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Hypercalcaemia associated with viral hepatitis
181
mitochondrial primers to ensure the viability of the DNA. Results were taken as positive if sequences were amplified by two or all three sets of primers. None of 13 HIV-exposed seronegative haemophiliac patients were positive by these criteria; all but 1 seropositive haemophiliac patients were. When we began this study we did find PCR-positive individuals among the high-risk seronegatives but were warned that these results might have been false positives by the detection of the same positive readings in seronegative blood donors who had signed a "low-risk group" donor declaration. With greater experience and obsessional attention to reducing false positives this no longer happens in our laboratory, and we agree with Lefrere et al that an international quality assurance programme for HIV-PCR is needed before the PCR assay/test can be used as a diagnostic tool for HIV infection.
Departments of Clinical Immunology and Clinical Biochemistry, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia
GRANT I. SHOEBRIDGE PAUL A. GATENBY BRIAN N. NIGHTINGALE LILLIAN BARONE AILEEN WING-SIMPSON BRUCE H. BENNETTS WILLIAM J. HENSLEY Serum corrected calcium concentration
(—W—W), alkaline phosphatase activity (x--x), and y-glutamyl transpeptidase activity (yGT, 0-0) during the course of the patient’s illness.
1. Loche M, Mach B. Identification of HIV-infected seronegative individuals by a direct
diagnostic test based on hybridisation to amplified viral DNA. Lancet 1988; ii: 418-21. 2. Sonano V, Hewlett I, Tor J, Clotet B, Epstein J, Foz M. Silent HIV infection in heterosexual partners of seropositive drug abusers in Spain. Lancet 1990; 335: 860. 3 Ameisen JC, Guy B, Lecoq JP, et al. Persistent antibody response to the HIV-1 negative regulatory factor m HIV-1 infected seronegative persons. N Engl J Med
Horizontal Ime represents upper !im!t of normal values. There was a significant correlation between the serum calcium concentration and the yGT activity (r=089, p<002).
1989; 320: 251-52.
Hypercalcaemia associated with viral hepatitis associated with viral illness is extremely Previous reports have been of patients with retrovirus infection.1,2 We describe here its occurrence in an immunocompetent 68-year-old woman referred with a four-week history of generalised malaise, anorexia, and arthralgia in her knees and ankles. She had been found to be hypercalcaemic when she first presented to her own doctor four weeks previously (corrected serum calcium [Ca] 3-43 mmol/1). Her history included mild osteoarthritis of the knees and mild hypertension, and she was on sulindac 100 mg twice daily, atenolol 50 mg daily, and cyclopenthiazide 0-5 mg daily. There was no history of blood transfusion, supplemental vitamins, or excessive intake of calcium or antacids. She was teetotal. She had a blood pressure of 140/90 mm Hg. There were no other abnormal physical signs. She was admitted to hospital and thiazide therapy was withdrawn. Initial investigation confirmed hypercalcaemia and abnormal liver function (figure)—albumin 31 mmol/1, bilirubin 27 mmol/1 (normal 2-20), and aspartate transaminase (AST) 15 U/1 (8-45), serum creatinine 0-11 mmol/1 (0-05-0-10), creatinine clearance 0-50 ml/s (1-5-2-5), serum phosphate 1.07 mmol/1 (0-7-1-5), and serum magnesium 0-5 mmol/1 (0-8-1-0). Serum immunoreactive parathyroid hormone concentration was compatible with normal parathyroid function for this degree of renal impairment. The thyroid and parathyroids were normal on ultrasonography and on subtraction scintigraphy with technetium-99m and thallium-201. Chest X-ray, skeletal survey, bone scan, mammography, and faecal occult bloods were all normal. Protein electrophoresis of serum and urine revealed no abnormal bands, and Mantoux test was negative. She was biochemically euthyroid. The biliary tree and liver were normal on ultrasonography. Hepatitis A and B and cytomegalovirus serology was negative, as were antinuclear and antimitochondrial antibodies. Complement fixation test with enterovirus pooled
SiR,—Hypercalcaemia
uncommon.
antigen (coxsackie A9, Bl-5, echovirus 4, 6, 9, 14, 24, 30) was strongly positive at a titre of 512, which fell to less than 32 as her hepatitis resolved. Liver biopsy showed features compatible with acute viral hepatitis. There was cholestasis but an orsein stain for hepatitis B virus was negative.
Spontaneous resolution of her symptoms, hypercalcaemia, and liver function abnormalities occurred over the following 6 months and has been maintained for 2 years. Serum creatinine concentration did not change from its baseline level. This patient had biochemical and histological evidence of hepatitis, with serological findings suggesting that an enterovirus was responsible. No explanation could be found for the hypercalcaemia despite extensive investigation; therapy with a thiazide was clearly an insufficient explanation for such striking hypercalcaemia, which persisted for 4-5 months after discontinuation of the drug. The very close temporal relation between the hypercalcaemia and the biochemical evidence of viral hepatitis strongly suggested a causal relation. In the absence of any evidence for increased calcium absorption from the gut or reduced renal calcium loss, an increase in bone resorption remains the most likely cause. Acute inflammatory response and specific immune response to a pathogen have in common a dependence on cytokines.3 Knowledge of the function of cytokines in human disease is growing fast, less so for viral disease than for bacterial and parasitic disease.’ Many cytokines, including interleukin-1(alpha and beta), transforming growth factor-beta, and tumour necrosis factor, have bone-resorbing activity.5 Perhaps virus-induced production of specific cytokines resulted in the hypercalcaemia in this patient. If so, it is unusual that it has not been reported in immunocompetent individuals. Department of Medicine, North Shore Hospital, Private Bag Takapuna, Auckland 9, New Zealand
D.
J. FORD
Department of Medicine, University of Auckland, Auckland, New Zealand
1.
I. R. REID
Zaloga GP, Chernow B, Eil C. Hypercalcaemia and disseminated cytomegalovirus infection in the acquired immuno-deficiency syndrome. Ann Intern Med 1985, 102: 331-33.
Jacobs MB. The acquired immuno-deficiency syndrome and hypercalcaemia. WestJ Med 1986; 144: 469-71. 3. Duff GW. Peptide regulatory factors in non-malignant disease. Lancet 1989; i:
2.
1432-35. 4.
Tracey KJ, Cerami
A. Cachectin/tumour necrosis factor and other cytokines in infection disease. Current Opinion in Immunology 1989; 1: 454-61. 5. Raisz LG. Local and systemic factors in the pathogenesis of osteoporosis. N Engl J Med 1988; 318: 818-28.
mitochondrial primers to ensure the viability of the DNA. Results were taken as positive if sequences were amplified by two or all three sets of primers. None of 13 HIV-exposed seronegative haemophiliac patients were positive by these criteria; all but 1 seropositive haemophiliac patients were. When we began this study we did find PCR-positive individuals among the high-risk seronegatives but were warned that these results might have been false positives by the detection of the same positive readings in seronegative blood donors who had signed a "low-risk group" donor declaration. With greater experience and obsessional attention to reducing false positives this no longer happens in our laboratory, and we agree with Lefrere et al that an international quality assurance programme for HIV-PCR is needed before the PCR assay/test can be used as a diagnostic tool for HIV infection.
Departments of Clinical Immunology and Clinical Biochemistry, Royal Prince Alfred Hospital, Camperdown, NSW 2050, Australia
GRANT I. SHOEBRIDGE PAUL A. GATENBY BRIAN N. NIGHTINGALE LILLIAN BARONE AILEEN WING-SIMPSON BRUCE H. BENNETTS WILLIAM J. HENSLEY Serum corrected calcium concentration
(—W—W), alkaline phosphatase activity (x--x), and y-glutamyl transpeptidase activity (yGT, 0-0) during the course of the patient’s illness.
1. Loche M, Mach B. Identification of HIV-infected seronegative individuals by a direct
diagnostic test based on hybridisation to amplified viral DNA. Lancet 1988; ii: 418-21. 2. Sonano V, Hewlett I, Tor J, Clotet B, Epstein J, Foz M. Silent HIV infection in heterosexual partners of seropositive drug abusers in Spain. Lancet 1990; 335: 860. 3 Ameisen JC, Guy B, Lecoq JP, et al. Persistent antibody response to the HIV-1 negative regulatory factor m HIV-1 infected seronegative persons. N Engl J Med
Horizontal Ime represents upper !im!t of normal values. There was a significant correlation between the serum calcium concentration and the yGT activity (r=089, p<002).
1989; 320: 251-52.
Hypercalcaemia associated with viral hepatitis associated with viral illness is extremely Previous reports have been of patients with retrovirus infection.1,2 We describe here its occurrence in an immunocompetent 68-year-old woman referred with a four-week history of generalised malaise, anorexia, and arthralgia in her knees and ankles. She had been found to be hypercalcaemic when she first presented to her own doctor four weeks previously (corrected serum calcium [Ca] 3-43 mmol/1). Her history included mild osteoarthritis of the knees and mild hypertension, and she was on sulindac 100 mg twice daily, atenolol 50 mg daily, and cyclopenthiazide 0-5 mg daily. There was no history of blood transfusion, supplemental vitamins, or excessive intake of calcium or antacids. She was teetotal. She had a blood pressure of 140/90 mm Hg. There were no other abnormal physical signs. She was admitted to hospital and thiazide therapy was withdrawn. Initial investigation confirmed hypercalcaemia and abnormal liver function (figure)—albumin 31 mmol/1, bilirubin 27 mmol/1 (normal 2-20), and aspartate transaminase (AST) 15 U/1 (8-45), serum creatinine 0-11 mmol/1 (0-05-0-10), creatinine clearance 0-50 ml/s (1-5-2-5), serum phosphate 1.07 mmol/1 (0-7-1-5), and serum magnesium 0-5 mmol/1 (0-8-1-0). Serum immunoreactive parathyroid hormone concentration was compatible with normal parathyroid function for this degree of renal impairment. The thyroid and parathyroids were normal on ultrasonography and on subtraction scintigraphy with technetium-99m and thallium-201. Chest X-ray, skeletal survey, bone scan, mammography, and faecal occult bloods were all normal. Protein electrophoresis of serum and urine revealed no abnormal bands, and Mantoux test was negative. She was biochemically euthyroid. The biliary tree and liver were normal on ultrasonography. Hepatitis A and B and cytomegalovirus serology was negative, as were antinuclear and antimitochondrial antibodies. Complement fixation test with enterovirus pooled
SiR,—Hypercalcaemia
uncommon.
antigen (coxsackie A9, Bl-5, echovirus 4, 6, 9, 14, 24, 30) was strongly positive at a titre of 512, which fell to less than 32 as her hepatitis resolved. Liver biopsy showed features compatible with acute viral hepatitis. There was cholestasis but an orsein stain for hepatitis B virus was negative.
Spontaneous resolution of her symptoms, hypercalcaemia, and liver function abnormalities occurred over the following 6 months and has been maintained for 2 years. Serum creatinine concentration did not change from its baseline level. This patient had biochemical and histological evidence of hepatitis, with serological findings suggesting that an enterovirus was responsible. No explanation could be found for the hypercalcaemia despite extensive investigation; therapy with a thiazide was clearly an insufficient explanation for such striking hypercalcaemia, which persisted for 4-5 months after discontinuation of the drug. The very close temporal relation between the hypercalcaemia and the biochemical evidence of viral hepatitis strongly suggested a causal relation. In the absence of any evidence for increased calcium absorption from the gut or reduced renal calcium loss, an increase in bone resorption remains the most likely cause. Acute inflammatory response and specific immune response to a pathogen have in common a dependence on cytokines.3 Knowledge of the function of cytokines in human disease is growing fast, less so for viral disease than for bacterial and parasitic disease.’ Many cytokines, including interleukin-1(alpha and beta), transforming growth factor-beta, and tumour necrosis factor, have bone-resorbing activity.5 Perhaps virus-induced production of specific cytokines resulted in the hypercalcaemia in this patient. If so, it is unusual that it has not been reported in immunocompetent individuals. Department of Medicine, North Shore Hospital, Private Bag Takapuna, Auckland 9, New Zealand
D.
J. FORD
Department of Medicine, University of Auckland, Auckland, New Zealand
1.
I. R. REID
Zaloga GP, Chernow B, Eil C. Hypercalcaemia and disseminated cytomegalovirus infection in the acquired immuno-deficiency syndrome. Ann Intern Med 1985, 102: 331-33.
Jacobs MB. The acquired immuno-deficiency syndrome and hypercalcaemia. WestJ Med 1986; 144: 469-71. 3. Duff GW. Peptide regulatory factors in non-malignant disease. Lancet 1989; i:
2.
1432-35. 4.
Tracey KJ, Cerami
A. Cachectin/tumour necrosis factor and other cytokines in infection disease. Current Opinion in Immunology 1989; 1: 454-61. 5. Raisz LG. Local and systemic factors in the pathogenesis of osteoporosis. N Engl J Med 1988; 318: 818-28.