Adrenal Gland Dysfunction.docx

Adrenal Gland Dysfunction Adrenal Gland Located in the retroperitoneal cavity above each kidney Considered “suprarenal” Two separate glands make it up: Medulla Cortex Adrenal cortex has 3 layers: Zona glomerulosa Cluster arrangement 10-15% of adrenal cortex Makes mineralocorticoids/aldosterone “Salt...

Adrenal Gland Dysfunction Adrenal Gland Located in the retroperitoneal cavity above each kidney Considered “suprarenal” Two separate glands make it up: Medulla Cortex Adrenal cortex has 3 layers: Zona glomerulosa Cluster arrangement 10-15% of adrenal cortex Makes mineralocorticoids/aldosterone “Salt” Zona fasciculata Thickest layer Column-like cell arrangement with lipid droplets between 70-80% of adrenal cortex Makes cortisol “Steroid” Zona reticularis Net-like appearance 5-10% of adrenal cortex Makes DHEAS, Androstenedione (Androgens/sex hormones) “Sex” Adrenal medulla Made of: Chromaffin cells and neural cells Chromaffin Cells Catecholamines (Epi and Norepi) Small amounts of dopamine Can be neurotransmitters and hormones (hormones in adrenal gland) “Stress” Adrenal Gland Pathology Layer Hyperfunction Hypofunction Neoplasms Zona glomerulosa (aldosterone) Hyperaldosteronism Conn syndrome Zona fasciculata Largest zone (cortisol) Hypercortisolism Cushings Adrenocortical insufficiency Primary Acute → Waterhous-Friderichsen Primary Chronic → Addison’s Dz Insufficiency from: Autoimmune Genetic Infection Metastasis of tumor Adrenocortical adenoma Adrenocortical carcinoma Zona reticularis (androgens) Androgenital syndromes Virilization syndromes Adrenal Medulla Chromaffin Cells (Pheochromocytoma) Neuronal Cells (Neuroblastic tumors) Hyperfunction of Adrenal Cortex Mineralocorticoid Excess, Hyperaldosteronism Over production of aldosterone from zona glomerulosa HTN due to high reabsorption of sodium and water (applies pressure to vessels) Can be primary and secondary Autonomous overproduction of aldosterone leading to suppression of the renin-angiotensin system Suppresses JG cells from releasing enough renin Renin ↓, Aldosterone↑ For blood testing it is checking of renin and aldosterone levels are high Primary hyperaldosteronism (↑Aldosterone, ↓ Renin) Caused by hyperfunctioning of the adrenal gland due to: Bilateral idiopathic hyperaldosteronism (60%) Most common Adrenal hyperplasia ➔ more replication and growth of adrenal cortex Bilateral enlargement and replication of adrenal cells in zona glomerulosa Diffuse hyperplasia of aldosterone-producing cells within the adrenal cortex (Zona glomerulosa) Pathogenesis unclear ➔ Could be due to mutations of KCNJ5 Found in older pts and less hypertension compared to adrenal adenoma Na/K pump disturbed, causes increase in Na retention (↑water retention) Aldosterone-producing adrenal cortical adenoma (35%) Unilateral mass Mostly benign Secretory Mutations of KCNJ5 (38%), CACNA1D (9.3%) and ATP1A1 (5.3%) --- All code for Na/K pump Activation of aldosterone synthase ➔ Autonomous aldosterone synthesis Increase in Na intake will trigger voltage gated Ca channel Overproduction of Na, Ca from aldosterone synthase ↑ Na = ↑ Depolarization of cell activates aldosterone synthesis = ↑ aldosterone Na increase also increases Ca Morphology: Glomerulosa cells look like fasciculata Solitary, unilateral Well circumscribed No visible mass, no lesion Small range Bright yellow on cut section Cells are lipid rich (zona fasciculata-like cells) and compact (eosinophilic) tumor cells Familial hyperaldosteronism (uncommon, 5%) Rare genetic condition Different genetic causes Secondary Hyperaldosteronism Due to extra-adrenal cause from renin-angiotensin system with elevated plasma levels of renin From hyperactive JG cells in kidney ↑ Renin ↑Aldosterone ↑Angiotensinogen receptor Hyperactive JG Cells in the kidney are due to: Less common: Tumor (Reninoma) More common: Poor renal perfusion (low cardiac output, vessel damage, etc.): Not enough blood reaching kidneys during cardiovascular dz High aldosterone, high renin, increased BP = HTN Hyperaldosteronism Complications Secondary HTN ↑ Aldosterone works at distal tubule Na/K channel (Na absorption, K Secretion) HYPERnatremia Na > 145 ↑ Aldosterone = ↑ Na leading to water following ↑ ADH = HTN, ↑ Blood volume HYPOkalemia ↓ K in blood (excreted in urine) Prolonged QT interval = arrhythmia = Torsade de Pointes (Inversely proportional to Ca) Metabolic Alkalosis Intercalated cells in distal tubule reabsorb HCO3 and excrete H+ Over reabsorption of HCO3 in blood ↑ pH BMP measures electrolyte balance Measures HCO3 Abg (arterial blood gas) + Vbg (venous blood gas) = blood pH 3+ more hypertensive agents = hyperaldosteronism Refractory HTN ADH ↑ Aquaporins ↑ water retention ↑ Blood pressure ↑ Blood volume Hyperaldosteronism Diagnosis Renin and Aldosterone Measurements Blood Test ↓ Increased Aldosterone, Renin Normal Plasma Aldosterone Renin (PAR) ratio ↓ Secondary Hyperaldosteronism (kidney issue) ↓ CT Scan Recognize underlying cause of poor renal perfusion Adenoma (less common) Blood Test ↓ Increased Aldosterone, PAR ratio Decreased Renin ↓ Primary Hyperaldosteronism (adrenal gland) ↓ Measure Adrenal Saline Suppression Test (IV saline, Na tablets to increase Na and decrease aldosterone in normal conditions) ↓ Inc Urine and Serum Aldosterone ↓ Supportive Primary Hyperaldosteronism ↓ Adrenal CT/MRI ↓ Adrenal Venous Sample (Ald. Lvls tested in both glands ↓ Unilateral Aldosterone Increase ↓ Adrenal Adenoma Bilateral Aldosterone Increase ↓ Adrenal Hyperplasia Hyperaldosteronism Treatment Adenoma Goal: Remove tumor Treatment: Adrenalectomy Hyperplasia (Bilateral) Goal: Suppress hyperplasia in zona glomerulosa Medications: Spironolactone or Eplerenone For Na/K ATPase channel Blocks aldosterone from expressing Na/K channel ↓Na reabsorption ↓ K excretion ↑ H+ ↓HCO3- Hypercortisolism Cortisol Hormone Main role: to increase blood glucose (gluconeogenesis, glycogenolysis) Activated under stress Hyperactive fasciculata cells Functions: Circadian rhythm Regulation ↓ cortisol secreted at night Gluconeogenesis, proteolytes, lipolysis Causes lipolysis → glycerol for gluconeogenesis AA from proteolysis Increases Blood glucose Glycogenolysis Liver adrenergic receptor activate causing glycogen to break → glucose Increases Blood glucose BP Regulation Vessel constriction w ↑ cortisol Overexpression of receptors on vessels and heart Immune system suppressed Cushing’s Syndrome Cushing syndrome is an endocrine disorder due to overproduction of cortisol Etiology: Exogenous Corticosteroid medications to treat autoimmune and inflammatory disorders Asthma or rheumatoid arthritis Similar to cortisol → mimics action on tissue (having effect of cortisol but no actual cortisol increase) Zona fasciculata cells shrink and become atrophic due to lack of utilization from exogenous causes Endogenous (made by the body) ACTH-Dependent: Pituitary microadenoma Excess ACTH overstimulates zona fasciculata and overproduce cortisol ↑ ACTH, ↑ Cortisol ACTH-Independent: Primary adrenocortical neoplasms (benign or malignant) Cells in zona fasciculata divide abnormally and secrete excess cortisol Suppress CRH and ACTH production Tumor cells autonomously producing cortisol ↓ACTH, ↑Cortisol Cushing’s Syndrome Symptoms Hyperglycemia Diabetes mellitus and obesity Insulin targets adipocytes, activating lipoprotein lipase → central truncal obesity HTN Increased risk of CVD from HTN and hyperglycemia Adrenergic receptors overactive in vessels and heart Vulnerable to infections Suppresses immune system Dysfunction of Ovarian and Testicular functions 2 functions: Microadenomas caused ↑ ACTH, Cortisol High cortisol inhibits GnRH = ↓LH, FSH release ↓CRH, ↓ACTH from negative feedback Hypogonadism = ↓ GnRH, which decreases LH and FSH release, ↓ACTH ↓ACTH = inhibits androgens in zona reticularis due to negative feedback Fatigue and muscle wasting (proteolysis, glycogenolysis) Easy bruising Truncal obesity Moon face Buffalo hump Abdominal Striae (from collagen loss due to ↑ cortisol) Fractures (↑ osteoclast activation) Cushing’s Diagnosis (1) Measure cortisol levels 24-hour urine sample Blood or saliva test (2) Measure ACTH levels Is it dependent, independent? If high with high cortisol → pituitary microadenoma and or adrenal neoplasms If normal or low with high cortisol → adrenal neoplasms (3) Dexamethasone suppression test Give low dose of dexamethasone (exogenous steroid) that should suppress ACTH production If cortisol levels drop → Pituitary microadenoma If cortisol levels remain high → adrenal neoplasms (4) Imaging: MRI of pituitary and CT for adrenals Cushing’s Treatment Exogenous medications Drug must be gradually decreased and eventually stopped if possible Avoid sudden withdrawal, this can lead to adrenal crisis (life threatening) Pituitary microadenoma Surgical resection of the tumor Adrenal adenoma or carcinoma Ketoconazole and metyrapone (adrenal steroid inhibitors) → enzymes → steroid synthesis Sex Hormone Excess: Adrenogenital Syndrome Sex Steroids Cells in the zona reticularis secretes sex steroids (weak androgens) that are later converted to testosterone and estrogen Weak androgens: dehydroepiandrosterone (DHEA) and androstenedione (A4) Under the control of ACTH, converted into testosterone in peripheral tissue (skin, fat and muscle) Functions: Responsible for the onset of adrenarche, leading to pubic and axillary hair growth before full sexual development (with the help of gonadal hormones) Adrenogenital Syndrome Disorders of sexual differentiation Virilization or feminization Terminologies: Hirsutism: Excessive growth of coarse hair in women in a male pattern (hair is found on face, chest and back) No other male sexual characteristics Virilization (in significant hormonal imbalance) Hirsuitism + other male characteristics, in a female or children Deep voice, increased muscle mass, reduction in breast size and enlargement of the clitoris Feminization Development of female physical characteristics in males Breast enlargement, reduced body hair and redistribution of body fat Disorders of sexual differentiation due to: (1) Primary gonadal disorders (2) Primary adrenal disorders Neoplasms (reticularis): Carcinoma more common than adenoma Congenital adrenal hyperplasia (CAH) Congenital Adrenal Hyperplasia Group of autosomal recessive disorders w different enzyme deficiencies involved in the production of cortical steroids Aldosterone, Cortisol CAH is classified into 3 categories depending on severity of mutation (1) Salt-Wasting (classic) adrenogenitalism Total absence of the enzyme No aldosterone, no cortisol Usually after few days of birth Clinical features of lack aldosterone – salt wasting, hyponatremia, and hyperkalemia which induce acidosis, hypotension, cardiovascular collapse, and possible death Clinical features of lack of cortisol- more testosterone formation which lead to virilization (2) Simple virilizing adrenogenitalism Aldosterone level is sufficient, very low cortisol Due to presence of aldosterone ➔ no salt wasting Low cortisol level still incapable to inhibit feedback regulation ➔ Virilization is present due to high androgens (3) Non classic (late-onset) adrenogenitalism Partial deficiency in 21-hydroxylase function Mild manifestations: hirsutism, acne, and menstrual irregularities (young women) and asymptomatic in young men CAH morphology Bilaterally hyperplastic cortex, 10 to 15 times of normal weight due to SUSTAINED ELEVATION OF ACTH from lack of cortisol (no feedback inhibition) Thickened with a nodular cortex Cut section of cortex is brownish ➔ due to lipid depletion Histopathology: Compact cell proliferation Eosinophilic lipid depleted cells Congenital Adrenal Hyperplasia Diagnosis Based on symptoms Blood and urine test In many countries, 21-hydroxylase deficiency is often screened at birth CAH is detected: Serum levels of aldosterone and cortisol are low Serum levels of 17-hydroxyprogesterone is elevated Genetic analysis of the CYP21A2 gene ➔ to predict the phenotypic severity Congenital Adrenal Hyperplasia Treatment Hormonal therapy and supplementation (cortisol and aldosterone) Early surgical correction of the genitals is sometimes recommended Endocrine Pathology II: Adrenal Gland Dysfunction Primary Adrenal Insufficiency Adrenal gland can’t produce enough hormones (aldosterone, cortisol) due to damage of the adrenal cortex Primary: problem localized to the adrenal gland Secondary: Problem of a hormone that acts on the adrenal gland or elsewhere in the body Can be either acute or chronic: Acute: Waterhouse-Friderichsen syndrome Chronic: Addison disease Addison Dz Due to progressive destruction of the adrenal gland from a variety of causes In high income countries: most common cause is autoimmune destruction Body’s immune cells mistakenly attack the healthy adrenal cortical tissues The pathology is not clear Other countries, most common cause is infectious due to tuberculosis The infection spreads from the lungs to the adrenal glands causing inflammation and destruction in the adrenal cortex Metastatic carcinoma is another important cause Cancer spread to the adrenal cortex from somewhere else in the body such as lung, breast, stomach and colon Addison Dz Clinical Manifestations Despite the causes, adrenal cortex has a high functional reserve Symptoms are dependent on the adrenal gland layer(s) destroyed: Zona glomerulosa: Aldosterone levels drops ➔ hyperkalemia, hyponatremia, hypovolemia, hypotension and metabolic acidosis Electrolyte changes and hypovolemia causes cravings for salty food, nausea, vomiting, fatigue and dizziness Zona fasciculata: Cortisol levels drops ➔Hypoglycemia (weak, tired and disoriented) ➔ Overactive pituitary gland producing proopiomelanocortin Precursor for ACTH Precursor for melanocyte-stimulating hormone (responsible for skin pigmentation) ➔ Hyperpigmentation in joints such as elbows, knees and knuckles Also, oral dark pigmentation on the tongue, palate, gingiva and mucosa In the Presence of Stressors (injury, sx, infection) and chronic low aldosterone and/or cortisol a sudden increased need for aldosterone and cortisol can lead to an Addisonian Crisis Extreme pain in back, abdomen or legs Vomiting, diarrhea → dehydration Hypotension → Loss of consciousness If untreated → death Waterhouse-Friderichsen Syndrome Addison Dz Diagnosis Cortisol Measurements ↓ Low Cortisol ↓ ACTH Measurements Low ACTH ↓ Possible Secondary Adrenal Insufficiency ↓ ACTH Stimulation Test Aldosterone & Renin Lvls ↓ High Cortisol Normal Aldosterone Normal Renin ↓ Secondary Adrenal Insufficiency ↓ Pituitary MRI High ACTH ↓ Possible Primary Adrenal Insufficiency ↓ ACTH Stimulation Test Aldosterone & Renin Lvls ↓ No change in Cortisol (low) Low Aldosterone High Renin ↓ Primary Adrenal Insufficiency ↓ 21-hydroxylase antibodies Adrenal CT/MRI FNA TB Sudden increase in blood pressure causing blood vessels in the adrenal cortex to rupture Due to severe bacterial infection (Endotoxins stimulate immune system inflammation → coagulation activates (DIC) Lead to adrenal crisis or acute adrenal insufficiency Adrenal gland stops producing hormones Classically associated w: Neisseria meningitidis septicemia, Pseudomonas species, pneumococci, Hemophilus influenzae, staphylococci, etc Adrenal cortex hemorrhage: Direct bacterial seeding of small vessels, DIC, or endothelial dysfunction due to microbial products and inflammatory mediators Clinical Signs: (1) Hypotension leading to shock (2) DIC with skin purpura (3) Addisonian crisis symptoms Treatment: Antibiotics (for bacteria) Glucocorticoids (for low cortisol, aldosterone) Supplementary hormones