ENDOCRINOLOGY ISarah E. French, MDJuly 19, 2014

DiabetesLipidsCalcium disordersMEN I and II

Medical-Content Category Relative PercentageCardiovascular Disease 14%

Pulmonary Disease 10%

Gastroenterology 9%

Infectious Disease 9%

Rheumatology/Orthopedics 8%

Endocrinology 8%

Medical Oncology 7%

Hematology 6%

Nephrology/Urology 6%

Psychiatry 4%

Neurology 4%

Allergy/Immunology 3%

Dermatology 3%

Miscellaneous 3%

Obstetrics/Gynecology 2%

Ophthalmology 2%

Otorhinolaryngology 2%

Endocrinology (8%) 17–19 questionsDiabetes 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

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)

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

A1c• Goal <7%• Can be unreliable if

• Blood transfusion• Decreased RBC lifespan• Hemoglobinopathies

• Alternative is fructosamine

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

• 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

• DDP-4 inhibitors• Increases insulin

production and sensitivity• Delays gastric emptying• Can be used in CKD with

dose reduction

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

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

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

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

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

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

ADJUSTING INSULIN

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

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 – 200-250Pre-Lunch FSG – 135-160Pre-Supper FSG – 130-150

Which of the following is the best next step in his management?1. Increase Novolog 70/30 dose in the evening to 40 units. 2. Begin acarbose therapy3. Increase Novolog 70/30 dose in the morning to 40 units4. Check blood sugar at 3 AM5. Change the patient’s regiment to Lantus and Regular Insulin

before each meal for better compliance.

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

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 gameB. Take his usual insulin and eat his usual breakfastC. Omit the insulin lispro but take the usual dose of NPH with breakfastD. Omit the NPH but take the usual dose of insulin lispro with breakfastE. Decrease the insulin lispro and NPH and eat his usual breakfast

GLUCOSE PATTERNS

8AM Noon6PM

250

200

150

100

50

Normal

8AM Noon6PM

250

200

150

100

50

Postprandial Hyperglycemia

Increased insulin requirementSteroid Effect

8AM Noon6PM

250

200

150

100

50

Somogyi or Dawn Phenomena

8AM Noon6PM

250

200

150

100

50

Dietary/Medical noncompliance

HYPOGLYCEMIA

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

• Symptoms associated with hypoglycemia• Glucose <70 at time of symptoms• Relief with glucose administration

• Have elevated insulin and C-peptide levels• Negative sulfonylurea screen

• 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 (0.5-2.5), 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

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.

Interpreting laboratory dataSigns Glucose Insulin C-

peptideProinsulin β-hydroxy-

butyrateGlucose

after glucagon

(+) 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 - InsulinomaGastric bypass

Yes < 55 ≥ 3 ≥ 0.2 ≥ 5 ≤ 2.7 > 25 Yes - Oralhypoglycemic

Yes < 55 >> 3 >> 0.2 >> 5 ≤ 2.7 > 25 No + InsulinAntibody

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• Familial hypercholesterolemia

• Reduction or absence of LDL receptor• Tendinous xanthomas

• Lipoprotein lipase (LPL) deficiency• Cannot degrade chylomicrons and VLDL• Triglycerides > 1000

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”)

Tendon xanthomaElevated LDL

Familial hypercholesterolemia

Eruptive xanthomas

Elevated triglycerides

Tuberous xanthomasElevated triglycerides

Palmar xanthomasElevated IDL

Familial dysbetalipoproteinemia

Normal retina Lipemia retinalis

Elevated triglycerides

Lipid disorder scenariosYoung 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.

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)

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.

CALCIUM DISORDERS

Hormonal regulation of calcium

Parathyroid hormone (PTH)

• 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

Vitamin D

• Increases serum calcium• Intestinal absorption

• Increases phosphorus

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

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 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”!!

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

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

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

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

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

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!

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

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)

• 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• Pamidronate + calcitonin if calcium >15• Steroids only for granulomatosis disease or hematologic

malignancies

• Lasix is only for volume overload!!

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

Albright Hereditary Osteodystrophy

Hypocalcemia• Give IV calcium if symptomatic

• Calcium gluconate preferred to calcium chloride• Otherwise, give oral calcium and vitamin D• Only treat to calcium of 8.0-8.5

• Enough to prevent symptoms• Not enough to cause hypercalciuria

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 MalignancyBe alert for diabetes insipidus with hypercalcemia → hypercalcemic crisis.

Calcium scenarios42 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.

Calcium scenarios65 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, HCO3- 32. Diagnosis?

Vitamin A toxicity – Periosteal resorption if taking >5000 units/day

Milk-Alkali Syndrome – metabolic alkalosis and hypercalcemia

Calcium scenarios42 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.

Calcium scenarios68 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

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 levelLikely Pseudohypoparathyroidism (PTH resistance)Albright’s Hereditary OsteodystrophyTherapy is calcium and vitamin D supplementation

MULTIPLE ENDOCRINE NEOPLASIAS (MEN I AND II)

MEN I• Have to have 2 out of 3 P’s• Pituitary

• Prolactinoma, acromegaly, Cushing’s disease• Pancreas

• Gastrinoma, insulinoma, glucagonoma, VIPoma• Parathyroid

• Primary hyperparathyroidism (multifocal)

MEN 2

• 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