Adrenal Insufficiency  

Adrenal Insufficiency – Introduction

• 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

• Primary adrenocortical insufficiency
• Addison disease

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

EPIDEMIOLOGY & DEMOGRAPHICS

Prevalence

10 to 15 per 100,000 persons

Predominant Gender

Female:male ratio of 2:1

PHYSICAL FINDINGS & CLINICAL PRESENTATION

• •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
• TABLE 1 Clinical Features of Primary Adrenal InsufficiencyFrom Melmed SZ et al: Williams textbook of endocrinology, ed 14, Philadelphia, 2019, Saunders.FeatureFrequency (%)SymptomsWeakness, tiredness, fatigue100Anorexia100Gastrointestinal symptoms92Nausea86Vomiting75Constipation33Abdominal pain31Diarrhea16Salt craving16Postural dizziness12Muscle or joint pains13SignsWeight loss100Hyperpigmentation94Hypotension (<110 mm Hg systolic)88-94Vitiligo10-20Auricular calcification5Laboratory FindingsElectrolyte disturbances92Hyponatremia88Hyperkalemia64Hypercalcemia6Azotemia55Anemia40Eosinophilia17
• •Hyperpigmentation of skin 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
• •Hypotension, postural dizziness
• •Generalized weakness, chronic fatigue, malaise, anorexia
• •Amenorrhea and loss of axillary hair in females

ETIOLOGY

• •Autoimmune destruction of the adrenal glands (80% of cases)
• •Tuberculosis (TB) (7% to 20% of cases)
• •Carcinomatous destruction of the adrenal glands, lymphoma
• •Adrenal hemorrhage (anticoagulants, trauma, coagulopathies, pregnancy, sepsis)
• •Adrenal infarction (antiphospholipid syndrome, arteritis, thrombosis)
• •AIDS (adrenal insufficiency develops in 30% of patients with AIDS, often cytomegalovirus [CMV] adrenalitis)
• •Genetic causes: Autoimmune polyglandular syndromes (APS) types 1 and 2, X-linked adrenoleukodystrophy, congenital adrenal hyperplasia
• •Other: Sarcoidosis, amyloidosis, hemochromatosis, Wegener 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

• •An early morning (8 a.m. ) serum cortisol <3 mcg/dl (82.8 mmol/L) is consistent with cortisol deficiency.FIG. 3Algorithm for the diagnosis of adrenal insufficiency. The adequacy of cortisol production is initially assessed with morning cortisol level measurement. Patients with low or borderline values undergo provocative adrenocorticotropic hormone (ACTH) stimulation testing, with serum cortisol levels measured before and 30 to 60 min after the administration of ACTH. Failure to mount an adequate response to ACTH usually establishes the diagnosis of adrenal insufficiency. The cause of adrenal insufficiency is then investigated with a morning ACTH level measurement.From Townsend CM et al: Sabiston textbook of surgery, ed 21, St Louis, 2022, Elsevier.
• •If the cortisol level is 3 to 15 mcg/dl, the diagnosis can be confirmed with the rapid adrenocorticotropic hormone (ACTH) test:
  • 1.Give 250 mcg ACTH (Synacthen, tetracosactrin) by IV push and measure cortisol levels at 0, 30, and 60 min.
  • 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.Measure plasma ACTH. A high ACTH level (>200 pg/ml [44 pmol/L]) confirms primary adrenal insufficiency.
• 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.
• •Secondary adrenocortical insufficiency (caused by pituitary dysfunction) can be distinguished from primary adrenal insufficiency by the following:
  • 1.Normal or low plasma ACTH level after rapid ACTH.
  • 2.Absence of hyperpigmentation.
  • 3.No significant impairment of aldosterone secretion (because aldosterone secretion is under control of the renin-angiotensin system).
  • 4.Additional evidence of hypopituitarism (e.g., hypogonadism, hypothyroidism).

LABORATORY TESTS

• •Hyponatremia, hyperkalemia
• •Decreased glucose
• •Increased blood urea nitrogen/creatinine ratio (prerenal azotemia)
• Mild normocytic, normochromic anemia, neutropenia, lymphocytosis, eosinophilia (significant dehydration may mask hyponatremia and anemia), hypercalcemia, metabolic acidosis
• •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”)
• •Additional evaluation may include 21-hydroxylase antibodies present in 90% of autoimmune adrenalitis cases. If negative, obtain computed tomographic (CT) scan of adrenal glands
• •PPD or QuantiFERON Gold test to rule out TB

IMAGING STUDIES

• •Imaging is not necessary for diagnosis but may help identify potential causes.
• •Abdominal CT scan: Small adrenal glands generally indicate either idiopathic atrophy or longstanding TB, whereas enlarged glands are suggestive of early TB or potentially treatable diseases. FLOAT NOT FOUND
• •Chest x-ray may reveal a small heart. FLOAT NOT FOUND
• •Abdominal x-ray: Adrenal calcifications may be noted if the adrenocortical insufficiency is secondary to TB or fungal infection.

Treatment

NONPHARMACOLOGIC THERAPY

• •Perform periodic monitoring of serum electrolytes, vital signs, and body weight; liberal sodium intake is suggested.
• •Periodic measurement of bone density may be helpful in identifying patients at risk for the development of osteoporosis.
• •Patients should carry a MedicAlert bracelet and an emergency pack containing hydrocortisone 100-mg ampule, syringe, and needle.
• •Patients and partners should be educated on how to give IM injection in case of vomiting or coma.

Acute General Treatment

• •Adrenal crisis is an acute complication of adrenal insufficiency characterized by circulatory collapse, dehydration, nausea, vomiting, hypoglycemia, and hyperkalemia. Table 2 summarizes the treatment of acute adrenal insufficiency (adrenal crisis) in adults.
  • 1.Draw plasma cortisol level; do not delay therapy while waiting for confirming laboratory results.2.Administer hydrocortisone 100 mg IV immediately and every 6 h; if patient shows good clinical response, gradually taper dosage over 1 to 3 days and change to oral maintenance dose (usually prednisone 7.5 mg/day).3.Provide adequate volume replacement with D ₅ NS 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 h to correct the volume deficit and hypoglycemia and to avoid further hyponatremia
  TABLE 2Treatment of Acute Adrenal Insufficiency (Adrenal Crisis) in AdultsFrom Melmed S et al: Williams textbook of endocrinology, ed 14, 2019, Elsevier.Emergency Measures
  • 1.Establish intravenous access with a large-gauge needle.2.Draw blood for immediate serum electrolytes and glucose and routine measurement of plasma cortisol and ACTH. Do not wait for laboratory results.3.Infuse 2-3 L of 154 mmol/L NaCl (0.9% saline) solution, or 50 g/L (5%) dextrose in 154 mmol/L NaCl (0.9% saline) solution, as quickly as possible. Monitor for signs of fluid overload by measuring central or peripheral venous pressure and listening for pulmonary rales. Reduce infusion rate if indicated.4.Inject intravenous hydrocortisone (100 mg immediately and every 6 h).5.Use supportive measures as needed.
  Subacute Measures after Stabilization of the Patient
  • 1.Continue intravenous 154 mmol/L NaCl (0.9% saline) solution at a slower rate for next 24-48 h.2.Search for and treat possible infectious precipitating causes of the adrenal crisis.3.Perform a short ACTH stimulation test to confirm the diagnosis of adrenal insufficiency (if patient does not have known adrenal insufficiency).4.Determine the type of adrenal insufficiency and its cause, if not already known.5.Taper glucocorticoids to maintenance dosage over 1-3 days, if precipitating or complicating illness permits.6.Begin mineralocorticoid replacement with fludrocortisone (0.1 mg by mouth daily) when saline infusion is stopped.
  ACTH, Adrenocorticotropic hormone.
• •Identify and correct any precipitating factor (e.g., sepsis, hemorrhage).

CHRONIC Rx

• •Table 3 summarizes the treatment of chronic primary adrenal insufficiency in adults.View full sizeTABLE 3Treatment of Chronic Primary Adrenal Insufficiency in AdultsFrom Melmed S et al: Williams textbook of endocrinology, ed 14, 2019, Elsevier.Maintenance TherapyGlucocorticoid Replacement
  • •Hydrocortisone 15-20 mg on awakening and 5-10 mg in early afternoon.•Monitor clinical symptoms and morning plasma ACTH.
  Mineralocorticoid Replacement
  • •Fludrocortisone 0.1 (0.05-0.4) mg orally.•Liberal salt intake.•Monitor lying and standing blood pressure and pulse, edema, serum potassium, and plasma renin activity.•Educate patient about the disease, how to manage minor illnesses and major stresses, and how to inject steroid intramuscularly.•Obtain MedicAlert bracelet/necklace, Emergency Medical Information card.
  Treatment of Minor Febrile Illness or Stress
  • •Increase glucocorticoid dose twofold to threefold for the few days of illness; do not change mineralocorticoid dose.•Contact physician if illness worsens or persists for more than 3 days or if vomiting develops.•No extra supplementation is needed for most uncomplicated, outpatient dental procedures with local anesthesia. General anesthesia or intravenous sedation should not be used in the office.
  Emergency Treatment of Severe Stress or Trauma
  • •Inject contents of prefilled dexamethasone (4-mg) syringe or contents of hydrocortisone hemisuccinate rapid reconstitution vial (100-mg) intramuscularly.•Get to physician as quickly as possible.
  Steroid Coverage for Illness or Surgery in Hospital
  • •For moderate illness, give hydrocortisone 50 mg bid PO or IV. Taper rapidly to maintenance dose as patient recovers.•For severe illness, give hydrocortisone 100 mg IV q8h. Taper to maintenance level by decreasing by half every day. Adjust dose according to course of illness.•For minor procedures under local anesthesia and most radiologic studies, no extra supplementation is needed.•For moderately stressful procedures such as barium enema, endoscopy, or arteriography, give a single 100-mg IV dose of hydrocortisone just before the procedure.•For major surgery, give hydrocortisone 100 mg IV just before induction of anesthesia and continue q8h for first 24 h. Taper dose rapidly, decreasing by half per day, to maintenance level.
  ACTH, Adrenocorticotropic hormone; bid, twice a day; IV, intravenous; PO, orally; q, every.
• •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.
• •Give oral fludrocortisone 0.05 mg/day to 0.4 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.
• •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.
• •The administration of dehydroepiandrosterone (DHEA) is controversial due to lack of robust data. 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.
• •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.
• •A plan for steroid replacement in patients withdrawing from chronic corticosteroid therapy is outlined in Table 4 .
• TABLE 4Suggested Plan for Steroid Replacement in Patients Withdrawing From Chronic Corticosteroid TherapyFrom Melmed S et al: Williams textbook of endocrinology, ed 14, 2019, Elsevier.Pred Dose (mg/day)Duration of Glucocorticoid Treatment≤3 wk ^a>3 wk≥7.5Can stop↓︎ rapidly (e.g., 2.5 mg q3-4d)THEN5-7.5Can stop↓︎ 1 mg q2-4wkORConvert 5 mg pred to 20 mg HC, then ↓︎ 2.5 mg/wk to 10 mg/dayTHENTHEN<5Can stop↓︎ 1 mg q2-4wkAfter 2-3 mo HC 10 mg/day, administer SST/ITT:
  Pass → Withdraw
  Fail → ContinueHC, Hydrocortisone; ITT, insulin tolerance test; pred, prednisolone; SST, short Synacthen test. Basal 0900h ACTH can be used to monitor for recovery of HPA axis and levels may be above the normal range ahead of a “pass” on an SST.

References

• Chakera A.J., Vaidya B.: Addison disease in adults: diagnosis and management . Am J Med 2010; 123: pp. 409-413.
• Charmandari E., et al.: Adrenal insufficiency . Lancet 2014; 383: pp. 2152-2167.
• Michels A., Michels N.: Addison disease: early detection and treatment principles . Am Fam Physician 2014; 89 (7): pp. 563-568.
• Rushworth R.L., et al.: Adrenal crisis . N Engl J Med 2019; 381: pp. 852-861.
• Werumeus B., et al.: Effects of hydrocortisone on the regulation of blood pressure: results from a randomized controlled trial . J Clin Endocrinol Metab 2016; 101: pp. 3681.