The clinical signs and symptoms of both acute and chronic adrenal insufficiency are a logical consequence of the underlying pathology, i.e. mostly the deficiency of adrenal corticosteroid production arising from primary or secondary adrenal failure (Table 1).
Table1. Clinical manifestations of adrenal insufficiency
Acute adrenal insufficiency (i.e. life- threatening adrenal crisis) typically presents with severe hypotension or hypovolaemic shock, acute abdominal pain, vomiting, and often with fever, and, therefore, is sometimes mistaken for acute abdomen. In a series of 91 patients with Addison’s disease, adrenal crisis led to the initial diagnosis of adrenal insufficiency in half of the patients. In children, acute adrenal insufficiency often presents as hypoglycaemic seizures. Deterioration of glycaemic control with recurrent hypoglycaemia may be the presenting sign of adrenal insufficiency in patients with pre- existing type 1 diabetes. In APS 2, onset of autoimmune hyperthyroidism (or thyroxine replacement for newly diagnosed hypothyroidism) may precipitate adrenal crisis due to enhanced cortisol clearance.
The leading symptom of chronic adrenal insufficiency is fatigue, accompanied by lack of stamina, loss of energy, reduced muscle strength, and increased irritability. In addition, chronic glucocorticoid deficiency leads to weight loss, nausea, and anorexia (in children, failure to thrive) and may account for muscle and joint pain. Unfortunately, most of these symptoms are non- specific. Thus, every second patient suffers from signs and symptoms of Addison’s disease for more than 1 year before diagnosis is established. In secondary adrenal insufficiency, diagnosis is mostly prompted by a history of pituitary disease, but may also be delayed (e.g. in isolated ACTH deficiency). A more specific sign for primary adrenal failure is hyperpigmentation, which is most pronounced in areas of the skin exposed to increased friction (e.g. hand lines, knuckles, scars, oral mucosa). Hyperpigmentation is due to enhanced stimulation of skin MC1- receptor by ACTH and other pro- opiomelanocortin- related pep tides. Accordingly, patients with secondary adrenal insufficiency often present with pale, alabaster- coloured skin. Laboratory findings in glucocorticoid deficiency may include mild anaemia, lymphocytosis, and eosinophilia. Cortisol physiologically inhibits thyrotropin (TSH) release. Thus, TSH is often increased at initial diagnosis of primary adrenal insufficiency, but returns to normal during glucocorticoid replacement, unless there is coincident autoimmune thyroid failure. In rare cases, glucocorticoid deficiency may result in hypercalcaemia, which is due to increased intestinal absorption and decreased renal excretion of calcium and usually coincides with autoimmune hyperthyroidism, facilitating calcium release from bone.
Mineralocorticoid deficiency, which is only present in primary adrenal insufficiency, leads to dehydration and hypovolaemia, resulting in low blood pressure, postural hypotension, and sometimes even in prerenal failure. Deterioration may be sudden and is often due to exogenous stress such as infection or trauma. Combined mineralocorticoid and glucocorticoid replacement in primary ad renal insufficiency reconstitutes the diurnal rhythm of blood pressure and reverses cardiac dysfunction. Glucocorticoids contribute to this amelioration not only by mineralocorticoid receptor binding, but also by permissive effects on catecholamine action. The latter may account for the relative unresponsiveness to catecholamines in patients with unrecognized adrenal crisis. Mineralocorticoid deficiency accounts for hyponatraemia (90%), hyperkalaemia (65%), and salt craving (15%). Low serum sodium may also be present in secondary adrenal insufficiency due to the syndrome of inappropriate antidiuretic hormone secretion, which results from the loss of physiological inhibition of pituitary vasopressin release by glucocorticoids.
Adrenal insufficiency inevitably leads to DHEA deficiency. DHEA is the major precursor of sex steroid synthesis and loss of its synthesis results in pronounced androgen deficiency in women. As a consequence, women with adrenal insufficiency frequently show loss of axillary and pubic hair (absence of pubarche in children), dry skin, and reduced libido. DHEA also exerts direct action as a neurosteroid with potential antidepressant properties. Thus, DHEA deficiency may contribute to the impairment of well- being that is observed in patients with adrenal insufficiency despite adequate glucocorticoid and mineralocorticoid replacement.
