Itsuro Kazama md, Division of Molecular Medicine, Center for Translational and Advanced Animal Research, Tohoku University School of Medicine, 2-1 Seiryo-Machi, Aoba-ku, Sendai 980-8575, Japan. Email: firstname.lastname@example.org
Abstract A 51-year-old woman with Cushing's syndrome underwent unilateral adrenalectomy for left adrenal adenoma. After 7 years of prednisolone treatment (with some interruptions), followed by 4 years of total withdrawal from prednisolone treatment, she presented with hypotension, weight loss, general fatigue, nausea, hyponatremia and hypoglycemia. These clinical features together with a low response in the rapid adrenocorticotropic hormone test led to the diagnosis of acute adrenal insufficiency. Relatively low serum adrenocorticotropic hormone levels in the face of increased demand for cortisol during adrenal crisis suggested a disordered hypothalamic-pituitary function, indicating secondary adrenal insufficiency. This patient demonstrated the etiology of acute adrenal insufficiency long after unilateral adrenalectomy in association with subsequent glucocorticoid therapy. A reduction in the reserved secretory capacity of cortisol after prolonged prednisolone treatment was considered to have induced secondary adrenal insufficiency, even after 4 years of total withdrawal from prednisolone.
Unilateral adrenalectomy is the mainstay of treatment for Cushing's syndrome with adrenal adenoma. Because the contralateral adrenal gland is suppressed by prolonged cortisol over-secretion, patients have primary adrenal insufficiency postoperatively, and require glucocorticoid replacement until the remaining adrenal gland recovers.1 However, excessive administration of exogenous glucocorticoids can cause secondary adrenal insufficiency, in which the hypothalamic-pituitary axis is suppressed.2
We experienced an adult patient with secondary adrenal insufficiency long after unilateral adrenalectomy for adrenal adenoma. Prolonged postoperative prednisolone administration was considered to have induced functional damage to the hypothalamic-pituitary axis, reducing the reserved secretory capacity of cortisol.
A 51-year-old woman came to St. Luke's International Hospital with a 5-year history of facial edema and abdominal fullness on 17 October 1992. On physical examination, the patient appeared Cushingoid, with a moon face and truncal obesity. Basal plasma cortisol was 22.3 µg/dL (normal, 5.6–21.3 µg/dL), whereas basal plasma adrenocorticotropic hormone (ACTH) was below the level of detection. The circadian rhythm of the plasma cortisol was completely lost (Table 1). Urinary excretion of 17-hydroxycorticosteroids (17-OHCS) was above normal. The dexamethasone suppression test (both low-dose and high-dose testing) demonstrated no suppression of the urinary excretion of 17-OHCS (Table 1), leading to a diagnosis of Cushing's syndrome. Magnetic resonance imaging (MRI) of the adrenal glands revealed a left adrenal mass with diameter of 3 cm, for which left unilateral adrenalectomy was performed on 20 January 1993. The pathological diagnosis was adrenocortical adenoma.
Table 1. Endocrinological examinations before left adrenalectomy
Oral administration of prednisolone (20 mg/day) was initiated postoperatively as a glucocorticoid replacement therapy, and was gradually tapered off over 15 months in the outpatient clinic. Three months after withdrawal, prednisolone treatment (10 mg/day) was started again for systemic pain, with gradual tapering off over 2 years. Six months later, prednisolone (60 mg/day) was started for a third time for left abducens palsy, then rapidly tapered off over 1 month. Treatment with 5 mg/day, then 2.5 mg/day was continued for 2 years thereafter. Plasma ACTH levels had returned to within normal range 3 years after the operation, followed by gradual recovery of the plasma cortisol levels (Fig. 1).
Four years after total withdrawal from the third incidence of prednisolone administration, the patient presented with general fatigue, anorexia and weight loss after upper respiratory infection. On physical examination, the patient looked exhausted and pale. Her blood pressure was 88/64 mmHg, pulse 66/min and body temperature 37.2°C. She weighed 49.5 kg, and was 160 cm tall. There were no palpable peripheral lymph nodes or tumors, and no pitting edema of either leg. Laboratory data showed severe hyponatremia and hypoglycemia (Table 2). Immediately after her admission to St. Luke's International Hospital on 12 April 2003, fluid replacement with 0.9% saline was started as a initial treatment. Although her blood pressure responded to the treatment, the hyponatremia didn’t improve, and her sodium levels remained low. The patient's plasma ACTH levels were in the normal range, despite the low plasma cortisol levels. Plasma arginine-vasopressin (AVP) was at low normal levels (Table 3). The short corticotropin stimulation test revealed poor responsiveness in the residual adrenal gland and enabled a diagnosis of acute adrenal insufficiency (Table 4). Oral administration of hydrocortisone (20 mg/day) was initiated immediately, which gradually moved the hyponatremia into the normal range. An abdominal computed tomography scan showed a normal right adrenal gland. A brain MRI revealed no abnormal findings in either the hypothalamus or the pituitary gland.
Table 4. Endocrinological examination: short corticotropin stimulation test (rapid ACTH test)
Patients with adrenal adenomas are successfully treated by unilateral adrenalectomy, and the outlook is excellent. Because the hypothalamic-pituitary axis and the contralateral adrenal gland are suppressed by prolonged cortisol over-secretion, these patients have a postoperative adrenal insufficiency and require glucocorticoid replacement therapy both during and following surgery until the remaining adrenal gland recovers.1 To date, cases a number of cases of acute adrenal insufficiency after unilateral adrenalectomy have been reported.3–5 Those reported have been primary adrenal insufficiency, caused by a disorder of the adrenal glands themselves, with an insufficient response to ACTH.
The present case also suggested the presence of primary adrenal insufficiency after unilateral adrenalectomy, since the serum cortisol levels remained low, whereas the serum ACTH levels normalized in 3 years. Contralateral adrenal atrophy was thought to continue even after the retrieval of pituitary function for secreting ACTH. After 7 years of prednisolone administration (with some interruptions) and following 4 years of total withdrawal, the patient presented with hypotension, weight loss, general fatigue, nausea, hyponatremia and hypoglycemia, which were consistent with the features of acute adrenal insufficiency. The condition was thought to be triggered by severe acute viral infection. An insufficient response to the short corticotropin stimulation test enabled the diagnosis of acute adrenal insufficiency. Although autoantibodies against the steroidogenic enzymes in the adrenal gland were not measured, a relatively normal adrenal gland and the absence of calcification in an abdominal computed tomography scan indicated the absence of primary adrenal insufficiency, which is occasionally complicated by tuberculosis infection or autoimmune diseases. Though the corticotrophin-releasing hormone (CRH) loading test and the metyrapone test were not carried out, relatively low serum ACTH in the face of increased demand for cortisol during adrenal crisis suggested a disordered hypothalamic-pituitary axis, indicating a secondary adrenal insufficiency. An absence of hypothalamic and pituitary lesions in a brain MRI suggested a functional disorder.
Hyponatremia in primary adrenal insufficiency is usually dominated by deficient mineralcorticoid activity, whereas in secondary adrenal insufficiency, it is mainly dominated by water retention caused by increased AVP secretion. Therefore, for acute adrenal crisis caused by secondary adrenal insufficiency, early initiation of steroid replacement is more important than the pure volume replacement therapy. In the present case, initial treatment with fluid replacement failed to improve hyponatremia, whereas following with administration of hydrocortisone gradually improved it. This suggests that water retention contributed to the hyponatremia, indicating secondary adrenal insufficiency. Low normal serum AVP levels despite severe hyponatremia in the present case indicates the presence of an AVP-independent mechanism of water retention in glucocorticoid deficiency, which has been demonstrated in both human and animal studies.6,7
Supra-physiological doses of exogenous glucocorticoids suppress both CRH production in the hypothalamus and ACTH production in the pituitary gland, which is a leading cause of secondary adrenal insufficiency.2 After removal of an adrenal tumor, supplemental cortisol of 10–15 mg/day may be necessary for several weeks or months to allow the remaining atrophic adrenal tissue to grow and to reestablish normal pituitary control of cortisol secretion.8 However, daily administration of more than 10–15 mg of cortisol will lead to delayed recovery of normal ACTH secretion.1 Henzen et al. reported that when glucocorticoids are used for more than 30 days, it may take up to a year for the hypothalamic-pituitary axis to recover.9 The degree of adrenal recovery in the unstressed patient can be determined by the response to 1 µg of corticotropin.
In the present case, prednisolone, which has greater strength than the same amount of cortisol, was administered after unilateral adrenalectomy. Furthermore, the administration period was more than 7 years, which is considered to be enough to cause the hypothalamic-pituitary axis suppression. However, over the following 4 years, the patient did not present with any symptoms of adrenal insufficiency until she was admitted to our hospital 4 years later. In the meantime, she did not take steroids or any drugs containing steroids. Such total withdrawal from steroids was thought to have allowed the recovery of the hypothalamic-pituitary axis function and cortisol secretion to the basal level. However, it was not enough to recover the reserved secretory capacity of cortisol for increased demand in severe acute viral infection, finally causing acute adrenal insufficiency. Therefore, it is important to pay attention to steroid use in patients after unilateral adrenalectomy. As suggested by Marik and Zaloga, the amount and duration of supplementary hydrocortisone should be decided on a case-by-case basis, according to periodical measurements of serum cortisol levels and close observations of clinical symptoms.10
In conclusion, the present case demonstrated the additional spectrum of secondary adrenal insufficiency long after unilateral adrenalectomy, which was thought to be induced by a reduction in the reserved secretory capacity of cortisol after prolonged glucocorticoid therapy.