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Background & Aims: The epidemiology of primary sclerosing cholangitis (PSC) in the United States is unknown. We report the incidence, clinical spectrum, and outcomes of PSC in Olmsted County, Minnesota., Methods: Using the Rochester Epidemiology Project, a medical records linkage system in Olmsted County, Minnesota, we identified county residents with PSC, and the diagnosis was confirmed according to clinical, biochemical, radiographic, and histologic criteria., Results: Twenty-two patients met diagnostic criteria for PSC in 1976-2000. The age-adjusted (to 2000 U.S. whites) incidence of PSC in men was 1.25 per 100,000 person-years (95% CI, 0.70 to 2.06) compared with 0.54 per 100,000 person-years (95% CI, 0.22 to 1.12) in women. The prevalence of PSC in 2000 was 20.9 per 100,000 men (95% CI, 9.5 to 32.4) and only 6.3 per 100,000 women (95% CI, 0.1 to 12.5). Seventy-three percent of cases had inflammatory bowel disease, the majority with ulcerative colitis. Survival among PSC patients was significantly less than expected for the Minnesota white population of similar age and gender (P < 0.001)., Conclusions: These data represent the first population-based estimates of the incidence and prevalence of PSC in the United States. The incidence and prevalence of PSC were approximately one third of those previously described for primary biliary cirrhosis in the same population. Our data suggest that the prevalence of PSC in the United States, with its attendant medical burdens, is significantly greater than previously estimated.

The prevalence and natural history of spontaneous bacterial peritonitis in asymptomatic patients with ascites secondary to cirrhosis is unknown. From a prospectively recorded database, we reviewed the clinical and laboratory features of all outpatients with cirrhotic ascites undergoing paracentesis between July 1994 and December 2000. The prevalence of spontaneous bacterial peritonitis in the population of 427 cirrhotic outpatients as defined by neutrocytic ascites (absolute neutrophil count >or=250 cells/mm(3)) was 3.5%. Of the 15 patients with neutrocytic ascites, 6 were culture positive (1.4%) and 9 culture negative (2.1%). Eight other patients (1.9%) had bacterascites. The organisms cultured from ascitic fluid in these asymptomatic patients with culture positive neutrocytic ascites and bacterascites were predominantly gram positive. No patient developed hepatorenal syndrome, and 1-year survival of 67% was better than historical data from hospitalized patients with spontaneous bacterial peritonitis. Moreover, patients who did not receive antibiotics for neutrocytic ascites fared no worse than patients who did receive antibiotics. In conclusion, spontaneous bacterial peritonitis in outpatients with cirrhotic ascites is less frequent, occurs in patients with less advanced liver disease, and may have a better outcome than its counterpart in hospitalized patients. In addition, the organisms cultured from ascitic fluid in outpatients are predominantly gram positive. A reassessment of diagnostic criteria for spontaneous bacterial peritonitis in outpatients may be required.

Objective: To determine the level of association between minimal listing criteria (MLC) recognition and outcomes associated with waiting list registration for liver transplantation (LT)., Patients and Methods: A total of 147 patients and 201 patients were identified as first-time referrals for LT evaluation between January 1, 1997, and November 30, 1997 (cohort A), and December 1,1997, and December 31, 1998 (cohort B), respectively. Relevant demographic and clinical information was abstracted from medical records. Minimal listing criteria were defined as a Child-Turcotte-Pugh (CTP) score of 7 or higher., Results: Patient age, sex, hepatic disease etiology, and mean CTP scores were similar between cohorts A and B. However, the proportion of registered patients in cohort B with CTP scores of 7 or higher increased significantly after formal MLC recognition (96% vs 82% for cohort A; P=.001). In cohort A, waiting list registration was based on patient age, male sex, nonalcohol-related hepatic disease, and a CTP score of 7 or higher in the absence of formal MLC. The rate of first-time patient referral was also increased in cohort B vs cohort A after formal MLC recognition (80% vs 69%, respectively; P=.002) despite similar clinical characteristics. Although the number of patients with a CTP score of 10 or higher was greater in cohort B vs cohort A, the proportion of patients with advanced end-stage liver disease was similar (29% vs 26%, respectively; P=.72)., Conclusion: The explicit recognition of MLC was strongly associated with improvements in appropriate waiting list registration for LT.

According to the third National Health and Nutrition Examination Survey (NHANES), 3.9 million of the U.S. civilian population have been infected with hepatitis C virus (HCV), of whom 2.7 million (74%) have chronic infection. Hepatitis C virus infection is most common among non-Caucasian men, ages 30 to 49 years. Moreover, the prevalence of antibody to hepatitis C virus in groups not represented in the NHANES sample, such as the homeless or incarcerated, may be as high as 40%. The age-adjusted death rate for non-A, non-B viral hepatitis increased from 0.4 to 1.8 deaths per 100,000 persons per year between 1982 and 1999. In 1999, the first year hepatitis C was reported separately, there were 3,759 deaths attributed to HCV, although this is likely an underestimate. There was a 5-fold increase in the annual number of patients with HCV who underwent liver transplantation between 1990 and 2000. Currently, more than one third of liver transplant candidates have HCV. Inpatient care of HCV-related liver disease has also been increasing. In 1998, an estimated 140,000 discharges listed an HCV-related diagnosis, accounting for 2% of discharges from non-federal acute care hospitals in the United States. The total direct health care cost associated with HCV is estimated to have exceeded $1 billion in 1998. Future projections predict a 4-fold increase between 1990 and 2015 in persons at risk of chronic liver disease (i.e., those with infection for 20 years or longer), suggesting a continued rise in the burden of HCV in the United States in the foreseeable future.

Hepatitis C is a prevalent infection in North America. However, the natural history of hepatitis C virus (HCV) infection in the general population is not fully understood. Available cohort-based studies suggest that only a relative minority of patients develop significant liver disease, such as cirrhosis and/or hepatocellular carcinoma. Other studies, mostly conducted based on referral patients with established disease, portray much more serious consequences of HCV infection. Although a substantial improvement has been made in the treatment for HCV, the overall impact of antiviral therapy in altering the natural course of HCV infection remains uncertain. Therapeutic trials involve narrow selection criteria that would exclude the majority of hepatitis C patients in the community, and are conducted in ideal settings that may not be generalizable to the average practice setting. Demographic groups that are at high risk of developing severe liver disease include older male patients who consume alcohol. In contrast, antiviral therapy is more effective in young and female patients and those who do not drink alcohol. Thus, patients who appear to be successfully treated may not be those for whom clearance of the virus would be beneficial. Cost-effectiveness studies published to date have not been able to fully address the complex and heterogeneous matrix of the factors that influence the natural history of HCV infection and treatment response. In summary, there is a significant degree of uncertainty about many assumptions that are necessary in creating computer models to estimate the cost-effectiveness of HCV therapy. When interpreting the results of cost effectiveness analyses regarding the treatment of HCV infection, it is important to be aware of the underlying assumptions that are incorporated in the model and the data on which they are based. Given these limitations, vis- -vis the expense, toxicity and yet limited effectiveness of the currently available antiviral agents, one should not blindly accept a conclusion that treatment for hepatitis C is cost effective.

This paper demonstrates the usefulness of combining simulation with Bayesian estimation methods in analysis of cost-effectiveness data collected alongside a clinical trial. Specifically, we use Markov Chain Monte Carlo (MCMC) to estimate a system of generalized linear models relating costs and outcomes to a disease process affected by treatment under alternative therapies. The MCMC draws are used as parameters in simulations which yield inference about the relative cost-effectiveness of the novel therapy under a variety of scenarios. Total parametric uncertainty is assessed directly by examining the joint distribution of simulated average incremental cost and effectiveness. The approach allows flexibility in assessing treatment in various counterfactual premises and quantifies the global effect of parametric uncertainty on a decision-maker's confidence in adopting one therapy over the other., (Copyright 2002 John Wiley & Sons, Ltd.)

AIH is a chronic liver disease that has been associated with hepatic failure and death in the absence of liver transplantation. As a result, AIH imparts significant medical and economic burdens on affected patients and health care delivery systems, respectively. The use of accepted methodologies for outcomes and health services research has identified emerging information on the epidemiology and natural history, HRQoL, and resource utilization for similar autoimmune chronic liver diseases such as PBC and PSC. Similar efforts are needed in AIH, and they are supported on the basis of existing data which suggest similar levels of disease burden compared to PBC and PSC. As a result, the ability to plan for disease management strategies in AIH that require the allocation of scarce resources will be feasible.

Objective: To develop a model for community-population- or health system-based registries of all patients with diagnosed hepatitis C, to facilitate clinical care and epidemiologic studies., Study Design: Geographically defined, population-based cohort study., Methods: Registry subjects were identified using January 1, 1990, to December 31, 1999, data from the Rochester Epidemiology Project (REP), which lists all diagnoses for Olmsted County residents recorded by clinicians during visits to Olmsted County medical providers. We supplemented diagnostic data with information from laboratory databases that record all hepatitis C testing in Olmsted County. All diagnoses based on the REP and laboratory databases were confirmed by medical record review. Proposed data elements to be included in a hepatitis C registry were identified and defined, and data collection methodology was tested., Results: A total of 355 subjects (62% male) were identified in the total community population of 130,000. Both the diagnostic summary database (n = 309, 87%) and the laboratory database (n = 46, 133%) were important in the identification of subjects for the registry. Nine additional subjects with diagnostic or laboratory evidence of hepatitis C refused the legislatively mandated (Minnesota statute) medical records research authorization and could not be included in the registry. Most desired data elements were available in the medical records., Conclusions: Both medical visit diagnostic summaries (administrative or billing data) and laboratory databases are required to identify subjects with physician-based diagnoses of hepatitis C. Few patients refused the authorization required for inclusion in a research registry.

Objective: To determine the health care follow-up and treatment associated with physician-diagnosed hepatitis C (HCV) in a community-based population., Study Design: We conducted a retrospective medical record review using records from all providers in Olmsted County, Minnesota., Population: The study incorporated all Olmsted County residents with physician-diagnosed hepatitis C from 1990 through 1999., Outcomes Measured: We assessed demographic and health status information as well as health services use in subjects with physician-diagnosed HCV., Results: Physicians diagnosed hepatitis C in 355 subjects (219 men [62%], 136 women [38%]), mean age 43 years, in the 10-year period studied. About half of diagnoses (45%, n = 159) were confirmed with polymerase chain reaction or liver biopsies. Identified risk factors included IV drug use (50%), multiple sex partners (36%), and blood transfusion (30%). Follow-up assessment with aspartate aminotransferase/amino alanine transferase (AST/ALT) tests occurred in about half (49%) of subjects, while 202 subjects (60%) were referred for gastrointestinal (GI) specialist evaluation and 49 patients (14% of all, 25% of those referred to a GI specialist) had specific treatment for hepatitis C. Although well over half of patients (60%) had possible contraindications to HCV treatment, including heavy alcohol use, few were referred for chemical dependency therapy., Conclusions: In this community, follow-up and treatment related to HCV were limited. Attention to prevention of disease-accelerating co- infections was only modest. Referral or documented recommendations for treatment of alcoholism or heavy chronic alcohol ingestion were minimal.

A recent mandate emphasizes severity of liver disease to determine priorities in allocating organs for liver transplantation and necessitates a disease severity index based on generalizable, verifiable, and easily obtained variables. The aim of the study was to examine the generalizability of a model previously created to estimate survival of patients undergoing the transjugular intrahepatic portosystemic shunt (TIPS) procedure in patient groups with a broader range of disease severity and etiology. The Model for End-Stage Liver Disease (MELD) consists of serum bilirubin and creatinine levels, International Normalized Ratio (INR) for prothrombin time, and etiology of liver disease. The model's validity was tested in 4 independent data sets, including (1) patients hospitalized for hepatic decompensation (referred to as "hospitalized" patients), (2) ambulatory patients with noncholestatic cirrhosis, (3) patients with primary biliary cirrhosis (PBC), and (4) unselected patients from the 1980s with cirrhosis (referred to as "historical" patients). In these patients, the model's ability to classify patients according to their risk of death was examined using the concordance (c)-statistic. The MELD scale performed well in predicting death within 3 months with a c-statistic of (1) 0.87 for hospitalized patients, (2) 0.80 for noncholestatic ambulatory patients, (3) 0.87 for PBC patients, and (4) 0.78 for historical cirrhotic patients. Individual complications of portal hypertension had minimal impact on the model's prediction (range of improvement in c-statistic: <.01 for spontaneous bacterial peritonitis and variceal hemorrhage to ascites: 0.01-0.03). The MELD scale is a reliable measure of mortality risk in patients with end-stage liver disease and suitable for use as a disease severity index to determine organ allocation priorities.

We describe mortality and resource utilization for inpatient care of hepatitis C (HCV) in comparison to alcohol-induced liver disease (ALD) in the United States and identify factors that affect outcomes. The Healthcare Cost and Utilization Project database, a national inpatient sample was used to identify hospitalization records with diagnoses related to liver disease from HCV and ALD. Outcome of hospitalizations was analyzed in terms of in-hospital deaths and health care resource utilization. For 1995, we estimate that there were 26,700 hospitalizations and 2,600 deaths in acute, nonfederal hospitals in the United States for liver diseases caused by HCV. Total charges for these hospitalizations were $514 million. In comparison, ALD was associated with 101,200 hospitalizations, 13,400 deaths, and $1.8 billion in charges. Simultaneous HCV and alcohol abuse was associated with younger ages at the time of hospitalization and death compared with HCV or ALD alone. In a logistic regression analysis, alcohol abuse (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.2-1.5) and human immunodeficiency virus (HIV) infection (OR, 4.5; 95% CI, 4.0-4.9) were associated with an increased risk of death among those with HCV. Liver transplantation and patient death were associated with the largest increase in hospitalization charges. Major complications of cirrhosis, such as variceal bleeding, encephalopathy, and hepatorenal syndrome, and sociodemographic factors, such as race and health insurance, were also significantly associated with the risk of death and hospitalization charges, which were similar in HCV and ALD. This study provides new estimates regarding the public health impact of HCV, for use in health policy decisions and cost-effectiveness analyses of preventive and therapeutic interventions.

Background & Aims: The epidemiology of primary biliary cirrhosis (PBC) has not been studied systematically in the United States. We report the incidence and prevalence of this condition in the general population. We also examined the validity of the Mayo natural history model for PBC among these unselected patients from the community., Methods: The Rochester Epidemiology Project entails a computerized index of diagnoses from the health care encounters of residents of Olmsted County, Minnesota. For potential cases identified using this database, the complete (inpatient and outpatient) medical records were reviewed to verify the diagnosis and extract information necessary for the application of the Mayo model. We estimated the incidence and prevalence of PBC in this population and compared the actual survival of patients with PBC in the community with the survival predicted for PBC patients by the Mayo natural history model., Results: The age-adjusted (to 1990 U.S. whites) incidence of PBC per 100,000 person-years for years 1975-1995 was 4.5 (95% confidence interval [CI], 3.1-5.9) for women, 0.7 (95% CI, 0.1-1.3) for men, and 2.7 (95% CI, 1.9-3.5) overall. The age- and sex-adjusted prevalence per 100,000 persons as of 1995 was 65.4 (95% CI, 43.0-87.9) for women, 12.1 (95% CI, 1.1-23.1) for men, and 40.2 (95% CI, 27.2-53.1) overall. The Mayo natural history model accurately predicted the actual survival of these patients., Conclusions: This first description of the epidemiology of PBC in the United States indicates that its incidence and prevalence in this country are among the highest reported. Outcomes among these unselected patients from a community population further validated the Mayo natural history model of PBC.

The NIDDK-QA instrument, developed and widely used in liver transplant recipients, assesses quality of life (QOL) in four domains, including liver disease symptoms, physical function, health satisfaction, and overall well-being. We investigated whether the instrument may be used as a disease-specific instrument in ambulatory patients with cholestatic liver disease. The NIDDK-QA instrument was administered in 96 patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) seen at the Mayo Clinic. The SF-36, a well-established generic instrument, was also administered. Standard measures for test-retest reliability, internal consistency, and discriminant and concurrent validity were examined. All patients were ambulatory with mostly normal levels of serum bilirubin and albumin concentrations. The reliability of the NIDDK-QA, as measured by test-retest correlation (Pearson coefficients: 0.82-0.99, P <.01) and by internal consistency (Cronbach's alpha: 0.87-0.94) exceeded conventional acceptability criteria. The correlation between domain scores of the NIDDK-QA and SF-36 was clear and logical in that the physical function domain of NIDDK-QA strongly correlated with the physical component summary score of SF-36 (r = 0.86, P <.01). The overall well-being domain of the NIDDK-QA was closely associated with the mental summary score of SF-36 (r = 0.69, P <.01). Among PBC patients, there was a modest yet significant correlation between the Mayo risk score and overall well-being (r = -0.26, P =.03). In the assessment of QOL in patients with cholestatic liver disease, NIDDK-QA is found reliable and valid. These data, combined with our previous study, demonstrate its applicability in a wide spectrum of disease severity, ranging from early, ambulatory-phase disease to decompensated cirrhosis necessitating liver transplantation.

Issues in the selection and timing of liver transplantation for primary sclerosing cholangitis (PSC) remain controversial. Although the Child-Pugh classification (CP) score and Mayo PSC model have similar abilities to estimate pretransplantation survival, a comparison of these 2 scores in predicting survival after liver transplantation has not been conducted. The aim of this study is to compare the Mayo PSC model and CP score in predicting patient survival and related economic outcomes after liver transplantation. Data from 128 patients with PSC, identified from the NIDDK database, were used to calculate patient-specific Mayo PSC and CP scores before transplantation. Levels reflecting a poor outcome were defined a priori. Receiver operating characteristic (ROC) curves and regression methods (Cox proportional hazards and linear regression models) were used to assess the relationship between these 2 scores and 5 post liver transplantation outcome measures. CP score was found to be a significantly (P <.05) better predictor of death 4 months or less after liver transplantation than: (a) length of hospital stay >21 days (or death before discharge) and (b) resource utilization >200,000 units (measured by area under the ROC curve). The Cox model identified statistically significant (P <.05) associations between CP score and each outcome after adjusting for the Mayo PSC risk score. Similar results were not observed for the Mayo PSC model when adjusted for CP score. Among patients with PSC undergoing liver transplantation, CP score was a better overall predictor of both survival and economic resource utilization compared with the Mayo PSC model.

The Mayo natural history model has been used widely as a tool to estimate prognosis in patients with primary biliary cirrhosis (PBC), particularly liver transplant candidates. We present an abbreviated model in which a tabular method is used to approximate the risk score, which may be incorporated in the minimal listing criteria for liver transplant candidates. Data used in the development and validation of the original Mayo model were derived from 418 patients with well-characterized PBC. To construct an abbreviated risk score in a format similar to that of Child-Turcotte-Pugh score, 1 to 3 cut-off criteria were determined for each variable, namely age (0 point for <38, 1 for 38 to 62 and 2 for >/=63 years), bilirubin (0 point for <1, 1 for 1 to 1.7, 2 for 1.7 to 6.4, and 3 for >6.4 mg/dL), albumin (0 point for >4.1, 1 for 2.8 to 4.1, and 2 for <2.8 g/dL), prothrombin time (1 point for normal and 2 for prolonged) and edema (0 point for absent and 1 for present). The intervals between these criteria were chosen in a way to enable a meaningful classification of patients according to their risk for death. This score is highly correlated with the original risk score (r = 0.93; P <.01). The Kaplan-Meier estimate at 1 year was 90.6% in patients with a score of 6. The abbreviated risk score is a convenient method to quickly estimate the risk score in patients with PBC. An abbreviated score of 6 may be consistent with the current minimal listing criteria in liver transplant candidates.

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.

Pulmonary hypertension has been associated with poor outcome after liver transplantation. We assessed the diagnostic accuracy of Doppler echocardiography in detecting significant pulmonary hypertension. Seventy-four potential liver transplant candidates underwent Doppler echocardiography in which the systolic right ventricular pressure (RVsys) was used to estimate the systolic pulmonary artery pressure (PAsys). Group 1 included 39 consecutive patients with RVsys >/=50 mm Hg who underwent elective right heart catheterization. Group 2 consisted of 35 patients with RVsys <50 mm Hg in whom pulmonary artery pressures were measured at the beginning of the transplantation procedure. The accuracy of the estimates by Doppler echocardiography was assessed against measurements made by direct catheterization. Patients in groups 1 and 2 were comparable in their demographic and liver disease characteristics. There was a strong correlation between RVsys by Doppler echocardiography and PAsys by right heart catheterization (r =.78, P <.01). Of the 39 patients in group 1, 29 (72%) had at least moderate pulmonary hypertension (mean pulmonary artery pressure [MPAP] >/=35 mm Hg), including 12 (30%) with severe pulmonary hypertension (MPAP >/=50 mm Hg). Only 1 of the group 2 patients had MPAP >/=35 mm Hg. Thus, in the diagnosis of moderate to severe pulmonary hypertension, the sensitivity of echocardiography was 97% and specificity was 77%. Doppler echocardiography is an accurate screening test to detect moderate to severe pulmonary hypertension. We advise that liver transplant candidates with RVsys >/=50 mm Hg undergo right heart catheterization to fully characterize pulmonary hemodynamics.

Objective: Cholestasis may result from diverse etiologies. We review chronic cholestatic disorders involving small intrahepatic bile ducts in the adult ambulatory care setting. Specifically, we discuss variant forms of primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) as well as other conditions that may present diagnostic and therapeutic difficulties., Methods: We conducted a MEDLINE search of the literature (1981-1997) and reviewed the experiences at the Mayo Clinic. All articles were selected that discussed antimitochondrial antibody (AMA)-negative PBC, small-duct PSC (formerly pericholangitis), and idiopathic adulthood ductopenia., Results: The most common chronic cholestatic liver diseases affecting adults are PBC and PSC. Patients without the hallmarks of either syndrome are diagnosed according to their clinical and histological characteristics. Autoimmune cholangitis is diagnosed if clinical and histological features are compatible with PBC but autoantibodies other than AMA are present. Isolated small duct PSC is diagnosed if patients have inflammatory bowel disease, biopsy features compatible with PSC, but a normal cholangiogram. If ductopenia (absence of interlobular bile ducts in small portal tracts) is found histologically in the absence of PSC, inflammatory bowel disease, and other specific cholestatic syndromes such as drug reaction or sarcoidosis, the most likely diagnosis is idiopathic adulthood ductopenia., Conclusions: Based on these definitions, an algorithm for diagnosis and therapy in patients with laboratory evidence of chronic cholestasis may be constructed, pending results of further investigations into the etiopathogenesis of these syndromes.

Background: We studied the economic impact of cytomegalovirus (CMV) disease and its effective reduction with antiviral prophylaxis in liver transplant recipients., Method: Analysis of institutional charge data accumulated during a prospective, randomized, controlled trial comparing oral acyclovir 800 mg four times daily for 120 days (ACV) and intravenous ganciclovir 5 mg/kg every 12 h for 14 days followed by ACV for 106 days (GCV) was performed., Results: Liver transplant recipients who developed CMV disease had significantly higher charges (median: $148,300) than those who developed asymptomatic CMV infection ($119,600) or experienced no CMV infection ($114,100) (P<0.01). A multiple linear regression analysis indicated that CMV disease is associated with a 49% increase in charges, independent of other factors influencing increased hospitalization charges. In CMV-seronegative patients who received a CMV-seropositive donor organ, GCV prophylaxis was associated with a significant reduction in charges, as compared to ACV prophylaxis ($113,900 vs. $153,300, respectively; P=0.02)., Conclusions: CMV disease is an independent risk factor for increased resource utilization associated with liver transplantation. The use of an effective prophylactic antiviral regimen provides savings in health care resources, particularly in patients at high risk for developing CMV disease.

Under the current environment of liver transplantation, there are several factors to be considered in the timing of liver transplantation. These include expected patient survival with and without liver transplantation, patient's morbidity and quality of life before and after liver transplantation and overall resource utilization. Statistical models have been developed for patients with chronic liver disease, particularly of cholestatic variety. By applying these models in patients being considered for liver transplantation, a window of optimal timing of liver transplantation may be defined in such way that the survival gain is maximized and perioperative mortality minimized. Likewise, a number of pretransplant morbidity indicators such as Child-Pugh score, UNOS status, and renal insufficiency have been found to have a profound influence on post-transplant morbidity, thus resource utilization. An increasing number of investigators have measured and documented a dramatic improvement in the quality of life of patients before and after liver transplantation. As the waiting time and uncertainty of the outcome of liver transplantation increase, consideration of these factors may be useful for physicians evaluating transplant candidates to make best-informed decisions in the selection of candidates and timing for liver transplantation.

The aim of our study was to quantitatively assess the impact of hepatic retransplantation on patient and graft survival and resource utilization. We studied patients undergoing hepatic retransplantation among 447 transplant recipients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) at 3 transplantation centers. Cox proportional hazards regression analysis was used for survival analysis. Measures of resource utilization included the duration of hospitalization, length of stay in the intensive care unit, and the duration of transplantation surgery. Forty-six (10.3%) patients received 2 or more grafts during the follow-up period (median, 2.8 years). Patients who underwent retransplantation had a 3.8-fold increase in the risk of death compared with those without retransplantation (P <.01). Retransplantation after an interval of greater than 30 days from the primary graft was associated with a 6.7-fold increase in the risk of death (P <.01). The survival following retransplantations performed 30 days or earlier was similar to primary transplantations. Resource utilization was higher in patients who underwent multiple consecutive transplantations, even after adjustment for the number of grafts during the hospitalization. Among cholestatic liver disease patients, poor survival following hepatic retransplantation is attributed to late retransplantations, namely those performed more than 30 days after the initial transplantation. While efforts must be made to improve the outcome following retransplantation, a more critical evaluation may be warranted for late retransplantation candidates.

The Child-Pugh classification is a simple, convenient prognostic measure in patients with liver cirrhosis. We investigated the relative role of the Child-Pugh classification and the Mayo model in the assessment of survival in patients with primary sclerosing cholangitis (PSC). Of the 173 patients described in the original Mayo PSC natural history model, 147 patients had sufficient information in the medical record to allow computation of the Child-Pugh score. We used our most recent modification of the Mayo model to compute the risk score, based on patient's age, serum levels of bilirubin, albumin, and aspartate aminotransferase and history of variceal bleeding. Using the risk score (R), patients were divided into the low- (R < 0), intermediate- (0 /= 2) groups. Kaplan-Meier estimates and proportional hazards analysis were used to evaluate the two prognostic models. Although there was a statistically significant correlation between the Child-Pugh and Mayo risk scores, two-thirds of the patients had a Child-Pugh score of 5 or 6 and a relatively wide range of risk scores (-1.1-4.3). The probability of survival for 7 years in patients in the low-, intermediate-, and high-risk groups was 92%, 74%, and 40% for Child-Pugh class A (n = 96) and 100%, 62%, and 28% for Child-Pugh class B patients (n = 44), respectively. There were only a small number (n = 7) of Child-Pugh class C patients. In our age-adjusted multivariate analysis, each unit increase in the Mayo risk score was associated with a 2.5-fold increase in the risk of death (95% confidence interval: 1.8-3.4, P <.01), whereas Child-Pugh classification had no significant impact on survival (Child-Pugh B vs. A: risk ratio = 1.1 [95% confidence interval: 0.6-2.0]; Child-Pugh C versus A: risk ratio = 0.6 [95% confidence interval: 0. 2-1.8]). In contrast to the Child-Pugh classification, which was developed for advanced liver cirrhosis, the Mayo model provides valid survival information, particularly in patients early in the course of PSC.

Objectives: Hepatitis G virus (HGV) is a recently discovered member of the flavivirus family that has been associated with acute and chronic hepatitis. HGV infection has been reported to coexist in 10-20% of patients with chronic hepatitis C. The significance of simultaneous infection with HGV and hepatitis C virus (HCV) remains to be clarified, as do the effects on HGV of therapeutic interventions such as interferon treatment or liver transplantation., The Aims of Our Study Were: 1) to examine the frequency of HGV infection in the settings of liver transplantation and interferon therapy for hepatitis C; and 2) to compare HGV RNA levels before and after liver transplantation or interferon treatment., Methods: Pre-treatment sera were available in 65 patients with chronic hepatitis C treated with interferon; pretransplant sera were available in 49 patients transplanted for end stage liver disease associated with chronic hepatitis C. Information collected included age, sex, risk factors for hepatitis, concurrent liver disease, patient and allograft survival, biochemical response to interferon, histological activity index, and degree of fibrosis/cirrhosis. HCV genotyping was performed by sequencing the NS-5 region. HGV quantitation was performed using a research-based branched DNA (bDNA) assay with a set of probes directed at the 5' untranslated region., Results: HGV was detected in 10 of 49 patients (20%) before transplant and in 13 of 65 patients (20%) treated with interferon. There was a female predominance among HGV-positive compared with HGV-negative transplant patients (80% vs 20%; p < 0.01), but such a difference was not observed in the interferon-treated group. Hepatic iron concentration was lower in hepatic explants from patients who were HGV-positive than in those who were HGV-negative (318 +/- 145 microg/g dry weight vs 1497 +/- 2202 microg/g dry weight; p = 0.02). HCV exposure after 1980 was more common in the HGV-positive patients than in those who were HGV-negative for the entire study population (10 of 20 [50%] vs 16 of 66 [24%]; p = 0.03), as well as for the nontransplant subgroup (8 of 12 [67%] vs 12 of 39 [31%]; p = 0.03). HGV RNA levels declined at 1 yr after transplant in seven of eight patients. Among nine patients tested during or after interferon treatment, HGV RNA levels declined from pretreatment levels in all and disappeared in three., Conclusions: Among patients with chronic hepatitis C treated with either interferon or liver transplantation, the frequency of coinfection with HGV is about 20%. HGV may be a more recent virus in the US than HCV. Coinfection with HGV does not appear to affect the likelihood of response to interferon in patients with hepatitis C. Finally, HGV RNA levels appear to decline after both liver transplantation and interferon therapy, suggesting possible suppression by increased HCV replication in the former case, and a possible drug treatment effect in the latter.

Liver transplantation (LT) is an established therapy for patients with end-stage primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). In this report, we describe the health status and quality of life (QOL) in patients with these cholestatic liver diseases before and after LT. A QOL questionnaire was completed by 157 adult patients with PBC or PSC before and 1 year after liver transplantation at the Mayo Clinic or Baylor University Medical Center. This questionnaire measured four aspects of QOL, including symptoms; physical, social, and emotional functioning; health perceptions; and overall QOL. Changes in these QOL parameters before and after LT were described, and regression analysis was used to assess the relationships between clinical and QOL factors. There were no differences in QOL parameters between patients with PBC and PSC. QOL following transplantation was substantially better than before transplantation. This was observed in all four aspects of QOL. The degree of improvement as measured by effect size (difference in mean scores divided by the pretransplantation standard deviation) was 0.53 for symptoms (P <.01), 1.16 for function (P <.01), 2.37 for health satisfaction (P <.01), and 1.16 for overall QOL (P <.01). Patients' overall QOL before transplantation was significantly related to subjective and objective health status indicators and clinical factors such as ascites and renal dysfunction. QOL at 1-year follow-up, however, could not be adequately predicted by the pretransplantation subjective health status and clinical factors. Patients with end-stage cholestatic disease undergoing LT experience substantial improvement in all aspects of QOL addressed in this study. The patients' QOL 1 year after LT could not be predicted by pretransplantation variables used in this study.

In 1989, we reported on the efficacy of liver transplantation in primary biliary cirrhosis (PBC) by demonstrating that the actual patient survival following transplantation was significantly better than without transplantation as predicted by a mathematical survival model ("Mayo natural history model"). Our aim in this investigation was to determine an optimal time to perform liver transplantation in PBC. One hundred forty-three patients with PBC undergoing liver transplantation were followed prospectively. Disease severity was measured immediately before transplantation by a summary score ("risk score") used in the Mayo natural history model, namely age, bilirubin, albumin, prothrombin time, and the presence or absence of edema. Proportional hazards analyses were performed assessing patient survival following transplantation. The influence of disease severity immediately pretransplantation on resource utilization for liver transplantation was assessed. Compared with our report in 1989, liver transplantation was performed at an earlier stage of disease (e.g., median risk score: 7.5 vs. 8.3; P < .01). Following transplantation, patient survival probabilities at 1, 2, and 5 years were 93%, 90%, and 88%, respectively. In the proportional hazards analysis, the risk of death following transplantation remained low until reaching a risk score of 7.8. In contrast, risk scores greater than 7.8 were associated with a progressively increased mortality. Resource utilization measured by the days in the intensive care unit (ICU) and hospital and the requirement for intraoperative blood transfusions was significantly greater in recipients who had higher risk scores before transplantation. Our data suggest that an optimal timing for liver transplantation, as determined by patient survival and resource utilization, appears to be at a risk score around 7.8 in patients with PBC.

In order to observe the morphological and endocrinological changes of the rat and mouse ovarian follicles by gamma-radiation, rats were whole-body irradiated with doses of 3.2 Gy and 8.0 Gy and mice with 2.9 Gy and 7.2 Gy. Sections of ovaria were examined by light microscopy. Concentrations of progesterone, testosterone, and estradiol in ovarian homogenate were determined by radioimmunoassay techniques. Gamma-radiation resulted in the increased percentage of atretic follicles in the groups killed on day 0, day 4, and day 8 after irradiation. The decrease in granulosa cell viability was found in animals killed on day 4 after irradiation. The finding of the high ratio of testosterone to estradiol compared to that of progesterone to testosterone suggests that aromatase activity--steroid biosynthesis from testosterone to estradiol--in granulosa cell could be affected by gamma-radiation.

Primary biliary cirrhosis is a slow, progressive disease. Although many years may elapse before asymptomatic primary biliary cirrhosis patients begin experiencing symptoms of liver disease, their overall survival is significantly lower than the normal population. The Mayo natural history model has been developed to depict patient survival in the absence of effective therapeutic intervention. Although there are a number of caveats in applying this model, it has been validated using external data sets and established as an accepted tool for clinical or research purposes. Furthermore, recent data suggest that the Mayo natural history model continues to provide useful, predictive information in the presence of ursodeoxycholic acid therapy, which has been shown to lower the serum bilirubin to the natural history model for patient survival. In addition to the natural history model for patient survival, mathematical models have been developed to describe histologic progression and development of esophageal varices.

Background: Interferon-alpha is effective in only a small number of patients with chronic hepatitis C, although prolonged treatment may increase the response rate. There is concern that the expense of interferon-alpha therapy may not be justified by the low response rates and uncertain long-term benefit., Objective: To compare clinical and economic outcomes after 6 months and 12 months of interferon-alpha therapy for chronic hepatitis C., Design: A Markov model depicting the natural progression of chronic hepatitis C. On the basis of this model, a simulated trial compared no therapy with 6 and 12 months of interferon-alpha therapy at standard doses (3 million U three times weekly)., Patients: Four age-specific cohorts (30, 40, 50, and 60 years of age) with chronic hepatitis C., Measurements: Number of deaths from liver disease, total costs, and cumulative quality-adjusted life-years (QALYs)., Results: Six and 12 months of interferon-alpha treatment gained 0.25 QALYs at an incremental cost of $1000 and 0.37 QALYs at an incremental cost of $1900, respectively. Thus, although 6 months of interferon-alpha therapy was less efficacious than 12 months of therapy, it was more cost-effective ($4000 per QALY gained compared with $5000 per QALY gained). Nonetheless, in patients younger than 60 years of age, both 6 and 12 months of therapy compared favorably with other established medical interventions, such as screening mammography and cholesterol reduction programs. Important variables affecting the cost-effectiveness of interferon-alpha treatment included the cost and efficacy of interferon-alpha, the cost of treatment for decompensated cirrhosis, and quality of life in patients with chronic hepatitis C., Conclusion: From the standpoint of cost-effectiveness, interferon-alpha therapy for 6 or 12 months may be justified in patients with chronic hepatitis C. The possible exception is patients older than 60 years of age.

Prognostic models have been developed for patients with primary biliary cirrhosis and primary sclerosing cholangitis to predict survival without transplantation. In patients undergoing liver transplantation, these models have been used in assessing postoperative mortality and morbidity. Recent data suggest that preoperative recipient physiology, such as impaired functional status or renal insufficiency, is the most important determinant of transplant outcome. Survival, quality of life, morbidities and resource use are the key variables to be considered in the timing of transplantation.

Approximately 5% to 10% of patients with features otherwise consistent with primary biliary cirrhosis (PBC) lack antimitochondrial antibodies (AMA). Most of these patients have other autoantibodies, a syndrome recently named "autoimmune cholangitis." We report our experience in patients with AMA-negative PBC treated with ursodeoxycholic acid (UDCA) and/or liver transplantation (OLT). The study of response to UDCA was performed as follows. While recruiting patients for a previously reported multicenter trial, we identified 8 patients with AMA-negative PBC. The patients were given UDCA and followed up at regular intervals. The characteristics of AMA-negative patients at presentation were similar to those of AMA-positive patients with PBC. The clinical outcomes and sequential liver biochemistries of UDCA treatment were also comparable with those of AMA-positive patients. The study of outcome of OLT was performed as follows. We identified OLT recipients at the Mayo Clinic who had clinical, radiological, and histological features compatible with PBC. Their pretransplant AMA status was determined, and each AMA-negative patient was paired with 2 AMA-positive patients. Of 85 OLT recipients with a diagnosis of PBC, 6 (7.1%) were AMA negative, including 1 who had undergone UDCA therapy. After a median of 36 months of follow-up, graft and patient survival rates and subsequent histological changes (disease recurrence and steroid-resistant or late rejections) were comparable in AMA-negative and -positive PBC patients. In summary, in our experience of 13 AMA-negative PBC patients (including 9 who met the criteria for a diagnosis of autoimmune cholangitis), treatment with UDCA or OLT resulted in similar outcomes to those found in AMA-positive patients. We conclude that AMA status does not affect the response in PBC patients to treatment with UDCA or OLT.

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.

Orthotopic liver transplantation (OLT) has been shown to be effective in prolonging life and improving its quality in patients with end-stage liver disease. However, it remains one of the most expensive surgical procedures performed today. In an era when economic efficiency and financial accountability are being emphasized, it is imperative to consider resource utilization in evaluating candidates for OLT. We prospectively followed 106 patients who underwent OLT at the Mayo Clinic for primary biliary cirrhosis and primary sclerosing cholangitis between 1990 and 1994. Hospital and professional charges for the initial hospitalization were obtained on all patients. Univariate and multivariate models were constructed using preoperative clinical variables that had been previously found to be important in predicting clinical outcomes. The preoperative variables considered were age, gender, diagnosis of liver disease, Mayo risk score, Child's score, nutritional status, Karnofsky score, INR, serum levels of albumin, bilirubin, and creatinine, and the presence/absence of ascites, edema, encephalopathy, renal failure (serum creatinine >2.0) and gastrointestinal bleeding. Of the 106 patients, 3 were excluded from the analysis because they received multiple transplants during the initial hospitalization. Of the hospital charges we analyzed, the surgical fee for transplantation and donor acquisition expense were fixed in advance and, therefore, excluded. The following preoperative variables were found to be significant in the univariate analysis: Mayo risk score, Child's score, nutritional status, Karnofsky score, INR, serum levels of bilirubin and creatinine, presence of renal failure, and gastrointestinal bleeding. In the multivariate analyses, Karnofsky score of 40 or less was associated with a 48% increase in total charges. Poor nutritional status and renal failure were associated with a 34% and 31% increase, respectively. We identified 3 preoperative variables as significant independent predictors of resource utilization in liver transplantation. In an effort to maximize the economic efficiency with which liver transplantation is performed, we believe these factors should be taken into consideration in determining both the timing of transplantation and the suitability of potential transplant recipients.