John J. Poterucha

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.

Interleukin‐28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection

Polymorphism in the interleukin‐28B (IL28B) gene region, encoding interferon (IFN)‐λ3, is strongly predictive of response to antiviral treatment in the nontransplant setting. We sought to determine the prevalence and impact on clinical outcomes of donor and recipient IL28B genotypes among liver transplant recipients. The cohort study included 189 consecutive patients infected with hepatitis C virus (HCV) who underwent liver transplantation between January 1, 1995, and January 1, 2005, at the Mayo Clinic, Rochester, MN. Genotyping of the polymorphism rs12979860 was performed on DNA collected from all donors and recipients in the cohort. Sixty‐five patients received IFN‐based antiviral therapy. The CC IL28B variant was less common in the chronic HCV‐infected recipients than in non‐HCV donor livers (33% versus 47%, P = 0.03). IL28B recipient genotype was significantly predictive of fibrosis stage, with TT genotype being associated with more rapid fibrosis (Pearson chi‐square P = 0.024 for the comparison G versus A). Donor and recipient IL28B genotype were independently associated with sustained virologic response (P < 0.005). The presence of IL28B CC variant in either the recipient (R) or donor (D) liver was associated with increased rate of sustained virologic response (D‐non‐CC/R‐non‐CC = 3/19 [16%] versus D‐CC/R‐non‐CC = 11/22 [50%] versus D‐non‐CC/R‐CC = 5/12 [42%] versus R‐CC/D‐CC = 6/7 [86%], P = 0.0095). IL28B genotype was not significantly associated with survival (overall/liver‐related). Conclusion: Recipient IL28B TT genotype is associated with more severe histological recurrence of HCV. Recipient and donor liver IL28B genotype are strongly and independently associated with IFN‐based treatment response in patients after orthotopic liver transplantation. The data suggest that CC donor livers might be preferentially allocated to patients with HCV infection. (Hepatology 2011;)

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.)

Natural History of Hepatitis B Virus Infection: An Update for Clinicians

Hepatitis B virus (HBV) is a common viral pathogen that causes a substantial health burden worldwide. Significant progress has been made in the past few decades in understanding the natural history of HBV infection. A dynamic balance between viral replication and host immune response is pivotal to the pathogenesis of liver disease. In immunocompetent adults, most HBV infections spontaneously resolve, whereas in most neonates and infants they become chronic. Those with chronic HBV may present in 1 of 4 phases of infection: (1) in a state of immune tolerance, (2) with hepatitis B e antigen (HBeAg)positive chronic hepatitis, (3) as an inactive hepatitis B surface antigen carrier, or (4) with HBeAg-negative chronic hepatitis. Of these, HBeAg-positive and HBeAg-negative chronic hepatitis may progress to cirrhosis and its long-term sequelae including hepatic decompensation and hepatocellular carcinoma. Several prognostic factors, such as serum HBV DNA concentrations, HBeAg status, serum aminotransferases, and certain HBV genotypes, have been identified to predict long-term outcome. These data emphasize the importance of monitoring all patients with chronic HBV infection to identify candidates for and select optimal timing of antiviral treatment, to recognize those at risk of complications, and to implement surveillance for early detection of hepatocellular carcinoma.

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

Endoscopic therapy of anastomotic bile duct strictures occurring after liver transplantation

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

Combined Liver Transplantation and Gastric Sleeve Resection for Patients With Medically Complicated Obesity and End‐Stage Liver Disease

BACKGROUND Optimal therapy for anastomotic biliary strictures occurring after orthotopic liver transplantation (OLT) remains to be defined. We reviewed our experience with endoscopic therapy for such strictures and contrasted it with reported data. METHODS Endoscopic therapy was performed with balloon dilation alone; no patients received an endoprosthesis. Responses were characterized as good if the patient improved clinically and no subsequent procedures were required after one or more dilations within a 3-month period; partial if clinically significant obstruction resolved but cholestasis persisted or there was a need for further endoscopic management beyond the initial 3 months; poor if subsequent surgery or percutaneous procedures were required; and failed if endoscopic access or dilation could not be accomplished. RESULTS Fifteen patients underwent 23 endoscopic retrograde cholangiopancreatographies for post-OLT anastomotic strictures. Postprocedure follow-up averaged 25.2 months. Cholangiography was successful in all 23 procedures; free duct access was achieved in 22 of 23 procedures. The strictures were successfully accessed for dilation in 11 of 15 patients and in 19 of 23 procedures. Outcome was deemed good in 4 (27%), partial in 3 (20%), and poor in 5 (33%) patients. Endoscopic therapy failed in 3 (20%). Poor outcomes were due to the early recognition of severe lesions (2 treated surgically) or to short-term responses to dilation alone (3). The procedural complication rate of 17.4% included 3 episodes of transient cholangitis (i.e., elevation of liver enzymes associated with fever that lasted less than 3 days) and 1 self-limited episode of postsphincterotomy bleeding, which required the transfusion of 2 units packed red blood cells. In published series the combined success rate of balloon dilation alone for treatment of anastomotic strictures is 41%, whereas for dilation plus stent placement it is 75%. CONCLUSION Endoscopic balloon dilation alone is not a reliable method of therapy for anastomotic strictures occurring after OLT. Dilation followed by short- to intermediate-term stent placement appears to provide a more durable result.

Relationship between hepatitis C genotype and severity of recurrent hepatitis C after liver transplantation

Obesity is increasingly common before and after liver transplantation (LT), yet optimal management remains unclear. Our aim was to analyze the effectiveness of a multidisciplinary protocol for obese patients requiring LT, including a noninvasive pretransplant weight loss program, and a combined LT plus sleeve gastrectomy (SG) for obese patients who failed to lose weight prior to LT. Since 2006, all patients referred LT with a BMI > 35 were enrolled. There were 37 patients who achieved weight loss and underwent LT alone, and 7 who underwent LT combined with SG. In those who received LT alone, weight gain to BMI > 35 was seen in 21/34, post‐LT diabetes (DM) in 12/34, steatosis in 7/34, with 3 deaths plus 3 grafts losses. In patients undergoing the combined procedure, there were no deaths or graft losses. One patient developed a leak from the gastric staple line, and one had excess weight loss. No patients developed post‐LT DM or steatosis, and all had substantial weight loss (mean BMI = 29). Noninvasive pretransplant weight loss was achieved by a majority, though weight gain post‐LT was common. Combined LT plus SG resulted in effective weight loss and was associated with fewer post‐LT metabolic complications. Long‐term follow‐up is needed.

Cost-effective analysis of surgical palliation versus endoscopic stenting in the management of unresectable pancreatic cancer.

BACKGROUND Recurrence of hepatitis C virus (HCV) infection after liver transplantation is universal, but the relationship between hepatitis C genotype and posttransplant outcome has been controversial. The aim of this study was to assess the relationship between hepatitis C genotype on posttransplant frequency of recurrent hepatitis, histologic severity of recurrence, and progression to cirrhosis. METHODS We studied 42 HCV RNA positive patients who received transplants between 1985 and 1994. Sera were tested for HCV RNA and protocol liver biopsies were in obtained the posttransplant period. Biopsies were scored according to the histologic activity index (HAI) and staged in a blinded fashion. RESULTS The distribution of hepatitis C genotypes distribution was as follows: 1a, 19 (45%); 1b, 17 (40%); 2b, 3 (7%); and 1 each of 2a, 3a, and 4a. There was histologic evidence of hepatitis in 38 of 42 (90.4%) of patients. Hepatitis C was mild, moderate, or severe (HAI>3) in 38% of grafts and minimal (HAI 0-3) in 62%. Overall HAI scores and histologic stage were higher in the genotype 1b group. Six of 17 (35%) genotype 1b patients had cirrhosis compared with 2 of 25 (8%) in the non-1b genotype group. CONCLUSIONS (1) Histologic evidence of recurrent hepatitis C is seen in 90% of liver allografts; (2) Histologic hepatitis C recurs with similar frequency in genotype 1b and non-1b recipients; (3) Genotype 1b is associated with more severe histologic disease recurrence than non-1b genotypes; (4) Genotype 1b appears to be associated with a higher degree of posttransplant fibrosis and cirrhosis than non-1b genotypes.