Cork University Hospital, Wilton, Cork, Ireland
Correspondence and offprint requests to: Aoife Brennan, Cork University Hospital, Wilton, Cork, Ireland. Email: itsaoife{at}eircom.net
Keywords: hypoadrenalism; nephrotic syndrome; rapid ACTH stimulation test
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Introduction |
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Case |
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Two months after her initial presentation, she complained of anorexia, lethargy and intermittent nausea. The intravenous rapid ACTH (250 mcg) stimulation test (SST) was performed due to suspected hypoadrenalism. The serum cortisol response was considered sub-optimal (Table 1) and a diagnosis of hypoadrenalism was made. She was started on steroid replacement therapy. She showed no improvement in symptoms and discontinued her steroids 2 weeks later. Repeat SST with simultaneous serum CBG measurement was performed at this time. Once again, serum cortisol levels failed to rise appropriately, but her serum CBG levels were found to be significantly sub-normal (Table 1). Plasma renin activity (8.7 ng/l), serum aldosterone concentration (528 pmol/l) and plasma ACTH concentration (6.6 pmol/l at 08.00) were all normal. A CT scan showed the adrenal glands to be of normal size and attenuation. Renal function continued to deteriorate and 9 months after her initial presentation she required renal replacement therapy. At this time, with a urine production of <30 ml per day, a repeat SST was performed. This revealed a normal serum cortisol response and a normal serum CBG concentration (Table 1).
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Discussion |
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The presence of amyloid in the renal biopsy initially raised the possibility of amyloid-induced hypoadrenalism as the cause of her positive SST. Although histological evidence of adrenal involvement has been shown to occur in 4796% of patients with systemic amyloidosis at autopsy [1,2], primary adrenal failure caused by amyloidosis has rarely been reported.
The nephrotic syndrome is characterized by a marked increase in the glomerular permeability to macromolecules. The associated urinary losses of albumin and hormone binding proteins are responsible for many of the apparent endocrine and metabolic abnormalities seen in these patients.
The free serum cortisol fraction represents the biologically active form of the hormone, yet constitutes only 510% of the total serum cortisol concentration. Cortisol predominantly circulates bound to specific CBG with a smaller fraction bound to albumin. Laboratory methods to measure free serum cortisol directly are not available for routine laboratory use. Therefore, the total serum cortisol that is routinely measured includes both bound and free serum cortisol. Like other hormone binding globulins, CBG (52 kDa) is lost in the urine of nephrotic patients. In accordance with the free hormone hypothesis [3], total serum cortisol levels are reduced, the percentage of unbound cortisol is increased and free serum cortisol levels, if measured, would be normal.
The standard diagnostic test for suspected primary adrenal insufficiency has been the rapid ACTH (250 mcg) stimulation test. After a baseline cortisol level is obtained, synthetic ACTH 124 is injected intramuscularly or intravenously. A normal result is a serum cortisol concentration of 550 nmol/l 3060 min post ACTH and this essentially excludes the diagnosis of primary adrenal insufficiency [4].
Recent investigators have explored mathematical models of estimating the free serum cortisol from calculations using both total cortisol and CBG concentrations. The modified free cortisol index (mFCI) is one such method [5]. When calculated using our patient's 30 mins post ACTH bloods (mFCI = total cortisol2/CBG) on the initial SST, a value in the normal range for healthy adults was reached.
A recently published study described four out of 21 study participants with renal amyloidosis as having hypoadrenalism on the basis of hormonal and radiological findings [6]. In this study, no consideration was given to the effect of urinary protein and CBG losses.
This case illustrates the need for caution in the interpretation of tests of the pituitaryadrenal axis in patients with the nephrotic syndrome. Allowance must be made for the low serum CBG concentrations accompanying this condition to avoid labelling patients erroneously as being functionally hypoadrenal.
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Acknowledgments |
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Conflict of interest statement. None declared.
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References |
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