No Improvement in Intention-to-treat Survival and Increasing Liver Nonutilization Rate During the MELD Era.

BACKGROUND: Although post liver transplant survival rates have significantly improved during the past 2-3 decades, the trend in intention-to-treat (ITT) survival (survival from waitlist addition) has not been well studied. METHODS: We conducted a retrospective analysis of Scientific Registry of Transplant Recipients data to determine the trend in ITT survival in liver transplant candidates. Adult (age ≧ 18 y) patients who were on the waitlist between the time period of March 1, 2002, to December 31, 2019 (n = 200 816) and deceased liver donors that were registered between the same time period (n = 152 593) were analyzed. RESULTS: We found a constant increase in posttransplant survival rates; however, the ITT survival rates showed no statistically significant improvement through the study period. We observed significant linear increase in waitlist dropout rates over time. We also observed linear increase in liver nonutilization rate in both entire cases and brain-dead cases. Donor risk index increased significantly over the years; however, it was mostly driven by increase in donation after circulatory death cases; without donation after circulatory death cases, donor risk index was stable throughout the 17 y we observed. CONCLUSIONS: The reason of the increased liver nonutilization rate is unclear; however, it is possible that reluctance to use high-risk organ to maintain better posttransplant outcomes contributed to this increase, which also could have led to increase in waitlist dropout rates and no improvements in ITT survival. Further investigation is warranted on the increased nonutilization rates to improve over all contribution of liver transplant to patient care.

The diagnostic yield of exome sequencing in liver diseases from a curated gene panel.

Exome sequencing (ES) has been used in a variety of clinical settings but there are limited data on its utility for diagnosis and/or prediction of monogenic liver diseases. We developed a curated list of 502 genes for monogenic disorders associated with liver phenotypes and analyzed ES data for these genes in 758 patients with chronic liver diseases (CLD). For comparison, we examined ES data in 7856 self-declared healthy controls (HC), and 2187 patients with chronic kidney disease (CKD). Candidate pathogenic (P) or likely pathogenic (LP) variants were initially identified in 19.9% of participants, most of which were attributable to previously reported pathogenic variants with implausibly high allele frequencies. After variant annotation and filtering based on population minor allele frequency (MAF ≤ 10-4 for dominant disorders and MAF ≤ 10-3 for recessive disorders), we detected a significant enrichment of P/LP variants in the CLD cohort compared to the HC cohort (X2 test OR 5.00, 95% CI 3.06-8.18, p value = 4.5e-12). A second-level manual annotation was necessary to capture true pathogenic variants that were removed by stringent allele frequency and quality filters. After these sequential steps, the diagnostic rate of monogenic disorders was 5.7% in the CLD cohort, attributable to P/LP variants in 25 genes. We also identified concordant liver disease phenotypes for 15/22 kidney disease patients with P/LP variants in liver genes, mostly associated with cystic liver disease phenotypes. Sequencing results had many implications for clinical management, including familial testing for early diagnosis and management, preventative screening for associated comorbidities, and in some cases for therapy. Exome sequencing provided a 5.7% diagnostic rate in CLD patients and required multiple rounds of review to reduce both false positive and false negative findings. The identification of concordant phenotypes in many patients with P/LP variants and no known liver disease also indicates a potential for predictive testing for selected monogenic liver disorders.

COVID-19 in solid organ transplant recipients: Initial report from the US epicenter.

Solid organ transplant recipients may be at a high risk for SARS-CoV-2 infection and poor associated outcomes. We herein report our initial experience with solid organ transplant recipients with SARS-CoV-2 infection at two centers during the first 3 weeks of the outbreak in New York City. Baseline characteristics, clinical presentation, antiviral and immunosuppressive management were compared between patients with mild/moderate and severe disease (defined as ICU admission, intubation or death). Ninety patients were analyzed with a median age of 57 years. Forty-six were kidney recipients, 17 lung, 13 liver, 9 heart, and 5 dual-organ transplants. The most common presenting symptoms were fever (70%), cough (59%), and dyspnea (43%). Twenty-two (24%) had mild, 41 (46%) moderate, and 27 (30%) severe disease. Among the 68 hospitalized patients, 12% required non-rebreather and 35% required intubation. 91% received hydroxychloroquine, 66% azithromycin, 3% remdesivir, 21% tocilizumab, and 24% bolus steroids. Sixteen patients died (18% overall, 24% of hospitalized, 52% of ICU) and 37 (54%) were discharged. In this initial cohort, transplant recipients with COVID-19 appear to have more severe outcomes, although testing limitations likely led to undercounting of mild/asymptomatic cases. As this outbreak unfolds, COVID-19 has the potential to severely impact solid organ transplant recipients.

Center-related Bias in MELD Scores Within a Liver Transplant UNOS Region: A Call for Standardization.

BACKGROUND: Model for End-Stage Liver Disease (MELD) score-based liver transplant allocation was implemented as a fair and objective measure to prioritize patients based upon disease severity. Accuracy and reproducibility of MELD is an essential assumption to ensure fairness in organ access. We hypothesized that variability in laboratory methodology between centers could impact allocation scores for individuals on the transplant waiting list. METHODS: Aliquots of 30 patient serum samples were analyzed for creatinine, bilirubin, and sodium in all transplant centers within United Network for Organ Sharing (UNOS) region 9. Descriptive statistics, intraclass correlation coefficients (ICCs), and linear mixed-effects regression were used to determine the relationship between center, bilirubin, and calculated MELD-sodium (MELD-Na) score. RESULTS: The mean MELD-Na score per sample ranged from 14 to 38. The mean range in MELD-Na per sample was 3 points, but 30% of samples had a range of 4-6 points. Correlation plots and intraclass correlation coefficient analysis confirmed bilirubin interfered with creatinine, with worsening agreement in creatinine at high bilirubin levels. Center and bilirubin were independently associated with creatinine reported in mixed-effects models. Unbiased hierarchical clustering suggested that samples from specific centers have consistently higher creatinine and MELD-Na values. CONCLUSIONS: Despite implementation of creatinine standardization, centers within a single UNOS region report clinically significant differences in MELD-Na on an identical sample, with differences of up to 6 points in high MELD-Na patients. The bias in MELD-Na scores based upon center choice within a region should be addressed in the current efforts to eliminate disparities in liver transplant access.

High post-transplant virological response in hepatitis C virus infected patients treated with pretransplant protease inhibitor-based triple therapy.

BACKGROUND & AIMS: Prevention of recurrent hepatitis C virus (HCV) following liver transplant (LT) with pre-LT antiviral therapy is limited by poor tolerability and efficacy. We aimed to evaluate the safety and efficacy of NS3/4A protease inhibitor (PI)-based triple therapy in patients awaiting LT. METHODS: Consecutive patients treated with triple therapy pre-LT from two centers were prospectively enrolled in an observational cohort. Overall 12 week sustained virological response (SVR12) was the primary outcome. Pre- and post-LT (pTVR) virological response rates and safety were secondary outcomes. RESULTS: Twenty-nine patients (mean age 57.9, 79% male, 66% prior non-responders) were treated with telaprevir (93%) or boceprevir-based (7%) triple therapy for a median (range) of 27 (3-50) weeks, including a pegylated-interferon and ribavirin lead-in in 18%. Median (range) MELD at treatment was 8 (6-16), 39% had hepatocellular carcinoma and all patients were Child-Turcotte-Pugh class A (62%) or B (38%). Twelve patients underwent LT, 75% with undetectable viral load. The overall SVR12 rate was 52%, including pre-LT SVR12 of 41% in patients who completed treatment and follow-up on the wait list and pTVR12 of 67% among transplanted patients. The pTVR12 rate was 89% among those patients with undetectable viral load at LT. Serious adverse events occurred in nine (31%) patients including one (3%) on-treatment death and eight (28%) hospitalizations. CONCLUSIONS: Overall SVR12 and pTVR12 rates are high among patients treated with PI-based triple therapy while awaiting LT, even in this difficult to treat population. However, caution is needed as early discontinuation and serious adverse events are common.

Decline in male sexual desire, function, and satisfaction during and after antiviral therapy for chronic hepatitis C.

BACKGROUND & AIMS: The recommended therapy for chronic hepatitis C, pegylated interferon and ribavirin for 24 or 48 weeks, has many known adverse side effects. The aim of this study was to evaluate the impact of antiviral therapy on male sexual health. METHODS: As part of the Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C (Virahep-C), 260 men treated with pegylated interferon alfa-2a and ribavirin completed self-administered questionnaires concerning sexual desire, sexual function, including erectile and ejaculatory function, and sexual satisfaction before, during, and after treatment. RESULTS: Before therapy, 37% of men reported at least some degree of impairment in sexual desire and 44% reported dissatisfaction with their sexual life, while 26% reported impairment in erectile and 22% in ejaculatory function. During therapy, significant declines were observed in all components of sexual health compared with pretreatment. At the end of therapy (24 or 48 weeks), an estimated 38%-48% of men reported that overall sexual function was worse than before treatment. African American patients reported less impairment in sexual desire and satisfaction than Caucasian American patients during therapy. By 24 weeks after treatment, sexual desire and satisfaction improved and were comparable to baseline levels. However, among men who received 48 weeks of therapy, the estimated percentage of men reporting posttreatment erectile or ejaculatory problems remained higher than baseline, although persistent erectile impairment was limited to Caucasian American patients. CONCLUSIONS: Sexual impairment is common among men with chronic hepatitis C undergoing therapy with pegylated interferon and ribavirin and should be considered as a potential side effect of antiviral therapy.

Three cases of autoimmune hepatitis in HIV-infected patients.

Autoimmune hepatitis (AIH) is an uncommon liver disease that has previously been reported only 4 times in HIV-infected patients. Our report describes 3 new cases of AIH, 2 probable, and 1 definite. Two of these cases developed while the patient was virologically suppressed on antiretroviral therapy. Liver biopsy findings were critical in establishing the diagnosis of AIH. Because abnormal liver function tests in HIV-positive patients are often ascribed to antiretroviral medications and/or comorbid conditions, AIH may be underdiagnosed in this population. These cases underscore the value of liver biopsy in evaluating hepatitis of unclear etiology in HIV-positive patients. The clinical course of these cases also suggests that standard immunosuppressive therapy for AIH remains the optimal treatment regimen, even in HIV-positive patients.

Contributions to hepatic fibrosis in HIV-HCV coinfected and HCV monoinfected patients.

OBJECTIVES: The aim of this study was to further explore the severity of liver disease and its predictors in a cohort of hepatitis C virus (HCV) infected patients, some of whom were coinfected with the human immunodeficiency virus (HIV). METHODS: This is a retrospective, cross-sectional study of patients undergoing liver biopsy to stage HCV disease prior to consideration of anti-HCV therapy. RESULTS: A total of 92 HIV-HCV coinfected and 372 HCV monoinfected patients were included. As might be expected, coinfected patients differed from monoinfected patients in a number of ways, including having lower body mass index (BMI), and lower alcohol intake. Liver disease was very similar between the two groups, with mean fibrosis score of 1.45 u for coinfected and 1.53 u for monoinfected (p = NS). Histological inflammation score dominated multivariate models of fibrosis when it was included in them. When only clinical predictors were used in multivariate models, BMI and type 2 diabetes had independent associations in monoinfected patients, whereas low CD4 count, current or nadir, was the only variable with an independent association in coinfected patients. CONCLUSIONS: Coinfected patients do not have uniformly worse liver disease than monoinfected patients. Immune compromise plays an important role in liver disease in coinfected patients, and the role of other clinical factors in liver disease may differ between these two groups, as well.

Predictors of candidate maturation among potential living donors.

The shortage of deceased donor allografts and improved outcomes in partial organ transplantation have led to widespread application of adult-to-adult living donor liver transplantation. Donor selection limits overall utilization of this technique and predictors of candidate maturation have been inadequately studied to date. We therefore collected data on 237 consecutive potential donors including their age, sex, ethnicity, relationship to the recipient, education, employment and religious beliefs and practices. Of these 237 candidates, 91 (38%) were excluded for medical and psychosocial reasons, 53 (22%) withdrew from the process predonation and 93 (39%) underwent partial liver donation. In multivariate analyses, the relationship between the donor and the recipient was highly predictive of successful donation. For pediatric recipients, no parents voluntarily withdrew from the evaluation process. For adult recipients, spouses are the most likely to donate, followed by parents, children and siblings. Additional predictors for donation included self-description as religious but not regularly practicing, part-time employment and higher education. Race, ethnicity, gender and age did not predict donation in multivariate analysis. Further understanding of the complex decision to donate may improve donation rates as well as permit more efficient and cost-effective donor evaluation strategies.

Hepatic steatosis in HIV/hepatitis C coinfection: prevalence and significance compared with hepatitis C monoinfection.

Liver disease in patients coinfected with HIV and hepatitis C virus (HCV) has received increasing attention in recent years. Steatosis is accepted as an important contributor to liver disease in patients with HCV, but despite coinfected patients having several reasons to have steatosis, the prevalence and significance of such changes has received scant attention. We examined steatosis in an unselected cohort of coinfected patients and compared its prevalence and predictors with findings in monoinfected patients, where these relationships have been established. We studied 92 coinfected and 372 monoinfected patients undergoing staging liver biopsy. Baseline characteristics of the two groups differed significantly, pointing at different contributors to steatosis in each. Histological inflammation and fibrosis were very similar in the two groups, but steatosis was less in coinfected patients. Steatosis had a univariate association with fibrosis in both groups, but retained a multivariate association only in monoinfected patients. Other multivariate predictors of steatosis in monoinfected patients were the accepted variables of elevated body mass index, male sex, and genotype 3a infection, as well as age. In coinfected patients, however, age was the only multivariate predictor. Undetectable HIV viral load was associated with steatosis in coinfected patients in univariate analysis, but highly active antiretroviral therapy or its individual components could not be initially linked to steatosis. In conclusion, steatosis is less common in HIV/HCV coinfected patients than similar HCV monoinfected patients, and predictors of steatosis differ between the two groups.

Management of hepatitis C after transplantation: a long way from success.

Recurrence of hepatitis C after transplantation is expected. Unfortunately, the outcome is poor in some, with as many as 25% of patients developing decompensated cirrhosis. Thus, developing treatment strategies to eradicate infection or slow the progression of hepatic fibrosis is crucial. The published data on treatment in this population is limited with viral response rates reported anywhere from 0-48%. Furthermore, the poor tolerability of therapy is highlighted in the Berenguer article. These data emphasize the importance of developing effective non-interferon based therapies for the post-transplant patient.

Interpretation of liver chemistries in adult donors after living donor liver transplantation.

OBJECTIVES: The safety of donors is paramount in adult living donor liver transplantation. Our goal is to compare the pattern of recovery of hepatic synthetic function and aminotransferases in healthy adult donors with and without complications. METHODS: We reviewed 47 consecutive patients undergoing right donor hepatectomy at our center. Laboratory data were collected through the first 2 postoperative weeks and results from donors with and without complications were compared. RESULTS: Donor morbidity was 25% and there were no donor deaths. Total bilirubin peaked on postoperative day 3, whereas aminotransferases and international normalized ratio peaked on postoperative day 1. Peak total bilirubin was higher in patients with fluid collections (n = 7) compared with those without fluid collections (n = 40), 4.6 mg/dL and 2.3 mg/dL, respectively, P = 0.02. On postoperative day 3 the peak total bilirubin was greater than 3.0 mg/dL in 86% of donors with fluid collections and 15% of donors without fluid collections, (P = 0.0005) whereas aminotransferases and alkaline phosphatase were not significantly different between these 2 groups. CONCLUSIONS: After right donor hepatectomy a total bilirubin greater than 3.0 mg/dL on postoperative day 3 should prompt an evaluation for a fluid collection, even if other liver tests are normal or declining.

A general approach to the management of chronic hepatitis C.

Hepatitis C virus (HCV) is the most common chronic blood-borne infection in the United States. Although many will live a lifetime unaffected by the consequence of chronic infection, some will develop cirrhosis and end-stage liver disease. Given the broad spectrum of disease outcomes, developing a careful systematic approach to infected patients is fundamental. This allows the practitioner to provide accurate education, develop treatment plans, and determine appropriate health care maintenance and screening. Care for the patient with HCV must be individualized. In this regard,the purpose of this article is not to present a guideline, but to provide a foundation of information that will aid the provider and patient in developing an appropriate treatment strategy.