Effect of ACTH on renal excretion of purine bases in a patient with isolated ACTH deficiency

Clinica Chimica Acta 294 (2000) 185–192 www.elsevier.com / locate / clinchim

Case report

Effect of ACTH on renal excretion of purine bases in a patient with isolated ACTH deficiency a, a b b Yuhei Shibutani *, Taro Ueo , Sumio Takahashi , Yuji Moriwaki , Tetsuya Yamamoto b a

Division of Endocrinology, Department of Internal Medicine, Nishi-Kobe Medical Center, Kobe, Japan b Third Department of Internal Medicine of Hyogo College of Medicine, Nishinomiya, Japan Received 26 July 1999; received in revised form 30 November 1999; accepted 5 December 1999

Abstract We investigated the renal transport of purine bases (uric acid, hypoxanthine and xanthine) after rapid and continuous ACTH loading tests in a patient with isolated ACTH deficiency, a rare cause of secondary adrenocortical insufficiency. Plasma uric acid concentration and the urinary ratio of uric acid / creatinine did not change in the rapid ACTH test, which did not increase plasma cortisol concentration. In the continuous ACTH loading test, the plasma concentration of uric acid and oxypurines (hypoxanthine and xanthine) decreased, and the urinary excretion and fractional clearance of them increased as well as the plasma concentrations and urinary excretion of cortisol. These findings suggest that glucocorticoid directly affects the common renal transport pathway for uric acid, hypoxanthine, and xanthine.  2000 Elsevier Science B.V. All rights reserved. Keywords: Purine bases; Uric acid; Hypoxanthine; Xanthine; Isolated ACTH deficiency; ACTH loading test

1. Introduction Although isolated adrenocorticotropin (ACTH) deficiency is a rare cause of secondary adrenocortical insufficiency, the number of case reports has been rapidly increasing with the development of hormonal examination [1–3]. Most *Corresponding author. Tel.: 1 81-78-997-2200; fax: 1 81-78-997-2220. 0009-8981 / 00 / $ – see front matter  2000 Elsevier Science B.V. All rights reserved. PII: S0009-8981( 99 )00263-6

186

Y. Shibutani et al. / Clinica Chimica Acta 294 (2000) 185 – 192

of these patients were suspected to have a primary pituitary dysfunction, but recent studies using corticotropin releasing hormone (CRH) test have suggested that ACTH deficiency is also caused by CRH deficiency in the hypothalamus [2,4]. Since isolated ACTH deficiency has been reported in patients with autoimmune diseases, such as Hashimoto’s thyroiditis [3,5], type 1 diabetes mellitus [3,6], and lymphocytic hypophysitis [7,8], the disease is presumed to be partly ascribable to an autoimmune mechanism [9]. However, it remains undetermined whether such autoimmunity play an important role in the etiology of this disease. Several studies have demonstrated that the urinary excretion of uric acid increases after the administration of ACTH or glucocorticoid in subjects with normal adrenal function [10–12]. However, in the past, there were few reports on purine bases (uric acid, hypoxanthine, and xanthine) metabolism in secondary adrenocortical insufficiency. Therefore, we investigated the renal transport of purine bases after both rapid and continuous ACTH loading tests in a patient with isolated ACTH deficiency.

2. Materials and methods The following tests of pituitary functions were done: CRH (100 mg, IV), luteinizing hormone-releasing hormone (LHRH) (100 mg, IV), thyrotropinreleasing hormone (TRH) (500 mg, IV), growth hormone-releasing hormone (GHRH, 100 mg, IV). Commercial immunoradiometric assay kits were used for measurements of thyroid-stimulating hormone (TSH), prolactin (PRL), luteinizng hormone (LH), follicle-stimulating hormone (FSH), growth hormone (GH), and ACTH (Spac-S TSH Kit, Spac-S Prolactin Kit, Spac-S LH Kit, Spac-S FSH Kit, GH Kit ‘Daiichi’: Daiichi Radioisotope Lab., Tokyo, Japan; and ACTH IRMA‘Mitsubishi’: Mitsubishi Chemical Co., Tokyo, Japan), respectively. The basal values of these hormones are as follows: TSH, 0.4–4.7 mU / l; PRL, 1.5–9.7 mg / l; LH, 0.2–20 IU / l; FSH, 0.8–23 IU / l; GH, , 1.5 mg / l; ACTH, , 13 pmol / l. The rapid ACTH test was performed by intravenous administration of 0.25 mg synthetic ACTH (1-24ACTH) after overnight fasting. The continuous ACTH test was performed as follows: 1.0 mg synthetic ACTH (1-24ACTH-Z) was administered intramuscularly for three days and urine was collected for 24 h. Dietary purine intake did not change before and during the continuous ACTH test. Both tests were done before glucocorticoid replacement therapy. Plasma and urinary free cortisol were measured by commercial radioimmunoassay (GammaCort Cortisol, DiaSorin Inc., MN, USA) and fluorescence polarization immunoassay (TDx Dinapac, Dinabot Co. Ltd., Tokyo, Japan), respectively. The normal values of plasma and urinary free cortisol were 154–588 nmol / l and

Y. Shibutani et al. / Clinica Chimica Acta 294 (2000) 185 – 192

187

96–440 nmol / day, respectively. Antidiuretic hormone (ADH), renin activity (PRA), aldosterone (PAC), angiotensin II (AII) and in the plasma, and testosterone and estradiol (E2) in the serum were measured by commercial radioimmunoassays (AVP RIA‘Mitsubishi’: Mitsubishi Chemical Co., Tokyo, Japan; Renin Riabead, Aldosterone RIA Kit II: Dibabot Co. Ltd., Tokyo, Japan; Angiotensin II RIA Kit: Nichols Ins. Diagnostics, CA, USA; Coat-A-Count Testosterone, and Coat-A-Count Estradiol: Diagnostic Products Co., CA, USA), respectively. The normal values of these hormones are as follows: ADH, 0.3–3.9 pmol / l; PRA, 0.2–2.7 ng / ml / h; PAC, 55–360 pmol / l; AII, 9–47 ng / l; testosterone, 9.4–37 nmol / l; and E2, 60–220 pmol / l. Plasma and urinary uric acid levels were measured by the uricase method using a chemistry analyzer (Hitachi 7250, Hitachi, Tokyo, Japan). Plasma and urinary oxypurines (hypoxanthine and xanthine) levels were quantified by high performance liquid chromatography [13]. For normal controls (n 5 7), plasma concentration of uric acid, hypoxanthine, and xanthine were 295660 mmol / l, 2.160.7 mmol / l, and 0.960.4 mmol / l, respectively, and urinary excretion of uric acid, hypoxanthine, and xanthine were 36.0612.5 mmol / day, 37.5613.1 mmol / day, and 34.2617.1 mmol / day, respectively. The percentage ratios of uric acid clearance / creatinine clearance (fractional uric acid clearance), hypoxanthine clearance / creatinine clearance (fractional hypoxanthine clearance), and xanthine clearance / creatinine clearance (fractional xanthine clearance) were calculated.

3. Case report A 55-year-old male was admitted because of general fatigue. He was 165 cm tall and weighed 53.6 kg. Blood pressure was 102 / 62 mmHg supine and 96 / 60 mmHg standing. Skin pigmentation and hair distribution were normal. The thyroid was not palpable. The chest and abdomen were normal, and no edema was detected. There were no pathological reflexes or sensory disturbances. Routine laboratory examination revealed a red blood cell count of 408 3 10 4 / mm 3 and a white blood cell count of 4100 / mm 3 with normal segmentation. The serum concentrations of Na, K, and Cl were 134, 4.5, and 96 mmol / l, respectively. Blood urea nitrogen was 8 mg / dl and Creatinine 0.7 mg / dl. Fasting plasma glucose was low at 64 mg / dl. The results of endocrinological examination are shown in Fig. 1. Both plasma cortisol and ACTH levels were undetectable and there was no response to CRH. Although plasma cortisol did not respond to IV administration of ACTH, both plasma cortisol and urinary excretion of free cortisol responded to ACTH continuous stimulation. The basal values of LH, FSH, GH, and PRL were within normal ranges and serum TSH level was slightly elevated with normal concentration of thyroid hormone. These

188

Y. Shibutani et al. / Clinica Chimica Acta 294 (2000) 185 – 192

Fig. 1. Endocrinological examination of patient in case report.

hormones increased normally following appropriate stimulation tests (LHRH, GHRH, and TRH). Based on these findings, the patient was diagnosed as having isolated ACTH deficiency. After diagnosis, he was treated with cortisol (20 mg / day) with improvement in his general condition and basal TSH concentration.

Y. Shibutani et al. / Clinica Chimica Acta 294 (2000) 185 – 192

189

4. Results The results of rapid and continuous ACTH loading tests are shown in Table 1. Plasma uric acid concentration and the urinary concentration ratio of uric acid / creatinine did not change during the rapid ACTH test. In the continuous ACTH loading test, the plasma concentrations of uric acid, hypoxanthine, and xanthine decreased from 387 to 315 mmol / l, from 2.82 to 2.23 mmol / l, and

Table 1 Plasma concentration and urinary excretion of uric acid, hypoxanthine, and xanthine in rapid and continuous ACTH tests a Rapid ACTH test (0.25 mg iv) Cortisol (nmol / l) Plasma uric acid (mmol / l) Urinary uric acid / creatine

Basal n.d. 393 0.39

Continuous ACTH test (1 mg im for 3 days) Basal Urinary free cortisol (nmol / day) n.d. (normal range: 96–440) Plasma uric acid (mmol / l) 387 Urinary uric acid (mmol / day) 24.5 Uric acid clearance (ml / min) 4.20 Fua (%) 3.65 Plasma hypoxanthine (mmol / l) 2.82 Urinary hypoxanthine (mmol / day) 21.4 Hypoxanthine clearance (ml / min) 4.93 Fhx (%) 4.29 Plasma xanthine (mmol / l) 0.82 Urinary xanthine (mmol / day) 8.8 Xanthine clearance (ml / min) 7.0 Fx (%) 6.09 Creatinine clearance (ml / min) 110 Urinary glucose (mmol / day) 0 Urinary sodium (mmol / day) 99 Plasma ADH (pmol / l) 2.1 Plasma renin activity (mg / l / h) 0.5 Plasma aldosterone (pmol / l) 72.1 Angiotensin II (ng / l) 10 Serum testosterone (nmol / l) 21.5 Serum estradiol (pmol / l) 62.4 a

30 min n.d. 393 0.40

1st 96 357 25.7 4.68 3.80 2.60 27.8 6.97 5.67 0.80 15.7 12.4 10.08 123 0 87 2.0 0.6 83.2 13 20.1 73.4

60 min n.d. 393 0.37

120 min n.d. 393 0.38

2nd 430

3rd 877

327 28.0 5.56 4.56 2.23 40 11.67 9.57 0.72 16.4 14.8 12.13 122 0 82 1.8 0.7 94.3 12 20.8 69.7

315 26.9 5.53 4.50

123 0 92 2.0 0.6 110 12 19.8 88.1

Fua; fractional uric acid clearance, Fhx; fractional hypoxanthine clearance, Fx; fractional xanthine clearance, ADH; antidiuretic hormone, n.d.; not detectable.

190

Y. Shibutani et al. / Clinica Chimica Acta 294 (2000) 185 – 192

from 0.82 to 0.72 mmol / l, respectively. Creatinine clearance increased from 110 to 123 ml / min. In contrast, urinary excretion of uric acid, hypoxanthine, and xanthine increased from 24.5 to 28.0 mmol / day, from 21.4 to 40 mmol / day, and from 8.8 to 16.4 mmol / day, respectively. Fractional clearances of uric acid, hypoxanthine, and xanthine also increased from 3.65 to 4.56%, from 4.29 to 9.57%, and from 6.09 to 12.13%, respectively. There was no change in the urinary excretion of glucose and sodium, and testosterone and estradiol in the serum, and antidiuretic hormone, renin activity, aldosterone, and angiotensin II in the plasma.

5. Discussion Previous studies have reported that the urinary excretion of uric acid increased after the administration of ACTH or glucocorticoid [10–12]. However, since hormonal assays for cortisol and aldosterone were not carried out in these studies, it remains undetermined whether the increased uric acid excretion is ascribable to the direct effect of ACTH on the renal uric acid transport or a secondary effect via cortisol or aldosterone. If the adrenal gland in patients with secondary adrenocortical insufficiency have been unstimulated for long time, cortisol often shows no response to single administration of ACTH, but it can respond to repeated ACTH administration. Therefore, we investigated the renal transport of purine bases using the discrepancy of responsiveness of cortisol to rapid and continuous ACTH loading tests in a patient with isolated ACTH deficiency. In the present study, plasma uric acid concentration was decreasing and both urinary excretion and fractional clearance of uric acid were increasing as well as urinary free cortisol during the continuous ACTH loading test. On the contrary, plasma uric acid concentration and the urinary concentration ratio of uric acid / creatinine did not change during the intravenous administration of ACTH, which could not increase plasma cortisol concentration. These findings suggest that the change in renal uric acid handling is attributable to the secondary effect rather than the direct effect of ACTH. However, it remains undetermined whether corticosteroid-induced hyperuricosuria is caused by glucocorticoid, aldosterone, or sex hormones. Several studies have reported that hypouricemia due to increased renal uric acid clearance is associated with hyperglycemia [14], primary aldosteronism [15], inappropriate secretion of antidiuretic hormone (SIADH) [16], and estrogen therapy [17]. In the present study, the continuous ACTH loading test did not affect the urinary excretion of glucose, sodium, the serum concentration of sex hormones, the plasma concentration of ADH, aldosterone, angiotensin II, or plasma renin activity. Therefore, these results suggest that increased excretion of uric acid is brought on by the direct action of glucocorticoid on uric acid transport in the renal

Y. Shibutani et al. / Clinica Chimica Acta 294 (2000) 185 – 192

191

tubules, since glucocorticoid did not affect the urinary excretion of glucose and sodium. In addition, the urinary excretion of cortisol increased to nearly upper normal limit at the second day during the continuous ACTH loading test, suggesting that the uricosuric action for cortisol develops within physiological concentration of cortisol. Since, in most of the previous studies [18,19], uricosuria was demonstrated by administration of large amounts of steroid hormone to subjects with normal adrenal function, the present result is of interest. There are few reports concerning the effect of ACTH and steroid hormone on the renal transport of oxypurines (hypoxanthine and xanthine). The present study demonstrated that in the continuous ACTH loading test, the plasma concentration of oxypurines (hypoxanthine and xanthine) decreased and the urinary excretion and fractional clearance of oxypurines increased, indicating that ACTH and / or glucocorticoid increased the clearance of oxypurines. The renal transport of oxypurines was investigated in normal subjects [20] and a xanthinuric patient [21], and it was suggested that uric acid and oxypurines share a common renal reabsorptive transport mechanism and that uric acid and xanthine partly share a common renal secretory transport mechanism different from that of hypoxanthine. In the present study, the renal handling of hypoxanthine and xanthine were similar to that of uric acid. Continuous ACTH administration increased the urinary excretion of oxypurines as well as that of uric acid, resulted in a decreased plasma concentration. These results suggest that glucocorticoid affects the common renal transport pathway of uric acid, hypoxanthine and xanthine since uric acid metabolism did not change in the rapid ACTH test. In the absence of glucocorticoids, glomerular filtration rate and renal blood flow are usually decreased. Although in the present case, creatinine clearance was within the normal range, it increased during continuous ACTH loading. Therefore, in addition to the direct effect of glucocorticoid on the common renal transport pathway for oxypurines, the increase in urinary excretion of uric acid, hypoxanthine, and xanthine may be partly attributable to a glucocorticoid-induced increase in glomerular filtration rate. However, since fractional clearance of uric acid and oxypurines also increased, increased renal transport of them seems to be attributed to direct effect of glucocorticoid rather than glucocorticoid-induced increase in glomerular filtration rate.

References [1] Shibutani Y. Prolactin dynamics in a patient with isolated ACTH deficiency accompanied by hyperprolactinemia. Am J Med Sci 1988;295:140–3. [2] Orme SM, Belchetz PE. Isolated ACTH deficiency. Clin Endocrinol (Oxf) 1991;35:213–7. [3] Hashimoto K, Kurokawa H, Nishioka T et al. Four patients with polyendocrinopathy with associated pituitary hormone deficiency. Endocrine J 1994;41:613–21.

192

Y. Shibutani et al. / Clinica Chimica Acta 294 (2000) 185 – 192

[4] Nishihara E, Kimura H, Ishimaru T et al. A case of adrenal insufficiency due to acquired hypothalamic CRH deficiency. Endocrine J 1997;41:121–6. [5] Kamijo K, Kato T, Saito A, Kawasaki K, Suzuki M, Yachi A. A case with isolated ACTH deficiency accompanying chonic thyroiditis. Endocrinol Jpn 1982;29:183–9. [6] Guistina A, Candrina R, Cimino A, Romanelli G. Development of isolated ACTH deficiency in a man with type 1 diabetes mellitus. J Endocrinol Invest 1988;11:375–7. [7] Jensen MD, Handberger BS, Scheithauer BW, Carpenter PC, Mirakian R, Banks PM. Lymphocytic hypophysitis with isolated corticotropin deficiency. Ann Intern Med 1986;105:200–3. [8] Escobar-Morreale H, Serrano-Gotarredona J, Varela C. Isolated corticotropin deficiency due to probable lymphocytic hypophysitis in a man. J Endocrinol Invest 1994;17:127–31. [9] Richtsmeier AJ, Henry RA, Bloodworth JMB, Ehlich EN. Lymphoid hypophysis with selective adenocorticotropic hormone deficiency. Arch Intern Med 1980;140:1243–4. [10] Friedman M, Byers SO. Mechanism by which ACTH increases the excretion of urate. Am J Physiol 1950;163:684–7. [11] Sprague RG, Power MH, Mason HL et al. Observations on the physiologic effects of cortisone and ACTH in man. Arch Intern Med 1950;85:199–258. [12] Ingbar SH, Kass EH, Burnett CH, Relman AS, Burrows BA, Sisson JH. The effects of ACTH and cortisone on the renal tubular transport of uric acid, phosphorus, and electrolytes in patients with normal renal and adrenal function. J Lab Clin Med 1951;38:533–41. [13] Yamamoto T, Moriwaki Y, Takahashi S, Hada T, Higashino K. Separation of hypoxanthine and xanthine from pyrazinamide and its metabolites in plasma and urine by high-performance liquid chromatography. J Chromatogr 1986;382:270–4. [14] Moriwaki Y, Yamamoto T, Takahashi S, Hada T, Higashino K. Effect of glucose infusion on the renal transport of purine bases and oxypurinol. Nephon 1995;69:424–7. [15] Nanba M, Kikuchi K, Komura H et al. Study on uric acid metabolism in patients with primary aldosteronism. Folia Endocrinol 1992;68:51–61, (abstract in English). [16] Beck LH. Hypouricemia in the inappropriate secretion of antidiuretic hormone. New Engl J Med 1979;301:528–30. [17] Nicholis A, Snaith ML, Scott JT. Effect of oestrogen therapy on plasma and urinary levels of uric acid. Br Med J 1973;1:449–51. [18] Miller JJ. Prolonged use of large intravenous steroid pulses in the rheumatic diseases of children. Pediatrics 1980;65:989–94. [19] Hisatome I, Ogino K, Kotake H, Mashiba H. Effect of steroid hormone on excretion of urate. J Rheumatol 1988;15:1044. [20] Yamamoto T, Moriwaki Y, Takahashi S, Hada T, Higashino K. Renal excretion of purine bases: effect of probenecid, benzbromarone and pyrazinamide. Nephon 1988;48:116–20. [21] Auscher C, Pasquier C, Pehuet P, Delbarre F. Study of urinary pyrazinamide metabolites and their action on the renal excretion of xanthine and hypoxanthine in a xanthinuric patient. Biomedicine 1978;28:129–33.