A Prospective Multimodal Education Intervention for Providers Does Not Increase Hepatic Encephalopathy Treatment Rates.

BACKGROUND: Over 50% of hospitalizations from hepatic encephalopathy (HE) are preventable, but patients often do not receive medical treatment. AIMS: To use a multimodal education intervention (MMEI) to increase HE treatment rates and to evaluate (1) trends in HE treatment, (2) predictors of receiving treatment, and (3) the impact of treatment on hospitalization outcomes. METHODS: Prospective single-center cohort study of patients hospitalized with HE from April 1, 2020-September 30, 2022. The first 15 months were a control ("pre-MMEI"), the subsequent 15 months (MMEI) included three phases: (1) prior authorization resources, (2) electronic order set, and (3) in-person provider education. Treatment included receiving any drug (lactulose or rifaximin), or combination therapy. Treatment rates pre- vs. post-MMEI were compared using logistic regression. RESULTS: 471 patients were included. There were lower odds of receiving any drug post-MMEI (p = 0.03). There was no difference in receiving combination therapy pre- or post-MMEI (p = 0.32). Predictors of receiving any drug included alcohol-related or cryptogenic cirrhosis (p's < 0.001), and the presence of ascites (p = 0.005) and/or portal hypertension (p = 0.003). The only significant predictor of not receiving any drug treatment was having autoimmune cirrhosis (p < 0.001). Patients seen by internal medicine (p = 0.01) or who were intoxicated (p = 0.02) were less likely to receive rifaximin. Any treatment was associated with higher 30-day liver disease-specific readmission (p < 0.001). CONCLUSION: This MMEI did not increase HE treatment rates, suggesting that alternative strategies are needed to identify and address barriers to treatment.

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.

Accuracy of liver stiffness, spleen stiffness, and LS-spleen diameter to platelet ratio score in detection of esophageal varices: Systemic review and meta-analysis.

BACKGROUND AND AIM: There is increasing evidence of non-invasive measurement using elastography such liver stiffness (LS), spleen stiffness (SS), and LS-spleen diameter to platelet ratio score (LSPS) for detection of esophageal varices (EV); however, data regarding comparison between these three parameters are limited. METHODS: We performed a systemic review and meta-analysis of studies evaluating performance of LS, SS, and LSPS for detection of EV and high risk/clinically significant EV (HREV). Pooled sensitivity, specificity, log diagnostic odd ratio (LDOR), and area under the receiver operating characteristic curve (AUC) of LS, SS, and LSPS for detection of EV and HREV were analyzed and compared. Publication bias was assessed by Deeks' funnel plot. RESULTS: SS and LSPS were superior to LS for detection of EV with higher sensitivity (0.90 and 0.91 vs 0.85), specificity (0.73 and 0.76 vs 0.64), LDOR (3.24 and 3.35 vs 2.26), and AUC (0.899 and 0.851 vs 0.817). For HREV, SS had the highest sensitivity (0.87) followed by LS (0.85) and LSPS (0.82); however, SS had the lowest specificity (0.52), LDOR (2.09), and AUC (0.807) whereas LSPS had the highest specificity (0.77), LDOR (2.74), and AUC (0.861). CONCLUSION: For detection of EV, we prefer using LSPS and SS over LS when available, while LS, SS, and LSPS cannot be recommended for detection of HREV due to their moderate sensitivity and specificity.

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.

Outcomes in Adults With Acute Liver Failure Between 1998 and 2013: An Observational Cohort Study.

BACKGROUND: Acute liver failure (ALF) is a rare syndrome of severe, rapid-onset hepatic dysfunction-without prior advanced liver disease-that is associated with high morbidity and mortality. Intensive care and liver transplantation provide support and rescue, respectively. OBJECTIVE: To determine whether changes in causes, disease severity, treatment, or 21-day outcomes have occurred in recent years among adult patients with ALF referred to U.S. tertiary care centers. DESIGN: Prospective observational cohort study. (ClinicalTrials .gov: NCT00518440). SETTING: 31 liver disease and transplant centers in the United States. PATIENTS: Consecutively enrolled patients-without prior advanced liver disease-with ALF (n = 2070). MEASUREMENTS: Clinical features, treatment, and 21-day outcomes were compared over time annually for trends and were also stratified into two 8-year periods (1998 to 2005 and 2006 to 2013). RESULTS: Overall clinical characteristics, disease severity, and distribution of causes remained similar throughout the study period. The 21-day survival rates increased between the two 8-year periods (overall, 67.1% vs. 75.3%; transplant-free survival [TFS], 45.1% vs. 56.2%; posttransplantation survival, 88.3% vs. 96.3% [P < 0.010 for each]). Reductions in red blood cell infusions (44.3% vs. 27.6%), plasma infusions (65.2% vs. 47.1%), mechanical ventilation (65.7% vs. 56.1%), and vasopressors (34.9% vs. 27.8%) were observed, as well as increased use of N-acetylcysteine (48.9% vs. 69.3% overall; 15.8% vs. 49.4% [P < 0.001] in patients with ALF not due to acetaminophen toxicity). When examined longitudinally, overall survival and TFS increased throughout the 16-year period. LIMITATIONS: The duration of enrollment, the number of patients enrolled, and possibly the approaches to care varied among participating sites. The results may not be generalizable beyond such specialized centers. CONCLUSION: Although characteristics and severity of ALF changed little over 16 years, overall survival and TFS improved significantly. The effects of specific changes in intensive care practice on survival warrant further study. PRIMARY FUNDING SOURCE: National Institutes of Health.

Impact of anti-thymocyte globulin during immunosuppression induction in patients with hepatitis C after liver transplantation.

BACKGROUND: Induction immunosuppression with anti-thymocyte globulin (ATG) provides potential benefits after liver transplantation (LT). However, its use in patients with LT and hepatitis C (HCV) is controversial. AIM: To evaluate the 1- and 2-year patient survival and HCV recurrence rate in patients receiving ATG during the induction phase of immunosuppression (IPI) after LT. METHODS: A total of 49 patients undergoing their first LT for HCV were randomized to receive ATG during IPI. Patient survival and HCV recurrence were determined at 1 and 2 years. The frequency of acute cellular rejection (ACR), infections, and neoplasms was also evaluated. RESULTS: Twenty-six patients were randomized to receive ATG (Arm-1) and 23 to standard induction therapy (Arm-2). Those given ATG had lower HCV recurrence (26.9 vs 73.9 %, p = 0.001). The 1- and 2-year patient survival rates were similar for both arms (p = 0.33). Infections occurred in 46.1 % subjects in Arm-1 and 34.7 % in Arm-2 (p = 0.562). There was a greater proportion of fungal infections in Arm-1 (19.2 vs 0 %, p = 0.032). CONCLUSIONS: ATG during the IPI was associated with lower frequency of recurrence of HCV in patients undergoing LT. This, however, did not affect the 1- and 2-year survival and the frequency of ACR, infections, or neoplasms.

Randomized, double-blind, controlled study of glycerol phenylbutyrate in hepatic encephalopathy.

UNLABELLED: Glycerol phenylbutyrate (GPB) lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion in the form of phenylacetyl glutamine, which is excreted in urine. This randomized, double-blind, placebo-controlled phase II trial enrolled 178 patients with cirrhosis, including 59 already taking rifaximin, who had experienced two or more hepatic encephalopathy (HE) events in the previous 6 months. The primary endpoint was the proportion of patients with HE events. Other endpoints included the time to first event, total number of events, HE hospitalizations, symptomatic days, and safety. GPB, at 6 mL orally twice-daily, significantly reduced the proportion of patients who experienced an HE event (21% versus 36%; P=0.02), time to first event (hazard ratio [HR]=0.56; P<0.05), as well as total events (35 versus 57; P=0.04), and was associated with fewer HE hospitalizations (13 versus 25; P=0.06). Among patients not on rifaximin at enrollment, GPB reduced the proportion of patients with an HE event (10% versus 32%; P<0.01), time to first event (HR=0.29; P<0.01), and total events (7 versus 31; P<0.01). Plasma ammonia was significantly lower in patients on GPB and correlated with HE events when measured either at baseline or during the study. A similar proportion of patients in the GPB (79%) and placebo groups (76%) experienced adverse events. CONCLUSION: GPB reduced HE events as well as ammonia in patients with cirrhosis and HE and its safety profile was similar to placebo. The findings implicate ammonia in the pathogenesis of HE and suggest that GPB has therapeutic potential in this population. (Clinicaltrials.gov, NCT00999167).

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.

High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis.

OBJECTIVES: Some studies have suggested that ursodeoxycholic acid (UDCA) may have a chemopreventive effect on the development of colorectal neoplasia in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). We examined the effects of high-dose (28-30 mg/kg/day) UDCA on the development of colorectal neoplasia in patients with UC and PSC. METHODS: Patients with UC and PSC enrolled in a prior, multicenter randomized placebo-controlled trial of high-dose UDCA were evaluated for the development of colorectal neoplasia. Patients with UC and PSC who received UDCA were compared with those who received placebo. We reviewed the pathology and colonoscopy reports for the development of low-grade or high-grade dysplasia or colorectal cancer. RESULTS: Fifty-six subjects were followed for a total of 235 patient years. Baseline characteristics (including duration of PSC and UC, medications, patient age, family history of colorectal cancer, and smoking status) were similar for both the groups. Patients who received high-dose UDCA had a significantly higher risk of developing colorectal neoplasia (dysplasia and cancer) during the study compared with those who received placebo (hazard ratio: 4.44, 95% confidence interval: 1.30-20.10, P=0.02). CONCLUSIONS: Long-term use of high-dose UDCA is associated with an increased risk of colorectal neoplasia in patients with UC and PSC.

The predictors of the presence of varices in patients with primary sclerosing cholangitis.

UNLABELLED: The predictors for developing varices in patients with primary sclerosing cholangitis (PSC) have not been well studied prospectively. We sought to define the predictors for the presence of varices at baseline and for newly developing varices in patients with PSC. We used prospectively collected data from a multicenter randomized trial of high dose ursodeoxycholic acid for PSC. All 150 patients enrolled were reviewed for predictors of varices and we excluded 26 patients who had esophageal varices at baseline so that predictors of newly developing varices could be determined. Clinical examination, blood tests, and upper endoscopy were done before randomization, at 2 years and after 5 years. Liver biopsy was performed at entry and at 5 years. The median age (interquartile range) of patients was 45.9 years (35.8, 54.9). In a multivariable logistic regression, a higher Mayo risk score (> or =0.87) or a higher aspartate/alanine aminotransferase (AST/ALT) ratio (> or =1.12) were significantly associated with the presence of varices at initial endoscopy (odds ratio = 1.9 and 3.9). By the end of the study, 25 patients had new varices (20.2%). In a Cox model, after adjustment for baseline variables lower platelet count and higher total bilirubin at 2 years were significantly associated with the presence of new varices. The platelet count of 205 (x 10(9)/L) and the total bilirubin level of 1.7 mg/dL were the best cutoff values for the detection of new varices. CONCLUSION: A higher Mayo risk score and higher AST/ALT ratio were significantly associated with the presence of varices at initial endoscopy. Lower platelet count and higher total bilirubin at 2 years were significantly associated with an increased risk of developing new varices in patients with PSC.

High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis.

UNLABELLED: Previous controlled trials are inconclusive regarding the efficacy of ursodeoxycholic acid (UDCA) for treating primary sclerosing cholangitis (PSC). One hundred fifty adult patients with PSC were enrolled in a long-term, randomized, double-blind controlled trial of high-dose UDCA (28-30 mg/kg/day) versus placebo. Liver biopsy and cholangiography were performed before randomization and after 5 years. The primary outcome measures were development of cirrhosis, varices, cholangiocarcinoma, liver transplantation, or death. The study was terminated after 6 years due to futility. At enrollment, the UDCA (n = 76) and placebo (n = 74) groups were similar with respect to sex, age, duration of disease, serum aspartate aminotransferase and alkaline phosphatase levels, liver histology, and Mayo risk score. During therapy, aspartate aminotransferase and alkaline phosphatase levels decreased more in the UDCA group than the placebo group (P < 0.01), but improvements in liver tests were not associated with decreased endpoints. By the end of the study, 30 patients in the UDCA group (39%) versus 19 patients in the placebo group (26%) had reached one of the pre-established clinical endpoints. After adjustment for baseline stratification characteristics, the risk of a primary endpoint was 2.3 times greater for patients on UDCA than for those on placebo (P < 0.01) and 2.1 times greater for death, transplantation, or minimal listing criteria (P = 0.038). Serious adverse events were more common in the UDCA group than the placebo group (63% versus 37% [P < 0.01]). CONCLUSION: Long-term, high-dose UDCA therapy is associated with improvement in serum liver tests in PSC but does not improve survival and was associated with higher rates of serious adverse events.

Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure.

BACKGROUND & AIMS: N-acetylcysteine (NAC), an antidote for acetaminophen poisoning, might benefit patients with non-acetaminophen-related acute liver failure. METHODS: In a prospective, double-blind trial, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were stratified by site and coma grade and assigned randomly to groups that were given NAC or placebo (dextrose) infusion for 72 hours. The primary outcome was overall survival at 3 weeks. Secondary outcomes included transplant-free survival and rate of transplantation. RESULTS: A total of 173 patients received NAC (n = 81) or placebo (n = 92). Overall survival at 3 weeks was 70% for patients given NAC and 66% for patients given placebo (1-sided P = .283). Transplant-free survival was significantly better for NAC patients (40%) than for those given placebo (27%; 1-sided P = .043). The benefits of transplant-free survival were confined to the 114 patients with coma grades I-II who received NAC (52% compared with 30% for placebo; 1-sided P = .010); transplant-free survival for the 59 patients with coma grades III-IV was 9% in those given NAC and 22% in those given placebo (1-sided P = .912). The transplantation rate was lower in the NAC group but was not significantly different between groups (32% vs 45%; P = .093). Intravenous NAC generally was well tolerated; only nausea and vomiting occurred significantly more frequently in the NAC group (14% vs 4%; P = .031). CONCLUSIONS: Intravenous NAC improves transplant-free survival in patients with early stage non-acetaminophen-related acute liver failure. Patients with advanced coma grades do not benefit from NAC and typically require emergency liver transplantation.

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.

Predictive value of actin-free Gc-globulin in acute liver failure.

Serum concentrations of the actin scavenger Gc-globulin may provide prognostic information in acute liver failure (ALF). The fraction of Gc-globulin not bound to actin is postulated to represent a better marker than total Gc-globulin but has been difficult to measure. We tested a new rapid assay for actin-free Gc-globulin to determine its prognostic value when compared with the King's College Hospital (KCH) criteria in a large number of patients with ALF. A total of 252 patients with varying etiologies from the U.S. ALF Study Group registry were included; the first 178 patients constituted the learning set, and the last 74 patients served as the validation set. Actin-free Gc-globulin was determined with a commercial enzyme-linked immunosorbent assay kit. The median (range) actin-free Gc-globulin level at admission for the learning set was significantly reduced compared with controls (47 [0-183] mg/L vs. 204 [101-365] mg/L, respectively, P < 0.001). Gc-globulin levels were significantly higher in spontaneous survivors than in patients who died or were transplanted (53 [0-129] mg/L vs. 37 [0-183] mg/L, P = 0.002). A receiver operating characteristic curve analysis showed that a 40 mg/L cutoff level carried the best prognostic information, yielding positive and negative predictive values of 68% and 67%, respectively, in the validation set. The corresponding figures for the KCH criteria were 72% and 64%. A new enzyme-linked immunosorbent assay for actin-free Gc-globulin provides the same (but not optimal) prognostic information as KCH criteria in a single measurement at admission.