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Endocrinology I Diabetes Lipids Calcium disorders MEN I and II

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1 Endocrinology I Diabetes Lipids Calcium disorders MEN I and II
Sarah E. French, MD July 19, 2014 Diabetes Lipids Calcium disorders MEN I and II

2 Medical-Content Category
Relative Percentage Cardiovascular Disease 14% Pulmonary Disease 10% Gastroenterology 9% Infectious Disease Rheumatology/Orthopedics 8% Endocrinology Medical Oncology 7% Hematology 6% Nephrology/Urology Psychiatry 4% Neurology Allergy/Immunology 3% Dermatology Miscellaneous Obstetrics/Gynecology 2% Ophthalmology Otorhinolaryngology

3 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 Hypothalamic disorders Anterior pituitary disorders Posterior pituitary/water metabolism Endocrine tumors and endocrine manifestations of tumors Hypoglycemia not due to insulinoma Polyglandular disorders Nutritional disorders Women’s health endocrine issues Miscellaneous endocrine disorders

4 Diabetes

5 Diagnostic criteria for diabetes
Random glucose >200 mg/dL with symptoms Polyuria, polydipsia, unexplained weight loss Fasting glucose > 126 mg/dL on 2 different days 2 hour glucose >200 mg/dL during 75-gram oral glucose tolerance test A1c > 6.5 (new)

6 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 Pancreatic failure Insulin resistance

7 A1c Goal <7% Can be unreliable if Alternative is fructosamine
Blood transfusion Decreased RBC lifespan Hemoglobinopathies Alternative is fructosamine

8 Oral agents in diabetes
Need to know contraindications and most side effects of different agents Metformin, TZDs and sulfonylureas are roughly equivalent on ability to decrease A1c Metformin, TZDs and sulfonylureas are FDA approved for combination with insulin DDP-4 inhibitors (sitagliptin, etc) are NOT FDA approved for combination with insulin

9 Metformin TZDs Sulfonylurea DDP-4 inhibitors
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 DDP-4 inhibitors Increases insulin production and sensitivity Delays gastric emptying Can be used in CKD with dose reduction

10 Indications for insulin
Significant hyperglycemia at presentation Acute decompensation Surgery Pregnancy Renal disease Poor control despite oral agents

11 Diabetic ketoacidosis
Total body potassium is low Even if patient presents with hyperkalemia Monitor potassium and replace Follow bicarb and anion gap Generally no need to follow ketones

12 Diabetes is not just hyperglycemia
Keep blood pressure <130/80 ACE inhibitor or ARB if proteinuria Manage any dyslipidemia If age >40, start statin even if LDL at goal Screen for complications Urine microalbumin, dilated eye exam Smoking cessation Immunizations

13 Lipid goals in diabetes
LDL < 100 for every diabetic < 70 if DM with CAD or CAD equivalent (PAD, AAA) First choice is statin 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

14 Complications of diabetes
Acute complications DKA Hyperosmolar hyperglycemic nonketotic state (HHNS) Microvascular Retinopathy Neuropathy Nephropathy Macrovascular CAD PVD CVD Atherosclerosis is most common cause of death

15 Diabetes in pregnancy Glargine and detemir are contraindicated
Use NPH for basal insulin Can use regular for prandial/bolus insulin A1c < 7% before conception and keep it there Retinopathy may worsen during pregnancy Remember: statins, ACEIs, and ARBs are contraindicated

16 Adjusting insulin

17 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 Adjustments should be 10-20% of dose

18 A 58 yo WM with HTN and DM is followed in your clinic and previously had good control of his diabetes with A1c of 6.9 on Novolog 70/30, taking 35 units before breakfast and supper. Has had recently begun complaining of highly variable blood sugars: Pre-breakfast FSG – Pre-Lunch FSG – Pre-Supper FSG – Which of the following is the best next step in his management? Increase Novolog 70/30 dose in the evening to 40 units. Begin acarbose therapy Increase Novolog 70/30 dose in the morning to 40 units Check blood sugar at 3 AM Change the patient’s regiment to Lantus and Regular Insulin before each meal for better compliance.

19 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

20 23-year-old man with 13-year history of type 1 DM is preparing for racquetball tournament. The first game of his tournament is at 8 AM and he asks for advice about his insulin regimen because he has never attempted to play racquetball so early in the day (usually plays late afternoon). Usual insulin dosage is 6 units NPH with 10 units insulin lispro with breakfast at 7 AM, 4 units insulin lispro with lunch at 12 PM, and 8 units NPH with 12 units insulin lispro with dinner at 6 PM. His last A1c was 6.4 and his fasting fingerstick readings at 7 AM ranges between 160 and 200 mg/dL. Assuming that his 7 AM glucose concentration is in usual range, which one of the following should he do? A. Not take his insulin or eat breakfast but drink 8oz of orange juice just before the game B. Take his usual insulin and eat his usual breakfast C. Omit the insulin lispro but take the usual dose of NPH with breakfast Omit the NPH but take the usual dose of insulin lispro with breakfast Decrease the insulin lispro and NPH and eat his usual breakfast

21 Glucose Patterns

22 250 200 150 100 50 8AM Noon 6PM Normal

23 Postprandial Hyperglycemia
Increased insulin requirement Steroid Effect 250 200 150 100 50 8AM Noon 6PM Postprandial Hyperglycemia

24 Somogyi or Dawn Phenomena
250 200 150 100 50 8AM Noon 6PM Somogyi or Dawn Phenomena

25 Dietary/Medical noncompliance
250 200 150 100 50 8AM Noon 6PM Dietary/Medical noncompliance

26 Hypoglycemia

27 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”

28 Insulinoma Extremely rare Typically fasting hypoglycemia
Whipple’s triad Symptoms associated with hypoglycemia Glucose <70 at time of symptoms Relief with glucose administration Have elevated insulin and C-peptide levels Negative sulfonylurea screen

29 Vitals are normal and physical exam is unremarkable.
18 yo woman evaluated for syncope. Has had 3 episodes in past month that resolved after she drank fruit juice with sugar. Has history of depression treated with citalopram and occasional insomnia treated with zolpidem as needed. Her mother has type 2 diabetes treated with NPH and glyburide. Several minutes into presentation, patient becomes confused and agitated with tachycardia and profuse sweating. Blood is drawn. IV glucose given with resolution of her symptoms. Vitals are normal and physical exam is unremarkable. Lab studies: C peptide 0.4 ( ), glucose 34, insulin 26 (2-20), sulfonylurea screen negative. What is most appropriate next step in management? Abdominal CT Abdominal octreotide scanning Gastric emptying study Psychiatric evaluation

30 Interpreting laboratory data
Remember that hypoglycemia is result of low glucose production rather than high glucose utilization. Plasma insulin, C-peptide, and pro-insulin concentrations don’t have to be high relative to normal values. Can be “inappropriately normal” for hypoglycemia Generally, only interpret results if glucose is <55 mg/dL. A concurrent illness can complicate interpretation of results.

31 Interpreting laboratory data
Signs Glucose Insulin C-peptide Proinsulin β-hydroxy-butyrate Glucose after glucagon (+) sulfonylurea screen Abs Dx No < 55 < 3 < 0.2 < 5 > 2.7 < 25 - Normal Yes >> 3 ≤ 2.7 > 25 Exogenous insulin ≥ 3 ≥ 0.2 ≥ 5 Insulinoma Gastric bypass Oral hypoglycemic >> 0.2 >> 5 + Antibody

32 Lipids

33 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

34 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

35 Familial hyperlipidemia
Familial hypercholesterolemia Reduction or absence of LDL receptor Tendinous xanthomas Lipoprotein lipase (LPL) deficiency Cannot degrade chylomicrons and VLDL Triglycerides > 1000

36 Familial hyperlipidemia
Familial combined hyperlipidemia Most common genetic hyperlipidemia (1%) Increase ApoB 100 → ↑LDL and ↑ VLDL Premature CAD No risk for xanthomas Familial dysbetalipoproteinemia Elevated IDL (total cholesterol and triglycerides) Associated with diabetes, obesity and alcohol abuse Palmar xanthomas (“yellow hands”)

37 Familial hypercholesterolemia
Tendon xanthoma Elevated LDL Familial hypercholesterolemia

38 Elevated triglycerides
Eruptive xanthomas Elevated triglycerides

39 Elevated triglycerides
Tuberous xanthomas Elevated triglycerides

40 Familial dysbetalipoproteinemia
Palmar xanthomas Elevated IDL Familial dysbetalipoproteinemia

41 Elevated triglycerides
Normal retina Lipemia retinalis Elevated triglycerides

42 Lipid disorder scenarios
Young child with TG of 8000, pancreatitis, eruptive xanthomas, lipemia retinalis, positive family history. Most likely diagnosis? 32 yo man with CAD, LDL 350, TG normal and tendon xanthomas. +Familly hx of premature CAD. Diagnosis? 48 yo woman with premature CAD and severe PVD. +Tuberous and palmar xanthomata. TC 380, TG 400, LDL 50. Diagnosis? Lipoprotein lipase deficiency – unable to degrade VLDL and chylomicrons. Familial hypercholesterolemia (LDL receptor defect; LDL >300). Autosomal dominant with variable penetrance. 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.

43 Secondary hyperlipidemia
Increased LDL Hypothyroidism Increased triglycerides Poorly controlled diabetes Oral estrogens Alcohol Increased LDL and triglycerides Nephrotic syndrome HCTZ Beta blockers Glucocorticoids

44 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

45 Treatment of hyperlipidemia
LDL Statins +/- ezetimibe Bile acid resins Triglycerides Fibrates Combined hyperlipidemia Statin and fenofibrate (safer than gemfibrozil) Niacin (best for HDL)

46 Other points Unless triglycerides >500, LDL is first target.
In patients on HAART, use pravastatin. Not metabolized through cytochrome P450s. Statins are contraindicated in pregnancy.

47 Calcium disorders

48 Hormonal regulation of calcium
Parathyroid hormone (PTH) Vitamin D Increases serum calcium Bone resorption Renal resorption Decreases phosphorus PTH = “phosphorus trashing hormone” Indirectly increases renal hydroxylation of 25-OH vitamin D to active form Increases serum calcium Intestinal absorption Increases phosphorus

49 Clinical manifestations of hypercalcemia
GI symptoms Anorexia Nausea Vomiting Constipation Nephrogenic diabetes inspidius Dehydration Myopathy Cardiac arrhythmias Sinus bradycardia AV block Shortening QT interval Nephrolithiasis Nephrocalcinosis Band keratopathy Pruritus Altered mental status Pancreatitis

50 Differential diagnosis of hypercalcemia
Hypervitaminosis A Hypervitaminosis D Tertiary hyperparathyroidism Familial hypocalciuric hypercalcemia Immobilization Milk-alkali syndrone Primary hyperparathyroidism Malignancy Granulomatous diseases Thyrotoxicosis Drugs HCTZ Lithium

51 Primary hyperparathyroidism
Most frequent case of hypercalcemia as outpatient Usually asymptomatic Calcium level typically within 1 mg/dL of ULN Solitary adenoma (80%) >> four gland hyperplasia (15-20%) >> carcinoma (< 1%) PTH > 25 with high calcium consistent with primary hyperparathyroidism Remember “inappropriate normals”!!

52 Management—primary hyperparathyroidism
Treatment any underlying vitamin D deficiency Vitamin D deficiency is secondary cause of hyperparathyroidism Stop any offending medications (if possible) Thiazides, lithium, calcium carbonate Treat any hyperphosphatemia Hyperphosphatemia is secondary cause

53 Indications for parathyroidectomy
Acute parathyroid crisis Osteitis fibrosa cystica Nephrolithiasis Azotemia with no other explanation Decreased bone mineral density Myopathy Pancreatitis Serum calcium >1 mg/dL above ULN 24-hour urinary calcium >400 mg Age < 50

54 Parathyroidectomy Four-gland exploration
Mandatory in familial forms of hyperparathyroidism Need experienced surgeon Minimally invasive parathyroidectomy Single gland involvement (adenoma) Pre-operative imaging should be performed Pre-operative localization Sestamibi scintigraphy Neck ultrasound

55 Malignancy-associated hypercalcemia
Predominate symptoms are altered mental status and dehydration. Tends to progress rapidly and have serum calcium >12 mg/dL 80% due to PTHrP production 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

56 Malignancy-associated hypercalcemia
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

57 Familial hypocalciuric hypercalcemia
Autosomal dominant mutation in calcium sensing receptor Usually asymptomatic PTH inappropriately normal Calcium clearance/creatinine clearance <0.01 Treatment: LEAVE THEM ALONE!

58 Granulomatous disease
Macrophages have 1-α-hydroxylase which produces 1,25 (OH)2 vitamin D3 Seen in sarcoidosis, tuberculosis, histoplasmosis, leprosy, silicone-induced granulomatosis Treatment: steroids

59 Drug-induced hypercalcemia
Thiazide Increased urinary calcium reabsorption Lithium Resets calcium setpoint for PTH Calcium carbonate (milk-alkali syndrome) Generally >10 grams daily Becoming more common (osteoporosis, ERSD)

60 Lab studies: BUN 37, calcium 15.7, creatinine 1.4, sodium 151.
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 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

61 Treatment of hypercalcemia
Hydration, hydration, hydration!! Bisphosphonates: pamidronate and zoledronic acid Pamidronate + calcitonin if calcium >15 Steroids only for granulomatosis disease or hematologic malignancies Lasix is only for volume overload!!

62 Hypocalcemia Low vitamin D: ↓Ca ↓Phos ↑PTH
Secondary hyperparathyroidism is compensatory mechanism 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

63 Albright Hereditary Osteodystrophy

64 Hypocalcemia Give IV calcium if symptomatic
Calcium gluconate preferred to calcium chloride Otherwise, give oral calcium and vitamin D Only treat to calcium of Enough to prevent symptoms Not enough to cause hypercalciuria

65 Calcium scenarios 64 yo man with Calcium 10.8, PTH 135 (10-65). Diagnosis? 64 yo man with Calcium 10.8, PTH 49 (10-65). Diagnosis? 70 yo smoker with dysphagia to solids, then liquids; presents with altered mental status and dehydration. Calcium 14, Albumin 2. Diagnosis? Primary Hyperparathyroidism Primary Hyperparathyroidism PTH is inappropriately normal - If >25 with hypercalcemia, then primary HPT Hypercalcemia of Malignancy Be alert for diabetes insipidus with hypercalcemia → hypercalcemic crisis.

66 Calcium scenarios 42 yo with serum calcium of 10.9, phosphate normal, PTH normal and no kidney stones, normal bones; +Hx of hypercalcemia in the past. Best next test? 53 yo with calcium 12.3, Phos 5.9 and mediastinal lymphadenopathy. Best therapy? 24 hour urine calcium/creatinine – Familial hypocalciuric hypercalcemia. Do NOT operate! Steroids – Sarcoidosis causes hypercalcemia by uncontrolled activation of Vitamin D.

67 Calcium scenarios 65 year old health food fanatic ingests high dose vitamin A supplements “to help with my eyes.” Calcium 11.7 with low PTH. Diagnosis? 43 year old with PUD eats 15 tums BID due to dyspepsia. Calcium 12.3, PTH low, HCO Diagnosis? Vitamin A toxicity – Periosteal resorption if taking >5000 units/day Milk-Alkali Syndrome – metabolic alkalosis and hypercalcemia

68 Calcium scenarios 42 yo with osteopenia, microcytic anemia and Calcium of 7.6. PTH is 125. Next step? 63 yo drunkard found passed out… again… Calcium 7.3, PTH is 23. Next step? \ Celiac Disease. Check 25-OH Vitamin D level and replace to >32. Look for dermatitis herpetiformis, Type I Diabetes Mellitus, Non-Hodgkins Lymphoma, Vitamin B or K deficiencies Check for Hypomagnesemia  causes reversible hypoparathyroidism. Replace magnesium to >2 mg/dL.

69 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. Therapy – Replace calcium and Vitamin D Palpitations – QRS prolongation

70 Check phosphorus level.
72 yo woman s/p parathyroidectomy due to primary hyperparathyroidism develops calcium 6.9 on POD #1. Magnesium is normal pre-op. Next step? 20 yo with round face, short stature, mental retardation, obesity, basal ganglia calcifications, shortened 4th & 5th metacarpals. Calcium 6.9, Phos 5.5. Next step? Check phosphorus level. Low Phosphorus – Hungry Bone Syndrome – Give calcium/D High Phosphorus – Hypoparathyroidism – Give Calcium/Rocaltrol Check PTH level Likely Pseudohypoparathyroidism (PTH resistance) Albright’s Hereditary Osteodystrophy Therapy is calcium and vitamin D supplementation

71 Multiple Endocrine Neoplasias (MEN I and II)

72 MEN I Have to have 2 out of 3 P’s Pituitary Pancreas Parathyroid
Prolactinoma, acromegaly, Cushing’s disease Pancreas Gastrinoma, insulinoma, glucagonoma, VIPoma Parathyroid Primary hyperparathyroidism (multifocal)

73 MEN 2 MEN 2B: MTC + ganglioneuromas and Marfaniod habitus
Medullary thyroid cancer (MTC) present in 100% Always malignant; usually bilateral MEN 2A: MTC + parathyroid hyperplasia MEN 2B: MTC + ganglioneuromas and Marfaniod habitus Perform genetic screening for RET mutations in all index patients If mutation found, screen family members Rule out pheo, then total thyroidectomy and cervical exploration


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