correspondence
Primary Biliary Cirrhosis to the editor: With respect to the review article on primary biliary cirrhosis by Kaplan and Gershwin (Sept. 22 issue),1 we would like to emphasize the value of alternative noninvasive methods for the diagnosis of this disorder, such as multiphasic computed tomography (CT) and magnetic resonance imaging (MRI). If they are used early in the course of the disease, both of these imaging methods demonstrate objective signs of portal hypertension, hepatomegaly, liver fibrosis, and lymphadenopathy. The identification of these signs has been shown to be helpful in the evaluation and surveillance of patients with primary biliary cirrhosis.2,3 Giuseppe Brancatelli, M.D. Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Saverio de Bellis 70013 Castellana Grotte (Bari), Italy
[email protected]
Michael P. Federle, M.D. University of Pittsburgh School of Medicine Pittsburgh, PA 15213
the prothrombin time are unaffected.1 Thus, the potential benefits are largely “cosmetic.” The authors suggest that colchicine and methotrexate are indicated for patients with an incomplete response to ursodiol. These recommendations do not seem to be based on the available evidence.2-4 In fact, methotrexate may increase mortality.4 We think that a more comprehensive look at the literature leads to conclusions that are different from those reached by Kaplan and Gershwin. Yan Gong, M.D. Copenhagen Trial Unit DK-2100 Copenhagen, Denmark
[email protected]
Erik Christensen, M.D. Bispebjerg University Hospital DK-2400 Copenhagen, Denmark
Christian Gluud, M.D. Copenhagen Trial Unit DK-2100 Copenhagen, Denmark 1. Gluud C, Christensen E. Ursodeoxycholic acid for primary
Arye Blachar, M.D. Tel Aviv University 64239 Tel Aviv, Israel 1. Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl
J Med 2005;353:1261-73. 2. Blachar A, Federle MP, Brancatelli G. Primary biliary cirrhosis: clinical, pathologic, and helical CT findings in 53 patients. Radiology 2001;220:329-36. 3. Wenzel JS, Donohoe A, Ford KL III, Glastad K, Watkins D, Molmenti E. Primary biliary cirrhosis: MR imaging findings and description of MR imaging periportal halo sign. AJR Am J Roentgenol 2001;176:885-9.
biliary cirrhosis. Cochrane Database Syst Rev 2002;1:CD000551. 2. Goulis J, Leandro G, Burroughs AK. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis. Lancet 1999;354:1053-60. 3. Gong Y, Gluud C. Colchicine for primary biliary cirrhosis. Cochrane Database Syst Rev 2004;2:CD004481. 4. Idem. Methotrexate for primary biliary cirrhosis. Cochrane Database Syst Rev 2005;3:CD004385.
to the editor: The association between primary biliary cirrhosis and celiac disease should have been emphasized more clearly in the recent review of primary biliary cirrhosis. The prevalence of celiac disease among patients with primary biliary cirrhosis is 10 times as high as in the general population.1 Moreover, Sorensen et al.2 found an incidence ratio of primary biliary cirrhosis of 27.6 among patients with celiac disease. Thus, in the event of primary biliary cirrhosis, clinicians should systematically rule out celiac disease. Certain symptoms of primary biliary cirrhosis, such as osteoporosis, asthenia, and liver anomalies, regress with a gluten-free diet in people who also have celiac disease. This screening is made even simpler because there are sensitive and specific markers for each of the two diseases.
to the editor: Kaplan and Gershwin conclude that patients with primary biliary cirrhosis should be treated initially by ursodeoxycholic acid (ursodiol). However, that recommendation is based on the results of only four randomized clinical trials, all of which favored the use of ursodiol. Their conclusion is flawed by selection bias. In fact, at least 16 randomized clinical trials have been published, and the results are conflicting.1 A metaanalysis of these trials indicated that ursodiol has no significant benefit in terms of mortality or disease progression. This was also the case when short-duration trials and long-duration tri- Xavier Roblin, M.D. als were analyzed separately.1 These results are Bruno Bonaz, M.D., Ph.D. supported by another meta-analysis.2 Ursodiol Grenoble University may reduce ascites and serum bilirubin and liver- 38000 Grenoble, France enzyme levels, whereas serum albumin levels and
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1. Dickey W, McMillan SA, Callender ME. High prevalence of
celiac sprue among patients with primary biliary cirrhosis. J Clin Gastroenterol 1997;25:328-32. 2. Sorensen HT, Thulstrup AM, Blomqvist P, Norgaard B, Fonager K, Ekbom A. Risk of primary biliary liver cirrhosis in patients with coeliac disease: Danish and Swedish cohort data. Gut 1999;44:736-8.
flammatory bowel disease, or whether patients with primary biliary cirrhosis respond very differently to medical treatment for other reasons, is not clear. However, lumping all patients with primary biliary cirrhosis together and using meta-analyses to summarize results of studies that overlook the heterogeneity of primary biliary cirrhosis will not advance our understanding of this disease. Drs. Roblin and Bonaz believe that we should have discussed the association of primary biliary cirrhosis with celiac sprue in more depth in our article. Although such an association may exist, it is controversial. We have observed clinically significant celiac sprue in only 2 of the 1200 patients with primary biliary cirrhosis whom we have followed in our practice (unpublished data) but cannot rule out the presence of asymptomatic celiac disease in other patients. Some investigators have reported a high rate of false positive tests for celiac sprue in patients with primary biliary cirrhosis and have questioned the association.3
the authors reply: Dr. Brancatelli and colleagues note that multiphasic CT and MRI detect portal hypertension, hepatomegaly, liver fibrosis, and lymphadenopathy in patients with primary biliary cirrhosis. We agree, but these are nonspecific findings that are found in many liver diseases and, except for hepatomegaly, occur late in the course of primary biliary cirrhosis. Hence, they do not replace liver biopsy. Dr. Gong and colleagues question the value of ursodiol, colchicine, and methotrexate in the treatment of primary biliary cirrhosis. The two metaanalyses of ursodiol to which they refer have been criticized for their methodology and were flawed by the inclusion of studies of only two years’ duration, too short a time to detect any change in Marshall M. Kaplan, M.D. survival in a disease with a very long natural hisTufts–New England Medical Center tory.1 Physicians who treat patients with primary Boston, MA 02111 biliary cirrhosis generally agree that ursodiol has
[email protected] dramatically improved its natural history. We agree M. Eric Gershwin, M.D. with Gong et al. that the use of colchicine and University of California at Davis methotrexate in primary biliary cirrhosis is contro- Davis, CA 95616 versial. For that reason, we acknowledged these 1. Lindor KD, Hoofnagle J, Maddrey WC, Mackay IE, Dickson negative studies in our review. We also noted that ER. Primary biliary cirrhosis clinical research single-topic we have found these drugs to be effective in many conference. Hepatology 1996;23:639-44. 2. Lee YM, Kaplan MM. Efficacy of colchicine in patients with patients who have not responded to ursodiol.2 primary biliary cirrhosis poorly responsive to ursodiol and Gong et al. do not recognize that the response methotrexate. Am J Gastroenterol 2003;98:205-8. to treatment in primary biliary cirrhosis is high- 3. Bizzaro N, Villalta D, Tonutti E, et al. IgA and IgG tissue transglutaminase antibody prevalence and clinical significance ly variable. Whether primary biliary cirrhosis is in connective tissue diseases, inflammatory bowel disease, and syndromic, similar to chronic hepatitis and in- primary biliary cirrhosis. Dig Dis Sci 2003;48:2360-5.
Academic–Industrial Relationships to the editor: With regard to the article by Stossel (Sept. 8 issue),1 the road of collaboration between academia and industry is dappled with episodes of squabbling and success. One such episode is known as the “insulin famine.” In the wake of the discovery of insulin by a team of Toronto academicians in May 1921 and the clinical trials six month later, the Toronto team was unable to increase production of insulin to satisfy even its own clinical needs. Furthermore, the potency of the hormone that was produced in the 2720
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laboratories in Toronto varied from batch to batch, and impurities commonly led to pain and injection-site abscesses among patients. The Toronto team, realizing the enormous potential of insulin in diabetes treatment, was nevertheless reluctant to relinquish control over insulin production. George H.A. Clowes, research director of Eli Lilly, convinced the Toronto team that the pharmaceutical industry was best able to solve the challenges of the scaling up, mass production, purification, and formulation of insulin. He
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