(I) Endocrine Disorders (II) Overview of Endocrine Disease (A) Negative feedback loops (1) Control an increase or decrease

in hormone production Example: increase calcium decreases PTH

(B) Stimulation tests (1) Evaluate hypofunctioning disorders Example: ACTH stimulation test used for hypocortisolism

(2) Causes of hypofunction Autoimmune (Addisons disease, Hashimotos thyroiditis) Infarction (Sheehans postpartum necrosis, WaterhouseFriderichsen syndrome) Decreased hormone stimulation (decreased TSH in hypopituitarism) Enzyme deficiency, infection, neoplasia, congenital disorder

(C) Suppression tests (1) Evaluate hyperfunctioning disorders Example: dexamethasone suppression test evaluates hypercortisolism (2) Most hyperfunctioning disorders cannot be suppressed Except: prolactinoma and pituitary Cushings syndrome

(3) Causes of hyperfunction (III) Adenoma, acute inflammation, hyperplasia, cancer

Hypothalamic Disorders

(A) Tumors altering hypothalamic function (1) Pituitary adenomaMC tumor affecting the hypothalamus (2) Craniopharyngioma (3) Midline hamartoma (not a neoplasm) (4) Langerhans histiocytosis (B) Inflammatory disorders altering hypothalamic function (1) Sarcoidosis: produces granulomatous inflammation (2) Meningitis (C) C/F: (1) Secondary hypopituitarism: no releasing hormones to stimulate anterior pituitary (2) Central diabetes insipidus (CDI): ADH synthesized in the hypothalamus (3) Hyperprolactinemia: loss of dopamine inhibition causes galactorrhea (4) Precocious puberty: MCC in boys is a midline hamartoma True precocious puberty (onset of puberty before 9 years of age in boys and before 8 years of age in girls) is CNS origin; pseudo-precocious puberty implies a peripheral cause (5) Visual field disturbances: usually bitemporal hemianopia (6) Mass effects: produces obstructive hydrocephalus (7) Growth disorders: dwarfism in children (8) Kallmanns syndrome (IV) Pineal gland disorders (A) Clinical anatomy

(1) Midline location above the quadrigeminal plate (2) Site of melatonin production: Superior cervical sympathetic ganglia stimulates receptors on pinealocytes Melatonin functions: (a) important in sleep/moods and circadian rhythms (release at night) (b) used in the treatment of sleep and mood disorders (B) Disorders (1) Dystrophic calcifications on the pineal gland begins in childhood (2) Pineal tumors Majority are germ cell tumors resembling seminomas; minority are teratomas (C) C/F: (1) Visual disturbances: paralysis of upward conjugate gaze (Parinauds syndrome) (2) Obstructive hydrocephalus: due to compression of the aqueduct of Sylvius in the third ventricle (V) Pituitary gland disorders (A) Anterior pituitary hypofunction (1) Partial or complete loss of secretion of one or more hormones Infarctions of pituitary lead to panhypopituitarism Increased incidence of vascular or cerebrovascular disease Types of pituitary dysfunction:

(a) Primary hypopituitarism (pituitary dysfunction): 75% of gland must be destroyed (b) Secondary hypopituitarism (hypothalamic dysfunction): decreased hypothalamic releasing factors (2) Causes of hypopituitarism Nonfunctioning pituitary adenomaMCC (a) Associated with MEN I syndrome Includes pituitary adenoma, hyperparathyroidism, pancreatic tumor (Zollinger-Ellison syndrome or Insulinoma) (b) CraniopharyngiomaMCC of hypopituitarism in children Benign pituitary tumor derived from Rathkes pouch remnants (ectodermal derivative derived from the oral cavitydevelops into the anterior lobe of the pituitary gland) Located above the sella turcica Cystic tumor with hemorrhage and calcification; commonly causes bitemporal hemianopia; may produce CDI (c) Sheehans postpartum necrosis Hypovolemic shock causes infarction Sudden cessation of lactation due to loss of prolactin (prolactin release is inhibited by progesterone and estrogen during pregnancy) (d) Pituitary apoplexy (sudden onset of neurologic dysfunction)

Most often due to hemorrhage/infarction of preexisting pituitary adenoma

Predisposing factors: trauma, pregnancy (Sheehans necrosis), treatment of a prolactinoma with bromocriptine

C/F: headache, mental status dysfunction, visual disturbances; hormone dysfunction

(e) Sickle cell anemia Pituitary infraction from vascular occlusion by irreversible sickled cells (f) Empty sella syndrome Radiologic studies show an empty sella turcica Primary typeanatomic defect above pituitary: (a) Subarachnoid space extends into sella turcica and fills up with CSF (increase pressure causes flattening of gland) (b) Associated with women who are obese and high BP Secondary type: (a) Regression in size due to radiation, trauma, surgery **See chart below for C/Fs in hypopituitarism**

(3) Dx: CT scan or MRI (better test) for sella turcica; stimulation tests (4) Treatment: surgery for tumors (usually transsphenoidal); hormone replacement for deficiencies (B) Posterior pituitary hypofunction (1) Normal function:

Stores ADH: controls total body water; presence of ADH produces concentration of urine; absence of ADH produces dilution of urine

Releases oxytocin: produces milk ejection and uterine contractions

(C) Pituitary hyperfunction disorders (1) Prolactinomaoverall MC pituitary tumor (benign adenoma) C/F: (a) Women: secondary amenorrhea (prolactin inhibits GnRH), galactorrhea (b) Men: impotence (loss of libido due to decrease in testosterone), headache (c) Serum prolactin level > 200ng/mL (d) Decreased FSH and LH (due to decreased GnRH) (e) Treatment: Dopamine analogues: tumor does respond to suppression; restores gonadal function Surgery if macroadenomas

(2) Growth hormone (GH) adenoma Functions of GH: (a) Stimulates liver synthesis/release of IGF-1 (b) Stimulates gluconeogenesis and amino acid uptake in muscle (c) Negative feedback relationship with glucose and IGF-1 (d) Antinatriuretic action (retains sodium) Functions of IGF-1:

(a) Stimulates growth of bone (linear and lateral), cartilage, soft tissue Clinical and Lab findings: (a) Children develop gigantism Due to increased linear bone growth (epiphyses have not fused); lateral bone growth also increased (b) Adults develop acromegaly Increased lateral bone growth (no linear growth because epiphyses have fused) Prominent jaw (spacing between teeth), frontal bossing (enlarged frontal sinus increases the hat size), macroglossia, cardiomegaly (cause of death) (c) Increased GH and IGF-1 (hormones not suppressed by glucose administration) (d) Hyperglycemia (due to increase in gluconeogenesis) (e) Hypertension (sodium retention related to increased GH and insulin) (f) Visceral organomegaly with dysfunction (heart, liver, kidneys, thyroid) (g) Muscle weakness (myopathy); cardiomyopathy (h) Headache and visual field defects (enlarged sella turcica) Dx: imaging with CT scan, MRI (best study); suppression tests Treatment: (a) Transsphenoidal surgery (b) If surgery does not correctSomatostatin and dopamine analogues; GH receptor antagonists

(3) Syndrome of inappropriate ADH (SIADH) Ectopic production of ADHsmall cell carcinoma of the lung (MCC) Drugs that enhance ADH effect: cyclophosphamide, phenothiazines, narcotics CNS injury, lung infections Pathophysiology of electrolyte abnormalities (a) Urine is always concentrated because ADH is always present Negative CH20; UOsm > POsm

(b) Hypotonic gain of water produces a dilutional hyponatremia (c) Increased plasma volume increases peritubular capillary hydrostatic pressure C/F: (a) Mental status abnormalities from cerebral edema (b) Mild SIADH treated by restricting water (c) Acute SIADH treated by combination of slow IV drip of hypertonic saline and IV furosemide (d) Demeclocyclineused in patients with small cell carcinoma of the lung (VI) Thyroid Gland Disorders (A) Steps in thyroid hormone synthesis: (1) Trapping of iodide is TSH-mediated (2) Oxidation of iodides to iodine is peroxidase-mediated (3) Organification:

Iodine incorporated into tyrosine to for MIT and DIT (TSHmediated)

(4) Coupling of MIT with DIT produces T3 (5) Coupling of DIT with DIT produces T4 (6) Hormones are stored as colloid; proteolysis of colloid by lysosomal proteases is TSH-mediated (7) T4 and T3 bind to thyroid-binding globulin (TBG)one third of TBG binding sites normally occupied (8) Free T4 is peripherally converted to free T3 by an outer ring deiodinase FT3-active hormone; FT4- considered a prohormone; FT4 and FT3 have negative feedback relationship with TSH (B) Functions of thyroid hormone: (1) Control of total energy expenditure; growth and maturation of tissue; turnover of hormones and vitamins; cell regeneration (C) Thyroid function tests (1) Total serum T4 Represents T4 bound to TBG and free (unbound) T4 Increase in TBG synthesis increases total serum T4: (a) Estrogen increases the synthesis of TBG (pregnancy, OCPs, hormone replacement) (b) No signs of thyrotoxicosis are present Decrease in TBG synthesis decrease total serum T4: (a) Causes of a decreased TBG (anabolic steroids, nephrotic syndromeurinary loss) (b) No signs of hypothyroidism

Normal TBG with increase or decrease in total serum T4: (a) Increase of decrease in FT4 must be present (b) Increase FT4 Graves disease, thyroiditis (c) Decreased FT4 Hypothyroidism

(2) Serum TSH Best overall screening test for thyroid function Increased TSH Primary hypothyroidism Decreased TSH Thyrotoxicosis, hypopituitarism/hypothalamic dysfunction (causes secondary/tertiary hypothyroidism, respectively) (3) 123I radioactive uptake Evaluates synthetic activity of the thyroid gland Increased uptake indicated increased synthesis of T4 (a) Examples: Graves disease, toxic nodular goiter Decreased uptake of
123

I:

(a) Inactivity of the gland (patient taking thyroid hormone) (b) Inflammation of the gland (acute/subacute/chronic thyroiditis) Evaluates functional status of thyroid nodules (a) Decreased uptake in a nodule Cold nodulecyst, adenoma, cancer

(b) Increased uptake in a nodule Hot noduletoxic nodular goiter

(4) Thyroglobulinmarker for thyroid cancer

(D)Lingual thyroidfailed decent of thyroid anlage from the base of the tongue (1) C/F: dysphagia for solids, mass lesion (2) Dx:
123

I scan locates the lesion

(3) Treatment: Suppression with thyroxine (lingual thyroids are hypofunctional) Ablation with radioactive iodine Surgery if obstructive

(E) Thyroglossal duct cystcystic midline mass that is close to or within the hyoid bone (1) Surgery with removal of the proximal duct and hyoid bone (F) Thyroiditis (1) Acute thyroiditisbacterial infection C/F: fever, tender gland with painful cervical adenopathy, initial thyrotoxicosis from gland destruction (increased serum T4, decreased serum TSH) Decreased
123

I uptake

Treatment: penicillin or ampicillin

(2) Subacute granulomatous thyroiditisviral infection MCC of painful thyroid gland; occurs in women 40-50 years old Granulomatous inflammation with multinucleated giant cells C/F:

(a) Often proceeded by an URI, cervical adenopathy is not prominent, initial thyrotoxicosis from gland destruction (increased serum T4, decreased serum TSH) Decreased
123

I uptake

Treatment: self-limited; does not require treatment

(3) Hashimotos thyroiditisautoimmune thyroiditis (MCC of primary hypothyroidism) Incidence increases with age; W > M; HLA-Dr3 and HLA-Dr5 associations Increased incidence in: turners syndrome, down syndrome, Klinefelters syndrome Pathogenesis: (a) Cytotoxic T cells destroy parenchyma (type IV hypersensitivity reaction) Initial thyrotoxicosis, followed by hypothyroidism

(b) Blocking antibodies against TSH receptors Decrease hormone synthesis; type II hypersensitivity reaction (c) Helper T cells release cytokines attracting macrophages that damage tissue (type IV HSR) (d) Antimicrosomal and thyroglobulin antibodies destroy parenchyma (type II HSR) Gross and microscopic findings: (a) Enlarged, gray gland (b) Lymphocytic infiltrate with prominent germinal follicles C/F:

(a) Initial thyrotoxicosis from gland destruction (b) Signs of hypothyroidism: Muscle weakness (common complaint); weight gain; dry, brittle hair; periorbital puffiness; hoarse voice; signs of myxedema; cold intolerance; constipation; hypertension from sodium retention; delayed reflexes (c) Risk factor for primary B-cell malignant lymphoma of the thyroid (4) Riedels thyroiditisfibrous tissue replacement of the gland Extension of fibrosis into surrounding tissue (can produce tracheal obstruction) Associated with other sclerosing conditions (sclerosing mediastinitis) Hypothyroidism may occur Treatment: initial treatment with corticosteroids, tamoxifen (first-line therapy or if corticosteroids are unsuccessful), surgery (G)Hypothyroidism (1) Reduced secretion of thyroid hormone (patients are hypometabolic) Decrease basal metabolic rate; decrease beta-receptor/LDL receptor synthesis (2) Causes: Hashimotos thyroiditis (90% of cases), subacute painless lymphocytic thyroiditis, hypopituitarism, iodine deficiency, enzyme deficiency, drugs (amiodarone, lithium, sulfonamides, phenylbutazone), hypothalamic dysfunction/hypopituitarism, congenital

(3) Cretinism Hypothyroidism in infancy or early childhood Brain requires thyroxine for its maturation Causes: (a) Maternal hypothyroidism (before the fetal thyroid is developed) (b) Enzyme or iodine deficiency C/F: severe mental retardation, increased weight and short stature Treatment: thyroid hormone replacement

(4) C/F in adult hypothyroidism: Proximal muscle myopathy (very common finding; increased serum CK) Weight gain (due to hypometabolic state with retention of water and salt) Dry and brittle hair; loss of outer 1/3rd of eyebrow Bradycardia (slow HR) Coarse yellow skin (due to less conversion of beta-carotenes into retinoic acid) Periorbital puffiness, hoarse voice (a) Both of these are due to myxedema; increased hyaluronic acid in interstitial tissue; nonpitting edema Fatigue, cold intolerance, constipation Menstrual irregularities (most often menorrhagia) Diastolic hypertension (due to retention of sodium and water)

Congestive (dilated) cardiomyopathy with biventricular HF Atherosclerotic CAD Delayed recovery of Achilles reflex, mental slowness, dementia

(5) Lab findings: Decreased serum T4, increased serum TSH Antimicrosomal, antiperoxidase, and antithyroglobulin antibodies (Hashimotos thyroiditis; subacute painless lymphocytic thyroiditis) Hypercholesterolemia (due to decreased synthesis of LDL receptors) (6) Treatment: Levothyroxine in small increments every 6-8 weeks; bring serum TSH into normal range (euthyroid state) (H) Thyroid hormone excess (1) Classification: Thyrotoxicosishormone excess regardless of cause Hyperthyroidismhormone excess due to increased synthesis (a) Examples: Graves disease, toxic nodular goiter (2) Patients are hypermetabolic (increase in the basal metabolic rate) (3) Graves diseaseMCC of hyperthyroidism and thyrotoxicosis Female dominant autoimmune disease; HLA-B8 and HLA-Dr3 association Pathogenesis:

(a) T cells induce specific B cells to produce IgG antibodies against the TSH-receptor Stimulating type antibody; type II HSR Antimicrosomal and thyroglobulin antibodies are present Predisposing factors that may initiate onset of disease: infection, withdrawal of steroids, iodide excess, postpartum Symmetrical, nontender thyromegaly (a) Scant colloid; papillary infolding of the glands C/F unique to Graves disease: (a) Infiltrative ophthalmopathy (exophthalmos) : Proptosis and muscle weakness of the eye Due to adipose and glycosaminoglycans deposited in orbital tissue (b) IgG-TSH receptor antibodies can cross placenta and produce transient hyperthyroidism in fetus (c) Pretibial myxedema (due to excess glycosaminoglycans in the dermis) (d) Thyroid acropachy Digital swelling and clubbing of fingers; nails separate from nail bed; exophthalmos and pretibial myxedema usually present (4) Graves disease in the elderly (apathetic hyperthyroidism) Cardiac abnormalities (A. Fib, CHF) Muscle weakness, apathy; thyromegaly

(5) Toxic multinodular goiter (Plummers disease) One or more nodules in a multinodular goiter become TSHindependent See hot nodules with
123

I scan

Distinctions from Graves disease (lack exophthalmos and pretibial myxedema)

Treatment: surgery

(6) C/F in all causes of thyrotoxicosis Constitutional signs: (a) Weight loss with good appetite; fine tremor of the hands; heat intolerance, diarrhea, anxiety; menstrual irregularities (oligomenorrhea); lid stare (due to increased sympathetic stimulation of eyelid muscles) Cardiac findings: (a) Sinus tachycardia; increased risk for atrial fibrillation (b) Systolic hypertension; high-output HF: Thyroid hormone increases beta-receptor synthesis in the heart Excess hormones increase inotropic and chronotropic effects on the heart Brisk reflexes, osteoporosis (increased bone turnover)

(7) Lab findings: Increased serum T4, decreased serum TSH Increased goiter)
123

I uptake (Graves disease and toxic multinodular

Decreased

123

I uptake (thyroiditis, patient taking excess

thyroid hormone) Hyperglycemia (increased glycogenolysis) Hypocholesterolemia (increased LDL receptor synthesis) Hypercalcemia (increased bone turnover) Absolute lymphocytosis

(8) Treatment of Graves disease Beta-blockers decreases adrenergic effects Thionamides decrease hormone synthesis Ablative
131

I therapy in 1 year if above regimen does not work

(9) Thyroid storm Causes: (a) Inadequately treated patients with Graves disease undergo surgery (b) Infection; trauma (c) Iodine; pregnancy C/F: (a) Tachyarrhythmias, hyperpyrexia, shock (volume depletion from vomiting), coma Treatment: (a) Inhibit hormone synthesis (propylthiouracil, iodide) (b) Sympathetic blockade with beta-blockers (c) Hydrocortisone (d) Cooling blanket

(10)

Euthyroid sick syndrome (ESS) Abnormalities in serum T3 and T4 but gland function appears normal (a) Associated with: Malignancy, HF, chronic renal failure, sepsis, MI

Pathogenesis: (a) Normally, a peripheral tissue outer ring deiodinase converts T4 into active reverse T3 In ESS, outer ring deiodinase is blocked (T4 to T3) and inner ring deiodinase converts T4 into inactive reverse T3 MC variant of ESS (1) Normal/decreased serum T4 (2) Decreased serum T3 (3) Normal/decreased serum TSH (4) Increased serum reverse T3

Treatment (a) Varies from no treatment to levothyroxine during the time of the illness

**See below for summary of Thyroid disease**

(I) Nontoxic goiterthyroid enlargement from excess colloid (1) Types of goiter Endemic type: due to iodide deficiency (MC) Sporadic type: due to Goitrogens (cabbage), enzyme deficiency, puberty, pregnancy (2) Pathogenesis: Absolute or relative deficiency of thyroid hormone Hyperplasia/hypertrophy (attempt to increase hormone synthesis) Hyperplasia/hypertrophy is followed by gland involution (failure of gland to sustain synthesis) Initial diffuse thyromegaly followed by multinodular goiter

(3) Complications: Hemorrhage into cyst (produces sudden, painful, gland enlargement) Compression of jugular vein causing neck congestion Primary hypothyroidism

Toxic nodular goiter (one or more nodules become TSHindependent, hot nodule)

Hoarseness (compresses laryngeal nerve) Dyspnea (compresses trachea)

(4) Treatment: Levothyroxine reduces gland size and achieves the euthyroid state Surgery if compressive symptoms persist

(J) Solitary thyroid nodule (1) Majority are cold nodules Causes in adult women: (a) Majority are cysts in goiter or a follicular adenoma (b) Majority of the solitary nodules are euthyroid (benign); 15% malignant Causes in adult men and children: (a) More likely to be malignant Prior history of radiation to head and neck (more likely to be malignant) (2) Dx: fine needle aspiration (FNA) most important initial step; thyroid hormone studies (3) Treatment: Depends on the FNA result If malignant, surgical removal If benign and asymptomatic, periodic follow up

(K) Benign and malignant tumors

(1) Follicular adenomaMC benign thyroid tumor Surrounded by a complete capsule Presents as a solitary cold nodule

(2) Papillary adenocarcinoma MC endocrine and thyroid cancer (a) W > M (3:1); occurs in 2nd and 3rd decades (b) Associated with radiation exposure Gross and microscopic findings: (a) Usually multifocal; papillary fronds intermixed with follicles (b) Psammoma bodies (dystrophically calcified cancer cells) (c) Empty-appearing nuclei (called Orphan Annie nuclei) (d) Lymphatic invasion Metastasize to cervical nodes, lung Dx: FNA Treatment: (a) Usually subtotal or near total thyroidectomy with sampling of cervical nodes (b) Followed in a few weeks by radiotherapy with
131

(c) Suppressive therapy with thyroid hormone (tumor is TSH dependent) (3) Follicular carcinoma MC thyroid cancer presenting as a solitary cold nodule (a) Female dominant cancer

Gross and microscopic findings: (a) Encapsulated or invasive (b) Neoplastic follicles invade blood vessels

Metastasize to lung and bone Treatment: similar to papillary cancer (above)

(4) Medullary carcinoma Types: (a) Sporadic (80% of cases) (b) Familial (20% of cases) Familial type (a) Associated with autosomal dominant MEN IIa/IIb MEN IIa syndrome: medullary carcinoma, HPTH, pheochromocytoma MEN IIb syndrome: medullary carcinoma, mucosal neuromas (lips/tongue), pheochromocytoma Familial type has better prognosis than sporadic type Ectopic hormones: ACTH which produces Cushing syndrome Pathogenesis: (a) Tumors derive from parafollicular C cells (b) C cells synthesize calcitonin (tumor marker) May produce hypocalcemia; converted to amyloid

(c) C-cell hyperplasia is a precursor lesion Calcitonin levels increase with infusion of pentagastrin

Dx: FNA; serum calcitonin

Treatment: (a) Total thyroidectomy (b) Genetic screening for familial cases: Detection of mutation of RET proto-oncogene Thyroidectomy is performed if patient is a gene carrier

(5) Primary B-cell malignant lymphoma Most often develops from Hashimotos thyroiditis

(6) Anaplastic thyroid cancer Occurs in elderly women Risk factors: multinodular goiter, history of follicular cancer Rapidly aggressive and uniformly fatal Treatment: (a) Palliative surgery; often compresses trachea (b) Irradiation or chemotherapy (VII) Parathyroid Gland Disorders (A) Clinical anatomy and physiology (1) Superior and inferior parathyroid glands Derive from 4th pharyngeal pouch and 3rd pharyngeal pouch, respectively (2) PTH Increases calcium reabsorption in the early distal tubule Decreases bicarbonate reclamation in the proximal tubule Decreases phosphorous reabsorption in the proximal tubule

Maintains ionized calcium level in blood (a) Increases bone resorption and renal reabsorption of calcium

Increases synthesis of 1-alpha-hydroxylase in proximal renal tubule (a) Increases synthesis of 1, 25-(OH)2D (calcitriol) (b) Inhibits 24-hydroxylase in proximal tubule, which normally converts 25-hydroxycholecalciferol synthesized in the liver to inactive 24,25-(OH)2D

Stimulated by hypocalcemia and hyperphosphatemia Suppressed by hypercalcemia and hypophosphatemia

(3) Role of vitamin D in calcium metabolism Preformed vitamin D in diet consists of cholecalciferol (fish) and ergocalciferol (plants) Endogenous synthesis of vitamin D in the skin occurs by photoconversion of 7-dehydrocholesterol via sunlight to vitamin D3 (cholecalciferol) Reabsorption of vitamin D occurs in the small intestine Liver hydroxylation of precursor vitamin D to 25hydroxyvitamin D (calcidiol) (a) Occurs in cytochrome P-450 system 25-(OH)D is secreted into the blood and bound to a protein for delivery to the proximal tubules of the kidneys Kidney hydroxylation of 25-(OH)D by 1-alpha-hydroxylase produces 1,25-(OH)2-D (active form of vitamin D; calcitriol)

(a) If PTH is decreased, 1-alpha-hydroxylase is decreased, and 24-hydroxylase in the proximal tubule converts 25(OH)D to metabolically inactive 24,25-(OH)2D Calcitriol attaches to nuclear receptors in target tissues Functions of calcitriol: (a) Increases calcium reabsorption in duodenum; increases phosphorous reabsorption in jejunum and ileum (b) Increases bone resorption (minor role) Induces monocytic stem cells to become osteoclasts

(c) Increases bone mineralization (major role) Feedback control of calcitriol is calcium-mediated (a) Decreased serum calcium: increase PTH increase synthesis of 1-alpha-hydroxylase decrease synthesis 1,25-(OH)2-D and via inhibition of 24-hydroxylase decrease synthesis of metabolically inactive 24,25-(OH)2D (b) Increased serum calcium: decrease PTH decrease synthesis of 1-alpha-hydroxylase increase synthesis 1,25-(OH)2-D and via activation of 24-hydroxylase increase synthesis of metabolically inactive 24,25-(OH)2D (4) Total serum calcium Calcium (bound to albumin) + free, ionized calcium (negative feedback with PTH) Hypoalbuminemia (a) Decreased total serum calcium (b) Normal free ionized level, normal PTH (c) No evidence of tetany

Effect of respiratory or metabolic alkalosis (a) Increases negative charge on albumin Extra negative charges bind some of the ionized calcium (b) Total serum calcium remains normal; decreased ionized calcium, increased PTH (c) Patient develops tetany Serum PTH cannot keep pace with the binding of ionized calcium to the negative charges on albumin (d) Tetany is due to a decreased ionized calcium level Causes partial depolarization of nerves and muscle (1) Lowers the threshold potential (Et) (2) A smaller stimulus is required to initiate an action potential C/F of tetany: (1) Carpopedal spasm (thumb flexes into the palm) (2) Chvosteks sign (facial twitch after tapping the facial nerve)

(B) Hypoparathyroidismhypofunction of the parathyroid glands leads to hypocalcemia (1) Causes: Autoimmune hypoparathyroidism (MCC) Previous thyroid surgery DiGeorge syndrome

(a) Failure of descent of 3rd and 4th pharyngeal pouches (absence of parathyroid glands) (b) Absent thymus (pure T-cell deficiency) HypomagnesemiaMC pathologic cause of hypocalcemia in the hospital (a) Magnesium is a cofactor for adenylate cyclase cAMP required for PTH activation

(b) Causes of hypomagnesemia: (2) C/F: Tetany Calcification of basal ganglia (a) Due to metastatic calcification; increased phosphorus drives calcium into the brain tissue) Cataracts, candida infections Diarrhea, aminoglycosides, diuretics, alcoholism

(3) Lab findings: Hypocalcemia, hyperphosphatemia, decrease PTH, decrease 1,25-(OH)2D (4) Treatment: Calcium and vitamin D (calcitriol); teriparatide (recombinant PTH) **See below for other causes of hypocalcemia**

(C) Primary hyperparathyroidism (HPTH) (1) MC nonmalignant cause of hypercalcemia Occurs most frequently in postmenopausal women Associated with MEN I and MEN IIa Causes: (a) Adenoma (MCC of primary HPTH) Usually a single adenoma; sheets of chief cells with no intervening adipose Remainder of the gland plus all other glands show atrophy (hypercalcemia suppresses PTH produced from normal tissue) Right inferior parathyroid gland most often involved

(b) Primary hyperplasia All four glands are involved Usually a chief cell hyperplasia; clear cell hyperplasia associated with markedly increased serum calcium levels (c) Carcinoma (uncommon) (2) C/F: Renal: (a) Calcium stones (MC presentation) (b) Nephrocalcinosis (causes polyuria and renal failure) GI: (a) PUD (calcium stimulates gastrin, which increases gastric acid)

(b) Acute pancreatitis (calcium activates phospholipase) (c) Constipation Bone and joints: (a) Osteitis fibrosa cystica Cystic and hemorrhagic bone lesion (caused by increased osteoclastic activity Commonly involves the jaw

(b) Radiographic findings: Subperiosteal bone resorption of phalanges and tooth sockets Salt and pepper appearance of the skull

(c) Osteoporosis (d) Chondrocalcinosis (pseudogout) Diastolic hypertension (due to hypercalcemia) Eyes (band keratopathy in the limbusdue to metastatic calcification) CNS (psychosis, confusion, anxiety, coma)

Remember: stones, bones, abdominal groans, and psychic moans (3) Lab findings: Increased serum PTH, increased calcium, decreased phosphorous (a) Intact serum PTH (best initial screening test) (b) Distinguishes it from hypercalcemia related to malignancy Normal anion gap metabolic acidosis

(a) Due to decreased proximal tubule reclamation of bicarbonate (b) Type II renal tubular acidosis Chloride: phosphorous ration > 33 (a) Ratio < 29:1 excludes primary HPTH Decreased serum 1,25-(OH)2D (a) Hypercalcemia decreases synthesis of 1-alphahydroxylase in proximal renal tubule ECG shows shortening of QT interval

(4) Dx: Technetium-99m-sestamibi radionuclide scan (5) Treatment: Surgical removal of the adenoma Treatment of hypercalcemia: (a) IV hydration with normal saline followed by IV furosemide (MC therapy) (b) Bisphosphonates (c) Cinacalcet directly lowers PTH levels Increases the calcium-sensing receptor to extracellular calcium (6) Other causes of hypercalcemia Serum PTH is increased in primary HPTH Serum PTH is decreased in hypercalcemia of malignancy Hypercalcemia in pregnancy can produce hypocalcemia in fetus (a) Suppression of PTH in the fetus

**See table on next page for other causes of hypercalcemia**

(D)Secondary hyperparathyroidism (1) Hyperplasia of all four parathyroid glands Compensation for hypocalcemia Examples: hypovitaminosis D due to renal failure and malabsorption

(2) Decreased calcium, increased PTH (3) May develop tertiary hyperparathyroidism Glands become autonomous regardless of calcium level

(E) Phosphorous disorders

(F) C/F in hypophosphatemia (1) Muscle weakness Decreased synthesis of ATP causes muscle weakness

(2) RBC hemolysis RBCs require ATP to maintain pumps and membrane integrity

(3) Osteomalacia (soft bones) Phosphorous is required to mineralize bon

**See below for causes of hyperphosphatemia**

C/F in hyperphosphatemia (a) Metastatic calcification Excess phosphorus drives calcium into normal tissue

(b) Hypovitaminosis D Hyperphosphatemia inhibits 1-alpha-hydroxylase

**See table summarizing calcium and phosphorous disorders**

(VIII) Adrenal Gland Disorders (A) Adrenal cortex hormones (1) Zona glomerulosa produces mineralocorticoids

(2) Zona fasciculata produces glucocorticoids 11-deoxycortisol and cortisol are 17-hydroxycorticoids (17OH) (3) Zona reticularis produces sex hormones 17-ketosteriods (17-KS) (a) DHEA and androstenedione Testosterone (a) Converted to DHT by 5-alpha-reductase in peripheral tissue sites (B) Adrenal medulla (1) Neural crest origin; produces catecholamines (epinephrine and norepinephrine) (2) Metabolic products of EPI and NOR (metanephrine and VMA) (3) Metabolic products of dopamine is homovanillic acid (HVA) (C) Adrenocortical hypofunction (primary hypocortisolism) (1) Acute adrenocortical insufficiency Causes: (a) Abrupt withdrawal of corticosteroids (b) Waterhouse-Friderichsen syndrome (c) Anticoagulation therapy Waterhouse-Friderichsen syndrome (a) Associated with septicemia from N. meningitidis (b) Patients develop endotoxic shock Release of tissue thromboplastin causes DIC

(c) Bilateral adrenal hemorrhage Fibrin clots inv vessels cause hemorrhagic infarction

(2) Chronic adrenal insufficiency (Addisons disease) Autoimmune destruction (MCC) Causes: (a) Miliary tuberculosis (MCC of Addisons disease in developing countries) (b) Adrenogenital syndrome (c) Metastasis (often from a primary lung cancer); AIDS C/F: (a) Weakness and hypotension (due to sodium loss from mineralocorticoid and glucocorticoid deficiency) (b) Diffuse hyperpigmentation Increase plasma ACTH stimulates melanocytes Buccal mucosa, skin, skin creases

Lab findings: (a) Short and prolonged ACTH stimulation test (no increase in cortisol or 17-OH) (b) Metyrapone test (increased ACTH but no increase in 11deoxycortisol) (c) Increased plasma ACTH (d) Electrolyte findings: hyponatremia, hyperkalemia, metabolic acidosis (e) Fasting hypoglycemia (due to a decrease in cortisol)

(f) Eosinophilia, lymphocytosis, and neutropenia (due to decrease in cortisol) Treatment: glucocorticoid and mineralocorticoid replacement (3) Adrenogenital syndrome (congenital adrenal hyperplasia) Autosomal recessive disorders Enzyme deficiency causes hypocortisolism and corresponding increase in ACTH (a) Increase in ACTH Causes adrenocortical hyperplasia and diffuse skin pigmentation (b) Increase in 17-KS, testosterone, and DHT; causes: Ambiguous genitalia in femalesdue to DHT; first step is to check the genetic sex of the newborn with a chromosome analysis Precocious puberty may develop in males and females (1) In girls, excess androgens are aromatized in peripheral tis sue to estrogen Girls experience irregular menses and infertility as adults Both sexes have rapid growth in childhood, but early fusion of epiphyses (majority have short stature as adults) (c) Decrease in 17-KS, testosterone, and DHT causes hypogonadism in both sexes

Females have delay in menarche and development of secondary sex characteristics (female hormones come from androgens)

Males develop pseudohermaphroditism (male external genitalia development requires DHT)

(d) Increase in mineralocorticoids (causes sodium retentionhypertension) (e) Decrease in mineralocorticoids; causes: Sodium loss (hyponatremia), hyperkalemia Hypotension and possible hypovolemic shock

Classic 21-hydroxylase (OHase) deficiencyMC enzyme deficiency (a) Increase in 17-KS, testosterone, and DHT (b) Decrease in mineralocorticoids (salt losers) (c) Decrease in 17-OH; increase in 17-hydroxyprogesteron

Nonclassic 21-hydroxylase deficiency (a) Impaired cortisol production but normal mineralocorticoid production (not salt wasting) (b) Ambiguous genitalia in females and virilization; precocious puberty in boys

11-hydroxylase deficiency (a) Increase in 17-KS, testosterone, and DHT (b) Increase in mineralocorticoids (11-deoxycorticosterone); salt retainers (c) Increase in 17-OH (11-deoxycortisol is proximal to the block)

(d) Increase in 17-hydroxyprogesterone 17-hydroxylase deficiency (a) Decrease in 17-KS, 17-OH, 17-hydroxyprogesterone, testosterone, and DHT (b) Increase in mineralocorticoids (salt retainers) Dx of adrenogenital syndrome (a) Serum 17-OH progesterone (excellent screening test) Increased in 21- and 11-OHase deficiency Decreased in 17-OHase deficiency Can measure prenatally with chorionic villous sampling

(b) Urine for 17-hydroxycorticoids and 17-ketosteroids Treatment: (a) Glucocorticoids (b) Mineralocorticoids (21-OHase deficiency) (c) Estrogen or testosterone at time of puberty **See chart below for summary of adrenogenital syndromes**

(D)Adrenocortical hyperfunction (1) Cushing syndrome Causes: (a) Prolonged corticosteroid therapy (MCC) (b) Pituitary Cushing syndrome (Cushing disease) Due to pituitary adenoma; increased ACTH and cortisol

(c) Adrenal Cushing syndrome Often due to an adenoma; decreased ACTH and increased cortisol (d) Ectopic Cushing syndrome Usually small cell carcinoma of the lung (ectopic ACTH production); increased ACTH and cortisol C/F: (a) Weight gain Due to hyperinsulinism from hyperglycemia (insulin increases storage of fat in adipose; also has mineralocorticoid effects and retains sodium) Fat deposition in face (moon facies), upper back (buffalo hump), and trunk (truncal obesity) (b) Muscle weakness

Cortisol breaks down muscles in the extremities (thin extremities)

Muscles supply amino acids for gluconeogenesis

(c) Diastolic hypertension Due to increase in weak mineralocorticoids and glucocorticoids Aldosterone is not increased

(d) Hirsutism (due to increased androgens) (e) Purple abdominal stria Cortisol weakens collagen, causing rupture of blood vessels in stretch marks (f) Osteoporosis Hypercortisolism causes increased breakdown of bone

Lab findings: (a) Increased urine for free cortisol (b) Low-dose dexamethasone (cortisol analogue) suppression test Cannot suppress cortisol in all types

(c) High-dose dexamethasone suppression test Can suppress cortisol in pituitary Cushing syndrome but not the other types (d) Hyperglycemia Cortisol enhances gluconeogenesis; stimulates the release of insulin (e) Hypokalemic metabolic alkalosis

Due to increased weak mineralocorticoids

Nelsons syndrome (a) Bilateral adrenalectomy causes enlargement of a preexisting pituitary adenoma Sudden drop in cortisol causes an increase in synthesis of ACTH (b) C/F: headache and diffuse hyperpigmentation

**See below for summary of Cushing syndromes**

(2) Hyperaldosteronism Primary aldosteronism (Conns syndrome): (a) Often due to a benign adenoma in the zona glomerulosa (b) C/F: Diastolic hypertension Muscle weakness, tetany (from metabolic alkalosis)

(c) Lab findings: Hypernatremia, hypokalemia, metabolic alkalosis Decreased plasma renin activity

Secondary aldosteronism (a) Compensatory reaction related to a decrease in CO (b) Decreased renal blood flow activates RAA system (c) Plasma renin activity is increased

(E) Adrenal medulla hyperfunctionincreased production of catecholamines causes hypertension (1) Pheochromocytoma Unilateral; benign adenoma Arises in the adrenal medulla N-methyltransferase coverts NOR to EPI (a) Adrenal medulla and the organ of Zuckerkandl contain the enzyme Pheochromocytoma produces NOR and EPI

Associations

(a) Neurofibromatosis (b) MEN IIa and IIb Mutation in RET protooncogene

(c) Von Hippel-Lindau disease (often bilateral tumors) Mutation in VHL gene

Tumor characteristics (a) Brown, hemorrhagic, and often necrotic

C/F: (a) Diastolic hypertension; pounding headache; palpitations; drenching sweats; anxiety; chest pain from subendocardial ischemia; orthostatic hypotension; ileus (catecholamines inhibit peristalsis)

Lab findings: (a) Increased plasma free metanephrines (best screening test) (b) Increased plasma normetanephrine; increased 24-hour urine for metanephrine (best test); increased 24-hour urine for VMA (c) Hyperglycemia (increased glycogenolysis and gluconeogenesis) (d) Neutrophilic leukocytosis (inhibition of neutrophil adhesion molecules)

Treatment: surgery (a) Preoperative stabilization

Phenoxybenzamine, beta-blockers, metyrosine (catecholamine synthesis inhibitor), liberal fluid and salt intake

(b) Preoperative or intraoperative hypertensive crisis Phentolamine or nitroprusside in concert with betaadrenergic blocker (2) Neuroblastoma Malignant tumor (a) Neoplasm of postganglionic sympathetic neurons (b) Often present in children < 5 years old (3rd MC cancer) (c) Located in adrenal medullasometimes located in the posterior mediastinum (paraspinal) (d) Amplification of N-MYC oncogene (nuclear transcriber) (e) Opsoclonus-myoclonus syndrome Paraneoplastic syndrome Myoclonic jerks of extremities; chaotic eye movements in all directions Metastasize to skin and bones Prognosis depends on age (children < 1year old have a good prognosis) Small cell tumorcomposed of malignant neuroblasts (a) Presence of Homer-Wright rosettes (b) EM shows neurosecretory granules Clinical and Lab findings:

(a) Palpable abdominal mass; diastolic hypertension; increased urine VMA and HVA Dx: (a) Urine collections of VMA and HVA (b) Imaging studies: Body scan with lesions Treatment: (a) Depends on age, stage of disease (b) Surgery; irradiation; multiagent chemotherapy
131

I-MIBG; bone scans to detect lytic

**See below for summary of Islet cell tumors**

(IX)

Diabetes Mellitus (DM) (A) Leading cause in the US for: (1) Legal blindness; peripheral neuropathy; chronic renal failure; below-the-knee amputation (2) Incidence increases with age (B) Classification: (1) Secondary causes: Pancreatic disease (examplescystic fibrosis, chronic pancreatitis) Drugs (glucocorticoids, pentamidine, thiazides, alpha interferon) Endocrine disease (pheochromocytoma, glucagonoma, Cushing syndrome) Genetic disease (hemochromatosis, MODY) Insulin-receptor deficiency (acanthosis nigricans is a phenotypic marker)

Infections (mumps, CMV in AIDS patients)

(2) Impaired glucose tolerance (IGT) (3) Gestational diabetes mellitus (GDM) (4) Maternal onset diabetes of the young (MODY)autosomal dominant (AD) Patients < 25 years old and are not obese Mild to severe hyperglycemia (impaired glucose-induced secretion of insulin release) May progress into type 2 DM Treatment: varies with regard to oral hypoglycemic agents or insulin (5) Metabolic syndrome Insulin resistance syndrome (a) Genetic defect causes insulin resistance that is exacerbated by obesity (b) Associated with polycystic ovary syndrome in women; acanthosis nigricans (c) Increased risk for developing Alzheimers disease Clinical and Lab findings: (a) Hyperinsulinemia; leads to: Increased synthesis of VLDL (hypertriglyceridemia) Hypertension (increased insulin increases sodium retention) CAD (increased insulin damages endothelial cells)

(b) Obesity exacerbates insulin resistance (increased adipose downregulates insulin receptor synthesis) (c) Serum HDL-CH < 40mg/dL in men and <50mg/dL in women (d) Fasting serum glucose > 110mg/dL Treatment: (a) Statin drugs to lower lipids (b) Treat hypertension (ACE inhibitors or diuretics) (c) Correct insulin resistance with weight loss (d) Correct insulin resistance with drugs (metformin, thiazolidinediones)

**See next page for comparison between Type 1 and Type 2 DM**

(C) Pathologic processes and complications in DM (1) Poor glycemic control Hyperglycemia is the key factor that produces organ damage Glucose control reduces onset and severity of complications (a) Related to retinopathy > neuropathy > nephropathy (2) Nonenzymatic glycosylation (NEG) Glucose combines with amino groups in proteins Produces advanced glycosylation products (a) Increased vessel permeability to protein; increased atherogenesis Role in diabetics (a) Production of glycosylated HbA1c

(b) Hyaline arteriolosclerosis (c) Diabetic glomerulopathy (d) Ischemic heart disease, strokes, peripheral vascular disease **See below chart for complications of DM**

(3) Osmotic damage Aldose reductaseconverts glucose to sorbitol (a) Sorbitol draws water into tissue causing damage Role in DM (a) Formation of cataracts (b) Peripheral neuropathy Osmotic damage of Schwann cells produces demyelination and sensorimotor peripheral neuropathy Peripheral neuropathy leads to neuropathic pressure ulcers (patient cannot feel pain) (c) Retinopathy Osmotic damage to pericytes produces microaneurysms of retinal vessels Diabetic microangiopathy (a) Increased synthesis of type IV collage in basement membranes and mesangium (b) Important in diabetic glomerulopathy

(D)C/F: (1) Insulin-induced hypoglycemiaMC complication Produces irreversible brain damage by destroying neurons C/F: (a) Sympathetic nervous system signs Sweating, tachycardia, palpitations, and tremulousness (b) Parasympathetic nervous system signs Nausea and hunger

(c) Focal neurologic deficits, mental confusion, coma (2) Diabetic ketoacidosis (DKA)complication of type 1 diabetes Precipitated by medical illness or omission of insulin Produces severe volume depletion and coma (a) Volume depletion due to loss of sodium and water with osmotic diuresis Mechanisms of hyperglycemia: (a) Increased gluconeogenesismost important mechanism Due to increase in glucagon and epinephrine

(b) Increased glycogenolysis in the liver Mechanism for ketone bodies: (a) Increased lipolysis with release of fatty acids (no inhibition of HSL) (b) Increased beta-oxidation of fatty acids increase production of acetyl CoA

No malonyl Co-A to inhibit carnitine acyltransferase, the rate-limiting enzyme of beta-oxidation

(c) Acetyl CoA is converted by the liver to ketone bodies Acetone (fruity odor), acetoacetic and betahydroxybutyric acid Mechanism for hypertriglyceridemia (a) Lack of insulin decrease capillary lipoprotein lipase activity in peripheral blood (b) Accumulation of chylomicrons and VLDL in the blood (type V hyperlipoproteinemia) (c) May precipitate acute pancreatitis and eruptive xanthomas in the skin Lab findings: (a) Hyperglycemia (b) Increased HbA1c 6% (c) Dilutional hyponatremia (d) Hyperkalemia (e) Increased anion gap metabolic acidosis (due to ketoacidosis and lactic acidosis) (f) Prerenal azotemia (due to volume depletion) (3) Hyperosmolar nonketotic comacomplication of type 2 diabetes Increased mortality ratepatients are older and usually have underlying cardiac and renal problems (E) Lab diagnosis (1) Criteria Random plasma glucose 200mg/dL plus classic symptoms

Fasting plasma glucose 126mg/dL (set for high sensitivity) Two-hour glucose level after 75-g glucose challenge is 200mg/dL

One of the preceding three criteria must be present on a subsequent day to confirm the diagnosis of diabetes

(2) Glycosylated hemoglobin (HbA1c)evaluates long-term glycemic control Represents the mean glucose value for the preceding 8-12 weeks Goal in therapy is <7 % (some use 6.5%)

(F) Impaired glucose tolerance (IGT) (1) Patient has hyperglycemia that is nondiagnostic of diabetes (2) Pathogenesis: Prediabetic state with insulin resistance

(3) Increased risk for macrovascular disease and neuropathy (4) Treatment: exercise regularly and to reduce sugar intake (G)Gestational diabetes (GDM) (1) Glucose tolerance develops during pregnancy Anti-insulin effect of human placental lactogen (HPL), cortisol, and progesterone Increased risk for GDM in future pregnancies

(2) Screening All pregnant women are screened between 24 and 28 weeks gestation 50-g glucose challenge followed by 1-hour glucose level

(a) Above 140mg/dL is a positive screen Positive screen is confirmed with a 3-hour oral glucose tolerance test (3) Newborn risks Macrosomia (a) Hyperglycemia in the fetus causes release of insulin (b) Insulin increases fat stored in adipose tissue (c) Insulin increases muscle mass by increasing amino acid uptake in muscle Respiratory distress syndrome (RDS) (a) Insulin inhibits fetal surfactant synthesis Increased risk for open neural tube defects Neonatal hypoglycemia (a) High insulin levels at birth drives glucose into the hypoglycemia range (give newborn glucose after birth) (4) Maternal risk (diabetes may develop at a later date) (X) Polyglandular deficiency syndromes (A) Type 1 polyglandular syndromeautosomal recessive (1) Mean age of onset is 12 years old (2) No HLA relationship (3) C/F: Addisons disease; primary hypoparathyroidism; mucocutaneous candidiasis (B) Type II polyglandular syndromeautosomal dominant (1) Mean age of onset is 24 years old

(2) HLA-DR3 and HLA-DR4 (3) C/F: Addisons disease; Hashimotos thyroiditis; Type I diabetes mellitus (XI) Hypoglycemia (A) Ranges have been anywhere from 40 to 70mg/dL (reasonable cut-off is <50mg/dL) (B) Fed state hypoglycemia (1) Reactive type of hypoglycemia (2) Causes: Insulin treatment in type 1 diabetesMCC (a) Sulfonylurea-related hypoglycemia is less common IGT or type 2 diabetes (a) Excessive amount of insulin is released for the glucose absorbed Develop adrenergic symptoms about 1 to 5 hours after eating (a) Sweating, trembling, anxiety (b) Palpitations, tachycardia, mydriasis (c) Numbness and tingling Treatment: (a) Carbohydrate intake (grape juice, candy) (b) Glucagon IM injection (C) Fasting type of hypoglycemia (1) Fasting state hypoglycemia

(2) Causes: Alcohol (a) Increased NADH converts pyruvate to lactate (b) Decreased glycogen stores in severe liver disease Renal failure (kidney is the site of gluconeogenesis) Malnutrition Chronic liver disease (a) Decreased gluconeogenesis, glycogen depletion Insulinoma, hypopituitarism (decreased GH and cortisol) Ketotic hypoglycemia in childhood (a) MCC of hypoglycemia form 18 months to mid-childhood (b) Multiple etiologies Maple syrup urine disease, galactosemia, hereditary fructose intolerance, von Gierkes glycogen storage disease Carnitine deficiency

(3) Neuroglycopenic symptoms (4) Dx: Prolonged fever Must satisfy Whipples triad: (a) Symptoms occur (b) Hypoglycemia is demonstrated Dizziness, confusion, headache, inability to concentrate Motor disturbances, seizures, visual disturbances, coma

(c) Symptoms are relieved by glucose