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Adrenal Insufficiency 

Adrenal Insufficiency
Adrenal Insufficiency

Palak Choksi

, and Robert W. Lash

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date: 29 June 2022

  1. A. Introduction

    1. a. Definitions. Adrenal insufficiency is defined as the inadequate production of glucocorticoids, mineralocorticoids, or both. However, glucocorticoid deficiency is more common and has greater clinical relevance. It is therefore the focus of this chapter.

      1. i. Glucocorticoid insufficiency occurs when glucocorticoid production by the adrenal gland is deficient. This may be due to adrenal gland dysfunction (primary adrenal insufficiency) or inadequate secretion of adrenocorticotropic hormone (ACTH) to stimulate the adrenal glands (secondary adrenal insufficiency).

      2. ii. Hypoaldosteronism occurs when mineralocorticoid production is impaired. It can occur with adrenal insufficiency (as in Addison’s disease) or as an isolated finding. When hypoaldosteronism occurs as an isolated finding, it is usually the result of defective renin secretion.

  2. B. Causes of Adrenal Insufficiency

    1. a. Primary adrenal insufficiency (Addison’s disease) results from destruction of the adrenal glands and is therefore accompanied by hypoaldosteronism. One way to remember the common causes of primary adrenal insufficiency is to use the mnemonic “ADDISON’S”:

      • MNEMONIC: Causes of Addison’s Disease (“ADDISON’S”)

      • Amyloidosis

      • Destruction (autoimmune or hemorrhage following trauma)

      • Drugs (anticoagulants leading to bilateral adrenal hemorrhage)

      • Infections (bacterial sepsis [especially meningococcus], tuberculosis, disseminated fungal infections, cytomegalovirus [CMV] in AIDS patients, syphilitic gummas)

      • Sarcoidosis

      • Overload of iron (hemochromatosis)

      • Neoplasm (bilateral metastatic disease, usually from the lung)

      • Surgical (perioperative or following bilateral adrenalectomy)

    2. b. Secondary adrenal insufficiency is caused by pituitary dysfunction. There are many causes of secondary adrenal insufficiency, but the most important are summarized in Table 80.1. All these causes affect the pituitary gland and lead to hypopituitarism. The most common disorders are ACTH suppression due to withdrawal of chronic exogenous corticosteroids and ACTH deficiency due to pituitary tumors.

    3. c. Tertiary adrenocortical insufficiency occurs with hypothalamic disorders, pituitary stalk destruction, and certain central nervous system (CNS) diseases. It is a rare cause of adrenal insufficiency.

      Table 80.1 Causes of Secondary Adrenal Insufficiency


      Specific Cause


      Familial hypopituitarism


      Pituitary apoplexy (hemorrhage)


      Sheehan’s syndrome


      Withdrawal of chronic exogenous corticosteroids


      Chronic renal failure, diabetes mellitus, hemochromatosis


      Tuberculosis, syphilis, fungal disease


      Irradiation of the pituitary gland


      Empty sella syndrome, sarcoidosis


      Pituitary tumors





  3. C. Clinical Manifestations of Adrenal Insufficiency

    1. a. Primary adrenal insufficiency. The clinical manifestations vary depending on the time course of adrenal destruction.

      1. i. Chronic insufficiency. Most patients (75%) present with chronic insufficiency due to gradual destruction of the adrenal gland. More than 90% of the gland must be destroyed before symptoms occur; therefore, symptoms occur over many months and, in some cases, years. Table 80.2 can be used to determine “WWHHOO” may have chronic insufficiency.

        Table 80.2 Clinical Manifestations of Chronic Adrenal Insufficiency (“WWHHOO”)

        Clinical Manifestations




        Weight loss








        Other (hyponatremia, hyperkalemia, non–anion gap metabolic acidosis, fever, hypoglycemia, eosinophilia, gastrointestinal symptoms such as nausea, vomiting, and diarrhea)


      2. ii. Hyperpigmentation may precede other manifestations. It tends to be generalized but is accentuated in sun-exposed areas, pressure points (e.g., knees and knuckles), and on the nail beds, nipples, and palmar creases. In dark-skinned patients, the only signs of hyperpigmentation may be on the tongue and in the perilimbal region of the eyes.

      3. iii. Acute insufficiency (adrenal crisis). Only 25% of patients with adrenal insufficiency present acutely. However, acute adrenal insufficiency (also called adrenal crisis) can be life-threatening. Adrenal crisis often occurs in a patient with preexisting adrenal insufficiency (usually undiagnosed) who experiences a significant stressor (e.g., infection, cardiac ischemia, surgery). It may also be seen in a previously healthy patient if acute adrenal destruction occurs (e.g., adrenal hemorrhage due to sepsis or anticoagulation).

        1. 1. Signs and symptoms

          • a. Profound anorexia, nausea, and vomiting may be seen.

          • b. Abdominal pain may be mistaken for a “surgical abdomen.”

          • c. Hypotension may be severe and is typically unresponsive to saline hydration.

          • d. Fever may occur, even in the absence of an initiating infection.

          • e. Hypoglycemia. Remember, glucocorticoids stimulate gluconeogenesis.

          • f. Hyperpigmentation may occur but is not as common as in chronic insufficiency.

        2. 2. Laboratory findings are similar to the findings in chronic adrenal insufficiency (see Table 80.2).

    2. b. Secondary adrenal insufficiency. The development of signs and symptoms can be chronic or acute. The clinical manifestations are the same as in primary adrenal insufficiency, with the following exceptions:

      1. i. Patients may have other evidence of pituitary dysfunction (e.g., hypothyroidism, hyperprolactinemia, diabetes insipidus, gonadotropin deficiency).

      2. ii. Hyperkalemia and a non–anion gap metabolic acidosis are usually not present (because aldosterone is still secreted appropriately).

      3. iii. Hyperpigmentation usually does not occur.

  4. D. Approach to the Patient

    1. a. The most difficult aspect of diagnosing adrenal insufficiency is thinking of the diagnosis in the first place. The pattern of clinical manifestations and laboratory findings should alert you to the possibility of adrenal insufficiency. When a patient presents with hypotension, weakness, abdominal pain, unexplained fever, hypoglycemia, or nonspecific findings, always consider Addison’s disease.

    2. b. Confirmation of the diagnosis is relatively straightforward.

      1. i. Plasma cortisol assay. If the plasma cortisol level is greater than 18 µg/dL, adrenal insufficiency is unlikely. If the plasma cortisol is less than 18 µg/dL, further testing is warranted.

      2. ii. Cosyntropin (ACTH) stimulation test. If the plasma cortisol level is less than 18 µg/dL, perform a 1-hour cosyntropin stimulation test. In this test, a plasma cortisol level is checked at baseline (usually in the early AM), followed immediately by administration of cosyntropin and subsequent cortisol plasma levels after 30 and 60 minutes. A normal response rules out primary (but not secondary) adrenal insufficiency.

      3. iii. Plasma ACTH level. ACTH levels are elevated in primary adrenal insufficiency. A low ACTH level in the setting of cortisol deficiency usually confirms the diagnosis of secondary adrenal insufficiency.

  5. E. Treatment

    1. a. Acute insufficiency (adrenal crisis). If there is strong clinical suspicion for adrenal crisis, appropriate treatment should not be delayed until diagnostic testing is completed. Initial treatment with dexamethasone does not interfere with the plasma cortisol assay and should be instituted as soon as possible.

      1. i. Intravenous glucocorticoids. High doses of glucocorticoids (e.g., hydrocortisone 100 mg every 8 hours) are administered initially. Because high doses of glucocorticoids have sufficient mineralocorticoid activity, mineralocorticoids are not routinely given until the cortisol dose has been tapered to lower levels.

      2. ii. Supportive treatment (e.g., intravenous fluids, oxygen) may be required and can be instituted in a monitored setting.

      3. iii. Precipitating causes should be identified and treated.

    2. b. Chronic adrenal insufficiency

      1. i. Primary adrenal insufficiency. Both glucocorticoids and mineralocorticoids are administered.

        1. 1. Doses vary, but a rough estimate for a maintenance dose is 20–25 mg of cortisol and 0.1 mg of fludrocortisone daily.

        2. 2. Patients should be counseled that treatment is lifelong and that doses should be increased during times of stress, such as planned surgeries or in the settings of infection. Patients should also carry a wallet card or wear a bracelet with their diagnosis.

      2. ii. Secondary or tertiary insufficiency. Usually only glucocorticoid therapy is needed.

Suggested Further Readings

Arlt W, Allolio B. Adrenal insufficiency. Lancet 2003;361:1881–93.Find this resource:

Bancos I, Hahner S, Tomlinson J, Arlt W. Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol 2015;3:216–26.Find this resource:

Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2016;101:364–89.Find this resource:

Nagarur A, Axelrod L, Dighe AS. Case 9-2017. N Engl J Med 2017;376:1159–67.Find this resource:

Oelkers W. Adrenal insufficiency. N Engl J Med 1996;335:1206–12. (Classic Article.)Find this resource:

Puar THK, Stikkelbroeck NMML, Smans LCCJ, Zelissen PMJ, Hermus ARMM. Adrenal crisis: still a deadly event in the 21st century. Am J Med 2016;129:339.e1–.e9.Find this resource: