Disorders of Adrenocortical Function (Physiology)

Cortisol increases plasma glucose levels by increasing gluconeogenesis, decreasing glucose utilization, increasing glycogenesis, and increasing glycogen storage.

Cortisol increases lipolysis, providing energy.

Cortisol causes proteins to be catabolized, releasing amino acids.

Cortisol promotes sodium and water retention, helping to maintain blood pressure.

Cortisol has anti-inflammatory properties.

Cortisol increases gastric acid production.

Cushing's Syndrome is a condition characterized by clinical features of chronic exposure to excessive levels of the steroid hormone cortisol.

Cushing's Syndrome was first described by Harvey Cushing in 1932.

Harvey Cushing first described the association between pituitary gland tumours and signs of excess steroid hormones.

The incidence rate of Cushing's Syndrome is 2 per 1,000,000 population.

Cushing's Syndrome typically onsets between 20-40 years old.

Cushing's Syndrome is characterized by excess cortisol in the blood.

Cushing's Disease is a specific form of Cushing's Syndrome caused by an ACTH-secreting pituitary tumor.

High blood pressure, fluid retention, depression, and anxiety.

Screening, confirmation of the diagnosis, and differentiation of the cause.

Urinary free cortisol, diurnal rhythm, and overnight dexamethasone suppression test.

Low dose dexamethasone suppression testing.

High dose dexamethasone suppression testing, ACTH, CRH test, and localisation.

Cushing’s Disease (pituitary adenoma), adrenal tumour (benign or malignant), and ectopic ACTH production (benign or malignant).

Hypokalaemia, metabolic alkalosis, and hyperglycaemia.

Glucocorticoids (cortisol), mineralocorticoids (aldosterone), and androgens.

Autoimmune condition, low circulating thyroid hormone (TH), high TSH, lethargy, intolerance to cold, lack of growth and development, and diffuse goitre.

Blood flows from the outer cortex to the inner medulla, with layer-specific enzymes and functional zonation affecting hormone synthesis.

Mineralocorticoids regulate salt and water balance, glucocorticoids affect metabolism and immune function, and androgens are weak androgens.

Cortisol is rapidly metabolized to inactive cortisone in the kidney by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2).

Decrease glucose utilization, promote lipolysis, stimulate gluconeogenesis, increase proteolysis, maintain blood glucose levels, ensure vascular integrity, and have anti-inflammatory and immunosuppressive effects.

ACTH is synthesized from pro-opiomelanocortin (POMC) and binds to melanocortin receptors. Excess ACTH can cause skin pigmentation.

Low circulating adrenal steroids, high ACTH, normal to low plasma sodium, normal to high plasma potassium, and elevated plasma renin.

Addison’s disease (primary), hypopituitarism (secondary hypocortisolism), failure in RAAS (secondary hypoaldosteronism), and enzyme defects in steroid synthesis pathways.

Hypercortisolism due to excess glucocorticoid. It can be ACTH-dependent (Cushing's disease, ectopic ACTH-secreting tumor) or ACTH-independent (adrenal adenoma or carcinoma, iatrogenic).

Hypertension, hyperglycaemia, truncal obesity, fatigue, muscle weakness, virilization, depression, and mood disturbances.

Confirm hypersecretion of cortisol using 24-hour urinary cortisol and cortisol at nadir of secretion.

To determine the cause of hypercortisolism by assessing ACTH levels and response to dexamethasone suppression.

Surgery and cortisol production blockers such as Metyrapone and Ketoconazole.

DXT/Deep X-Ray Therapy (three field or gamma knife) and CXT/Chest Radiography (Mitotane).

Transsphenoidal surgery (TSS) and DXT. Patients may also require replacement of other pituitary hormones following treatment.

Steroid replacement tablets.

The adrenal tumour suppresses the function of the normal gland.

Many patients will not need the steroid tablets long-term.

Tiredness, weakness, anorexia, weight loss, postural hypotension, myalgia, salt craving, nausea, vomiting, hyperpigmentation, and vitiligo.

Hyponatremia, hyperkalemia, and hypercalcemia.

Acidosis and hypoglycemia.

Increased urea and creatinine, eosinophilia, and lymphocytosis.

Autoimmune disorders.

TB (tuberculosis), fungal histoplasmosis, viral HIV, and bacterial TB.

Amyloidosis, haemochromatosis, Waterhouse-Freidrichson syndrome, and apoplexy.

Congenital adrenal hyperplasia, adrenoleukodystrophy, and adrenomyeloneuropathy.

Withdrawal from long-term steroid therapy.

Metastases, infection, and drugs.

9 AM cortisol, ACTH (adrenocorticotropic hormone), electrolytes, FBC (full blood count), adrenal imaging, adrenal antibodies, investigations for other causes of adrenal failure, infection screen, imaging for cancer, and biochemical testing for enzyme deficiency.

It helps assess cortisol levels, which are typically highest in the morning.

ACTH levels can indicate whether adrenal insufficiency is primary (due to adrenal gland dysfunction) or secondary (due to pituitary or hypothalamic dysfunction).

Adrenal imaging and imaging for cancer to assess for any structural abnormalities or malignancies.

Adrenal insufficiency can lead to electrolyte imbalances, particularly hyponatremia and hyperkalemia.

Adrenal antibodies, infection screen, and biochemical testing for enzyme deficiency to identify specific causes such as autoimmune disorders or enzyme deficiencies.

Short Synacthen test (250mcg), Long Synacthen test (1mg), insulin tolerance test, and glucagon test.

It evaluates adrenal response to ACTH stimulation by administering synthetic ACTH (Synacthen) and measuring cortisol levels.

The Long Synacthen test uses a higher dose of Synacthen (1mg) and measures cortisol levels over a longer period, providing more comprehensive assessment of adrenal function.

Hydrocortisone (10mg in the morning, 5mg at noon, and 5mg in the afternoon) to mimic the diurnal rhythm, with the last dose before 6pm. Fludrocortisone (50-200mcg once daily) may also be prescribed.

CAH is a group of autosomal recessive disorders characterized by enzyme deficiencies in cortisol biosynthesis, leading to adrenal gland hyperplasia and impaired cortisol and aldosterone production.

21-hydroxylase deficiency is the most common form of CAH.

It is an inherited disorder caused by mutations in the CYP21A2 gene, which encodes the enzyme 21-hydroxylase. This enzyme is essential for cortisol synthesis, and its deficiency leads to impaired cortisol production.

Approximately 1 in 10,000 live births.

It is autosomal recessive and has an increased incidence in populations with specific HLA haplotypes, such as HLA-A3, Bw47, and DR7, with a higher prevalence observed in certain ethnic groups like Yupik Eskimos.

Excess sex steroids can cause virilization, hirsutism, premature adrenarche, and infertility. Additionally, due to the lack of aldosterone, patients may experience salt-losing crisis characterized by hyperkalemia and hypotension.

It accounts for approximately 5% of reported cases of congenital adrenal hyperplasia (CAH).

The incidence is around 0.5 per 100,000 live births, and it follows an autosomal recessive inheritance pattern.

There's an increased prevalence among Moroccan Jews, with an incidence of 1 in 6,000 live births.

It's also linked to specific HLA haplotypes, including HLA-B14 and DR1.

Excess sex steroids can result in virilization, hirsutism, premature adrenarche, and infertility. Additionally, due to the lack of aldosterone but high levels of deoxycorticosterone (DOC), patients may experience hypertension and hypokalemia.

Synacthen (ACTH Stimulation) Test:

What it reveals: When given synthetic ACTH (Synacthen), patients with 11β-hydroxylase deficiency do not show an increase in cortisol levels. Instead, they have high levels of 17-hydroxyprogesterone (17-OHP), a precursor hormone.

Prednisolone Suppression Test:

What it reveals: Administering prednisolone, a type of glucocorticoid, should lower androgen levels to within the normal range. This is because prednisolone reduces ACTH production, which in turn decreases the production of excess androgens.

Glucocorticoid therapy is primarily used to replace cortisol and inhibit ACTH production, thus reducing adrenal testosterone production.

Surgery may be required for virilized female genitalia. Treatment of the mother may be necessary to prevent fetal virilization. Fludrocortisone is utilized to replace absent mineralocorticoid activity.

Aldosterone is primarily produced in the zona glomerulosa of the adrenal cortex.

Aldosterone acts on the kidney via receptors and binds glucocorticoids with equal affinity.

Aldosterone primarily interacts with intranuclear receptor type 1.

Primary aldosterone excess is characterized by high aldosterone levels and low renin levels.

Conditions include Conn's Syndrome, bilateral adrenal hyperplasia, steroid-treatable hypertension, and aldosterone-producing adrenal carcinoma.

Secondary aldosterone excess is characterized by high aldosterone levels and high renin levels.

Conditions include renal artery stenosis, renin-secreting tumours, and malignant nephrosclerosis.

Aldosterone excess can be present without hypertension in conditions such as congestive heart failure (CCF), cirrhosis, nephrotic syndrome, and dehydration.

Treatment options include Spironolactone or Eplerenone, Amiloride or Triampterine, potassium supplementation, and surgery to address the primary tumour.

Adrenal glands comprise two parts: the adrenal cortex and the adrenal medulla. Adrenal overactivity can manifest as Cushing’s syndrome, Conn’s syndrome, or adrenal hyperplasia. Adrenal underactivity includes Addison’s disease and congenital adrenal hyperplasia (CAH).

Phaeochromocytoma is a tumor of the enterochromaffin cells of the adrenal medulla.

Extra-adrenal phaeochromocytoma can occur in sympathetic ganglia or the organ of Zuckerkandl.

Phaeochromocytoma can produce epinephrine, norepinephrine, and dopamine.

The "Rule of 10" states that approximately 10% of phaeochromocytomas are bilateral, 10% are malignant, and 10% are extra-adrenal.

Current estimates suggest that over 40% of phaeochromocytomas are related to an inherited germline mutation, while more than 30% are associated with a somatic mutation.

Symptoms include sweating, headache, tachycardia, anxiety, fever, paroxysmal hypertension, constipation, abdominal pain, fits, visual disturbance, pallor or flushing, palpitation, and sometimes hypotension or angor animii.

Laboratory findings may include eosinophilia, hyperglycemia, and hypercalcemia. Urinary tests may reveal elevated levels of metanephrines and catecholamines.

Imaging modalities include CT, MRI, MIBG scan (I131 meta-iodobenzylguanidine), and 68 Ga-DOTA-NOC PET CT scan.

Emergency management includes alpha blockade with non-competitive alpha antagonists like phenoxybenzamine or phentolamine, followed by beta blockade with nonselective beta blockers such as propranolol. Fluid resuscitation is also essential.

Alpha blockade can be achieved with non-competitive alpha antagonists like phenoxybenzamine or phentolamine, as well as competitive antagonists like doxazosin.

Beta blockade is typically achieved with nonselective beta blockers such as propranolol.

Surgery is the definitive treatment for Phaeochromocytoma.