CASE REPORTS
Treatment of Sarcoidosis-Associated Hypercalcemia With Ketoconazole Margaret J.Bia, MD, and Karllnsogna, MD • A 47-year-old patient presented with hypercalcemia secondary to sarcoidosis and was successfully treated with 1 year of corticosteroids leading to improvement in his hypercalcemia, hypercalcuria, and elevated levels of 1,25dihydroxyvitamin D. Angiotensin-converting enzyme levels (ACE) normalized and serum creatinine improved. When hypercalcemia recurred after a 3-year symptom-free interval, the patient refused repeat corticosteroid treatment and was placed on ketoconazole (initially 600 and eventually 800 mg/d). Ketoconazole controlled the patient's hypercalcemia (serum calcium, 3.2 to 2.6 mmol/L [12.8 to 10.4 mg/dL]), but only the larger dose suppressed serum 1,25-dihydroxyvitamin D levels into the normal range. Hypercalcuria was markedly improved with ketoconazole, decreasing from a peak of 23 mmol/d (940 mg/d) to less than 8.7 mmol/d (350 mg/d) on a dose of 800 mg. However, serum ACE levels remained elevated on ketoconazole. An attempt to taper the ketoconazole after 1 year resulted in rapid recurrence of hypercalcemia (serum calcium, 2.8 mmol/L [11.1 mg/dL]) and hypercalcuria (urinary calcium excretion, 11 mmol/d [451 mg/d]). After a total of 2 years of ketoconazole treatment, his defect in calcium metabolism remains well controlled despite persistent elevation in ACE levels. Serum cortisol levels and liver function tests remain normal on therapy, although there has been a slight decrease in serum testosterone levels accompanied by some decrease in libido. These data suggest that long-term use of ketoconazole may be a safe and effective alternative to corticosteroid treatment for sarcoidassociated hypercalcemia. Further study is needed to determine whether the long-term side effects of ketoconazole therapy or its failure to control disease activity in sarcoidosis outweigh its advantages in avoiding the known side effects of glucocorticoids. © 1991 by the National Kidney Foundation, Inc. INDEX WORDS: Sarcoidosis; hypercalcemia; ketoconazole; 1,25-dihydroxyvitamin D.
K
ETOCONAZOLE, a drug that inhibits several enzymes in the cytochrome P450 enzyme system, has been shown to inhibit the production of several steroid hormones such as glucocorticoids I and androgens. 2 The drug has also been shown to inhibit the production of 1,25dihydroxyvitamin D both in vitro 10 and in vivo. 3,4, 10 We recently had the opportunity to use this information to treat a patient with sarcoidosis and hypercalcemia due to excess 1,25-dihydroxyvitamin D production. The following case report describes our experience. CASE REPORT The patient was first admitted to Yale New Haven Hospital for an evaluation of hypercalcemia and renal failure. At that time, he was 47 years old and had had renal failure first recognized 6 months previously when a creatinine of274 mmol/ L (3.1 mg/dL) was noted on routine serum chemistries. An intravenous pyelogram (IVP) showed a large single right kidney From the Department 0/ Internal Medicine, Yale University School 0/ Medicine, New Haven , CT. Address reprint requests to Margaret J. Bia, MD, Yale University, Department o/Nephrology, 2070 LMP, 333 Cedar St, New Haven, CT 06510. © 1991 by the National Kidney Foundation, Inc. 0272-6386/ 91/ 1806-0013$3.00/ 0 702
without evidence for hydronephrosis or nephrocalcinosis. Serum calcium levels were also elevated (2.9 to 3.2 mmol/L [11.8 to 12.7 mgjdL]) and renal function deteriorated over the subsequent 24 weeks (creatinine up to 504 J'mol/L [5.7 mg/dL)). Serum complement levels, antinuclear antibodies (ANA), and serum protein electrophoresis were normal. On admission, physical examination was normal and urinalysis showed I + proteinuria, 0 to I red blood cells (RBC), 0 to I white blood cells (WBC), and no casts. A chest x-ray demonstrated prominent hilar adenopathy, and a transbronchial biopsy showed noncaseating granulomata. Initial level of angiotensin-converting enzyme (ACE) was elevated (Table I) and pulmonary function tests demonstrated the presence of mild restrictive lung disease. The patient was felt to have sarcoidosis with renal failure secondary to the associated hypercalcemia and he was begun on prednisone (I mg/kg/d) tapering to 20 mg/d by 6 months. The corticosteroids were tapered completely after I year of therapy. Renal function and calcium metabolism parameters before and during steroid treatment are presented in Table I. During steroid therapy, levels of 1,25-dihydroxyvitamin D rapidly normalized; hypercalcemia resolved, and renal function improved considerably. ACE levels also improved. Despite this improvement, the patient experienced significant glucocorticoid related side effects, including weight gain, anxiety, insomnia, and the development of early cataracts. Following cessation of corticosteroids, the patient remained symptom-free for 3 years with normal serum calcium concentrations of2.4 to 2.6 mmol/L (9.5-10.4 mg/dL) and a serum creatinine concentration of 195 J'mol/L (2.2 mg/dL). However, during this time period, levels of 1,25-dihydroxyvitamin D remained slightly above normal (122 to 173 pmol/L) and
American Journal of Kidney Diseases, Vol XVIII, No 6 (December), 1991: pp 702-705
KETOCONAZOLE TREATMENT OF HYPERCALCEMIA
703
Table 1. Laboratory Values Before and After Corticosteroid Therapy Before Corticosteroids (5/84)
Creatinine (/Lmol/L) Calcium (mmoIfL) Phosphorus (mmol/l) Alkaline phosphate (U/L) Urinary calcium excretion (mmol/d) 1,25 dihydroxyvitamin 0 (pmoI/L)* Intact PTH (ng/L)t ACE (lUlL):\:
530 (6 mg/dL) 2.9 (11 .7 mg/dl) 1.74 (5.4 mg/dL) 37 8.7 (350 mg/d) 156 409 56
On Corticosteroids (6/84-5/85)
203 (2.3 mg/dL) 2.4 (9.6 mg/dL) 1.0 (3.1 mg/dl) 39 5.7 (228 mg/d) 43-82 33-38
• Normal levels, 60 to 148 pmol/L. t Normal levels, up to 450 ng/L. :\: Normal levels, up to 48 lUlL.
he had occasional urinary calcium excretion rates of 8.4 to 10 mmol/d (350 to 400 mg/d). Serum ACE levels were frequently elevated (56 to 76/IU/L). During the fourth year after corticosteroid cessation, urinary calcium excretion increased markedly and he again became hypercalcemic (Fig I) with a deterioration in renal function (creatinine, 248 /Lmol/L [2.8 mg/dL]). Because of the patient's reluctance to resume glucocorticoids, treatment was begun with ketoconazole in an attempt to inhibit 1,25-dihydroxyvitamin 0 production and improve his hypercalcemia and hypercalcuria. Ketoconazole doses varied initially between 600 and 800 mg/d (Fig I). Hypercalcemia resolved promptly and urinary calcium excretion decreased markedly. Serum creatinine decreased from 248 /Lmol/ L (2.8 mg/dL) to the patient's baseline value of 195 /Lmol/L (2.2 mg/dL). After I year of treatment, the ketoconazole was discontinued briefly. However, arapid return of hypercalcemia and hypercalcuria necessitated reinstitution of therapy (Fig 26
2.83.2
i 1 l'j'
2 .6
1
2.8
'j'I'j'
2 .4
1
'1.5
I). Ketoconazole was restarted at a dose of 80a mg/d, since examination of the data during his first year of treatment indicated that 600 mg/d failed to completely normalize 1,25dihydroxyvitamin 0 levels into the normal range (Fig I). Currently, the patient remains on 800 mg of ketoconazole per day, with maintenance of normal blood levels of 1,25-dihydroxyvitamin 0 and calcium, although urinary calcium excretion is still intermittently elevated. He has now been on ketoconazole for a total of 2 years. Renal function has remained stable (serum creatinine, 194 /Lmol/L [2.2 mg/dL]). Ketoconazole has had no effect on serum phosphate or parathyroid hormone (PTH) levels during this time, nor has there been evidence for liver toxicity (normal serum transaminases when measured every 3 months). Serum cortisol levels, before and after corsyntropin stimulation, have also remained normal, but there has been a slight decrease in serum testosterone levels accompanied by some decrease in libido. Pulmonary function studies, performed once yearly, have demonstrated persistence of a mild restrictive lung pattern, and chest x-ray continues to show stable hilar adenopathy. Serum levels of ACE remain elevated on ketoconazole.
DISCUSSION
Fig 1. Urinary calcium excretion (A, .) and 1,25-dihydroxyvitamin D levels (B, 0) in the patient treated with ketoconazole during a recurrence of sarcoid-associated hypercalcemia. Dashed line indicates normal upper limits of levels of 1,25-c1ihydroxyvitamin D. (C) Ketoconazole dosage. Representative serum calcium values at given times are shown in parenthesis at the top of the graph.
Ketoconazole is known to inhibit several cytochrome P450 enzymes involved in the biosynthesis of steroid hormones, including glucocorticoids l and androgens. 2 More recently, the drug has been shown to produce a dose dependent decrease in the level of 1,25-dihydroxyvitamin D in both normal subjects3 and in patients with hyperparathyroidism. 4 Hypercalcemia in sarcoidosis is secondary to overproduction of 1,25-dihydroxyvitamin D 5 by activated macrophages within sarcoid granuloma6-8 and has been traditionally treated with glucocorticoids. 9 Since the 1a-hydroxylase enzyme complex includes a cytochrome P450 component, it is plausible that ketoconazole would be useful in controlling hypercalcemia in this condition, thereby obviating
704
the need for glucocorticoids. Indeed, in a recent report where ketoconazole was used for 9 days to treat a patient with sarcoid-associated hypercalcemia, serum levels of 1,25 decreased by more than 50% during therapy and in vitro studies documented a dose-dependent inhibitory effect of the drug on 1,25-dihydroxyvitamin D production in the host's pulmonary alveolar macrophages. IO Our case extends these observations and demonstrates that ketoconazole can inhibit 1,25-dihydroxyvitamin D production and hypercalcemia for up to 2 years in a patient with sarcoidosis with minimal side effects. Our patient was initially treated with corticosteroids, which successfully normalized his 1,25dihydroxyvitamin D production and corrected the hypercalcemia (Table I). Although his initial level of 1,25-dihydroxyvitamin D was only slightly elevated above the normal limits, this was distinctly abnormal in view of his degree of renal failure. The decrease in ACE levels with glucocorticoid treatment suggests that the activity of his sarcoidosis may have been suppressed by corticosteroids. II It is likely that the renal failure present at the time of his initial evaluation was related to the hypercalcemia, rather than sarcoid interstitial nephritis, since the initial urine sediment was benign and since hypercalcemia is a much more common reason for azotemia in sarcoidosis than is interstitial nephritis. After corticosteroids were discontinued, he remained stable for nearly 3 years, although he intermittently had elevations in levels of ACE, 1,25-dihydroxyvitamin D, and urinary calcium excretion. He then became frankly hypercalcemic, but was reluctant to resume corticosteroids because of their side effects. He was therefore begun on ketoconazole. Although serum calcium levels returned to normal rapidly (3.2 to 2.6 mmol/L), serum levels of 1,25-dihydroxyvitamin D did not suppress into the normal range until a dose of 800 mg/d (200 mg 4 times daily) was used (Fig 1). At doses of600 mg/d, his 1,25-dihydroxyvitamin D level and urine calcium excretion were still elevated and frank hypercalcemia recurred when the drug was tapered below this dose. The lack of an exact correlation between levels of 1,25-dihydroxyvitamin D and urine or serum calcium levels (Fig I) is likely explained by variations in the patient's calcium and sodium intake. These data confirm previous reports of the ra-
BIA AND INSOGNA
pidity of action and dose dependency of inhibition of 1,25-dihydroxyvitamin D production with ketoconazole. 3,JO Glass and Eil demonstrated a concentration-dependent inhibitory effect of ketoconazole on renal 1,25-dihydroxyvitamin D synthesis in normal human subjects. 3 Adams et al verified that these same results hold true for extrarenal production of the vitamin D in pulmonary macrophages from a patient with sarcoidosis. JO In these studies, ketoconazole doses of 600 to 900 mg/d produced a 40% reduction or more in baseline levels of 1,25-dihydroxyvitamin D. 3,4,7 Our inability to produce this degree of suppression of hormone production may be due to our patient's large body mass (122 kg), which would reduce his ketoconazole dpse on a mg/kg basis. Extrarenal overproduction of 1,25dihydroxyvitamin D with resultant hypercalcuria and less commonly hypercalcemia occurs in up to 20% of patients with sarcoidosis.1 2 It is also the mechanism of hypercalcemia in other granulomatous diseases such as tuberculosis,13 candidiasis,14 histoplasmosis,15 silicone toxicity, 16 and in some cases oflymphoma. 17 Further study is needed to determine whether ketoconazole will prove efficacious in these disorders as well. Side effects with prolonged ketoconazole therapy in our patient were surprisingly few. Liver and adrenal function studies remained normal. However, he did experience a decrease in libido in association with a decrease in testosterone levels. However, the patient felt that this effect was less troublesome compared with the central nervous system and psychological side effects he experienced during the initial treatment with corticosteroids. He did not complain of headache or loss of concentration, which have been described previously with ketoconazole doses of 800 mg and greater. 3,JO It is likely that ketoconazole has not suppressed the activity of the patient's sarcoidosis as effectively as corticosteroids, since ACE levels remain elevated with treatment. Furthermore, he had a rapid recurrence of hypercalcemia and increased levels of 1,25-dihydroxyvitamin D when the drug was tapered off after 1 year of therapy compared with a disease-free interval of more than 3 years after I year of corticosteroid therapy. Further study is needed to determine whether this failure of ketoconazole to suppress disease activity in sarcoidosis or its potential side effects at the higher
KETOCONAZOLE TREATMENT OF HYPERCALCEMIA
705
doses which may be required to adequately suppress 1,25-dihydroxyvitamin D production outweigh the advantage of obviating the need for corticosteroid therapy. Perhaps lower doses of ketoconazole could be used in conjunction with lower doses of glucocorticoids to achieve an additive effect on the control of hypercalcemia while minimizing the side effects of both drugs. When using ketoconazole, careful attention must be
paid to drug dosage to ensure adequate suppression of 1,25-dihydroxyvitamin D overproduction. In addition, levels of several hormones, especially cortisol, must be followed during therapy. Despite these cautions, the data suggest that ketoconazole offers a reasonable alternative to steroid therapy as treatment for sarcoidosis associated hypercalcemia and may be used safely for up to 2 years.
REFERENCES 1. Pont A, Williams PL, Loose D, et al: Ketoconazole blocks adrenal steroid synthesis. Ann Intern Med 97:370-373, 1982 2. Pont A, Williams PL, Azhars S, et al: Ketoconazole blocks testosterone synthesis. Arch Intern Med 142:2137-2140, 1982 3. Glass AR, Ei1 C: Ketoconazo1e-induced reduction in serum 1,25 dihydroxyvitamin D. J Clin Endocrinol Metab 63:766-769, 1986 4. Glass AR, Eil C: Ketoconazole-induced reduction in serum 1,25 dihydroxyvitamin D and total serum calcium in hypercalcemic patients. J Clin Endocrinol Metab 66:934-938, 1988 5. Insogna KL, Dreyer BE, Mitnick M: Enhanced production rate of 1,25 dihydroxyvitamin D in sarcoidosis. J Clin Endocrinol Metab 66:72-75, 1988 6. Barbour GL, Coburn JW, Slatopolsky E, et al: Hypercalcemia in an anephric patient with sarcoidosis: Evidence of extra renal generation of 1,25 dihydroxyvitamin D. N Eng! J Med 305:440-443, 1981 7. Adams JS, Singer FR, Gacod MA, et al: Isolation and structural identification of 1,25 dihydroxyvitamin D3 produced by cultured alveolar macrophages in sarcoidosis. J Clin Endocrinol Metab 60:960-966, 1985 8. Mason RS, Frinkel T, Chan YL, et al: Vitamin D conversion be sarcoid lymph node homogenate. Ann Intern Med 100:59-61, 1984 9. Zerwekh JE, Pak CY, Kaplan RA: Pathogenic role of
1,25 dihydroxyvitamin D in sarcoidosis and absorptive hypercalcemia: Different response to prednisone therapy. J Clin Endocrinol Metab 51 :381-386, 1980 10. Adams JS, Sharma OP, Diz M: Ketoconazole decreases the serum 1,25 dihydroxyvitamin D and calcium concentration in sarcoidosis associated hypercalcemia. J Clin Endocrinol Metab 70:1090-1095, 1990 . II. DeRemee RA: Serum angiotensin converting enzyme activity in evaluating the clinical course of sarcoidosis. Ann Intern Med 92:361-365, 1980 12. Mayock RL, Bertrand P, Morrison CE, et al: Manifestations of sarcoidosis. Analysis of 145 patients with review of nine selected from the literature. Am J Med 35:67-89, 1963 13. Abbas AA, Chemplavil JK, Samir F: Hypercalcemia in active pulmonary tuberculosis. Ann Intern Med 90:324328, 1979 14. Kantatjian HM, Saad MF, Estey EH, et al: Hypercalcemia in disseminated candidiasis. Am J Med 74:721-724, 1983 15. Walker JV, Baran D, Hakub N, et al: Histoplasmosis with hypercalcemia, renal failure and papillary necrosis. JAMA 237:1350-1353,1977 16. Kozeny GA, Barbato AL, Bansal VK, et al: Hypercalcemia associated with silicone-induced granulomas. N Engl J Med 311:1103-1105, 1984 17. Rosenthal N, Insogna K, Godshell JW: Elevations in circulating 1,25 dihydroxyvitamin D in three patients with lymphoma associated hypercalcemia. J Clin Endocrinol Metab 60:29-33, 1985
Treatment of Sarcoidosis-Associated Hypercalcemia With Ketoconazole Margaret J.Bia, MD, and Karllnsogna, MD • A 47-year-old patient presented with hypercalcemia secondary to sarcoidosis and was successfully treated with 1 year of corticosteroids leading to improvement in his hypercalcemia, hypercalcuria, and elevated levels of 1,25dihydroxyvitamin D. Angiotensin-converting enzyme levels (ACE) normalized and serum creatinine improved. When hypercalcemia recurred after a 3-year symptom-free interval, the patient refused repeat corticosteroid treatment and was placed on ketoconazole (initially 600 and eventually 800 mg/d). Ketoconazole controlled the patient's hypercalcemia (serum calcium, 3.2 to 2.6 mmol/L [12.8 to 10.4 mg/dL]), but only the larger dose suppressed serum 1,25-dihydroxyvitamin D levels into the normal range. Hypercalcuria was markedly improved with ketoconazole, decreasing from a peak of 23 mmol/d (940 mg/d) to less than 8.7 mmol/d (350 mg/d) on a dose of 800 mg. However, serum ACE levels remained elevated on ketoconazole. An attempt to taper the ketoconazole after 1 year resulted in rapid recurrence of hypercalcemia (serum calcium, 2.8 mmol/L [11.1 mg/dL]) and hypercalcuria (urinary calcium excretion, 11 mmol/d [451 mg/d]). After a total of 2 years of ketoconazole treatment, his defect in calcium metabolism remains well controlled despite persistent elevation in ACE levels. Serum cortisol levels and liver function tests remain normal on therapy, although there has been a slight decrease in serum testosterone levels accompanied by some decrease in libido. These data suggest that long-term use of ketoconazole may be a safe and effective alternative to corticosteroid treatment for sarcoidassociated hypercalcemia. Further study is needed to determine whether the long-term side effects of ketoconazole therapy or its failure to control disease activity in sarcoidosis outweigh its advantages in avoiding the known side effects of glucocorticoids. © 1991 by the National Kidney Foundation, Inc. INDEX WORDS: Sarcoidosis; hypercalcemia; ketoconazole; 1,25-dihydroxyvitamin D.
K
ETOCONAZOLE, a drug that inhibits several enzymes in the cytochrome P450 enzyme system, has been shown to inhibit the production of several steroid hormones such as glucocorticoids I and androgens. 2 The drug has also been shown to inhibit the production of 1,25dihydroxyvitamin D both in vitro 10 and in vivo. 3,4, 10 We recently had the opportunity to use this information to treat a patient with sarcoidosis and hypercalcemia due to excess 1,25-dihydroxyvitamin D production. The following case report describes our experience. CASE REPORT The patient was first admitted to Yale New Haven Hospital for an evaluation of hypercalcemia and renal failure. At that time, he was 47 years old and had had renal failure first recognized 6 months previously when a creatinine of274 mmol/ L (3.1 mg/dL) was noted on routine serum chemistries. An intravenous pyelogram (IVP) showed a large single right kidney From the Department 0/ Internal Medicine, Yale University School 0/ Medicine, New Haven , CT. Address reprint requests to Margaret J. Bia, MD, Yale University, Department o/Nephrology, 2070 LMP, 333 Cedar St, New Haven, CT 06510. © 1991 by the National Kidney Foundation, Inc. 0272-6386/ 91/ 1806-0013$3.00/ 0 702
without evidence for hydronephrosis or nephrocalcinosis. Serum calcium levels were also elevated (2.9 to 3.2 mmol/L [11.8 to 12.7 mgjdL]) and renal function deteriorated over the subsequent 24 weeks (creatinine up to 504 J'mol/L [5.7 mg/dL)). Serum complement levels, antinuclear antibodies (ANA), and serum protein electrophoresis were normal. On admission, physical examination was normal and urinalysis showed I + proteinuria, 0 to I red blood cells (RBC), 0 to I white blood cells (WBC), and no casts. A chest x-ray demonstrated prominent hilar adenopathy, and a transbronchial biopsy showed noncaseating granulomata. Initial level of angiotensin-converting enzyme (ACE) was elevated (Table I) and pulmonary function tests demonstrated the presence of mild restrictive lung disease. The patient was felt to have sarcoidosis with renal failure secondary to the associated hypercalcemia and he was begun on prednisone (I mg/kg/d) tapering to 20 mg/d by 6 months. The corticosteroids were tapered completely after I year of therapy. Renal function and calcium metabolism parameters before and during steroid treatment are presented in Table I. During steroid therapy, levels of 1,25-dihydroxyvitamin D rapidly normalized; hypercalcemia resolved, and renal function improved considerably. ACE levels also improved. Despite this improvement, the patient experienced significant glucocorticoid related side effects, including weight gain, anxiety, insomnia, and the development of early cataracts. Following cessation of corticosteroids, the patient remained symptom-free for 3 years with normal serum calcium concentrations of2.4 to 2.6 mmol/L (9.5-10.4 mg/dL) and a serum creatinine concentration of 195 J'mol/L (2.2 mg/dL). However, during this time period, levels of 1,25-dihydroxyvitamin D remained slightly above normal (122 to 173 pmol/L) and
American Journal of Kidney Diseases, Vol XVIII, No 6 (December), 1991: pp 702-705
KETOCONAZOLE TREATMENT OF HYPERCALCEMIA
703
Table 1. Laboratory Values Before and After Corticosteroid Therapy Before Corticosteroids (5/84)
Creatinine (/Lmol/L) Calcium (mmoIfL) Phosphorus (mmol/l) Alkaline phosphate (U/L) Urinary calcium excretion (mmol/d) 1,25 dihydroxyvitamin 0 (pmoI/L)* Intact PTH (ng/L)t ACE (lUlL):\:
530 (6 mg/dL) 2.9 (11 .7 mg/dl) 1.74 (5.4 mg/dL) 37 8.7 (350 mg/d) 156 409 56
On Corticosteroids (6/84-5/85)
203 (2.3 mg/dL) 2.4 (9.6 mg/dL) 1.0 (3.1 mg/dl) 39 5.7 (228 mg/d) 43-82 33-38
• Normal levels, 60 to 148 pmol/L. t Normal levels, up to 450 ng/L. :\: Normal levels, up to 48 lUlL.
he had occasional urinary calcium excretion rates of 8.4 to 10 mmol/d (350 to 400 mg/d). Serum ACE levels were frequently elevated (56 to 76/IU/L). During the fourth year after corticosteroid cessation, urinary calcium excretion increased markedly and he again became hypercalcemic (Fig I) with a deterioration in renal function (creatinine, 248 /Lmol/L [2.8 mg/dL]). Because of the patient's reluctance to resume glucocorticoids, treatment was begun with ketoconazole in an attempt to inhibit 1,25-dihydroxyvitamin 0 production and improve his hypercalcemia and hypercalcuria. Ketoconazole doses varied initially between 600 and 800 mg/d (Fig I). Hypercalcemia resolved promptly and urinary calcium excretion decreased markedly. Serum creatinine decreased from 248 /Lmol/ L (2.8 mg/dL) to the patient's baseline value of 195 /Lmol/L (2.2 mg/dL). After I year of treatment, the ketoconazole was discontinued briefly. However, arapid return of hypercalcemia and hypercalcuria necessitated reinstitution of therapy (Fig 26
2.83.2
i 1 l'j'
2 .6
1
2.8
'j'I'j'
2 .4
1
'1.5
I). Ketoconazole was restarted at a dose of 80a mg/d, since examination of the data during his first year of treatment indicated that 600 mg/d failed to completely normalize 1,25dihydroxyvitamin 0 levels into the normal range (Fig I). Currently, the patient remains on 800 mg of ketoconazole per day, with maintenance of normal blood levels of 1,25-dihydroxyvitamin 0 and calcium, although urinary calcium excretion is still intermittently elevated. He has now been on ketoconazole for a total of 2 years. Renal function has remained stable (serum creatinine, 194 /Lmol/L [2.2 mg/dL]). Ketoconazole has had no effect on serum phosphate or parathyroid hormone (PTH) levels during this time, nor has there been evidence for liver toxicity (normal serum transaminases when measured every 3 months). Serum cortisol levels, before and after corsyntropin stimulation, have also remained normal, but there has been a slight decrease in serum testosterone levels accompanied by some decrease in libido. Pulmonary function studies, performed once yearly, have demonstrated persistence of a mild restrictive lung pattern, and chest x-ray continues to show stable hilar adenopathy. Serum levels of ACE remain elevated on ketoconazole.
DISCUSSION
Fig 1. Urinary calcium excretion (A, .) and 1,25-dihydroxyvitamin D levels (B, 0) in the patient treated with ketoconazole during a recurrence of sarcoid-associated hypercalcemia. Dashed line indicates normal upper limits of levels of 1,25-c1ihydroxyvitamin D. (C) Ketoconazole dosage. Representative serum calcium values at given times are shown in parenthesis at the top of the graph.
Ketoconazole is known to inhibit several cytochrome P450 enzymes involved in the biosynthesis of steroid hormones, including glucocorticoids l and androgens. 2 More recently, the drug has been shown to produce a dose dependent decrease in the level of 1,25-dihydroxyvitamin D in both normal subjects3 and in patients with hyperparathyroidism. 4 Hypercalcemia in sarcoidosis is secondary to overproduction of 1,25-dihydroxyvitamin D 5 by activated macrophages within sarcoid granuloma6-8 and has been traditionally treated with glucocorticoids. 9 Since the 1a-hydroxylase enzyme complex includes a cytochrome P450 component, it is plausible that ketoconazole would be useful in controlling hypercalcemia in this condition, thereby obviating
704
the need for glucocorticoids. Indeed, in a recent report where ketoconazole was used for 9 days to treat a patient with sarcoid-associated hypercalcemia, serum levels of 1,25 decreased by more than 50% during therapy and in vitro studies documented a dose-dependent inhibitory effect of the drug on 1,25-dihydroxyvitamin D production in the host's pulmonary alveolar macrophages. IO Our case extends these observations and demonstrates that ketoconazole can inhibit 1,25-dihydroxyvitamin D production and hypercalcemia for up to 2 years in a patient with sarcoidosis with minimal side effects. Our patient was initially treated with corticosteroids, which successfully normalized his 1,25dihydroxyvitamin D production and corrected the hypercalcemia (Table I). Although his initial level of 1,25-dihydroxyvitamin D was only slightly elevated above the normal limits, this was distinctly abnormal in view of his degree of renal failure. The decrease in ACE levels with glucocorticoid treatment suggests that the activity of his sarcoidosis may have been suppressed by corticosteroids. II It is likely that the renal failure present at the time of his initial evaluation was related to the hypercalcemia, rather than sarcoid interstitial nephritis, since the initial urine sediment was benign and since hypercalcemia is a much more common reason for azotemia in sarcoidosis than is interstitial nephritis. After corticosteroids were discontinued, he remained stable for nearly 3 years, although he intermittently had elevations in levels of ACE, 1,25-dihydroxyvitamin D, and urinary calcium excretion. He then became frankly hypercalcemic, but was reluctant to resume corticosteroids because of their side effects. He was therefore begun on ketoconazole. Although serum calcium levels returned to normal rapidly (3.2 to 2.6 mmol/L), serum levels of 1,25-dihydroxyvitamin D did not suppress into the normal range until a dose of 800 mg/d (200 mg 4 times daily) was used (Fig 1). At doses of600 mg/d, his 1,25-dihydroxyvitamin D level and urine calcium excretion were still elevated and frank hypercalcemia recurred when the drug was tapered below this dose. The lack of an exact correlation between levels of 1,25-dihydroxyvitamin D and urine or serum calcium levels (Fig I) is likely explained by variations in the patient's calcium and sodium intake. These data confirm previous reports of the ra-
BIA AND INSOGNA
pidity of action and dose dependency of inhibition of 1,25-dihydroxyvitamin D production with ketoconazole. 3,JO Glass and Eil demonstrated a concentration-dependent inhibitory effect of ketoconazole on renal 1,25-dihydroxyvitamin D synthesis in normal human subjects. 3 Adams et al verified that these same results hold true for extrarenal production of the vitamin D in pulmonary macrophages from a patient with sarcoidosis. JO In these studies, ketoconazole doses of 600 to 900 mg/d produced a 40% reduction or more in baseline levels of 1,25-dihydroxyvitamin D. 3,4,7 Our inability to produce this degree of suppression of hormone production may be due to our patient's large body mass (122 kg), which would reduce his ketoconazole dpse on a mg/kg basis. Extrarenal overproduction of 1,25dihydroxyvitamin D with resultant hypercalcuria and less commonly hypercalcemia occurs in up to 20% of patients with sarcoidosis.1 2 It is also the mechanism of hypercalcemia in other granulomatous diseases such as tuberculosis,13 candidiasis,14 histoplasmosis,15 silicone toxicity, 16 and in some cases oflymphoma. 17 Further study is needed to determine whether ketoconazole will prove efficacious in these disorders as well. Side effects with prolonged ketoconazole therapy in our patient were surprisingly few. Liver and adrenal function studies remained normal. However, he did experience a decrease in libido in association with a decrease in testosterone levels. However, the patient felt that this effect was less troublesome compared with the central nervous system and psychological side effects he experienced during the initial treatment with corticosteroids. He did not complain of headache or loss of concentration, which have been described previously with ketoconazole doses of 800 mg and greater. 3,JO It is likely that ketoconazole has not suppressed the activity of the patient's sarcoidosis as effectively as corticosteroids, since ACE levels remain elevated with treatment. Furthermore, he had a rapid recurrence of hypercalcemia and increased levels of 1,25-dihydroxyvitamin D when the drug was tapered off after 1 year of therapy compared with a disease-free interval of more than 3 years after I year of corticosteroid therapy. Further study is needed to determine whether this failure of ketoconazole to suppress disease activity in sarcoidosis or its potential side effects at the higher
KETOCONAZOLE TREATMENT OF HYPERCALCEMIA
705
doses which may be required to adequately suppress 1,25-dihydroxyvitamin D production outweigh the advantage of obviating the need for corticosteroid therapy. Perhaps lower doses of ketoconazole could be used in conjunction with lower doses of glucocorticoids to achieve an additive effect on the control of hypercalcemia while minimizing the side effects of both drugs. When using ketoconazole, careful attention must be
paid to drug dosage to ensure adequate suppression of 1,25-dihydroxyvitamin D overproduction. In addition, levels of several hormones, especially cortisol, must be followed during therapy. Despite these cautions, the data suggest that ketoconazole offers a reasonable alternative to steroid therapy as treatment for sarcoidosis associated hypercalcemia and may be used safely for up to 2 years.
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