Hormone Pathophysiology

SIADH

Syndrome of Inappropriate Antidiuretic Hormone

• Pathophysiology: Characterized by abnormally high levels of antidiuretic hormone (ADH), most commonly caused by ectopic secretion from tumors or following surgery High ADH increases renal collecting duct permeability to water, causing excessive water reabsorption by the kidneys.

• Clinical Manifestations: Hypervolemia, weight gain, dilutional hyponatremia (serum sodium mEq/L, serum hypoosmolality mOsm/kg, and urine hyperosmolality. If serum sodium falls below mEq/L, severe and potentially irreversible neurological damage can occur

Diabetes Insipidus (DI)

• Pathophysiology: Characterized by an insufficiency of ADH or an inability of the kidneys to respond to ADH, leading to a partial or complete inability to concentrate urine23.

• Clinical Manifestations: Excretion of large volumes of dilute urine 8-12 L/day compared to normal 1-2 L/day, polyuria, polydipsia, nocturia, hypernatremia, low urine specific gravity (<1.010), and low urine osmolality (<200 mOsm/kg ). Neurogenic DI is treated with desmopressin acetate (DDAVP)

DI Subtypes

• Neurogenic DI: Insufficient production or release of ADH from the brain.

• Nephrogenic DI: Insensitivity of the renal collecting tubules to ADH.

• Dipsogenic DI: Excessive fluid intake that lowers plasma osmolality below the threshold required to trigger ADH release

Hypopituitarism (Panhypopituitarism)

• Pathophysiology: Characterized by the selective absence of specific anterior pituitary hormones or the complete failure of all anterior pituitary functions (panhypopituitarism). Because the pituitary gland is highly vascular, it is exceptionally vulnerable to ischemia and infarction.

• Causes: Head trauma, stalk damage, pituitary infarction, surgical removal, or hypothalamic releasing-hormone deficiencies

Hyperpituitarism (Primary Pituitary Adenoma)

• Pathophysiology: Overactivity of the anterior pituitary, most commonly caused by a benign, slow-growing pituitary adenoma.

• Clinical Manifestations: Headaches, fatigue, visual disturbances, hypersecretion of the tumor's specific hormone, and compression leading to hyposecretion of neighboring pituitary hormones

Gigantism

Pathophysiology: Hypersecretion of growth hormone (GH) during childhood and adolescence prior to epiphyseal plate closure

Acromegaly

• Pathophysiology: Hypersecretion of GH during adulthood, most often driven by a slow-growing pituitary adenoma.

• Clinical Manifestations: Connective tissue proliferation (enlarged tongue, interstitial edema, coarse skin/hair, sweat gland enlargement) and bony proliferation (enlargement of facial bones, hands, feet, lower jaw protrusion, and kyphosis). Causes significant mortality via cardiac hypertrophy, hypertension, atherosclerosis, and type 2 diabetes mellitus leading to coronary artery disease

General Hyperthyroidism / Thyrotoxicosis:

Excess circulating levels of thyroid hormone (TH) secreted by the thyroid gland, leading to an increased metabolic rate, heat intolerance, sympathetic nervous system overstimulation, and a goiter (thyroid enlargement)

Graves Disease

An autoimmune hyperthyroid condition where autoantibodies stimulate the thyroid gland. Manifests uniquely with ophthalmopathy (exophthalmos / protruding eyes due to orbital fat accumulation, inflammation, and hyaluronic acid secretion; double vision) and pretibial myxedema (leg swelling). Antithyroid drugs or surgery do not reverse established ophthalmopathy or pretibial dermopathy

Nodular Thyroid Disease

• Toxic Multinodular Goiter: Multiple hyperfunctioning nodules secreting excess thyroid hormone.

• Solitary Toxic Adenoma: A single hyperfunctioning thyroid nodule.

• Note: Manifests with hyperthyroid symptoms that develop slowly, but lacks exophthalmos and pretibial myxedema

Thyrotoxic Crisis (Thyroid Storm)

A sudden, severe, life-threatening escalation of hyperthyroidism

Primary Hypothyroidism

Deficient TH production directly originating within the thyroid gland. Primary causes include:

• Iodine Deficiency (Endemic Goiter): The most common cause of hypothyroidism worldwide.

• Autoimmune Thyroiditis (Hashimoto Disease): The most common cause of hypothyroidism in the United States, characterized by progressive immune destruction of the gland.

• Subacute, Painless, Iatrogenic, and Postpartum Thyroiditis

Congenital Hypothyroidism

TH deficiency present at birth. If left untreated, it leads to cretinism (severe physical and cognitive impairment); managed early via neonatal screening and synthetic T4 administration

Myxedema

Low basal metabolic rate, cold intolerance, tiredness, lethargy, slightly lowered basal body temperature, and diastolic hypertension. Features myxedema—nonpitting boggy edema around the eyes, hands, and feet, along with tongue thickening. Treated with levothyroxine

Myxedema Coma

A severe medical emergency characterized by a diminished level of consciousness, hypothermia without shivering, hypoventilation, hypotension, hypoglycemia, and lactic acidosis; requires urgent ventilatory/circulatory support and IV thyroid hormone

Thyroid Carcinoma

The most common endocrine malignancy associated with ionizing radiation exposure. Tumor growth can impinge on the trachea or esophagus, altering voice and swallowing; T3 and T4 levels may remain normal

Hyperparathyroidism Primary

Primary: Excess Parathyroid Hormone (PTH) secretion caused by a parathyroid tumor (80-85% parathyroid adenomas), resulting in hypercalcemia and hypophosphatemia

Hyperparathyroidism Secondary

Increased PTH secondary to a chronic systemic condition (such as chronic renal failure or vitamin D/calcium deficiency); hypercalcemia does not occur (serum calcium is low)

Hyperparathyroidism Tertiary

Autonomous PTH hypersecretion and hypercalcemia resulting from long-standing secondary hyperparathyroidism

Familial Hypocalciuric Hypercalcemia

A benign, autosomal dominant genetic disorder

Hyperthyroidism

Hyperthyroidism Clinical Features

Kidney stones (from hypercalciuria), alkaline urine, pathologic bone fractures, hypercalcemia, and hypophosphatemia

Hypoparathyroidism

• Pathophysiology: Abnormally low PTH levels, most commonly caused by accidental parathyroid gland damage during thyroid surgery, autoimmune destruction, or genetic defects. Includes inherited pseudohypoparathyroidism.

• Clinical Features: Hypocalcemia and hyperphosphatemia. Lowers the threshold for nerve and muscle excitation, causing muscle spasms, hyperreflexia, Chvostek and Trousseau signs, tonic-clonic convulsions, and potentially fatal laryngeal spasms leading to asphyxiation. Treated with calcium, vitamin D, and phosphate binders

Type 1 Diabetes Mellitus

Characterized by pancreatic atrophy and loss of insulin-producing beta cells in the Islets of Langerhans

Symptoms: The classic "3 Ps"—polyuria, polydipsia, polyphagia—along with weight loss and fatigue

Type 1A (Autoimmune)

T-cell, macrophage, and autoantibody destruction (targeting GAD, insulin, and islet cells) causes an absolute lack of insulin and amylin with a relative excess of glucagon. Strongly linked to MHC genes, viral infections, H. pylori, cow's milk protein, and vitamin D deficiency

Type 1B (Nonimmune / Idiopathic)

Secondary to pancreatic diseases or fulminant idiopathic disorders

Type 2 Diabetes Mellitus

More common than Type 1; driven by a combination of insulin resistance in peripheral tissues and progressive beta-cell dysfunction. Strongly associated with obesity, aging, physical inactivity, and metabolic syndrome (central obesity, dyslipidemia, prehypertension, elevated fasting glucose). Adipose dysfunction (leptin resistance, free fatty acids, inflammatory cytokines) impairs insulin signaling

Maturity Onset Diabetes of Youth (MODY)

A set of six specific autosomal dominant genetic mutations impairing beta-cell function occurring before 25 years of age

Gestational Diabetes Mellitus

Any degree of glucose intolerance with onset or first recognition during pregnancy; significantly increases the future risk of developing Type 2 DM

Hypoglycemia (Insulin Shock)

Plasma Glucose < 70 mg/dL in adults

<47mg/dL in newborns

Triggers tachycardia, palpitations, diaphoresis, tremors, pallor, and anxiety; treated with oral/IV glucose or emergency glucagon

Diabetic Ketoacidosis (DKA)

Most common in Type 1 DM

Absolute insulin deficiency leads to massive lipolysis, releasing fatty acids that form ketone bodies

Features serum glucose > 250 mg/dL, pH < 7.30, serum bicarbonate < 18 mg/dL , anion gap, Kussmaul Respirations, and acetone (fruity) breath odor

Hyperosmolar Hyperglycemic Nonketotic Syndrome (HHNKS / HHS)

most common in type 2 DM

characterized by profound hyperglycemia (glucose often >600 mg/dL) and severe fluid deficiency, but absent or low urine ketones because residual insulin prevents severe ketoacidosis

Somogyi Effect

Nocturnal hypoglycemia triggers counter-regulatory hormones, causing a rebound morning hyperglycemia

Dawn Phenomenon

Early morning glucose elevation caused by normal nocturnal growth hormone surges without preceding nighttime hypoglycemia

Microvascular Disease

(Capillary damage from basement membrane thickening, endothelial hyperplasia, and pericyte degeneration)

• Diabetic Retinopathy: Leading cause of blindness worldwide; features maculopathy, vessel occlusion, and macular edema.

• Diabetic Kidney Disease (Nephropathy): Most common cause of end-stage kidney disease; marked by microalbuminuria and glomerular basement membrane thickening.

• Diabetic Neuropathies: Most common diabetic complication; Schwann cell and axonal degeneration producing distal symmetrical polyneuropathy (loss of pain sensation, proprioception, or tingling)

Macrovascular Disease

(Large artery damage driven by Advanced Glycation End-products [AGE/RAGE], oxidative stress, and inflammation)

• Cardiovascular Disease: Accelerated atherosclerosis causing CAD, myocardial infarction, and heart failure (cause of death in up to $68\%$ of diabetic patients)3940.

• Stroke: Twice as common in individuals with diabetes4041.

• Peripheral Artery Disease (PAD): Causes peripheral ischemia, leg ulcers, gangrene, and amputations

Infections from Chronic DM complications

Morbidity/mortality increases due to impaired senses, hypoxia, rapid pathogen replication in glucose-rich tissue, suppressed immunity, and delayed wound healing

Cushing Syndrome & Cushing Disease (Cortisol Excess)

• Cushing Syndrome: Chronic excess of cortisol, regardless of the underlying cause.

• Cushing Disease: Specific overproduction of ACTH by a pituitary adenoma, causing a loss of diurnal/circadian cortisol rhythms.

• Cushing-like Syndrome: Induced by exogenous glucocorticoid administration.

• Clinical Features: Truncal (central) obesity, "moon face," "buffalo hump," sodium/water retention, glucose intolerance, purple striae, renal stones, and bronze skin hyperpigmentation

Congenital Adrenal Hyperplasia

An autosomal recessive enzyme deficiency in cortisol biosynthesis. Low cortisol causes elevated ACTH, driving adrenal hyperplasia and overproduction of mineralocorticoids or androgens (causing virilization in female infants and salt wasting in both genders)

Hyperaldosteronism (Aldosterone Excess)

• Primary (Conn Disease): Adrenal cortex abnormality producing excess aldosterone.

• Secondary: Driven by extra-adrenal stimuli (angiotensin II) via a renin-dependent pathway.

• Clinical Features: Hypervolemia, severe hypertension, hypokalemia, renal potassium wasting, muscle weakness/paralysis, polyuria, and metabolic alkalosis. Treated with aldosterone antagonists like spironolactone

Hypersecretion of Adrenal Sex Hormones

• Estrogen Hypersecretion: Causes feminization; results in gynecomastia, testicular atrophy, and decreased libido in men, and precocious secondary sex characteristics in female children.

• Androgen Hypersecretion: Causes virilization; results in hirsutism, clitoral enlargement, voice deepening, amenorrhea, acne, and breast atrophy in women, and precocious sexual development in children

Addison Disease (Primary Adrenal Insufficiency)

Rare autoimmune destruction of the adrenal cortex causing hypocortisolism and hypoaldosteronism alongside elevated ACTH. Manifests with weakness, hyperpigmentation, vitiligo, hypotension, and hypoglycemia; requires lifetime cortisol and mineralocorticoid replacement

Secondary Hypocortisolism

Caused by prolonged exogenous glucocorticoid administration suppressing ACTH. Symptoms mirror Addison disease, but skin hyperpigmentation does not occur

Pheochromocytoma

A tumor arising from the chromaffin cells of the adrenal medulla that autonomously secretes excessive catecholamines (epinephrine and norepinephrine). Presents with episodic severe hypertension, diaphoresis, tachycardia, palpitations, and pounding headaches. Managed with alpha- and beta-adrenergic blockers followed by surgical excision