Adrenal Gland Function, Symptoms and Disorders

Adrenal Gland

Adrenal glands Normal Structure:

Anatomy Adrenal glands lie at the upper pole of each kidney. Each gland weighs approximately 4 gm in the adult but in children, the adrenals are proportionately larger. On sectioning, the adrenal is composed of 2 distinct parts an outer yellow-brown cortex and an inner grey medulla. The anatomic and functional integrity of adrenal cortices is essential for life, while it does not hold true for the adrenal medulla.

Adrenal glands Histology And Physiology Microscopically and functionally, the cortex and medulla are quite distinct.

Read And Learn More: Systemic Pathology Notes

Adrenal Cortex It is composed of 3 layers:

1. Zona glomerulosa: is the outer layer and comprises about 10% of the cortex. It consists of cords or columns of polyhedral cells just under the capsule. This layer is responsible for the synthesis of mineralocorticoids, the most important of which is aldosterone, the salt and water-regulating hormone.
2. Zona fasciculata: is the middle layer and constitutes approximately 70% of the cortex. It is composed of columns of lipid-rich cells which are precursors of various steroid hormones manufactured in the adrenal cortex such as glucocorticoids (for example cortisol) and sex steroids (for example dehydroepiandrosterone, DHEAS)
3. Zona reticularis: is the inner layer which makes up the remainder of the adrenal cortex. It consists of cords of more compact cells than those of zona fasciculata but has similar functional
   characteristics of synthesis and secretion of glucocorticoids and androgens.

The synthesis of glucocorticoids and adrenal androgens is under the control of ACTH from the hypothalamus-anterior pituitary. In turn, ACTH release is under the control of a hypothalamic-releasing factor called corticotropin-releasing factor.

The release of aldosterone, on the other hand, is independent of ACTH control and is largely regulated by the serum levels of potassium and renin-angiotensin mechanism.

Adrenal Medulla: The adrenal medulla is a component of the dispersed neuroendocrine system derived from primitive neuroectoderm; the other components of this system are paraganglia distributed in the vagi, paravertebral and visceral autonomic ganglia.

• The cells comprising this system are neuroendocrine cells, the major function of which is the synthesis and secretion of catecholamines (epinephrine and norepinephrine). Various other peptides such as calcitonin, somatostatin and vasoactive intestinal polypeptide (VIP) are also secreted by these cells.
• The major metabolites of catecholamines are metanephrine, nor-metanephrine, vanillylmandelic acid (VMA) and homovanillic acid (HVA). In case of damage to the adrenal medulla, its function is taken over by other paraganglia.
• Diseases affecting the two parts of adrenal glands are quite distinctive in view of the distinct morphology and function of the adrenal cortex and medulla.
• While the disorders of the adrenal cortex include adrenocortical hyperfunction (hyperadrenalism), adrenocortical insufficiency (hypoadrenalism) and adrenocortical tumours, the main lesions affecting the adrenal medulla are the medullary tumours.

Adrenocortical Hyperfunction (Hyperadrenalism):

Hypersecretion of each of the three types of corticosteroids elaborated by the adrenal cortex causes distinct corresponding hyper adrenal clinical syndromes:

1. Cushing’s syndrome is caused by an excess of glucocorticoids (i.e. cortisol); also called chronic hypercortisolism.
2. Conn’s syndrome is caused by the oversecretion of mineralocorticoids (i.e. aldosterone); also called primary hyperaldosteronism.
3. Adrenogenital syndrome is characterised by excessive production of adrenal sex steroids (i.e. androgens); also called adrenal virilism.

Mixed forms of these clinical syndromes may also occur.

Cushing’S Syndrome (Chronic Hypercortisolism):

Cushing’s syndrome is caused by excessive production of cortisol of whatever cause. The full clinical expression of the syndrome, however, includes the contribution of secondary derangements.

Etiopathogenesis: There are 4 major etiologic types of Cushing’s syndrome which should be distinguished for effective treatment.

1. Pituitary Cushing’s syndrome: About 60-70% of cases of Cushing’s syndrome are caused by excessive secretion of ACTH due to a lesion in the pituitary gland, most commonly a corticotroph adenoma or multiple corticotroph microadenomas.

• This group of cases was first described by Harvey Cushing, an American neurosurgeon, who termed the condition Cushing’s disease. Also included in this group are cases with the hypothalamic origin of excessive ACTH levels without apparent pituitary lesions.
• All cases with pituitary Cushing’s syndrome are characterised by bilateral adrenal cortical hyperplasia and elevated ACTH levels.
• These cases show a therapeutic response to the administration of high doses of dexamethasone which suppresses ACTH secretion and causes a fall in plasma cortisol levels.

2. Adrenal Cushing’s syndrome:  Approximately 20-25% of cases of Cushing’s syndrome are caused by disease in one or both the adrenal glands. These include adrenal cortical adenoma, carcinoma, and less often, cortical hyperplasia.

This group of cases is characterised by low serum ACTH levels and the absence of a therapeutic response to the administration of high doses of glucocorticoid.

3. Ectopic Cushing’s syndrome:  About 10-15% of cases of Cushing’s syndrome have an origin in ectopic ACTH elaboration by non-endocrine tumours. Most often, the tumour is small cell carcinoma of the lung but other lung cancers, malignant thymoma and pancreatic tumours have also been implicated.

The plasma ACTH level is high in these cases and cortisol secretion is not suppressed by dexamethasone administration.

4. Iatrogenic Cushing’s syndrome: Prolonged therapeutic administration of high doses of glucocorticoids or ACTH may result in Cushing’s syndrome e.g. in organ transplant recipients and in autoimmune diseases. These cases are generally associated with bilateral adrenocortical insufficiency.

Cushing’S Syndrome (Chronic Hypercortisolism) Clinical Features: Cushing’s syndrome occurs more often in patients between the age of 20-40 years with three times higher frequency in women than in men. The severity of the syndrome varies considerably, but in general, the following features characterise a case of Cushing’s syndrome:

1. Central or truncal obesity contrasted with relatively thin arms and legs, buffalo hump due to prominence of fat over the shoulders, and rounded oedematous moon-face.
2. Increased protein breakdown results in wasting and thinning of the skeletal muscles, atrophy of the skin and subcutaneous tissue with the formation of purple striae on the abdominal wall, osteoporosis and easy bruising of the thin skin from minor trauma.
3. Systemic hypertension is present in 80% of cases because of the associated retention of sodium and water.
4. Impaired glucose tolerance and diabetes mellitus are found in about 20% of cases.
5. Amenorrhoea, hirsutism and infertility in many women.
6. Insomnia, depression, confusion and psychosis.

Conn’S Syndrome (Primary Hyperaldosteronism):

This is an uncommon syndrome occurring due to the overproduction of aldosterone, the potent salt-retaining hormone.

Etiopathogenesis: The condition results primarily due to adrenocortical diseases as follows:

1. Adrenocortical adenoma, producing aldosterone.
2. Bilateral adrenal hyperplasia, especially in children (congenital hyperaldosteronism).
3. Rarely, adrenal carcinoma.

• Primary hyperaldosteronism from any of the above causes is associated with low plasma renin levels.
• Secondary hyperaldosteronism, on the contrary, occurs in response to high plasma renin level due to overproduction of renin by the kidneys such as in renal ischaemia, reninoma or oedema.

Primary Hyperaldosteronism Clinical Features: Conn’s syndrome is more frequent in adult females. Its principal features are as under:

1. Hypertension is usually mild to moderate diastolic hypertension.
2. Hypokalaemia and associated muscular weakness, peripheral neuropathy and cardiac arrhythmias.
3. Retention of sodium and water.
4. Polyuria and polydipsia due to reduced concentrating power of the renal tubules.

Adrenogenital Syndrome (Adrenal Virilism):

The adrenal cortex secretes a smaller amount of sex steroids than the gonads. However, adrenocortical hyperfunction may occasionally cause sexual disturbances.

Adrenogenital Syndrome Etiopathogenesis: Hypersecretion of sex steroids, mainly androgens, may occur in children or in adults:

• In children, it is due to congenital adrenal hyperplasia in which there is a congenital deficiency of a specific enzyme.
• In adults, it is caused by an adrenocortical adenoma or a carcinoma. Cushing’s syndrome is often present as well.
• Clinical Features The clinical features depend upon the age and sex of the patient. In children, there is the distortion of the external genitalia in girls and precocious puberty in boys.
• In adults, the features in females show virilisation (for example hirsutism, oligomenorrhoea, deepening of voice, hypertrophy of the clitoris); and in males may rarely cause feminisation. There is generally increased excretion of 17-ketosteroids in the urine.

Adrenocortical Insufficiency (Hypoadrenalism):

Adrenocortical insufficiency may result from a deficient synthesis of cortical steroids from the adrenal cortex or may be secondary to ACTH deficiency. Three types of adrenocortical hypofunction are distinguished:

1. Primary adrenocortical insufficiency is caused primarily by the disease of the adrenal glands. Two forms are described: acute or ‘adrenal crisis’, and chronic or ‘Addison’s disease’.
2. Secondary adrenocortical insufficiency resulting from diminished secretion of ACTH.
3. Hypoaldosteronism is characterised by deficient secretion of aldosterone.

Primary Adrenocortical Insufficiency:

Primary adrenal hypofunction occurs due to a defect in the adrenal glands and normal pituitary function. It may develop in 2 ways:

1. Acute primary adrenocortical insufficiency or ‘adrenal crisis’.
2. Chronic primary adrenocortical insufficiency or ‘Addison’s disease’.

Primary Acute Adrenocortical Insufficiency (Adrenal Crisis):

Sudden loss of adrenocortical function may result in an acute condition called adrenal crisis.

Primary Acute Adrenocortical Insufficiency Etiopathogenesis: Causes of acute insufficiency are as under:

1. Bilateral adrenalectomy e.g. in the treatment of cortical hyperfunction, hypertension and in selected cases of breast cancer.
2. Septicaemia e.g. in endotoxic shock and meningococcal infection produces grossly haemorrhagic and necrotic adrenal cortex termed adrenal apoplexy. The acute condition so produced is called Waterhouse-Friderichsen’s syndrome.
3. Rapid withdrawal of steroids.
4. Any form of acute stress in a case of chronic insufficiency i.e. in Addison’s disease.

Acute Adrenocortical Insufficiency Clinical Features: Clinical features of acute adrenocortical insufficiency are due to a deficiency of mineralocorticoids and glucocorticoids. These are as follows:

1. Deficiency of mineralocorticoids (aldosterone deficiency) results in salt deficiency, hyperkalaemia and dehydration.
2. Deficiency of glucocorticoids (cortisol deficiency) leads to hypoglycaemia, increased insulin sensitivity and vomiting.

Primary Chronic Adrenocortical Insufficiency (Addison’s Disease):

• Progressive chronic destruction of more than 90% of the adrenal cortex on both sides results in an
  uncommon clinical condition called Addison’s disease.
• Etiopathogenesis Any condition which causes marked chronic adrenal destruction may produce Addison’s disease. These include tuberculosis, autoimmune or idiopathic adrenalitis, histoplasmosis, amyloidosis, metastatic cancer, sarcoidosis and haemochromatosis.
• However, currently, the first two causes tuberculosis and autoimmune chronic destruction of adrenal glands, are implicated in the majority of cases of Addison’s disease. Irrespective of the cause, the adrenal glands are bilaterally small and irregularly shrunken.
• Histologic changes, depending upon the cause, may reveal specific features as in tuberculosis and histoplasmosis, or the changes may be in the form of nonspecific lymphocytic infiltrate as in idiopathic (autoimmune) adrenalitis.

Adrenocortical Insufficiency Clinical Features: Clinical manifestations develop slowly and insidiously. The usual features are as under:

1. Asthenia i.e. progressive weakness, weight loss and lethargy is the cardinal symptom.
2. Hyperpigmentation is initially most marked on exposed areas but later involves unexposed parts and mucous membranes as well.
3. Arterial hypotension.
4. Vague upper gastrointestinal symptoms such as mild loss of appetite, nausea, vomiting and upper abdominal pain.
5. Lack of androgen causes loss of hair in women.
6. Episodes of hypoglycaemia.
7. Biochemical changes include reduced GFR, acidosis, hyperkalaemia and low levels of serum sodium, chloride and bicarbonate.

Secondary Adrenocortical Insufficiency:

Adrenocortical insufficiency resulting from a deficiency of ACTH is called secondary adrenocortical insufficiency.

Secondary Adrenocortical Insufficiency Etiopathogenesis: Acth deficiency may appear in 2 settings:

1. Selective ACTH deficiency due to prolonged administration of high doses of glucocorticoids. This leads to suppression of ACTH release from the pituitary gland and selective deficiency.
2. Panhypopituitarism due to hypothalamus-pituitary diseases is associated with a deficiency of multiple trophic hormones.

Secondary Adrenocortical Insufficiency Clinical Features: The clinical features of secondary adrenocortical insufficiency are like those of Addison’s disease except for the following:

1. These cases lack hyperpigmentation because of suppressed production of melanocyte-stimulating hormone (MSH) from the pituitary.
2. Plasma ACTH levels are low-to-absent in secondary insufficiency but are elevated in Addison’s disease.
3. Aldosterone levels are normal due to stimulation by renin.

Hypoaldosteronism:

Isolated deficiency of aldosterone with normal cortisol levels may occur in association with reduced renin secretion.

Hypoaldosteronism Etiopathogenesis: The causes of such hyporeninism are as follows:

1. Congenital defect due to deficiency of an enzyme required for its synthesis.
2. Prolonged administration of heparin.
3. Certain diseases of the brain.
4. Excision of an aldosterone-secreting tumour.

Hypoaldosteronism Clinical Features: The patients of isolated hypoaldosteronism are adults with mild renal failure and diabetes mellitus. The predominant features are hyperkalaemia and metabolic acidosis.

Tumours Of Adrenal Glands

Primary tumours of the adrenal glands are uncommon and include distinct adrenocortical tumours and medullary tumours. However, the adrenal gland is a more common site for metastatic carcinoma.

Adrenocortical Tumours

Cortical Adenoma:

• The commonest cortical tumour is adenoma. They are indistinguishable from hyperplastic nodules except that lesions smaller than 2 cm in diameter are labelled hyperplastic nodules. A cortical adenoma is a benign and slow-growing tumour.
• It is usually small and non-functional. A few large adenomas may, however, produce an excess of cortisol, aldosterone or androgen. The association of cortical adenomas with systemic hypertension has been suggested by some workers.
• Occasionally, a cortical adenoma may be a part of multiple endocrine neoplasia type I (MEN-I) in which patients have associated adenomas of parathyroid, islet cells and anterior pituitary.

Morphologic Features Grossly, an adenoma is usually a small (2–5 cm), solitary, spherical and encapsulated tumour which is well-delineated from the surrounding normal adrenal gland. The Cut section is typically bright yellow.

Microscopically, the tumour cells are arranged in trabeculae and generally resemble the cells of zona fasciculate. Less frequently, the cells of adenoma are like those of zona glomerulosa or zona reticularis.

Cortical Carcinoma:

Carcinoma of the adrenal cortex is an uncommon tumour occurring mostly in adults. It invades locally as well as spreads to distant sites. Most cortical carcinomas secrete one of the adrenocortical hormones excessively.

Morphologic Features Grossly, an adrenal carcinoma is generally large, spherical and well-demarcated tumour. On the cut section, it is predominantly yellow with intermixed areas of haemorrhages, necrosis and calcification.

Microscopically, cortical carcinoma may vary from well-differentiated to anaplastic growth. Well-differentiated carcinoma consists of foci of atypia in an adenoma, while anaplastic carcinoma shows large, pleomorphic and bizarre cells with high mitotic activity.

Medullary Tumours:

The most significant lesions of the adrenal medulla are neoplasms. These include the following:

1. Benign tumours These are less common and include pheochromocytoma and myelolipoma.
2. Tumours arising from embryonic nerve cells These are more common and include neuroblastoma, ganglioneuroblastoma and ganglioneuroma.

These tumours together with extra-adrenal paraganglioma are described below.

Pheochromocytoma (Chromaffin Tumour):

• Pheochromocytoma is a tumour arising from pheochromocytes (i.e. chromaffin cells) of the adrenal medulla. Its name is derived from its characteristic dark brown-black appearance caused by the chromaffin oxidation of catecholamines.
• The extra-adrenal pheochromocytomas arising from other paraganglia are preferably called paragangliomas, named along with the anatomic site of origin, as described later.
• Pheochromocytoma may occur at any age but most patients are 20-60 years old. Most pheochromocytomas are slow-growing and benign but about 10% of the tumours are malignant, invasive and metastasising.
• These tumours are commonly sporadic but 10% are associated with familial syndromes of multiple endocrine neoplasia (MEN) having bilaterality and association with medullary carcinoma of the thyroid, hyperparathyroidism, pituitary adenoma, mucosal neuromas and von Recklinghausen’s neurofibromatosis in varying combinations. Thus, the traditional “10% rule” for pheochromocytoma is:
  • 10% are familial (may go up to 50% in familial pheochromocytomas),
  • 10% are malignant,
  • 10% are extra-adrenal (called paragangliomas), and
  • 10% are not associated with hypertension.
• However, currently, malignant pheochromocytoma is diagnosed by metastasis (most often osseous) rather than by morphology.
• The aetiology of pheochromocytoma remains unknown but a quarter of cases have gen inactivation of VHL, NF1 and SDH genes, while germline mutation of RET gene activates tyrosine kinase activity.
• The clinical features of pheochromocytoma are predominantly due to the secretion of catecholamines, both epinephrine and norepinephrine. The most common feature is hypertension.
• Other manifestations due to sudden release of catecholamines are congestive heart failure, myocardial infarction, pulmonary oedema, cerebral haemorrhage, and even death. The diagnosis is established by measuring 24-hour urinary catecholamines or their metabolites such as metanephrine and VMA.

Morphologic Features Grossly, the tumour is soft, spherical may be quite variable in size and weight, and well-demarcated from the adjacent adrenal gland. On the cut section, the tumour is grey to dusky brown with areas of haemorrhages, necrosis, calcification and cystic change. On immersing the tumour in dichromate fixative, it turns brown-black due to oxidation of catecholamines in the tumour and hence the name chromaffin tumour.
Microscopically, the tumour has the following characteristics:

1. The tumour cells are arranged characteristically as well-defined nests (also termed a zellballen pattern) separated by an abundant fibrovascular stroma.
2. Other arrangements are solid columns, sheets, trabeculae or clumps.
3. The tumour cells are large, polyhedral and pleomorphic with abundant granular amphophilic or basophilic cytoplasm and vesicular nuclei.
4. The tumour cells of pheochromocytoma stain positively with neuroendocrine substances such as neuron-specific enolase (NSE) and chromogranin.

Myelolipoma:

Myelolipoma is an uncommon benign adrenal medullary tumour, found either incidentally at autopsy or during radiological workup for other reasons. Less often, it may produce symptoms due to excessive hormone elaboration. Hence an association is seen between myelolipoma and other adrenocortical tumours presenting with Cushing’s syndrome.

Morphologic Features Grossly, a myelolipoma is usually a small tumour, measuring 0.2-2 cm in diameter.

Microscopically, it consists of well-differentiated adipose tissue in which scattered clumps of haematopoietic cells with a predominance of megakaryocytes are seen. It is almost always associated with normal bone marrow function.

Neuroblastoma:

• Neuroblastoma, also called sympathicoblastoma, is a common malignant tumour of neural crest cells, occurring most commonly in children under 4 years of age. It is the most common extracranial solid tumour in childhood.
• The vast majority of cases occur within the abdomen (either in the adrenal medulla or in the retroperitoneal sympathetic ganglia) and rarely in the cerebral hemisphere. Most cases are sporadic but 1-2% of cases are familial with autosomal dominant transmission.
• Familial cases are known to have germline mutation of the ALK (anaplastic lymphoma kinase) gene; however, activating mutations of the ALK gene may also be seen in sporadic cases of neuroblastoma.
• The clinical manifestations of neuroblastoma are related to its rapid local growth, metastatic spread or development of hormonal syndrome. Local symptoms include abdominal distension, fever, weight loss and malaise. Foci of calcification may be observed on radiologic examination of the abdomen.
• Metastatic spread occurs early and widely through haematogenous as well as lymphatic routes and involves bones (especially the skull), liver, lungs and regional lymph nodes. Neuroblastoma produces variable amounts of catecholamines and its metabolites such as vanillyl mandelic acid (VMA) and homovanillic acid (HVA), which can be detected in the 24-hour urine.
• Less often, the patient develops carcinoid-like syndrome, probably due to the production of kinins or prostaglandins by the tumour. The features in such a case include watery diarrhoea, flushing of the skin and hypokalaemia. Rarely, the tumour may produce sufficient catecholamines to cause hypertension.

Morphologic Features Grossly, the tumour is generally a large, soft and lobulated mass with extensive areas of necrosis and haemorrhages. The tumour is usually diffusely infiltrating into the adjacent tissues. The cut surface of the tumour is grey-white and may reveal minute foci of calcification.

Microscopically, neuroblastoma has the following characteristics:

1. The tumour cells are small, round and oval, slightly larger than lymphocytes, and have scanty and poorly-defined cytoplasm and hyperchromatic nuclei.
2. They are generally arranged in irregular sheets separated by a fibrovascular stroma.
3. Classical neuroblastomas show Homer-Wright’s rosettes (pseudorosettes) which have a central fibrillar eosinophilic material surrounded by radially arranged tumour cells. The central fibrillar material stains positively by silver impregnation methods indicating their nature as young nerve fibrils.
4. The tumour cells stain positively with immunohistochemical markers such as neuron-specific enolase (NSE), neurofilaments (NF) and chromogranin.

The prognosis of neuroblastoma depends upon a few variables; favourable prognostic features are as under:

1. Age of child below 2 years.
2. Extra-abdominal location of the tumour than abdominal masses.
3. Tumour histology with schwannian or ganglionic differentiation.
4. Patients in clinical stage I (confined to the organ of origin) or stage II (tumour extending in continuity beyond the organ of origin but not crossing the midline).
5. Favourable genetic features are hyperdiploid, lack of amplification of N-MYC oncogene and absence of telomerase expression.

Ganglioneuroma:

A ganglioneuroma is a mature, benign and uncommon tumour occurring in adults. It is derived from ganglion cells, most often in the posterior mediastinum and retroperitoneum, and uncommonly in other peripheral ganglia and the brain.

The tumour produces symptoms because of its size and location. Catecholamines and their metabolites can be detected in large amounts in the 24-hour urine specimen of patients with ganglioneuroma.

Morphologic Features Grossly, the tumour is spherical, firm and encapsulated.

Microscopically, it contains a large number of well-formed ganglionic nerve cells scattered in the fibrillar stroma and myelinated and non-myelinated nerve fibres.

Extra-adrenal Paraganglioma (Chemodectoma):

• Parasympathetic paraganglia located in extra-adrenal sites such as the carotid bodies, vagus, jugulotympanic and aorticosympathetic (pre-aortic) paraganglia may produce neoplasms, collectively termed paragangliomas with the anatomic site of origin example carotid body paraganglioma, intravaginal paraganglioma, jugulotympanic paraganglioma etc.
• These tumours are also called chemodectomas because of their responsiveness to chemoreceptors. They are uncommon tumours found in adults and rarely secrete an excess of catecholamines, except in aorticosympathetic paraganglioma (also termed extra-adrenal pheochromocytoma).

Paragangliomas are generally benign but recurrent tumours. A small proportion of them may metastasise widely.

Diseases of Adrenal Gland:

• Hyperadrenal clinical syndromes are Cushing’s syndrome caused by excess of glucocorticoids (i.e. cortisol), Conn’s syndrome caused by oversecretion of mineralocorticoids (i.e. aldosterone), and adrenogenital syndrome characterised by excessive production of adrenal sex steroids (i.e. androgens).
• Adrenocortical hypofunction may be primary adrenocortical insufficiency caused by the disease of the adrenal glands (acute or ‘adrenal crisis’, and chronic or ‘Addison’s disease’), or secondary resulting from diminished secretion of ACTH, and hypoaldosteronism characterised by deficient secretion of aldosterone.
• Adrenocortical tumours are adenomas and rarely cortical adenocarcinoma.
• Medullary tumours include pheochromocytoma, myelolipoma, neuroblastoma, ganglioneuroma, and chemodectoma.