Addisonian Syndrome

Progressive weakness, anemia, hypoglycemia, and hyperpigmentation of the skin. Vomiting, apneic spells, cyanosis, vascular collapse, and cardiovascular shock may be consequential.

Addison Disease; Adrenal Insufficiency; Adrenal Hypoplasia/Aplasia.

First described in 1849 by Thomas Addison, the English physician, in patients suffering from tuberculosis with suprarenal involvement.

Most cases are sporadic, but depending on the etiology solid evidence exists for autosomal recessive and X-linked recessive forms.

Complete or partial deficit of mineralocorticoids and glucocorticoid hormones, excreted by the zonae fasciculata (aldosterone) and glomerulosa (glucocorticoids) of the adrenal cortex, caused by different mechanisms. Autoimmune mechanisms (which may be associated with other autoimmune diseases, e.g. chronic lymphocytic thyroiditis, hyperthyroidism, diabetes mellitus, celiac disease), adrenal aplasia, X-linked congenital adrenal hypoplasia, cytomegalic adrenocortical hypoplasia, familial hypoadrenocorticism, pituitary gland hypoplasia, isolated ACTH deficiency, X-linked adrenoleukodystrophy, and Waterhouse Friderichsen Syndrome (fulminant form caused by meningococcemia). Dysfunction of the adrenal cortex leads to interrupted hypothalamic and anterior pituitary gland feedback inhibition, resulting in continuous and uninhibited secretion of ACTH. Cleavage of the prohormone pro-opiomelanocortin in the adenohypophysis results in simultaneous secretion of ACTH and melanocyte-stimulating hormone (MSH). The elevated MSH level is responsible for the typical bronze hyperpigmentation in patients with primary adrenal insufficiency.

Vomiting, cyanosis, apneic spells, hypoglycemia, seizures, and vascular collapse are the usual presenting symptoms of an adrenal crisis. Cardiovascular collapse may occur. Plasma and urinary concentrations of all adrenal steroids are low. Serum glucose level usually is low. Sodium plasma concentrations are decreased (but rarely <120 mmol/l) but potassium plasma concentrations are increased (but rarely >7.0 mmol/l). Moderate metabolic acidosis with plasma bicarbonate levels between 15 and 20 mmol/l is common. BUN typically is elevated. Urinary excretion of sodium and chloride is increased, whereas potassium excretion is decreased. Plasma cortisol levels—if measured before treatment—are low. However, the final diagnosis of adrenocortical insufficiency is based on the finding of an absent or decreased response in adrenal steroid synthesis to stimulation with external (intravenous or intramuscular) ACTH. Increased serum concentrations of cortisol and aldosterone are signs of a functional adrenal cortex. Under normal conditions, cortisol synthesis increases by a factor of two to five times above normal levels after administration of ACTH. Failure of aldosterone serum level to double within 30 minutes of ACTH administration indicates a problem with mineralocorticoid synthesis. A normal ACTH stimulation test result excludes the diagnosis of primary adrenocortical insufficiency. The adrenal glands may appear enlarged on abdominal CT scan or sonography in patients with Addison disease secondary to infection, hemorrhage, or malignancies involving the adrenals. Primary adrenal insufficiency results in atrophic adrenal glands secondary to inactivity. Idiopathic autoimmune adrenocortical insufficiency usually resulting from autoimmune lymphocytic infiltration of the adrenal cortex is the most common cause of Addisonian syndrome, accounting for approximately 80% of cases. Another significant percentage results from adrenal cortex destruction by tuberculosis.

Idiopathic autoimmune Addison disease may occur in isolation or in combination with other autoimmune diseases, such as diabetes mellitus type I, systemic lupus erythematosus, Hashimoto thyroiditis, Graves disease, vitiligo, alopecia (areata, totalis, universalis), pernicious anemia, myasthenia gravis, idiopathic hypophysitis, idiopathic hypoparathyroidism, primary biliary cirrhosis, and chronic active hepatitis. Other diseases may have the potential to cause Addisonian syndrome (e.g. tuberculosis, sarcoidosis, blastomycosis, histoplasmosis, cryptococcosis, meningococcemia, AIDS, cytomegalovirus infection). Hodgkin and non-Hodgkin lymphomas and metastases from different carcinomas (lung, breast, kidney) may affect the adrenal glands. Addisonian syndrome in patients with Allgrove Syndrome is caused by a congenital adrenocortical unresponsiveness to ACTH. Several drugs may interfere with adrenal steroidogenesis (ketoconazole, busulfan, etomidate, aminoglutethimide) or ACTH storage in the pituitary (methadone). Addisonian syndrome has been described as a complication of pregnancy and anticoagulant therapy with heparin or warfarin resulting in adrenocortical hemorrhage. Heparin-induced (thrombocytopenia and) thrombosis may result in thrombosis of adrenal vessels followed by necrosis of the gland. An acute adrenal crisis can be precipitated by trauma, surgery, and significant physical and/or emotional stress. Another common cause of an adrenal crisis is the failure to appropriately replace steroids in patients receiving long-term steroid medication.

Progressive weakness, anemia, and hyperpigmentation are salient features. Pigmentation is caused by increased levels of ACTH. Laboratory findings depend on the type of hypoadrenalism: hyponatremia, hyperkalemia, metabolic acidosis, and anemia are present in primary adrenal insufficiency. Elevated BUN and creatinine concentrations are common and result from hypovolemia, decreased renal plasma flow, and decreased glomerular filtration rate. Fasting and increased sensitivity to insulin with increased peripheral glucose utilization may result in hypoglycemia. Hypoglycemia without electrolyte imbalance may occur in patients with secondary adrenal insufficiency.

Treatment of known adrenal insufficiency is daily administration of cortisol and fludrocortisone. During stress, the dosages must be increased by 50 to 100%. Acute adrenal insufficiency is treated with 5 to 10% dextrose in isotonic saline. Hydrocortisone initially is given as a bolus, followed by an infusion until symptoms subside. Intramuscular injections of cortisone acetate are given daily and then progressively reduced when the patient's clinical status improves. The salt-retaining hormone desoxycorticosterone (DOCA) is administered daily to maintain electrolyte balance. Anesthetic management of patients with documented adrenal insufficiency must include provision of exogenous corticosteroids and focus on the adequacy of the dose supplemented. Serum electrolytes and blood glucose levels (fasting hypoglycemia is common) should be checked on a regular basis.

There is no direct influence of anesthetic agents (except etomidate) on the rise of cortisol in response to surgical stress (which is reduced or suppressed only by high central neuraxial blockade). Untreated or partially treated patients may develop an acute adrenal crisis, which is potentially lethal and requires the same treatment as the other forms of acute adrenal insufficiency.

Careful titration of the anesthetic agents may be necessary because patients with Addisonian syndrome are prone to myocardial depression following administration of potent anesthetics.

Allgrove Syndrome: This is a genetic autosomal recessive disease characterized by the triad of ACTH-resistant insufficiency, achalasia, and alacrima. It presents in the first decade of life with severe hypoglycemic episodes that can result in death. Mixed pattern of upper and lower motor neuropathy, autonomic neuropathy, sensory impairment, and mental retardation.

X-Linked Adrenoleukodystrophy (XLA): Disorder characterized by progressive demyelinization of the central nervous system and peripheral adrenal insufficiency.