• Autoimmune pancreatic beta cell destruction leads to insulin deficiency and abnormal glucose metabolism
• Classically presents with polyuria, polydypsia, polyphagia, and rapid, unexplained weight loss. May also present with ketoacidosis.
• HLA-DR3 and DR4

• Must have at least 1 of the following:
• fasting (>8 hrs) glucose of 126 or more on 2 separate occasions
• Random glucose of 200 or more, plus sx
• 2-hr postprandial glucose of 200 or more after OGTT, on 2 separate occasions if results of initial test are equivocal
• HbA1c > 6.5 

• Dawn phenomenon = morning hyperglycemia due to nocturnal release of counterregulatory hormones (eg. glucagon, epi, cortisol), which increase insulin resistance and blood gluocose levels. Solution = increase pm NPH
• Somogyi effect = Rebound hyperglycemia results from excess exogenous insulin, which causes hypoglycemia overnight and stimulates release of counterregulatory hormones that then increase blood glucose levels. Solution = decrease pm NPH. 

• often precipitated by stress, i.e. infxn, MI, trauma, alcohol or by noncompliance with insulin tx
• Presentation: abdominal pain, vomiting, Kussmaul respirations, fruity (acetone) breath,  severe dehydration & electrolyte abnormalities, +/- mental status changes
• Tx: fluids, K+, insulin, bicarb (if pH<7), tx of initiating event/underyling disease process

• Occurs in T2DM.
• Precipitated by acute stress (dehydration, infxn) and can often be fatal.
• Presenation: severe dehydration, mental status changes, hyperosmolarity, very high glucose (>600) without acidosis and with small or absent ketones.
• Tx: aggressive fluid, electrolyte replacement, and insulin. Treat initiating event. 

• appears at least 2-3 years after DM onset
• Preventive measures include: control hyperglycemia and HTN, annual eye exams, laser photocoagulation tx for retinal neovascularization

• glomerular hyperfiltration followed by microalbuminuria (= 30-300 mg albumin in 24 hrs)
• Preventive measures: ACE-Is, ARBs, BP/glucose control

• peripheral, symmetric sensorimotor neuropathy leading to burning pain, foot trauma, infxns, and diabetic ulcers
• Prevention/Tx: foot care, analgesics
• Late complications associated with autonomic neuropathy: gastroparesis, esophageal dysmotility, impotence, orthostatic hypotension

• cardiovascular, cerebrovascular, and peripheral vascular dz
• CV dz = MC cause of death in diabetic pts
• BP goal: 130/80. ACE-I and ARBs = 1st line drugs
• LDL goal < 100
• TG goal < 150
• Pts should take low-dose ASA (> 40 yo)

• Patients with no risk factors: Test HbA1c at age 45; retest q 3 years if HbA1c < 5.7% and no other risk factors develop
• Pts with impaired fasting glucose (100-125) or impaired glucose tolerance: f/u with frequent retesting.

BG: 80 - 120

HbA1c: < 7%

• Glipizide, glyburide, glimepiride
• They increase endogenous insulin secretion
• SE: hypoglycemia, weight gain.

• inhibits hepatic gluconeogenesis and increases peripheral sensitivity to insulin
• SE: weight loss, GI upset, & rarely lactic acidosis
• CI in elderly (> 80) and in renal insufficiency, hepatic failure, & heart failure

• rosiglitazone and pioglitazone
• increase insulin sensitivity
• SE: weight gain, edema, hepatotoxicity, bone loss
• CI: heart failure

• Acarbose
• decreases intestinal absorption of carbohydrates
• SE: flatulence, hypoglycemia

• sitagliptin
• inhibits degradation of glucagon-like peptide 1 (GLP1)
• GLP-1 increases insulin secretion, decreases glucagon secretion

• Exenatide
• GLP-1 agonists: delay absorption of food, increase insulin secretion, and decrease glucagon secretion
• SE: nausea and rarely pancreatitis

• Must have 3 out of 5:
• Abdomiinal obesity: waist circumference > 40" in men or >35" in women
• TGs of 150 or more
• HDL of 40 or less in men, 50 or less in women
• BP of 130/85 or more, or on antihypertensive drugs
• Fasting glucose of 100 or more

• It is useful for differentiation of hyperthyroid states (but has a limited role in determining malignancy)
• Graves dz: RAI % uptake is high and scan shows diffuse uptake
• Toxic adenoma/multinodular goiter: RAI % uptake is normal to high; scan shows nodules/regions of increased uptake
• Thyroiditis: RAI % uptake is low and scan shows low uptake

• exophthalmos
• pretibial myxedema
• thyroid bruits

• symptomatic tx: propranolol
• pharmacologic tx: anti-thyroid drugs: methimazole or PTU
• definitive tx: radioactive iodine thyroid ablation or surgical thyroidectomy; pts must take levothyroxine after

• an acute, life-threatening form of thyrotoxicosis
• Sx: atrial fibrillaton, fever, delirium
• Tx: IV propranolol, PTU, corticosteroids, high dose potassium iodide (SSKI)

• Hashimoto's thyroiditis
• autoimmune destruction of thyroid associated with + antithyroglobulin and antimicrosomal (anti-TPO) antibodies.
• May have hyperthyroid phase preceding hypothyroid phase

• signs of secondary sexual development in girls < 8 yo or boys < 9 yo

• no testicular enlargement in boys by age 14
• no breast development or pubic hair in girls by age 13

• Grave's Disease: autoimmune thyroid-stimulating antibodies act on the TSH receptor. This leads to increased levels of T3/T4, decreased TSH.

• Myxedema coma - occurs with severe hypothyroidism and involves:
• decline in mental status
• hypothermia
• parasympathetic sx
• mortality is 30-60%
• tx: admit to ICU and administer IV levothyroxine and IV hydrocortisone (if adrenal insufficiency has not been excluded).

• Sx: painful/tender thyroid (unique to this form of thyroiditis!), malaise, URI sx
• Dx: thyroid dysfxn usually with thyrotoxicosis followed by hypothyroidism. Decreased uptake on RAI and scan during hyperthyroid phase
• Tx: Beta blockers for hyperthroidism, levothyroxine for hypo. Usually self-limited. In severe cases, may use NSAIDs and/or oral corticosteroids. 

• radiation
• autoimmune
• postpartum
• drug-induced (amiodarone).

• h/o childhood neck irradiation
• "cold" nodules (minimal uptake on RAI scan)
• Male sex
• Age <20 or >70
• firm & fixed solitary nodules
• + FHx (esp. medullary thyroid CA)
• rapidly growing nodules with hoarseness

1. Papillary - MC (75-85% of thyroid CA). Found in thyroid-hormone producing follicular cells. Good px (>90% survival at 10 years)
2. Follicular - 17% of thyroid CA. Also in follicular cells. Also good px.
3. Medullary - 6-8%. Found in calcitonin-producing C ceels. Px related to degree of vascular invasion, 80% survival at 10 years. Consider with MEN2A/2B if there's FHx.
4. Anaplastic - <2%. Poor px.

*note: tumors may have mixed papillarly and follicular histology

• Histology: papillae (branching)
• Palpable lymph nodes
• "Pupil" (Orphan Annie) nuclei
• Psammoma bodies often within lesion
• F:M is 3:1.

• TFTs - detects hyperfunctioning nodules, followed by RAI scan, which will show a "hot" nodule. Hot nodules are not cancerous and shouldn't be biopsied.
• Ultrasound - to determine if nodule is solid vs cystic. Cystic are more likely to be benign.
• FNA - best method to assess nodule for malignancy. "Cold" nodules on RAI should be biopsied. 

• Benign FNA - f/u PE and US to assess for continued nodule growth and development of suspicious characteristics (ex. calcification, increased vascular flow).
• Malignant FNA - Surgical resection with hemi or total thyroidectomy is 1st line. Sometimes followed by adjunctive RI ablation. 
• Indeterminate FNA - watchful waiting vs. hemithyroidectomy. 10-30% chance of malignancy. If resected, pathology guides further tx. 

• BMD < 2.5 SDs from normal peak bone mass (@ 30 yo). Measured by DEXA scan. 
• Most often affects thin, postmenopausal women, Caucasianns and Asians, with risk doubling after age 65. 

• Smoking
• Age
• Excessive caffeine or alcohol intake
• H/o estrogen-depleting conditions in women (amenorrhea, eating d/o) or hypogonadism in men
• Uncontrolled hyperthyroidism
• Chronic inflammatory dz
• Corticosteroid use

• hip fx (50% chance of mortality within the next yr)
• vertebral compression fx's which cause loss of height and progressive thoracic kyphosis
• distal radius fx (Colles' fx)
• All of the fx following minimal trauma
• Vertebral fx may be asymptomatic 

• Lifestyle/diet: Ca and VitD supplementation, smoking cessation, weight bearing exercise can help maintain and even restore some bone density
• Pharmacologic: antiresorptive agents can prevent further bone loss: bisphosphonates (ex. alendronate, zoledronic acid), SERMs (raloxifene), intranasal calcitonin, denosumab (Monoclonal Ab to RANK-L). 

• Pathophysiology: increased rate of bone turnover with both excessive resorption and formation of bone
• "Mosaic" lamellar bone pattern
• Pts may also have primary hyperparathyroidism (20%), pathologic fx's, high-output cardiac failure, osteosarcoma (1%). 

• Labs: elevated serum alk. phosphatase with normal Ca and phosphate levels. Must be distinguished from metastatic bone dz.
• Imaging: Radionuclide bone scan is most sensitive test in early Paget's, but must do plain films to make dx.
• Plain film "classic" findings: thickened cortex and trabeculae of femur and expansion of femoral head. [May affect 1 bone or multiple bones.]

• Most pts are asymptomatic and do not require tx.
• If pts are symptomatic, i.e. severe pain, involvement of vulnerable site (femoral neck) or fx, bisphosphonates and calcitonin can slow bone resorption.
• Analgesics (NSAIDs, acetaminophen) for pain control.

• Pathophysiology: increased serum PTH due to (inappropriately) increased production by parathyroid gland
• 80% are d/t a single, hyperfunctioning adenoma
• 15% are d/t parathyroid hyperplasia
• 5% are d/t parathyroid carcinoma. 

• physiologic increase in PTH in response to low calcium levels that are caused by:
• calcium deficiency, vitamin D deficiency, renal insufficiency.

• Seen in dialysis patients with long-standing secondary hyperparathyroidism that leads to hyperplasia of parathyroid glands.
• When gland becomes autonomous = tertiary hyperparathyroidism.

• Most cases are asymptomatic
• Sx of hypercalcemia can include:
• stones (kidney stones)
• bones (pain, fx)
• groans (abdominal pain, NV, pancreatitis)
• moans (psych problems, ex. depression, altered mental status)
• Labs: hypercalcemia, hypophosphatemia, hypercalciuria; PTH is inappropriately elevated relative to Ca level

• some cases require parathyroidectomy
• if caused by a solitary adenoma, 1 gland may be removed
• if cause by hyperplasia, 3.5 glands must be removed

• IV fluids
• loop diuretics
• IV bisphosphonate
• In pts with renal insufficiency, administer oral phosphate binders (ex. aluminum hydroxide) and restrict dietary phosphate intake to prevent 2ndary hyperparathyroidism.
• Cinacalcet = calcimimetic, lowers serum PTH levels and approved for use in hyperparathyroidism d/t renal failure

• Promotes release of calcium and phosphate from bone.
• Promotes phosphate excretion and calcium reabsorption in kidneys
• Promotes GI calcium uptake by catalzying activation of VitD in the kidney.

• Inherited disorder d/t mutations in Ca-sensing receptor in parathyroid and kidney
• Presents with elevated serum calcium levels and low urinary calcium levels (the latter distinguishes this condition from primary hyperparathyroidism).
• Asymptomatic; no tx required

• HTN
• T2DM
• depression
• weight gain, esp central obesity
• proximal muscle weakness and wasting
• easy bruisability and increased susceptibility to infxn
• oligmenorrhea
• hirsutism
• acne
• striae
• moon facies
• supraclavicular and retrocervical fat pads

[HA or cranial nerve deficits can occur with increasing size of pituitary mass if sx are d/t Cushing's dz]

• MC: iatrogenic = prolonged tx with exogenous corticosteroids
• MC endogenous cause = ACTH-secreting adenoma (=Cushing's disease)
• Excess adrenal secretion of cortisol: bilateral adrenal hyperplasia, adenoma, cancer)
• Ectopic ACTH from an occult neoplasm (carcinoid tumor, medullary thyroid CA, small cell lung CA).

• Dexamethasone is a steroid that does not cross the BBB. It acts on ACTH receptors on the pituitary gland and inhbiits further ACTH secretion.
• Low dose dexamethasone (1-2 mg) suppresses cortisol levels in someone with normal endogenous cortisol production. It will not suppress cortisol in a patient's with Cushing's syndrome (from any cause).
• High doses (8 mg) will suppress cortsiol levels in someone with Cushing's disease, but not in someone with ectopic ACTH production or someone with primary hypercortisolism.

• Do 2 of 3 screening tests:
• 24-hour free urine cortisol
• midnight salivary cortisol on 2 separate occasions
• Low dose dexamethasone suppression test
• These tests will have elevated cortisol in Cushing's syndrome d/t any cause.

• Distinguish ACTH-dependent (pituitary/ectopic) from ACTH-independent (adrenal) causes.
• Measure morning cortisol and ACTH levels.
• Elevated ACTH suggests Cushing's dz or ectopic ACTH. 
• Do high-dose dexamethasone suppression test to distinguish Cushing's dz from ectopic ACTH (suppressed in Cushing's dz).

• If lab suggests ACTH-dependent cause, do MRI of pituitary
• If lab suggests ACTH-independent cause, do adrenal imaging. 

• surgical resection of the source (pituitary, adrenal, neoplasm)
• Inhibitors of adrenal steroidogenesis (spironolactone, eplerenoone) are helpful for cases of bilateral adrenal hyperplasia.
• Permanent hormone replacement therapy after tx of primary lesion. 

• Acromegaly = elevated GH levels in adults
• MC d/t benign pituitary GH-secreting adenoma (note: GH from pituitary stimulates IGF-1 secretion from liver which is what directly produces s/sx)
• S/Sx: enlargement of skull, hands, feet, and coarsening of facial features; +/- bitemporal hemianopsia.
• Increased risk of carpal tunnel, OSA, T2DM/glucose intolerance, heart dz (diastolic dysfxn), HTN, arthritis

• Dx: (1) labs - measure IGF-1 levels (elevated w/ acromegaly) and confirm dx with oral glucose suppression tests (GH will remain elevated despite glucose administration). Note: baseline GH is not a reliable test. (2) imaging - MRI shows sellar lesion.
• Tx: transphenoidal surgical resection of tumor, external beam radiation of tumor, octreotide (somatostatin analog) to suppress GH secretion, or pegvisomant (GH receptor antagonist) to block peripheral actions of GH.

• MC d/t pituitary adenoma - *Prolactinoma = MC functioning pituitary tumor*
• pituitary stalk compression d/t other mass (e.g. craniopharyngioma, meningioma)
• drugs (dopamine antagonists)
• renal failure
• cirrhosis

• Elevated prolactin inhibits GnRH which results in decreased LH/FSH secretion.
• This causes infertility, galactorrrhea, and amenorrhea.
• Can also have bitemporal hemianopsia.

• Dx - serum prolactin level usually > 200 mg/mL (typical nonpregnant value < 20); MRI shows sellar lesion. Always r/o pregnancy!
• Tx: 1st line - DA agonists (cabergoline, bromocriptine). Surgery is indicated for adenomas refractory to medical management or w/ compressive effects (vision loss).

• Posterior pituitary fails to secrete ADH.
• Can be caused by
• tumor
• ischemia (Sheehan's syndrome)
• pituitary hemorrhage
• TBI
• infxn
• metatstatic dz
• autoimmune d/o

• Kidneys do not respond to circulating ADH.
• Causes include
• renal disease
• drugs - lithium, demeclocycline (=tetracycline antibiotic that's also used to treat SIADH)

• polydypsia, polyuria with dilute urine. Most cases are normonatremic.
• If access to water is limited, pts may present with dehydration and severe hypernatremia that causes altered mental status, lethargy, seizures, coma. 

• Treat underlying cause
• Central DI - administer intranasal or oral DDAVP
• Nephrogenic DI
• first line = salt restriction & increased water intake
• thiazide diuretics can be used to promote mild volume depletion and stimulate water reabsportion

• SIADH = common cause of euvolemic hyponatremia; results from persistent ADH release independent of serum osmolality
• Causes include
• CNS dz (head injury, tumor)
• pulmonary dz (sarcoid, COPD, pneumonia)
• ectopic tumor production/paraneoplastic syndrome (small cell lung CA)
• drugs (antipsychotics, antidepressants)

• Urine osmolality > 50-100 mgOsm/kg in setting of serum hypoosmolarity (w/o physiologic reason for elevated ADH).
• Urinary sodium level of 20 mEq/L or more shows that pt is not hypovolemic.
• Serum uric acid < 4 mg/dL. 

• fluid restriction = cornerstone of tx
• tx of underying cause
• if hyponatremia is severe (<100 mEq/L) or if pt has serious sx (coma, seizing), slowly correct hyponatremia by giving hypertonic salne. Pts must be monitored in ICU to prevent central pontine myelinolysis.
• Demeclocycline - ADH receptor antagonist.

• Addison's dz (autoimmune destruction of adrenal cortex) = MC cause in U.S.
• congenital enzyme deficiencies
• adrenal hemorrhage
• infxn
• MC cause worldwide = TB

• Neisseria meningitidis
• HIV
• Histoplasmosis
• TB

• weakness, fatigue, anorexia with weight loss
• GI sx
• hypoglycemia
• hypotension
• salt craving
• Hyperpigmentation seen in Addison's dz (d/t increased ACTH).

• check 8 am plasma cortisol levels and synthetic ACTH stimulation test
• 8 am plasma cortisol <3 (in absence of exogenous glucocorticoid administration) is diagnostic of AI
• Failure of cortisol to rise > 18 following ACTH administration confirms dx
• Random plasma cortisol >18 r/o dx.

• Hyponatremia and eosinophilia seen in both primary and secondary AI.
• Hyperkalemia is specific to primary AI.
• Hypercalcemia seen in up to 1/3 of cases.

• Primary AI - glucocorticoid and mineralocorticocid replacement
• Secondary AI - only glucocorticoid replacement necessary (mineralocorticoid production is not ACTH-dependent).
• Increase doses during periods of stress (major surgery, trauma, infection)

• IV steroids: hydrocortisone (don't delay!!)
• Correct electrolyte abnormalities
• 50% dextrose to correct hypoglycemia
• Aggressive volume resuscitation

• patients consume large volumes of fluid which causes polyuria
• most often occurs in pts with psychiatric d/o's
• sx similar to diabetes insipidus, but following water deprivation tests, urine osmolarity increases (whereas in diabetes insipidus it would remain dilute).

• MEN2A/2B
• von Hippel-Lindau
• Neurofibromatosis

• 10% extra-adrenal
• 10% bilateral
• 10% malignant
• 10% occur in children
• 10% familial

• Sx: Paroxysmal tachycardia, palpitations, chest pain, diaphoresis, HTN, HA, tremor, anxiety.
• Dx: Imaging with CT, MRI, or nuclear MIBG scan. Labs show elevated plama free-metanephrines or 24 hr urine metanephrines and catecholamines.

• surgical resection
• Preoperatively - use alpha adrenergic blocker first to control HTN, then a beta blocker to control tachycardia. Do not give beta blocker first - can cause hypertensive crisis!

• 70% of cases are due to adrenocortical hyperplasia
• Can also be due to adrenal adenoma (Conn's syndrome).

• HTN (cause of secondary HTN in younger adults), HA, polyuria, muscle weakness
• severe cases: tetany, paresthesias, peripheral edema

• Pts have diastolic HTN w/o edema
• Labs: hypokalemia, mild hypernatremia, metabolic alkalosis, hypomagnesemia, hyper-aldo, elevated aldo:PRA ratio (usually > 30)
• CT or MRI may show adrenal mass
• Adrenal venous sampling may be necessary to localize adenoma or confirm bilateral hyperplasia.

• surgical resection if caused by adenoma (first correct bp and potassium)
• Treat bilateral hyperplasia with spironolactone = aldo receptor antagonist

• 95% due to autosomal recessive 21-hydroxylase deficiency
• may also be caused by 11-hydroxylase deficiency or 17-hydroxylase deficiency
• types of CAH include salt-losing form and non-salt-losing form

• females: present at birth with ambiguous genitalia
• males: in salt-losing form, presents in neonate with adrenal crisis; in non-salt-losing form presents with precocious puberty

• elevated serum 17-hydroxyprogesterone is diagnostic
• abnromal labs: hyponatremia, hyperkalemia, metabolic acidosis (severe cases of mineralocorticoid deficiency can lead to life-threatening salt-wasting)

• Medical tx: immediate fluid resuscitation, salt repletion, and administration of cortisol (to decrease ACTH and androgens). 
• Also give fludrocortisone (mineralocorticoid replacement) if there is severe 21-hydroxylase deficiency.
• Surgical - correct ambiguous genitalia in females.

Multiple Endocrine Neoplasia (MEN) type 1

(Wermer's syndrome)

• autosomal dominant inheritance
• 3 P's:
• Pancreatic islet cell tumors: gastrinoma (Zollinger-Ellison syndrome), insulinoma, VIPoma
• Parathyroid hyperplasia
• Pituitary adenoma

• BOTH: medullary carcinoma of thyroid, pheochromocytoma, autosomal dominant mutations in RET proto-oncogene, 
• MEN2A: also can have adrenal and parathyroid gland hyperplasia
• MEN2B: also can have mucosal neuromas (oral and intestinal ganglioneuromatosis), marfanoid habitus