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.

Secondary Prophylaxis of Gastric Variceal Bleeding: A Systematic Review and Network Meta-Analysis.

There is no clear consensus regarding the optimal approach for secondary prophylaxis of gastric variceal bleeding (GVB) in patients with cirrhosis. We conducted a systematic review and network meta-analysis (NMA) to compare the efficacy of available treatments. A comprehensive search of several databases from each database's inception to March 23, 2021, was conducted to identify relevant randomized controlled trials (RCTs). Outcomes of interest were rebleeding and mortality. Results were expressed as relative risk (RR) and 95% confidence interval (CI). We followed the Grading of Recommendations Assessment, Development, and Evaluation approach to rate the certainty of evidence. We included 9 RCTs with 647 patients who had histories of GVB and follow-ups >6 weeks. A total of 9 interventions were included in the NMA. Balloon-occluded retrograde transvenous obliteration (BRTO) was associated with a lower risk of rebleeding when compared with ß-blockers (RR, 0.04; 95% CI, 0.01-0.26; low certainty), and endoscopic injection sclerotherapy (EIS)-cyanoacrylate (CYA) (RR, 0.18; 95% CI, 0.04-0.77; low certainty). ß-blockers were associated with a higher risk of rebleeding compared with most interventions and with increased mortality compared with EIS-CYA (RR, 4.12, 95% CI, 1.50-11.36; low certainty), and EIS-CYA + nonselective ß-blockers (RR, 5.61; 95% CI, 1.91-16.43; low certainty). Analysis based on indirect comparisons suggests that BRTO may be the best intervention in preventing rebleeding, whereas ß-blocker monotherapy is likely the worst in preventing rebleeding and mortality. Head-to-head RCTs are needed to validate these results.

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.

Impact of geography on organ allocation: Beyond the distance to the transplantation center.

AIM: To illustrate the application and utility of Geographic Information System (GIS) in exploring patterns of liver transplantation. Specifically, we aim to describe the geographic distribution of transplant registrations and identify disparities in access to liver transplantation across United Network of Organ Sharing (UNOS) region 1. METHODS: Based on UNOS data, the number of listed transplant candidates by ZIP code from 2003 to 2012 for Region 1 was obtained. Choropleth (color-coded) maps were used to visualize the geographic distribution of transplant registrations across the region. Spatial interaction analysis was used to analyze the geographic pattern of total transplant registrations by ZIP code. Factors tested included ZIP code log population and log distance from each ZIP code to the nearest transplant center; ZIP code population density; distance from the nearest city over 50000; and dummy variables for state residence and location in the southern portion of the region. RESULTS: Visualization of transplant registrations revealed geographic disparities in organ allocation across Region 1. The total number of registrations was highest in the southern portion of the region. Spatial interaction analysis, after adjusting for the size of the underlying population, revealed statistically significant clustering of high and low rates in several geographic areas could not be predicted based solely on distance to the transplant center or density of population. CONCLUSION: GIS represents a new method to evaluate the access to liver transplantation within one region and can be used to identify the presence of disparities and reasons for their existence in order to alleviate them.

Sofosbuvir and ribavirin prevent recurrence of HCV infection after liver transplantation: an open-label study.

BACKGROUND & AIMS: Patients with detectable hepatitis C virus (HCV) RNA at the time of liver transplantation universally experience recurrent HCV infection. Antiviral treatment before transplantation can prevent HCV recurrence, but existing interferon-based regimens are poorly tolerated and are either ineffective or contraindicated in most patients. We performed a trial to determine whether sofosbuvir and ribavirin treatment before liver transplantation could prevent HCV recurrence afterward. METHODS: In a phase 2, open-label study, 61 patients with HCV of any genotype and cirrhosis (Child-Turcotte-Pugh score, ≤7) who were on waitlists for liver transplantation for hepatocellular carcinoma, received up to 48 weeks of sofosbuvir (400 mg) and ribavirin before liver transplantation. The primary end point was the proportion of patients with HCV-RNA levels less than 25 IU/mL at 12 weeks after transplantation among patients with this HCV-RNA level at their last measurement before transplantation. RESULTS: Sixty-one patients received sofosbuvir and ribavirin, and 46 received transplanted livers. The per-protocol efficacy population consisted of 43 patients who had HCV-RNA level less than 25 IU/mL at the time of transplantation. Of these 43 patients, 30 (70%) had a post-transplantation virologic response at 12 weeks, 10 (23%) had recurrent infection, and 3 (7%) died (2 from nonfunction of the primary graft and 1 from complications of hepatic artery thrombosis). Of all 61 patients given sofosbuvir and ribavirin, 49% had a post-transplantation virologic response. Recurrence was related inversely to the number of consecutive days of undetectable HCV RNA before transplantation. The most frequently reported adverse events were fatigue (in 38% of patients), headache (23%), and anemia (21%). CONCLUSIONS: Administration of sofosbuvir and ribavirin before liver transplantation can prevent post-transplant HCV recurrence. ClinicalTrials.gov: NCT01559844.

An interferon-free antiviral regimen for HCV after liver transplantation.

BACKGROUND: Hepatitis C virus (HCV) infection is the leading indication for liver transplantation worldwide, and interferon-containing regimens are associated with low response rates owing to treatment-limiting toxic effects in immunosuppressed liver-transplant recipients. We evaluated the interferon-free regimen of the NS5A inhibitor ombitasvir coformulated with the ritonavir-boosted protease inhibitor ABT-450 (ABT-450/r), the nonnucleoside NS5B polymerase inhibitor dasabuvir, and ribavirin in liver-transplant recipients with recurrent HCV genotype 1 infection. METHODS: We enrolled 34 liver-transplant recipients with no fibrosis or mild fibrosis, who received ombitasvir-ABT-450/r (at a once-daily dose of 25 mg of ombitasvir, 150 mg of ABT-450, and 100 mg of ritonavir), dasabuvir (250 mg twice daily), and ribavirin for 24 weeks. Selection of the initial ribavirin dose and subsequent dose modifications for anemia were at the investigator's discretion. The primary efficacy end point was a sustained virologic response 12 weeks after the end of treatment. RESULTS: Of the 34 study participants, 33 had a sustained virologic response at post-treatment weeks 12 and 24, for a rate of 97% (95% confidence interval, 85 to 100). The most common adverse events were fatigue, headache, and cough. Five patients (15%) required erythropoietin; no patient required blood transfusion. One patient discontinued the study drugs owing to adverse events after week 18 but had a sustained virologic response. Blood levels of calcineurin inhibitors were monitored, and dosages were modified to maintain therapeutic levels; no episode of graft rejection was observed during the study. CONCLUSIONS: Treatment with the multitargeted regimen of ombitasvir-ABT-450/r and dasabuvir with ribavirin was associated with a low rate of serious adverse events and a high rate of sustained virologic response among liver-transplant recipients with recurrent HCV genotype 1 infection, a historically difficult-to-treat population. (Funded by AbbVie; CORAL-I ClinicalTrials.gov number, NCT01782495.).

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.

Living donor liver transplantation for hepatocellular carcinoma: Increased recurrence but improved survival.

In regions with a limited deceased donor pool, living donor adult liver transplantation (LDALT) has become an important treatment modality for patients with hepatocellular carcinoma (HCC) and cirrhosis. Studies have shown higher recurrence rates of HCC after LDALT in comparison with deceased donor liver transplantation (DDLT). The aim of our study was to examine the outcome results and recurrence rates for patients with HCC who underwent LDALT at our center. During an 8-year period, 139 patients underwent LDALT, of whom 28 (20.1%) had HCC in their explanted livers. The median follow-up was 40.8 months. The mean explant tumor size was 3.3 +/- 1.2, and the mean number of tumors was 1.5 +/- 0.8. Twenty-one patients (75%) had tumors within the Milan criteria, 5 patients had tumors outside the Milan criteria but within the University of California San Francisco (UCSF) criteria, and 2 patients were beyond the UCSF criteria. The overall 1- and 5-year patient and graft survival rates were 96% and 81%, respectively. Survival following LDALT was significantly better than survival following DDLT for HCC during the same time period (P = 0.02). Eight patients (28.6%) developed tumor recurrence. Poor differentiation of tumor cells was the most significant determinant of recurrence. Despite high recurrence rates of HCC following LDALT, overall 5-year survival appears to be excellent.