Addison’s disease

Addison’s disease

John Davenport

Addison’s disease (primary adrenocortical insufficiency) is an uncommon endocrine disorder characterized by cortisol and/or aldosterone deficiency, resulting in a variety of nonspecific symptoms and signs (Table 1).(1-3) Once Addison’s disease is considered, the laboratory diagnosis is usually straightforward. However, to formulate a proper treatment plan, the etiology of adrenal insufficiency must be determined.

Illustrative Case

A 37-year-old man presented to the emergency department with a five-week history of nausea, vomiting and weakness. He reported a 25-lb weight loss. He had been evaluated on several occasions for symptoms of fatigue, nausea and anorexia. Because of the gastrointestinal nature of his symptoms, he was treated with cimetidine and antacids, without improvement.

At physical examination, the patient appeared chronically ill. Blood pressure was 100/47 mm Hg while the patient was supine; the blood pressure dropped to 65/20 mm Hg when the patient was in the upright position. His temperature was 39 [degrees] C (102 [degrees] F). Physical examination was otherwise normal.

Laboratory studies revealed the following: serum potassium, 22.7 mg per dL (5.8 mmol per L); serum sodium, 127 mEq per L (127 mmol per L); white blood cell count, 12,400 per MM[.sup.3] (12.4 x 10[.sup.9] per L), and serum alkaline phosphatase, 272 U per L (272 U per L). The tuberculin skin test was positive (10 mm of induration 48 hours after administration of 5 TU purified protein derivative). Chest radiograph was normal. The patient was admitted to the hospital for hydration, broad-spectrum antibiotic therapy and further evaluation.

Computed tomographic (CT) scan of the abdomen revealed a 6 x 4 cm mass in the right adrenal gland and enlargement of the left adrenal gland (Figure 1). Because of the symptoms, electrolyte abnormalities and abnormal CT scan, a baseline morning cortisol level was obtained. It was 2.5 [mu]g per dL (69 nmol per L); the normal value is 5 to 23 [mu]g per dL (138 to 635 nmol per L).

A rapid screening test for adrenal function was performed. Serum cortisol levels at 30, 60 and 90 minutes after injection of cosyntropin (Cortrosyn) were 2.6 [mu]g per dL (72 nmol per L), 2.7 [mu]g per dL (74 nmol per L) and 2.0 [mu]g per dL (55 nmol per L), respectively. At 90 minutes, the serum aldosterone level was less than 1 ng per dL (28 pmol per L); the normal incremental increase is greater than 4 ng per dL (111 pmol). Thus, the patient’s response was significantly blunted. The plasma adrenocorticotropic hormone (ACTH) level was 249 pg per mL (54.8 pmol per L); normal values range from 9 to 52 pg per mL (2.0 to 11.5 pmol per L).

Steroid replacement therapy with hydrocortisone and fludrocortisone acetate was begun, and almost immediate improvement in the patient’s condition was noted. His temperature decreased, his weight increased and he experienced an improved sense of well-being. After 21 days, the patient was discharged from the hospital.

He continued to complain of flank pain, however. A repeat abdominal CT scan showed persistent enlargement of the right adrenal gland and interval enlargement of the left adrenal gland. Surgical exploration and biopsy of the right adrenal gland revealed multiple caseating granulomas, with total destruction of the adrenal cortex. Stains for acid-fast organisms and cultures were positive for tuberculosis. Therapy with isoniazid, rifampin and ethambutol was begun, and the patient continued to receive maintenance steroid therapy.

Etiology

Addison’s disease occurs at a rate of 39 persons per 1 million population.(4)

Although autoimmune destruction of the adrenal gland has replaced tuberculosis as the principal cause of Addison’s disease,(2) tuberculosis still accounts for about 18 percent of cases. Because the incidence of extrapulmonary tuberculosis is increasing, this disease should be considered as a possible etiology in patients with Addison’s disease, especially those at high risk for tuberculosis.(4-7) Causes of Addison’s disease are listed in Table 2.

Symptoms and Signs

When adrenal destruction is insidious, maximal pituitary ACTH stimulation may result in normal glucocorticoid and mineralocorticoid production for a long period. However, the adrenal reserve is eventually exhausted. Symptoms usually do not occur until 80 to 90 percent of the gland is destroyed, and even then they are usually nonspecific. The patient often complains of fatigue, weakness, irritability, anorexia and depression. The classic hyperpigmentation of Addison’s disease is diffuse but is often accentuated on exposed portions of the skin, over pressure points (e.g., knuckles, knees, elbows) and in the mucous membranes. Hyperpigmentation may sometimes precede the onset of other symptoms.

In the early stages, mild hyperkalemia is common and may be accompanied by mild hyponatremia and hypoglycemia.(8,9) As adernal insufficiency worsens, postural hypotension often occurs. Gastrointestinal symptoms include nausea, vomiting, diarrhea and weight loss.(10) The patient with Addison’s disease usually craves salt.

When adrenal destruction is rapid or when a patient who is maintaining adrenal function through maximal ACTH stimulation is exposed to physical or psychologic stress, catastrophic symptoms may occur. These include fever, severe vomiting, diarrhea and abdominal pain. The patient is weak and restless, with shock-like symptoms of profound hypotension and volume depletion. Left untreated, Addison’s disease may become life-threatening.

Diagnosis

Specific diagnostic tests should be performed when symptoms or signs suggest the possibility of Addison’s disease. A single normal serum cortisol level does not rule out Addison’s disease, although a high value would make the diagnosis very unlikely.

The rapid ACTH stimulation test is the best screening test for adrenal insufficiency. It measures the ability of the adrenal gland to produce cortisol after ACTH administration.(3) ATCH, 250 [mu]g, is administered intravenously. Serum cortisol levels are determined at baseline and at 30, 60 and 90 minutes following the injection. The definition of a normal response is a matter of some disagreement, but the strictest rule requires doubling of the peak cortisol level over basal value and an increase of at least 10 [mu]g per dL (276 nmol per L) over basal level.(11) If this criterion is not met, adrenocortical insufficiency is considered likely.(12)

If the rapid test of adrenal function is abnormal, the more specific, prolonged ACTH stimulation test is recommended. To perform this test, urinary 17-hydroxycorticosteroid excretion is measured for the first 24 hours. Urine collection is continued for three additional days, during which 500 [mu]g of ACTH in 500 mL of normal saline is administered each day. Normal persons show at least a doubling of urine steroid levels during the first day of ACTH stimulation. Patients with Addison’s disease, however, show a characteristic flat response to the test (i.e., no rise in urinary 17-hydroxycorticosteroid excretion). On the other hand, patients with pituitary disorders as a cause of ACTH deficiency have a stepwise increase of urinary 17-hydroxycorticosteroid excretion and, by day 3, have about a threefold increase over basal values.

Treatment of a severely ill patient who is experiencing adrenal crisis should not be delayed until diagnostic tests can be performed. The patient’s condition should be stabilized with dexamethasone (Decadron), 0.5 mg twice daily. This agent will not interfere with testing for endogenous steroids.(13)

ACTH and aldosterone levels are also helpful in distinguishing primary from secondary adrenal insufficiency. Plasma ACTH levels that exceed 250 pg per mL (55 pmol per L) or serum aldosterone levels that do not increase by at least 4 ng per dL (111 pmol per L) over basal levels indicate primary adrenal insufficiency.(14) Primary adrenal insufficiency is almost certainly present when a high ACTH level is associated with a low cortisol response to ACTH challenge.

Recent studies have extolled the value of CT scanning for identifying the cause of Addison’s disease.(15,16) Typically, autoimmune adrenal insufficiency is associated with atrophy of the adrenal glands, whereas disorders such as tuberculosis, fungal infections, amyloidosis, bilateral hemorrhage, primary tumor and metastatic disease are associated with adrenal enlargement.(17-19) Longstanding tuberculosis, however, may also cause adrenal atrophy and calcification.(20) Adrenal tuberculosis or other causes may be identified by percutaneous needle biopsy of an enlarged adrenal gland.(21-23)

Treatment

Treatment of acute adrenal insufficiency must not be delayed. High doses of intravenous steroids usually produce improvement within hours. The patient with an acute adrenal crisis is typically volume-depleted and has associated hyponatremia. Saline infusion should be aggressively administered, with careful monitoring for signs of fluid overload. Intravenous doses may be replaced by oral maintenance doses in three to five days(24) (Table 3).(25)

Maintenance therapy consists of hydrocortisone, 15 to 20 mg in the morning and 10 to 15 mg between 4 p.m. and 6 p.m. This schedule simulates the natural diurnal rhythm of the adrenal gland. Fludrocortisone (Florinef Acetate), 0.05 to 0.1 mg, is given concurrently to treat mineralocorticoid deficiency. The fludrocortisone dose may be increased in 0.05-mg increments if the patient continues to manifest postural hypotension, hyperkalemia or increased renin level. The dose may be decreased if the patient shows signs of edema, hypokalemia, congestive heart failure or hypertension.(26) Titration of steroid doses is also based on the overall clinical response and the severity of symptoms.

The hydrocortisone dose should be increased during periods of stress. When the patient experiences a minor illness, the dose may be doubled or tripled for a short period. If vomiting occurs within one hour after an oral dose, the dose should be repeated. If vomiting persists, hydrocortisone should be administered intravenously. The dose of fludrocortisone does not generally need to be increased during minor stress, but should be increased to doses similar to those given in adrenal crisis when the stress is severe, such as with major illness or surgery.

Patients with Addison’s disease who are likely to encounter situations in which medical care is unavailable should carry a 100-mg vial of hydrocortisone succinate with a syringe for self-administration. Patients should also wear medical alert jewelry indicating their diagnosis.

REFERENCES

1. Irvine WJ, Barnes EW. Addison’s disease, ovarian failure and hypoparathyroidism. Clin Endocrinol Metab 1975;4:379-434.

2. Nerup J. Addison’s disease–clinical studies. A report of 108 cases. Acta Endocrinol 1974;76:127-41.

3. Kannan CR. Diseases of the adrenal cortex. Dis Mon 1988;34:601-74.

4. Mason AS, Meade TW, Lee JA, Morris JN. Epidemiological and clinical picture of Addison’s disease. Lancet 1968;2(6571):744-7.

5. Shapiro M, Zalewski S, Steiner Z, et al. Adrenal insufficiency in a general hospital over a 14-year period. Isr J Med Sci 1984;20:381-7.

6. Ward S, Evans CC. Sudden death due to isolated adrenal tuberculosis. Postgrad Med J 1985;61:635-6.

7. Rieder HL, Cauthen GM, Kelly GD, Bloch AB, Snider DE Jr. Tuberculosis in the United States. JAMA 1989;262:385-9.

8. Samaan NA. Hypoglycemia secondary to endocrine deficiencies. Endocrinol Metab Clin North Am 1989;18:145-54.

9. Burke CW. Adrenocortical insufficiency. Clin Endocrinol Metab 1985;14:947-76.

10. Tobin MV, Aldridge SA, Morris Al, Belchetz PE, Gilmore IT. Gastrointestinal manifestations of Addison’s disease. Am J Gastroenterol 1989;84:1302-5.

11. Speckart PF, Nicoloff JT, Bethune JE. Screening for adrenocortical insufficiency with cosyntropin (synthetic ACTH). Arch Intern Med 1971;128:761-3.

12. Baxter JD, Tyrrell JB. The adrenal cortex. In: Felig P, et al., eds. Endocrinology and metabolism. New York: McGraw-Hill, 1981:511-650.

13. Federman DD. The adrenal. In: Rubenstein E, Federman DD, eds. Scientific American medicine. Vol 1. New York: Scientific American, 1988:1-14.

14. Dluhy RG, Himathongkam T, Greenfield M. Rapid ACTH test with plasma aldosterone levels. Improved diagnostic discrimination. Ann Intern Med 1974;80:693-6.

15. Vita JA, Silverberg SJ, Goland RS, Austin JH, Knowlton Al. Clinical clues to the cause of Addison’s disease. Am J Med 1985;78:461-6.

16. McMurry JF Jr, Long D, McClure R, Kotchen TA. Addison’s disease with adrenal enlargement on computed tomographic scanning. Report on two cases of tuberculosis and review of the literature. Am J Med 1984;77:365-8.

17. Wilms GE, Baert AL, Kint EJ, Pringot JH, Goddeeris PG. Computed tomographic findings in bilateral adrenal tuberculosis. Radiology 1983;146:729-30.

18. Morgan HE, Austin JH, Follet DA. Bilateral adrenal enlargement in Addison’s disease caused by tuberculosis. Nephrotomographic demonstration. Radiology 1975;115:357-8.

19. Hauser H, Gurret JP. Miliary tuberculosis associated with adrenal enlargement: CT appearance. J Comput Assist Tomogr 1986;10:254-6.

20. Doppman JL, Gill JR Jr, Nienhuis AW, Earll JM, Long JA Jr. CT findings in Addison’s disease. J Comput Assist Tomogr 1982;6:757-61.

21. Sawczuk IS, Reitelman C, Libby C, Grant D, Vita J, White RD. CT findings in Addison’s disease caused by tuberculosis. Urol Radiol 1986;8:44-5.

22. Zornoza J, Ordonez N, Bernardino ME, Cohen MA. Percutaneous biopsy of adrenal tumors. Urology 1981;18:412-6.

23. Yee AC, Gopinath N, Ho CS, Tao LC. Fine-needle aspiration biopsy of adrenal tuberculosis. Can Assoc Radiol J 1986;37:287-9.

24. Stewart PM, Edwards CR. The medical treatment of adrenal disease. Br J Hosp Med 1989;42:20-9.

25. Tyrrell JB, Baxter JD. Disorders of the adrenal cortex. In: Wyngaarden JB, Smith LH Jr, eds. Cecil Textbook of medicine. 18th ed. Philadelphia: Saunders, 1988:1340-58.

26. Claman HN. Glucocorticosteroids. II.The clinical responses. Hosp Pract [Off]983;18:143-6,149-51.

The Authors

JOHN DAVENPORT, M.D., J.D. is a family physician in the Southern California Permanente Medical Group, Anaheim. Dr. Davenport is a graduate of the Medical University of South Carolina College of Medicine, Charleston.

CHARLES KELLERMAN, M.D. is a general internist in the Southern California Permanente Medical Group. Dr. Kellerman graduated from the University of Washington School of Medicine, Seattle.

DAVID REISS, M.D. is an endocrinologist in the Southern California Permanente Medical Group. Dr. Reiss graduated from the Universidad Autonoma de Guadalajara, Mexico.

LAWRENCE HARRISON, M.D. is a radiologist in the Southern California Permanente Medical Group. Dr. Harrison graduated from the Universidad Autonoma de Guadalajara.

TABLE 1

Symptoms and Signs of Addison’s Disease

Symptoms and signs Frequency (%)

Malaise and weight loss >90

Dermatologic-pigmentary >80

changes

Anorexia, nausea >50

and abdominal cramps

Hypotension and orthostasis >80

Weakness and fatigue >90

Hyponatremia >85

Hyperkalemia >60

Data from Irvine WJ and Barnes EW,(1) Nerup J(2) and

Kannan CR.[.sup.3]

TABLE 2

Causes of Addison’s Disease

~

Autoimmune destruction ~ Invasive disorders

Tuberculosis ~ Cancer

Fungal infection ~ Amyloidosis

Hemorrhage ~ Sarcoidosis

Sepsis ~ Hemochromatosis

Anticoagulation ~ Infarction

Surgery ~ Thrombosis

Pregnancy ~ Arteritis

Coagulopathy ~ Cytotoxic agents

Trauma ~ Congenital hypoplasia

TABLE 3

Steroid Regimens for Addison’s Disease

Adrenal crisis

Hydrocortisone, 100 mg intravenously every six hours for four doses, then hydrocortisone, 50 mg intravenously every six hours for four doses; taper to oral maintenance level over a period of four to five days

Chronic adrenal insufficiency

Hydrocortisone, 15 to 20 mg every morning and hydrocortisone, 10 to 15 mg between 4 p.m. and 6 p.m., with fludrocortisone, 0.05 to 0.1 mg daily (increase dose if postural hypotension, hyperkalemia or increased renin level is noted; decrease dose for edema or hypokalemia)

Derived from Tyrrell IB and Baxter JD. (25) Figuration Omitted.

COPYRIGHT 1991 American Academy of Family Physicians

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