Adrenal Insufficiency

• Fred F. Ferri, M.D.

 Basic Information

Definition

Adrenal insufficiency is characterized by inadequate secretion of corticosteroids resulting from partial or complete destruction of the adrenal glands (primary adrenal failure). Inadequate secretion of cortisol from the adrenals due to critical illness and pituitary insufficiency is known as secondary cortisol deficiency.

Synonyms

1. Primary adrenocortical insufficiency

2. Addison disease

ICD-10CM CODES
E27.1	Primary adrenocortical insufficiency
E27.2	Addisonian crisis
E27.40	Unspecified adrenocortical insufficiency
E27.49	Other adrenocortical insufficiency
E27.3	Drug-induced adrenocortical insufficiency
E23.3	Hypopituitarism

Epidemiology & Demographics

Prevalence

10 to 15 per 100,000 persons

Predominant Sex

Female/male ratio of 2:1

Physical Findings & Clinical Presentation

1. •

   Adrenal insufficiency may present insidiously with nonspecific symptoms. A high index of suspicion is required for diagnosis. About half of patients may present acutely with adrenal crises. Table 1 summarizes the clinical features of primary adrenal insufficiency.

   TABLE1 Clinical Features of Primary Adrenal InsufficiencyFrom Melmed S, Polonsky KS, Larsen PR, Kronenberg HM: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, Saunders.

   Feature	Frequency (%)
   Symptoms
   Weakness, tiredness, fatigue	100
   Anorexia	100
   Gastrointestinal symptoms	92
   Nausea	86
   Vomiting	75
   Constipation	33
   Abdominal pain	31
   Diarrhea	16
   Salt craving	16
   Postural dizziness	12
   Muscle or joint pains	13
   Signs
   Weight loss	100
   Hyperpigmentation	94
   Hypotension (<110 mm Hg systolic)	88-94
   Vitiligo	10-20
   Auricular calcification	5
   Laboratory Findings
   Electrolyte disturbances	92
   Hyponatremia	88
   Hyperkalemia	64
   Hypercalcemia	6
   Azotemia	55
   Anemia	40
   Eosinophilia	17

2. •

   Hyperpigmentation of skin (Figs. E1 and E2) and mucous membranes is a cardinal sign of adrenal insufficiency: more prominent in palmar creases, buccal mucosa, pressure points (elbows, knees, knuckles), perianal mucosa, and around areolas of nipples

   

   

3. •

   Hypotension, postural dizziness

4. •

   Generalized weakness, chronic fatigue, malaise, anorexia

5. •

   Amenorrhea and loss of axillary hair in females

Etiology

1. •

   Autoimmune destruction of the adrenal glands (80% of cases)

2. •

   Tuberculosis (TB) (7%-20% of cases)

3. •

   Carcinomatous destruction of the adrenal glands, lymphoma

4. •

   Adrenal hemorrhage (anticoagulants, trauma, coagulopathies, pregnancy, sepsis)

5. •

   Adrenal infarction (antiphospholipid syndrome, arteritis, thrombosis)

6. •

   AIDS (adrenal insufficiency develops in 30% of patients with AIDS, often cytomegalovirus [CMV] adrenalitis)

7. •

   Genetic causes: autoimmune polyglandular syndromes (APS) types 1 and 2, X-linked adrenoleukodystrophy, congenital adrenal hyperplasia

8. •

   Other: sarcoidosis, amyloidosis, hemochromatosis, Wegener’s granulomatosis, postoperative, fungal infections (candidiasis, histoplasmosis)

Diagnosis

Differential Diagnosis

Sepsis, hypovolemic shock, acute abdomen, apathetic hyperthyroidism in the elderly, myopathies, gastrointestinal malignancy, major depression, anorexia nervosa, hemochromatosis, salt-losing nephritis, chronic infection

Workup

1. •

   An early morning (8 am) serum cortisol <3 mcg/dl (82.8 mmol/L) is consistent with cortisol deficiency.

2. •

   If the clinical picture is highly suggestive of adrenocortical insufficiency, the diagnosis can be confirmed with the rapid adrenocorticotropic hormone (ACTH) test:

   1. 1.

      Give 250 mcg ACTH (Sinachten, tetracosatrin) by IV push and measure cortisol levels at 0, 30, and 60 min.

   2. 2.

      An increase in serum cortisol level to peak concentration >500 nmol/L (18 mcg/dl) indicates a normal response. Cortisol level <18 mcg/dl at 30 or 60 min is suggestive of adrenal insufficiency.

   3. 3.

      Measure plasma ACTH. A high ACTH level (>200 pg/mL [44 pmol/L]) confirms primary adrenal insufficiency.

3. •

   Critical illness-related corticosteroid insufficiency (e.g., in sepsis) is best established with the 1-mcg ACTH stimulation test in which cortisol levels are measured at baseline and 30 min after administration of ACTH. A level <25 mcg/dl (690 nmol/L) or an increment over baseline of <9 mcg (250 nmol/L) represents an inadequate adrenal response.

4. •

   Secondary adrenocortical insufficiency (caused by pituitary dysfunction) can be distinguished from primary adrenal insufficiency by the following:

   1. 1.

      Normal or low plasma ACTH level after rapid ACTH

   2. 2.

      Absence of hyperpigmentation

   3. 3.

      No significant impairment of aldosterone secretion (because aldosterone secretion is under control of the renin-angiotensin system)

   4. 4.

      Additional evidence of hypopituitarism (e.g., hypogonadism, hypothyroidism)

Laboratory Tests

1. •

   Hyponatremia, hyperkalemia

2. •

   Decreased glucose

3. •

   Increased BUN/creatinine ratio (prerenal azotemia)

4. •

   Mild normocytic, normochromic anemia, neutropenia, lymphocytosis, eosinophilia (significant dehydration may mask hyponatremia and anemia), hypercalcemia, metabolic acidosis

5. •

   A morning cortisol level >500 mmol/L (18 mcg/dl) generally excludes the diagnosis whereas a level <165 mmol/L (6 mcg/dl) is suggestive of Addison disease and a level <3 mcg/dl requires further evaluation (see “Workup”)

6. •

   Useful tests in evaluating the cause of adrenal insufficiency are: PPD (rule out TB), adrenal cortex antibodies and 21-hydroxylase antibodies (rule out autoimmune Addison disease), plasma very-long-chain fatty acids (rule out adrenoleukodystrophy)

Imaging Studies

1. •

   Imaging is not necessary for diagnosis but may help identify potential causes.

2. •

   Abdominal CT scan (Fig. 3): small adrenal glands generally indicate either idiopathic atrophy or longstanding TB, whereas enlarged glands are suggestive of early TB or potentially treatable diseases.

   

3. •

   Chest radiograph may reveal a small heart (Fig. E4).

   

4. •

   Abdominal radiograph: adrenal calcifications may be noted if the adrenocortical insufficiency is secondary to TB or fungal infection.

Treatment

Nonpharmacologic Therapy

1. •

   Perform periodic monitoring of serum electrolytes, vital signs, and body weight; liberal sodium intake is suggested.

2. •

   Periodic measurement of bone density may be helpful in identifying patients at risk for the development of osteoporosis.

3. •

   Patients should carry a MedicAlert bracelet and an emergency pack containing hydrocortisone 100-mg ampule, syringe, and needle.

4. •

   Patients and partners should be educated on how to give IM injection in case of vomiting or coma.

Acute General Rx

1. •

   Addisonian crisis is an acute complication of adrenal insufficiency characterized by circulatory collapse, dehydration, nausea, vomiting, hypoglycemia, and hyperkalemia.

   1. 1.

      Draw plasma cortisol level; do not delay therapy while waiting for confirming laboratory results.

   2. 2.

      Administer hydrocortisone 100 mg IV immediately, followed by 100 to 200 mg of hydrocortisone every 24 hours divided into 3 or 4 doses; if patient shows good clinical response, gradually taper dosage and change to oral maintenance dose (usually prednisone 7.5 mg/day).

   3. 3.

      Provide adequate volume replacement with D₅NS solution until hypotension, dehydration, and hypoglycemia are completely corrected. Large volumes (2 to 3 L) under continuous cardiac monitoring may be necessary in the first 2 to 3 hr to correct the volume deficit and hypoglycemia and to avoid further hyponatremia.

2. •

   Identify and correct any precipitating factor (e.g., sepsis, hemorrhage).

Chronic Rx

1. •

   Give hydrocortisone 15 to 20 mg PO every morning and 5 to 10 mg in late afternoon or prednisone 5 mg in morning and 2.5 mg hs.

2. •

   Give oral fludrocortisone 0.05 mg/day to 0.20 mg/day: this mineralocorticoid is necessary if the patient has primary adrenocortical insufficiency. The dose is adjusted based on the serum sodium level and the presence of postural hypotension or marked orthostasis.

3. •

   Instruct patients to increase glucocorticoid replacement in times of stress and to receive parenteral glucocorticoids if diarrhea or vomiting occurs. Typical supplementation varies from 25 mg PO qd of hydrocortisone for minor medical and surgical stress to 50 to 100 mg IV hydrocortisone q8h for sepsis-induced hypotension or shock.

4. •

   The administration of dehydroepiandrosterone (DHEA) is controversial. It is not indicated in men but may be considered in women with primary adrenal failure. A dose of 50 mg PO qd may improve well-being and sexuality in women with adrenal insufficiency.

5. •

   Patients with concomitant hypothyroidism should be treated with glucocorticoids first before correcting hypothyroidism because correction of thyroid hormone deficiency will accelerate cortisol clearance and can precipitate adrenal crisis.

Suggested Readings

• A.J. Chakera, B. Vaidya: Addison disease in adults: diagnosis and management. Am J Med. 123:409–413 2010 20399314

• E. Charmandari, et al.: Adrenal insufficiency. Lancet. 383:2152–2167 2014 24503135

• A. Michels, N. Michels: Addison disease: early detection and treatment principles. Am Fam Physician. 89 (7):563–568 2014 24695602

• B. Werumeus, et al.: Effects of hydrocortisone on the regulation of blood pressure: results from a randomized controlled trial. J Clin Endocrinol Metab. 101:3681 2016

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