Outcomes of Liver Transplantation for Hepatocellular Carcinoma Beyond the University of California San Francisco Criteria: A Single-center Experience.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor. Currently, liver transplantation may be the optimal treatment for HCC in cirrhotic patients. Patient selection is currently based on tumor size. We developed a program to offer liver transplantation to selected patients with HCC outside of traditional criteria. METHODS: Retrospective review for patients transplanted with HCC between April 2008 and June 2017. Patients were grouped by tumor size according to Milan, University of California San Francisco (UCSF), and outside UCSF criteria. Patient demographics, laboratory values, and outcomes were compared. Patients radiographically outside Milan criteria were selected based on tumor control with locoregional therapy (LRT) and 9 months of stability from LRT. α-fetoprotein values were not exclusionary. RESULTS: Two hundred twenty HCC patients were transplanted, 138 inside Milan, 23 inside UCSF, and 59 beyond UCSF criteria. Patient survival was equivalent at 1, 3, or 5 years despite pathologic tumor size. Waiting time to transplantation was not significantly different at an average of 344 days. In patients outside UCSF, tumor recurrence was equivalent to Milan and UCSF criteria recipients who waited >9 months from LRT. Although tumor recurrence was more likely in outside of UCSF patients (3% versus 9% versus 15%; P = 0.02), recurrence-free survival only trended toward significance among the groups (P = 0.053). CONCLUSIONS: Selective patients outside of traditional size criteria can be effectively transplanted with equivalent survival to patients with smaller tumors, even when pathologic tumor burden is considered. Tumor stability over time can be used to help select patients for transplantation.

Evaluation of INK4A promoter methylation using pyrosequencing and circulating cell-free DNA from patients with hepatocellular carcinoma.

BACKGROUND: Hyper-methylation of CpG dinucleotides in the promoter region of inhibitor of cyclin-dependent kinase 4A (INK4A) has been reported in 60%-80% of hepatocellular carcinoma (HCC). As INK4A promoter hypermethylation event occurs early in HCC progression, the quantification of INK4A promoter methylation in blood sample may represent a useful biomarker for non-invasive diagnosis and prediction of response to therapy. METHODS: We examined INK4A promoter methylation using circulating cell-free DNA (ccfDNA) in a total of 109 serum specimens, including 66 HCC and 43 benign chronic liver diseases. Methylation of the individual seven CpG sites was examined using pyrosequencing. RESULTS: Our results showed that there were significantly higher levels of methylated INK4A in HCC specimens than controls and that the seven CpG sites had different levels of methylation and might exist in different PCR amplicons. The area under receiver operating characteristic (ROC) curve was 0.82, with 65.3% sensitivity and 87.2% specificity at 5% (LOD), 39.0% sensitivity and 96.5% specificity at 7% LOD, and 20.3% sensitivity and 98.8% specificity at 10% LOD, respectively. CONCLUSIONS: Our results support additional studies incorporating INK4A methylation testing of ccfDNA to further validate the diagnostic, predictive, and prognostic characteristics of this biomarker in HCC patients. The knowledge of the existence of epi-alleles should help improve assay design to maximize detection.

Etiopathogenesis of nonalcoholic steatohepatitis: role of obesity, insulin resistance and mechanisms of hepatotoxicity.

Incidence of nonalcoholic fatty liver disease is increasing with an estimated prevalence of 20-30% in developed nations. This is leading to increased incidence of chronic liver disease, cirrhosis, and hepatocellular cancer. It is critical to understand the etiology and pathogenesis of any disease to create therapeutic targets and develop new treatments. In this paper we discuss the etiology and pathogenesis of nonalcoholic steatohepatitis with special focus on obesity, role of insulin resistance, and molecular mechanisms of hepatotoxicity.

Hepatitis A vaccination in healthcare personnel.

BACKGROUND AND AIMS: Despite effective vaccine available, hepatitis A remains a significant cause of morbidity and mortality worldwide including acute liver failure, transplantation and death. Vaccination rates for hepatitis A in the general population are low. Rates of hepatitis A vaccination in healthcare personnel (HCP) are unknown. We studied vaccination rate to hepatitis A in a cohort of HCP at a large US academic center. MATERIAL AND METHODS: An anonymous survey was circulated between 499 HCP at-risk of hepatitis A exposure at our Institution. Results were corrected for non-response rate and compared with the general US population using the 2007 CDC-National Immunization Survey. Rate of hepatitis A vaccination was compared with Institutional rate of vaccination for the Influenza 2009-2010 season. RESULTS: Rate of vaccination for hepatitis A in HCP was 28.8% (response rate 41.4%; 207/499), with 58.9% having completed the full series and 24.7% being tested for post-vaccination immunity. Acceptance rate among non-vaccinated subjects was 70.7%. HCP hepatitis A vaccination rate was statistically greater than the national general population (28.8 vs. 12.1%, p ≤ 0.031). A statistically significant greater vaccination rate was found among US born responders vs. foreign-born HCP (34.3 vs. 19.3%, p = 0.0324). Vaccination for hepatitis A was statistically inferior to that of Influenza (28.8 vs. 90%; P = 0.01). CONCLUSIONS: HCP have statistically higher vaccination rate for hepatitis A than the general population, but overall protection remains suboptimal with vaccination rate below those for mandatory vaccines. Further studies to determine whether hepatitis A vaccine is cost-effective in HCP are recommended.

Liver transplantation in acute alcoholic hepatitis: Current status and future development.

Acute alcoholic hepatitis (AH) is a distinct clinical entity amongst patients with chronic alcohol abuse. Patients with severe AH are at risk of dying in about 20%-25% cases despite specific treatment with corticosteroids and/or pentoxifylline. Clearly, a need for an additional more effective treatment option is unmet currently. Liver transplantation (LT), a definitive treatment option for alcoholic cirrhosis requires 6 mo abstinence. However, this rule cannot be applied to patients with AH as these patients are actively drinking prior to their presentation. Shortage of donors, ethical issues, and fear of recidivism after transplantation with less than 6 mo pre-transplant abstinence are some of the reasons behind this rule of 6 mo of abstinence and hesitancy of transplanting patients with AH. These issues are debated at length in this manuscript. Further, retrospective studies have shown that patients undergoing transplantation for alcoholic cirrhosis and having histological changes of AH have been shown to fare as well when compared to patients without these histological changes. Recently, French workers have reported a case matched prospective study showing encouraging data on the usefulness of LT for patients who are non-responders to corticosteroid and/or pentoxifylline therapy. Future studies are needed to identify patients with severe AH who are going to benefit most with LT. In the light of emerging data on the efficacy of LT in improving survival of patients with severe acute AH who do not respond to corticosteroids, the time is ripe to re-evaluate our policy of LT in patients with AH.

Non-Alcoholic Steatohepatitis in Myotonic Dystrophy: DMPK Gene Mutation, Insulin Resistance and Development of Steatohepatitis.

Myotonic dystrophy is a multisystemic disorder characterized by repeat expansion mutations of the dystrophia myotonica protein kinase (DMPK) gene resulting in a defective muscular insulin receptor and insulin resistance. We describe a patient with myotonic dystrophy who developed biopsy-proven non-alcoholic steatohepatitis. We suggest that patients with myotonic dystrophy are at risk of developing steatohepatitis. The relationship between defective insulin receptor and development of steatohepatitis should be further investigated.

Predicting poor outcome following hepatectomy: analysis of 2313 hepatectomies in the NSQIP database.

BACKGROUND: For the past two decades multiple series have documented that liver resection has become safer. The purpose of this study was to determine the current status of hepatic resection in the USA by analysing the multi-institutional experience within the National Surgical Quality Improvement Program (NSQIP) dataset. METHODS: Of the 363,897 cases in the 2005-2007 NSQIP Participant Use File, 2313 elective open hepatectomy cases were identified (1344 partial, 230 left, 510 right and 229 extended hepatectomies). A total of 57 perioperative risk factors and 28 postoperative complications were compared. To determine the applicability of NSQIP general risk models to hepatic surgery, the prognostic value of standard multivariate analysis was compared with the NSQIP general surgery aggregate risk indices (expected probability of morbidity [morbprob], expected probability of mortality [mortprob]). RESULTS: The median age of patients listed in the database was 60 years; sex distributions were equivalent; 78% were White; 65% of patients had an ASA score of 3 or 4, and the most prevalent co-morbidity was hypertension (46%). A total of 41% of patients had disseminated cancer, 19% of whom had received chemotherapy within 30 days of surgery. The overall 30-day mortality rate was 2.5% (57/2313) and the 30-day major morbidity rate was 19.6% (453/2313). Multivariate analysis identified nine risk factors associated with major morbidity and two risk factors associated with mortality. In contrast, the morbprob and mortprob statistics did not predict outcomes accurately. For those patients who developed major morbidity, the median length of stay was longer (10 vs. 6 days; P = 0.001) and the mortality rate was higher (11.3% vs. 0.3%; P = 0.001). CONCLUSIONS: Analysis of the NSQIP experience with hepatectomy indicates that the current mortality and major morbidity rate benchmarks are 2.5% and 19.6%, respectively. Poor outcomes were associated with nutritional status, liver function and the extent of hepatectomy. The NSQIP general surgery morbprob and mortprob values were relatively poor predictors of post-hepatectomy observed morbidity, indicating the need for specialty-specific NSQIP modelling.

Vaccinations for adult solid-organ transplant recipients: current recommendations and protocols.

Recipients of solid-organ transplantation are at risk of severe infections due to their life-long immunosuppression. Despite emerging evidence that vaccinations are safe and effective among immunosuppressed patients, most vaccines are still underutilized in these patients. The efficacy, safety, and protocols of several vaccines in this patient population are poorly understood. Timing of vaccination appears to be critical because response to vaccinations is decreased in patients with end-stage organ disease and in the first 6 months after transplantation. For these reasons, the primary immunizations should be given before transplantation, as early as possible during the course of disease. Vaccination strategy should include vaccination of household contacts and health care workers at transplant centers unless contraindicated. No conclusive data are available on the use of immunoadjuvants and screening for protective titers. Most vaccines appear to be safe in solid-organ transplantation recipients, but live vaccines should be avoided until further studies are available. The risk of rejection appears minimal. Recommended vaccines include pneumovax, hepatitis A and B, influenza, and tetanus-diphtheria. We outline specific protocols and recommendations in this particular patient population. Specific contraindications exist for other vaccines, such as yellow fever, oral polio vaccine, bacillus Calmette-Guerin, and vaccinia. We conclude that solid-organ recipients will benefit from consistent immunization practices. Further studies are recommended to improve established protocols in this patient population.

Immune thrombocytopenic purpura in patients with chronic hepatitis C virus infection.

OBJECTIVE: Hepatitis C virus (HCV) infection has been associated with the production of autoantibodies and the development of several autoimmune disorders. Immune thrombocytopenic purpura (ITP) is an immune-mediated syndrome of unknown etiology characterized by the presence of autoantibodies against platelet membrane proteins. METHODS: Retrospective chart review. RESULTS: Seven patients with chronic HCV infection (five with cirrhosis and two with chronic active hepatitis) developed thrombocytopenia, out of proportion to their liver disease, and were diagnosed with ITP based on the presence of anti-platelet antibodies and their response to treatment. The number of patients with ITP which occurred in a population of 3440 HCV patients seen over this time interval is much greater than would be expected by chance (p < 0.00001). Six patients required treatment and four required hospitalization. Four of the six responded to corticosteroids alone. Both of the patients who failed to respond to corticosteroids responded to cyclophosphamide. No mortality occurred from complications of thrombocytopenia. CONCLUSIONS: ITP occurs more commonly in patients with chronic HCV infection than would be expected by chance. This should be considered in patients with liver disease and unexplained thrombocytopenia, as well as in patients with newly diagnosed ITP. Evaluation of antiplatelet antibodies, using an antigen-specific assay, was useful in supporting this diagnosis. Therapy with either corticosteroids or cyclophosphamide was successful in the six patients who required treatment.

Aspergillosis in liver transplant recipients: successful treatment and improved survival using a multistep approach.

BACKGROUND: Invasive aspergillosis is a life-threatening complication in liver transplant recipients, with a reported mortality rate of more than 90%. Treatment is difficult, and no single agent is uniformly effective in treating this patient population. METHODS: We retrospectively reviewed all fungal cultures from 200 liver transplant patients between 1996 and 1999 at a single tertiary referral center. RESULTS: A diagnosis of aspergillosis was made in 6 patients. Five patients had pulmonary involvement; 1 presented with an inguinal mass. Time from transplant to infection ranged from 1 week to 34 months. Treatment included surgical intervention and medical treatment. All patients infected with Aspergillus fumigatus were treated with a sequential protocol of lipid complex amphotericin followed by itraconazole. The major side effect of treatment was worsening renal function. One patient died of intracranial hemorrhage during treatment. CONCLUSION: Successful treatment of aspergillosis in liver transplant recipients should include early diagnosis, sequential medical treatment with lipid amphotericin B and itraconazole, and surgical intervention for invasive disease.