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Chronic pancreatitis linked to the cystic fibrosis gene
SCIENCE AND MEDICINE
Chronic pancreatitis linked to the cystic fibrosis gene wo new studies report a strong link between idiopathic chronic pancreatitis and mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. Jonathan Cohn (Duke Medical Center, Durham, NC, USA) and his team studied the CFTR gene in 27 patients who presented with unexplained pancreatitis but no signs of the lung disease typical of cystic fibrosis. Eight patients had mutations known to cause classical cystic fibrosis; five had an allele that predisposes patients to obstructive azospermia without lung disease. The mutation frequency was 11 times that in the general population. In three patients both CFTR alleles were mutated (N Engl J Med 1998; 339: 653–58). Cohn concludes that “many patients with a diagnosis of unexplained chronic pancreatitis have a
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disease where genetics plays a major and previously unsuspected role”. Joan Braganza (Manchester Royal Infirmary, Manchester, UK) and her team studied 134 consecutive patients with chronic pancreatitis, 60 of whom had idiopathic disease. Overall, 18 patients had a CFTR mutation on one chromosome— two and a half times the expected frequency. 12 of these patients had idiopathic disease (N Engl J Med 1998; 339: 645–52) . Studies of chloride transport in epithelial tissues should clarify whether CFTR function is impaired in patients who have CFTR mutations and pancreatitis. If such a defect occurs, this might support the suggestion that, in patients with specific genotypes, pancreatitis might be associated with conditions such as obstructive azospermia and
Studies on diet drugs and valve damage disagree esults reported in Paris, France, at the International Congress on Obesity (Aug 29–Sept 3) did not end the debate about whether the diet drugs phentermine and fenfluramine (phen-fen), and dexfenfluramine cause heart-valve abnormalities. Fenfluramine and dexfenfluramine were withdrawn last year after reports of high rates of valve abnormalities associated with their use. But in March this year, a randomised, placebo-controlled study found no effect of the drugs on valve abnormalities. In an open-label, dose-ranging study of phen-fen which was discontinued last year, G Blackburn (Boston, MA, USA) reported that among 226 study participants who had an echocardiogram, the rate of valve abnormalities was similar to that of controls from the Framingham Offspring Study. But Donna Ryan (Baton Rouge, LA, USA) found a 24·4% rate of valve abnormalities among 213 patients treated with the diet drugs. Patients treated for more than 3 months had an elevated risk of valve
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abnormalities. Among 86 patients who had previously had an echocardiogram, about a third had pre-existing disease, so the rate of new cases was 16%. A 21·3% rate of valve abnormalities in about 160 patients who took phen-fen was reported by Richard Bowen (Naples, FL, USA). No symptomatic valve problems were reported in either study. The only remaining diet drug on the market, sibutramine, does not seem to cause valve problems. In a study of 210 obese patients with lateonset diabetes, the rate of valve problems was 2·3% in the sibutramine group and 2·6% in the placebo group, reported David Bach (Ann Arbor, MI, USA). Larry Husten
Leptin reduces fat mass, not lean mass Leptin—the hormone that caused a stir before it was ever given as a drug— looks promising in its first clinical trial. Steven Heymsfield (New York City, NY, USA) reported on 123 lean and obese people injected with placebo or one of four doses of leptin. At 6 months, the high-dose leptin group had lost 7·5% of their body weight, compared with a 1·6% loss in the placebo group. Nearly all the weight loss was a reduction in fat—ie, lean tissue was preserved.
recurrent sinusitis. Another intriguing question is whether the patients in both studies who were found to have one CFTR mutation do indeed have a normal copy of the CFTR gene, or whether they are compound heterozygotes with a second, undetected, abnormal allele. “Comprehensive testing of DNA from these patients should resolve this”, says Cohn. Finally, Cohn estimates that “fewer than 1% of individuals with CFTR mutations develop idiopathic chronic pancreatitis”. Additional factors probably determine which predisposed individuals develop the disorder. Identifying these factors— genetic or environmental—should provide new clues about pathogenesis and possibly prevention. Kathryn Senior
Cancer risk after nonmelanoma skin cancer eople with a history of nonmelanoma skin cancer (NMSC) have an increased risk of dying from certain non-skin cancers. 1·1 million volunteers aged over 30 years were followed for 12 years from 1982. Men who had had NMSC had a 30% increased cancer-mortality risk, and women a 26% increased risk. Mortality was increased for melanoma, pharyngeal cancer, lung cancer, and non-Hodgkin lymphoma in men and women. In men, mortality was increased for cancers of the salivary glands, prostate, testis, urinary bladder, and leukaemia. Women had excess breast-cancer mortality (JAMA 1998; 280: 910–12). “The biological mechanisms underlying the excess mortality are unknown”, says lead author Henry Kahn (Emory University School of Medicine, Atlanta, GA, USA), but immune suppression or somatic mutations could have been caused by the exposure to ultraviolet radiation that had caused NMSC. Intensified medical surveillance of people with NMSC is unlikely to account for the association between NMSC and fatal cancers, say the authors. The clinical and public-health implications of these findings are not yet clear, they add, but physicians should check carefully for selected cancers in patients who have had NMSC.
P
Dorothy Bonn
THE LANCET • Vol 352 • September 12, 1998
885
Chronic pancreatitis linked to the cystic fibrosis gene wo new studies report a strong link between idiopathic chronic pancreatitis and mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. Jonathan Cohn (Duke Medical Center, Durham, NC, USA) and his team studied the CFTR gene in 27 patients who presented with unexplained pancreatitis but no signs of the lung disease typical of cystic fibrosis. Eight patients had mutations known to cause classical cystic fibrosis; five had an allele that predisposes patients to obstructive azospermia without lung disease. The mutation frequency was 11 times that in the general population. In three patients both CFTR alleles were mutated (N Engl J Med 1998; 339: 653–58). Cohn concludes that “many patients with a diagnosis of unexplained chronic pancreatitis have a
T
disease where genetics plays a major and previously unsuspected role”. Joan Braganza (Manchester Royal Infirmary, Manchester, UK) and her team studied 134 consecutive patients with chronic pancreatitis, 60 of whom had idiopathic disease. Overall, 18 patients had a CFTR mutation on one chromosome— two and a half times the expected frequency. 12 of these patients had idiopathic disease (N Engl J Med 1998; 339: 645–52) . Studies of chloride transport in epithelial tissues should clarify whether CFTR function is impaired in patients who have CFTR mutations and pancreatitis. If such a defect occurs, this might support the suggestion that, in patients with specific genotypes, pancreatitis might be associated with conditions such as obstructive azospermia and
Studies on diet drugs and valve damage disagree esults reported in Paris, France, at the International Congress on Obesity (Aug 29–Sept 3) did not end the debate about whether the diet drugs phentermine and fenfluramine (phen-fen), and dexfenfluramine cause heart-valve abnormalities. Fenfluramine and dexfenfluramine were withdrawn last year after reports of high rates of valve abnormalities associated with their use. But in March this year, a randomised, placebo-controlled study found no effect of the drugs on valve abnormalities. In an open-label, dose-ranging study of phen-fen which was discontinued last year, G Blackburn (Boston, MA, USA) reported that among 226 study participants who had an echocardiogram, the rate of valve abnormalities was similar to that of controls from the Framingham Offspring Study. But Donna Ryan (Baton Rouge, LA, USA) found a 24·4% rate of valve abnormalities among 213 patients treated with the diet drugs. Patients treated for more than 3 months had an elevated risk of valve
R
abnormalities. Among 86 patients who had previously had an echocardiogram, about a third had pre-existing disease, so the rate of new cases was 16%. A 21·3% rate of valve abnormalities in about 160 patients who took phen-fen was reported by Richard Bowen (Naples, FL, USA). No symptomatic valve problems were reported in either study. The only remaining diet drug on the market, sibutramine, does not seem to cause valve problems. In a study of 210 obese patients with lateonset diabetes, the rate of valve problems was 2·3% in the sibutramine group and 2·6% in the placebo group, reported David Bach (Ann Arbor, MI, USA). Larry Husten
Leptin reduces fat mass, not lean mass Leptin—the hormone that caused a stir before it was ever given as a drug— looks promising in its first clinical trial. Steven Heymsfield (New York City, NY, USA) reported on 123 lean and obese people injected with placebo or one of four doses of leptin. At 6 months, the high-dose leptin group had lost 7·5% of their body weight, compared with a 1·6% loss in the placebo group. Nearly all the weight loss was a reduction in fat—ie, lean tissue was preserved.
recurrent sinusitis. Another intriguing question is whether the patients in both studies who were found to have one CFTR mutation do indeed have a normal copy of the CFTR gene, or whether they are compound heterozygotes with a second, undetected, abnormal allele. “Comprehensive testing of DNA from these patients should resolve this”, says Cohn. Finally, Cohn estimates that “fewer than 1% of individuals with CFTR mutations develop idiopathic chronic pancreatitis”. Additional factors probably determine which predisposed individuals develop the disorder. Identifying these factors— genetic or environmental—should provide new clues about pathogenesis and possibly prevention. Kathryn Senior
Cancer risk after nonmelanoma skin cancer eople with a history of nonmelanoma skin cancer (NMSC) have an increased risk of dying from certain non-skin cancers. 1·1 million volunteers aged over 30 years were followed for 12 years from 1982. Men who had had NMSC had a 30% increased cancer-mortality risk, and women a 26% increased risk. Mortality was increased for melanoma, pharyngeal cancer, lung cancer, and non-Hodgkin lymphoma in men and women. In men, mortality was increased for cancers of the salivary glands, prostate, testis, urinary bladder, and leukaemia. Women had excess breast-cancer mortality (JAMA 1998; 280: 910–12). “The biological mechanisms underlying the excess mortality are unknown”, says lead author Henry Kahn (Emory University School of Medicine, Atlanta, GA, USA), but immune suppression or somatic mutations could have been caused by the exposure to ultraviolet radiation that had caused NMSC. Intensified medical surveillance of people with NMSC is unlikely to account for the association between NMSC and fatal cancers, say the authors. The clinical and public-health implications of these findings are not yet clear, they add, but physicians should check carefully for selected cancers in patients who have had NMSC.
P
Dorothy Bonn
THE LANCET • Vol 352 • September 12, 1998
885