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Primary biliary cirrhosis.
Xavier Roblin, Bruno Bonaz
To cite this version:
Xavier Roblin, Bruno Bonaz. Primary biliary cirrhosis.. New England Journal of Medicine, Mas-sachusetts Medical Society, 2005, 353 (25), 2719-20; author reply 2719-20. �inserm-00410568�
correspondence
n engl j med 353;25 www.nejm.org december 22, 2005 2719
Primary Biliary Cirrhosis
to the editor: With respect to the review article
on primary biliary cirrhosis by Kaplan and Gersh-win (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 reso-nance 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 evalu-ation 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 gbranca@yahoo.com
Michael P. Federle, M.D.
University of Pittsburgh School of Medicine Pittsburgh, PA 15213
Arye Blachar, M.D.
Tel Aviv University 64239 Tel Aviv, Israel
Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med 2005;353:1261-73.
Blachar A, Federle MP, Brancatelli G. Primary biliary cirrho-sis: clinical, pathologic, and helical CT findings in 53 patients. Radiology 2001;220:329-36.
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.
to the editor: Kaplan and Gershwin conclude
that patients with primary biliary cirrhosis should be treated initially by ursodeoxycholic acid (urso-diol). 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 pub-lished, and the results are conflicting.1
A meta-analysis 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-als were analyzed separately.1
These results are
supported by another meta-analysis.2
Ursodiol may reduce ascites and serum bilirubin and liver-enzyme levels, whereas serum albumin levels and
1. 2.
3.
the prothrombin time are unaffected.1
Thus, the potential benefits are largely “cosmetic.”
The authors suggest that colchicine and meth-otrexate are indicated for patients with an incom-plete response to ursodiol. These recommendations do not seem to be based on the available evi-dence.2-4
In fact, methotrexate may increase mor-tality.4
We think that a more comprehensive look at the literature leads to conclusions that are differ-ent from those reached by Kaplan and Gershwin.
Yan Gong, M.D.
Copenhagen Trial Unit DK-2100 Copenhagen, Denmark yangong@ctu.rh.dk
Erik Christensen, M.D.
Bispebjerg University Hospital DK-2400 Copenhagen, Denmark
Christian Gluud, M.D.
Copenhagen Trial Unit DK-2100 Copenhagen, Denmark
Gluud C, Christensen E. Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database Syst Rev 2002;1:CD000551.
Goulis J, Leandro G, Burroughs AK. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrho-sis: a meta-analysis. Lancet 1999;354:1053-60.
Gong Y, Gluud C. Colchicine for primary biliary cirrhosis. Cochrane Database Syst Rev 2004;2:CD004481.
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 re-view of primary biliary cirrhosis. The prevalence of celiac disease among patients with primary biliary cirrhosis is 10 times as high as in the gen-eral 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. Cer-tain 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.
Xavier Roblin, M.D. Bruno Bonaz, M.D., Ph.D. Grenoble University 38000 Grenoble, France xroblin@chu-grenoble.fr 1. 2. 3. 4.
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
T h e n e w e n g l a n d j o u r n a l o f m e d i c i n e
n engl j med 353;25 www.nejm.org december 22, 2005
2720
Dickey W, McMillan SA, Callender ME. High prevalence of celiac sprue among patients with primary biliary cirrhosis. J Clin Gastroenterol 1997;25:328-32.
Sorensen HT, Thulstrup AM, Blomqvist P, Norgaard B, Fon-ager K, Ekbom A. Risk of primary biliary liver cirrhosis in pa-tients with coeliac disease: Danish and Swedish cohort data. Gut 1999;44:736-8.
the authors reply: Dr. Brancatelli and
col-leagues 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 nonspe-cific findings that are found in many liver dis-eases 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 treat-ment of primary biliary cirrhosis. The two meta-analyses of ursodiol to which they refer have been criticized for their methodology and were flawed by the inclusion of studies of only two years’ du-ration, too short a time to detect any change in survival in a disease with a very long natural his-tory.1
Physicians who treat patients with primary biliary cirrhosis generally agree that ursodiol has dramatically improved its natural history. We agree with Gong et al. that the use of colchicine and methotrexate in primary biliary cirrhosis is contro-versial. For that reason, we acknowledged these negative studies in our review. We also noted that we have found these drugs to be effective in many patients who have not responded to ursodiol.2
Gong et al. do not recognize that the response to treatment in primary biliary cirrhosis is high-ly variable. Whether primary biliary cirrhosis is syndromic, similar to chronic hepatitis and
in-1.
2.
flammatory bowel disease, or whether patients with primary biliary cirrhosis respond very dif-ferently 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 bili-ary 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 sig-nificant celiac sprue in only 2 of the 1200 patients with primary biliary cirrhosis whom we have fol-lowed in our practice (unpublished data) but can-not 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 cir-rhosis and have questioned the association.3
Marshall M. Kaplan, M.D.
Tufts–New England Medical Center Boston, MA 02111
mkaplan@tufts-nemc.org
M. Eric Gershwin, M.D.
University of California at Davis Davis, CA 95616
Lindor KD, Hoofnagle J, Maddrey WC, Mackay IE, Dickson ER. Primary biliary cirrhosis clinical research single-topic conference. Hepatology 1996;23:639-44.
Lee YM, Kaplan MM. Efficacy of colchicine in patients with primary biliary cirrhosis poorly responsive to ursodiol and methotrexate. Am J Gastroenterol 2003;98:205-8.
Bizzaro N, Villalta D, Tonutti E, et al. IgA and IgG tissue transglutaminase antibody prevalence and clinical significance in connective tissue diseases, inflammatory bowel disease, and primary biliary cirrhosis. Dig Dis Sci 2003;48:2360-5.
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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 clini-cal trials six month later, the Toronto team was unable to increase production of insulin to sat-isfy even its own clinical needs. Furthermore, the potency of the hormone that was produced in the
laboratories in Toronto varied from batch to batch, and impurities commonly led to pain and injec-tion-site abscesses among patients. The Toronto team, realizing the enormous potential of insu-lin in diabetes treatment, was nevertheless reluc-tant to relinquish control over insulin produc-tion. 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 produc-tion, purificaproduc-tion, and formulation of insulin. He
Copyright © 2005 Massachusetts Medical Society. All rights reserved.