Endocrinology I
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Endocrine Board Review LILLIAN F. LIEN, MD DIVISION CHIEF DIVISION OF ENDOCRINOLOGY, METABOLISM, & DIABETES PROFESSOR OF MEDICINE, UMMC Part I Diabetes Lipids Bone and Calcium Thyroid WITH APPRECIATION TO: SARAH E. FRENCH, MD Disclosures for Dr. Lillian F. Lien The Department of Medicine requests the following disclosures to the lecture audience: Disclose relevant financial relationships with any commercial interest: Commercial Interest Role Medtuit Co-owner Springer Book royalties Sanofi-Aventis Consultant Merck Consultant Eli Lilly Consultant Novo Nordisk Consultant Endocrinology (8%) 17–19 questions Diabetes mellitus 5–8 Thyroid disorders 2–4 Lipid disorders 2–3 Calcium metabolism and bone 1–5 Male reproductive health 1–2 Adrenal disorders 0–2 Hypertension 0–1 Female reproductive health 0–1 Hypothalamic disorders 0–1 Anterior pituitary disorders 0–1 Posterior pituitary/water metabolism 0–1 Endocrine tumors and endocrine manifestations of tumors 0–1 Hypoglycemia not due to insulinoma 0–1 Polyglandular disorders 0–1 Nutritional disorders 0–1 Women’s health endocrine issues 0–1 Miscellaneous endocrine disorders 0–1 Diabetes Predict the results of laser photocoag therapy for diabetic retinopathy Treat Type 1, Diagnose Type 2 Differentiate Type 1 from Type 2 DM Treat DKA Diagnose cushing’s as a secondary cause of diabetes Identify nocturnal hypoglycemia Interpret A1c in pt with blood transfusion Interpret A1c (vs post prandial excursions) Treat diabetic neuropathy Hypoglycemia workup Hypoglycemia in the elderly / delayed / sulfonylurea Diagnose post exercise hyperglycemia Treat hypoglycemia unawareness Counsel about the risks to infant of the mother’s gestational diabetes Diabetes Definitions FPG >126 mg/dl (7.0 mmol/l): Fasting is defined as no caloric intake for at least 8 h. Two-hr plasma glucose >200 mg/dl (11.1 mmol/l) during an oral glucose tolerance test (OGTT): using a glucose load containing the equivalent of 75 g glucose In a patient with classic symptoms of hyperglycemia, a random plasma glucose >200 mg/dL (11.1 mmol/l). A1C >6.5%: The test should be performed in a laboratory using a method that is National Glycohemoglobin Standardization Program (NGSP) certified and standardized to the DCCT assay. DIABETES CARE, VOLUME 37 SUPPLEMENT 1, JANUARY 2014 Diabetes Mellitus Type 1 Diabetes Insulin deficiency Type 2 Diabetes Insulin resistance Why Type 1 is very different from Type 2 Diabetes Mellitus! Always give Basal Insulin (Lantus, Levemir, NPH) to your Type 1 patient Never Hold Basal insulin in Type 1, UNLESS BG is <80mg/dL In that case, treat the patient. Once BG is above 80mg/dL, then be sure to give the Basal insulin at that point, to avoid DKA later Even if the patient is “NPO”, it is SAFE for all diabetic patients, and NECESSARY for Type 1, to give the BASAL insulin, for any BG over 80mg/dL Pump patients with Type 1 As soon as pump is off, GIVE BASAL SQ INSULIN injection If need help, call Endocrine Consults ASAP Why Type 1 is very different from Type 2 Diabetes Mellitus! Patients with Type 1 are Very Insulin Sensitive so need Small Amounts! Many patients with Type 1 have a total basal dose < 10 units Correction for Type 1 should only be 1 to 4 units at the most – whereas Correction for Type 2 can be much more. Always ask “Does the pt have Type 1 or Type 2” Patients with Type 1 can go into DKA at only Slightly Elevated BGs Even sugars of 200’s – 300’s can drive a Type 1 pt into DKA Types of Diabetes Mellitus Type 1 diabetes (5-10%) Type 2 diabetes (90-95%) Formerly “Type II”, “NIDDM”, “Adult Onset” Gestational diabetes Formerly “Type I”, “IDDM”, “Juvenile Onset” Caused by destruction of insulin producing cells Diabetes develops during pregnancy and resolves after pregnancy LADA –Latent Autoimmune Diabetes of Adulthood MODY –Maturity Onset Diabetes of the Young Other causes (Cystic Fibrosis, MedicationInduced) Genetics of Type 1 and LADA Testing for Autoantibodies may help establish DM1 diagnosis GAD65, insulin(IAA), IA-2, Islet cell (ICA), ZnT8 Autoantibody clustering is different in LADA vs DM1 Clustering is characteristic in DM1; pts often + for multiple autoantibodies Alternatively, LADA pts usually positive for only one (usually anti-GAD or ICA, possibly IA-2) Secondary causes of diabetes Chronic pancreatitis Cystic fibrosis Hemochromatosis Polycystic ovarian syndrome Cushing’s syndrome Acromegaly Drugs: glucocorticoids, thyroid hormone, thiazides, dilantin, alpha interferon Somatostatinoma A1c Goal Can <7% be unreliable if Blood transfusion Decreased RBC lifespan Hemoglobinopathies Metformin Only oral agent that is weight loss/weight neutral Generally first line agent Contraindicated if Cr >1.5 in men, >1.4 in females Sulfonylurea Insulin secretagogue Contraindicated in renal failure TZDs Can have fluid retention and edema Contrainidicated in NYC Class III and IV heart failure DPP-4 inhibitors Has direct effects on insulin and glucagon Delays gastric emptying Can be used in CKD with dose reduction Non-Insulin Anti-Diabetic Medication •Class Approve d Pre2005 Glipizide (Glucotrol), Glimepiride (Amaryl ), Glyburide (Diaßeta, Glynase PresTabs, Micronase) Sulfonylurea Metformin (Glucophage, Glucophage XR) Biguanide Pioglitazone (Actos ), Rosiglitazone (Avandia ) Thiazolidinedione Repaglinide (Prandin), Nateglinide (Starlix) Meglitinide Acarbose (Precose), Miglitol (Glyset) Alpha-glucosidase inhibitor Sitagliptin (Januvia), Saxagliptin (Onglyza) DPP-IV inhibitor Exenatide (Byetta), Liraglutide (Victoza) GLP-1 mimetic Pramlintide (Symlin) Amylin mimetic Bromocriptine mesylate (Cycloset) Dopamine receptor agonist Canagliflozin (Invokana) SGLT2 inhibitor Approved Post-2005 DKA and HONK(HHNK…) Acute,life-threatening consequences of uncontrolled diabetes are hyperglycemia with Diabetic Ketoacidoses = “DKA” “THE WORSE I’VE EVER FELT” Nausea, Vomiting Weakness Lethargy Fruity Breath Abdominal Pain Hyperventilation or the Hyperosmolar nonketotic syndrome. DKA: Management Insulin drip Fluid Potassium Insulin drip EKG Follow bicarb and anion gap Diabetes is not just hyperglycemia Acute complications DKA Hyperosmolar hyperglycemic nonketotic state (HHNS) Microvascular Retinopathy Neuropathy Nephropathy Follow Blood Pressure Manage any dyslipidemia Macrovascular ACE inhibitor or ARB if proteinuria Statins have the most data Screen for complications Urine microalbumin, dilated eye exam, feet CAD PVD Smoking cessation CVD Immunizations Atherosclerosis is most common cause of death Complications of Diabetes: Retinopathy “uncontrolled neovascularization, termed proliferative diabetic retinopathy (PDR), can result in severe and permanent vision loss.” E, Neovascularization elsewhere (NVE) and two small vitreous hemorrhages (VH), also illustrating high-risk proliferative diabetic retinopathy. F, Extensive vitreous hemorrhage arising from severe neovascularization of the disc (NVD). Panretinal laser photocoagulation therapy typically results in Retained CENTRAL vision But poorer peripheral and night vision Diabetic Neuropathy First Line Classes of Therapy Voltage gated calcium channel ligand anticonvulsants Serotonin norepi reuptake inhibitors Pregabalin* and Gabapentin Venlafaxine and Duloxetine* Tricyclic Antidepressants – low dose Amitriptyline Desipramine If on the maximally effective and or tolerated dosage of one medication with no improvement, drug therapy should be changed to a first line agent of a different class *FDA approved for treatment of painful diabetic peripheral neuropathy Early morning hyperglycemia Dawn phenomenon Rise in GH and cortisol lead to morning hyperglycemia No associated hypoglycemia Somogy effect Nocturnal hypoglycemia leads to morning hyperglycemia Only way to differentiate is to check 3 AM FSG Hypoglycemia Hints Treat hypoglycemia unawareness Often by decreasing total daily insulin dose Sulfonylureas (especially those with long half lives such as glyburide) should not be used in the Elderly patient or with impaired kidney function In a patient with DM, Vigorous exercise should be followed by consumption of Complex Carbohydrates – especially if exercising in the evening (concern nocturnal hypoglycemia) IF NO evidence of nocturnal hypoglycemia, then can suspect insufficient insulin as a cause of hyperglycemia … 3 am glucose Adjusting insulin Basal insulin—controls fasting glucoses If fasting hyperglycemia—increase dose If fasting hypoglycemia—decrease dose Prandial insulin—controls post-prandial glucoses If post-prandial hyperglycemia—increase dose If post-prandial hypoglycemia—decrease dose Definition of hypoglycemia Whipple’s triad Symptoms, signs or both consistent with hypoglycemia A low plasma glucose concentration Resolution of symptoms/signs after raising plasma glucose “In the absence of Whipple’s triad, the patient may be exposed to unnecessary evaluation, costs and potential harms, without expectation of benefit.” From “Evaluation and Management of Adult Hypoglycemic Disorders: An Endocrine Society Clinical Practice Guidelines” Insulinoma Extremely rare Typically fasting hypoglycemia Whipple’s triad Have elevated insulin and C-peptide levels Negative sulfonylurea screen Interpreting laboratory data Signs Glucose Insulin Cpeptid e Proinsulin β-hydroxybutyrate Glucose after glucago n (+) sulfonylurea screen Abs Dx No < 55 <3 < 0.2 <5 > 2.7 < 25 No - Normal Yes < 55 >> 3 < 0.2 <5 ≤ 2.7 > 25 No - Exogenous insulin Yes < 55 ≥3 ≥ 0.2 ≥5 ≤ 2.7 > 25 No - Insulinoma Gastric bypass Yes < 55 ≥3 ≥ 0.2 ≥5 ≤ 2.7 > 25 Yes - Oral hypoglycem ic Yes < 55 >> 3 >> 0.2 >> 5 ≤ 2.7 > 25 No + Insulin Antibod y ADA Glycemic Goals for Diabetes in pregnancy For women with pre-existing type 1 or type 2 diabetes who become pregnant, a recent consensus statement (106) recommended the following as optimal glycemic goals, if they can be achieved without excessive hypoglycemia: premeal, bedtime, and overnight glucose 60–99 mg/dL (3.3–5.4 mmol/L) peak postprandial glucose 100–129 mg/dL (5.4–7.1 mmol/L) A1C <6.0% ADA Standards, DIABETES CARE, VOLUME 36, SUPPLEMENT 1, JANUARY 2013 Levemir and Lantus Lantus: Pregnancy category C: Use during pregnancy only if the potential benefit justifies the potential risk to the fetus … There are no well-controlled clinical studies of the use of LANTUS in pregnant women. Levemir: Pregnancy Category B “In an open-label clinical study, women with type 1 diabetes who were (between weeks 8 and 12 of gestation) or intended to become pregnant were randomized 1:1 to LEVEMIR® (once or twice daily) or NPH insulin (once, twice or thrice daily). Insulin aspart was administered before each meal. A total of 152 women in the LEVEMIR® arm and 158 women in the NPH arm were or became pregnant during the study (total pregnant women = 310). In the 310 pregnant women, the mean glycosylated hemoglobin (HbA1c) was < 7% at 10, 12, and 24 weeks of gestation in both arms. In the intent-totreat population, the adjusted mean HbA1c (standard error) at gestational week 36 was 6.27% (0.053) in LEVEMIR®-treated patient (n=138) and 6.33% (0.052) in NPH-treated patients (n=145); the difference was not clinically significant. No differences in pregnancy outcomes or the health of the fetus and newborn were seen with LEVEMIR® use.” Insulins in Pregnancy Castorino K, Jovanovič L. Pregnancy and diabetes management: advances and controversies. Clin Chem. 2011 Feb;57(2):221-30. Diabetes in pregnancy A1c < 7% before conception Retinopathy may worsen during pregnancy Remember: statins, ACEIs, and ARBs are contraindicated Gestational Diabetes Infant has an increased risk of Childhood Obesity 50% of patients may go on to develop Type 2 over 10 years NOT associated with MODY NOT associated with Type 1 Lipids Lipid profile Ideally after 14 hour fast and no alcohol for 3 days LDL is calculated Total cholesterol – HDL – triglycerides/5 Not accurate if triglycerides > 400 VLDL and chylomicrons are rich in triglycerides Hyperlipidemias May be primary (genetic) or secondary (meds, other diseases). Hypercholesterolemia—elevated cholesterol with normal triglycerides Hypertriglyceridemia—elevated triglycerides with normal cholesterol Mixed hyperlipidemia—elevated cholesterol and triglycerides Familial hyperlipidemia Lipoprotein lipase (LPL) deficiency “TYPE 1” (HIGH TRIG, nl chol) Cannot degrade chylomicrons and VLDL Triglycerides > 1000 Eruptive xanthomas with high triglycerides Familial hypercholesterolemia “TYPE 2A” (nl trig, HIGH CHOL) Reduction or absence of LDL receptor Tendinous xanthomas Familial hyperlipidemia Familial combined hyperlipidemia “Type 2B” (BOTH HIGH) Most common genetic hyperlipidemia (1%) Increase ApoB 100 → ↑LDL and ↑ VLDL Premature CAD No risk for xanthomas – just isolated xanthelasma Familial dysbetalipoproteinemia “Type 3” (BOTH HIGH) Elevated IDL (total cholesterol and triglycerides) Associated with diabetes, obesity and alcohol abuse Palmar xanthomas (“yellow hands”) Other classical hyperlipidemias Primary hypertriglyceridemia “TYPE 4” (HIGH TRIG, nl chol) May or may not be associated with premature CAD Mixed Hyperlipidemia “TYPE 5” (BOTH HIGH) High Cholesterol and High Triglycerides Eruptive xanthoma Only “may be associated” with premature CAD Do not confuse with Type 2B Familial Combined Tendon xanthoma Elevated LDL Familial hypercholesterolemia Eruptive xanthomas Elevated triglycerides Tuberous xanthomas Elevated triglycerides Palmar xanthomas Elevated IDL Familial dysbetalipoproteinemia Normal retina Lipemia retinalis Elevated triglycerides Lipid disorder scenarios Young child with TG of 8000, pancreatitis, eruptive xanthomas, lipemia retinalis, positive family history. Most likely diagnosis? Lipoprotein lipase deficiency – unable to degrade VLDL and chylomicrons. 32 yo man with CAD, LDL 350, TG normal and tendon xanthomas. +Familly hx of premature CAD. Diagnosis? Familial hypercholesterolemia (LDL receptor defect; LDL >300). Autosomal dominant with variable penetrance. 48 yo woman with premature CAD and severe PVD. +Tuberous and palmar xanthomata. TC 380, TG 400, LDL 50. Diagnosis? Familial dysbetalipoproteinemia—High levels of IDL cause severe PVD and early CAD. Treat with statins and fibrates. TC and TG roughly equal with low LDL. Secondary hyperlipidemia Increased LDL Hypothyroidism Increased triglycerides Poorly controlled diabetes Oral estrogens Alcohol Increased LDL and triglycerides Nephrotic syndrome HCTZ Beta blockers Glucocorticoids Secondary hyperlipidemia Treat secondary causes FIRST! If hypothyroid, normalize TSH and then repeat lipid profile. If uncontrolled diabetes, normalize A1c and repeat lipid profile. If oral estrogens, change to patch or change method of birth control. If excessive alcohol intake, work on cessation Treatment of hyperlipidemia LDL Statins +/- ezetimibe Bile acid resins Triglycerides Fibrates Combined hyperlipidemia Statin and fenofibrate (safer than gemfibrozil) Niacin (best for HDL) Lipid goals in diabetes LDL < 100 for every diabetic < 70 high risk First choice is statin – caution in female of child bearing age Triglycerides <150 First treatment is glycemic control Fenofibrate safer than gemfibrozil when in combo with statin (less rhabdo) Secondary target (treat LDL first) unless >500 BONE and calcium Treat hypercalcemia Diagnose FHH Diagnose TB induced hypercalcemia Diagnose humoral hypercalcemia of malignancy Diagnose Paget’s disease Diagnose Vitamin D deficiency Manage post thyroidectomy hypoparathyroidism Diagnose hungry bone Manage hypocalcemia in alcoholism Treat a female with low bone mass Manage secondary osteoporosis Hormonal regulation of calcium Parathyroid hormone (PTH) Increases serum calcium Bone resorption Renal resorption Decreases phosphorus Indirectly increases renal hydroxylation of 25-OH vitamin D to active form of 1,25 (OH)2 vitamin D3 Vitamin D Increases serum calcium Intestinal absorption Increases phosphorus Clinical manifestations of hypercalcemia GI symptoms Cardiac arrhythmias Anorexia Sinus bradycardia Nausea AV block Vomiting Shortening QT interval Constipation Nephrogenic diabetes inspidius Dehydration Myopathy Nephrolithiasis Nephrocalcinosis Band keratopathy Pruritus Altered mental status Pancreatitis Differential diagnosis of hypercalcemia Primary hyperparathyroidism Malignancy Granulomatous diseases Thyrotoxicosis Drugs HCTZ Lithium Hypervitaminosis A Hypervitaminosis D Tertiary hyperparathyroidism Familial hypocalciuric hypercalcemia Immobilization Milk-alkali syndrone Primary hyperparathyroidism Most frequent cause of hypercalcemia as outpatient Often asymptomatic Solitary adenoma (80%) >> four gland hyperplasia (15-20%) >> carcinoma (< 1%) Elevated or “inappropriately normal” PTH at the same time as a high calcium consistent with primary hyperparathyroidism (or FHH –non surgical) Secondary hyperparathyroidism Treatment any underlying vitamin D deficiency Vitamin D deficiency is secondary cause of hyperparathyroidism Watch renal function Unlike primary and tertiary, will not have elevated calcium Tertiary hyperparathyroidism Autonomous function; loss of negative feedback Hypercalcemia Indications for parathyroidectomy Asymptomatic patients with Age < 50 Severe hypercalcemia - usually >1 mg/dL above upper normal Decreased glomerular filtration rate Decreased bone density (revealing a T score <-2.5) [3,4]. Symptomatic patients with Polydipsia and polyuria Nephrolithiasis debilitating hyperparathyroid bone disease - osteitis fibrosa cystica bone pain and radiographically by subperiosteal bone resorption on the radial aspect of the middle phalanges tapering of the distal clavicles a "salt and pepper" appearance of the skull bone cysts, and brown tumors of the long bones Pancreatitis Ulcer disease and GERD Significant neurocognitive dysfunction Recurrent Primary Hyperpara Familial syndromes – MEN, Familial hyperparathyroidism Parathyroid cancer (rare) Parathyroid crisis severe hypercalcemia with the serum calcium concentration usually above 14 mg/dL (3.8 mmol/L), and marked symptoms of hypercalcemia, in particular, central nervous system dysfunction, nausea, and vomiting. In pts with ESRD Refractory pruritus (see "Uremic pruritus") in pt with ESRD Progressive extraskeletal calcification or calciphylaxis Otherwise unexplained myopathy ( Parathyroidectomy Four-gland exploration Mandatory in familial forms of hyperparathyroidism Need experienced surgeon Minimally invasive parathyroidectomy Single gland involvement (adenoma) Localization Sestamibi scintigraphy Neck ultrasound Intra-operative measurements Calcium scenarios 64 yo man with Calcium 10.8, PTH 135 (10-65). Diagnosis? Primary Hyperparathyroidism PTH is inappropriately normal - If >25 with hypercalcemia, then primary HPT 70 yo smoker with dysphagia to solids, then liquids; presents with altered mental status and dehydration. Calcium 14, Albumin 2. Diagnosis? Hypercalcemia of Malignancy Malignancy-associated hypercalcemia Altered mental status and dehydration Tends to progress rapidly and have serum calcium >12 mg/dL 80% due to PTHrP –Humoral hyperca of malignancy Hypercalcemia, hypophosphatemia, ↓PTH Most commonly associated malignancies: Squamous cell carcinoma of lung, esophagus, cervix, head/neck Breast cancer Lymphoma Carcinoma of kidney, bladder and ovary Local osteolytic hypercalcemia remaining 20% Lytic metastasis with extensive destruction Mediated by cytokines Multiple myeloma and breast carcinoma Rarely 1,25 (OH)2 vitamin D3 production Hodgkin, B cell lymphoma, HTLV-1 Treatment: steroids Familial hypocalciuric hypercalcemia Autosomal dominant mutation in calcium sensing receptor Usually asymptomatic PTH inappropriately normal Calcium clearance/creatinine clearance ratio <0.01 Treatment: NO SURGERY Granulomatous disease Macrophages have 1-α-hydroxylase which produces the active form 1,25 (OH)2 vitamin D3 Seen in sarcoidosis, tuberculosis, histoplasmosis, leprosy, siliconeinduced granulomatosis Treatment: steroids Drug-induced hypercalcemia Thiazide Lithium Increased urinary calcium reabsorption Resets calcium setpoint for PTH Calcium carbonate (milk-alkali syndrome) Generally >10 grams daily Becoming more common (osteoporosis, ERSD) 62 yo woman evaluated for 1 week history of fatigue, lethargy, constipation and nocturnal polyuria and polydipsia. Patient has advanced breast cancer, which has metastasized to liver. Conventional therapy is no longer helpful and she is scheduled to see oncologist to discuss treatment. Physical exam shows pale and somnolent woman. BP 98/65 and resting pulse 103. Mucous membranes dry. Liver edge palpated 3 cm below costal margin. Lab studies: BUN 37, calcium 15.7, creatinine 1.4, sodium 151. What is most appropriate immediate next step in treating this patient? IV bisphosphonate IV furosemide IV glucocorticoids IV normal saline Treatment of hypercalcemia Hydration, hydration, hydration! Bisphosphonates: pamidronate and zoledronic acid Effect is not immediate Need to know Vitamin D status if pre-op patient (to avoid post-op Hungry Bone Syndrome) Steroids mainly for granulomatosis disease or hematologic malignancies Lasix is mainly for volume overload Paget’s Disease Disease of increased bone turnover Bone pain with elevated alkaline phosphatase Bone scan: focal uptake with no evidence of cancer. If affecting skull osteoporosis circumscripta Risk of cranial nerve palsies, particularly CN VIII Risk of fracture at site of bone turnover Therapy–bisphosphonate Osteoporosis circumscripta Hypocalcemia Low vitamin D: ↓Ca ↓Phos ↑PTH Secondary hyperparathyroidism is compensatory mechanism Diagnosis of D deficiency – 25-OH-vitamin D level Treatment: give vitamin D Hypoparathyroidism: ↓ Ca ↑Phos ↓ PTH Usually complication of total thyroidectomy Treatment: calcium and calcitriol Pseudohypoparathyroidism: ↓ Ca ↑Phos ↓ PTH Defect in PTH receptor → PTH resistance Characteristic phenotype: short, obese, round face, mental retardation, short 4th and 5th metacarpals and metatarsals Albright Hereditary Osteodystrophy Hypocalcemia Give IV calcium if symptomatic Otherwise, give oral calcium and vitamin D Calcium gluconate preferred to calcium chloride Calcium chloride vs calcium citrate Only treat to calcium of 8.0-8.5 (low normal) Enough to prevent symptoms Not enough to cause hypercalciuria In a malnourished pt with alcoholism … suspect both hypocalcemia and hypoMAGNESEMIA Hungry bone syndrome Usually occurs after parathyroidectomy Hypocalcemia and Hypophosphatemia (even with normal PTH) These are minerals consumed by the bone The unmineralized bone matrix (produced during the period of hyperpara) Begins To Mineralize after the PTH level becomes more normal Potentially also HypoMagnesemia and HyperK Requires an abrupt decrease in PTH release that upsets the equilibrium between calcium efflux from bone and influx into the skeleton during bone remodeling. Risk Factors Volume of the resected adenoma Preoperative blood urea nitrogen concentration Preoperative alkaline phosphatase concentration Older age Also – Vitamin D deficiency MKSAP, UpToDate Risk factors for osteoporosis Thin Alcohol Caucasian Smoking Female gender First degree relative with osteoporosis Rheumatoid arthritis Use of glucocorticoids Indications for bone mineral density Female > 65 years old Post-menopausal female <65 years if: 1st degree relative, smoker, weight < 127 lbs Male >70 years old Fragility fracture Glucocorticoids >3 months Medical condition associated with osteoporosis Hyperparathyroidism, Cushing’s disease, etc Interpreting DEXA results T-score compares patient to 30-year woman Z-score compares patient to age-related controls Normal—T-score > -1 Osteopenia—T-score > -1 but < -2.5 Use FRAX score to determine who to treat If risk >3% hip and >20% any, treat patient Osteoporosis—T-score < -2.5 Note causes of “Secondary osteoporosis / osteopenia” Malabsorption/celiac dz Hypogonadism Vitamin D deficiency Primary Hyperparathyroidism Multiple myeloma Osteoporosis therapy Drug Spine Hip Bisphosphonates + + Raloxifene + - Tamoxifen + + Calcitonin + - Teriparatide + + Useful for bone pain. Tachyphylaxis limits use. Stop use after 2 years → risk of osteosarcoma. Osteomalacia Decreased bone mineralization usually from vitamin D deficiency In kids, we call it rickets Typically older patient with bone pain and proximal muscle weakness Check 25-OH vitamin D and replace to >30 • Also see ↓ Ca, ↓ PO4, ↑ alk phos, ↑ PTH Work-up vitamin D deficiency Calcium scenarios 68 yo woman with newly diagnosed osteoporosis starts zoledronic acid therapy 2 days before presentation and presents to the ER with tetany and palpitations. What happened? Bisphosphonate Induced Hypocalcemia - Most common several days after infusion in Vitamin D deficient patients. Always replace Vitamin D to 30 before starting bisphosphonate therapy. 72 yo woman s/p parathyroidectomy due to primary hyperparathyroidism develops calcium 6.9 on POD #1. Magnesium is normal pre-op. Next step? Check phosphorus level. Low Phosphorus – Hungry Bone Syndrome – Give calcium/D High Phosphorus – Hypoparathyroidism – Give Calcium/Rocaltrol thyroid Diagnose subacute thyroiditis Treat Graves’ ophthalmopathy Treat multinodular goiter Thyroid storm Treat hyperthyroidism in pregnancy Evaluate thyroid nodules with FNA Diagnose thyroid lymphoma Manage medullary thyroid carcinoma Treat Stage III thyroid ca with RAIManage subclinical hypothyroidism Manage hypothyroidism in pregnancy Diagnose hypothyroidism in a critically ill patient Treat myxedema coma Diagnose a TSH stimulating pituitary tumor #28 Thyroid function tests (TFTs) TSH If ↓ TSH → hyperthyroidism OR SECONDARY HYPOthyroidism In secondary hypothyroidism, replacement is adjusted with thyroid hormone levels, not TSH If ↑ TSH → Primary hypothyroidism Use to screen and follow thyroid replacement Total T4 All T4 (but 99.98% protein-bound) ↑TBG , ↑ total T4, normal free T4 Pregnancy, estrogens, tamoxifen, HIV, phenothiazines ↓ TBG , ↓ total T4, normal free T4 Androgens, glucocorticoids, nephrotic syndrome, cirrhosis Thyroid function tests (TFTs) Free T4 Key in diagnosis of central / secondary hypothyroidism Diagnosis and response to therapy in hyperthyroidism Total/free T3 Check if suspect T3 toxicosis Thyroglobulin Low in factitious thyrotoxicosis Used to monitor thyroid cancer Thyroid function tests (TFTs) Thyroid uptake Normal uptake approximately15% ↑uptake: Graves, toxic multinodular goiter, solitary toxic adenoma ↓uptake: thyroiditis, factitious hyperthyroidism Thyroid scan Hot nodule = benign Cold nodule > 1 cm needs FNA Euthyroid sick syndrome Seen in critically ill patients Impairs body’s ability to peripherally convert T4 to T3 “Euthyroid sick” T4 converts to reverse T3 See normal TSH, and abnormal free T3 and/or T4 “NON THYROIDAL ILLNESS SYNDROME “ Is the terminology when TSH is off – but still shouldn’t be more than 10 uu/mL DON’T CHECK TFTs IN SICK PATIENTS unless you think it’s thyroid storm or myxedema coma Thyroid replacement would be controversial in euthyroid sick Causes of hyperthyroidism Graves disease (TSI/Trab, Leakage or ExtraThyroidal Sources … LO RAI UPTAKE Toxic multinodular goiter - Subacute Thyroiditis Increased Production of Thyroid Hormones - exophthalmos*) - (If goiter impinges on trachea/esophagus/RLNerve, consider thyroidectomy) - Molar Pregnancy (hCG) - Iodine-induced (JodBasedow) - TSH-pituitary adenoma *Graves’ ophthalmopathy: • Ophtho Referral! • Steroids if severe • Avoid radioactive iodine therapy - Silent/post-partum thyroiditis - Thyrotoxicosis factitia - Struma ovarii Therapy for hyperthyroidism Medical Beta blocker (propranolol has T4 to T3 conversion blocking) Antithyroid Therapy – only works if hi-uptake Propylthiouracil—pregnant patients (1st trimester), thyroid storm Monitor for hepatic failure, agranulocytosis, vasculitis Methimazole—everybody else Radioactive iodine—delayed effect CAUTION IF BAD Grave’s orbitopathy NOT in pregnancy Monitor for cholestasis, agranulocytosis, vasculitis Steroids (stress-dose if concerned about thyroid storm) – works if inflammatory/lo-uptake Antithyroid therapies will not work in low uptake states Steroids also help with T4 to T3 conversion block Unusual options more likely for thyroid storm: SSKI – only 1 hour AFTER antithyroid therapy given Lithium Cholestyramine Plasmapheresis Surgery requires preop preparation Amiodarone and the thyroid Amiodarone-induced thyrotoxicosis Type 1: + underlying synthetic process Type 2: destructive thyroiditis / inflammatory Dx: Doppler ultrasound (vascular type 1; low flow in type 2) Both have low RAI uptake but Type 1 has a tiny bit of uptake whereas Type 2 has none Amiodarone-induced hypothyroidism Underlying + TPO antibodies Give levothyroxine Risk factors for thyroid cancer Family history History of head/neck radiation New nodule in patient <20 or >60 years old Nodule that is firm, fixed and growing Nodule with regional cervical LAD or Horner’s syndrome Cold nodule on scan Microcalcifications ± central bloodflow on US Dysphagia, hoarseness, respiratory obstruction, pain Evaluation of thyroid nodule Obtain TSH. If hyperthyroid, get thyroid scan If hot nodule, treat with RAI ablation Do NOT biopsy a hot nodule! If euthyroid or hypothyroid and >1 cm, perform FNA American Thyroid Association Guidelines Smaller lesions with concerning features may be considered for biopsy Cancer derived from follicles Anaplastic thyroid cancer Extremely poor prognosis Differentiated thyroid cancer (follicular epithelial cells) Papillary thyroid cancer Most common 85% of differentiated cancers Grows slowly Lymphangetic spread Follicular thyroid cancer 10% of differentiated cancers Hematogenous spread Hurthle cell 3% of differented thyroid cancers Oxyphil tumors American Thyroid Association Guidelines RECOMMENDATION 24 For patients with an isolated indeterminate solitary nodule who prefer a more limited surgical procedure, thyroid lobectomy is recommended Thyroid lobectomy alone may be sufficient treatment for small (<1 cm), low-risk RECOMMENDATION 25 (a) Because of an increased risk for malignancy, total thyroidectomy is indicated in patients with indeterminate nodules who have large tumors (>4 cm) …, in patients with a family history of thyroid carcinoma, and in patients with a history of radiation exposure. (b) Patients with indeterminate nodules who have bilateral nodular disease, or those who prefer… should also undergo total or near total thyroidectomy RECOMMENDATION 26 -For patients with thyroid cancer >1 cm, the initial surgical procedure should be a near-total or total thyroidectomy Central neck dissection-often accompanies total thyroidectomy (may not Post-op Radioactive Iodine (remnant) Ablation -for all patients with known distant metastases, gross extrathyroidal extension of the tumor regardless of tumor size, or primary tumor size >4 cm do prophylactic dissection only if SMALL T1 or T2 non invasive PTC, follicular) Medullary thyroid cancer Most are sporadic (>80%) but can be familial (MEN IIA/B, Familial nonMEN MTC) Calcitonin levels helpful Genetic tests available (RET oncogene) Because MTC is often familial/MEN, always exclude pheochromocytoma Radioactive iodine is not taken up by C cells (parafollicular cells) so NO RAI for MTC! Nearly 30% -100% have bilateral disease – do total thyroidectomy, NOT just lobectomy Thyroid cases Young patient with soft goiter, bruit, weight loss Grave’s Disease RAI ablation Patient with sore throat, fever, painful goiter Subacute thyroiditis Supportive care +/steroids Thyroid cases • Old pt. with weakness, weight loss, atrial fibrillation, goiter – Apathetic hyperthyroidism (Toxic MNG) • Young woman with molar pregnancy, hyperthyroid – Very High hCG acts as TSH analog • Health care worker with hyperthyroidism, no goiter, low RAIU – Facticious (taking synthroid) Check thyroblobulin (suppression) Primary vs Secondary Hypothyroidism Primary hypothyroidism Problem is the gland itself Will see ↑TSH and ↓free T4 Secondary hypothyroidism Problem is outside the gland (ie pituitary, etc) Will see ↓ or ↔TSH and ↓free T4 Monitoring the TSH for treatment is not useful – follow Free T4 instead Question An 84 yo lady with a history of dementia and no other medical problems presents from the nursing home with altered mental status. She is on no medications. She is unable to provide any history but on your examination of her you find that she has a well healed transverse scar across her neck. She is hypothermic, bradycardic, has doughy skin and brittle hair. Labs are pending, but you find a fingerstick glucose of 52. Which of the following is the most reasonable next step in her care? 1. Give her one amp of D50 2. Levothyroxine 300mcg IV 3. Levothyroxine 300mcg IV and hydrocortisone 100mg IV 4. Levothyroxine 300mcg IV and one amp of D50 IV 5. Levothyroxine 200mcg PO Management of Myxedema Coma Question A psychiatrist in your community refers an 80 year old woman being treated for depression. She reports generalized weakness, fatigue, dry skin, weight gain and constipation. Her past medical history includes CHF and stable angina. Your examination reveals periorbital edema, skin that is cool and dry, loss of the lateral third of her eyebrow, mild bradycardia and a slow relaxation phase of her deep tendon reflexes. You strongly suspect hypothyroidism and check TSH and Free T4. The TSH is 95 units/mL and Free T4 is 0.1ng/dL (0.7-1.5ng/dL). She obviously has severe hypothyroidism. Which of the following should you do next? 1. Administer thyroxine 500mcg IV daily for 5 doses 2. Administer thyroxine 500mcg IV and triiodothyronine 20mcg IV daily for three days. 3. Begin levothyroxine 300mcg PO daily 4. Begin levothyroxine 100mcg PO daily 5. Begin levothyroxine 25mcg PO daily Replace levothyroxine slowly in elderly or cardiac patients Hypothyroidism cases 27 year old woman with Hashimotos on levothyroxine 88mcg daily, 2 weeks pregnant. Estrogens increase TBG, so increase levothyroxine dose by at least 30% during pregnancy 45 year old woman with Hashimotos has a rapidly enlarging goiter Thyroid Lymphoma - FNA diagnosis and irradiate Subclinical Hypothyroidism Defined as Elevated TSH but with all thyroid hormone levels within the reference range When do you treat these patients with levothyroxine(synthroid)? (Not all of them): TSH greater than 10 uu/mL Presence of anti-thyroid peroxidase antibodies Desire to become pregnant High risk for progression to Overt Hypothyoiridms with goiter or positive family history
