Primary hyperparathyroidism

THE LANCET

Bornu, the Hausa (29%) in Kano State, and in the high grasslands of Cameroon and Nigeria (both 32%); where malaria is or was holoendemic, the gene frequency is not more than 0·125 (sickle-cell trait 25%), for example, around Ibadan.4,5 Where malaria is holoendemic, those with sickle-cell trait probably experience a survival advantage for one short period in infancy and early childhood, when maternally derived antibodies have declined and before protective immunity is acquired; in contrast, where malaria is hyperendemic, the advantage either lasts longer, up to about four years of age, or recurs every rainy season. These observations on HbS gene frequency provide indirect evidence for the suggestion of Snow and colleagues that cumulative rates of severe malaria and probably malarial deaths are greater where transmission is less than holoendemic. Alan F Fleming Laboratory Services, Department of Pathology and Microbiology, University Teaching Hospital, Private Bag RW 1X, Lusaka, Zambia

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Snow RW, Omumbo JA, Lowe B, et al. Relation between severe malaria morbidity in children and level of Plasmodium falciparum transmission in Africa. Lancet 1997; 349: 1650–54. Raper AB. Sickling and malaria. Trans R Soc Trop Med Hyg 1960; 54: 503–04. Livingstone FB. Malaria and human polymorphisms. Annu Rev Genet 1971; 5: 33–64. Fleming AF, Storey J, Molineaux L, et al. Abnormal haemoglobins in the Sudan savanna of Nigeria I: prevalence of haemoglobins and relationships between sickle cell trait, malaria and survival. Ann Trop Med Parasitol 1979; 73: 161–72. Nagel RL, Fleming AF. Genetic epidemiology of the ␤s gene. Baillière’s Clin Haematol 1992; 5: 331–65.

Severe hepatitis in patients with AIDS and haemophilia B treated with indinavir SIR—Norbert Braü and colleagues (March 29, p 924)1 describe three patients who developed severe hepatitis after the start of indinavir. We report such complications in an AIDS patient with haemophilia B. A 27-year-old man with mild haemophilia B had intramuscular and joint haemorrhage two to three times a year, with successful recovery after two packs (800 U) of factor IX concentrates for each episode. Since March, 1993, he received zidovudine (600 mg daily) in combination with the inhalation of pentamidine isethionate twice a month (CD4 lymphocyte 108/µL, CD8 lymphocyte 297/µL), followed by

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didanosine, zalcitabine, lamivudine, alone or in combination. After 3·5 years of treatment, he became a nonresponder to all of these regimens (CD4 lymphocyte 13/µL, CD8 lymphocyte 116/µL). He was also positive for hepatitis C virus RNA with mild liver dysfunction, but no obvious fluctuations of aspartate aminotransferase (AST; maximum 49 IU [normal range 7–21]) and alanine aminotransferase (ALT; maximum 94 IU [normal range 4–17 IU]) were noticed during treatment with anti-HIV drugs. In August, 1996, he was entered in the indinavir trial and started to receive 800 mg indinavir alone every 8 h (CD4 lymphocyte 7/ µL, CD8 lymphocyte 119/µL, eosinophils 216/µL, AST 49/IU, ALT 60 IU, IgE not done). 2 months later, he began to have haemorrhagic episodes in the shoulder, elbows, and knee joints two to three times a month. He also needed two to three times more factor IX concentrate to treat each haemorrhage. He was told that this increase could be a side-effect of indinavir, but chose to continue with this drug because of its effect on CD4 (277/µL) and CD8 (616/µL) counts. 1 month later, he complained of severe left back pain with haematuria, and was diagnosed as having a ureter stone by abdominal echogram. The stone was discharged with anticholinergic drugs and supplementation of water without sequelae. Indinavir was continued at half the original dosage. At this time, his serum concentrations of AST and ALT gradually increased, but in January, 1997, worsened (AST 557 IU, ALT 807 IU) in association with pronounced eosinophilia (897/µL) and raised IgE (4662 IU/mL [normal 0–165 IU/mL]) without any clinical symptoms. These adverse events suggest severe drugallergy hepatitis due to indinavir. Nevertheless, he did not want to stop indinavir in combination with zidovudine and lamivudine, which was therefore continued with careful monitoring of his liver function. We also obtained his consent to treat the liver disorder with extract of Chinese sweet herb (twice or thrice weekly), which is approved by the Ministry of Health and Welfare of Japan for the treatment of liver dysfunction and allergy (Strong Minophagen C, SMC, Minophagen Co, Japan). After 2 weeks his AST and ALT gradually decreased to 119 IU and 263 IU, respectively. We have continued this treatment and his liver function remains stable (AST 119 IU, ALT 187 IU, eosinophils 376/µL, IgE 4669 IU/mL). We have treated 12 haemophiliacs, including this case, in this way, and have had to reduce or discontinue indinavir in ten. Our observations suggest that indinavir may affect blood coagulation and the fibrinolysis system,

causing a tendency to haemorrhage, which may be rare in nonhaemophiliacs. However, we have not yet identified any causative factor. Attention should be paid to the occurrence of renal stones, liver dysfunction, and haemorrhage episodes in HIV-infected patients who are treated with indinavir, especially in haemophiliacs. *Juzo Matsuda, Kengo Gohchi, Masami Yamanaka Department of Medicine, Teikyo University School of Medicine, 11-1, Kaga 2-Chome, Itabashi-Ku, Tokyo 173, Japan

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Braü N, Leaf HL, Wieczorek RL, Margolis DM. Severe hepatitis in three AIDS patients treated with indinavir. Lancet 1997; 349: 924–25.

Primary hyperparathyroidism SIR—It is a shame that in their otherwise excellent, comprehensive and up to date review of primary hyperparathyroidism (April 26, p 1233),1 Ali Al Zahrani and Michael A Levine repeat, without reference or further discussion, the old mantra that thiazides are contraindicated in patients with hyperparathyroidism. In 13 patients who we studied there was no difference, on or off thiazides, in plasma total calcium (corrected for albumin) or whole blood ionised calcium.2 Since then, I have continued to treat my patients with these drugs, and have encountered no problems. Occasionally the plasma calcium may rise transiently, but this has no clinical effect: presumably the rise is due to temporary effects on plasma volume, and homoeostatic mechanisms soon eliminate it. These drugs not only reduce the hypercalciuria that is often found in these patients, but they also reduce the risk of renal stones, and have been shown to have an effect on bone mineral density comparable to that of previous hormone-replacement therapy.3 They would therefore seem to be a drug of choice for the hypertension that is frequently found in patients with hyperparathyroidism (and which if not treated may lead to renal impairment). I hope that others may be emboldened to challenge this myth, and, if they confirm our findings, enable more of their patients to enjoy the postulated benefits of this therapy. G S Spathis St Helier Hospital, Carshalton, Surrey SM5 1AA, UK

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Zahrani AA, Levine MA. Primary hyperparathyroidism. Lancet 1997; 349: 1233–38.

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Farquhar CW, Spathis GS, Barron JL, Levin GE. Failure of thiazide diuretics to increase plasma calcium in mild primary hyperparathyroidism. Postgrad Med J 1990; 66: 714–16. Orwoll ES, Bauer DC, Vogt TM, Fox KM. Axial bone mass in older women. Ann Intern Med 1996; 124: 187–96.

of these drugs in these patients. Ali Al Zahrani, *Michael A Levine Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

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Authors’ reply SIR—We are grateful to G S Spathis for both his complimentary and provocative comments. Spathis takes exception to our recommendation that diuretics, particularly thiazides, should be avoided in patients with primary hyperparathyroidism, and cites our lack of references supporting this position. On the contrary, he suggests that his own experiences, both published1 and anecdotal, provide evidence that thiazides are not contraindicated in these patients. His study was a retrospective analysis of 13 patients with mild and asymptomatic primary hyperparathyroidism who took thiazide diuretics intermittently over several years (range 1·5–10·7). Although this small study failed to demonstrate significant worsening of hypercalcaemia during periods when patients were actually taking the thiazides, other reports have documented the precipitation of severe hypercalcaemia in occasional patients with primary hyperparathyroidism who were taking these drugs.2 Although Spathis cites several important benefits that may derive from the use of thiazide diuretics, including prevention of kidney stones and improvement in bone mineral density, it remains unproved whether these salutatory effects occur in patients with primary hyperparathyroidism. Based on the sparse information concerning the safety, or benefit, of thiazides in patients with primary hyperparathyroidism, we felt it was reasonable to recommend against the routine use of these drugs. We did not assert, and the available data do not support, the proposition that thiazides are absolutely contraindicated in patients with primary hyperparathyroidism, however. Rather, we share Spathis’s hope that others will be emboldened to challenge current convention about the use of thiazides in patients with primary hyperparathyroidism, but would urge them to do so in the setting of a large, prospective, and well-designed clinical study that will provide meaningful information. With the excellent outcome of surgery in primary hyperparathyroidism, and the wide selection of alternative drugs available for the treatment of hypertension, it seems imprudent to use thiazide diuretics in patients with primary hyperparathyroidism until we know more about the long-term risks and benefits

Vol 350 • August 2, 1997

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Farquahar CW, Spathis GS, Barron JL, Levin GE. Failure of thiazide diuretics to increase plasma calcium in mild primary hyperparathyroidism. Postgrad Med J 1990; 66: 714–16. Strong P, Jewell S, Rinker J, Hoch D, Crapo L. Thiazide therapy and severe hypercalcemia in a patient with hyperparathyroidism. West J Med 1991; 154: 338–40.

SIR—In their informative seminar Ali Al Zahrani and Michael A Levine1 include treatment with lithium and familial hypocalciuric hypercalcaemia in the differential diagnosis of primary hyperparathy-roidism. They state that familial hypocalciuric hypercalcaemia is characterised, among other features, by hypocalciuria. In this respect, it is of interest to add one point. Urine calcium excretion per 24 h among hypercalcaemic patients shows overlap between familial hypocalciuric hypercalcaemia and typical primary hyperparathyroidism. Part of the overlap is caused by variation in creatinine clearance, and with adjustment for this index the overlap of absolute values between the two conditions is diminished. A ratio of calcium clearance to creatinine clearance of 0·02 or more is most characteristic of patients with primary hyperparathyroidism, and a value of 0·01 or less is suggestive of familial benign hypercalcaemia. Values between 0·01 and 0·02 are common in both disorders. Francisco J Fernández-Fernández Department of Internal Medicine, Hospital Arquitecto Marcide, 15405 Ferrol, Spain

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Zahrani AA, Levine MA. Primary hyperparathyroidism. Lancet 1997; 349: 1233–38.

Breast cancer genetics SIR—The Breast Cancer Linkage Consortium’s (BCLC) report (May 24, p 1505)1 describes the field of breast cancer genetics in a way that is misleading to physicians caring for breast cancer patients and families. In their introduction, the investigators introduce BRCA1 and BRCA2 and then go on to describe the “other genes that are known to increase the risk of breast cancer”. They fail to mention the ataxia-telangiectasia (A-T) gene despite the compelling, widely known, and highly cited, evidence that this gene is responsible for a high proportion, perhaps 6·6%, of all breast

cancer cases.2 This proportion of female breast cancer is higher than the proportion due to mutations at the BRCA1/BRCA2 loci, according to the most recent data.3,4 There are no reliable data that refute the predisposition of A-T heterozygotes to breast cancer. One of the three members of the BCLC writing committee, Douglas Easton, reviewed the relation between A-T heterozygosity and breast cancer for a published symposium volume,5 so he is certainly aware of it. Physicians can be misled by incorrect or obsolete information in the rapidly advancing field of breast cancer genetics. In turn, patients may be harmed or unduly alarmed if a distorted account of breast cancer genetics leads to inappropriate referral for genetic testing or prophylactic surgery. Michael Swift Institute for the Genetic Analysis of Common Diseases, New York Medical College, Hawthorne, NY 10532, USA

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Breast Cancer Linkage Consortium Pathology of familial lung cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet 1997; 349: 1505–10. Athma P, et al. Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet Cytogene 1996; 92: 130–34. FitzGerald MG, MacDonald DJ, Krainer N, et al. Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset breast cancer. N Engl J Med 1996; 334: 143–49. Anton-Culver H, Kurosaki T, Taylor TH, et al. Validation of family history of breast cancer and identification of the BRCA1 and other syndromes using a population-based registry. Genet Epidemiol 1996; 13: 193–205. Easton DF. Cancer risks in A-T heterozygotes. Int J Radiat Biol 1994; 66: S177–82.

SIR—The Breast Cancer Linkage Consortium1 has highlighted the morphological attributes of breast cancers associated with BRCA1 and BRCA2 mutations.Their results and the accompanying commentary from I Craig Henderson and Anthony J Patek2 have clearly suggested that the such tumours are biologically and histologically more aggressive than sporadic breast cancers. Do the aggressive features such as the higher histological grade (which includes tubular differentiation, proliferation rate, and nuclear pleomorphism) actually mean that the heritable breast cancers respond poorly to therapy or imply decreased survival. There have been only a few studies addressing the issue of prognosis in heritable breast cancers. Contrary to our expectations, these studies have suggested a better survival among the

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