Evaluation of the Patient with Markedly Abnormal Liver Enzymes.

Liver enzyme tests are very commonly ordered by physicians, and when they return as abnormal, they can pose a clinical challenge to the provider. Markedly abnormal liver enzymes indicate severe hepatic injury and require immediate evaluation. There are various causes for abnormal liver tests, including infectious, autoimmune, genetic, metabolic, drug, and vascular causes. An understanding of the patterns of aminotransferase and alkaline phosphatase elevations is useful in narrowing the differential diagnosis. A thorough history and physical examination, appropriate blood testing, and imaging are typically key to evaluating the patient with abnormal liver enzymes.

Posttransplant complications in the setting of acute-on-chronic liver failure and considerations regarding immunosuppression.

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Refractory Hepatic Hydrothorax Is an Independent Predictor of Mortality When Compared to Refractory Ascites.

BACKGROUND: Hepatic hydrothorax (HHT) is an uncommon but significant complication of cirrhosis and portal hypertension, associated with a worse prognosis and mortality. Nearly 25% of patients with HHT will have refractory pleural effusion. It is unclear if refractory HHT has a different prognosis compared to refractory ascites. AIMS: We aim to evaluate the prognostic significance of refractory HHT when compared to refractory ascites. METHODS: Forty-seven patients who had refractory HHT in a tertiary care center were identified, and matched, retrospectively, one-to-one by age, gender and MELD-Na with 47 patients with refractory ascites. One-year mortality rate was compared between both groups. Cox proportional hazard regression was used to identify the association between different covariates and primary endpoint. RESULTS: The 1-year mortality was 51.06% in the HHT group compared to 19.15% in the refractory ascites group. The median survival for patients with refractory hepatic hydrothorax was 4.87 months while the median survival for patients with refractory ascites exceeded 1 year. The presence of HHT was statistically significant in predicting the development of 1-year mortality [Hazard Ratio (HR) 4.45, 95% Confidence Interval (CI) 2.25-8.82; P value < 0.001]. Furthermore, refractory HHT remained associated with one-year mortality after adjusting for all other covariates. In a subgroup of patients with MELD-Na ≤ 20, HHT continued to be a significant predictor of one-year mortality (HR 3.30, 95% CI 1.47-7.40; P value 0.004). CONCLUSIONS: Refractory HHT is a significant independent predictor of mortality and offers additional prognostic value.

A Prospective Study of the Prevalence of Parkinsonism in Patients With Liver Cirrhosis.

Acquired hepatocerebral degeneration refers to a neurological syndrome consisting of various movement disorders and cognitive impairment in advanced liver cirrhosis or portosystemic shunt. Neurological signs and symptoms may be attributed to the accumulation of toxic substances in the brain. The most common neurological presentation of this is parkinsonism. Our prospective study aimed to investigate the prevalence of parkinsonism in patients with cirrhosis who were evaluated for liver transplant and to identify any correlation between findings on brain magnetic resonance imaging (MRI) and severity of parkinsonism. Of the 120 enrolled participants with liver cirrhosis, 62 (52%) exhibited signs of parkinsonism and all had MRI basal ganglia hyperintensity. Eighteen patients from this group were transplanted and showed statistically significant improvements in their Unified Parkinson's Disease Rating Scale (UPDRS) scores. Conclusion: The data suggest the reversibility of the neurological impairment seen in cirrhosis, and therefore the effectiveness of transplantation in improving parkinsonian symptoms. There was no correlation between severity of MRI findings and clinical motor UPDRS part III. Laboratory findings showed no correlation among the abnormal levels, MRI brain signal abnormality, or UPDRS scores.

Enteric tube placement in patients with esophageal varices: Risks and predictors of postinsertion gastrointestinal bleeding.

BACKGROUND AND AIM: Enteric tube (ET) placement is approached with caution in patients with esophageal varices (EV) due to concern of causing variceal bleeding. Data are limited on rates and predictors of gastrointestinal bleeding (GIB) in these patients. This study aims to assess the rate and predictors of bleeding from EV after ET placement. METHODS: We performed a retrospective chart review on patients requiring ET access with known EV. Inclusion criteria were age >18 with endoscopically proven EV who required ET placement. Patients who were admitted with, or developed a GIB prior to placement of ET were excluded, as were patients admitted for liver transplantation. Primary outcome was incidence of GIB within 48 h of tube placement. Secondary outcome was a >2 g/dL drop in hemoglobin within 48 h of placement without evidence of bleed. Statistical analysis was performed using Fischer's exact test, Mann-Whitney U test, and univariate logistic regression model. RESULTS: A total of 75 patients were included in the analysis. The most common etiology of cirrhosis was alcohol (44%). The most common location of EV was in the lower third of the esophagus (61%). The primary outcome was observed in 11 (14.6%) patients. The secondary outcome was found in eight (10.6%) patients. On univariate analysis, GIB was associated with higher MELD-Na (P = 0.026) and EV located in the lower third of the esophagus (P = 0.048). CONCLUSION: ET placement in patients with EV is associated with low risk of bleeding. Elevated MELD-Na and lower EV location conferred a higher risk of bleeding after ET placement.

Prognosis of Hepatic Encephalopathy.

The presence of hepatic encephalopathy is often associated with worse clinical outcomes and increased mortality. Even subclinical hepatic encephalopathy has clinical impacts on daily life and has been linked to increased falls, motor vehicle accidents, and hospitalizations. The presence and degree of hepatic encephalopathy can also affect survival outcomes in cirrhosis, acute liver failure, and liver transplant recipients. Patients may have improved clinical outcomes after treatment of hepatic encephalopathy, but the long-term impact of treatment on prognosis is unclear.

Iron-related markers are associated with infection after liver transplantation.

Though serum iron has been known to be associated with an increased risk of infection, hepcidin, the major regulator of iron metabolism, has never been systematically explored in this setting. Finding early biomarkers of infection, such as hepcidin, could help identify patients in whom early empiric antimicrobial therapy would be beneficial. We prospectively enrolled consecutive patients (n = 128) undergoing first-time, single-organ orthotopic liver transplantation (OLT) without known iron overload disorders at 2 academic hospitals in Boston from August 2009 to November 2012. Cox regression compared the associations between different iron markers and the development of first infection at least 1 week after OLT; 47 (37%) patients developed a primary outcome of infection at least 1 week after OLT and 1 patient died. After adjusting for perioperative bleeding complications, number of hospital days, and hepatic artery thrombosis, changes in iron markers were associated with the development of infection post-OLT including increasing ferritin (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.12-2.05), rising ferritin slope (HR, 1.10; 95% CI, 1.03-1.17), and increasing hepcidin (HR, 1.43; 95% CI, 1.05-1.93). A decreasing iron (HR, 1.76; 95% CI, 1.20-2.57) and a decreasing iron slope (HR, 4.21; 95% CI, 2.51-7.06) were also associated with subsequent infections. In conclusion, hepcidin and other serum iron markers and their slope patterns or their combination are associated with infection in vulnerable patient populations. Liver Transplantation 23 1541-1552 2017 AASLD.

Recurrent primary sclerosing cholangitis in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study: Comparison of risk factors between living and deceased donor recipients.

Primary sclerosing cholangitis (PSC) recurs in 15%-25% of patients transplanted for PSC. In the United States, PSC transplant patients are more likely to receive an organ from a living donor (LD) than patients without PSC. Our aims were to (1) compare risk of PSC recurrence in LD versus deceased donor recipients and (2) identify risk factors for PSC recurrence. There were 241 living donor liver transplantations (LDLTs) and 65 deceased donor liver transplantation (DDLT) patients transplanted between 1998 and 2013 enrolled in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study who were evaluated. PSC recurrence risk for LDLT and DDLT recipients was compared using Kaplan-Meier survival curves and log-rank tests. Cox models were used to evaluate PSC risk factors. Overall PSC recurrence probabilities were 8.7% and 22.4% at 5 and 10 years after liver transplantation (LT), respectively. The risk of PSC recurrence was not significantly different for DDLT versus LDLT recipients (P = 0.36). For DDLT versus LDLT recipients, unadjusted 5- and 10-year PSC recurrence was 9.4% versus 9.5% and 36.9% versus 21.1%. Higher laboratory Model for End-Stage Liver Disease (MELD) score at LT, onset of a biliary complication, cholangiocarcinoma, and higher donor age were associated with increased risks of PSC recurrence: for MELD (hazard ratio [HR] = 1.06; 95% confidence interval [CI] 1.02-1.10 per MELD point, P = 0.002); for biliary complication (HR, 2.82; 95% CI, 1.28-6.25; P = 0.01); for cholangiocarcinoma (HR, 3.98; 95% CI, 1.43-11.09; P = 0.008); for donor age (per 5-years donor age; HR, 1.17; 95% CI, 1.02-1.35; P = 0.02). Factors not significantly associated with PSC recurrence included the following: first-degree relative donor (P = 0.11), post-LT cytomegalovirus infection (P = 0.38), and acute rejection (P = 0.22). Risk of recurrent PSC was not significantly different for DDLT and LDLT recipients. Biliary complications, cholangiocarcinoma, MELD, and donor age were significantly associated with risk of PSC recurrence. Liver Transplantation 22 1214-1222 2016 AASLD.

Impact of EGF, IL28B, and PNPLA3 polymorphisms on the outcome of allograft hepatitis C: a multicenter study.

Hepatitis C virus (HCV) infection is accelerated following liver transplantation (LT). Single nucleotide polymorphisms (SNPs) near the epidermal growth factor (EGF) (rs4444903), IL28B (rs12979860), and PNPLA3 (rs738409) loci are associated with treatment response, fibrosis, and hepatocellular carcinoma in non-transplant hepatitis C, but allograft population data are limited. We sought to determine the role of these SNPs in 264 patients with HCV who underwent LT between 1990 and 2008. Genotypes were determined from donor wedge/allograft biopsies and recipient explants. Cox proportional hazards model was used to assess time to cirrhosis, liver-related death, and retransplantation, adjusting for donor age and sustained virological response (SVR). Over a median follow-up of 6.3 yr, a trend toward increased progression to graft cirrhosis was observed among recipients of an EGF non-AA vs. AA donor liver (adjusted HR 2.01; 95% CI 0.93-4.34; p = 0.08). No other genotypes predicted cirrhosis development or graft survival. The CC IL28B variant in both recipients and donors was associated with increased rate of SVR (R-CC/D-CC 8/12[67%], R-non-CC/D-CC or R-CC/D-non-CC 23/52[44%], R-non-CC/D-non-CC 12/45[27%], p linear trend = 0.009). Recipient EGF, IL28B, and PNPLA3, and donor IL28B and PNPLA3 genotypes do not predict adverse outcomes in HCV LT recipients. A potential association exists between donor EGF genotype and cirrhosis.

Peginterferon-α-2b and ribavirin for hepatitis C recurrence postorthotopic liver transplantation.

GOALS: To evaluate the safety and efficacy of peginterferon-α-2b plus ribavirin in patients with recurrent hepatitis C after orthotopic liver transplant. BACKGROUND: Reinfection of liver allografts in hepatitis C virus -infected transplant recipients begins immediately after transplantation. Treatment of these patients is challenging because of poor tolerability. STUDY: A multicenter, open-label study enrolling patients with persistent viremia after primary orthotopic liver transplant for cirrhosis related to hepatitis C virus infection. Patients received peginterferon-α-2b (1.5 µg/kg/wk) plus ribavirin (400 to 1200 mg/d administered using a dose-escalating regimen and according to body weight) for 48 weeks. The primary endpoint was sustained virologic response (SVR). RESULTS: In total, 125 patients started treatment and 58.4% completed 48 weeks. SVR rate was 28.8% (G1, 23.8%; G2/3, 55.0%), end-of-treatment response rate was 40.8%, and relapse rate was 18.2%. SVR was 55% among patients who completed treatment. Genotype 2/3 infection, male sex, baseline hemoglobin>14 g/dL, 80:80:80 compliance, rapid virologic response (RVR), and complete early virologic response (cEVR) were predictors of SVR. SVR was higher among patients with RVR compared with those without RVR (83.3% vs. 25.7%; P=0.0098), and among patients with cEVR compared with those without EVR (66.7% vs. 1.8%; P<0.0001). Thirty-eight patients discontinued because of an adverse event and 69 required dose reduction or interruption. Anemia (74%) and neutropenia (30%) were common, and rejection was low (3.2%). CONCLUSIONS: SVR was low in this study. Anemia was a particular challenge in achieving maximal ribavirin therapeutic exposure and may account in part for the lower SVR.

Ascites.

Ascites is the pathologic accumulation of fluid in the peritoneum. It is the most common complication of cirrhosis, with a prevalence of approximately 10%. Over a 10-year period, 50% of patients with previously compensated cirrhosis are expected to develop ascites. As a marker of hepatic decompensation, ascites is associated with a poor prognosis, with only a 56% survival 3 years after onset. In addition, morbidity is increased because of the risk of additional complications, such as spontaneous bacterial peritonitis and hepatorenal syndrome. Understanding the pathophysiology of ascites is essential for its proper management.

Successful outcomes following living donor liver transplantation for portopulmonary hypertension.

Pulmonary arterial hypertension (PAH) associated with portal hypertension [portopulmonary hypertension (PPHTN)] occurs in 2% to 10% of patients with advanced liver disease and carries a very poor prognosis without treatment. Most hepatic transplantation centers consider moderate to severe PPHTN to be a contraindication to liver transplantation because of the high rate of perioperative complications. We present 3 patients with PPHTN who were managed with intravenous prostacyclin therapy followed by living donor liver transplantation (LDLT). These individuals demonstrated subsequent resolution of their pulmonary hypertension and were weaned off all PAH-specific medical therapy. We present their demographics, clinical courses, and hemodynamics. We discuss the potential indications for LDLT and risks with respect to this patient population. Limitations of the Model for End-Stage Liver Disease scoring system and outcome data for this patient population are reviewed. Future studies should be directed toward better defining indications for LDLT in patients with PPHTN, improving medicosurgical management, and assessing long-term outcomes.

Detection of WA B cells in hepatitis C virus infection: a potential prognostic marker for cryoglobulinemic vasculitis and B cell malignancies.

OBJECTIVE: An uncommon manifestation of hepatitis C virus (HCV) infection is systemic vasculitis associated with type II cryoglobulinemia (cryoglobulinemic vasculitis), a proliferative B cell disorder that transforms into B cell malignancy in 5-10% of patients. The monoclonal rheumatoid factors (mRF) that bear the WA cross-idiotype (Xid) are responsible for most cases of cryoglobulinemic vasculitis in patients with HCV infection. The purpose of this study was to determine whether WA B cells can be detected in asymptomatic patients with HCV infection, using sequence analysis of B cell clonal expansions (BCEs) to identify the WA Xid. METHODS: Asymptomatic patients with HCV infection and those without HCV infection as well as respective control patients with cryoglobulinemic vasculitis, whose serum was either negative or positive for WA mRF, were studied. BCEs were isolated in the patients' blood, and WA BCEs were identified by sequencing analysis. RESULTS: BCEs were detected in all control patients with cryoglobulinemic vasculitis, but only control patients with HCV infection had WA BCEs. None of the 33 asymptomatic patients without HCV infection had a BCE. WA BCEs were detected in 4 (7.4%) of 55 asymptomatic patients with HCV infection, in none of 14 patients with HCV infection and type III cryoglobulinemia, and in 5 (13.5%) of 37 patients with HCV infection and serum RF positivity. One patient with a WA BCE had splenic lymphoma markers and villous lymphocytes, and the villous lymphocytes were found to be WA B cells. CONCLUSION: By identification of the WA Xid, WA B cells can be detected in asymptomatic HCV-infected patients. WA B cells in asymptomatic patients with HCV infection may be a marker for the development of cryoglobulinemic vasculitis and associated B cell malignancies. The results of this study provide a basis for the development of the first practical clinical application of cross-idiotype analysis.

Treatment of hepatitis C in liver transplant recipients.

Recurrent hepatitis C after liver transplantation is a universal phenomenon. Graft reinfection occurs rapidly; once it is established, allograft cirrhosis and decompensation rapidly ensue in many patients. Treatment with pegylated interferon plus ribavirin is the standard of care among nontransplant patients with hepatitis C; however, the applicability of these therapies in liver transplant patients is severely limited. Before transplantation, many patients are simply too ill to endure the long treatment duration necessary to achieve viral eradication; thus, treatment-related toxicity is a frequent barrier to success. Clinical trials in the pretransplantation population have yielded poor outcomes, with sustained virologic response rates only as high as 25%. Early after transplantation, treatment may be initiated prophylactically, or it may be initiated therapeutically in patients with evidence of recurrent disease. In small studies, prophylactic therapy has been associated with sustained virologic response rates lower than 20%, whereas in therapeutic intervention studies, sustained virologic response rates have ranged from 20% to 37%. In the setting of therapeutic intervention, preliminary indications suggest that rapid and early virologic response may become important clinical tools enabling the early identification of patients likely to respond to treatment. Two important clinical trials, PHOENIX (Pegasys and Copegus Administered After Liver Transplantation for Hepatitis C) in the prophylactic setting and PROTECT (Pegylated Interferon Alpha-2b and Ribavirin After Orthotopic Liver Transplantation: Efficacy and Safety in Hepatitis C Recurrence Therapy) in the therapeutic setting, are under way and should further advance our understanding of the management of hepatitis C in patients undergoing liver transplantation.

Primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a generally progressive, sometimes fatal chronic hepatobiliary disorder for which no effective medical therapy now exists. This article describes the epidemiology of this disease, along with diagnosis and treatment options. Future research directions concerning PSC also are discussed.

Methasteron-associated cholestatic liver injury: clinicopathologic findings in 5 cases.

BACKGROUND & AIMS: Methasteron is a nutritional supplement used to increase weight or accelerate the build-up of muscle mass. The aim of this study was to describe 5 cases of hepatotoxicity in patients using methasteron seen at tertiary-care medical centers. METHODS: A case report design was used. RESULTS: Five previously healthy patients who used methasteron developed jaundice 2 weeks after discontinuation; they presented to a tertiary-care medical center 2 weeks later. Within another 2 to 3 weeks, bilirubin levels peaked. About 12 weeks after initial presentation, all cases resolved with no identifiable residual hepatic dysfunction. CONCLUSIONS: Methasteron use can result in severe hepatotoxicity. Liver failure can worsen after initial presentation, especially within 2 weeks. With close observation and supportive care, acute hepatic injury should resolve.

Cyclooxygenase-2 expression in hepatocellular carcinoma, cirrhosis and chronic hepatitis in the United States.

UNLABELLED: Aberrant expression of cyclooxygenase-2 in hepatocellular carcinoma was described in Asia. Using immunohistochemistry, we studied the expression of cyclooxygenase-2 in hepatocellular carcinoma, chronic hepatitis, and cirrhosis in a US institution. A staining score of 0-5 representing the sum of an intensity score and a distribution score was used. The mean scores were 2.2+/-1.60 for chronic hepatitis, 4.37+/-1.15 for cirrhosis, and 4.76+/-0.54 for hepatocellular carcinoma. We found a significant difference in mean staining scores between chronic hepatitis and cirrhosis (p < 0.0001), as well as between chronic hepatitis and hepatocellular carcinoma (p < 0.0001). Fibrosis correlated with cyclooxygenase-2 staining score (r=0.65). IN CONCLUSION: (1) Cyclooxygenase-2 expression is higher in cirrhosis and hepatocellular carcinoma when compared to chronic hepatitis. (2) Cyclooxygenase-2 expression correlates with the stage of fibrosis. (3) These results imply that in chronic hepatitis and possibly in cirrhosis, hepatocarcinogenesis may be a cyclooxygenase-2 dependent mechanism.