HYPOFUNCTION OF THE ADRENAL CORTEX Adrenal anatomy and function

The human adrenals weigh 8-10g together and comprise an outer cortex with three zones(reticularis,fasciculata and glomerulosa) producing steroids, and an inner medulla that synthesizes, stores and secretes catecholamines

The adrenal steroids are grouped into three classes based on their predominant physiological effects y y y Glucocorticoids Mineralocorticoids Androgens

Mineralocorticoids
y Their predominant effect is on the extracellular balance of sodium and potassium in the distal tubule of the kidney. Aldosterone, produced solely in the zone glomerulosa, is the predominant mineralocorticoid in humans (about 50%)

Androgens
y Although secreted in considerable quantities, most have only relatively weak intrinsic androgenic activity until metabolized peripherally to testosterone or dihydrotestosterone.

Physiology
y Glucocorticoid production by the adrenal is under hypothalamic-pituitary control. Corticotropin-releasing hormone (CRH) is secreted in the hypothalamus in response to circadian rhythm, stress and other stimuli. CRH travels down the portal system to stimulate ACTH release from the anterior pituitary corticotrophs ACTH is derived from the prohormone proopiomelanocortin, which undergoes complex processing within the pituitary to produce ACTH and a number of other peptides. Many of these peptides, including ACTH, contain melanocyte-stimulating hormone(MSH) like sequences which cause pigmentation when levels of ACTH are markedly raised. Circulating ACTH stimulates cortisol production in the adrenal The cortisol secreted (or any other synthetic corticosteroid administered to the patient) causes negative feedback on the hypothalamus and pituitary to inhibit further CRH/ACTH release. The set-point of this system clearly varies through the day according to the circadian rhythm, and is usually overridden by severe stress.

HYPOFUNCTION OF THE ADRENAL CORTEX

Cases of adrenal insufficiency can be divided into two general categories y y (1) those associated with primary inability of the adrenal to elaborate sufficient quantities of hormone, and (2) those associated with a secondary failure due to inadequate ACTH formation or release.

PRIMARY ADRENOCORTICAL DEFICIENCY (ADDISONS DISEASE) y

The original description of Addisons disease- general languor and debility, feebleness of the hearts action, irritability of the stomach, and a peculiar change of the color of the skin summarizes the dominant clinical features. Advanced cases are usually easy to diagnose, but recognition of the early phases can be a real challenge.

Incidence. y
y Primary insufficiency is relatively rare with prevalence of 40-60/million, may occur at any age. Because of the common therapeutic use of steroids, secondary Primary hypoadrenalism shows a marked female preponderance and is now most often caused by autoimmune disease (> 90% in UK) rather than tuberculosis (<10%). All other causes are rare. Autoimmune adrenalitis results from the destruction of the adrenal cortex by organ-specific autoantibodies.

Pathophysiology and causes y

y In this condition there is destruction of the entire adrenal cortex Glucocorticoid, mineralocorticoid and sex steroid production are therefore all reduced. This differs from hypothalamic-pituitary disease, in which mineralocorticoid secretion remains largely intact, being predominantly stimulated by angiotensin II. Adrenal sex steroid production is also largely independent of pituitary action. In Addisons disease reduced cortisol levels lead, through feedback, to increased CRH and ACTH production, the latter being directly responsible for the hyperpigmentation.

y y

Causes of primary hypoadrenalism

y y y y y y y y Autoimmune disease(approx. 90% in UK) Tuberculosis (<10% in UK) Surgical removal Haemorrhage/ infarction Meningococcal septicemia Venography Malignant destruction Amyloid

Clinical Signs and Symptoms

Adrenocortical insufficiency caused by gradual adrenal destruction is characterized by an insidious onset of y y y y y y y y Fatigability Weakness Anorexia Nausea and vomiting Weight loss Cutaneous and mucosal pigmentation Hypotension And occasionally hypoglycemia

Asthenia y
Asthenia is the cardinal symptom. Early it may be sporadic, usually most evident at time of stress, as adrenal function becomes more impaired, the patient is continuously fatigued, and bed rest is necessary.

Hyperpigmentation y
Hyperpigmentation may be striking/absent. It commonly appears as a diffuse brown tan, or bronze darkening of parts such as the elbows or creases of the hand and of the areas that normally are pigmented such as the areolae about the nipples. Bluish black patches may appear on the mucous membrane. Some patient develops dark freckles and irregular areas of vintiligo may be present.

Arterial hypotension y
Arterial hypotension with postural accentuation is frequent, and blood pressure may be in the range of 80/50 or less

Abnormalities of gastrointestinal function y

Abnormalities of gastrointestinal function are often the presenting complaint. Symptoms vary from mild anorexia with weight loss to fulminating nausea, vomiting, diarrhea, and ill-defined abdominal pain, which may be so severe as to be confused with an acute abdomen.

y y

Patients may have personality changes usually consisting of excessive irritability and restlessness. Axillary and pubic hair may be decreased in women due to loss of adrenal androgens.

Diagnosis y
The diagnosis of adrenal insufficiency should be made only with ACTH stimulation testing to assess adrenal reserve capacity for steroid production. The best scrrening test is the cortisol response60 min after 250 g of cosyntropin given intramuscularly/ intravenously. Cortisol levels should exceed 495 nmol/L(18g/dL). If the response is abnormal, the primary & secondary adrenal insufficiency can be distinguished by measuring aldosterone levels from the same blood samples. In secondary, but not primary, adrenal insufficiency, the aldosterone increment will be normal.

Treatment y
All patient with adrenal insufficiency should receive specific hormone replacement. Like diabetics, these patients require careful education about the disease. Replacement therapy should correct both glucocorticoid & mineral corticoid deficiency.

ACUTE ADRENOCORTICAL INSUFFICIENCY Acute adrenocortical insufficiency may result from several processes

y y

y y

On the one hand, adrenal crisis may be a rapid and overwhelming intensification of chronic adrenal insufficiency, usually precipitated by sepsis or surgical stress Alternatively, acute hemorrhagic destruction of both adrenal glands can occur in previously well subjects. In children, this event is usually associated with septicemia with Pseudomonas or meningococcemia (Waterhouse-Friderichsen syndrome). In adults, anticoagulant therapy or a coagulation disorder may result in bilateral adrenal hemorrhage. The third and most frequent cause of acute insufficiency is the rapid withdrawal of steroids from patients with adrenal atrophy owing to chronic steroid administration. Acute adrenocortical insufficiency may also occur in patients with congenital adrenal hyperplasia or those with decreased adrenocortical reserve when they are given drugs capable of inhibiting steroid synthesis (mitotane, ketoconazole) or of increasing steroid metabolism(phenytoin,rifampin)

Adrenal Crisis
The long term survival of patient with adrenocortical insufficiency depends largely on the prevention and treatment of adrenal crisis. Consequently, the occurrence of infection, trauma (including surgery), gastrointestinal upsets, or other stresses necessitates an immediate increase in hormone. In untreated patients, preexisting symptoms are intensified. y Nausea, vomiting, and abdominal pain may become intractable

y y

Fever may be severe or absent Lethargy deepens into somnolence, and hypovolemic vascular collapse unsues

In contrast, patient previously maintained on chronic glucocorticoid therapy may not exhibit dehydration or hypotension until they are in a preterminal state, since meneralocorticoid secretion is usually preserved. In all patients in crisis, a precipitating cause should be sought.

TREATMENT y y
Treatment is directed primarily toward repletion of circulating glucocorticoids and replacement of the sodium and water deficits Hence an intravenous infusion of 5% glucose in normal saline solution should be started with a bolus intravenous infusion of 100 mg hydrocortisone followed by a continuous infusion of hydrocortisone at a rate of 10 mg/h.