -. Investigations first line test: serum 1GF-1 (expected to be elevated ) glucose suppression test is the most specific test (75 g of glucose PO suppresses GH levels in healthy individuals but not in patients with acromegaly) O', MKI or skull x -rays may show cortical thickening, enlargement of the frontal sinuses, and enlargement and erosion of the sella turcica MKI of the sella turcica is needed to look for a tumour. Treatment surgery is the recommended initial therapy for the majority of patients with acromegaly; second line options include somatostatin analogue (octreotide), dopamine agonist (cabergoline), GH receptor antagonist (pegvisomant ), radiation « radiation may be considered in patients whose disease is not controlled by surgery or medical treatment Prolactin Hyperprolactinemia Etiology prolactinoma: most common pituitary adenoma sellar masses, disease with pituitary stalk compression, or damage causing reduced dopamine inhibition of PKL release primary hypothyroidism ( increased TRH ), PCOS, acromegaly decreased clearance due to CKD or severe liver disease ( PRL is metabolized by both the kidney and liver) medications with anti-dopaminergic properties are a common cause of high PRL levels: antipsychotics (common ), antidepressants, antihypertensives ( verapamil / methyldopa ), bowel motility agents (metoclopramide/domperidone), H2-blockers, opiates ( morphine ), estrogens (e.g. oral contraceptives) macroprolactinemia ( high molecular weight PRL also known as big-big PRL ) that has no action but results in falsely elevated serum prolactin physiologic causes: pregnancy, stress, sleep, nipple stimulation , factors affecting the chest wall & Approach to Nipple Discharge Differentiate between galactorrhea (fat droplets present ) vs. breast discharge (usually unilateral, may be bloody or serous) If galactorrhea , determine if physiologic (e.g. pregnancy, lactation ) vs. pathologic If abnormal breast discharge, must rule out a breast malignancy. t j + Clinical Features galactorrhea ( secretion of breast milk in women and, in rare cases, men ), infertility, hypogonadism, amenorrhea, oligomenorrhea, erectile dysfunction Activate Windows Go to Settings to activate Windows. E 21 Endocrinology Toronto Notes 2023 Investigations serum PRL, l'SH, liver enzyme tests, creatinine, hCG in all women of reproductive age macroprolactin level in patients with hyperprolactinemia but no symptoms of PRL excess MRI of the sella turcica when a secondary cause is not identified or when PRL levels suggest that there may be underlying tumoural hyperprolactinemia Treatment first line: dopamine agonists ( bromocriptine, cabergoline, quinagolide) surgery ± radiation ( rare) PRL-secreting tumours are often slow-growing; treatment may not be necessary in the setting of small tumours associated with hyperprolactinemia which does not result in hypogonadism or bothersome galactorrhea if medication -induced , consider stopping medication if possible in certain cases if microprolactinoma and not planning on becoming pregnant, may consider OCP Thyroid Stimulating Hormone. see 'thyroid,£24 Diagnosis and Treatment of Hyperprolactinemia: An Endocrine Society Clinical Practice Guideline J Clin Endocr Mctab 2011:96:273 88 Indications to treat: Symptomatic patients. in particular those with galactorrhea, hypogonadism amenorrhea low libido, or infertility Aden omas >1 cm or any size causing structural compression For patients with symptomatic prolactinomas, dopamine agonist therapy should be used to lower prolactin levels, decrease tumour size, and restore gonadal function Cabergoline should be preferentially used due to higher efficacy in normalizing PRL levels and shrinking pituitary tumours For symptomatic patients with treatment resistant prolactinomas, increase the dose to maximal tolerable dose before referring for.. Adrenocorticotropic Hormone tee Adrenal Cortex, £ 33 - - surgery Luteinizing Hormone and Follicle Stimulating Hormone Hypergonadotropic Hypogonadism hypogonadism due to impaired release of PSH and LH Most women with prolactinomas should discontinue dopamine agonist therapy immediately if they become pregnant (except for patients with large invasive tumours) Etiology congenital: Kallmann syndrome, CHARGE syndrome, GnRH insensitivity secondary : CNS or pituitary tumours, pituitary apoplexy, hypothalamic - pituitary radiation , drugs (GnRH agonists/antagonists, glucocorticoids, narcotics, chemotherapy, drugs causing hyperprolactinemia , opioids), functional deficiency due to another cause ( hyperprolactinemia , chronic systemic illnesses, eating disorders, hypothyroidism , DM, Cushing’s disease), systemic diseases involving the hypothalamus/ pituitary ( hemochromatosis, sarcoidosis, histiocytosis) Clinical Features amenorrhea, low libido, decrease in energy, erectile dysfunction (see Urology. U33), loss of body hair, thin skin, testicular atrophy, decrease in muscle mass, and failure of pubertal development Treatment treat underlying cause if present combined l SH / LH hormone therapy, hCG, recombinant l SH , or pulsatile GnRH analogue if fertility ' ' desired symptomatic treatment with estrogen /testosterone hypergonadotropic Hypogonadism hypogonadism due to impaired response of the gonads to ESH and LH Etiology congenital: chromosomal abnormalities ( Turner 's syndrome, Klinefelter syndrome, XX gonadal dysgenesis ) enzyme defects ( I 7a- hydroxylase deficiency, 17,20-lyase deficiency) gonadotropin resistance ( Leydig cell hypoplasia, ESH insensitivity, pseudohypoparathyroidism type 1A) acquired: gonadal toxins (chemotherapy, radiation ) drugs (antiandrogens, alcohol ) infections (S'l'ls , mumps) gonadal failure in adults (androgen decline and testicular failure in men , premature ovarian insufficiency and menopause in women ) rn LJ Clinical Features amenorrhea, erectile dysfunction (see Urology, U33), loss of body hair, fine skin, testicular atrophy, failure of pubertal development, low libido, decrease in energy, and infertility + Treatment hormone replacement therapy consisting of androgen ( for males) and estrogen and progesterone ( for females) administration Activate Windows Go to Settings to activate Windows. 1 E22 Endocrinology Toronto Notes 2023 Antidiuretic Hormone Diabetes Insipidus ( see Nephrology. NP12) Definition disorder of ineffective ADH (decreased production or peripheral resistance ) resulting in passage of large volumes of dilute urine Etiology and Pathophysiology central Dl: insufficient ADH due to pituitary surgery, tumours, idiopathic/autoimmune, infiltration or lesion of the stalk, hydrocephalus, Langerhans cell histiocytosis, trauma, familial central Dl nephrogenic Dl: collecting tubules in kidneys resistant to ADH due to drugs (e.g. lithium ), hypercalcemia, hypokalemia, CKD, hereditary nephrogenic Dl psychogenic polydipsia and osmotic diuresis must be ruled out Clinical Features passage of large volumes of dilute urine, polydipsia, and dehydration; hypernatremia can develop with inadequate water consumption or secondary to an impaired thirst mechanism central Dl: visual field defect , headache, other neurological features , or evidence of other pituitary hormone deficiencies may be present Diagnostic Criteria fluid deprivation will differentiate true Dl ( high urine output persists, urine osmolality < plasma osmolality) from psychogenic polydipsia response to exogenous ADH (DDAVP) will distinguish central Dl from nephrogenic Dl Treatment central Dl: first line = desmopressin; second line = chlorpropamide, thiazides, NSAlDs, and carbamazepine nephrogenic Dl: solute restriction, thiazide diuretics Syndrome of Inappropriate ADH Secretion Diagnostic Criteria Diagnosing Subtypes of Diabetes Insipidus with Desmopressin Response - Concentrated urine Central No effect * Nephrogenic $ Syndrome of inappropriate ADH secretion (SIADH ) vs. Cerebral Salt Wasting (CSW) CSW can occur in cases of subarachnoid hemorrhage. Na» is excreted by malfunctioning renal tubules, mimicking findings of SIADH: hallmark is hypovolemia - 1) hyponatremia (serum Nat < 135 mEq / L ) with 2 ) plasma hypo osmolality (< 275 mOsm / kg ), 3) urine Na t concentration > 40 mEq/ L, 4) urine osmolality >100 mOsm / kg ), 5) euvolemia ( no edema ), and 6) absence of adrenal, renal, or thyroid insufficiency Etiology and Pathophysiology stress ( post-surgical) malignancy (ectopic ADH production by tumours including small cell carcinoma of the lung, extrapulmonary small cell carcinomas, squamous cell carcinoma of the head and neck) CNS disease (inflammatory, hemorrhage, tumour, Guillain-Barre syndrome ) respiratory disease (tuberculosis, pneumonia, empyema ) drugs (SSRls, vincristine, chlorpropamide, cyclophosphamide, carbamazepine, nicotine, morphine, DDAVP, oxytocin ) Clinical Features symptoms of hyponatremia: headaches, nausea, vomiting, muscle cramps , tremors, cerebral edema if severe (confusion, mood swings, hallucinations, seizures, coma ) Treatment goal is to increase serum sodium treat underlying cause, fluid restriction (800-1000 mL/d ), vasopressin receptor antagonists (tolvaptan, conivaptan ), demeclocycline (antibiotic with anti-ADH properties; rarely used ), and furosemide Pituitary Pathology Pituitary Adenoma (see Neurosurgery. NS17) Clinical Features local mass effects visual held defects ( bitemporal hemianopsia due to compression of the optic chiasm ), diplopia (due to oculomotor nerve palsies; rare), headaches; increased ICR is rare hypofunction hypopituitarism hyperfunction PRL (galactorrhea, hypogonadism ), GH (acromegaly in adults, gigantism in children ), ACT H ' (Cushing’s disease = Cushing’s syndrome caused by a pituitary tumour) tumours secreting TSH are rare r Important Deficiencies to Recognite are: Adrenal Insufficiency Hypothyroidism Concurrent adrenal insufficiency and + hypothyroidism should be treated with glucocorticoids first and then with thyroid hormone to avoid adrenal crisis Activate Windows Go to Settings to activate Windows. E 23 Endocrinology Toronto Notes 2023 Investigations (§) radiological evaluation ( MKI sella is imaging procedure of choice) formal visual field testing for tumours compressing the optic chiasm laboratory tests of hypothalamic - pituitary hormonal function The Pituitary Hormones Compression of the pituitary by a mass leads to loss of pituitary hormones in the following usual order: T5o Look For The Adenoma Please" GH. LH FSH, TSH, ACTH PRL + posterior pituitary hormones: ADH and oxytocin Hypopituitarism. Etiology (The Eight I’s) Invasive. pituitary tumours, craniopharyngioma, cysts ( Kathke's deft , arachnoid , or dermoid ), metastascs Infarction / hemorrhage Sheehan’s syndrome ( pituitary infarction due to excessive postpartum blood loss and hypovolemic shock) pituitary apoplexy (acute hemorrhage / infarction of a pituitary tumour; presents with sudden loss of pituitary hormones, severe headache, and altered LOC; can be fatal if not recognized and treated early) Infiltrative/ inflammatory sarcoidosis, hemochromatosis, histiocytosis Infectious syphilis, tuberculosis, fungal ( histoplasmosis), parasitic (toxoplasmosis) Injury severe head trauma Immunologic autoimmune destruction ( hypophysitis) Iatrogenic follow ing surgery or radiation Idiopathic familial forms, congenital midline defects Clinical Features symptoms depend on which hormone is deficient: » ACTH: fatigue, weight loss, hypoglycemia, anemia, hyponatremia, failure to thrive, and delayed puberty in children CiH : short stature in children; adults exhibit increased fat and decreased lean body mass, decreased BMD, fatigue TSH: tiredness, cold intolerance, constipation , weight gain LH and 1 SH: oligo or amenorrhea, infertility, decreased facial / body hair and muscle mass in men, erectile dysfunction, delayed puberty Prolactin: usually asymptomatic, inability to breastfeed ADH: symptoms of D1 (extreme thirst, polydipsia, hypernatremia) Oxytocin: usually asymptomatic only needed during labour and breastfeeding - - - Investigations - 8 am cortisol, PRL, TSH, Free T4, LH, FSH , Estradiol or Testosterone, GH, IGF I, Na +, Osmolality insulin tolerance test: insulin ( usual dose 0.1 unit / kg of human regular insulin ) -> hypoglycemia -» increased GH and cortisol (normal response) initial test: cosyntropin stimulation test ( if results equivocal, proceed to insulin tolerance test ) triple bolus test ( rarely done) rt LJ + Activate Windows Go to Settings to activate Windoi E2‘l Endocrinology Toronto Notes 2023 Thyroid Thyroid Hormones Extra -Thyroidal (actors Impacting Thyroid Hormone Homeostasis:A Review JRM 2015:4|l ):40 -49 Most peripheral thyroid metabolism occurs in the liver and kdnejs. thus severe twer disease and CKO can ugnifrcantiy alter the 13:T4 ratio. Alcohol dependence results m hypothalamic pituitaryry to d axis dysiunction demonstrated hy decreased TSH 14, and T3 levels. Smoking is associated with lower TSH levels in a dose-dependent manner, with heavy smokers 18-12 ciqarettes'd ) beaig associated with more TSH C- L r Cap tan ' Thyroid follicle Section of the Thyroid Gland. Follicular cell suppression than light smokers [«4 cigarettes/d). Heavy metal exposure including lead, mecenry.and cadmmm has been shown to altar thyroid hormone function and peripheral melabohsm. Follicular cell & Coupling t v: - Patterns of Hormone Levels r Hyper r Hyper 1° Hypo y »ypo JUT - diodotyrosina; L = lysosome; MU - monoiodotyrosine; Tg - thyroglobulin; NIC. - thyroid paroxidase enzyme ^ sodium iodide cotransporter TP. TSH Il Tr * t t t t * * j Figure 12. Thyroid hormone synthesis Synthetic Function of the Thyroid Gland the synthesis of thyroid hormones '14 and '13 by the thyroid gland involves trapping and oxidation of iodide, iodination of thyroglobulin, proteolysis of thyroglobulin , and release of 14 and T3 more than 90% of thyroid hormone secreted by the thyroid is T4 free T4 (0.02%) and free T'3 (0.3%) represent the hormonally active fraction of thyroid hormones the remaining fraction is bound to TBG, albumin, and transthyretin, and is biologically inactive T3 is more biologically active (approximately 4 x as potent as 14), but T3 is present in the blood in smaller quantities and has a shorter half life compared to T4 85% of '14' is converted to T'3 or reverse T'3 in the periphery by dciodinase enzymes reverse T 3 is metabolically inactive but produced in times of stress to decrease metabolic activity most of the plasma T'3 pool is derived from the peripheral conversion of T4 calcitonin, a peptide hormone, is also produced in the thyroid by the parafollicular cells (C cells) calcitonin functions by inhibiting osteoclast activity and increasing renal calcium excretion ' - Role of Thyroid Hormones thyroid hormones act primarily through modifying gene transcription hy binding to nuclear receptors diffuse actions, affecting nearly every organ system tissue-specific effects determined by the expression of the types of thyroid receptor isoform and the local production of T3 increase basal metabolic rate through increased Na + / K + ATPase activity, increased 02 consumption, increased respiration, heat generation , and increased cardiovascular activity when present at higher than normal levels, potentiate the actions of GH , catecholamines (epinephrine, norepinephrine ), glucagon, and cortisol, resulting in increased gluconeogenesis, ketogenesis, and proteolysis, mimicking what happens in starvation increase sensitivity to catecholamines by up- regulating their receptors, but do not alter their blood concentrations required for normal growth in the fetus and child, including the CNS, via stimulation of GH release, in rT \. LJJ synergism with cortisol Regulation of Thyroid Function extrathyroid + stimulation of thyroid by 'TSH, epinephrine, prostaglandins (cAMP stimulators); T3 negatively feeds back on anterior pituitary to inhibit TSH and on hypothalamus to inhibit T'RH Activate Windows Go to Settings to activate Windows. Toronto Notes 2023 E 25 Endocrinology T3 intrathyroid ( autoregulation ) synthesis ( Wolff -Chaikoff effect,|od - Basedow effect ) varying thyroid sensitivity to TSH in response to iodide availability increased ratio ofT3 to T 4 in iodide deficiency increased activity of peripheral 5’-deiodinase in hypothyroidism increases T3 production despite low T4 levels Tests of Thyroid Function and Structure TSH third generation TSH is the best test for assessing thyroid function hyperthyroidism primary': TSH is low because of negative feedback from increased levels of circulating T4 and 1'3 secondary: increased TSH results in increased 14 and T3 hypothyroidism » primary: increased T SH ( most sensitive test ) because of less negative feedback from T4 and T'3 secondary: T SH is low or inappropriately normal with variable response to TRH depending on the site of the lesion ( pituitary or hypothalamic) Free T4 and Free T3 standard assessment of thyroid function measures TSH and, if necessary, free T4. Tree T3 should only be measured in the small subset of patients with hyperthyroidism and suspected T3 toxicosis. In this e. Thyroid Assessment TSH Serum free thyroid hormones (T», T3) Antibodies (TRAb TgAb. and TPOAb) Thyroglobulin (to monitor thyroid cancer ) Thyroid U/ S when there is a palpable thyroid abnormality or suspected thyroid mass Nuclear uptake and scan (for hyperthyroidism) Biopsy (FNA) of thyroid nodules warranting a cytological evaluation.. case, T SH would be suppressed , free 14 normal , and free 1 3 elevated Thyroid Autoantibodies TgAb, TPOAb, and TRAb of the blocking variety are increased in Hashimoto’s disease; normal variant - in 10 20% of individuals TKAb of the stimulating variety are also referred to as TSI and can cause Graves' disease. TRAb receptor blocking and stimulating antibodies are seen in patients with Graves' disease Plasma Thyroglobulin used to monitor for residual thyroid tissue post-thyroidectomy, e.g. tumour marker for thyroid cancer recurrence detectable or elevated levels may suggest persistent, recurrent , or metastatic disease assay can be impacted by presence of TgAb. Therefore, both must be tested to ensure accurate thyroglobulin results Serum Calcitonin not routinely done to investigate thyroid nodules ordered if suspicion of MTC (e.g. in patients with a thyroid nodule and suspected or confirmed MEN 2 A or 2 B syndromes or those who have a pathogenic mutation in RET gene) used to monitor for residual or recurrent MTC Thyroid Imaging/Scans normal gland size 15-20 g (estimated by palpation ) thyroid U /S to measure size of gland , characterize thyroid nodules, facilitate ENA biopsy ( ENAB ) U/S is the first line tool for identification of thyroid nodules that require ENAB; exception is. hyperthyroid patients with thyroid nodules where use of a radioisotope thyroid scan and RA1U (see below) permits identification of hyperfunctioning nodules, which generally do not need to be Does this Patient have a Goitre? from The Rational Clinical Examination JAUA 2009: https:// jamaevidence.mhmediial.com/ ccnte t aspi ?l)O0 « ld 8454 secto i d 6 ? S08 Study: Systematic review of articles assessing the accuracy and precision ot theclinical eum I n the diagnosis of a goitre. Results: Clinical diagnosis was based on degree of lateral prominence, visibility,and palpability of the thyroid gland. Nn evidence eiiststo support the superiority of any one method the combined results of 4 stain detail the predictive hbty of assessing grades of thyroid gland weight: - - - -m , Weight Reference US* 95% Cl 0-20 g Normal 0.15 (0.10-0.21) 1.9 25.0 (11-3.0) 20-40 g 1- 2x » >2 40 g > (2.6-175). Mtemathrtly defining a goitre asa mass larger than the distal phalanrof the thumb has been shown to have an LR* of 3.0 (95% Cl 25 3.5) and 1R - of 0.30 (95% a:0.24 0.37) in children, and an LR of 4.7 (95% 0 3.6 0) and LR of 0.08 (95% Cl 0.02 0.27) for the presence of a govtre. Conclusions: Use 0!we ightof thyroid tissue Isan appropriate method of dagnosmga goitre, while com paring the six of the thyroid nasslo the distal pbaia n of the thumb may be a useful alternative. - - - - - - biopsied radioisotope thyroid scan (Technetium 99) only if 1 ) one or more thyroid nodule (s) and 2) patient is hyperthyroid to determine whether nodules are hot ( functioning -> excess thyroid hormone production ) or cold ( non functioning ) hot nodule > very low chance of malignancy; treat hyperthyroidism cold nodule -» further workup required ( U /S, then ENAB if concerning sonographic features) - -. RA1U test of function: order if patient is thyrotoxic RAIU measures the turnover of iodine by thyroid gland in vivo if t uptake (e g. incorporated ), gland is overproducing thyroid hormone ( hyperthyroid ) if * uptake (e g not incorporated ), gland is leaking thyroid hormone (e.g. thyroiditis), exogenous thyroid hormone use, or excess iodine intake (e.g. amiodarone or contrast dye, which has high iodine content) see figure 12 for further information regarding the utility of these scans... rt LJ Thyroid Biopsy ENA for cytology « + differentiates between benign and malignant disease best done under U /S guidance accuracy decreased if nodule is greater than 50% cystic, or if nodule is located posteriorly in the gland Activate Windows Go to Settings to activate Window: E26 Endocrinology Toronto Notes 2023 Table 15. Summary of Diagnostic Testing in Hyperthyroidism and Hypothyroidism Hyperthyroidism Hypothyroidism TSH Decreased in 1° hyperthyroidism Increased in 2° hyperthyroidism Increased in 1° hypothyroidism Decreased in 2‘ hypothyroidism Freeti Increased in 1" hyperthyroidism Increased in 2" hyperthyroidism Decreased in 1‘ hypothyroidism Decreased in 2‘ hypothyroidism Antibodies Graves': TRAb Hashimoto's: TPOAb, TgAb RAIU Increased uptake Graves' Toxic multinodular goitre Toxic adenoma Decreased uptake Subacute thyroiditis Recent iodine load Exogenous thyroid hormone Radioisotope Thyroid Scan Drugs Affecting Thyroid Function Thyroid 2010:20(71:763-770 Lithium plays in inhibitory role in thyroid hormone release, resulting n chnical hypothyroidism end goitre. AimadaroceTndyred Hypothyroidism glH|: Ant oderone a class III anbarrhythmic drug, contains 2 atoms ol iodine per molecule and is structurahy similar to thyroid hormones, and may exert antagonist effects on lift receptors. It a also shorn to inhibit type I deiodnoses resulting in high T4 acd lnwT3 levels.AIH occurs in 5-15% nf patients on amiodarone.UH can also occur in people without pre exisbng thyso d dysfunction. Arniodarone Induced ihyrotoxicovs |JU1): occurs In 2-12\ of patents on amiodarone. Iha may be due to either art increased iodine load in patients with a prer.ousty autonomous thyroid such as in Graves' disease and toxic multinodular goitre (AIT type l|or amiodarone- induceddestructive thyroid tis 1 11 type It).. * Graves': homogenous diffuse uptake Multinodular goitre:heterogeneous uptake loxic adenoma: single intense area of uptake with suppression elsewhere - Thyrotoxicosis Definition * clinical, physiological, and biochemical findings in response to elevated thyroid hormone Epidemiology 1% of general population have hyperthyroidism I :M= 5: 1 Signs and Symptoms of HYPERthyroidism Etiology and Pathophysiology. THYROIDISM Tremor Heart rate up Yawning (fatigue due to insomnia) Restlessness Oligomenorrhea / amenorrhea Intolerance to heat Diarrhea Table 16. Differential Diagnosis of Thyrotoxicosis Disorder TSH Free T /Ti Thyroid Antibodies RAIU Other Decreased Increased TRAb Increased Homogenous uptake HYPERTHYROIDISM Graves' Disease on scan Muscle wasting / weight loss Toxic Nodular Goitre Decreased Increased None Increased Heterogeneous uptake on scan Toxic Nodule Decreased Increased None Increased Intense uptake in hot nodule on scan with suppressed uptake in the rest of the gland Decreased Increased Decreased (increases once entering hypothyroid phase, when TSH rises) In classical subacute painful thyroiditis THYROIDITIS. Subacute, Silent Postpartum Up to 50% of cases. ( TPOAb TgAb ) ESR increased. Decreased Exogenous (drugs) Decreased Increased None Decreased Low thyroglobulin since endogenous thyroid hoimone production suppressed Increased (Ti would be decreased if taking Tj) None Decreased Common Etiologies Thyrotoxicosis EXTRATHYROIDAL SOURCES OF THYROID HORMONE Endogenous (struma ovarii, ovarian teratoma, metastatic follicular carcinoma) Irritability Sweating Hypothyroidism Graves' Disease Hashimoto's Toxic Nodular Goitre Congenital Toxic Nodule Iatrogenic (thionamides.. radioactive iodine o< surgery) Hyperthyroid phase of Hypothyroid phase ol thyroiditis thyroiditis EXCESSIVE THYROID STIMULATION Pituitary Thyrotropinoma Increased or inappropriately normal Increased None Increased Pituitary Thyroid Hormone Receptor Resistance Increased or normal Increased None Increased.. Increased hCG (e g pregnancy) Pituitary mass; possible PRL or GH excess Abnormal THRB gene analysis Decreased Increased None Test is contraindicated p1 in pregnancy LJ + Activate Windows Go to Settings to activate Windows. Toronto Notes 2023 E 27 Endocrinology Clinical Features Table 17. Clinical Features of Thyrotoxicosis General Fatigue , heat intolerance, irritability, fine tremor CVS Tachycardia. alrial fibrillation, palpitations Elderly patients may have only cardiovascular symptoms, commonly new onset atrial fibrillation Gl Weight loss with increased appetite , thirst, increased frequency of bowel movements |hyperdefecalion) Neurology Proximal muscle weakness , hypokalemic periodic paralysis (more common in Asian individuals) GU Oligomenorrhea , amenorrhea , decreased feitilily Dermatology Fine hair, moist and warm skin , vitiligo, soli nails with onycholysis (Plummer ’s nails), palmar erythema, pruritus Graves' disease: clubbing (acropadiy), prelibial myxedema (rare) MSK Decreased bone mass, proximal muscle weakness Hematology Graves' disease: leukopenia, lymphocytosis , splenomegaly, lymphadenopathy (occasionally) Eye Graves’ disease: lid lag. retraction , proptosis, diplopia, decreased acuity, puffiness, conjunctival injection NOTE: Lid lag is a reflection of a hyperadrenergic state and can be present in any form of thyrotoxicosis Treatment p blockers for control of adrenergic symptoms antithyroidals ( thionamidcs): propylthiouracil ( R U ) or methimazole ( MMl ); MMI recommended to prepare patients with endogenous hyperthyroidism for surgery, for patients with Graves' disease, and for patients with toxic nodules who do not wish to have definitive treatment with - radioactive iodine or surgery radioactive iodine thyroid ablation for Graves' disease and toxic nodules/ adenoma surgery in the form of hemi, subtotal, or complete thyroidectomy for toxic nodules surgery in the form of total thyroidectomy for Graves’ disease Graves’ Disease Definition an autoimmune disorder characterized by autoantibodies that stimulate the TSH receptor leading to hyperthyroidism Epidemiology most common cause of hyperthyroidism occurs at any age with peak in 3rd and 4 th decade F:M =7:1, 1.5-2% of women in the United States 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 DR 3 may be associated with other autoimmune disorders (e.g. pernicious anemia, Hashimoto’s disease ) Graves' Ophthalmopathy NO SPECS (In the usual order of changes) No signs Only signs: lid lag, lid retraction Soft tissue: periorbital puffiness, conjuctival injection, diemosis Proptosis/ exophthalmos Extraocular (diplopia ) Corneal abrasions (unable to close eyes) Sight loss Etiology and Pathophysiology autoimmune disorder due to breakdown in thyroid tolerance likely due to a combination of factors including autoreactive B lymphocytes and an imbalance favouring a TH 2 vs. TH 1 immune response B lymphocytes produce 1 SI that binds and stimulates the I SH receptor, and thus, the thyroid gland immune response can be triggered by postpartum state, iodine excess, viral or bacterial infections, and glucocorticoid withdrawal ophthalmopathy ( thyroid associated orbitopathy) is a result of increased connective and extraocular muscle tissue volume due to inflammation and accumulation of glycosaminoglycans, stimulated by TS1, that increase osmotic pressure within the orbit; this leads to fluid accumulation and forward displacement of the eyeball dermopathy ( pretibial or localized myxedema ) may be related to cutaneous glvcosaminoglycan deposition ' Clinical Features signs and symptoms of thyrotoxicosis diffuse goitre ± thyroid bruit secondary to increased blood flow through the gland ophthalmopathy: proptosis, diplopia, conjunctival injection , corneal abrasions, periorbital puffiness, lid lag, decreased visual acuity ( plus signs of hyperthyroidism: lid retraction, characteristic stare) dermopathy ( rare ): pretibial myxedema ( thickening of dermis that manifests as non - pitting edema ) acropachy: clubbing and thickening of distal phalanges Investigations low TSH increased free T4 (and /or increased T3) positive for TR Ab ( the currently available third - generation T'RAb tests have sensitivity and specificity over 98%, allowing their use for determining the etiology of hyperthyroidism ) increased RA 1 U homogeneous uptake on thyroid scan AL GRAWANY Other Medications Used in the Treatment of Graves' G lucocorticoids have been useful in the treatment of severe Graves’ hyperthyroidism and thyroid storm, by inhibiting the conversion of peripheral T« to T3 Lithium can also be used to treat Graves' hyperthyroidism. It acts by blocking thyroid hormone release, but its toxicity has limited its use in practice m Caution with Thionamides These drugs are highly effective inhibitors of thyroid hormone synthesis, inducing permanent remission in 20-30% of patients with Graves' disease. They are most often employed to achieve a euthyroid state before definitive treatment. Adverse effects include teratogenicity, agranulocytosis, hepatotoxicity. and ANCApositive vasculitis rn LJ + Activate Windows Go to Settings to activate Windows. Toronto Xotcs 2023 E28 Endocrinology Treatment thionamides (antithyroid medications): PTU or methimazole MMI. In 2020, PTU became unavailable in Canada and it is unclear whether it will be available in the future PT U and MMI inhibit thyroid hormone synthesis by inhibiting peroxidase catalyzed reactions, thereby inhibiting organification of iodide, blocking the coupling of iodoty rosines PTU also inhibits peripheral deiodination of T4 to T3 treat for approximately 12 18 mo aiming for a normal TSH and TKAb prior to consideration of treatment discontinuation small goitre, mild hyperthyroidism , and low TRAb titres are good predictors for long- term remission with medical therapy remission ( normal thyroid indices one vr after discontinuation of PTU or MMI ) rates range between 20 30% following 12 18 mo of antithyroid medication major side effects: hepatotoxicity (cholestasis, hepatitis), agranulocytosis, vasculitis minor side effects: minor rash, pruritus MMI is preferred to PTU due to longer duration of action (once daily dosing for most ), more rapid resolution of hyperthyroidism , and lower incidence of side effects in pregnancy: use PTU during first 16 wk of pregnancy and MMI after. MMI is contraindicated in the first trimester due to risk of aplasia cutis; MMI is preferred in the second and third trimester due to the potential risk of hepatotoxicity with PTU in the second and third trimesters symptomatic treatment with p blockers thyroid ablation with radioactive 1-131 if PT U or MMI trial does not produce disease remission or patient prefers definitive treatment with RA1 high incidence of hypothyroidism after 1 131 requiring lifelong thyroid hormone replacement contraindicated in pregnancy may worsen ophthalmopathy; concurrent treatment with prednisone if high risk for or if ophthalmopathy present total or near total thyroidectomy (indicated for large goitres, suspicious nodule for cancer, if patient is intolerant to thionamides and dedines/is not a candidate for RAI ablation , women who wish to conceive in the near future warranting rapid control of hyperthyroidism , uncontrolled hyperthyroidism not responding to anti-thyroid drugs in pregnancy (surgery safest in second trimester), patient preference) risks: permanent hypothyroidism , hypoparathyroidism , and vocal cord palsy due to potential laryngeal nerve damage ophthalmopathy/orbitopathy smoking cessation is important prevent drying of eyes and ulceration of cornea by using artificial tears during the day and lubricants at night high dose prednisone or IV methylprednisolone in severe cases high dose glucocorticoids preferably IV as well as potential orbital decompression surgery for sight threatening orbitopathy orbital radiation, surgical decompression - - - - - - Prognosis course involves remission and exacerbation unless gland is destroyed by radioactive iodine or surgery total and subtotal thyroidectomy are rapid cures with low - risk of recurrence ( 2% and 10%, respectively) radioactive iodine is less invasive than surgery, but also results in permanent hypothyroidism and requires precautions in contacts several days after treatment - medical therapy with thionamides is not invasive, but has high recurrence rate at 50% lifetime follow- up needed ri L j + Activate Windows Go to Settings to activate Windows. E29 Endocrinology Toronto Notes 2023 Subacute Thyroiditis ( Thyrotoxic Phase) there are two main types: painful (de Quervain’s) and painless (silent ) Table 18. Painful vs. Painless Subacute Thyroiditis Painful Thyroiditis (de Ouervain’s, granulomatous) Pathophysiology Presumed lo be caused by viral infection or postviral inflammatory process - Painless Thyroiditis (silent, autoimmune ) Considered variant ol Hashimoto 's thyroiditis Associated with HLA 0 R 3 Postpartum subtype occurs following pregnancy Strongly associated with HLA D 35 Thyroid inflammation damages thyroid follicles, resulting in release Also caused by inflammatory damage leading lo unregulated release ol Ii and 1i into circulation ol large amounts ol T 4 and 13 until stores are exhausted Slate ol hypothyroidism often persists until thyroid can generate suflicient thyroid hormones. Clinical Features Painful swelling of the thyroid ( may radiate to jaw and ears) transient vocal cord paresis, malaise, fatigue , myalgia , fever Often preceded by IIRTI Painful condition lasts for a week to lew months Signs of hyperthyroidism during hyperthyroid phase (palpitations. tachycardia , stare) Thyroid enlargement without discomlorl in association with the typical thyroid function test abnormalities consisting of hyperthyroidism , hypothyroidism , and recovery Signs of hyperthyroidism during hyperthyroid phase ( palpitations, tachycardia , stare) Allects women more than men Laboratory Investigations Initial elevated Tiandh Near absentRAIU ( SR and CRP often elevated Initial elevated Ti and I: Near absent RAIU NSAID/ prednisone for pain P -adrenergic blockage is usually eflective in reversing treatment hypcrmctabollc and cardiac symptoms fl adrenergic blockage is usually effective in reversing most of the Prognosis - most ol the hypermetabolic and cardiac symptoms II symptomatically llypolhyroid , may treat short term - If symptomatically hypothyroid , may treat short term with thyroxine with thyroxine Complete spontaneous recovery to normal thyroid lunction in 90% 10 % ol patients may become permanently hypothyroid ol patients Al risk ol recunen! episodes of thyroiditis 10% of patients may become hypothyroid and require permanent replacement Toxic Adenoma / Toxic Multinodular Goitre Etiology and Pathophysiology autonomous thyroid hormone production from a functioning adenoma that is hypcrsecreting T4 and T3 may be singular ( toxic adenoma ) or multiple ( toxic multinodular goitre ( Plummer’s disease)) more common in elderly people as opposed to Graves' disease which is more common in younger individuals Clinical Features multinodular goitre tachycardia , heart failure , arrhythmia , weight loss, nervousness , weakness , tremor, and sweats local neck compression symptoms such as dysphagia, dysphonia, or dyspnea may be present with large goitres Investigations low TSH , high free T4 and free T 3 thyroid scan with increased RAIU in nodule (s ) and suppression of the remainder of the gland Treatment use high dose radioactive iodine (1- 131) to ablate hyperfunctioning nodules - blockers often necessary for symptomatic treatment prior to definitive therapy surgical excision may also he used as first - line treatment p initiate therapy with PTU or MM 1 to attain euthyroid state in individuals who do not wish to have definitive treatment of their disease, in preparation for thyroidectomy, or prior to RA1 in patients at risk for complications due to exacerbation of hyperthyroidism following RA 1 such as the elderly with cardiovascular disease Thyrotoxic Crisis/ Thyroid Storm Definition medical emergency - acute exacerbation of all of the symptoms of thyrotoxicosis presenting in a life - threatening state secondary to uncontrolled hyperthyroidism rare, but serious with mortality rate between 10 - 30% + Etiology and Pathophysiology often precipitated by infection , trauma , or surgery in a hvperthyroid patient Activate Windows Go to Settings to activate Windows. E30 Endocrinology Toronto Notes 2023 Differential Diagnosis sepsis, pheochromocytoma, malignant hyperthermia, drug overdose, neuroleptic malignant syndrome Clinical Features hyperthyroidism extreme hyperthermia (S40°C), tachycardia, vomiting, diarrhea, hepatic failure with jaundice, atrial fibrillation , CHE CNS manifestations including agitation , delirium , psychosis, lethargy, seizures, coma Laboratory Investigations increased free T4 and T3, undetectable TSH ± anemia, leukocytosis, hyperglycemia, hypercalcemia , elevated LET* General Measures fluids, electrolytes, and vasopressor agents should be used as indicated a cooling blanket and acetaminophen can be used to treat the pyrexia propranolol or other (1 blockers can additionally be used, but should be used with caution in patients with decompensated heart failure as they may worsen condition propranolol is frequently used because it decreases peripheral conversion of T4 to T3 - Specific Measures PTU is the anti-thyroid drug of choice and is used in high doses ( 200 mg q4 h ) give iodide, which acutely inhibits the release of thyroid hormone, 1 h after the first dose of PTU is given sodium iodide I g IV drip over 12 h q 12 h OR Lugol’s solution 10 drops q8 h OR potassium iodide (SSKI ) 5 drops q6 h hydrocortisone 100 mg IV q8 h or clexamethasone 2 4 mg IV q6 h for the first 24 48 h; inhibits peripheral conversion of T4 to T3 - - Hypothyroidism Definition clinical syndrome caused by insufficient thyroid hormone production Epidemiology 2-3% of general population F:M =10:1 10 20% of women >50 have subclinical hypothyroidism ( normal '14, TSH mildly elevated ) iodine deficiency is the most common cause worldwide, but not in North America. - Etiology and Pathophysiology primary hypothyroidism (90%) inadequate thyroid hormone production due to an intrinsic thyroid defect - - iatrogenic: post ablative (1 131 or surgical thyroidectomy ) autoimmune: Hashimoto's thyroiditis hypothyroid phase of subacute thyroiditis drugs: goitrogens ( iodine), PTU , MM I, lithium infiltrative disease ( progressive systemic sclerosis, amyloid ) iodine deficiency » congenital (1/4000 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 ( Refetoif syndrome ) u f adore Affecting Gastrointestinal Absorption of levothyrorine: A Review Cl* Titer 201); 39|2):3 403 (I disorders such as cebac disease, atrophic gastritis, lactose intolerance H. pylori infection nay impede levotbyroiine absorption. t i t , - net -fr - ; : v tv : c:. i - q ;:: to significantly reduce exogenous Ibyroid hormone absorption from the Gi tract These wictude proton pump inhibitors H2 receptor antagonists, calcium carbonate, sucralfate, and aluminum bydronde. - te- i t i n a l :: : i I c r a t e s s o o - :: oflerothyrorine. food, especially soybeans andcoffee hare been shown to leduce absorption of levoUiyroxine significantly. Roughly 80% of lerotfiyroiine is absorbed within 3 h after administration of the drug. Thus, patients Should be educated to take levothyroniae on empty stomach at least 1 b prior to eating breakfast. «.... ‘. -. '.. Table 19. Interpretation of Serum TSH and Free T« in Hypothyroidism Serum TSH FreeTi Subclinical Primary Hypothyroidism Increased Increased Decreased Normal Secondary Hypothyroidism Decreased or not appropriately elevated Decreased Overt Primary Hypothyroidism rn LJ + Activate Windows Go to Settin to a ivate Window E 31 Endocrinology Toronto Notes 2023 Clinical Features Table 20. Clinical Features of Hypothyroidism General Fatigue, cold intolerance , slowing of mental and physical performance , hoarseness, macroglossia CVS Pericardial effusion, bradycardia , hypotension. worsening CHF * angina. hypercholesterolemia, hypcihomocystcincmia , myxedema heart Respiratory Decreased exercise capacity, hypoventilation secondary to weak muscles, decreased pulmonary responses lohypoxia, sleep apnea due to macroglossia Gl Weightgain despite poor appetite. constipation Neurology Paresthesia , slow speech, muscle Clamps , delayed deep tendon reflex relaxation |“hung reflexes") , carpal tunnel syndrome , asymptomatic elevated CK. scuures GU Menorrhagia, amenorrhea, impotence, pre- menopausal abnormal vaginal bleeding Dermatology Facial pulfmess. periorbital edema , cool and pale, dry and rough skin dry and coarse hair, eyebrows thinned ( lateral 1/ 3), discolouration (carotenemia) Hematology Anemia: 1D\ pernicious due to piesencc ol anti parietal cell antibodies with Hashimoto' sthyioidilis , Subclinical Hypothyroidism: A Review JAMA 2019;322:153-160 Ebckground Up a MS ot the adultpop ialion tiptnencn jubtlinital hypethyro dism, defined a elevated ISH (»4.4 mUfl| with notmalleeeIs ol fiee 14. The deqiee of abnormality that warrants management is controversial. Observations: Sjbtlinical hypotfiyrodism is most often caused byautoimmune thyroiditis, ttmay be associated w th increased nskof OIF and CAD events Further substantial portion of patients with subclinical hypothyroidism progress to overt hypothyroidism,hrdence from large RCIs to support levotbyroiine therapy in these patients is lacking. The rationale for treatment is therefore based on levathyronme 'spotential to prevent cardiovascular events and progress on to overt hypothyroidism Recommendations : Most individuals with subclinical hypothyioidismcan beobsetvedvi thou! treatment. Candidates for levotbyroiine therapy include those with serum ISH levels >10 mU/Land young and middle -aged patients with symptor sof mild hypothyroidism. -..* - Treatment L-thyroxine (dose range: 0.05-0.2 mg PO once daily, up to 1.6 pg / kg /d) elderly patients and those with CAD: start at 0.025 mg daily and increase gradually every 6 wk (start loss’, go slow) after initiating L thyroxine, TSH needs to be evaluated in 6 wk ; adjust dose until TSH returns to normal reference range once maintenance dose achieved, follow up TSH with patient annually secondary/tertiary hypothyroidism: monitor via measurement of free T4 ( TSH is unreliable in this setting ) CONGENITAL HYPOTHYROIDISM see Paediatrics, P34.. Signs and Symptoms of HYPOthyroidism HIS FIRM CAP Hypoventilation Intolerance to cold Slow HR Fatigue Hashimoto’s Thyroiditis Definition most common form of primary hypothyroidism in North America chronic autoimmune thyroiditis characterized by both cellular 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 of lymphocytic infiltration, fibrosis, and thyroid follicular cell hyperplasia goitrous variant usually presents with a small, rubbery goitre and euthyroidism, then hypothyroidism becomes evident associated with fibrosis atrophic variant patients arc hypothyroid from onset Impotence Renal Impairment Menorrhagia /amenorrhea Constipation Anemia Paresthesia risk factor for rare primary thyroid lymphoma Etiology and Pathophysiology defect in a T-suppressor clone leads to cell - mediated destruction of thyroid follicles B lymphocytes produce antibodies against thyroid components including thyroglobulin , thyroid peroxidase, TSH receptor, Nat / I symporter - Risk Factors F:M=7:1 genetic susceptibility: increased frequency in patients with Down's syndrome, Turner's syndrome, certain HLA alleles, cytotoxic T lymphocyte associatcd protein 1 ( CTLA 4 ) family Hx or personal Hx of other autoimmune diseases cigarette smoking high iodine intake - - - - Investigations high TSH, low T4 ( not necessary to measure T3 as it will be low as well ) presence of TPOAb and TgAb in serum Treatment r » - if hypothyroid, replace with L thyroxine ( analog of '1'4) L J Myxedema Coma Definition - +. medical emergency severe hypothyroidism complicated by trauma , sepsis , cold exposure Ml, inadvertent administration of hypnotics or narcotics, and other stressful events rare; high level of mortality ( up to 40%, despite therapy ) Activate Windows Go to Settings to liveate Windows. E32 Endocrinology Toronto Notes 2023 Clinical Features decreased mental status and hypothermia are hallmark symptoms hyponatremia , hypotension , hypoglycemia , bradycardia, hypoventilation, and generalized non - pitting edema often present Investigations decreased T4, increased TSH, decreased glucose check ACTH and cortisol for evidence of adrenal insufficiency Treatment aggressive and immediate treatment required ABCs: 1CU admission corticosteroids ( for risk of concomitant adrenal insufficiency ): hydrocortisone 100 mg q8 h L thyroxine 0.2 0.5 mg IV loading dose, then 0.1 mg IV once daily until oral therapy tolerated: also consider T3 therapy supportive measures: mechanical ventilation, vasopressors, passive rewarming, IV' dextrose, fluids if necessary ( risk of overload ) monitor for arrhythmia - - Non-Thyroidal Illness ( Sick Euthyroid Syndrome) Definition changes in the regulation of the hypothalamic-pituitarv-thyroid axis, and thyroid hormone metabolism and transport among patients with severe illness, trauma , surgery, or starvation not due to intrinsic thyroid, pituitary, or hypothalamic disease initially low free T3 may be followed by low TSH and, if severe illness, low free T4 with recovery of illness, TSH may become transiently high Pathophysiology abnormalities include alterations in: peripheral transport and metabolism of thyroid hormone regulation of TSH secretion may be protective during illness by reducing tissue catabolism Labs initially decreased free T3 followed by decreased TSH and Anally decreased free T4 with recovery of illness, TSH may become elevated Treatment treat the underlying disease; thyroid hormone replacement has not shown to be benefleial thyroid function tests normalize once patient is well (initially with a transient increase in TSH ) 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 to present during adolescence, pregnancy, and lactation due to 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 ftbrosis Etiology iodine deftciency or excess goitrogens: brassica vegetables (e.g. turnip, cassava ) drugs: iodine, lithium, para aminosalicylic acid - any disorder of hormone synthesis with compensatory growth peripheral resistance to thyroid hormone Treatment remove goitrogens n LJ radioiodine therapy ( very high doses required given low iodine uptake, used as last resort in very highly selected cases where the goiter is causing symptoms and surgery is not feasible ) suppression with L thyroxine ( rarely done ) surgery may be necessary’ if severe compressive symptoms develop ( rare); patients are often asymptomatic - + Complications compression of neck structures causing stridor, dysphagia, pain, and hoarseness of voice multinodular goitre may become autonomous leading to toxic multinodular goitre and hy'perthyroidism Activate Windows Go to Settings to activate Windows. E33 Endocrinology Toronto Notes 2023 Thyroid Nodules Definition discrete lesion that can be distinguished sonographically from the rest of the thyroid parenchyma 19-67% prevalence based on incidentally found nodules on U /S 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 Investigations approach to thyroid biopsy depending on U /S characteristics of the nodule benign or very small nodules suspicious for thyroid cancer do not require ongoing surveillance small nodules suspicious for thyroid cancer require up to five years of surveillance larger nodules suspicious for thyroid cancer require biopsy Thyroid nodule on U/S Third generation TSH Normal/elevated TSH LowTSH - Thyroid scan Hot nodule No biopsy Treat hyperthyroidism Cold nodule - U/S guided biopsy if indicated based on U/S characteristics 1 U/S guided biopsy it indicated based on U/S characteristics Treat hyperthyroidism Figure 13. Approach to the evaluation of a thyroid nodule. Adapted from Of. J Goguen University of Toronto. MMMD 2013 Thyroid Malignancies see Otolaryngology. OT 37 Adrenal Cortex Adrenocorticotropic Hormone a polypeptide ( cleaved from prohormone POMC ) , secreted in a pulsatile fashion from the anterior pituitary with diurnal variability ( peak: 0200 -0400 h; trough: 1800 - 2400 h ) secretion regulated by CRH and AV'P stimulates growth of adrenal cortex and release of glucocorticoids, adrenal androgens and , to a very limited extent, mineralocorticoids ACTH can directly bind to MSH receptors on melanocytes, enhancing melanogenesis Adrenocortical Hormones Aldosterone a mineralocorticoid which regulates ECPV through Na '(and C1- ) retention and R ' (and H ’ ) excretion (stimulates distal tubule Na 1/ K+ ATPase) regulated by the RA AS and hyperkalemia negative feedbac