Review of Medical Management of Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with presumed autoimmune etiology. Current treatment options include ursodeoxycholic acid, obeticholic acid, and fibrate, which target mainly cholestasis. There is no effective therapy against autoimmune or hepatic fibrosis components. We can still achieve adequate biochemical response with monotherapy or a combination of medications in non-cirrhotic and compensated cirrhotic PBC patients. Several criteria are available for risk stratification and assess treatment response. Liver stiffness measurement by transient elastography is also a useful tool for evaluating disease progression. Lack of treatment or inadequate response are predictors of poor outcome. There is a strong need for additional therapies for PBC.

Impact of sarcopenia on mortality in patients undergoing liver re-transplantation.

BACKGROUND: Sarcopenia, which is a loss of skeletal muscle mass, has been reported to increase post-transplant mortality and morbidity in patients undergoing the first liver transplant. Cross-sectional imaging modalities typically determine sarcopenia in patients with cirrhosis by measuring core abdominal musculatures. However, there is limited evidence for sarcopenia related outcomes in patients undergoing liver re-transplantation (re-OLT). AIM: To evaluate the risk of mortality in patients with pre-existing sarcopenia following liver re-OLT. METHODS: This is a retrospective study of all adult patients who had undergone a liver re-OLT at the University of Nebraska Medical Center from January 1, 2007 to January 1, 2017. We divided patients into sarcopenia and no sarcopenia groups. "TeraRecon AquariusNet 4.4.12.194" software was used to evaluate computed tomography or magnetic resonance imaging of the patients done within one year prior to their re-OLT, to calculate the Psoas muscle area at L3-L4 intervertebral disc. We defined cutoffs for sarcopenia as < 1561 mm2 for males and < 1464 mm2 for females. The primary outcome was to compare 90 d, one, and 5-year survival rates. We also compared complications after re-OLT, length of stay, and re-admission within 30 d. Survival analysis was performed with Kaplan-Meier survival analysis. Continuous variables were evaluated with Wilcoxon rank-sum tests. Categorical variables were evaluated with Fisher's exact tests. RESULTS: Fifty-seven patients were included, 32 males: 25 females, median age 50 years. Two patients were excluded due to incomplete information. Overall, 47% (26) of patients who underwent re-OLT had sarcopenia. Females were found to have significantly more sarcopenia than males (73% vs 17%, P < 0.001). Median model for end stage liver disease at re-OLT was 28 in both sarcopenia and no sarcopenia groups. Patients in the no sarcopenia group had a trend of longer median time between the first and second transplant (36.5 mo vs 16.7 mo). Biological markers, outcome parameters, and survival at 90 d, 1 and 5 years, were similar between the two groups. Sarcopenia in re-OLT at our center was noted to be twice as common (47%) as historically reported in patients undergoing primary liver transplantation. CONCLUSION: Overall survival and outcome parameters were no different in those with and without the evidence of sarcopenia after re-OLT.

Castleman's Disease and Posttransplant Lymphoproliferative Disorder after Liver Transplant: 3-Year Follow-Up.

A 59-year-old male with a history of hepatitis C cirrhosis and history of hepatitis B exposure presented 8 months after orthotopic liver transplant (LT) with fever, fatigue, myalgia, night sweats, nonproductive cough, and shortness of breath. Bone marrow biopsy for pancytopenia was positive for Epstein-Barr virus (EBV) DNA. Lymph node biopsy for lymphadenopathy on imaging showed human herpes virus 8 (HHV8) associated Castleman's disease. Treatment included valganciclovir, rituximab, and prednisone taper with eventual discontinuation. Quantitative HHV8 DNA was initially 611,000 DNA copies/mL and was later undetectable at 6 months following treatment and remained undetectable at 3-year follow-up.

Predictive Value of Dobutamine Stress Perfusion Echocardiography in Contemporary End-Stage Liver Disease.

BACKGROUND: The assessment of cardiac risk in contemporary liver transplantation (LT) has required more sensitive testing for the detection of occult coronary artery disease as well as microvascular and functional cardiac abnormalities. Because dobutamine stress perfusion echocardiography provides an assessment of both regional systolic and diastolic function as well as microvascular perfusion (MVP), we sought to examine its incremental value in this setting. METHODS AND RESULTS: We evaluated the predictive value of dobutamine stress perfusion echocardiography in 296 adult patients with end-stage liver disease and preserved systolic function who underwent LT between 2008 and 2014. The primary outcome was cardiovascular death, nonfatal myocardial infarction, and/or sustained ventricular arrhythmias following LT. The main causes of liver failure were hepatitis C (25%) and nonalcoholic fatty liver disease (13%). Abnormal MVP during stress was observed in 18 patients (6%), whereas diastolic dysfunction was present in 109 patients (94 grade 1, 15 grade 2). Half of the patients (7 of 14) referred for angiography with abnormal MVP had significant epicardial disease by angiography, and these patients were revascularized prior to LT. Despite these interventions, the primary outcome still occurred in 9 patients (3%). Patients with abnormal MVP during dobutamine stress perfusion echocardiography had a 7-fold higher risk of a cardiovascular event following LT. Cox proportional hazards modeling examining clinical variables, left ventricular ejection fraction, diastolic function, and stress-induced wall motion abnormalities or MVP defects demonstrated that abnormal MVP was the only independent predictor of the primary outcome (P=0.004; hazard ratio 7.7). CONCLUSIONS: Stress MVP assessments are highly predictive of cardiovascular outcome in current LT candidates.

True versus Pseudo-Intestinal Malrotation: Case Series and Review.

Intestinal malrotation is an anomaly of fetal intestinal rotation that can present with symptoms after birth or in early childhood, but is rarely diagnosed in adults. Patients who have symptomatic presentations require surgery. Other entities may mimic intestinal malrotation and respond to non-surgical management. We present 2 adult cases with the radiological diagnosis of intestinal malrotation: one with true malrotation presenting as a duodenal mass, and another with "pseudo-malrotation" due to altered anatomy. These cases illustrate the importance of recognizing and differentiating these rare adult presentations of true malrotation from "pseudo-malrotation" in regards to their acute management.

Risk of cytomegalovirus disease in high-risk liver transplant recipients on valganciclovir prophylaxis: a systematic review and meta-analysis.

Valganciclovir (VGC) was approved by the Food and Drug Administration in 2004 as cytomegalovirus (CMV) prophylaxis except for liver transplant recipients because of their high incidence of CMV disease with this drug. However, surveys have shown its common off-label use for CMV prophylaxis in liver transplant recipients. We aimed to evaluate the risk of CMV disease with VGC prophylaxis in liver transplant recipients. All studies that evaluated liver transplant recipients and used VGC (900 or 450 mg daily) for the prevention of CMV disease were included. Five controlled studies (n = 483) were pooled with a random effects model; five single-arm studies (n = 380) were pooled for the prevalence rate of CMV disease. The risk of CMV disease with VGC versus ganciclovir was 1.81 [95% confidence interval (CI) = 1.00-3.29, P = 0.05, I(2) = 0%]. For high-risk (donor-positive/recipient-negative) patients, the risk of CMV disease was 1.96 (95% CI = 1.05-3.67, P = 0.035, I(2) = 0%). The risk of CMV disease remained significant with 900 mg of VGC daily (P = 0.04) but not with 450 mg of VGC daily (P = 0.76). The risk of leukopenia with VGC was 1.87 (95% CI = 1.03-3.37, P = 0.04, I(2) = 0%). In single-arm trials, the overall CMV disease rate was 12% (95% CI = 9%-16%, P < 0.001), and the rate for high-risk patients was 20% (95% CI = 10%-38%, P = 0.002). In conclusion, 900 mg of VGC daily may not be safe as CMV prophylaxis in high-risk liver transplant recipients because of the significant 2-fold increase in the risk of CMV disease and the 1.9-fold increase in the risk of leukopenia. Alternative CMV prophylaxis should be used for liver transplant recipients.

Risk for immune-mediated graft dysfunction in liver transplant recipients with recurrent HCV infection treated with pegylated interferon.

BACKGROUND & AIMS: Patients with recurrent hepatitis C virus infection treated with pegylated interferon (PEG) after liver transplantation can develop severe immune-mediated graft dysfunction (IGD) characterized by plasma cell hepatitis or rejection. METHODS: We conducted a multicenter case-control study of 52 liver transplant recipients with hepatitis C to assess the incidence of, risk factors for, and outcomes of PEG-IGD. Data from each patient were compared with those from 2 matched patients who did not develop PEG-IGD (n = 104). We performed a multivariate analysis of risk factors and analyzed treatment and outcomes of graft dysfunction subtypes. RESULTS: Overall incidence of PEG-IGD during a 10-year study period was 7.2%. Risk factors included no prior PEG therapy (odds ratio = 5.3; P < .0001), therapy with PEGα-2a (odds ratio = 4.7; P = .03), and immune features (mainly plasma cell hepatitis) on pre-PEG therapy liver biopsies (odds ratio = 3.9; P = .005). The PEG-IGD group had lower long-term patient (61.5% vs 91.3% of controls) and graft (38.5% vs 85.6% of controls) survival and higher rates of retransplantation (34.6% vs 6.7% of controls) (all, P < .0001), without increases in sustained virologic response. Variables associated with increased mortality included acute rejection as the PEG-IGD sub-type (hazard ratio [HR] = 2.4; P = .002), a high level of alkaline phosphatase at PEG initiation (HR = 1.003; P = .005), and lack of a sustained virologic response (HR = 3.3; P = .04). Variables associated with graft failure included a high level of alkaline phosphatase at PEG initiation (HR = 1.002; P = .04) and lack of a sustained virologic response (HR = 2.1; P = .04). CONCLUSIONS: PEG-IGD has high morbidity and mortality and is not associated with increased rates of virologic response. It is important to avoid PEG therapy in liver transplant recipients with specific clinical, biochemical, and histologic risk factors for PEG-IGD.

Management of liver transplant recipients with recurrent hepatitis C.

PURPOSE OF REVIEW: Hepatitis C virus infection is the leading indication for liver transplantation, with recurrent hepatitis C almost universal. Although posttransplant treatment of hepatitis C virus infection remains suboptimal, active investigation continues to inform patient selection and risk-benefit analysis. RECENT FINDINGS: Several key studies have identified components in the immunological response that are associated with the necroinflammatory and fibrotic response. Hepatitis C virus infection is associated with a higher rate of diabetes mellitus after transplant. Patients with diabetes and metabolic syndrome have poorer outcomes, and aggressive management is necessary. Differentiation of acute rejection from recurrent hepatitis C is difficult; however, the use of hepatitis C virus RNA tissue levels, immunohistochemistry and Councilman body/portal tract ratio may help with this diagnostic dilemma. The use of a specific calcineurin inhibitor appears not to influence recurrent hepatitis C, but rapid steroid taper is detrimental and, if steroids are used, long slow taper should be used. Use of rapid and early virological responses is very helpful in the management of hepatitis C after transplantation. In the patients with sustained virological response, histological and survival benefits are noted. SUMMARY: The present review highlights advances in our understanding of the pathophysiology and treatment of hepatitis C virus infection after liver transplantation in the last few years.

Prevalence of hepatic iron overload and association with hepatocellular cancer in end-stage liver disease: results from the National Hemochromatosis Transplant Registry.

BACKGROUND: It is unclear whether mild to moderate iron overload in liver diseases other than hereditary haemochromatosis (HH) contributes to hepatocellular carcinoma. This study examined the association between hepatic iron grade and hepatocellular carcinoma in patients with end-stage liver disease of diverse aetiologies. METHODS: The prevalence of hepatic iron overload and hepatocellular carcinoma was examined in 5224 patients undergoing liver transplantation. Explant pathology reports were reviewed for the underlying pathological diagnosis, presence of hepatocellular carcinoma and degree of iron staining. The distribution of categorical variables was studied using chi(2) tests. RESULTS: Both iron overload and hepatocellular carcinoma were the least common with biliary cirrhosis (1.8 and 2.8% respectively). Hepatocellular carcinoma was the most common in patients with hepatitis B (16.7%), followed by those with hepatitis C (15.1%) and HH (14.9%). In the overall cohort, any iron overload was significantly associated with hepatocellular carcinoma (P=0.001), even after adjustment for the underlying aetiology of liver disease. The association between hepatic iron content and hepatocellular carcinoma was the strongest in patients with biliary cirrhosis (P<0.001) and hepatitis C (P<0.001). CONCLUSIONS: Iron overload is associated with hepatocellular carcinoma in patients with end-stage liver disease, suggesting a possible carcinogenic or cocarcinogenic role for iron in chronic liver disease.

Racial variation in colorectal polyp and tumor location.

OBJECTIVES: The incidence and mortality from colorectal cancer among whites have decreased, but they have remained unchanged among African Americans. To explain this disparity, we used the multicenter endoscopy database of the Clinical Outcomes Research Initiative to compare the prevalence of proximal polyps and tumors among asymptomatic African Americans and whites undergoing routine screening colonoscopy. METHODS: African Americans and whites undergoing colonoscopy between January 1, 2002 and September 30, 2003 were considered for analysis. RESULTS: There were 145,175 index colonoscopy reports on unique patients. After applying exclusion criteria, 46,726 patients remained for analysis. Adjusting for age, gender, American Society of Anesthesiologists level, bowel preparation and endoscopic setting, African Americans were less likely to have polyps [adjusted odds ratio (OR) = 0.77; 95% confidence interval (CI) = 0.70-0.84]. However, the odds of having proximal polyps was higher in African Americans (OR = 1.30; 95% CI: 1.11-1.52) compared to whites. In regards to tumors, African Americans were more likely to have tumors (OR = 1.78; 95% CI: 1.14-2.77) and more likely to have proximal tumors than whites (OR = 4.37; 95% CI: 1.16-16.42). CONCLUSIONS: After adjusting for confounders, African Americans undergoing screening colonoscopy in multiple practice settings had higher odds of proximal polyps and tumors than whites, suggesting current colorectal cancer screening recommendations in African Americans should be expanded.

Recurrent hepatitis C posttransplant: early preservation injury may predict poor outcome.

Organ cold/warm ischemia is thought to be a risk factor for increased severity of recurrence of hepatitis C (HCV) post liver transplantation. We had noted some HCV patients with preservation injury (PI) to have particularly poor outcomes. Our goal was to determine if PI on biopsy in HCV patients is associated with earlier, more rapidly progressive recurrence or graft and patient survival. Sixty-nine patients from the University of Nebraska transplant database were included: 23 HCV patients with PI (group = 1), 23 non-HCV patients with PI (group = 2), and 23 HCV patients without PI (group = 3). Patient groups were matched for gender, age, immunosuppression, and time of transplantation for analysis. No difference in time to recurrence was noted between HCV groups (256 vs. 316 days posttransplant). More patients in group 1 had progression to stage 3 or 4 fibrosis, compared to group 3 (43 vs. 9%, P = 0.02). One-year survival for groups 1, 2, and 3 was 78, 82, and 100% respectively, whereas 3-yr survival was 59, 82, and 88% (group 1 vs. group 2 or 3 respectively, P = 0.0055). There was no difference in survival between groups 2 and 3. Patients in group 1 that received antiviral treatment had improved survival, compared to those who did not (P = 0.012). Risk factors for poor survival on univariate analysis included severity of PI (Relative Risk = 2.78, P < 0.001) and donor age of >55 (P = 0.014). Multivariate analysis shows HCV is the most important factor. In conclusion, HCV transplant patients with evidence of early PI on biopsy have poorer survival outcomes than non-HCV transplant patients with PI or HCV transplant patients without PI. Consideration for antiviral therapy early in the posttransplant course may be warranted in this subset of patients.

Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis.

This placebo-controlled, randomized, multicenter trial compared the effects of MTX plus UDCA to UDCA alone on the course of primary biliary cirrhosis (PBC). Two hundred and sixty five AMA positive patients without ascites, variceal bleeding, or encephalopathy; a serum bilirubin less than 3 mg/dL; serum albumin 3 g/dL or greater, who had taken UDCA 15 mg/kg daily for at least 6 months, were stratified by Ludwig's histological staging and then randomized to MTX 15 mg/m2 body surface area (maximum dose 20 mg) once a week while continuing on UDCA. The median time from randomization to closure of the study was 7.6 years (range: 4.6-8.8 years). Treatment failure was defined as death without liver transplantation; transplantation; variceal bleeding; development of ascites, encephalopathy, or varices; a doubling of serum bilirubin to 2.5 mg/dL or greater; a fall in serum albumin to 2.5 g/dL or less; histological progression by at least two stages or to cirrhosis. Patients were continued on treatment despite failure of treatment, unless transplantation ensued, drug toxicity necessitated withdrawal, or the patient developed a cancer. There were no significant differences in these parameters nor to the time of development of treatment failures observed for patients taking UDCA plus MTX, or UDCA plus placebo. The trial was conducted with a stopping rule, and was stopped early by the National Institutes of Health at the advice of our Data Safety Monitoring Board for reasons of futility. In conclusion, methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone.

Interferon alpha 2b and ribavirin for the treatment of recurrent hepatitis C after liver transplantation: cohort study of 38 patients.

AIM: Recurrent hepatitis C virus (HCV) is universal following liver transplantation. Patients are often treated with interferon and ribavirin in an attempt to eradicate the virus. We describe our experience with 38 patients with recurrent HCV from a single liver transplant program. METHODS: Between October 2000 and November 2001, 38 patients with recurrent HCV were treated with interferon alpha 2b 3 million units three times a week and ribavirin 1000-1200 mg per day. HCV RNA and liver biopsies were performed before treatment at the end of treatment (EOT), and 6 months after EOT in patients who were HCV RNA negative at EOT. RESULTS: There were 29 males and nine females. Median age was 49 years. In total, 34 patients were genotype 1 and two each were genotype 3 and 4. Six patients received HCV positive donors and 24 patients (63%) completed treatment. The most common indication for discontinuation of treatment was severe fatigue in 14 patients (37%). On intention to treat analysis, a sustained biochemical and virological response occurred in 10 patients (26%). Unchanged or improved fibrosis scores were present in 37% of patients, of whom 71% were non-responders to therapy. CONCLUSIONS: Interferon alpha 2b and ribavirin were poorly tolerated in this series of recurrent HCV patients, with sustained HCV eradication occurring in only 26% of patients. However, the majority of non-responders demonstrated unchanged or improved fibrosis scores, suggesting that a subset of patients may benefit from maintenance antiviral therapy to prevent the development of cirrhosis.

Evaluation of reliability in the use of endoscopic terminology.

Variability in the reporting of gastrointestinal endoscopic findings may affect the validity of analyses of data collected from clinical reports of those findings. In this project, images of 10 endoscopic findings were collected from the data repository of the Clinical Outcomes Research Initiative (CORI), all of which had been described by the reporting endoscopist. These images were presented to 52 experienced endoscopists recruited from the clinical affiliates of CORI who were asked to assign each a term from the Minimum Standard Terminology for Digestive Endoscopy. Proportion of agreement with the endoscopist varied by finding from 84.3% to 51.0% (overall 67.6% with 95% CI 63.4-71.8%). Proportion of agreement among the subjects varied by finding from 76.3% to 38.5%.(overall 55.6% with 95% CI 52.4-58.8%). Possible reasons for this lack of agreement are discussed.

Transplantation in the alcoholic patient.

Alcoholic liver disease (ALD) is the second leading indication for transplantation in the United States. Most transplant programs in the United States require a minimum of 6 month's abstinence before transplantation is performed. Most studies have shown a recidivism rate of between 20 and 30% by 2 years after orthotopic liver transplantation (OLT). Higher rates of recidivism are reported if pre-OLT abstinence was < 6 months. The impact of recidivism on patient and graft survival is not clear because most reports include patients who consume alcohol in small amounts or infrequently. Equal post-OLT survival for ALD patients and non-ALD patients has been demonstrated, and ALD patients are not thought to suffer greater morbidity post transplant than non-ALD patients. Careful pretransplant assessment for concomitant medical and psychosocial ailments associated with alcoholism is important. Posttransplant monitoring for cardiovascular disease and withdrawal syndromes is required in the early postoperative setting, whereas monitoring for recidivism and malignancy are late postoperative issues.

Retransplantation for recurrent hepatitis C: positive aspects.

1. The prevalence of retransplantation for hepatitis C (HCV) patients is stable (around 40%). 2. Survival models to predict outcome of retransplantation do not show that HCV is an independent variable with poor outcomes. 3. Using Model for End-Stage Liver Disease (MELD) scores from the United Network for Organ Sharing (UNOS) database from 1996-2002, retransplantation for HCV had similar outcomes to other causes of retransplantation. 4. Poorer outcomes were noted for retransplantation with MELD scores greater than 25. 5. Minimal survival thresholds need to be developed for retransplantation for all causes of retransplantation.

Poor survival after liver retransplantation: is hepatitis C to blame?

Data from 1990 to 1996 suggest that the prevalence of hepatitis C virus (HCV) infection in repeated orthotopic liver transplantation (re-OLT) is increasing, and patient survival may be worse. Aims of the study are to: (1) assess the prevalence of HCV in re-OLT, (2) compare survival between primary OLT and re-OLT for HCV versus non-HCV diseases, and (3) evaluate Model for End-Stage Liver Disease (MELD) scores in re-OLT. The United Network for Organ Sharing database for adult patients undergoing primary OLT or re-OLT from January 1996 to June 2002 was analyzed. Patients with malignancy or those who underwent re-OLT within 30 days of primary OLT were excluded. A total of 22,120 primary OLTs and 2,129 re-OLTs were performed. HCV was noted in 9,564 primary OLTs (43.2%) and 899 re-OLTs (42.2%). Overall 1, 3, and 5-year patient survival rates were 86%, 79%, and 73% for primary OLT, but 67%, 56%, and 52% for re-OLT (P <.001). Survival rates of patients with HCV at 1, 3, and 5 years were 86%, 76%, and 68% for primary OLT and 61%, 50%, and 45% for re-OLT (P <.001). Survival was less for patients with HCV compared with those with autoimmune hepatitis (AIH) and hepatitis B for re-OLT (P <.01). However, survival after re-OLT was no different for those with HCV than for those with all other causes. MELD scores between 11 and 20 were the most common for re-OLT. A marked decreased in survival was noted in all patients who underwent re-OLT with MELD scores greater than 25. HCV prevalence in OLT has reached a plateau in recent years. Survival after re-OLT is inferior to that for primary OLT, but re-OLT survival appears to have improved. Survival after re-OLT is lower in patients with HCV compared with those with AIH and hepatitis B, but no different than for those with most other liver diseases. Survival appeared worse in patients who underwent re-OLT with a MELD score greater than 25.

Current use of transjugular intrahepatic portosystemic shunts.

The principal indication for transjugular intrahepatic portosystemic shunts (TIPS) continues to be rescue therapy for variceal hemorrhage that cannot be controlled by endoscopic or medical therapy. TIPS provide no survival advantage in prevention of rebleeding or refractory ascites. The indications for TIPS continue to expand, however, especially for Budd-Chiari syndrome and hydrothorax. Other more novel indications include bleeding portal hypertensive gastropathy or ectopic varices, Budd-Chiari syndrome, veno-occlusive disease, hepatorenal syndrome, hepatopulmonary syndrome, hepatocellular carcinoma, and polycystic liver disease. Great strides have been made recently in models to predict mortality and complications following TIPS placement. Graft stents hold promise based on early studies. Finally, complications are common and may be life threatening.

Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States.

BACKGROUND: Because acute liver failure is rare, related data have been sparse. Studies have suggested that viral hepatitis is the most common underlying cause of this condition. OBJECTIVE: To describe the clinical features, presumed causes, and short-term outcomes of acute liver failure. DESIGN: Prospective cohort study. SETTING: 17 tertiary care centers participating in the U.S. Acute Liver Failure Study Group. PATIENTS: 308 consecutive patients with acute liver failure, admitted over a 41-month period. MEASUREMENTS: Detailed clinical and laboratory data collected during hospitalization, including outcome 3 weeks after study admission. RESULTS: 73% of patients were women; median age was 38 years. Acetaminophen overdose was the most common apparent cause of acute liver failure, accounting for 39% of cases. Idiosyncratic drug reactions were the presumptive cause in 13% of cases, viral hepatitis A and B combined were implicated in 12% of cases, and 17% of cases were of indeterminate cause. Overall patient survival at 3 weeks was 67%. Twenty-nine percent of patients had liver transplantation, and 43% survived without transplantation. Short-term transplant-free survival varied greatly, from 68% for patients with acetaminophen-related liver failure to 25% and 17% for those with other drug reactions and liver failure of indeterminate cause, respectively. Coma grade at admission appeared to be associated with outcome, but age and symptom duration did not. CONCLUSIONS: Acetaminophen overdose and idiosyncratic drug reactions have replaced viral hepatitis as the most frequent apparent causes of acute liver failure. Apparent cause and coma grade at admission were associated with outcome. Although transplantation may improve patient survival, it was unavailable or unnecessary for most patients.