1692
EDITORIALS
GASTROENTEROLOGY
Vol. 103, No. 5
Hepatitis B-Related End-Stage Liver Disease Among digestive diseases, cirrhosis of the liver is the leading nonmalignant cause of death in the United States and throughout most of the developed world. Importantly, deaths due to cirrhosis, unlike those caused by gastrointestinal malignancies, occur largely among young and middle-aged adults. Thus, three fifths of the 26,694 deaths due to chronic liver disease and cirrhosis listed on U.S. death certificates in 1989 occurred among persons between the ages of 25 and 64 years.’ These grim statistics underscore the public health importance of chronic liver disease and the need for advances in its prevention and treatment. Declines in mortality due to cirrhosis in the United States in the last 20 years suggest that progress is being made in its control. Age-adjusted cirrhosis mortality rates have decreased from a peak of 15 per 100,000 persons in 1973 to about 9 per 100,000 current1y.l” Between 1979 and 1989, the death rate due to cirrhosis fell 26%, a percentage decline comparable with that of the well-publicized decline in mortality due to ischemic heart disease. The cause of this important decline in mortality due to liver disease, however, is not at all clear. Part of the difficulty in identifying the cause for the decline in mortality from cirrhosis is that cirrhosis is not really a disease but rather a consequence of several diseases that in themselves differ markedly in pathogenesis, natural history, and response to treatment. Indeed, the term “cirrhosis” is quite inadequate as a diagnosis and has connotations that are confusing to both the medical profession and the lay public. Cirrhosis is a pathological, not a clinical, term, and it affects an unknown number of persons, only some of whom develop clinical symptoms and die of liver disease. What is really being described on death reports and in mortality figures is more properly called end-stage liver disease (ESLD). Use of the term ESLD does not really answer the question of what has caused the recent decline in the mortality rate, but it helps to focus on various explanations. The causes of ESLD are many; probably only half of all cases can be attributed solely to alcoholic liver disease: other important causes are hepatitis B and C and autoimmune and “cryptogenic” liver disease. Which of these diseases has declined in incidence or has begun to be treated successfully during the last 20 years? Alcoholic liver disease is a major cause of ESLD. Accordingly, there should be a correlation between per capita ethanol consumption and mortality rate from liver disease. Indeed, ethanol consumption in
the United States has decreased recently, but the pattern of decrease has not paralleled that of mortality rates from ESLD. The first sustained decline in calculated, per capita ethanol consumption since the repeal of prohibition has occurred only since 1981. This modest 12% decline has largely been driven by a 35% decrease in consumption of spirits.3 Thus, a decrease in alcoholic liver disease is unlikely to entirely explain the decrease in mortality due to ESLD. An important recent advance in liver disease has been the development of liver transplantation as an acceptable therapy for ESLD. In 1989, approximately 2200 liver transplants were performed in the United States, and the average l-year survival rate was 72%.4 With this success rate, liver transplantation should account for less than a 10% decrease in mortality due to ESLD, not enough to account for the overall decline in mortality. In addition, a decrease in mortality due to liver transplantation would only have begun in the mid-1980s, when this procedure became a generally accepted therapy for ESLD. Other explanations for decreasing mortality rates from ESLD are the other modern, more conventional modes of prevention and therapy for chronic liver disease. These advances include therapies for variteal hemorrhage such as B-adrenergic blockade, sclerotherapy, and vascular shunting procedures. However, improved survival has been difficult to prove with any of these techniques.5-7 Advances in treatments for specific diseases include glucocorticoids for autoimmune hepatitis, phlebotomy for hemochromatosis, copper chelation for Wilson’s disease, and recently, interferon alfa for chronic hepatitis B, C, and D, as well as a vaccine for hepatitis B. It is rather optimistic, however, to suggest that these treatments have made major inroads into mortality due to ESLD. For instance, interferon alfa has only recently been introduced as therapy for chronic viral hepatitis. Furthermore, it has yet to be shown that interferon therapy improves survival in chronic viral hepatitis. The issue of whether interferon prolongs survival in chronic hepatitis is a particularly important one. Interferon therapy is expensive and not without side effects. The usual endpoints for successful treatment in chronic hepatitis have not been prolonged survival or even prevention of cirrhosis but rather a decline in serum aminotransferase activities and a disappearance of viral markers such as hepatitis B virus DNA and hepatitis B e antigen (HBeAg) in chronic hepatitis B.’ Are these serological and serum biochemical markers accurate intermediate end points
November
1992
that reflect a true improvement in survival? The answer to this question has not been addressed directly in randomized prospective studies of therapy. Nevertheless, indirect evidence from studies on the natural history of chronic hepatitis B suggest that these end points are significant. One such natural history study is the article by de Jongh et al. of the Netherlands in this issue of GASTROENTEROLOGY.g de Jongh et al. have evaluated a large cohort of patients with chronic hepatitis B and histologically documented cirrhosis for clinical features that might help predict death from ESLD. The 5-year survival rate was 71%, a rate similar to that found in several other studies of hepatitis B-related cirrhosis.‘O-13 The major predictive factors for mortality that they identified were age, serum bilirubin concentration, and presence of ascites. These predictive factors reconfirm findings from many studies of cirrhosis showing that being older and having signs of advanced liver disease increase the risk of death.‘0~‘4-‘e These signs of advanced liver disease (most of which are included in the well-known Child-Pugh scoring system] appear to be important predictors of mortality regardless of etiology of cirrhosis. Attempts to use more precise measures of liver function (such as elimination tests or drug-metabolism assays) as predictive factors have generally not significantly improved accuracy or have not been validated among other cohorts.‘7-21 de Jongh et al. found one other important prognostic factor for ESLD mortality in this group that was specific for this disease: HBeAg status. Although the presence of HBeAg at baseline examination did not meet conventional statistical significance as a risk factor for mortality (P = 0.08), it was clearly associated with mortality when analysis was restricted to the 77 patients with compensated disease. In addition, the change in HBeAg status from positive to negative during follow-up was associated with a 55% reduction in death rate. The loss of HBeAg usually indicates a decrease in viral replication and theoretically the removal of the source of liver injury. In this cohort, it could be inferred that the removal of the source of liver injury stabilized the pathological process and prevented or delayed the onset of ESLD. Similarly, abstinence in alcoholic liver disease can be considered removal of the source of liver injury and has been shown to be a favorable predictive factor for survival. The findings of de Jongh et al. complement a recent study on the natural history of chronic hepatitis B from Fattovich et al. of Italy*’ who analyzed initial predictive factors for development of cirrhosis among 105 patients who were followed up for a mean of 3.7 years. They found that the persistence of hepatitis B virus (HBV) DNA was an important correlate
EDITORIALS
1693
with development of cirrhosis. Interestingly, none of these “precirrhotic” patients died of ESLD during the period of study. These findings indicate that serological markers of active viral replication (again the putative cause of liver injury) may be predictive of progressive liver injury in chronic hepatitis B without cirrhosis. The closer correlation of HBV DNA than HBeAg with progressive liver disease in the Italian study probably was related to the frequency of the HBeAg- mutant of HBV that is found in ItalyZ3 but is rare in the Netherlands and the United States. The findings of de Jongh et al. help support the use of loss of HBeAg as an important end point in therapy for chronic hepatitis B. These results also indicate that once symptomatic cirrhosis is present, the prognosis in chronic hepatitis B is extremely poor (the 5-year survival rate was only 14%). It is obvious that antiviral therapies should be applied before the development of clinical features of cirrhosis and ESLD. Once these features have developed, liver transplantation is a more appropriate therapy. It is doubtful that the recently developed therapies for chronic viral hepatitis have already had much impact on the mortality rate for ESLD. The decline in mortality rates for cirrhosis more likely reflects several advances in medical management of liver disease as well as other socioeconomic and population changes. Nevertheless, antiviral therapies for chronic viral hepatitis may eventually have an important impact on the mortality rate for ESLD and help to continue its recent decline. JAMES E. EVERHART, M.D., M.P.H. JAY H. HOOFNAGLE, M.D. Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive Kidney Diseases National Institutes of Health Bethesda, Maryland
and
References National Center for Health Statistics. Advance report of final mortality statistics, 1989.Monthly vital statistics report. Volume 40,no. 8 (Suppl 2). Hyattsville, MD: U.S. Public Health Service, 1992. Grant BF, DeBakey S, Zobeck TS. Liver cirrhosis mortality in the United States, 1973-1988. National Institute on Alcohol Abuse and Alcoholism Surveillance report no. 18.Rockville, MD: U.S. Public Health Service, 1991. Williams GD, Stinson FS, Brooks SH, Clem D, Noble J. Apparent per capita alcohol consumption: national, state, and regional trends, 1977-1989. National Institute on Alcohol Abuse and Alcoholism Surveillance report no. 20. Rockville, MD: U.S. Public Health Service, 1991. Annual Report of the U.S. Scientific Registry for Organ Transplantation and the Organ Procurement and Transplantation Network 1990.Richmond, VA: UNOS, and Bethesda, MD: Division of Organ Transplantation, Health Resources and Services Administration.
1694
GASTROENTEROLOGY Vol. 103, No. 5
EDITORIALS
5. Poynard T, Cales P, Pasta L, Ideo G, Pascal JP, Pagliaro L, Lebrec D. Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. N Engl J Med 1991;324:1532-1538. 6. Pagliaro L, D’Amico G, Sorensen TIA, Lebrec D, Burroughs AK, Morabito A, Tine F, Politi F, Traina M. Prevention of first bleeding in cirrhosis. A meta-analysis of randomized trials of nonsurgical treatment. Ann Intern Med 1992;117:59-70. 7. Infante-Rivard C, Esnaola S, Villeneuve JP. Role of endoscopic variceal sclerotherapy in the long-term management of variteal bleeding: a meta-analysis. Gastroenterology 1989;96: 1087-1092. 8. Perrillo RP, Schiff ER, Davis GL, Bodenheimer HC, Lindsay K, Payne J, Dienstag JL, O’Brien C, Tamburro C, Jacobson IM, Sampliner R, Feit D, Lefkowitch J, Kuhns M, Meschievitz C, Sanghvi B, Albrecht J, Gibas A. A randomized, controlled trial of interferon alfa-2b alone and following prednisone withdrawal for the treatment of chronic hepatitis B. N Engl J Med 1990;323:295-301. 9. de Jongh FE, Janssen HLA, de Man RA, Hop WCJ, Schalm SW, van Blankenstein M. Survival and prognostic indicators in HBsAg-positive cirrhosis of the liver. The role of HBeAg seroconversion. Gastroenterology 1992;103:1630-1635. 10. Weissberg JI, Ljudevit LA, Coleman IS, Weick S, Nichols JE, Garcia G, Robinson WAS, Merigan TC, Gregory PB. Survival in chronic hepatitis B. An analysis of 379 patients. Ann Intern Med 1984;101:613-616. 11. Lo K-J, Tong MJ, Chien Y-T, Tsai Y-F, Liaw K-C, Yang H, Chian HC, Liu H-C, Lee S-D. The natural course of hepatitis B surface antigen-positive chronic active hepatitis in Taiwan. J Infect Dis 1982;146:205-210. 12. Tanaka R, Itoshima T, Nagashima H. Follow-up study of 582 liver cirrhosis patients for 26 years in Japan. Liver 1987;7:316324. 13. Liaw YF, Lin DY, Chen TJ, Chu CM. Natural course after the development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Liver 1989;9:235-241. 14. Infante-Rivard C, Villeneuve JP, Esnaola S. A framework for
15.
16.
17.
18.
19.
20.
21.
22.
23.
evaluating and conducting prognostic studies: an application to cirrhosis of the liver. J Clin Epidemiol 1989;42:791-805. Dickson ER, Grambsch PM, Fleming TR, Fisher LD, Langworthy A. Prognosis in primary biliary cirrhosis: model for decision making. Hepatology 1989;10:1-7. Fargion S, Mandelli C, Piperno A, Cesana B, Fracanzani AL, Fraquelli M, Bianchi PA, Fiorelli G, Conte D. Survival and prognostic factors in 212 Italian patients with genetic hemochromatosis. Hepatology 1992;15:655-659. Oellerich M, Burdelski M, Lautz HU, Rodeck B, Duewel J, Schulz M, Schmidt FW, Brodehl J, Pichlmayr R. Assessment of pretransplant prognosis in patients with cirrhosis. Transplantation 1991;51:801-806. Zoli M, Cordiani MR, Marchesini G, Iervese T, Labate AM, Bonazzi C, Bianchi G, Pisi E. Prognostic indicators in compensated cirrhosis. Am J Gastroenterol 1991;86:1508-1513. Picard D, Infante-Rivard C, Villeneuve JP, Chartrand R, Picard M, Carrier L. Extrahepatic uptake of technetium-99mphytate: a prognostic index in patients with cirrhosis. J Nucl Med 1990;31:436-440. Adler M, Van Laethem J, Glibert A, Gelin M, Bourgeois N, Vereerstraeten P, Cremer M. Factors influencing survival at one year in patients with nonbiliary hepatic parenchymal cirrhosis. Dig Dis Sci 1990;35:1-5. Beuers U, Jager F, Wahllander A, Ansari H, Kirsch CM. Prognostic value of the intravenous ‘%-aminopyrine breath test compared to the Child-Pugh score and serum bile acids in 84 cirrhotic patients. Digestion 1991;50:212-218. Fattovich G, Brollo L, Giustina G, Noventa F, Pontisso P, Alberti A, Realdi G, Ruol A. Natural history and prognostic factors for chronic hepatitis type B. Gut 1991;32:294-298. Bonino F, Brunetto MR, Rizzetto M, Will H. Hepatitis B virus unable to secrete e antigen. Gastroenterology 1991;100:11381141.
Address requests for reprints to: James Everhart, M.D., M.P.H., 5333 Westbard Avenue, Room 3A-10, Westwood Building, Bethesda, Maryland 20892. This is a U.S. government work. There are no restrictions on its use.
EDITORIALS
GASTROENTEROLOGY
Vol. 103, No. 5
Hepatitis B-Related End-Stage Liver Disease Among digestive diseases, cirrhosis of the liver is the leading nonmalignant cause of death in the United States and throughout most of the developed world. Importantly, deaths due to cirrhosis, unlike those caused by gastrointestinal malignancies, occur largely among young and middle-aged adults. Thus, three fifths of the 26,694 deaths due to chronic liver disease and cirrhosis listed on U.S. death certificates in 1989 occurred among persons between the ages of 25 and 64 years.’ These grim statistics underscore the public health importance of chronic liver disease and the need for advances in its prevention and treatment. Declines in mortality due to cirrhosis in the United States in the last 20 years suggest that progress is being made in its control. Age-adjusted cirrhosis mortality rates have decreased from a peak of 15 per 100,000 persons in 1973 to about 9 per 100,000 current1y.l” Between 1979 and 1989, the death rate due to cirrhosis fell 26%, a percentage decline comparable with that of the well-publicized decline in mortality due to ischemic heart disease. The cause of this important decline in mortality due to liver disease, however, is not at all clear. Part of the difficulty in identifying the cause for the decline in mortality from cirrhosis is that cirrhosis is not really a disease but rather a consequence of several diseases that in themselves differ markedly in pathogenesis, natural history, and response to treatment. Indeed, the term “cirrhosis” is quite inadequate as a diagnosis and has connotations that are confusing to both the medical profession and the lay public. Cirrhosis is a pathological, not a clinical, term, and it affects an unknown number of persons, only some of whom develop clinical symptoms and die of liver disease. What is really being described on death reports and in mortality figures is more properly called end-stage liver disease (ESLD). Use of the term ESLD does not really answer the question of what has caused the recent decline in the mortality rate, but it helps to focus on various explanations. The causes of ESLD are many; probably only half of all cases can be attributed solely to alcoholic liver disease: other important causes are hepatitis B and C and autoimmune and “cryptogenic” liver disease. Which of these diseases has declined in incidence or has begun to be treated successfully during the last 20 years? Alcoholic liver disease is a major cause of ESLD. Accordingly, there should be a correlation between per capita ethanol consumption and mortality rate from liver disease. Indeed, ethanol consumption in
the United States has decreased recently, but the pattern of decrease has not paralleled that of mortality rates from ESLD. The first sustained decline in calculated, per capita ethanol consumption since the repeal of prohibition has occurred only since 1981. This modest 12% decline has largely been driven by a 35% decrease in consumption of spirits.3 Thus, a decrease in alcoholic liver disease is unlikely to entirely explain the decrease in mortality due to ESLD. An important recent advance in liver disease has been the development of liver transplantation as an acceptable therapy for ESLD. In 1989, approximately 2200 liver transplants were performed in the United States, and the average l-year survival rate was 72%.4 With this success rate, liver transplantation should account for less than a 10% decrease in mortality due to ESLD, not enough to account for the overall decline in mortality. In addition, a decrease in mortality due to liver transplantation would only have begun in the mid-1980s, when this procedure became a generally accepted therapy for ESLD. Other explanations for decreasing mortality rates from ESLD are the other modern, more conventional modes of prevention and therapy for chronic liver disease. These advances include therapies for variteal hemorrhage such as B-adrenergic blockade, sclerotherapy, and vascular shunting procedures. However, improved survival has been difficult to prove with any of these techniques.5-7 Advances in treatments for specific diseases include glucocorticoids for autoimmune hepatitis, phlebotomy for hemochromatosis, copper chelation for Wilson’s disease, and recently, interferon alfa for chronic hepatitis B, C, and D, as well as a vaccine for hepatitis B. It is rather optimistic, however, to suggest that these treatments have made major inroads into mortality due to ESLD. For instance, interferon alfa has only recently been introduced as therapy for chronic viral hepatitis. Furthermore, it has yet to be shown that interferon therapy improves survival in chronic viral hepatitis. The issue of whether interferon prolongs survival in chronic hepatitis is a particularly important one. Interferon therapy is expensive and not without side effects. The usual endpoints for successful treatment in chronic hepatitis have not been prolonged survival or even prevention of cirrhosis but rather a decline in serum aminotransferase activities and a disappearance of viral markers such as hepatitis B virus DNA and hepatitis B e antigen (HBeAg) in chronic hepatitis B.’ Are these serological and serum biochemical markers accurate intermediate end points
November
1992
that reflect a true improvement in survival? The answer to this question has not been addressed directly in randomized prospective studies of therapy. Nevertheless, indirect evidence from studies on the natural history of chronic hepatitis B suggest that these end points are significant. One such natural history study is the article by de Jongh et al. of the Netherlands in this issue of GASTROENTEROLOGY.g de Jongh et al. have evaluated a large cohort of patients with chronic hepatitis B and histologically documented cirrhosis for clinical features that might help predict death from ESLD. The 5-year survival rate was 71%, a rate similar to that found in several other studies of hepatitis B-related cirrhosis.‘O-13 The major predictive factors for mortality that they identified were age, serum bilirubin concentration, and presence of ascites. These predictive factors reconfirm findings from many studies of cirrhosis showing that being older and having signs of advanced liver disease increase the risk of death.‘0~‘4-‘e These signs of advanced liver disease (most of which are included in the well-known Child-Pugh scoring system] appear to be important predictors of mortality regardless of etiology of cirrhosis. Attempts to use more precise measures of liver function (such as elimination tests or drug-metabolism assays) as predictive factors have generally not significantly improved accuracy or have not been validated among other cohorts.‘7-21 de Jongh et al. found one other important prognostic factor for ESLD mortality in this group that was specific for this disease: HBeAg status. Although the presence of HBeAg at baseline examination did not meet conventional statistical significance as a risk factor for mortality (P = 0.08), it was clearly associated with mortality when analysis was restricted to the 77 patients with compensated disease. In addition, the change in HBeAg status from positive to negative during follow-up was associated with a 55% reduction in death rate. The loss of HBeAg usually indicates a decrease in viral replication and theoretically the removal of the source of liver injury. In this cohort, it could be inferred that the removal of the source of liver injury stabilized the pathological process and prevented or delayed the onset of ESLD. Similarly, abstinence in alcoholic liver disease can be considered removal of the source of liver injury and has been shown to be a favorable predictive factor for survival. The findings of de Jongh et al. complement a recent study on the natural history of chronic hepatitis B from Fattovich et al. of Italy*’ who analyzed initial predictive factors for development of cirrhosis among 105 patients who were followed up for a mean of 3.7 years. They found that the persistence of hepatitis B virus (HBV) DNA was an important correlate
EDITORIALS
1693
with development of cirrhosis. Interestingly, none of these “precirrhotic” patients died of ESLD during the period of study. These findings indicate that serological markers of active viral replication (again the putative cause of liver injury) may be predictive of progressive liver injury in chronic hepatitis B without cirrhosis. The closer correlation of HBV DNA than HBeAg with progressive liver disease in the Italian study probably was related to the frequency of the HBeAg- mutant of HBV that is found in ItalyZ3 but is rare in the Netherlands and the United States. The findings of de Jongh et al. help support the use of loss of HBeAg as an important end point in therapy for chronic hepatitis B. These results also indicate that once symptomatic cirrhosis is present, the prognosis in chronic hepatitis B is extremely poor (the 5-year survival rate was only 14%). It is obvious that antiviral therapies should be applied before the development of clinical features of cirrhosis and ESLD. Once these features have developed, liver transplantation is a more appropriate therapy. It is doubtful that the recently developed therapies for chronic viral hepatitis have already had much impact on the mortality rate for ESLD. The decline in mortality rates for cirrhosis more likely reflects several advances in medical management of liver disease as well as other socioeconomic and population changes. Nevertheless, antiviral therapies for chronic viral hepatitis may eventually have an important impact on the mortality rate for ESLD and help to continue its recent decline. JAMES E. EVERHART, M.D., M.P.H. JAY H. HOOFNAGLE, M.D. Division of Digestive Diseases and Nutrition National Institute of Diabetes and Digestive Kidney Diseases National Institutes of Health Bethesda, Maryland
and
References National Center for Health Statistics. Advance report of final mortality statistics, 1989.Monthly vital statistics report. Volume 40,no. 8 (Suppl 2). Hyattsville, MD: U.S. Public Health Service, 1992. Grant BF, DeBakey S, Zobeck TS. Liver cirrhosis mortality in the United States, 1973-1988. National Institute on Alcohol Abuse and Alcoholism Surveillance report no. 18.Rockville, MD: U.S. Public Health Service, 1991. Williams GD, Stinson FS, Brooks SH, Clem D, Noble J. Apparent per capita alcohol consumption: national, state, and regional trends, 1977-1989. National Institute on Alcohol Abuse and Alcoholism Surveillance report no. 20. Rockville, MD: U.S. Public Health Service, 1991. Annual Report of the U.S. Scientific Registry for Organ Transplantation and the Organ Procurement and Transplantation Network 1990.Richmond, VA: UNOS, and Bethesda, MD: Division of Organ Transplantation, Health Resources and Services Administration.
1694
GASTROENTEROLOGY Vol. 103, No. 5
EDITORIALS
5. Poynard T, Cales P, Pasta L, Ideo G, Pascal JP, Pagliaro L, Lebrec D. Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. N Engl J Med 1991;324:1532-1538. 6. Pagliaro L, D’Amico G, Sorensen TIA, Lebrec D, Burroughs AK, Morabito A, Tine F, Politi F, Traina M. Prevention of first bleeding in cirrhosis. A meta-analysis of randomized trials of nonsurgical treatment. Ann Intern Med 1992;117:59-70. 7. Infante-Rivard C, Esnaola S, Villeneuve JP. Role of endoscopic variceal sclerotherapy in the long-term management of variteal bleeding: a meta-analysis. Gastroenterology 1989;96: 1087-1092. 8. Perrillo RP, Schiff ER, Davis GL, Bodenheimer HC, Lindsay K, Payne J, Dienstag JL, O’Brien C, Tamburro C, Jacobson IM, Sampliner R, Feit D, Lefkowitch J, Kuhns M, Meschievitz C, Sanghvi B, Albrecht J, Gibas A. A randomized, controlled trial of interferon alfa-2b alone and following prednisone withdrawal for the treatment of chronic hepatitis B. N Engl J Med 1990;323:295-301. 9. de Jongh FE, Janssen HLA, de Man RA, Hop WCJ, Schalm SW, van Blankenstein M. Survival and prognostic indicators in HBsAg-positive cirrhosis of the liver. The role of HBeAg seroconversion. Gastroenterology 1992;103:1630-1635. 10. Weissberg JI, Ljudevit LA, Coleman IS, Weick S, Nichols JE, Garcia G, Robinson WAS, Merigan TC, Gregory PB. Survival in chronic hepatitis B. An analysis of 379 patients. Ann Intern Med 1984;101:613-616. 11. Lo K-J, Tong MJ, Chien Y-T, Tsai Y-F, Liaw K-C, Yang H, Chian HC, Liu H-C, Lee S-D. The natural course of hepatitis B surface antigen-positive chronic active hepatitis in Taiwan. J Infect Dis 1982;146:205-210. 12. Tanaka R, Itoshima T, Nagashima H. Follow-up study of 582 liver cirrhosis patients for 26 years in Japan. Liver 1987;7:316324. 13. Liaw YF, Lin DY, Chen TJ, Chu CM. Natural course after the development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Liver 1989;9:235-241. 14. Infante-Rivard C, Villeneuve JP, Esnaola S. A framework for
15.
16.
17.
18.
19.
20.
21.
22.
23.
evaluating and conducting prognostic studies: an application to cirrhosis of the liver. J Clin Epidemiol 1989;42:791-805. Dickson ER, Grambsch PM, Fleming TR, Fisher LD, Langworthy A. Prognosis in primary biliary cirrhosis: model for decision making. Hepatology 1989;10:1-7. Fargion S, Mandelli C, Piperno A, Cesana B, Fracanzani AL, Fraquelli M, Bianchi PA, Fiorelli G, Conte D. Survival and prognostic factors in 212 Italian patients with genetic hemochromatosis. Hepatology 1992;15:655-659. Oellerich M, Burdelski M, Lautz HU, Rodeck B, Duewel J, Schulz M, Schmidt FW, Brodehl J, Pichlmayr R. Assessment of pretransplant prognosis in patients with cirrhosis. Transplantation 1991;51:801-806. Zoli M, Cordiani MR, Marchesini G, Iervese T, Labate AM, Bonazzi C, Bianchi G, Pisi E. Prognostic indicators in compensated cirrhosis. Am J Gastroenterol 1991;86:1508-1513. Picard D, Infante-Rivard C, Villeneuve JP, Chartrand R, Picard M, Carrier L. Extrahepatic uptake of technetium-99mphytate: a prognostic index in patients with cirrhosis. J Nucl Med 1990;31:436-440. Adler M, Van Laethem J, Glibert A, Gelin M, Bourgeois N, Vereerstraeten P, Cremer M. Factors influencing survival at one year in patients with nonbiliary hepatic parenchymal cirrhosis. Dig Dis Sci 1990;35:1-5. Beuers U, Jager F, Wahllander A, Ansari H, Kirsch CM. Prognostic value of the intravenous ‘%-aminopyrine breath test compared to the Child-Pugh score and serum bile acids in 84 cirrhotic patients. Digestion 1991;50:212-218. Fattovich G, Brollo L, Giustina G, Noventa F, Pontisso P, Alberti A, Realdi G, Ruol A. Natural history and prognostic factors for chronic hepatitis type B. Gut 1991;32:294-298. Bonino F, Brunetto MR, Rizzetto M, Will H. Hepatitis B virus unable to secrete e antigen. Gastroenterology 1991;100:11381141.
Address requests for reprints to: James Everhart, M.D., M.P.H., 5333 Westbard Avenue, Room 3A-10, Westwood Building, Bethesda, Maryland 20892. This is a U.S. government work. There are no restrictions on its use.
