Adrenal gland pathology

Zona glomerulosa

Zona fasciculata

Zona reticularis

Adrenal medulla
Neural crest origin Produces catecholamines

Epinephrine

(EPI) and norepinephrine (NOR) and vanillylmandelic acid (VMA)

Metabolic products of EPI & NOR

Metanephrine

Metabolic product of dopamine is homovanillic acid (HVA)

Adrenal cortex

Adrenal cortex : 3 regions: 3 steroids

Zona

glomerulosa mineralocorticoids Zona fasciculata Glucocorticoids Zona reticularis Sex steroids

Diseases of adrenal cortex:

Associated

with hyperfunction Associated with hypofunction Mass lesions

Adrenal cortex hyperfunction = hyperadrenalism

Three different steroids from adrenal cortex, therefore, Three different hyper-adrenal syndromes:

Excess

of aldosterone Hyperaldosteronism Excess of cortisol Cushings syndrome Excess of androgens Adrenogenital syndrome.

Excess cortisol = hypercortisolism = Cushing's syndrome

Cushing syndrome: Caused by any condition that produces elevation in cortisol levels.

Four sources of cortisol:

1.
2. 3. 4.

Iatrogenic Excess cortisol due to excess of ACTH Excess cortisol from adrenal adenoma, Ca or hyperplasia Excess ACTH from ectopic sites (neuroendocrine tumors)

Cushings syndrome subdivided into:

Iatrogenic Cushings 2. Pituitary Cushings (Cushings disease) 3. Adrenal Cushings 4. Ectopic Cushing's
1.

Iatrogenic Cushings
Most common cause of Cushings syndrome Due to long term glucocorticoid therapy.

SLE, transplant patients. Bilateral cortical atrophy

Effect on adrenals:

Cause:
1.

Pituitary Cushings (Cushings disease)

ACTH secreting pituitary adenoma

Increased Plasma ACTH adrenal cortex hyperplasia cortisol. cortisol negative feedback on neoplastic corticotrophs produce degeneration in cells known as Crookes hyaline change. (Intermediate keratin filaments). Effect on adrenals:

Adrenal hyperplasia

Adrenal Cushings

Cause:
Most often due to an adrenal adenoma. Less commonly due to adrenal hyperplasia and carcinoma.

cortisol production negative feed back effect on pituitary ACTH Lab:

Decreased plasma ACTH and increased cortisol

Effect on adrenals:

Unilateral adenoma (or carcinoma) atrophy of the same gland and opposite gland.

Ectopic Cushing's:

Usually due to

small cell carcinoma of lung with ectopic ACTH production.

Increased ACTH (hyperpigmentation) and cortisol. Effect on adrenals:

Bilateral hyperplasia.

Cushings syndrome: Clinical findings

Weight gain: due to excess fat deposition in:

Face moon facies Upper back buffalo hump and Trunk (truncal obesity) with sparing of limbs.

Fat distribution due to hyperinsulinism from hyperglycemia. Due to increased catabolism of muscle tissue.

Thin extremities:

Purple abdominal striae:

Due to ruptured vessels Cortisol weakens collagen.

Glucose intolerance/diabetes :

Glucocorticoids are gluconeogenic

Buffalo hump

Central obesity Thin limbs

Buffalo hump
Cushings

Moon face and Plethoric appearance

After removal Of pituitary adenoma

Purple striae indicating vessel instability

Hirsutism

Cushings syndrome: Clinical findings

Hypertension:
Due Due

to increase in mineralocorticoids. to increase in androgens

Hirsutism:

Other findings:
Plethoric

face, menstrual irregularities, acne, easy bruisability, osteoporosis, depression and insomnia. Cutaneous hyperpigmentation.

Laboratory findings

Screening test:

Confirmatory test:

Free Urine cortisol : Increased (best screening test) Serum cortisol: Increased Plasma ACTH: low in Adr Cu, very high in Ec Cu and normal to slightly increased in Pit Cu. Low dose DST ( cortisol analogue): Unable to suppress cortisol in all types of Cushings (pituitary, adrenal, ectopic) High dose DST : Can suppress cortisol in pituitary Cushings only by inhibiting ACTH.

Localization studies:

Other laboratory findings

MRI, CT

Hyperglycemia Nelson's syndrome: bilateral adrenalectomy causes enlargement of preexisting pituitary adenoma

Lab test

Pituitary Cushings Increased Cortisol not suppressed Increased

Adrenal Cushings Increased Cortisol not suppressed Increased

Ectopic Cushings Increased Cortisol not suppressed Increased

Serum cortisol Low-dose DST Urine for free cortisol

Plasma ACTH Normal* to increased

High dose DST Cortisol suppressed

Low
Cortisol not suppressed

Markedly increased
Cortisol not suppressed

Adrenal cortex hyperfunction = hyperadrenalism

Three different steroids from adrenal cortex, therefore, Three different hyper-adrenal syndromes:

Excess

of cortisol Cushings syndrome Excess of aldosterone Hyperaldosteronism Excess of androgens Adrenogenital syndrome.

Hyperaldosteronism

Group of closely related disorders characterized by excess of aldosterone secretion. Excess aldosterone Na retention & K excretion hypertension and Hypokalemia. Hyperaldosteronism may be:
Primary 2. Secondary
1.

Primary Hyperaldosteronism

Also known as Conns syndrome. Represents excess production of aldosterone. Causes:

Most commonly due to aldosterone producing benign adenoma in zona glomerulosa. Others:

Adrenocortical carcinoma Hyperplasia of zona glomerulosa

Primary Hyperaldosteronism

Clinical findings:

Laboratory findings

Hypertension (Na retention) Muscle weakness (hypokalemia) Tetany (alkalosis the ionized calcium levels). Polyuria, polydipsia and nocturia secondary to hypokalemic nephropathy. Hypernatremia Hypokalemia Increased plasma aldosterone level. Decreased plasma renin activity ( due to negative feedback of increased BP on renin secretion) Metabolic alkalosis

Secondary hyperaldosteronism
Aldosterone is released in response to activation of the renin - angiotensin aldosterone system. Chr. by increased levels of plasma renin. Associated with:

Decreased cardiac output. Decreased renal perfusion

Renal artery stenosis, arteriolar nephosclerosis.

Adrenogenital syndromes

Adrenal disorders characterized by excess production of androgens causing

Virilization in females and precocious puberty in males.

Etiology:
Androgen secreting adrenal cortical neoplasm 2. Congenital adrenal hyperplasia
1.

Congenital adrenal hyperplasia

Group of autosomal recessive inherited metabolic errors characterized by deficiency or total lack of enzyme required for synthesis of cortical steroids (esp cortisol) 1. Deficiency of cortisol causes ACTH. 2. Increase in ACTH causes:

adrenal cortex hyperplasia and skin pigmentation.

3.

in 17-ketosteroids, testosterone and dihydrotestosterone produces:

ambiguous genitalia in females and precocious puberty in males.

4.

Increase in mineralocorticoids causes hypertension

21-hydroxylase deficiency: Most common enzyme deficiency:

Clinical findings:

Ambiguous genitalia in females Precocious puberty may develop in males and females.

In girls, excess androgens are aromatized in peripheral tissue to estrogen.

Hypotension due to sodium loss. Both sexes have rapid growth in childhood, but early fusion of epiphyses Short stature

Adrenal insufficiency
Hypofunction of adrenal cortex. May be due to:

Primary

adrenal disease = Primary hypoadrenalism Deficiency of ACTH

= Secondary hypoadrenalism

Primary Adrenal insufficiency

Refers to hypocortisolism resulting from disorders involving the adrenal glands. Can be of two types: 1. Primary acute adrenocortical insufficiency

1. 2.

Causes include:
Abrupt withdrawal of corticosteroids (MCC). Waterhouse-Friderichsen syndrome. Addisons disease.

2.

Chronic adrenocortical insufficiency

1.

Characterized by:

Waterhouse-Friderichsen syndrome

Bilateral hemorrhagic infarction of adrenal glands with adrenal insufficiency. Usually associated with septicemia from N. meningitidis. Patients develop Endotoxic shock which causes

Endothelial damage and DIC (purpuric rash).

Commonly occurs in children. Often fatal.

Treatment: Antibiotics and steroid replacement.

Primary chronic adrenocortical insufficiency (Addisons Disease)

Destruction of the adrenal cortex, leading to a deficiency of glucocorticoids, mineralocorticoids and androgens. Etiology:
1.
2. 3. 4. 5.

Autoimmune adrenalitis Tuberculosis (MCC worldwide) Disseminated histoplasmosis (MC systemic fungal cause) Disseminated CMV infection (Common in AIDS) Metastasis to adrenals (from lung cancer)

PIC ON EXAM

Addisons Disease: Presentation

Weakness and Hypotension

Due to sodium loss from mineralocorticoid deficiency.

Due to increase in plasma ACTH, which has melanocyte stimulating properties.

Skin hyperpigmentation

Treatment: Steroid replacement

LAB

Short and prolonged ACTH stimulation test

No increase in cortisol or 17-OH

Increased ACTH but no increase in 11-deoxycortisol

Metyrapone test

Increased plasma ACTH Electrolyte findings -Hyponatremia, hyperkalemia, and metabolic acidosis Fasting hypoglycemia

Due to decrease in cortisol (cortisol is gluconeogenic)

Eosinophilia, lymphocytosis, and neutropenia Due to decrease in cortisol

Tumors of adrenal cortex

Adrenal adenomas:
Yellow to orange lesions May protrude into subcapsular region 1. Functional (may produce Cortisol / aldosterone) 2. Nonfunctional

Adrenal cortical carcinoma

Highly malignant tumors Yellow but contain area of hemorrhage and necrosis. Rare inherited causes: Li-Fraumeni syndrome and Beckwith Wiedmann syndrome. Functional : (may produce androgens virilization) Nonfunctional

Adrenal gland adenoma from a patient with Cushing's syndrome

Adrenal adenoma from a patient with Conn's syndrome

Adrenal adenoma With no associated clinical findings

Adrenal cortical carcinoma

Adrenal medulla

Neural crest origin Synthesizes catecholamines : epinephrine (EPI) and Norepinephrine EPI and NOR : metabolized into metanephrine and vanillylmandelic acid (VMA) respectively. Important diseases:

Neoplasms:
1.
2.

Pheochromocytoma Neuroblastoma

Pheochromocytoma
Tumors cells secrete Catecholamine causing hypertension. Majority occur in adrenal medulla

Pheochromocytoma

Others occur in extra-adrenal sites.

autonomic ganglia paraganglioma carotid body chemodectoma

Most commonly occur in patients between 30-50 yrs of age.

Clinical findings

Hypertension (sustained with occasional bursts)

Palpitations Sense of apprehension and anxiety . Drenching Sweats and Headache

Skin pale : due to vasoconstriction CVS: sinus tachycardia, chest pain (catecholamine Cardiomyopathy) . Abdominal pain (decreased bowel motility)

Pheochromocytoma

Occur in two forms:

Sporadic (90%) In association with Familial syndrome (10%)

1. 2. 3. 4.

von-Hippel-Lindau syndrome von Recklinghausens disease Sturge-Weber syndrome MEN II a and MEN IIb syndromes
- Tend to be bilateral tumors.

Von-Hippel-Lindau syndrome: visceral cysts, RCC, pheochromocytoma, angiomatosis, cerebellar hemangioblastoma. Von Recklinghausens disease: neurofibromatosis, Caf-au lait spots, schwannomas, meningiomas, gliomas, pheochromocytomas.

Sturge-Weber syndrome: cavernous hemangiomas in trigeminal nerve distribution, pheochromocytomas.

Pheochromocytoma

Follow rule of 10s:

10% : familial (majority are sporadic) 10% : extra adrenal (majority are in the adrenal medulla) 10% : bilateral (majority are unilateral) 10% : biologically malignant (majority are benign) 10% : childhood (majority are in adults)

Pheochromocytoma
Gross Small circumscribed to large hemorrhagic lesions. Fresh tumor on incubation with potassium dichromate turns brown due to oxidation of catecholamines (Chromaffin tumor).

Chromaffin reaction.

Dichromate fixative

Pheochromocytoma

Microscopy :Tumor composed of

polygonal to spindle cells arranged in small nests (Zell-Ballen pattern). Nuclear pleomorphism common.

Malignancy excluded by absence of vessel invasion and metastasis. Ultra-structurally : contain dense core neurosecretory granules.

Laboratory tests

24 hour urine:
increased vanillylmandelic acid (VMA) and metanephrine

(metabolic end products of epinephrine and norepinephrine).

Neutrophilic leukocytosis (inhibition of neutrophil adhesion molecules)

Neuroblastoma

Malignant tumor of neural crest origin

MC site of origin : Adrenal medulla (abdominal cavity) Occasionally located in posterior mediastinum Median age: 2 years. 3rd or 4th most common malignancy in children Beckwith- Wiedemann syndrome and neurofibromatosis. deletion or rearrangement of short arm of chr 1 leading to amplification of n-myc oncogene.

Primarily seen in children younger than 5 years of age.

Associations:

Genetics:

Clinical findings:
Palpable

abdominal mass with abdominal distention Diastolic hypertension Metastasis to skin and bone (MC site)

Neuroblastoma

Gross:

Soft in consistency and invade surrounding tissue.

Micro:
Composed of small round blue cells (neuroblasts) and Homer Wright rosettes. Neuroblasts:

S100 positive Contain neurosecretory granules.

Differential diagnosis:

Neuroblastoma

May spontaneously differentiate into less aggressive tumor.

ALL Ewings sarcoma .

Prognosis:

neuroblastoma ganglioneuroblastoma ganglioneuroma.

Laboratory Findings:

Age of the patient is the single most important factor determining prognosis Cure rate of 85-90% under 1 year age 15-40 cure rate in older children. Increased Urinary VMA and Metanephrine and Homovanillic Acid (Metabolic End Product Of Dopamine)

Multiple endocrine neoplasia syndromes

MEN syndromes : autosomal dominant syndromes characterized by

Hyperplasia or tumors of several endocrine glands simultaneously.

Variants:
MEN I (Wermer syndrome) 2. MEN IIa (Sipple syndrome) 3. MEN IIb (MEN III)
1.

MEN I (Wermer syndrome)

Includes hyperplasia or tumors of pituitary, parathyroid or pancreatic islets (3 Ps) May manifest as HPTH, Zollinger Ellison syndrome. Is linked to mutations in MEN I gene
Includes Pheochromocytoma, medullary carcinoma and parathyroid hyperplasias (causing HPTH) Is linked to mutations in RET protooncogene.

MEN IIa (Sipple Syndrome)

MEN IIb (William syndrome)

Includes Pheochromocytoma, medullary carcinoma in contrast to MEN IIa does not induce hyperparathyroidism Extraendocrine manifestations:

Mucosal neuromas Marfanoid features.