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Hypercalcaemia in sarcoidosis
CASE REPORT
Case report
Hypercalcaemia in sarcoidosis C Young, R Burrows, J Katz, H Beynon A 43-year-old woman came to the outpatient department in March, 1998, for management of her steroid-resistant hypercalcaemia. She had increasing lethargy, nausea, and vomiting. On examination she was cushingoid with a significant proximal myopathy and bilateral band keratopathy. Non-insulin-dependent diabetes mellitus had been diagnosed when she was 15. In May, 1997, fever, lymphadenopathy, and acute renal failure (creatinine 530 mmol/L) led to a diagnosis of sarcoidosis complicated by hypercalcaemia (corrected calcium 2·9 mmol/L). A renal biopsy specimen showed a noncaseating granulomatous interstitial nephritis, and non-caseating granulomas were also present on mediastinal biopsy. Serum angiotensin-converting-enzyme concentrations were raised, and a gallium scan showed increased uptake in the salivary glands and mediastinal and inguinal lymph nodes (figure). Oral prednisolone (60 mg daily) had no effect on the hypercalcamia and caused a deterioration in her diabetic control. Serum parathyroid hormone concentrations were found to be raised (59 pg/mL, usual range 10–55 pg/mL), supporting a diagnosis of hyperparathyroidism. A thallium/technetium 99 subtraction scan showed an area of increased uptake in the parathyroid glands, and parathyroidectomy was undertaken. Tissue specimens showed parathyroid hyperplasia with no granulomatous infiltration. Postoperatively, parathyroid hormone concentrations fell to less than 10 pg/mL. Serum calcium remained high (corrected 3·09 mmol/L), despite 40 mg prednisolone daily. At this stage, she was referred to the sarcoidosis clinic where serum concentrations of 1,25-dihydroxyvitamin D3 were measured (88 pmol/L; normal range 43–144 pmol/L), ketoconazole was started at an initial dose of 200 mg daily, increased to 600 mg daily and rapidly produced reductions in serum calcium to 2·4 mmol/L, serum 1,25-dihydroxyvitamin D3 to 11 pmol/L, and serum creatinine to 230 mmol/L. Prednisolone dose was reduced to 10 mg daily, and hydroxychloroquine (200 mg daily) was given as maintenance treatment. In December, 1998, she was well with serum calcium of 2·2 mmol/L and creatinine of 250 mmol/L. The association between sarcoidosis and hypercalcaemia is seen in about 10% of patients.1 The underlying mechanism is thought to involve high circulating concentrations of 1,25-dihydroxyvitamin D3, produced by extrarenal 1a hydroxylation of vitamin D in pulmonary macrophages and sarcoid granulomas.2 Granulomatous production of parathyroid-hormonerelated protein may also play a part.2 Although Lancet 1999; 353: 374 Departments of Rheumatology (C Young MRCP), Endocrinology (J Katz MRCP); Rheumatology, Royal Free Hospital, London NW3 2QG, UK (H Beynon FRCP); and Department of Renal Medicine, Hammersmith Hospital, London (R Burrows MRCP) Correspondence to: Dr C Young
374
Gallium scan There is pronounced inguinal and femoral lymph node uptake in addition to typical patterns highly suggestive of sarcoidosis.
hypercalcaemia in sarcoidosis is usually responsive to steroids,3 they were not effective in this case. Further investigation revealed hyperparathyroidism, subsequently shown not to be the sole cause of the hypercalcaemia. Although concentrations of 1,25-dihydroxyvitamin D3 were within the normal range, this was inappropriately high after parathyroidectomy and felt largely to be related to extra-renal vitamin D 1a hydroxylation.1 Hypercalcaemia complicating sarcoidosis most often results in suppression of parathyroid function.3 In contrast, an association with hyperparathyroidism, as described here, is far less common only having been reported in 50 cases of sarcoidosis in the past 40 years.3 Although mechanisms have been suggested to account for this combination of disorders,4 the frequency of the relation is so low that chance association cannot be excluded. Ketoconazole is now considered an appropriate second-line treatment in hypercalcaemic sarcoidosis when oral steroids are ineffective or contraindicated.5 Ketoconazole is an imidazole antifungal agent which inhibits cytochromeP450-linked 1-a hydroxylation of 25-hydroxyvitamin D3.5 References 1 2 3 4
5
Sharma OP. Vitamin D, calcium, and sarcoidosis. Chest 1996; 109: 535–39. Zeimer HJ, Greenaway TM, Salvin J, et al. Parathyroid-hormonerelated protein in sarcoidosis. Am J Pathol 1998; 152: 17–21. Tomita A. Primary hyperparathyroidism associated with sarcoidosis. Nippon Ronsho 1995; 53: 949–52. Hartmann F, Lehmann H. A case of sarcoidosis with simultaneous primary hyperparathyroidism, coincidence or consequence? Med Klin 1975; 70: 904–08. Bia MJ, Insogna K. Treatment of sarcoidosis-associated374 hypercalcaemia with ketoconazole. Am J Kidney Dis 1991; 18: 702–05.
THE LANCET • Vol 353 • January 30, 1999
Case report
Hypercalcaemia in sarcoidosis C Young, R Burrows, J Katz, H Beynon A 43-year-old woman came to the outpatient department in March, 1998, for management of her steroid-resistant hypercalcaemia. She had increasing lethargy, nausea, and vomiting. On examination she was cushingoid with a significant proximal myopathy and bilateral band keratopathy. Non-insulin-dependent diabetes mellitus had been diagnosed when she was 15. In May, 1997, fever, lymphadenopathy, and acute renal failure (creatinine 530 mmol/L) led to a diagnosis of sarcoidosis complicated by hypercalcaemia (corrected calcium 2·9 mmol/L). A renal biopsy specimen showed a noncaseating granulomatous interstitial nephritis, and non-caseating granulomas were also present on mediastinal biopsy. Serum angiotensin-converting-enzyme concentrations were raised, and a gallium scan showed increased uptake in the salivary glands and mediastinal and inguinal lymph nodes (figure). Oral prednisolone (60 mg daily) had no effect on the hypercalcamia and caused a deterioration in her diabetic control. Serum parathyroid hormone concentrations were found to be raised (59 pg/mL, usual range 10–55 pg/mL), supporting a diagnosis of hyperparathyroidism. A thallium/technetium 99 subtraction scan showed an area of increased uptake in the parathyroid glands, and parathyroidectomy was undertaken. Tissue specimens showed parathyroid hyperplasia with no granulomatous infiltration. Postoperatively, parathyroid hormone concentrations fell to less than 10 pg/mL. Serum calcium remained high (corrected 3·09 mmol/L), despite 40 mg prednisolone daily. At this stage, she was referred to the sarcoidosis clinic where serum concentrations of 1,25-dihydroxyvitamin D3 were measured (88 pmol/L; normal range 43–144 pmol/L), ketoconazole was started at an initial dose of 200 mg daily, increased to 600 mg daily and rapidly produced reductions in serum calcium to 2·4 mmol/L, serum 1,25-dihydroxyvitamin D3 to 11 pmol/L, and serum creatinine to 230 mmol/L. Prednisolone dose was reduced to 10 mg daily, and hydroxychloroquine (200 mg daily) was given as maintenance treatment. In December, 1998, she was well with serum calcium of 2·2 mmol/L and creatinine of 250 mmol/L. The association between sarcoidosis and hypercalcaemia is seen in about 10% of patients.1 The underlying mechanism is thought to involve high circulating concentrations of 1,25-dihydroxyvitamin D3, produced by extrarenal 1a hydroxylation of vitamin D in pulmonary macrophages and sarcoid granulomas.2 Granulomatous production of parathyroid-hormonerelated protein may also play a part.2 Although Lancet 1999; 353: 374 Departments of Rheumatology (C Young MRCP), Endocrinology (J Katz MRCP); Rheumatology, Royal Free Hospital, London NW3 2QG, UK (H Beynon FRCP); and Department of Renal Medicine, Hammersmith Hospital, London (R Burrows MRCP) Correspondence to: Dr C Young
374
Gallium scan There is pronounced inguinal and femoral lymph node uptake in addition to typical patterns highly suggestive of sarcoidosis.
hypercalcaemia in sarcoidosis is usually responsive to steroids,3 they were not effective in this case. Further investigation revealed hyperparathyroidism, subsequently shown not to be the sole cause of the hypercalcaemia. Although concentrations of 1,25-dihydroxyvitamin D3 were within the normal range, this was inappropriately high after parathyroidectomy and felt largely to be related to extra-renal vitamin D 1a hydroxylation.1 Hypercalcaemia complicating sarcoidosis most often results in suppression of parathyroid function.3 In contrast, an association with hyperparathyroidism, as described here, is far less common only having been reported in 50 cases of sarcoidosis in the past 40 years.3 Although mechanisms have been suggested to account for this combination of disorders,4 the frequency of the relation is so low that chance association cannot be excluded. Ketoconazole is now considered an appropriate second-line treatment in hypercalcaemic sarcoidosis when oral steroids are ineffective or contraindicated.5 Ketoconazole is an imidazole antifungal agent which inhibits cytochromeP450-linked 1-a hydroxylation of 25-hydroxyvitamin D3.5 References 1 2 3 4
5
Sharma OP. Vitamin D, calcium, and sarcoidosis. Chest 1996; 109: 535–39. Zeimer HJ, Greenaway TM, Salvin J, et al. Parathyroid-hormonerelated protein in sarcoidosis. Am J Pathol 1998; 152: 17–21. Tomita A. Primary hyperparathyroidism associated with sarcoidosis. Nippon Ronsho 1995; 53: 949–52. Hartmann F, Lehmann H. A case of sarcoidosis with simultaneous primary hyperparathyroidism, coincidence or consequence? Med Klin 1975; 70: 904–08. Bia MJ, Insogna K. Treatment of sarcoidosis-associated374 hypercalcaemia with ketoconazole. Am J Kidney Dis 1991; 18: 702–05.
THE LANCET • Vol 353 • January 30, 1999