endogenous hypercortisolism caused by:

pituitary adenoma (Cushing disease, CRH-dependent pituitary hyperplasia)

ectopic corticotropin syndrome (pulmonary small cell carcinoma, bronchial carcinoid)

bilateral diffuse hyperplasia of adrenal cortex

expanded lipid poor zona reticularis = compact, eosinophilic cells surrounded by an outer zone of vacuolated lipid-rich cells, like those in the ZF

Hypercortisolism caused by:

Adrenal adenoma

Adrenal carcinoma

macronodular hyperplasia (ectopic expression of hormone receptors, including GIPR, LHR, vasopressin, and serotonin receptors)

primary pigmented nodular adrenal disease (PRKARIA, PDE11 mutations)

McCune-Albright syndrome (GNAS mutations)

morphologically

hypercortisolism with cortical atrophy characterized by a

zona glomerulosa of normal thickness and an atrophied zona fasciculata and reticularis 

often encountered in steroid abuse

ACTH-indendepent cause of Cushing syndrome

replacement of adrenals with prominent nodules of varying sizes containing an admixture of lipid-poor and lipid-rich cells

areas between the prominent nodules also demonstrate evidence of microscopic nodularity

ACTH-independent cause of Cushing syndrome

adrenal is replaced by darkly pigmented (brown/black) micronodules with atrophic intervening areas

lipofuscin pigment from wear and tear

ACTH-independent cause of Cushing syndrome

includes benign and malignant neoplasms

Adenomas = yellow tumors with thin or well-developed capsule composed of cells similar to ZF

Carcinomas = larger than adenomas unencapsulated

**if functional, adjacent adrenal cortex and contralateral adrenal gland are atrophic due to suppression of endogenous ACTH by high cortisol levels

hypertension and weight gain

central pattern of fat deposition (truncal obesity), buffalo hump, moon facies

atrophy of fast-twitch myofibers

hyperglycemia, glucosuria, polydipsia (secondary diabetes)

easily bruised skin,abdominal striae, osteoporosis (due to loss of collagen and bone resorption)

mental disturbances (mood swings, depression, psychosis)

hirsutism, menstrual abnormalities

bilateral nodular hyperplasia of the adrenal glands

cause of primary hyperaldosteronism

unclear pathogenesis

diffuse and focal hyperplasia of ZG-like cells

hyperplasia is often wedge-shaped, from periphery to center

increased aldosterone, decreased plasma renin

aldosterone-producing adenoma or adrenocortical carcinoma

cause of primary hyperaldosteronism

uncommon cause of familial primary hyperaldosteronism

caused by chimeric gene with fusion of 11β-hydroxylase gene and aldosterone synthase gene (CYP11B1-CYP11B2)

leads to sustained production of hybrid steroids in addition to cortisol and aldosterone

suppressible by exogenous dexamethasone administration

general syndrome characterized by hypertension and potential hypokalemia from renal potassium wasting

aldosterone contributes to endothelial dysfunction by decreasing G6PD levels, which leads to reduced NO synthesis and causes oxidative stress

dx by elevated ratio of aldosterone:renin; confirm with aldosterone suppression test

adenomas are resected surgically; otherwise, spironolactone

Salt wasting adrenogenitalism

(21-hydroxylase deficiency)

adrenogenital syndrome characterized by total lack of 21-hydroxylase

no hydroxlase to convert progesterone into deoxycorticosterone thus, no synthesis of mineralocorticoids

no mineralocorticoids leads to block in conversion of hydroxyprogesterone into deoxycorticosterol resulting in NO cortisol synthesis

presents soon after birth with salt wasting, hyponatremia, hyperkalemia

acidosis, hypotension, cardiovascular collapse, death

female virilization, male salt-wasting

Simple virilizing adrenogenitalism

(21-hydroxylase deficiency)

adrenogenital syndrome that presents as genital ambiguity

some mineralocorticoid synthesis; no salt wasting

failure of feedback inhibition of ACTH secretion due to decreased glucocorticoid levels

leads to excess testosterone and progressive virilization

adrenogenital syndrome with only partial deficiency in 21-hydroxylase

more common than classic patterns with a later onset

asymptomatic or mild symptoms, such as hirsutism, acne, menstrual irregularites

cannot be diagnosed on routine newborn screening

adrenogenital morphology includes bilaterally hyperplastic adrenals

cortex is thickened and nodular, appears brown

proliferating cells are compact, eosinophilic, lipid-depleted cells intermixed with lipid-laden clear cells

hyperplastic corticotroph cells in anterior pituitary

usually present with ambiguous genitalia, clitoral hypertrophy, pseudohermaphroditism, hirsutism, acne

(symptoms all related to androgen excess)

tx with exogenous glucocorticoids with addition of mineralocorticoid supplementation in salt-wasting variant

rapidly developing adrenocortical insufficiency characterized by overwhelming bacterial infection (classically N. meningitidis septicemia), rapidly progressing hypotension (leading to shock), and DIC (widespread purpura of the skin)

bilateral massive hemorrhage of the adrenals

more common in children, adrenals turn to sacs of clotted blood; hemorrhage starts in medulla near venous sinuses

can be treated with antibiotics, but if not recognized promptly, clinical course is abrupt and devastating

Addison Disease

(chronic adrenocortical insufficiency)

progressive destruction of the adrenal cortex

caused by:

autoimmune adrenalitis = irregularly shrunken glands, often with antibodies to 21-hydroxylase or 17-hydroxylase

tuberculosis = granulomatous inflammation

mestastic carcinoma = enlarged adrenals

AIDS

progressive weakness, easy fatigability, GI disturbances, hyperpigmentation

 decreased minerolcorticoid activity: hyperkalemia, hyponatremia, volume depletion, hypotension

stress can precipitate an acute adrenal crisis

autoimmune disorder characterized by:

chronic mucocutaneous candidiasis

skin, dental enamel, and nail abnormalities (ectodermal dystrophy)

organ specific autoimmune disorders (esp. autoimmune adrenalitis --> causes primary adrenocortical insufficiency/Addison disease)

caused by mutation in AIRE gene on chr 21q22

compromise of central tolerance

autoimmune syndrome that starts in early adulthood

presents as a combo of adrenal insufficiency and autoimmune thyroiditis or type 1 diabetes

NO autoimmune hypoparathyroidism, candidiasis, or ectodermal dysplasia

caused by any disorder of the hypothalamus or pituitary that causes decreased ACTH

NO hyperpigmentation

deficient cortisol and androgen output, but near-normal aldosterone synthesis

moderately to markedly reduced size of adrenals

cortex may only be thin ribbon of mainly ZG

usually an incidentally found tumor

well-circumscribed, nodular lesions that expands the adrenal

functional = atrophy of adjacent cortex; nonfunctional = cortex is normal

usually yellow to yellow-brown

neoplastic cells are vacuolated due to intracytoplasmic lipid

mild nuclear pleomorphism (endocrine atypia)

more common in children

more likely functional, often associated with virilism

large, invasive lesion with marked anaplasia

on cut section, typically variegated, poorly demarcated with areas of necrosis, hemorrhage, and cystic change

have a strong tendency to invade the adrenal vein, vena cava, and lymphatics

metastases to regional and periaortic nodes are common

hematogenous spread to lungs and other viscera is common

neoplasm of the adrenal medulla composed of chromaffin cells, which release catecholamines and peptide hormones

rule of 10's: 10% extra-adrenal, 10% are bilateral, 10% are malignant, 10% assoc. w/ hypertension, 10% familial (now 25%)

have richly vascular fibrous trabeculae, lobular pattern

smaller lesions are yellow-tan; larger lesions are hemorrhagic, necrotic, cystic, typically efface the whole gland

incubation with potassium dichromate turns the tumor brown due to oxidation of stored catecholamines

polygonal to spindle-shaped chromaffin or chief cells clustered into small nests (zellballen)

round to ovoid nuclei, salt and pepper chromatin

malignancy is determined solely by metastases

hypertension w/ paroxysmal episodes

dx by increased urinary excretion of catecholamines their metabolites (vanillylmandelic acid, metanephrines)

Multiple endocrine neoplasia type 1

(Wermer syndrome)

3 P's: parathyroid, pancreas, pituitary glands

Parathyroid: primary hyperparathyroidism; monoclonal hyperplasia or adenomas

Pancreas: aggressive endocrine tumors, often metastatic; pancreatic polypeptide is commonly secreted

Pituitary: prolactinoma; sometimes acromegaly due to somatotrophin secreting tumor

often a gastrinoma in the duodenum

mutation in MEN1, encoding menin

clinical picture dominated by effects of secreted hormones

Multiple endocrine neoplasia type 2A

(Sipple syndrome)

pheochromocytoma, medullary carcinoma, parathyroid hyperplasia

medullary carcinoma = assoc. w/ C cell hyperplasia of the adjacent thyroid

Pheochromocytoma = 50%, often bilateral

Gain of function mutation in RET proto-oncogene on chr 10q11.2

early screening is important to allow for thyroidectomy if necessary

Multiple Endocrine Neoplasia Type 2B

(MEN-2B)

medullary thyroid carcinoma (more aggressive) and pheochromocytomas

NO PRIMARY HYPERPARATHYROIDISM

in addition, neuromas or ganglioneuromas and a marfinoid habitus

amino acid substitution on RET leads to autophosphorylation and constitutive activation of RET

variant of MEN-2A

strong predisposition to medullary thyroid cancer but no other clinical manifestations

hyperaldosteronism distinguished by INCREASED levels of renin

encountered in conditions of: 

decreased renal perfusion = arteriolar nephrosclerosis, renal artery stenosis

arterial hypovolemia and edema = congestive heart failure, cirrhosis, nephrotic syndrome

pregancy = due to estrogen-induced increases in plasma renin substrate

autosomal-recessive inherited metabolic error characterized by a loss of enzyme in the biosynthesis of cortical steroids, especially cortisol

21-hydroxylase deficiency is responsible for 90% of cases:

defective conversion of progesterone to 11-DOC

high frequency in Hispanics and Ashkenazi Jews

gene inactivation involves recombination of CYP21A2 with a neighboring pseudogene on chr 6p21 called CYP21A1

can result in three syndromes: salt wasting, simple virilizing, or nonclassic