Adrenal Insufficiency Case File

Adrenal Insufficiency Case File

Eugene C. Toy, MD, Gabriel M. Aisenberg, MD

Case 49

A 58-year-old woman comes to the office after she experienced a near-fainting spell 1 day ago. She was outside playing tennis when she vomited and felt lightheaded. She spent the rest of the day lying down with mild, diffuse abdominal pain and nausea. She had no fever or diarrhea. She reports several months of worsening fatigue; mild, intermittent, generalized abdominal pain; and loss of appetite with a 10- to 15-lb unintentional weight loss. Her medical history is significant for hypothyroidism, for which she takes levothyroxine. She takes no other medications. On examination, her temperature is 99.8 °F, heart rate is 90 beats per minute (bpm), blood pressure is 89/62 mm Hg, and respiratory rate is 14 breaths per minute. Upon standing, she becomes lightheaded, her pulse increases to 112 bpm, and her systolic blood pressure drops to 70 mm Hg. She is alert and tanned, with hyperpigmented creases in her hands. Her lungs are clear, and her heart rhythm (after standing) is tachycardic but regular. On abdominal examination, she has normal bowel sounds and mild diffuse tenderness without guarding. Her pulses are rapid and thready. She has no peripheral edema. Initial laboratory studies are significant for sodium 121 mEq/L, potassium 5.8 mEq/L, bicarbonate 16 mEq/L, glucose 52 mg/dL, and creatinine 2 mg/dL.

▶ What is the most likely diagnosis?

▶ What is your next step?

ANSWERS TO CASE 49:

Adrenal Insufficiency

Summary: A 58-year-old woman presents with

• Near-fainting episode 1 day ago with vomiting, feeling lightheaded, and abdominal pain
• Orthostatic hypotension
• Intermittent chronic abdominal pain
• Constitutional symptoms such as fatigue and unintentional weight loss
• Hyponatremia, hyperkalemia, acidosis, and hypoglycemia
• Hyperpigmented creases in her hands along with darker skin

Most likely diagnosis: Primary adrenal insufficiency. The most common cause of primary adrenal insufficiency in adults is autoimmune adrenalitis. Her presentation was likely exacerbated by levothyroxine use.

Next step: After drawing a cortisol level, immediate administration of intravenous saline with glucose and an intravenous stress dose of corticosteroids.

ANALYSIS

Objectives

1. Recognize the presentation of primary and secondary adrenal insufficiency and of adrenal crisis. (EPA 1, 10)
2. Recognize the most common causes of primary and secondary adrenal insufficiency. (EPA 2)
3. Describe the treatment of adrenal insufficiency. (EPA 4)

Considerations

This patient has a low-grade fever, which may be a feature of adrenal insufficiency or may signify infection, which can precipitate an adrenal crisis or produce a similar clinical picture. It is important to diagnose and treat any underlying infection. Because of the adrenal insufficiency and the aldosterone deficiency, she has volume depletion, hypoglycemia, and hypotension. Additionally, she has an acute kidney injury secondary to hypovolemia, as evidenced by her elevated creatinine. Furthermore, she began thyroid hormone replacement (for hypothyroidism) prior to her office visit; this likely exacerbated the adrenal crisis. Thus, immediate intravenous replacement with normal saline with 5% glucose is critical. A low serum cortisol level with the patient’s clinical presentation and without other explanation confirms the diagnosis of adrenal insufficiency.

APPROACH TO:

Adrenal Insufficiency

DEFINITIONS

ACTH STIMULATION TEST: An examination to evaluate the cortisol level after an intravenous (IV) injection of adrenocorticotropic hormone (ACTH; corticotropin). A normal individual should have a sufficient increase in cortisol, whereas a patient with adrenal insufficiency will have either an insufficient or no cortisol increase.

ADDISON DISEASE: Failure of the adrenal cortex leading to underproduction of corticosteroids.

CLINICAL APPROACH

Pathophysiology

Primary adrenal insufficiency (Addison disease) refers to adrenal failure or destruction or infiltration of the adrenal glands. The most common cause worldwide is autoimmune destruction of the adrenal glands. Tuberculosis adrenalitis remains a frequent cause in the developing world. Among children, the most common cause is congenital adrenal hyperplasia. Other causes include chronic granulomatous infections (histoplasmosis, coccidiomycosis), bilateral adrenal hemorrhage (usually in the setting of sepsis with disseminated intravascular coagulation), adrenal metastases (commonly from lung, breast, or stomach cancers), or X-linked adrenoleukodystrophy, a genetic disorder with adrenal and neurologic manifestations. Patients with acquired immunodeficiency syndrome (AIDS) often develop adrenal involvement as a result of infection with cytomegalovirus or Mycobacterium avium-intracellulare.

In primary adrenal insufficiency, the glands themselves are destroyed so that the patient becomes deficient in cortisol and aldosterone. Primary adrenal insufficiency is a relatively uncommon disease seen in clinical practice. A high level of suspicion, particularly in individuals who have suggestive signs or symptoms or who are susceptible by virtue of associated autoimmune disorders or malignancies, must be maintained. The nonspecific symptoms might otherwise be missed for many years until a stressful event leads to crisis and death.

Secondary and tertiary adrenal insufficiency are types of central adrenal insufficiency. Secondary adrenal insufficiency is adrenal failure caused by a lack of ACTH stimulation from the pituitary gland. Any disease of the pituitary can cause this, including infectious, malignant, traumatic, or autoimmune etiologies. Tertiary adrenal insufficiency is adrenal failure from lack of corticotropin-releasing hormone (CRH) secretion from the hypothalamus. Chronic exogenous administration of corticosteroids preferentially suppresses the hypothalamic CRH secretion. Because of the widespread use of corticosteroids, tertiary adrenal insufficiency is relatively common. In both secondary and tertiary adrenal insufficiencies, the renin-angiotensin system usually is able to maintain near-normal levels of aldosterone so that the patient is deficient only in cortisol.

Clinical Presentation

The clinical presentation of primary adrenal insufficiency depends on the relative deficiency of glucocorticoids and mineralocorticoids, ACTH excess, and other associated disorders. An adrenal crisis may present with fatigue, reduced strength, weight loss, nausea, vomiting, abdominal pain, and hypotension. Laboratory findings may include hyponatremia, hyperkalemia, metabolic acidosis, and azotemia because of aldosterone deficiency, as well as hypoglycemia and eosinophilia resulting from cortisol deficiency.

Patients with adrenal insufficiency may go into crisis when stressed by infection, trauma, or surgery. The clinical features may appear identical to those of septic shock; the only clues that the cause is adrenal disease may be the hypoglycemia (blood sugar is often elevated in sepsis) and profound hypotension that is refractory to administration of pressors but is reversed almost immediately when intravenous fluids and steroids (preferentially hydrocortisone, which has both glucocorticoid and mineralocorticoid activity) are given.

Chronic adrenal insufficiency has nonspecific clinical features, such as malaise, weight loss, chronic fatigue, and gastrointestinal symptoms such as anorexia, nausea, and vomiting. A patient may have hypoglycemia and postural hypotension as a result of volume depletion. Hyperpigmentation is seen over time in primary adrenal insufficiency; this is caused by elevated melanocyte-stimulating hormone production from the pituitary as a by-product of high ACTH levels. It is typically seen as generalized hyperpigmentation of the skin and mucous membranes. It is increased in sun-exposed areas or over pressure areas, such as elbows and knees, and may be noted in skin folds. In contrast, patients with secondary adrenal insufficiency may be pale due to lack of ACTH and its by-products. Additionally, these patients maintain aldosterone production due to the renin-angiotensin system, despite the lack of cortisol production. Therefore, volume depletion and hyperkalemia are not present.

Diagnosis. Cortisol levels show a diurnal variation. Cortisol levels are high in the morning and low as the day progresses, and levels should be elevated in stressful situations such as acute medical illness, surgery, or trauma. A morning plasma cortisol level less than or equal to 5 μg/dL in an acutely ill patient is definitive evidence of adrenal insufficiency. Conversely, a random cortisol level more than 18 μg/dL usually is interpreted as evidence of intact adrenal function. As in other endocrine deficiency states, the diagnostic test in this case is a stimulation test (conversely, in endocrine excess states, the diagnostic test is often a suppression test). The ACTH stimulation test is used to confirm adrenal insufficiency. Synthetic ACTH (cosyntropin) 250 μg is administered intravenously, and serum cortisol levels are measured at baseline and then at 30- and 60-minute intervals. A maximal stimulated level of more than 18 μg/dL is considered normal and indicates intact adrenal function. If cosyntropin stimulation testing indicates probable adrenal insufficiency, ACTH levels can then be measured to distinguish between primary adrenal insufficiency (high ACTH) and secondary/tertiary adrenal insufficiency (low ACTH).

The insulin-glucose tolerance test is the gold standard for testing the entire hypothalamic-pituitary axis. It is based on the principle that if a stressful situation is induced (in this case, hypoglycemia), the ACTH level should rise with a consequent increase in cortisol levels. Computed tomography and magnetic resonance imaging are helpful in evaluating adrenal and pituitary disease after biochemical confirmation.

Treatment

Treatment of Addisonian crisis includes intravenous 5% glucose with normal saline to correct volume depletion and hypoglycemia and administration of corticosteroid therapy. Hydrocortisone usually is given intravenously at doses of 100 mg every 6 to 8 hours, or it can be given as a bolus followed by a continuous infusion. At high doses, the hydrocortisone provides both glucocorticoid and mineralocorticoid activity. A cortisol level should be drawn before treatment to confirm the diagnosis. Causes of the acute crisis should be identified and treated; in particular, there should be a search for infection.

Long-term treatment of patients with primary adrenal insufficiency includes replacement doses of glucocorticoids (eg, hydrocortisone 15–25 mg/d) and mineralocorticoids (eg, fludrocortisone 0.1–0.2 mg/d). Patients with secondary adrenal insufficiency still produce aldosterone, as mentioned previously, so only glucocorticoids must be replaced. In both cases, to prevent the long-term complications of glucocorticoid excess (diabetes, hypertension, obesity, osteoporosis, cataracts), patients should not be overtreated. Stress doses of steroids should be given for intercurrent illnesses. Patients should wear a medical alert bracelet.

Stress Dose Steroids. When a patient has adrenal insufficiency or adrenal suppression due to chronic supraphysiologic corticosteroid use (equivalent of prednisone 15 mg/d for 3 weeks or longer during the prior 12 months), then stress dose steroids are needed for events such as surgery or acute illness. Hydrocortisone 100 mg IV every 6 to 8 hours is the standard dose.

Thyroid Hormone and Adrenal Insufficiency. Many patients with adrenal insufficiency also have hypothyroidism. As the administration of thyroid hormone treatment increases the overall metabolic rate, the rate of urinary cortisol secretion is increased. This can exacerbate existing adrenal insufficiency. It is ideal to begin steroid therapy first, then add thyroid hormone replacement. The situation may be challenging, as adrenal insufficiency is a much less common disease than hypothyroidism, and its development can occur over a period of several years.

CASE CORRELATION

• See also Case 47 (Hyponatremia, Syndrome of Inappropriate Secretion of Antidiuretic Hormone), Case 48 (Oligomenorrhea Caused by Hypothyroidism and Hyperprolactinemia), Case 52 (Diabetic Ketoacidosis, Type 1 Diabetes), and Case 53 (Thyrotoxicosis/Graves Disease).

COMPREHENSION QUESTIONS

49.1 A 40-year-old man with rheumatoid arthritis presents to the postop unit after an irrigation and debridement of a methicillin-resistant Staphylococcus aureus (MRSA)–positive septic joint. His blood pressure is 84/60 mm Hg, rectal temperature is 101.5 °F, and his heart rate is 95 bpm. Total blood loss from the surgery was 500 mL. The anesthesia staff give him a bolus 2 L of normal saline with dopamine and norepinephrine for pressors. His blood pressure elevates to 89/61 mm Hg. You are called to the postop unit to assess the situation. Which of the following is the best decision?

A. Start broad vancomycin to combat MRSA infection from septic joint.

B. Administer 1 unit of packed red blood cells due to blood loss.

C. Bolus hydrocortisone due to possible steroid dependence.

D. Order a cosyntropin stimulation test to assess for adrenal insufficiency.

49.2 A 30-year-old woman takes oral prednisone 15 mg/d for systemic lupus erythematosus, which is largely in remission. She is admitted to the hospital for a cholecystectomy. Which of the following is the most important intervention for her?

A. Hydrocortisone intravenously before surgery and every 6 hours for 24 hours

B. Double the prednisone the night before and hold her steroids the day of the surgery

C. Use of cyclophosphamide in lieu of corticosteroids for 2 weeks following surgery to promote wound healing

D. Cancel the surgery and use lithotripsy to break up the stones

49.3 A 30-year-old woman who is 12 weeks’ postpartum is noted to have adrenal insufficiency and a very distinct tan, although she hardly ventures outside. Which of the following is the most likely etiology?

A. Long-term steroid use

B. Sheehan syndrome (pituitary insufficiency)

C. Brain tumor

D. Autoimmune adrenal destruction

ANSWERS

49.1 C. This patient is experiencing adrenal insufficiency in the setting of chronic steroid dependence. His history of rheumatoid arthritis points to this dependence, and his steroids may have been prematurely discontinued. Septic shock (answer A) should react to the bolus and pressor therapy. Half a liter of blood loss (answer B) is not sufficient to cause this profound hypotension. Additionally, the emergent situation makes the cosyntropin test (answer D) inadequate.

49.2 A. A stress dose of corticosteroids (hydrocortisone) is important to prevent adrenal insufficiency before surgery, which is a physiologically stressful event. Doubling the prednisone the night before and holding the steroids on the day of surgery (answer B) would not supply the sufficient stress dose of steroids needed. Using cyclophosphamide instead of steroids (answer C) would likely lead to a flare-up of the lupus; also, corticosteroids need to be discontinued at least 1 to 2 months prior to surgery so that wound healing is not affected. Lithotripsy (answer D) would also likely require stress dose steroids and can lead to sepsis; this modality has limited utility, and patients need to be carefully selected (eg, patients with small stones).

49.3 D. Hyperpigmentation occurs as a result of increased melanocyte-stimulating factor, a byproduct of ACTH, and occurs in primary adrenal insufficiency. Secondary causes of adrenal insufficiency such as Sheehan syndrome (answer B) result in low ACTH levels and do not cause the “tanned” appearance. A brain tumor (answer C), such as an ACTH-producing pituitary adenoma, would cause overactivation of the adrenal glands, resulting in a Cushingoid appearance and hyperpigmentation due to the excess ACTH. There is no history of long-term steroid use (answer A) or the discussion of a disease process for which long-term steroid use would be indicated.

CLINICAL PEARLS

▶ Primary adrenal insufficiency presents with weakness, fatigue, abdominal pain with vomiting, hyperpigmentation, and hyponatremia with hypotension refractory to pressors.

▶ Treatment of adrenal crisis is immediate administration of salt (saline), sugar (glucose if patient is hypoglycemic), and steroids (hydrocortisone).

▶ The most common cause of primary adrenal insufficiency worldwide is autoimmune destruction. Tuberculosis remains a common cause in the developing world.

▶ Tertiary adrenal insufficiency is a common presentation of adrenal insufficiency due to suppression of the hypothalamic-pituitary axis by exogenous corticosteroids.

REFERENCES

Arlt W. Disorders of the adrenal cortex. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw Hill; 2018:2323-2327. 

Betterle C, Dal Pra C, Mantero F, Zanchetta R. Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction. Endocr Rev. 2002;23(3):327-364. 

Carroll TB, Aron DC, Findling JW, et al. Glucocorticoids and adrenal androgens. In: Gardner DG, Shoback D, eds. Basic and Clinical Endocrinology. 9th ed. New York, NY: McGraw Hill Education; 2011:334-377. 

Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet. 2014;383(9935): 2152-2167. 

Fonseca V, Brown R, Hochhauser D, Ginsburg J, Havard CW. Acute adrenal crisis precipitated by thyroxine. Br Med J (Clin Res Ed). 1986;292(6529):1185-1186.

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