Primary Biliary Cirrhosis
http://www.100md.com
《新英格兰医药杂志》
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
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
References
Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med 2005;353:1261-1273.
Blachar A, Federle MP, Brancatelli G. Primary biliary cirrhosis: clinical, pathologic, and helical CT findings in 53 patients. Radiology 2001;220:329-336.
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;176:885-889.
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 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 trials 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 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.2,3,4 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
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
References
Gluud C, Christensen E. Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database Syst Rev 2002;1:CD000551-CD000551.
Goulis J, Leandro G, Burroughs AK. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis. Lancet 1999;354:1053-1060.
Gong Y, Gluud C. Colchicine for primary biliary cirrhosis. Cochrane Database Syst Rev 2004;2:CD004481-CD004481.
Gong Y, Gluud C. Methotrexate for primary biliary cirrhosis. Cochrane Database Syst Rev 2005;3:CD004385-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.
Xavier Roblin, M.D.
Bruno Bonaz, M.D., Ph.D.
Grenoble University
38000 Grenoble, France
xroblin@chu-grenoble.fr
References
Dickey W, McMillan SA, Callender ME. High prevalence of celiac sprue among patients with primary biliary cirrhosis. J Clin Gastroenterol 1997;25:328-332.
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;44:736-738.
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 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' duration, too short a time to detect any change in survival in a disease with a very long natural history.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 controversial. 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 highly variable. Whether primary biliary cirrhosis is syndromic, similar to chronic hepatitis and inflammatory 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
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
References
Lindor KD, Hoofnagle J, Maddrey WC, Mackay IE, Dickson ER. Primary biliary cirrhosis clinical research single-topic conference. Hepatology 1996;23:639-644.
Lee YM, Kaplan MM. Efficacy of colchicine in patients with primary biliary cirrhosis poorly responsive to ursodiol and methotrexate. Am J Gastroenterol 2003;98:205-208.
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;48:2360-2365.
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
References
Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med 2005;353:1261-1273.
Blachar A, Federle MP, Brancatelli G. Primary biliary cirrhosis: clinical, pathologic, and helical CT findings in 53 patients. Radiology 2001;220:329-336.
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;176:885-889.
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 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 trials 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 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.2,3,4 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
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
References
Gluud C, Christensen E. Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database Syst Rev 2002;1:CD000551-CD000551.
Goulis J, Leandro G, Burroughs AK. Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis. Lancet 1999;354:1053-1060.
Gong Y, Gluud C. Colchicine for primary biliary cirrhosis. Cochrane Database Syst Rev 2004;2:CD004481-CD004481.
Gong Y, Gluud C. Methotrexate for primary biliary cirrhosis. Cochrane Database Syst Rev 2005;3:CD004385-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.
Xavier Roblin, M.D.
Bruno Bonaz, M.D., Ph.D.
Grenoble University
38000 Grenoble, France
xroblin@chu-grenoble.fr
References
Dickey W, McMillan SA, Callender ME. High prevalence of celiac sprue among patients with primary biliary cirrhosis. J Clin Gastroenterol 1997;25:328-332.
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;44:736-738.
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 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' duration, too short a time to detect any change in survival in a disease with a very long natural history.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 controversial. 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 highly variable. Whether primary biliary cirrhosis is syndromic, similar to chronic hepatitis and inflammatory 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
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
References
Lindor KD, Hoofnagle J, Maddrey WC, Mackay IE, Dickson ER. Primary biliary cirrhosis clinical research single-topic conference. Hepatology 1996;23:639-644.
Lee YM, Kaplan MM. Efficacy of colchicine in patients with primary biliary cirrhosis poorly responsive to ursodiol and methotrexate. Am J Gastroenterol 2003;98:205-208.
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;48:2360-2365.