Daniel S. Pratt

Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure

Objective:The HepatAssist liver support system is an extracorporeal porcine hepatocyte-based bioartificial liver (BAL). The safety and efficacy of the BAL were evaluated in a prospective, randomized, controlled, multicenter trial in patients with severe acute liver failure. Summary Background Data:In experimental animals with acute liver failure, we demonstrated beneficial effects of the BAL. Similarly, Phase I trials of the BAL in acute liver failure patients yielded promising results. Methods:A total of 171 patients (86 control and 85 BAL) were enrolled. Patients with fulminant/subfulminant hepatic failure and primary nonfunction following liver transplantation were included. Data were analyzed with and without accounting for the following confounding factors: liver transplantation, time to transplant, disease etiology, disease severity, and treatment site. Results:For the entire patient population, survival at 30 days was 71% for BAL versus 62% for control (P = 0.26). After exclusion of primary nonfunction patients, survival was 73% for BAL versus 59% for control (n = 147; P = 0.12). When survival was analyzed accounting for confounding factors, in the entire patient population, there was no difference between the 2 groups (risk ratio = 0.67; P = 0.13). However, survival in fulminant/subfulminant hepatic failure patients was significantly higher in the BAL compared with the control group (risk ratio = 0.56; P = 0.048). Conclusions:This is the first prospective, randomized, controlled trial of an extracorporeal liver support system, demonstrating safety and improved survival in patients with fulminant/subfulminant hepatic failure.

ACG practice guidelines: Esophageal reflux testing

Investigations and technical advances have enhanced our understanding and management of gastroesophageal reflux disease. The recognition of the prevalence and importance of patients with endoscopy-negative reflux disease as well as those refractory to proton pump inhibitor therapy have led to an increasing need for objective tests of esophageal reflux. Guidelines for esophageal reflux testing are developed under the auspices of the American College of Gastroenterology and its Practice Parameters Committee and approved by the Board of Trustees. Issues regarding the utilization of conventional, catheter-based pH monitoring are discussed. Improvements in the interpretation of esophageal pH recordings through the use of symptom-reflux association analyses as well as limitations gleaned from recent studies are reviewed. The clinical utility of pH recordings in the proximal esophagus and stomach is examined. Newly introduced techniques of duodenogastroesophageal reflux, wireless pH capsule monitoring and esophageal impedance testing are assessed and put into the context of traditional methodology. Finally, recommendations on the clinical applications of esophageal reflux testing are presented.

Liver transplantation outcomes for early‐stage hepatocellular carcinoma: Results of a multicenter study

The incidence of hepatocellular carcinoma (HCC), a frequent and incurable complication of cirrhosis, continues to rise. Orthotopic liver transplantation (OLT) has been proposed as a treatment for unresectable, intrahepatic HCC limited in extent to the Milan criteria adopted by the United Network of Organ Sharing (UNOS) in 1998. More recently, somewhat less restrictive University of California, San Francisco (UCSF) 10 , criteria were proposed. To examine the long‐term outcomes of OLT for HCC patients and to assess the UNOS policy of assigning weighted allocation points to patients with HCC, we retrospectively analyzed 144 patients (113 after 1998) with HCC who underwent OLT over an 11‐year period at 3 institutions from UNOS Region 1. We compared their outcomes with 525 patients (272 after 1998) who underwent OLT for nonmalignant liver disease. The 1‐ and 5‐year survival rates were 80.3% and 46.7%, respectively, for patients with HCC and 81.5% and 70.6%, respectively, for patients without HCC (P = .020). However, there was no difference in survival between HCC and non‐HCC patients after implementation of disease‐specific allocation for HCC in 1998. A higher proportion of the HCC cohort was older and male and had chronic HCV infection and alcoholic liver disease. In univariate analysis, having alpha‐fetoprotein (AFP) levels of 10 ng/mL or less and meeting clinical and pathologic UCSF criteria were each significant predictors of improved survival (P = .005, P = .02, and P = .03, respectively). AFP greater than 10 ng/mL and exceeding pathologic UCSF criteria were also significant predictors of recurrence (P = .003 and P = .02, respectively). In conclusion, taken together, our data suggest that OLT is an acceptable option for patients with early HCC and that UCSF criteria predict outcome better than Milan or UNOS criteria. Regardless of which criteria are adopted to define eligibility, strict adherence to the criteria is important to achieve acceptable outcomes. (Liver Transpl 2004;10:1343–1354.)

IgG4-associated cholangitis: a comparative histological and immunophenotypic study with primary sclerosing cholangitis on liver biopsy material

IgG4-associated cholangitis is a steroid-responsive hepatobiliary inflammatory condition associated with autoimmune pancreatitis that clinically and radiologically mimics primary sclerosing cholangitis. In this study, we conducted a morphological and immunohistochemical analysis of liver material obtained from individuals with IgG4-associated cholangitis, and compared these with well-characterized cases of primary sclerosing cholangitis. The study group consisted of 10 patients (9 biopsy and 1 hepatectomy case) with IgG4-associated cholangitis and 17 patients with primary sclerosing cholangitis (16 needle biopsy and 1 hepatectomy case). All patients with IgG4-associated cholangitis had pancreatic involvement as well, and six pancreatectomy samples revealed characteristic histopathological features of autoimmune pancreatitis. Primary sclerosing cholangitis cases were defined by the presence of a characteristic ERCP appearance. Clinical, pathological, radiological, and follow-up data were recorded for all cases. Portal and periportal inflammation was graded according to Ishaks guidelines. Immunohistochemical stains for IgG and IgG4 were performed. The cohort of patients with IgG4-associated cholangitis (mean age: 63 years) was older than individuals with primary sclerosing cholangitis (mean age: 44 years). Seven of these cases showed intrahepatic biliary strictures. IgG4-associated cholangitis liver samples showed higher portal (P=0.06) and lobular (P=0.009) inflammatory scores. Microscopic portal-based fibro-inflammatory nodules that were composed of fibroblasts, plasma cells, lymphocytes, and eosinophils were exclusively observed in five of the IgG4-associated cholangitis cases (50%). More than 10 IgG4-positive plasma cells per HPF (high power field) were observed in 6 of the IgG4-associated cholangitis cases (mean: 60, range: 0–140 per HPF), whereas all primary sclerosing cholangitis cases showed significantly lesser numbers (mean: 0.08, range: 0–1 per HPF). On a liver biopsy, the histological features of IgG4-associated cholangitis may be distinctive, and in conjunction with IgG4 immunohistochemical stain, may help distinguish this disease from primary sclerosing cholangitis.

Expanded Criteria Donor Grafts for Deceased Donor Liver Transplantation Under the MELD System: A Decision Analysis

Expanded criteria donor (ECD) liver grafts have a higher likelihood of primary graft failure (PGF) compared with standard criteria donor (SCD) grafts. Given a choice between an available ECD graft versus waiting for an SCD graft that may not always become available, what should liver transplant candidates do? The studys aim was to estimate 1‐year survival comparing immediate ECD liver grafting with waiting for an SCD organ. Using UNOS data, published literature estimates, and expert opinion, we constructed a Markov decision analytic model to estimate survival while waiting for an SCD transplant and survival with immediate ECD transplant. Sensitivity analyses were performed by varying model parameters individually and simultaneously with a second‐order Monte Carlo simulation. For all patients with MELD scores >20, survival was higher with immediate ECD transplant despite the additional increased risk for PGF. Survival was better with an immediate ECD transplant unless the probability of PGF exceeded 23%, 72%, and 88% for recipients with MELD scores of 11–20, 21–25, and 26–30 respectively. For patients with MELD scores >30, the survival benefit with the immediate ECD strategy persisted at even higher rates of PGF. In conclusion, our results suggest that, despite the higher risk for PGF, transplantation with an available ECD graft should be preferred over waiting for an SCD organ for patients with advanced MELD scores. At less advanced MELD scores, the survival benefit depends on the risk of PGF associated with the ECD organ. (Liver Transpl 2004;10:1468–1475.)

Living-donor versus cadaveric liver transplantation for non-resectable small hepatocellular carcinoma and compensated cirrhosis: a decision analysis.

Background. Cadaveric liver transplantation is effective for nonresectable early hepatocellular carcinoma. However, the scarcity of cadaveric organs has prompted some centers to use living donors, which guarantees transplantation, but entails a risk to the donor. In the absence of controlled trials, decision analysis can be used to help explicate the tradeoffs involved when considering living donor versus cadaveric liver transplantation for nonresectable early hepatocellular carcinoma. Methods. Using a Markov model, a hypothetical cohort of patients with Child’s A cirrhosis and a single 3.5-cm tumor received one of three strategies: 1) no transplant; 2) intent to perform cadaveric liver transplantation; or 3) living donor liver transplantation. Data were obtained from natural history and retrospective studies. All probabilities in the model were varied simultaneously using a Monte Carlo simulation. Results. Living-donor liver transplantation was the best strategy, improving life expectancy by 4.5 years compared with cadaveric liver transplantation. This strategy remained dominant even when varying severity of cirrhosis, age, tumor doubling time, tumor growth pattern, blood type, regional transplant volume, initial tumor size, and rate of progression of cirrhosis. Conclusions. Living-donor liver transplantation should confer a substantial survival advantage for patients with compensated cirrhosis and non-resectable early stage hepatocellular carcinoma.

Aerobic capacity is associated with 100-day outcome after hepatic transplantation.

The shortage of donor organs highlights the need to better identify patients most likely to benefit from hepatic transplantation. Reduced aerobic capacity (decreased peak oxygen consumption [V̇O2] during symptom‐limited cardiopulmonary exercise testing) is frequently present in cirrhosis. Peak V̇O2 during cardiopulmonary exercise testing may predict short‐term outcome after hepatic transplantation. Symptom‐limited testing was performed on a cycle ergometer (continuous ramp protocol) and V̇O2 determined using a metabolic cart. One hundred fifty‐six patients were tested; 59 subsequently underwent hepatic transplantation. Results showed that survivors and nonsurvivors were similar in age, duration of liver disease, Child‐Pugh score, MELD score, resting cardiovascular function, pulmonary function, and gas exchange. The 6 (10.2%) patients dying within 100 days of transplantation were more likely to have reduced aerobic capacity (peak V̇O2 <60% predicted and V̇O2 at anaerobic threshold [V̇O2‐AT] <50% predicted peak V̇O2) compared to survivors (4/6 vs. 7/53, P < .01). Using a multiple logistic regression model controlling for duration and severity of liver disease and time to transplantation, reduced aerobic capacity was independently associated with 100‐day mortality. In conclusion, reduced aerobic capacity during cardiopulmonary exercise testing is associated with decreased short‐term survival after hepatic transplantation. Further study is needed to determine if cardiopulmonary exercise testing can be used to improve allocation of donor organs. To ensure optimum allocation of donor organs, it is important to identify patients most likely to benefit from transplantation. Investigators have identified a number of preoperative, intraoperative, and postoperative factors that predict increased risk for postoperative mortality. Unfortunately, predictive accuracy has not been high, and the timing of factor identification does not optimize organ utilization. Identification of predictors of survival at the time of listing for transplantation might lead to better resource allocation. (Liver Transpl 2004;10:418–424.)

The Impact of Cirrhosis on CD4+ T Cell Counts in HIV-Seronegative Patients

BACKGROUND Studies of the progression liver fibrosis in human immunodeficiency virus (HIV) and hepatitis C virus-coinfected patients suggest that cirrhosis is associated with immunosuppression, as measured by low absolute CD4(+) T cell counts. However, we hypothesized that, in patients with advanced liver disease, low CD4(+) T cell counts may occur secondary to portal hypertension and splenic sequestration, regardless of the presence or absence of HIV infection. METHODS Sixty HIV-seronegative outpatients with cirrhosis were enrolled during the period 2001-2003 in a prospective, cross-sectional study of the association between liver disease and CD4(+) T cell counts and percentages. Demographic characteristics, liver disease-related characteristics, and laboratory results--including CD4(+) T cell parameters--were collected. RESULTS A total of 39 patients (65%) had a low CD4(+) T cell count; 26 patients (43%) and 4 patients (7%) had CD4(+) T cell counts <350 and <200 cells/mm(3), respectively. Abnormal CD4(+) T cell counts were associated with splenomegaly (P=.03), thrombocytopenia (P=.002), and leukopenia (P<.001). The percentage of CD4(+) T cells was normal in 95% of patients who had a low absolute CD4(+) T cell count. CD4(+) T cell counts were significantly lower among cirrhotic patients than among 7638 HIV-seronegative historic control subjects without liver disease. CONCLUSIONS Cirrhosis is associated with low CD4(+) T cell counts in the absence of HIV infection. Discordance between low absolute CD4(+) T cell counts and normal CD4(+) T cell percentages may be attributable to portal hypertension and splenic sequestration. Our findings have significant implications for the use and interpretation of absolute CD4(+) T cell counts in HIV-infected patients with advanced liver disease.

Cholangiocarcinoma: natural history, treatment, and strategies for surveillance in high-risk patients.

Cholangiocarcinoma is a primary malignancy of biliary epithelium. Risk factors for cholangiocarcinoma include primary sclerosing cholangitis and other conditions that produce chronic inflammation of the biliary tree. The diagnosis of cholangiocarcinoma can be elusive; it is often not made until advanced disease is present and at a stage when a curative surgical resection is not feasible. Currently used diagnostic modalities include serum and bile tumor markers, radiologic and endoscopic imaging, and pathologic analysis. Surveillance strategies to increase the chance of early diagnosis should be strongly considered in individuals at high risk for cholangiocarcinoma. Patients with long-standing primary sclerosing cholangitis would be the ideal candidates for a screening program.

Enhanced innate immune responsiveness and intolerance to intestinal endotoxins in human biliary epithelial cells contributes to chronic cholangitis.

Pattern recognition receptors (PRRs) orchestrate the innate immune defence in human biliary epithelial cells (BECs). Tight control of PRR signalling provides tolerance to physiological amounts of intestinal endotoxins in human bile to avoid constant innate immune activation in BECs.