ENDOCRINOLOGY

1 DIABETES MELLITUS
Impaired glucose tolerance o Fasting glucose between 110 and 125 mg/dL (6.1-6.9 mmol/L) or a 2-hour postprandial glucose between 140 and 199 mg/dL (7.8-11 mmol/L) o One percent to five percent annual increase in risk of developing type II diabetes o Increased risk for cardiovascular disease Type I Diabetes: o Pathogenesis: HLA-DR3/DR4, DQ environmental factors e.g. Coxsackie virus or mumps activation production of autoantibodies (Islet Cell Antibodies; ICA) destruction of pancreas o Only 30% of people with ICA will develop DM

1.1

TREATMENT
Treatment goals: o Fasting blood glucose 70-130 mg/dl (3.9-7.2 mmol/L) & post-prandial blood glucose <180 mg/dL (10 mmol/L) o HBA1c: ideal <7%, good 7-8.5%, 8.5-10% fair, and >10% is poor control o LDL <100 mg/dL (2.6 mmol/L) o BP <130/85 mmHg (140/90 mmHg acceptable) Oral Hypoglycemics:
Class Examples Glibenclamide (5 mg) Gliclazide (30 mg) MOA Secretagogue SE/Precautions Weight gain Hypoglycemia AVOID in: (1) Liver/renal impairment; hold if Cr >160 (>1.5) Lactic acidosis (2) Contrast studies (3) Advanced CHF Flatulence, distension, soft stool AVOID in CKD Notes Safe in liver/renal impairment patients -Acts only in the presence of insulin -Mild weight loss -NO hypoglycemia

Sulphonylurea

Biguanide

Metformin (500, 850, 1000 mg)

(1) Enhances sensitivity to insulin (2) Inhibits gluconeogenesis

-Glucosidase Inhibitor

Acarbose (50, 100 mg)

Inhibits absorption of carbohydrates

Used for post-prandial hyperglycemia -Rapid onset of action -For post-prandial hyperglycemia (taken immediately before meals) -Alone or +MTF

Meglitinides

Repaglinide

Secretagogue

Weight gain

Thiozolidinediones

Rosiglitazone (4 mg) Pioglitazone (15 mg)

(1) Reduces insulin resistance (2) Promotes glucose uptake in skeletal ms & fat (3) Inhibits gluconeogenesis

-Weight gain -Monitor LFTs (hepatotoxic) AVOID in: (1) CHF (2) Osteoporosis

-Adjunct (+MTF/Sulphonylurea)

DPP-4 Inhibitor

Sitagliptin (100 mg)

Secretagogue Prevents breakdown of GLP-1 & GIP by DPP-4 insulin release & glucagon Secretagogue - insulin release & glucagon -Slows down gastric emptying

AVOID in: CKD

-Monotherapy but better +MTF/TZD -Weight neutral -NO hypoglycemia -Weight loss -Reduces liver fat content -Monotherapy or as an adjunct (+MTF/TZD/sulpha)

GLP-1 Agonist

Exenatide (SC)

GI upset

Plan:

Well-validated If goals not Step 1: Lifestyle changes + Metformin achieved within 2-3 months or Step 2: Lifestyle changes + Metformin + Sulphonylurea/basal insulin HBA1c > 7% Step 3: Lifestyle changes + Metformin + intensive insulin Less well-validated: Step 2: + pioglitazone (hypoglycemia undesirable) or Exenatide (weight loss desired) Step 3: + Sulphonylurea + pioglitazone/Exenatide Or + basal insulin

Insulin: o Initiation & adjustment: in type 2, switch to insulin if FBG >240 mg/dL (13.3 mmol/L) or HBA1c >9%

Regimens (many) Typical:

0.5 U/Kg/d e.g. 36 U for 70-Kg adult 2/3 A.M. = 24 U 24 U "70/30"

16 U NPH 8 U Reglar

1/3 P.M. = 12 U 12 U "70/30"

8 U NPH 4 U Regular

Intensive therapy: Long-acting insulin is given once daily in the evening. Regular insulin is given 30 to 45 minutes before each meal, and should be adjusted according to pre-prandial home glucose measurements. Patients on basal bolus insulin therapy often take 40% to 50% of their total daily dose as basal insulin (glargine) and 50% to 60% as meal boluses (lispro or aspart) If the patient is unable/unwilling to carry out an intensive insulin program: Give 70/30 units before breakfast and before the evening meal for basal coverage Give short-acting insulin (regular) for prandial control if necessary In-patient: An insulin sliding scale (SSI) of regular insulin doses given according to bedside finger-stick glucose determinations is helpful in controlling blood glucose levels in the hospital setting. 1

SSI should be used in addition to a regimen of intermediate-acting insulin. If given alone, hyperglycemia usually results. Monitor blood glucose four times per day: before meals and at bedtime. If the home insulin dose is unclear, or if the patient anticipates greater requirements of insulin due to an illness, use the following approach to adjust appropriate insulin doses: o Take the total number of units of regular insulin that the patient required in 1 day (while on the sliding scale). o Add two-thirds of this to the pre-breakfast dose and one-third before dinner. o It should be given as 70/30 (i.e., 70% NPH/30% regular).

Modification: Physical activitydepending on the intensity of the activity, decrease insulin dosage 1 to 2 units per 20 to 30 minutes of activity. During illness, administer all of the routine insulin. Many episodes of DKA occur during episodes of illness. Stress and changes in diet require dosing adjustments. Patients undergoing surgery should get 1/3 to 1/2 of the usual daily insulin requirement that day, with frequent monitoring and adjustments as necessary. Surgery: Surgical weight loss therapy (i.e., gastric bypass) is an effective treatment for some patients Islet cell transplantation offers definitive treatment for selected qualified patients

1.2

DIAGNOSIS
Screening: o Indications All adults >45 y/o every 3 years Adults who are overweight + one or more risk factors: 1) 1st degree relative w/DM 2) High risk ethnic group 3) Delivered a baby >9 lb (4 Kg) or Dx w/GDM 4) IGT or IFG 5) PCOS 6) Hypertension 7) Cardiovascular disease 8) Other conditions associated with insulin resistance (e.g. acanthosis nigricans) 9) HDL < 35 mg/dL (0.9 mmol/L), or TAGs >250 mg/dL (2.8 mmol/L) (characteristic of insulin resistance) 10) Physical inactivity Consider Metformin if IFG + age <60, FHx, obese, HDL low, TAG high, HTN Diagnosis: o Symptomatic: 1 test o Asymptomatic: repeated test or 2 tests (on 2 separate occasions)
Test RBG FBG OGTT HBA1c Normal <200 mg/dL (11.1 mmol/L) <100 mg/dL (5.6 mmol/L) <140 (7.8 mmol/L) <6% Impaired Fasting Glucose ____ 110-125 mg/dL (6.1-6.9 mmol/L) ____ ____ Impaired Glucose Tolerance ____ ____ 140-199 mg/dL (7.8-11 mmol/L) 5.7-6.4% Diabetes 200 mg/dL (11.1 mmol/L) 126 mg/dL (7 mmol/L) 200 mg/dL (11.1 mmol/L) 6.5%

Follow-Up: o HBA1c: every 3 months for insulin, every 6 months for controlled o Urea & creatinine: annually 2

o o o o o o o

Lipid profile: annually, abnormal statins 24-hr urine collection: annually, if microalbuminuria ACEI/ARBs Eyes: ophthalmology annually Feet: every visit refer if abnormal BP: every visit, if high ACEI/ARB Give aspirin Pneumococcal & influenza vaccines

Dawn Phenomenon and Somogyi Effect Both cause morning hyperglycemia. o The dawn phenomenon is probably due to an increase in the nocturnal secretion of growth hormone. This phenomenon is independent of the Somogyi effect. o The Somogyi effect is a rebound response to nocturnal hypoglycemiai.e., counter-regulatory systems are activated in response to hypoglycemia, leading to morning hyperglycemia. If morning hyperglycemia is present, check the glucose level at 3:00 am. o If the glucose level is elevated, the patient has the dawn phenomenon and his or her evening insulin should be increased to provide additional coverage in the overnight hours. o If the glucose level is low, the patient has the Somogyi effect and his or her evening insulin should be decreased to avoid nocturnal hypoglycemia.

Education: o Foot care o Glycemic control: All diabetic patients should monitor daily glycemic levels with home blood glucose determinations. Patients on insulin therapy should check blood glucose levels before meals and at bedtime. Patients should monitor blood glucose 90 to 120 minutes after meals control postprandial hyperglycemia

1.3

DM: CHRONIC COMPLICATIONS

Macrovascular complications: o Risk of CAD 2-4 fold = #1 killer of diabetics Silent MIs common o PAD in 60% o Stroke o Other CVS risk factors should be eliminated Microvascular complications: o Nephropathy: DM is most common cause of ESRD Kimmelstiel-Wilson syndrome (nodular sclerosis) Microalbuminuria: 30-300 mg/d (24 hr collection) takes 1-5 years to advance to proteinuria Albumin to creatinine ratio 0.02-0.2 Aggressive glycemic & BP control necessary HTN precipitates condition. Giving ACEI/ARBs is essential Radiocontrast: Patients with diabetes are particularly susceptible to developing radiocontrast-induced acute renal failure. If IV contrast is necessary, give generous hydration before administering the contrast agent to avoid precipitating acute renal failure. Hold metformin for 48 hours after radiocontrast is given to prevent renal damage, and make sure renal function has returned to baseline before resuming it. o Eye Disease & Retinopathy: 75% after 20 years rd 3 nerve palsy, cataracts, glaucoma, major: retinal detachment (proliferative retinopathy) Annual screening of all diabetic patients by an ophthalmologist is recommended. Rx: referral +/- photocoagulation (laser therapy) o Neuropathy: 3

Peripheral neuropathy (distal symmetric neuropathy) Usually affects sensory nerves in a stocking/glove patternUsually begins in feet, later involves hands (longest nerves affected first). Numbness and paresthesias are common. Loss of sensation leads to the following: ulcer formation (patients do not shift their weight) with subsequent ischemia of pressure point areas; Charcots joints. Painful diabetic neuropathyhypersensitivity to light touch; severe burning pain (especially at night) that can be difficult to tolerate. Treatment is with gabapentin, tricyclic antidepressants or pregabalin. CN complicationssecondary to nerve infarction Most often involves CN III, but may also involve CN VI and IV Diabetic third nerve palsy: eye pain, diplopia, ptosis, inability to adduct the eye; pupils are spared Mononeuropathiessecondary to nerve infarction Median nerve neuropathy, ulnar neuropathy, common peroneal neuropathy Diabetic lumbosacral plexopathysevere, deep pain in the thigh; atrophy and weakness in thigh and hip muscles; recovery takes weeks to months Diabetic truncal neuropathypain in distribution of one of the intercostal nerves Autonomic neuropathy Impotence in men (most common presentation) Neurogenic bladderretention, incontinence Gastroparesischronic nausea and vomiting, early satiety Constipation and diarrhea (alternating) Postural hypotension

Diabetic foot: o Caused by a combination of artery disease (ischemia) and nerve disease (neuropathy)can lead to ulcers/infections and may require amputation o With neuropathy, the patient does not feel pain, so repetitive injuries go unnoticed and ultimately lead to nonhealing. In addition, neuropathy may mask symptoms of PVD (claudication/rest pain). o Also, calcific medial arterial disease is common and can cause erroneously high BP readings in lower extremities. Infections: o This results from impaired WBC function, reduced blood supply, and neuropathy. o Wound healing is impaired in diabetic patients, and this can be problematic postoperatively. o Diabetic patients are at increased risk for the following infections: cellulitis, candidiasis, pneumonia, osteomyelitis, and polymicrobial foot ulcers. o Infections of ischemic foot ulcers may lead to osteomyelitis and may require amputation

1.4

DM: ACUTE COMPLICATIONS

DKA (see DKA outline) Causes of fasting hypoglycemia: HHNS (hyperosmolar hyperglycemic non-ketotic syndrome) Exogenous insulin o Severe hyperosmolarity (>320 mOsm/L) Pituitary disease o Hyperglycemia (>600 mg/dL) Liver disease o Dehydration Addisons disease o Acidosis and ketosis are absent (unlike in DKA) Insulinoma o Dx: plasma glucose, U&E Neoplasm Na+ concentration is an excellent marker of free water deficits. Although normal on admission, the sodium concentration belies actual free water deficit because it requires correction for the degree of hyperglycemia. Conventionally, 1.6 mEq/L of sodium should be added to the measured sodium for every 100 mg/dL of glucose exceeding 100 mg/dL. E.g. if Na is 145, glucose is 900 corrected sodium ~ 158 o Rx: Generous fluid replacement + insulin (= DKA) Hypoglycemia: o Causes: Drug induced 4

Factitious: measure C-peptide, insulin-antibodies, or sulphonylurea in urine Insulinoma Ethanol ingestiondue to: Poor nutrition that leads to decreased glycogen (and loss of glycogenolysis) Metabolism of alcohol that lowers nicotinamide adenine dinucleotide (NAD) levels and decreases gluconeogenesis Postoperative complications after gastric surgery (due to rapid gastric emptying) Reactive (idiopathic) hypoglycemia symptoms occur 2 to 4 hours after a meal; rarely indicates a serious underlying disorder Adrenal insufficiency Liver failure Critical illness Disorders of carbohydrate metabolism (e.g., glycogen storage diseases) usually diagnosed at a much younger age Diagnosis: Blood glucose levelSymptoms generally begin when levels drop below 50. Whipples triad is used to diagnose true hypoglycemia (i.e., hypoglycemia due to underlying disease) Laboratory testsfor measurement of serum insulin, C-peptide, and glucose when symptoms occur (an overnight fast may be sufficient to produce symptoms) 72-hour fast (24 hours is usually sufficient)used to diagnose insulinoma (if suspected) Treatment: Acute treatment of hypoglycemia If the patient can eat, give sugar-containing foods; if not, give 1/2 to 2 ampules of D50W intravenously. Repeat administration of D50W as necessary, but switch to D10W as clinical condition improves and glucose level is approximately >100 mg/dL. Appropriate management of underlying cause (e.g., diabetes, insulinoma) If reactive hypoglycemia is suspected, dietary interventions are appropriate. If the patient is an alcoholic (or suspected alcoholic), give thiamine before administering glucose to avoid Wernickes encephalopathy.

2 2.1

OTHER PANCREATIC PROBLEMS INSULINOMA

A. General characteristics a. Insulin-producing tumor arising from the b cells of the pancreas b. Associated with MEN I syndrome c. Usually benign (in up to 90% of the cases) B. Clinical features: Hypoglycemia, which leads to: a. Sympathetic activationdiaphoresis, palpitations, tremors, high blood pressure, anxiety b. Neuroglycopenic symptomsheadache, visual disturbances, confusion, seizures, coma C. Diagnosis (see also Table 4-9) a. 72-hour fast i. The patient becomes hypoglycemic. Normally, the insulin level should decrease as hypoglycemia develops. ii. In persons with insulinoma, insulin does not respond appropriately to hypoglycemia. It may decrease or increase, or it may not change. Nevertheless, the insulin levels are still higher than they would be in a normal individual for any given glucose concentration. b. Whipples triad i. Hypoglycemic symptoms brought on by fasting ii. Blood glucose <50 mg/dL during symptomatic attack iii. Glucose administration brings relief of symptoms c. Elevated fasting serum insulin level. C-peptide levels should also be elevated, which distinguishes insulinoma from exogenous insulin administration. 5

D. Treatment: Surgical resection of tumor (up to 80% to 90% cure rate)

2.2

ZOLLINGER ELLISON SYNDROME (ZES ) (GASTRINOMA)

A pancreatic islet cell tumor that secretes high gastrin, which leads to profound gastric acid hypersecretion, resulting in ulcers. Up to 60% are malignant; 20% associated with MEN I (80% are sporadic); 90% located in the gastrinoma triangle (formed by the following points: cystic duct superiorly, junction of second and third portions of the duodenum inferiorly, and neck of pancreas medially) Possible complications: GI hemorrhage, GI perforation, gastric outlet obstruction/stricture, and metastatic disease (liver is the most common site) Clinical features: peptic ulcers, diarrhea, weight loss, abdominal pain Secretin injection test is diagnostic test of choice. Normally, secretin inhibits gastrin secretion. In patients with ZES, gastrin levels increase substantially after being given secretin. Fasting gastrin level is elevated in patients with ZES. Normal basal acid output is <10 mEq/hour; in patients with ZES, it is >15 mEq/hour. Treatment consists of high-dose proton pump inhibitors. All patients with ZES should undergo exploration to attempt curative resection (20% of patients are cured with complete resection). If there is widely metastatic or incurable gastrinoma, debulking surgery and chemotherapy are indicated.

2.3

GLUCAGONOMA
A glucagon-producing tumor located in the pancreas Clinical manifestations include necrotizing migratory erythema (usually below the waist), glossitis, stomatitis, DM (mild), and hyperglycemia (with low amino acid levels and high glucagon levels). Treatment is surgical resection.

2.4

SOMATOSTATINOMA
A rare, malignant pancreatic tumor (metastases usually present by diagnosis) Poor prognosis Classic triad of gallstones, diabetes, and steatorrhea

2.5

VIPOMA (VERNER MORRISON OR WATERY DIARRHEA, HYPOKALEMIA, ACHLORHYDRIA SYNDROME)

A rare pancreatic tumor (>50% are malignant) Clinical features include watery diarrhea (leading to dehydration, hypokalemia, acidosis), achlorhydria (VIP inhibits gastric acid secretion), hyperglycemia, and hypercalcemia. Treatment is surgical resection.

MULTIPLE ENDOCRINE NEOPLASIA

Inherited condition: propensity to develop multiple endocrine tumors Autosomal dominant inheritance with incomplete penetrance Types o MEN type I (Wermers syndrome) 3 Ps Parathyroid hyperplasia (in 90% of the patients with MEN I) Pancreatic islet cell tumors (in two-thirds of the patients with MEN I)ZES (50%), insulinoma (20%) Pituitary tumors (in two-thirds of the patients with MEN I) o MEN type IIA (Sipples syndrome)MPH Medullary thyroid carcinoma (in 100% of the patients with MEN IIA) Pheochromocytoma (in more than one-third of the patients with MEN IIA) Hyperparathyroidism (in 50% of the patients with MEN IIA) o MEN type IIBMMMP Mucosal neuromas (in 100% of the patients with MEN IIB) in the nasopharynx, oropharynx, larynx, and conjunctiva 6

Medullary thyroid carcinoma (in 85% of the patients with MEN IIB)more aggressive than in MEN IIA Marfanoid body habitus (long/lanky) Pheochromocytoma

4 4.1

THYROID GLAND HYPERTHYROIDISM

Treatment: o For ophthalmopathy in Graves: high dose steroids, or ocular radiation or surgery o Medications: Propranolol Antithyroid: Methimazole: more potent Propylthiouracil: for thyroid storm, pregnancy or methimazole allergy Antithyroid drug doses are titrated every 4 weeks until thyroid functions normalize. Monitor CBC for agranulocytosis. Sodium ipodate or iopanoic acidlowers serum T3 and T4 levels and causes rapid improvement of hyperthyroidism; appropriate for acute management of severe hyperthyroidism that is not responding to conventional therapy Super saturated potassium iodine: given for 2 weeks to decrease thyroid function 131 o Radioablation (I ): definitive Consider in: Elderly patients with Graves disease Patients with a solitary toxic nodule Patients with Graves disease in whom therapy with antithyroid drugs fails Hypothyroidism is expected Pregnancy, breast feeding, and recent lactation are contraindications Radioactive iodine is usually not given to patients with severe ophthalmopathy o Surgery: Pregnant women who are noncompliant with or intolerant of antithyroid medication Patients with very large goiters or severe ophthalmopathy Patients who refuse radioactive iodine therapy S/E: permanent hypothyroidism, permanent hypoparathyroidism, recurrent laryngeal nerve palsy

4.1.1 THYROID STORM

This is a rare, life-threatening complication of thyrotoxicosis characterized by an acute exacerbation of the manifestations of hyperthyroidism. There is usually a precipitating factor, such as infection, diabetic ketoacidosis (DKA), or stress (e.g., severe trauma, surgery, illness, childbirth). High mortality rate: up to 20% of patients enter a coma or die Clinical manifestations include o marked fever o tachycardia o agitation or psychosis o confusion o GI symptoms (e.g., nausea, vomiting, diarrhea) Treatment: 1) Provide supportive therapy with IV fluids, cooling blankets 2) Glucose 3) Give anti-thyroid agents (PTU every 2 hours) 4) Follow with iodine to inhibit thyroid hormone release 5) Administer -blockers for control of heart rate. 6) Give dexamethasone to impair peripheral generation of T3 from T4 and to provide adrenal support 7

4.2

HYPOTHYROIDISM
Causes: o Hashimotos (most common): Patients with Hashimotos thyroiditis are at an increased risk of thyroid carcinoma and thyroid lymphoma. o Iatrogenic o Ablative surgery or radioablation o Drugs: ASA, lithium. Also, amiodarone, interferon, sulphonamides. o Iodine deficiency o Hereditary o Secondary or tertiary Diagnosis: o TSH o T4 o Lipid profile: LDL o CBC: anemia o Antimicrosomal antibodies Treatment: o Levothyroxine. o Otherwise young and healthy patients can be started on LT4 at anticipated full replacement doses o In elderly patients and those with known ischemic heart disease, begin with one fourth to one half the expected dose and adjust the dose in small increments after no less than 4-6 weeks o For most cases of mild to moderate hypothyroidism, a starting LT4 dose of 50-75 g daily will suffice o In pregnancy: increase by 30-40% o Monitoring & F/U Clinical benefits begin in 3-5 days and level off after 4-6 weeks Achieving a TSH level within the reference range may take several months LT4 dosing changes should be made every 6-8 weeks until the patients TSH is in target range After dose stabilization, patients can be monitored with annual clinical evaluations and TSH monitoring. Patients should be monitored for symptoms and signs of overtreatment (hyperthyroidism) In patients with central (2) hypothyroidism, monitor free T4 instead of TSH

Subclinical Hypothyroidism Thyroid function is inadequate, but increased TSH production maintains T4 level within the reference range of normalcy; therefore, TSH level is elevated and T4 level is normal. Look for nonspecific or mild symptoms of hypothyroidism, as well as elevated serum LDL levels. Treat with thyroxine if patients develop: o Goiter o Hypercholesterolemia o Symptoms of hypothyroidism o Significantly elevated TSH level (>10 U/mL) o High positive anti-thyroid antibodies

4.2.1 MYXEDEMA COMA

See Hypothyroidism notes.