ADRENAL GLAND PATHOLOGY

The adrenal glands are paired with two regions, cortex and medulla.
The cortex consists of three layers of distinct cell types & synthesizes three

different types of steroids:

Glucocorticoids (principally cortisol), primarily in the zona fasciculata.

Mineralocorticoids, the most important being aldosterone, in zona
glomerulosa.
Sex steroids (estrogens and androgens), in zona reticularis.

The adrenal medulla is composed of chromaffin cells, which synthesize and

secrete catecholamines, mainly epinephrine.
 ADRENOCORTICAL HYPERFUNCTION
(HYPERADRENALISM)
 There are three distinctive hyperadrenal clinical syndromes, each caused
by abnormal production of one or more of the hormones produced by
the three layers of the cortex:
 Cushing syndrome: characterized by an excess of cortisol
 Hyperaldosteronism: caused by an excess of mineralocorticoid
 Adrenogenital or virilizing syndromes: caused by an excess of
androgens.
 Hypercortisolism: Cushing Syndrome
 Cushing's syndrome result from excess glucocorticoids.
 Causes:
 Iatrogenic : administration of exogenous glucocorticoids (most common).
 The remaining cases are endogenous & include:
 Primary hypothalamic-pituitary diseases associated with hypersecretion of ACTH
 Ectopic ACTH seretion by non-pituitary neoplasms.
 Primary adrenocortical neoplasms (adenoma or carcinoma) and primary cortical
hyperplasia occurs most commonly in adult women
 Sometimes there is also excess androgen production causing virilization.
 Primary hypothalamic-pituitary disease:
 Also known as Cushing disease.
 Accounts for 70% of cases of endogenous Cushing syndrome.
 There is hypersecretion of ACTH by pituitary adenoma.
 Rarely corticotroph cell hyperplasia; primary or secondary to
hypothalamic corticotropin releasing hormone (CRH)–producing tumor.
 leads to bilateral adrenal cortical hyperplasia secondary to the elevated
levels of ACTH (“ACTH dependent” Cushing syndrome).
 Plasma ACTH is raised.
 Ectopic ACTH secretion:
 Accounts for about 10% of cases of Cushing syndrome.
 Causes:
 Small-cell carcinoma of the lung (most common).
 Other neoplasms, include carcinoids, medullary carcinomas of the thyroid
 The adrenal glands undergo bilateral cortical hyperplasia secondary to
elevated ACTH.
 Primary adrenal neoplasms:
 As adrenal adenoma and carcinoma, and rarely, primary cortical
hyperplasia, are responsible for about 15% to 20% of cases
 knowon as ACTH-independent Cushing syndrome, because the adrenals
function autonomously.
 There is elevated levels of cortisol and low serum levels of ACTH.
 Morphology:
 In adrenal gland:
 Cortical atrophy- Seen with exogenous glucocorticoids which cause
feedback inhibition of ACTH leading to cortical atrophy except in zona
glomerulosa (it functions independent of ACTH).
 Diffuse hyperplasia
 Nodular hyperplasia
 Clinical Features:
 An exaggeration of the known actions of glucocorticoids.
 Early: hypertension and weight gain.
 Later: truncal obesity, “moon facies,” and accumulation of fat in the posterior
neck and back (“buffalo hump”).
 Proximal limb weakness.
 Hyperglycemia, glucosuria, and polydipsia.
 Cutaneous striae; common in the abdominal area.
 Osteoporosis, with increased susceptibility to fractures.
 Hirsutism and menstrual abnormalities.
 Mental disturbances, including mood swings, depression, and frank psychosis.
 Increased skin pigmentation (Extraadrenal Cushing syndrome), secondary to
melanocyte-stimulating activity in the ACTH precursor molecule.
 Diagnosis:
 Elevated plasma levels of cortisol
 There is an increased 24 hour free cortisol level in the urine.
 Pituitary Cushing: ↑ ACTH, ↑ Cortisol
 Adrenal Cushing: ↓ ACTH, ↑ Cortisol
 Ectopic Cushing: ↑↑ ACTH, ↑ Cortisol
 For differentiating between the causes of Cushing syndrome, we use
dexamethasone suppression test.
 The dexamethasone suppression test:
 Administration of the synthetic potent steroid, dexamethasone; a fall in cortisol
levels will result due to the suppression of pituitary ACTH secretion.
 Treatment:
 The ideal treatment is surgical removal of the pituitary adenoma.
 Removal of the adrenals (once the main form of treatment) is
unsatisfactory because the adenohypophysial tumour is left to grow
and, in addition to secreting ACTH, may produce a peptide
(melanocyte-stimulating hormone) with an amino acid sequence similar
to that of the ACTH molecule.
 In 20% of cases this leads to marked enlargement of the pituitary
adenoma (Nelson's syndrome).
 Skin pigmentation will occur in most cases.
 Hyperaldosteronism

 Characterized by elevated aldosterone levels leading to retention of

sodium and excretion of potassium and hydrogen ions.

 May be primary, or secondary.

 Primary hyperaldosteronism
 Refers to autonomous overproduction of aldosterone.
 Causes:
 Bilateral idiopathic hyperaldosteronism, characterized by bilateral nodular
hyperplasia of the adrenal glands, ( the most common cause, accounting for
about 60% of cases). The pathogenesis is unclear.
 Adrenocortical neoplasm, either adenoma (the most common cause; a
condition referred to as Conn syndrome.) or, carcinoma.
 Rarely, familial from a genetic defect leads to over activity of the aldosterone
synthase gene, CYP11B2.
 Secondary hyperaldosteronism
 Aldosterone release occurs in response to activation of the renin-angiotensin
system.
 There is increased levels of plasma renin.
 Causes:
 Decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis)
 Arterial hypovolemia and edema (congestive heart failure, cirrhosis,
nephrotic syndrome)
 Pregnancy (caused by estrogen-induced increases in plasma renin substrate).
 Secondary hyperaldosteronism is the commonest type of hyperaldosteronism.
 Clinical features:
 The clinical hallmark of hyperaldosteronism is hypertension (renal
retention of sodium and water).
 Potassium loss leads to muscular weakness and cardiac arrhythmias.
 The hypokalaemia is associated with metabolic alkalosis, causing tetany
and paraesthesiae.
 Diagnosis & treatment:
 The diagnosis of primary hyperaldosteronism is confirmed by elevated ratios of
plasma aldosterone concentration to plasma renin activity.
 If this screening test is positive, a confirmatory aldosterone suppression test must
be performed, because many unrelated causes can alter the plasma aldosterone
and renin ratios.
 In primary hyperaldosteronism, the therapy varies according to cause.
 Adenomas are amenable to surgical excision.
 Bilateral hyperplasia, which often occurs in children and young adults best
managed medically with an aldosterone antagonist such as spironolactone.
 The treatment of secondary hyperaldosteronism is the correction of the
underlying cause.
 CONGENITAL ADRENAL HYPERPLASIA
 Excess sex steroids with hyperplasia of both adrenal glands
 Inherited 21-hydroxylase deficiency is the most common cause.
 21-hydroxylase is required for the production of aldosteroine and
corticosteroids.
 In enzyme deficiency, steroidogenesis is predominantly shunted toward
sex steroid production (which does not require 21 -hydroxylase).
 Deficiency of Cortisol leads to increased ACTH secretion (lack of
negative feedback), which results in bilateral adrenal hyperplasia.
 Clinical features:

 Salt wasting with hyponatremia, hyperkalemia, and hypovolemia due to

lack of aldosterone.

 Life-threatening hypotension due to lack of Cortisol.

 Clitoral enlargement (females) or precocious puberty (males) due to

excess androgens
 Adrenal cortical insufficiency
 Adrenocortical hypofunction can be primary, due to lesions within the
adrenal gland, or secondary, due to failure of ACTH secretion by the
adenohypophysis.
 The patterns of insufficiency can be divided into three general
categories:
 Primary acute adrenocortical insufficiency (adrenal crisis)
 Primary chronic adrenocortical insufficiency (Addison disease)
 Secondary adrenocortical insufficiency.
 Acute insufficiency
 Causes:
 Massive adrenal hemorrhage: This condition may occur in:
 Patients on anti-coagulant therapy, DIC, during pregnancy, and in patients
with overwhelming sepsis (known as the Waterhouse-Friderichsen syndrome;
classically associated with Neisseria meningitidis septicemia but can also be
caused by other organisms)
 Sudden withdrawal of long-term corticosteroid therapy or failure to increase
steroid doses in response to an acute stress, because of the inability of the
atrophic adrenals to produce glucocorticoid hormones.
 Stress in patients with underlying chronic adrenal insufficiency
 The adrenal cortices are necrotic and the medullae contain acute
haemorrhage.
 The adrenal necrosis is due to disseminated intravascular coagulation
(DIC).
 The symptoms are due to lack of mineralocorticoids (salt and water loss
with hypovolaemic shock) and of glucocorticoids (failure of
gluconeogenesis resulting in hypoglycaemia).
The patient with Waterhouse-Friderichsen syndrome has
sepsis with DIC and marked purpura.
 Chronic insufficiency: Addison Disease
 Causes:
 Autoimmune adrenalitis: accounts for 60% to 70% of cases; most common cause in
countries where infectious causes are uncommon.
 Infections: tuberculosis; fungi (Histoplasma capsulatuma and Coccidioides
immitis), AIDS.
 Metastatic tumours: carcinomas of the lung and breast
 Infiltrative diseases: amyloidosis, haemochromatosis, sarcoidosis.
 Autoimmune adrenalitis selectively damages and destroys the adrenal cortex,
sparing the medulla.
 tuberculosis destroys the cortex and medulla.
 Secondary Adrenocortical Insufficiency
 Any disorder of the hypothalamus and pituitary that reduces the output
of ACTH, such as:
 Metastatic cancer
 Infection
 Infarction
 Irradiation
 Clinical features:
 The effects are due to a combined lack of mineralocorticoids and glucocorticoids:
 Progressive weakness and easy fatigability.
 GIT disturbances: anorexia, nausea, vomiting, weight loss, and diarrhea.
 Hyperpigmentation of the skin and mucosal surfaces (primary).
 Hyperkalemia, hyponatremia, volume depletion, and hypotension (primary).
 Hypoglycemia
 Sexual dysfunction.
 Stresses such as infections, trauma, or surgical procedures in affected

patients may precipitate an acute adrenal crisis, manifested by

intractable vomiting, abdominal pain, hypotension, coma, and

vascular collapse.

 Death follows rapidly unless corticosteroids are replaced immediately.

 Diagnosis:
 Plasma cortisol levels are low.
 Estimation of ACTH levels enables a distinction to be made between
primary adrenocortical insufficiency (ACTH raised) and secondary
insufficiency (ACTH low).
 Na+& K+ (due to mineralocorticoid), glucose (due to cortisol).
 Short ACTH stimulation test (Synacthen test): Do plasma cortisol
before and .h after tetracosactide (SynacthenR) 250μg IM. Addis on’s
is excluded if 30min cortisol >550nmol/L.
 Treatment:
 Replace steroids: hydrocortisone.
 Mineralocorticoids to correct postural hypotension, Na+, K+:
fludrocortisone .
 Adjust both on clinical grounds. If there is a poor response, suspect an
associated auto immune disease1 (check thyroid, do coeliac serology).
Hyper pigmentation in
Addison's disease
 A caseating granuloma of tuberculosis in the adrenal gland.

 Tuberculosis used to be the most common cause of chronic

adrenal insufficiency
 ADRENAL MEDULLA
 Phaeochromocytoma:
 Derived from the adrenal medullary chromaffin cells & synthesize and
release catecholamines.
 They give rise to a surgically correctable form of hypertension.
 They usually subscribe to a convenient “rule of 10s”:
 10% are extraadrenal, occurring in sites such as the carotid body.
 10% are bilateral; (rise to 50% familial cases).
 10% are malignant.
 10% are not associated with hypertension.
 Clinical Features:
 The dominant clinical manifestation is hypertension, observed in 90% of patients.
 Two-thirds of patients with hypertension demonstrate paroxysmal episodes
 Hypertension is associated with tachycardia, palpitations, headache, sweating &
tremors.
 There also be associated pain in the abdomen or chest, nausea, and vomiting.
 Precipitate congestive heart failure, pulmonary edema, myocardial infarction,
ventricular fibrillation, and cerebrovascular accidents.
  The laboratory diagnosis is based on demonstration of increased urinary

excretion of free catecholamines and their metabolites, such as

vanillylmandelic acid and metanephrines.

 Localization of the tumour is assisted by computerised tomography of

the abdomen and by radio-isotope scanning.

 Isolated benign pheochromocytomas are treated with surgical excision.

 Multifocal lesions: long-term medical treatment for hypertension.