Clinical considerations

Many clinical symptoms of adrenal pathology result from abnormalities of adrenal steroids.

Cortisol

• Increases protein breakdown, nitrogen excretion, hepatic gluconeogenesis, extracellular fluid, appetite, fat deposition in the upper body, chance of infection
• Decreases Leukocyte adhesion and diapedesis, inflammation, bacterial lysis in leukocytes, numbers of T-cells, and inhibits migration of water into cells

• Major regulator of extracellular fluid
• Major regulator of potassium metabolism
• Excess aldosterone results in sodium retention, loss of potassium, expansion of extracellular fluid compartment, and hypertension
• Decreased aldosterone results in contraction of extracellular fluid and potassium retention

• Accentuates male characteristics and suppresses female characteristics

Pathology of the Adrenal

There are four major types of adrenal pathologies

1. Disorders that decrease output of steroids
   • Adrenal Hypoplasia
     • Anencephalic type--may have adrenal agenesis
     • Cytomegalic type--not from cytomegalovirus. Large eosinophilic cells, may be X-linked
2. Disorders that increase output of steroids
   • Hyperplasia or neoplasia
   • Developmental anomalies--Adrenocortical Hyperplasias are the most significant since all cause steroid secretion abnormalities, inducing Adrenogenital Syndromes
   • Ectopic adrenal--accessory adrenal (cortex) can be found from diaphragm to pelvis in the retroperitoneum (Medulla can also be found if near celiac ganglion).
     • May be seen in hernial sacs (Marchand rests)
     • These may give origin to neoplasms or undergo hyperplasia
3. Lesions with no hormonal function defect
4. Inflammation or infection

Images of Adrenal Rest

Low power adrenal rest

High power adrenal rest--Notice that the tissue is identical to normal adrenal. This adrenal rest was found incidentally in a hernia sac.

Clinical Workup in Hypofunction of Adrenal

• If cortisol levels at 0800 hrs are <10mcg/dL and the 24hr urinary free cortisol is < 50 mcg then the following stimulation tests are warranted:
  • Cosyntropin stimulation test
  • Metyrapone stimulation test
  Insulin induced hypoglycemia (a subnormal level of glucocorticoid response reveals hypothalamic-pituitary deficiency)Skin pigmentation, high ACTH and low response to cosyntropin reveals a primary adrenal failure
• ACTH levels

Primary features

1. Loss of Cortex--autoimmune, bacterial, hemorrhage, amyloidosis, sarcoidosis, Hemochromatosis, metastatic disease, surgical ablation.
2. Metabolic Failure--Congenital adrenal hyperplasia, drug induced inhibition of adrenocortical function

Secondary features

1. Hypothalamic/pituitary diseaseNeoplasm, infection
2. Hypothalamic/pituitary suppression--long term steroid administration

Addison's Disease

1. Primary: due to adrenal insufficiency. Should be suspected when there is marked skin pigmentation due to high ACTH levels.
2. Secondary: Pituitary or hypothalamic Insufficiency (no skin pigmentation).

Addison's disease is rare.

• Autoimmune--most cases of Additions show anti-adrenal Antibodies 60-75%
  • Two types exist
    • Type I Addison's--defect in suppressor cells--hypoparathyroidism, mucocutaneous candidiasis
    • Type II Schmidt's syndrome Addison's--autoimmune thyroid disease--insulin dependent diabetes, no Candidiasis or PTH deficiency. Associated with HLA-A1 and HLA-B8 haplotype.
  TB--25% of cases
• Other causes--Histoplasmosis, amyloid, sarcoid, mets

Clinical

Insidious, progressive weakness, fatigue, anorexia, nausea & vomiting, weight loss, hypotension, hyperpigmentation in skin and oral mucosa due to >ACTH and POMC precursor.

There may be a lymphocytic infiltrate or a "burned out" fibrotic appearance. Medulla is untouched. In TB and other diseases, evidence for these is usually apparent.

Sodium, chloride, bicarbonate, glucose, cortisol, and 17-keto and 17-hydrocorticoids fall late in the disease. Potassium increases due to aldosterone deficiency.

• Precipitated by stress in a patient with Addison's Precipitated by withdrawal of steroids in an adrenalectomized patient
• In patients with acute bilateral hemorrhagic necrosis of adrenals

Acute Hemorrhagic Necrosis of Adrenals

Waterhouse-Friderichsen syndrome. In adults usually due to bacteremia. Newborns due to perinatal trauma.
Bacterial often due to meningococcemia, less commonly Staph, pneumococcus, or Haemophilus.

DIC (disseminated intravascular coagulation) with multiple petechiae, diffuse hemorrhages in various tissues. Shock often occurs. Death may occur in 24 hrs. Shock in these cases is a combination of toxemia and decrease or loss of steroids.

Hemorrhagic necrosis, some islands of tissue spared. Hemorrhage starts in reticularis.

Any pathologic condition that results in decreased ACTH--metastatic disease, autoimmunity, infection, chronic use of glucocorticoids

• No skin pigmentation, symptoms related to decreased cortisol and sex steroidsAldosterone normalACTH levels are diagnosticACTH therapy corrects the deficiency
• Adrenals may be very small

Hyperadrenal Syndromes

1. Cushing's Aldosteronism Conn's Syndrome
2. Adrenogenital Syndrome

Clinical pathology

• A 24 hr urinary free cortisol levels assay is very good screening testA normal level makes Cushing’s unlikelyObtain at least two ACTH baseline levelsHypercortisolism with very low levels of ACTH are consistent with adrenal-dependent Cushing’s. Hypercortisolism and moderately high ACTH levels suggest pituitary-dependent Cushing’sHypercortisolism and very high ACTH levels suggest ectopic-dependent (tumor i.e., lung Ca) Cushing’s
• Early diagnosis essential before cardiovascular changes are irreversible

• HypertensionGlucose intolerancediabetes--20% of casesCentripetal obesity--moon facies, buffalo hump, abdominal striaeIn men, oss of libido, impotence, oligospermia
• In women, hirsutism, amenorrhea, osteoporosis

Types

1. Pituitary (ACTH-dependent Cushing’s)

• Diffuse cortical hyperplasia with or without nodularity60% of cases of Cushing's are due to Cushing's DiseaseMost secondary to pituitary adenoma, some are hypothalamic in origin (these cases are associated with high ACTH
• Dexamethasone therapy induces a drop of cortisol and urinary 17-ketosteroids (diagnostic)

2. Adrenal neoplasm:

• Adenoma and carcinoma (carcinoma more frequent in children) Cushing's Disease--20-25% of casesFunctioning neoplasm, usually adenoma in adultsCancer results in severe Cushing'sContralateral gland atrophic due to ACTH
• ACTH low, dexamethasone resistant

3. Ectopic production of ACTH or CRH

• Diffuse cortical hyperplasia10-15% casesbronchogenic cancer in 60% of non endocrine tumorsThymoma 15%Pancreatic cancer 10%Adrenals undergo hyperplasia
• Cortisol excretion not blocked by steroids

4. Diffuse cortical hyperplasia with or without nodularity. Microadenomatous dysplasia (small pigmented nodules)
5. Iatrogenic--bilateral adrenal atrophy may be present

• Pituitary
  • Crooke's hyalin degeneration of basophilic cells in anterior pituitaryhyalin composed of intermediate filaments
  • Pituitary Cushing's--adenoma composed of corticotrophs
• In adrenals
  • Bilateral hyperplasia, cortex widened at expense of lipid-poor reticularisAdrenal cortical neoplasm Nodular hyperplasia- more often seen in pituitary type of Cushing's If  iatrogenic, atrophy
  • Diagnosis of carcinoma may be difficult; some characteristics are
    • Large tumors with necrosis and fibrous bands
    • nuclear anaplasia and mitoses

Cushing's SyndromeUsually due to adrenal adenoma. Female to male ratio 3:1.Images of Cortical Adenoma

Gross Image of Cortical Adenoma--cross section of an adrenal adenoma in a fresh state Low Power Microscopic Image--cortical adenoma at 1X magnification

High Power Microscopic Image--cortical adenoma at 10X magnification

Corticotropic pituitary adenomas that have been adrenalectomized due to refractory pituitary lesions,. Patients have intense pigmentation due to >ACTH.

Termed Conn's syndrome. Elevated aldosterone with resulting neuromuscular symptoms, renal sodium retention and potassium wasting (hypokalemia and hypokalemic alkalosis) in patients with a cortical adenoma.

• Adreno-cortical adenomas--50-90% of cases2cm in diameter, bright yellow, nonencapsulatedLipid-layden clear cells and compact cellsHyperplasia of zona glomerulosa (congenital hyperaldosteronism)Rare cases are suppressed by corticosteroids
• Carcinomas very rarely causative

Clinical

In the absence of complicating Heart Failure, edema is usually not present in these cases.

Secretion of aldosterone as a response to increased levels of renin-angiotensin.

• Renal ischemia (renal artery stenosis and malignant nephrosclerosis) Any edematous state ( i.e. Nephrotic syndrome) Barter's syndrome: juxtaglomerular-cell hyperplasia
• Renin producing neoplasms.

Adrenal virilism is readily recognizable in females, not in males until advanced.

• Androgen secreting adenoma, usually larger than those associated with Cushing's syndrome and are frequently very hyperpigmented. More often associated with masculinization than feminization. Carcinoma: Rare.
• Associated with a congenital metabolic error. Depending on the site in the metabolic pathway that is altered:
  1. Pure virilization Salt wasting
  2. Mixed

The most common is due to a 21- hydroxylase deficiency- clitoral enlargement fused labio-scrotal folds (internal reproductive organs appear normal). In males it manifests as cryptorchidism and hypospadias. 65% have aldosterone abnormalities (salt wasting -low sodium and hyperkalemia).Requires treatment or death may ensue 2 weeks after birth.

Mixed type may result in early virilization and 21-hydroxylase deficiency (3% of European Jews)

• HLA Bw 60 -salt wasting type HLA Bw 51 -virilization HLA Bw 14,DR1- Mixed
• Next most common is an 11-Hydroxylase deficiency:

• More common in Moroccan Jews11-deoxycortisol is not converted to cortisol,accumulated precursors are converted into androgensIn addition deoxycorticosterone is not converted into corticosterone causing hypertension and hypokalemiaIn 17-hydroxylase deficiency there is a diminished secretion of glucocorticoids and sex steroidsThe precursors are therefore converted into aldosterone causing aldosteronismThe deficiency in androgens leads to pseudohermaphroditism in these cases
• Untreated females have sexual infantilism

Adrenals are very enlarged and have a cerebriform aspect. Microscopically they exhibit nodular hyperplasia. In desmolase deficiency (crucial for testosterone synthesis), there is extensive cell vacuolization, as well as cholesterol clefts and giant cells.

Most of these syndromes respond to corticosteroid replacement therapy, but the genital malformations must be corrected surgically.

Non-functioning adenomas are found in up to 2% of adult autopsies. Bronchogenic carcinomas often metastasize to adrenal. Some adrenal non-steroid secreting primary carcinomas may grow to large masses. Metastasis are via adrenal vein, to lung and other viscera, rarely to bone.Other lesions

Cysts, some of which are parasitic. Adrenal myelolipoma (fat and hemopoietic cells).

Adrenocortical carcinoma is rare (about 2 per million population). Functionally active tumors may be as frequent as 96% of cases and is usually a combined endocrine malfunction that includes virilism and Cushing's syndrome. These tumors tend to be large (>12cm) in diameter. Malignancy is diagnosed when mytoses are >5/high-power field (hpf) or if there is vascular invasion. These lesions are also composed of very pleomorphic cells but this criterion cannot alone support the diagnosis of malignancy. The following images 5-7a show a case of adrenal-cortical cancer.Images of Adrenal Cortical Carcinoma

Cat Scan--this computerized tomography shows the large adrenal tumor labeled AT

Gross Image--notice the variegated appearance of the cut surface with areas of hemorrhage

Microscopic, low power--notice that the tumor emulates the normal adrenal trabecular pattern

Microscopic Higher power

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Updated August 1, 2007