Adrenal insufficiency is a condition that develops when most of the adrenal gland is not functioning normally. Primary adrenal insufficiency arises due to the damage of the glands or because of using drugs that halt synthesis of cortisol. On the other hand, secondary adrenal insufficiency stems from processes that inhibit the secretion of the adrenocorticotropic hormone (ACTH) by the hypophysis as a result of a hypothalamic or pituitary pathology. The former is sometimes also referred to as tertiary adrenal insufficiency.

Adrenal insufficiency is still a significant challenge for both patients and their physicians, but also scientists and researchers. In the past decade, long-term studies with adequate follow-up have shown a surge in mortality and morbidity, as well as impaired quality of life in individuals with this condition.

Primary Adrenal Insufficiency

In developed countries, the most common cause of primary adrenal insufficiency is autoimmune adrenalitis, whereas in the developing world tuberculosis is still considered a primary causative factor. Moreover, in young males, an X-linked adrenoleukodystrophy (also known as the less severe form of adrenomyeloneuropathy) must also be considered.

Histopathologically, in autoimmune primary adrenal insufficiency, there is a diffuse mononuclear cell infiltrate that can gradually progress to atrophy. Primary adrenal insufficiency is linked to both cortisol and mineralocorticoid deficiency.

Recent research drew attention to drug-related and infectious causes of adrenal insufficiency. Antifungal agents are known to substantially reduce cortisol synthesis, while imunosuppression associated with human immunodeficiency virus (HIV) has resulted in a resurgence of infectious causes, most notably tuberculous and CMV adrenalitis.

Secondary Adrenal Insufficiency

Secondary adrenal insufficiency has three principal causes: adrenal suppression after exogenous glucocorticoid or ACTH administration, abnormalities of the hypothalamus or pituitary gland that lead to ACTH deficiency, as well as adrenal suppression upon the correction of endogenous glucocorticoid hypersecretion.
 

Any lesion of the hypophysis or hypothalamus can result in secondary adrenal insufficiency; some of the examples are space-occupying lesions such as adenomas, craniopharyngiomas, sarcoidosis, fungal infections, trauma, and also metastases from distant malignant processes.

The histologic appearance of the adrenal glands in secondary adrenal insufficiency can range from normal to complete atrophy of the cortex (with preserved medulla). In contrast to primary adrenal insufficiency, secondary types are associated with the lack of cortisol, but not mineralocorticoid deficiency.

Clinical Features of Adrenal Insufficiency

The clinical presentation of adrenal insufficiency is related to the rate of onset and severity of adrenal deficiency. In a large number of cases, the disease has a gradual onset, thus the diagnosis can be made only when the affected individual presents with an acute crisis due to an inadequate rise in cortisol secretion during a physiologic stress. Such acute adrenal insufficiency (also known as the Addisonian crisis) is a medical emergency.

On the other hand, the course of chronic adrenal insufficiency is more subtle and insidious, with the predomination of symptoms such as fatigue, weakness, weight loss, diarrhea or constipation, muscle cramps, pain in joints and postural hypotension (low blood pressure). Salt craving and low-grade fever may also be present.

The classic physical finding that can help in differentiating primary from secondary adrenal failure is hyperpigmentation of the skin or the “suntan that does not fade”. Furthermore, patients with secondary adrenal insufficiency may present with additional symptoms related to pituitary disease (e.g., menstrual disturbances, loss of libido, galactorrhea, or hypothyroidism).

Laboratory Findings and Management

In cases of adrenal insufficiency, the complete blood count usually reveals anemia, neutropenia, eosinophilia, and relative lymphocytosis. Common chemical abnormalities include metabolic acidosis and prerenal azotemia, while hyponatremia, hypoglycemia, and hyperkalemia may also be present.

A cosyntropin stimulation test (also known as ACTH or Synacthen test) is required to establish the diagnosis of adrenal insufficiency. Magnetic resonance imaging (MRI) of the hypophysis in secondary adrenal insufficiency and computed tomography (CT) of the adrenal glands in primary adrenal insufficiency can aid in establishing a diagnosis. The adrenal glands appear normal in cases of autoimmune disorder.

Glucocorticoid replacement in patients with adrenal insufficiency can be lifesaving. Nevertheless, renal crisis is still a threat to patients’ lives, which is why awareness and adequate preventative measures receive increasing attention in the recent years.