E. Rolland Dickson

Ursodeoxycholic acid in the treatment of primary biliary cirrhosis

BACKGROUND/AIMS A double-blind, placebo-controlled trial of ursodeoxycholic acid (UDCA) was conducted in 180 patients with primary biliary cirrhosis (PBC) to define the efficacy and safety of UDCA. Efficacy was assessed by time to treatment failure defined as death; liver transplantation; histological progression; development of varices, ascites, or encephalopathy; doubling of total serum bilirubin levels; progression of fatigue or pruritus; drug toxicity; or voluntary withdrawal. METHODS Patients with well-defined PBC underwent complete history, physical examination, liver chemistries, ultrasonography, upper endoscopy, and liver biopsy at entry as well as at 2 years. Liver chemistries were determined every 3 months. RESULTS In patients receiving UDCA, treatment failure was delayed compared with the placebo-treated group (P = 0.0003, log rank test). Seven patients receiving UDCA died or required transplantation compared with 12 in the placebo group (P = 0.18). No patients discontinued UDCA because of side effects of toxicity. CONCLUSIONS UDCA was extraordinarily safe and well tolerated, and its use was associated with delayed progression of the disease as defined in this study. However, the lack of effects on symptoms, histology, and the need for liver transplantation or survival indicate that further evaluation is necessary to determine the ultimate role of UDCA in the treatment of PBC.

A Revised Natural History Model for Primary Sclerosing Cholangitis

OBJECTIVE To describe a natural history model for primary sclerosing cholangitis (PSC) that is based on routine clinical findings and test results and eliminates the need for liver biopsy. PATIENTS AND METHODS Using the Cox proportional hazards analysis, we created a survival model based on 405 patients with PSC from 5 clinical centers. Independent validation of the model was undertaken by applying it to 124 patients who were not included in the model creation. RESULTS Based on the multivariate analysis of 405 patients, a risk score was defined by the following formula: R = 0.03 (age [y]) + 0.54 loge (bilirubin [mg/dL]) + 0.54 loge (aspartate aminotransferase [U/L]) + 1.24 (variceal bleeding [0/1]) - 0.84 (albumin [g/dL]). The risk score was used to obtain survival estimates up to 4 years of follow-up. Application of this model to an independent group of 124 patients showed good correlation between estimated and actual survival. CONCLUSIONS A new model to estimate patient survival in PSC includes more reproducible variables (age, bilirubin, albumin, aspartate aminotransferase, and history of variceal bleeding), has accuracy comparable to previous models, and obviates the need for a liver biopsy.

Primary sclerosing cholangitis: Refinement and validation of survival models

The natural history of primary sclerosing cholangitis was studied in 426 patients from five medical centers. The median follow-up time was 3.0 years (range, 0.01-16.6 years); 100 patients had died by the time of last follow-up. Survival analysis (Cox proportional-hazards regression) was used to identify the variables most useful in predicting survival of patients with primary sclerosing cholangitis. Serum bilirubin concentration, histological stage on liver biopsy, age, and the presence of splenomegaly were independent predictors of a high risk of dying. A mathematical model to predict survival of patients with primary sclerosing cholangitis (based on referral values of those predictors) was statistically validated using two methods. Confidence intervals for predicting patient-specific survival probabilities are also presented. This model to predict survival could be used to stratify participants in therapeutic trials, counsel patients and their families, decide on candidacy for and timing of liver transplantation, and provide mathematical controls for evaluating the efficacy of therapies for primary sclerosing cholangitis, including transplantation.

Bone Loss and Reduced Osteoblast Function in Primary Biliary Cirrhosis

The association of bone loss with primary biliary cirrhosis is poorly understood. In 15 premenopausal female patients, only 2 of whom had fractures, mean bone mineral density was reduced at the lumbar spine but not at the midradius or distal radius. Bone loss was not statistically related to the duration or severity of liver disease. Urinary hydroxyproline excretion, an index for bone resorption, was not different from that of 15 age-matched normal women, but the serum concentration of bone Gla-protein (osteocalcin), a specific marker for bone turnover, was decreased (p less than 0.001). Bone histomorphometric examination in 13 patients showed no osteomalacia but a reduced bone formation rate despite normal values for fractional osteoblast-osteoid interface. The substantial early loss of trabecular bone is mediated by a severe reduction in osteoblast function, which may be caused by retained toxic substances associated with cholestasis.

Outcome of liver transplantation for hepatitis B in the United States

Important innovations, such as hepatitis B immune globulin (HBIG) and lamivudine, have been introduced to the care of patients undergoing liver transplantation (OLT) for viral hepatitis B (HBV) (over the last 15 years). We analyzed survival of OLT recipients with HBV in the United States to examine the effect of these innovations. A retrospective analysis was conducted based on data collected prospectively by the United Network for Organ Sharing in all adult (older than 18) patients undergoing primary OLT in the United States between 1987 and 2002. OLT recipients with HBV were identified by the principal diagnosis of acute or chronic HBV or positive results on HBV markers. Patients were divided into Era 1 (1987‐1991), Era 2 (1992‐1996), and Era 3 (1997‐2002). Era 1 consisted of 6,708 patients (675 with HBV), Era 2 consisted of 13,995 patients (1,005 with HBV), and Era 3 consisted of 20,730 patients (1,723 with HBV). More recent patients were older and had less advanced liver disease and shorter ischemic time. The survival of patients with HBV was significantly better for Era 2 than for Era 1 (P < .01) and for Era 3 than for Era 2 (P < .01). There was no difference in survival between patients with HBV and all other diagnoses for Era 3 (P = .14). In the multivariable analysis, the effect of these eras persisted when other variables such as recipient and donor age, warm ischemic time, pre‐OLT disease severity, and hepatocellular carcinoma (HCC) were taken into account. Unlike previous reports, fulminant disease and Asian race had no effect on patient survival. In conclusion, these data underscore the effectiveness of therapeutic innovations that have occurred in the past two decades and indicate timely and widespread adoption of these measures by transplant centers nationwide. (Liver Transpl 2004;10:968–974.)

A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis

Primary biliary cirrhosis is a progressive disease of the liver characterized by the immunologic destruction of bile ducts; effective therapy is lacking. We therefore evaluated the safety and efficacy of low-dose cyclosporine in 29 patients with primary biliary cirrhosis without evidence of damage to the lobular architecture (precirrhotic disease) or portal hypertension. The patients were randomly assigned to receive either cyclosporine (4 mg per kilogram of body weight per day) or placebo. After one year 17 of the 19 patients assigned to cyclosporine had improvement or stability in their degree of fatigue, and 18 in their degree of pruritus. In contrast, among the 10 patients assigned to placebo, fatigue increased in 4 (P less than 0.06) and pruritus worsened in 6 (P less than 0.001). Those assigned to cyclosporine also had significant decreases in serum levels of bilirubin, alanine aminotransferase, alkaline phosphatase, gamma globulin, and the titer of antimitochondrial antibodies. For the 20 patients who have completed two years in the study, liver biopsies (coded specimens) showed evidence of histologic progression in only 1 of 13 patients in the cyclosporine group, as compared with 5 of 7 in the placebo group (P less than 0.003). No patient has permanently discontinued cyclosporine because of side effects; however, signs of nephrotoxicity developed in 12 of 19, and 9 of 19 had increased blood pressure. We conclude that in patients with precirrhotic primary biliary cirrhosis, immunosuppressive therapy with cyclosporine is promising and deserves further evaluation.

Comparison of the Clinicopathologic Features of Primary Sclerosing Chol-angitis and Primary Biliary Cirrhosis

Primary sclerosing cholangitis and primary biliary cirrhosis are chronic cholestatic syndromes that may be difficult to differentiate clinically. Destructive cholangitis occurs in both diseases and leads to similar clinical and biochemical abnormalities. Therefore, we compared the clinical, biochemical, immunologic, radiologic, and hepatic histologic features of these syndromes in two large groups of patients prospectively selected by predefined criteria. Primary biliary cirrhosis (n = 258) occurred predominantly in middle-aged women who were usually symptomatic with fatigue and pruritus, commonly had keratoconjunctivitis sicca, and often were hyperpigmented. Tests for antimitochondrial antibodies were always positive, usually in very high titer. Although the extrahepatic bile ducts were normal radiographically, smooth tapering and narrowing of the intrahepatic bile ducts was occasionally noted. Hepatic histology was diagnostic when a florid duct lesion was present. In contrast, primary sclerosing cholangitis (n = 60) occurred primarily in young men who were usually symptomatic with fatigue and pruritus and frequently had chronic ulcerative colitis. Tests for antimitochondrial antibodies were nearly always negative and cholangiography demonstrated abnormalities of the extrahepatic and intrahepatic bile ducts in all cases. Although hepatic histology was often compatible with the diagnosis, it was usually not diagnostic, and considerable overlap existed with the abnormalities seen in primary biliary cirrhosis. Likewise, biochemical tests of copper metabolism were similar in both syndromes. These results call attention to the differences and similarities in the clinicopathologic features of these two cholestatic syndromes and provide a basis for a rational diagnostic strategy.

Recurrence of nonalcoholic steatohepatitis following liver transplantation.

Patients with nonalcoholic steatohepatitis (NASH) may develop progressive liver dysfunction necessitating liver transplantation (OLT). We report the incidence of recurrent disease and outcome in patients undergoing OLT for NASH. Patients transplanted for NASH were identified according to pretransplant and explant liver histology. Patients with significant alcohol consumption were excluded. Medical records were reviewed to extract pre- and posttransplant data, including sequential body weight, biochemistry, and graft histology. Of 622 liver explants, eight patients had features consistent with NASH. All patients were female with a median age of 58. Seven patients were diagnosed with NASH preoperatively, including three who had undergone jejunoileal bypass. One patient was diagnosed as cryptogenic cirrhosis. At a median of 15 months following OLT, all of the eight patients were alive with no graft failure. Six patients developed persistent fatty infiltration in their graft, three of whom had accompanying hepatocellular degeneration, consistent with a diagnosis of recurrent NASH. In two patients, transition from mild steatosis to steatohepatitis and early fibrosis was observed over one to two years. The patients who did not develop recurrent steatosis had significant weight loss following transplantation, although the length of follow-up was relatively short. Patients undergoing OLT for NASH may develop recurrent steatosis shortly after transplantation, with possible progression to steatohepatitis and fibrosis. Although longer follow-up is necessary to determine the eventual prognosis related to the recurrent fat and fibrosis in the graft, patients with endstage liver disease due to NASH should be considered good candidates for OLT.

Cost-Effectiveness of 6 and 12 Months of Interferon-α Therapy for Chronic Hepatitis C

Hepatitis C virus (HCV) is a major cause of liver-related illness and death in the United States. A recent report from the Centers for Disease Control and Prevention [1] estimated that 35 000 to 180 000 persons develop HCV infection and more than 8000 die of HCV-related illness each year. One reason that hepatitis C continues to be an important public health concern is the lack of effective therapy to eliminate HCV. Despite an initial biochemical response in up to 76% of patients after 6 months of interferon- therapy, only about 10% achieve a sustained response (defined as disappearance of biochemical, histologic, and virologic evidence of chronic hepatitis C) [2-5]. An additional 5% to 7% of patients may attain a sustained response when treatment is extended to 12 months [5, 6]. Because of the low efficacy and high cost of interferon-, the cost-effectiveness of the drug in the treatment of chronic hepatitis C has been questioned [7]. One of the difficulties in evaluating the cost-effectiveness of interferon- is lack of clinical data. The long-term effectiveness of interferon- remains undetermined because follow-up in most studies has lasted no more than 1 year. The effect of interferon- on the development of decompensated cirrhosis and hepatocellular carcinoma is also unknown. Moreover, our understanding of the natural history of chronic hepatitis C without treatment is incomplete. Investigators have therefore relied on computer-generated models to evaluate cost-effectiveness [8, 9]. Previous analyses have suggested that 6 months of interferon- treatment yields substantial health care cost savings [8, 9]. We analyzed the cost-effectiveness of 6 and 12 months of interferon- treatment for chronic hepatitis C by using a computer model that incorporated prognostic variables associated with the progression of liver disease and response to interferon-. Methods Overview of Analysis We first used probabilities derived from an analysis of the current literature to construct a Markov model that describes the natural progression of liver disease from chronic hepatitis C in a cohort of patients. This model is described in detail in the Appendix. On the basis of this natural history model, we simulated a randomized treatment trial comparing no treatment, 6 months of interferon- treatment, and 12 months of interferon- treatment. The cost-effectiveness of interferon- treatment from the point of view of society was assessed by comparing the number of liver-related deaths, quality-adjusted survival, and costs among the treatment strategies. Simulations and analyses were performed and verified by using a statistical software package (SAS, SAS Institute, Cary, North Carolina) and spread-sheet software (Excel, Microsoft Corp., Redmond, Washington). Natural History Model for Chronic Hepatitis C Our Markov model consisted of six disease states: chronic hepatitis C, compensated cirrhosis, decompensated cirrhosis, orthotopic liver transplantation, hepatocellular carcinoma, and death (Figure 1). The entry point of our model was chronic hepatitis C without cirrhosis, as determined by liver biopsy. As shown in Figure 1, patients may progress from chronic hepatitis C to compensated and decompensated cirrhosis over time. Compensated cirrhosis is diagnosed when the patient has histologically progressed to cirrhosis but has neither developed any symptoms nor required ongoing medical treatment. Once a patient experiences symptoms related to cirrhosis, he or she is classified as having decompensated cirrhosis and incurs expenses for health care services. Some patients with decompensated cirrhosis may develop hepatocellular carcinoma or undergo liver transplantation. As the population ages, an increasing number of patients die of natural causes independent of liver disease. We modeled four age-specific cohorts (30, 40, 50, and 60 years of age) of 1000 patients each. Figure 1. Disease states in a Markov model describing the natural history of chronic hepatitis C. The rate at which simulated patients moved from one state to another was obtained by critically reviewing the literature. The reported rate of progression from chronic hepatitis C to cirrhosis varies from 1.1% to 10.8% [10-18]. We assumed that patients with chronic hepatitis C may be divided into two groups according to their rate of progression (Table 1). Patients in the indolent disease group would progress from chronic hepatitis to cirrhosis at the lower end of the range (1% per year) reported in the literature. In contrast, chronic hepatitis C in patients in the aggressive disease group would progress to cirrhosis at the higher end of the reported range (10% per year). The rates of progression from compensated to decompensated cirrhosis, from cirrhosis to hepatocellular carcinoma, and from decompensated cirrhosis to death were also obtained from the literature (Appendix Table) [19-24]. We assumed that once cirrhosis developed, the rate of occurrence of complications (that is, hepatic decompensation, hepatocellular carcinoma, and liver-related death) was the same in the indolent and aggressive disease groups. Age-related mortality rates from all causes were based on the 1990 U.S. Vital Statistics [25]. Table 1. Subgroups of Patients with Chronic Hepatitis C according to Virulence of Infection: Estimates Used in the Base-Case Scenario Appendix Table. Estimates Used in the Base-Case Scenario of the Markov Model Interferon- Treatment We simulated a randomized trial that compared the three study groups (no treatment, 6 months of interferon- treatment, and 12 months of interferon- treatment) in each of the four cohorts. Patients in the two treatment groups received 3 million U of interferon- three times a week by self-injection and were monitored every 3 months by clinical examination and laboratory tests. Interferon- therapy was discontinued at 12 weeks in patients in whom aminotransferase levels did not return to normal. Sustained response to treatment was defined as complete and continued disappearance of symptoms and normal liver biochemistry 6 months after discontinuation of treatment. Sustained biochemical response would be accompanied by histologic remission and disappearance of viral RNA from the blood. We assumed that patients who achieved sustained remission would follow the mortality pattern of the general population (cure state in the Markov model [Figure 1]). Patients who did not respond, had relapse, or were not treated would follow the clinical course prescribed by the natural history model. With regard to the proportion of sustained response, we applied different response rates to the indolent and aggressive disease groups (Table 1). Many studies have shown that the factors associated with a more aggressive clinical course of chronic hepatitis C are also predictive of worse response to interferon- treatment [5, 26-28]. For example, multivariate analyses have shown that patients with HCV genotype 1b or high virus levels were up to 10 times less likely to have a sustained response to interferon- therapy than were patients with other genotypes or low virus levels [28]. This association must be considered in the analysis of cost-effectiveness of interferon- because the cost-effectiveness of the drug will otherwise be overestimated. Patients who attain a sustained response to interferon- may be those who would not have had progressive disease without treatment. Conversely, patients who are more likely to die of long-term complications of HCV infection are those who are less likely to respond to interferon- [7]. Costs The costs of treating decompensated cirrhosis and hepatocellular carcinoma were based on a report from the National Institute of Diabetes and Digestive and Kidney Diseases after adjustment for inflation [29]. Costs of liver transplantation were also obtained from the literature and supplemented with institutional data [30, 31]. The cost of interferon- was the average wholesale price plus 20% for costs of injection supplies, clinical and biochemical monitoring, and treatment of side effects from interferon- [32]. These cost estimates are summarized in the Appendix Table. Monetary figures were discounted at an annual rate of 3%. Assessment of Outcome and Sensitivity Analysis Our main outcome measures were the number of deaths from liver disease and total costs. A third outcome, the effect on quality of life over time, was assessed as cumulative quality-adjusted life-years (QALYs) [33]. In computing QALYs, a panel of hepatologists and a nurse specialist used a generic instrument to estimate the utility weight for each disease state [34]. For example, we assigned a utility weight of 0.5 to decompensated cirrhosis, estimating that 1 year of life in a person with decompensated cirrhosis would be equivalent to 0.5 years of healthy life. The other utility weights assigned were 0.95 for chronic hepatitis, 0.8 for compensated cirrhosis, 0.8 for the time after liver transplantation, 0.25 for hepatocellular carcinoma, and 0 for death. We discounted the benefits of interferon- treatment (QALYs) at the same rate used for discounting costs (3%). Incremental cost-effectiveness was assessed by computing cost per QALY gained; the three strategies were compared in a pairwise fashion. Sensitivity analyses were performed by varying the value of the variables used in the model to identify those that had the greatest effect on the conclusions. Variables associated with a more than twofold change in cost-effectiveness in this process were considered influential and are presented in the Results section. All cost figures were rounded to the nearest

Ursodeoxycholic acid delays the onset of esophageal varices in primary biliary cirrhosis

100. Results Natural History Model of Chronic Hepatitis C Figure 2 shows the results of the Markov model that describes the progression of liver disease in the cohort of a representative age group (40 years of age). At time zero, all patients have chronic hepatitis C. During the ensuing years, an increasing proportion of patients moves throug