ADVANCES IN HEPATOLOGY C u r r e n t D e v e l o p m e n t s i n t h e Tr e a t m e n t o f H e p a t i t i s a n d H e p a t o b i l i a r y D i s e a s e
Section Editor: Eugene R. Schiff, MD
Primary Biliary Cirrhosis: Challenges for the Future Jenny Heathcote, MD, FRCPC
Senior Scientist Head Clinical Studies Resource Centre Toronto Western Research Institute G&H What is the major challenge in primary biliary cirrhosis at this time? JH Currently, the major challenge in primary biliary cirrhosis (PBC) is to predict at the time of diagnosis which patients will develop progressive liver disease. The importance of being able to predict who will develop progressive liver disease is closely linked to the age of the patient of diagnosis, which ranges from 15 to 80 years. In North America, the median age of diagnosis is 52, while a recent study in England found that the median age of diagnosis there is almost 10 years older. At the present time, there are One of the major questions in improving prediction of patients likely to develop progressive liver disease is why there is a difference in this median age of diagnosis. The method of diagnosis may be the only reason, but more likely both genetic and environmental factors influence presentation and progression. At the present time, there are invasive and noninvasive methods available. The Mayo Risk Score is a noninvasive method but was developed in the early 1980s, before liver transplantation was widely available. The patients assessed with this score were symptomatic, were being treated at the Mayo Clinic, and had not undergone transplantation. G&H How is PBC diagnosed? JH Today, at least 60% of patients are asymptomatic at the time of diagnosis. PBC is typically identified through a routine rheumatological or autoantibody assessment at the time of a rheumatology work-up during which a patient tests positive for antimitochondrial antibodies (AMA), or through a routine physical in which elevations
in a liver blood test, particularly alkaline phosphatase and/or gamma-glutamyltransferase, are identified. However, it is important to note that being asymptomatic is not synonymous with having early disease. There are patients who are asymptomatic at diagnosis but who are found to have cirrhosis upon biopsy. Even for patients who are symptomatic, predicting whether or not a patient will develop progressive liver disease is not always feasible. When PBC was initially named in the 1950s, most patients had cirrhosis at diagnosis, while today most patients do not. The invasive method of diagnosing PBC is by liver biopsy. Studies in the 1980s clearly established that patients with cirrhosis have a worse outcome than those without cirrhosis, but predicting outcome for patients without cirrhosis is very difficult. Recently, the Poupon group in France found that among PBC patients who do not have cirrhosis at diagnosis, the presence of severe interface hepatitis is associated with a 50% chance of progressing to cirrhosis at 10 years, even if they are undergoing treatment with ursodiol, whereas patients with mild interface hepatitis have a 5% chance of progressing. This study contains the hardest data available regarding predicting disease outcome, but a liver biopsy is required. G&H Is it possible to screen patients for the presence of AMA? JH The problem with screening a large part of the population for AMA is that .5% would test positive for this antibody, but only 10% of AMA-positive individuals appear to develop liver disease. The triggers that prompt the development of PBC in AMA-positive individuals are unknown. It is not reasonable to screen the population for AMA, as we can predict neither outcome nor cure. G&H Have any noninvasive predictive tests been explored? JH Many investigators have conducted cohort studies evaluating risk factors for disease progression based on simple blood tests. However, only one of these was a serial study. Nakamura and colleagues plotted the survival in patients with PBC according to gp210 antibody titers
Gastroenterology & Hepatology Volume 2, Issue 3 March 2006
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and found a significantly different rate of progression between those with a high antibody titer and those with a low antibody titer. We have conducted another study that supports these data. However, the challenge with this approach is that only about one third of patients with PBC test positive for this antibody. This test is the only noninvasive approach thus far, aside from the various prognostic scores, none of which were evaluated in patients with very early-stage disease. The survival time among patients who are asymptomatic at diagnosis and who remain so is exactly the same as for the age- and gender-matched control population. Further, at least half of patients who are asymptomatic at diagnosis die of a comorbidity, not liver disease.However, when a patient is diagnosed, it is impossible to know whether that patient will remain asymptomatic or not. G&H What are the challenges related to the treatment of PBC? JH In patients who have or appear likely to develop progressive disease, it is clear that therapy should be initiated very early on. In the clinical trials evaluating ursodiol in which we participated with the Poupon and Mayo Clinic groups, nearly all patients included in the studies had symptomatic disease, and many already had cirrhosis. These studies were conducted nearly 20 years ago, and the presentation of the disease has changed dramatically since then. Our findings suggested that ursodiol did delay the development of hepatic failure. An analysis by the Cochrane committee of several heterogeneous studies, some of which included a treatment course of only 6–12 months, suggested that survival was not prolonged by ursodiol. However, no change would be expected among patients treated less for a year, since PBC affects patients over 10–20 years, not over 6–12 months. Pares and colleagues conducted a randomized controlled trial of 82 patients, the majority of whom had early disease and no symptoms, treated for 6 years. In this study, patients who were treated with ursodiol experienced a delay in histologic progression. G&H Is immunosuppressive therapy being incorporated into the treatment of PBC? JH Immunosuppressive therapy with agents such as prednisolone or budesonide (Entocort, Prometheus) may be the next additive therapy. First, it is necessary to consider the results of a study by Mitchison and colleagues, published in 1992. This 3-year study of prednisolone was stopped early due to the occurrence of osteoporosis as a possible side effect of steroids but also possibly due to severe PBC. However, the data showed that among patients with noncirrhotic disease at baseline, 1 out of 9
172
patients receiving prednisolone progressed to cirrhosis versus 4 out of 7 patients receiving placebo. The population size of this study was too small for meaningful statistical analysis, but the results are encouraging. Two pilot studies of budesonide were conducted in the late 1990s. Budesonide is a corticosteroid that is completely metabolized by the liver on the first pass, and so should not cause any peripheral side effects. Leuschner and coworkers showed that among 39 patients undergoing treatment with ursodiol, patients who also received budesonide experienced a marked diminution in inflammation and scar tissue in the liver. A second study, conducted at the Mayo Clinic, showed no benefit with adding budesonide to ursodiol, and in fact found some deterioration in the Mayo Risk Score and in bone mineral density. However, this study included patients with cirrhosis, and once a patient has cirrhosis, the benefit of budesonide being metabolized by the liver completely on the first pass is negated because there is shunting in the liver; some of the drug bypasses the liver cells and enters the systemic circulation. The Mayo Clinic study showed that budesonide should not be given to patients who have cirrhosis due to PBC. Interestingly, a more recent randomized controlled trial by Rautiainan and coworkers, from Finland, evaluated ursodiol with or without budesonide in 71 patients. Patients receiving both drugs experienced a dramatic improvement in liver histology versus those receiving ursodiol alone. The sample size was small and the observation was only histology, but the results are exciting nevertheless. Recently, Poupon and colleagues evaluated patients according to whether they had interface hepatitis. As mentioned above, this French group was the first to recognize that interface hepatitis is a marker for PBC that progresses more rapidly to cirrhosis. In this small study, the authors found that patients given steroid therapy did experience a benefit. G&H Has ursodiol been evaluated in combination with other immunosuppressive agents? JH Combes and associates conducted an 8-year study of ursodiol with or without methotrexate that showed no difference in survival. Azathioprine and cyclosporine have also been evaluated. Cyclosporine was found to have too many systemic side effects and is therefore not an appropriate therapy for patients who may be asymptomatic for 10–20 years. G&H What studies are needed regarding the treatment of PBC? JH The next large trial that needs to be conducted in PBC is one evaluating ursodiol with or without budesonide
Gastroenterology & Hepatology Volume 2, Issue 3 March 2006
in noncirrhotic patients, with survival as an endpoint, although liver histology may suffice. Such a study needs to include at least 500 patients. Budesonide is associated with certain side effects that could be limited by recruiting only patients with early disease. However, the possibility of side effects raises the point made above that it is essential to try to determine which patients will experience progressive disease. Patients who will die naturally of old age should not be receiving a drug that could have toxic effects with long-term use. To address this issue, any new trial will also evaluate markers. Gene expression should be evaluated at the time a patient enters a study, and the expression pattern may eventually be useful in predicting outcome, once the outcome of the patients entered into the study is known. G&H Are there other ways to improve treatment besides adding an immunosuppressive agent to therapy? JH It has been suggested that further enhancing choleresis and overcoming the retention of bile in the liver and the consequences of that retention with more potent agents may improve outcomes. The more potent agents that have been suggested are those that control the nuclear receptors within the liver that are important in bile flow. There is another category of agents that lessen retention of bile acids. The agent bezafibrate (Bezalip, Roche), which upregulates MDR3, one of the transporters on the canaliculus may be effective in the treatment of PBC. Preliminary studies have suggested that treating PBC patients with bezafibrate leads to decreases in alkaline phosphatase and immunoglobulin M, although it is not clear how these changes affect histology and survival. Another group of agents interferes with the pathogenesis of PBC. Many infecting organisms have been implicated in PBC, such as beta retrovirus. A pilot study of lamivudine-zidovudine (Combivir, GlaxoSmithKline), an antiretroviral drug with a nucleoside analog, has been conducted but provided few answers regarding benefit. No biochemical benefits were observed, but the authors observed a histologic benefit in that bile duct damage was less in those who received the experimental treatment. A larger randomized trial of lamivudine-zidovudine in earlystage PBC is being conducted that should better address the question of improving treatment.
Along with having a primed host with the right immunologic profile, PBC may also be triggered by xenobiotics, agents that alter host proteins and become antigenic, possibly even carcinogenic. In PBC, the first xenobiotic that comes to mind is cigarettes. Two epidemiologic studies have shown that smoking is more common among patients with PBC than among age- and gender-matched controls. Finally, an agent that inhibits apoptosis of the small interlobular bile ducts could be an effective approach, but such an agent has yet to be developed. G&H Could you summarize what is on the horizon for PBC? JH First, now that we are diagnosing patients with very early disease, some of whom will never progress, we need to identify markers of disease progression. The current standard of care deals only with the complications of already established disease, and although therapy improves cholestasis and histology and lessens the development of decompensation, there is still much debate regarding whether or not the current approach improves overall survival. Clearly, therapy needs to become more targeted at the cause of PBC, but until we know the cause, it will be difficult to target it with therapy. Early intervention to treat the interface hepatitis and bile duct damage with a steroid may be an effective approach. Suggested Reading Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005;353:1261-1273. Erratum in: N Engl J Med. 2006;354:313. Leung PS, Coppel RL, Gershwin ME. Etiology of primary biliary cirrhosis: the search for the culprit. Semin Liver Dis. 2005;25:327-336. Leuschner U, Manns MP, Eisebitt R. Ursodeoxycholic acid in the therapy for primary biliary cirrhosis: effects on progression and prognosis. Z Gastroenterol. 2005;43:1051-1059. Invernizzi P, Selmi C, Mackay IR, Podda M, Gershwin ME. From bases to basis: linking genetics to causation in primary biliary cirrhosis. Clin Gastroenterol Hepatol. 2005;3:301-410. Bergasa NV, Mason A, Floreani A, et al. Primary biliary cirrhosis: report of a focus study group. Hepatology. 2004;40:1013-1020. Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management and treatment of hepatitis C. Hepatology. 2004;39:1147-1171.
Gastroenterology & Hepatology Volume 2, Issue 3 March 2006
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Section Editor: Eugene R. Schiff, MD
Primary Biliary Cirrhosis: Challenges for the Future Jenny Heathcote, MD, FRCPC
Senior Scientist Head Clinical Studies Resource Centre Toronto Western Research Institute G&H What is the major challenge in primary biliary cirrhosis at this time? JH Currently, the major challenge in primary biliary cirrhosis (PBC) is to predict at the time of diagnosis which patients will develop progressive liver disease. The importance of being able to predict who will develop progressive liver disease is closely linked to the age of the patient of diagnosis, which ranges from 15 to 80 years. In North America, the median age of diagnosis is 52, while a recent study in England found that the median age of diagnosis there is almost 10 years older. At the present time, there are One of the major questions in improving prediction of patients likely to develop progressive liver disease is why there is a difference in this median age of diagnosis. The method of diagnosis may be the only reason, but more likely both genetic and environmental factors influence presentation and progression. At the present time, there are invasive and noninvasive methods available. The Mayo Risk Score is a noninvasive method but was developed in the early 1980s, before liver transplantation was widely available. The patients assessed with this score were symptomatic, were being treated at the Mayo Clinic, and had not undergone transplantation. G&H How is PBC diagnosed? JH Today, at least 60% of patients are asymptomatic at the time of diagnosis. PBC is typically identified through a routine rheumatological or autoantibody assessment at the time of a rheumatology work-up during which a patient tests positive for antimitochondrial antibodies (AMA), or through a routine physical in which elevations
in a liver blood test, particularly alkaline phosphatase and/or gamma-glutamyltransferase, are identified. However, it is important to note that being asymptomatic is not synonymous with having early disease. There are patients who are asymptomatic at diagnosis but who are found to have cirrhosis upon biopsy. Even for patients who are symptomatic, predicting whether or not a patient will develop progressive liver disease is not always feasible. When PBC was initially named in the 1950s, most patients had cirrhosis at diagnosis, while today most patients do not. The invasive method of diagnosing PBC is by liver biopsy. Studies in the 1980s clearly established that patients with cirrhosis have a worse outcome than those without cirrhosis, but predicting outcome for patients without cirrhosis is very difficult. Recently, the Poupon group in France found that among PBC patients who do not have cirrhosis at diagnosis, the presence of severe interface hepatitis is associated with a 50% chance of progressing to cirrhosis at 10 years, even if they are undergoing treatment with ursodiol, whereas patients with mild interface hepatitis have a 5% chance of progressing. This study contains the hardest data available regarding predicting disease outcome, but a liver biopsy is required. G&H Is it possible to screen patients for the presence of AMA? JH The problem with screening a large part of the population for AMA is that .5% would test positive for this antibody, but only 10% of AMA-positive individuals appear to develop liver disease. The triggers that prompt the development of PBC in AMA-positive individuals are unknown. It is not reasonable to screen the population for AMA, as we can predict neither outcome nor cure. G&H Have any noninvasive predictive tests been explored? JH Many investigators have conducted cohort studies evaluating risk factors for disease progression based on simple blood tests. However, only one of these was a serial study. Nakamura and colleagues plotted the survival in patients with PBC according to gp210 antibody titers
Gastroenterology & Hepatology Volume 2, Issue 3 March 2006
171
and found a significantly different rate of progression between those with a high antibody titer and those with a low antibody titer. We have conducted another study that supports these data. However, the challenge with this approach is that only about one third of patients with PBC test positive for this antibody. This test is the only noninvasive approach thus far, aside from the various prognostic scores, none of which were evaluated in patients with very early-stage disease. The survival time among patients who are asymptomatic at diagnosis and who remain so is exactly the same as for the age- and gender-matched control population. Further, at least half of patients who are asymptomatic at diagnosis die of a comorbidity, not liver disease.However, when a patient is diagnosed, it is impossible to know whether that patient will remain asymptomatic or not. G&H What are the challenges related to the treatment of PBC? JH In patients who have or appear likely to develop progressive disease, it is clear that therapy should be initiated very early on. In the clinical trials evaluating ursodiol in which we participated with the Poupon and Mayo Clinic groups, nearly all patients included in the studies had symptomatic disease, and many already had cirrhosis. These studies were conducted nearly 20 years ago, and the presentation of the disease has changed dramatically since then. Our findings suggested that ursodiol did delay the development of hepatic failure. An analysis by the Cochrane committee of several heterogeneous studies, some of which included a treatment course of only 6–12 months, suggested that survival was not prolonged by ursodiol. However, no change would be expected among patients treated less for a year, since PBC affects patients over 10–20 years, not over 6–12 months. Pares and colleagues conducted a randomized controlled trial of 82 patients, the majority of whom had early disease and no symptoms, treated for 6 years. In this study, patients who were treated with ursodiol experienced a delay in histologic progression. G&H Is immunosuppressive therapy being incorporated into the treatment of PBC? JH Immunosuppressive therapy with agents such as prednisolone or budesonide (Entocort, Prometheus) may be the next additive therapy. First, it is necessary to consider the results of a study by Mitchison and colleagues, published in 1992. This 3-year study of prednisolone was stopped early due to the occurrence of osteoporosis as a possible side effect of steroids but also possibly due to severe PBC. However, the data showed that among patients with noncirrhotic disease at baseline, 1 out of 9
172
patients receiving prednisolone progressed to cirrhosis versus 4 out of 7 patients receiving placebo. The population size of this study was too small for meaningful statistical analysis, but the results are encouraging. Two pilot studies of budesonide were conducted in the late 1990s. Budesonide is a corticosteroid that is completely metabolized by the liver on the first pass, and so should not cause any peripheral side effects. Leuschner and coworkers showed that among 39 patients undergoing treatment with ursodiol, patients who also received budesonide experienced a marked diminution in inflammation and scar tissue in the liver. A second study, conducted at the Mayo Clinic, showed no benefit with adding budesonide to ursodiol, and in fact found some deterioration in the Mayo Risk Score and in bone mineral density. However, this study included patients with cirrhosis, and once a patient has cirrhosis, the benefit of budesonide being metabolized by the liver completely on the first pass is negated because there is shunting in the liver; some of the drug bypasses the liver cells and enters the systemic circulation. The Mayo Clinic study showed that budesonide should not be given to patients who have cirrhosis due to PBC. Interestingly, a more recent randomized controlled trial by Rautiainan and coworkers, from Finland, evaluated ursodiol with or without budesonide in 71 patients. Patients receiving both drugs experienced a dramatic improvement in liver histology versus those receiving ursodiol alone. The sample size was small and the observation was only histology, but the results are exciting nevertheless. Recently, Poupon and colleagues evaluated patients according to whether they had interface hepatitis. As mentioned above, this French group was the first to recognize that interface hepatitis is a marker for PBC that progresses more rapidly to cirrhosis. In this small study, the authors found that patients given steroid therapy did experience a benefit. G&H Has ursodiol been evaluated in combination with other immunosuppressive agents? JH Combes and associates conducted an 8-year study of ursodiol with or without methotrexate that showed no difference in survival. Azathioprine and cyclosporine have also been evaluated. Cyclosporine was found to have too many systemic side effects and is therefore not an appropriate therapy for patients who may be asymptomatic for 10–20 years. G&H What studies are needed regarding the treatment of PBC? JH The next large trial that needs to be conducted in PBC is one evaluating ursodiol with or without budesonide
Gastroenterology & Hepatology Volume 2, Issue 3 March 2006
in noncirrhotic patients, with survival as an endpoint, although liver histology may suffice. Such a study needs to include at least 500 patients. Budesonide is associated with certain side effects that could be limited by recruiting only patients with early disease. However, the possibility of side effects raises the point made above that it is essential to try to determine which patients will experience progressive disease. Patients who will die naturally of old age should not be receiving a drug that could have toxic effects with long-term use. To address this issue, any new trial will also evaluate markers. Gene expression should be evaluated at the time a patient enters a study, and the expression pattern may eventually be useful in predicting outcome, once the outcome of the patients entered into the study is known. G&H Are there other ways to improve treatment besides adding an immunosuppressive agent to therapy? JH It has been suggested that further enhancing choleresis and overcoming the retention of bile in the liver and the consequences of that retention with more potent agents may improve outcomes. The more potent agents that have been suggested are those that control the nuclear receptors within the liver that are important in bile flow. There is another category of agents that lessen retention of bile acids. The agent bezafibrate (Bezalip, Roche), which upregulates MDR3, one of the transporters on the canaliculus may be effective in the treatment of PBC. Preliminary studies have suggested that treating PBC patients with bezafibrate leads to decreases in alkaline phosphatase and immunoglobulin M, although it is not clear how these changes affect histology and survival. Another group of agents interferes with the pathogenesis of PBC. Many infecting organisms have been implicated in PBC, such as beta retrovirus. A pilot study of lamivudine-zidovudine (Combivir, GlaxoSmithKline), an antiretroviral drug with a nucleoside analog, has been conducted but provided few answers regarding benefit. No biochemical benefits were observed, but the authors observed a histologic benefit in that bile duct damage was less in those who received the experimental treatment. A larger randomized trial of lamivudine-zidovudine in earlystage PBC is being conducted that should better address the question of improving treatment.
Along with having a primed host with the right immunologic profile, PBC may also be triggered by xenobiotics, agents that alter host proteins and become antigenic, possibly even carcinogenic. In PBC, the first xenobiotic that comes to mind is cigarettes. Two epidemiologic studies have shown that smoking is more common among patients with PBC than among age- and gender-matched controls. Finally, an agent that inhibits apoptosis of the small interlobular bile ducts could be an effective approach, but such an agent has yet to be developed. G&H Could you summarize what is on the horizon for PBC? JH First, now that we are diagnosing patients with very early disease, some of whom will never progress, we need to identify markers of disease progression. The current standard of care deals only with the complications of already established disease, and although therapy improves cholestasis and histology and lessens the development of decompensation, there is still much debate regarding whether or not the current approach improves overall survival. Clearly, therapy needs to become more targeted at the cause of PBC, but until we know the cause, it will be difficult to target it with therapy. Early intervention to treat the interface hepatitis and bile duct damage with a steroid may be an effective approach. Suggested Reading Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005;353:1261-1273. Erratum in: N Engl J Med. 2006;354:313. Leung PS, Coppel RL, Gershwin ME. Etiology of primary biliary cirrhosis: the search for the culprit. Semin Liver Dis. 2005;25:327-336. Leuschner U, Manns MP, Eisebitt R. Ursodeoxycholic acid in the therapy for primary biliary cirrhosis: effects on progression and prognosis. Z Gastroenterol. 2005;43:1051-1059. Invernizzi P, Selmi C, Mackay IR, Podda M, Gershwin ME. From bases to basis: linking genetics to causation in primary biliary cirrhosis. Clin Gastroenterol Hepatol. 2005;3:301-410. Bergasa NV, Mason A, Floreani A, et al. Primary biliary cirrhosis: report of a focus study group. Hepatology. 2004;40:1013-1020. Strader DB, Wright T, Thomas DL, Seeff LB. Diagnosis, management and treatment of hepatitis C. Hepatology. 2004;39:1147-1171.
Gastroenterology & Hepatology Volume 2, Issue 3 March 2006
173
