Curcumin reactivates epigenetically silenced tumor suppressor gene tissue factor pathway inhibitor-2 in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and the third most fatal, with a rising incidence in the US as a result of the increase in alcoholic liver disease and obesity. Current therapeutic strategies are unsatisfactory with poor treatment outcomes and efficacious therapies are acutely needed for better management of this deadly disease. Curcumin, a phenolic compound from the rhizome of the plant Curcuma longa has been shown to inhibit growth and induce cell death in various types of cancer cells including HCC. However, the anti-HCC mode of action of curcumin has not yet been elucidated. In HCC, aberrant promoter methylation and histone deacetylation are implicated in the inactivation of tumor suppressor genes which has a significant impact on carcinogenesis. Tissue factor pathway inhibitor-2 (TFPI-2), a Kunitztype serine protease inhibitor, is a tumor suppressor gene that is frequently epigenetically silenced in human HCC and HCC cell lines. Restoration of TFPI-2 expression in tumor tissue has been shown to not only inhibit invasion, tumor growth, metastasis and angiogenesis but also induce apoptosis. We examined the effects of curcumin on tumor suppressor genes in HCC and observed robust reactivation of TFPI-2 in HepG2 cells upon curcumin treatment. We confirmed that TFPI-2 was under epigenetic control in HepG2 cells by using demethylating agent 5-Aza-2\u27deoxycytidine (5-AZA) and histone deacetylase inhibitor trichostatin A (TSA), both of which induced gene expression. Further, we investigated the epigenetic modifications at the TFPI-2 promoter and the alterations induced by curcumin in these epigenetic states. Histone H3 acetylation at the transcription factor binding sites of the TFPI-2 promoter region was increased by curcumin and correlated with the induction of gene expression. The reactivation of TFPI-2 also corresponded with a decrease in cell invasiveness and increase in cell death in HepG2 cells. Overall, our data strongly suggest that curcumin can reverse the epigenetic alterations at the TFPI-2 promoter and thus, reactivate this silenced tumor suppressor gene. These results support a potential therapeutic role for curcumin in the management of HCC

Acute Hepatic Porphyrias: Recommendations for Diagnosis and Management with Real-World Examples

Acute hepatic porphyria (AHP) is a group of four rare inherited diseases, each resulting from a deficiency in a distinct enzyme in the heme biosynthetic pathway. Characterized by acute neurovisceral symptoms that may mimic other medical and psychiatric conditions, lack of recognition of the disease often leads to a delay in diagnosis and initiation of effective treatment. Biochemical testing for pathway intermediates that accumulate when the disease is active forms the basis for screening and establishing a diagnosis. Subsequent genetic analysis identifies the pathogenic variant, supporting screening of family members and genetic counseling. Management of AHP involves avoidance of known exogenous and hormonal triggers, symptomatic treatment, and prevention of recurrent attacks. Here we describe six case studies from our own real-world experience to highlight current recommendations and challenges associated with the diagnosis and long-term management of the disease

Hepatitis C related hepatocellular carcinoma in the era of direct-acting antivirals

Globally, hepatocellular carcinoma (HCC) is the second leading cause of cancer related death. Hepatitis C virus infected patients with cirrhosis or bridging fibrosis are particularly at risk. The risk is reduced among patients who achieve viral clearance with interferon-based regimens. Direct-acting antivirals (DAA) have revolutionized the management of HCV as the treatment is well tolerated, convenient to administer and is highly effective. Earlier studies showed conflicting results in the effect of DAA induced sustained virologic response (SVR) on the subsequent development or recurrence of HCC, with some studies showing an increased risk. More recently, two large retrospective studies provided convincing evidence that DAA induced SVR reduces the risk of HCC development. Irrespective of viral clearance, patients with cirrhosis and advanced fibrosis and those with treated HCC continue to be at increased risk requiring long-term surveillance studies

Acute hepatic porphyrias - a guide for Hepatologists

The acute hepatic porphyrias (AHPs) are a group of rare, inherited disorders of the heme biosynthesis pathway, usually manifesting with attacks of acute abdominal pain and other neurovisceral symptoms, with or without cutaneous manifestations. AHP are characterized by the accumulation of porphyrin precursors, porphobilinogen (PBG) and/or aminolevulinic acid (ALA), in the blood. The diagnosis is often missed or delayed due to both inadequate testing and the improper use of available laboratory tests. In this review, we describe the various clinical presentations of the four AHPs, elucidate the approach to diagnosis, and provide recommendations for immediate as well as long-term management. We also describe the different complications that can occur with long-standing AHP, including the development of hepatocellular carcinoma. The AHPs are very treatable conditions, with excellent outcomes if diagnosed and treated early. A high index of suspicion for the presence of these disorders along with accurate testing and timely treatment will help reduce the burden of disease and prevent irreversible complications in patients with AHP

Histone modifications and alcohol-induced liver disease: Are altered nutrients the missing link?

Alcoholism is a major health problem in the United States and worldwide, and alcohol remains the single most significant cause of liver-related diseases and deaths. Alcohol is known to influence nutritional status at many levels including nutrient intake, absorption, utilization, and excretion, and can lead to many nutritional disturbances and deficiencies. Nutrients can dramatically affect gene expression and alcohol-induced nutrient imbalance may be a major contributor to pathogenic gene expression in alcohol-induced liver disease (ALD). There is growing interest regarding epigenetic changes, including histone modifications that regulate gene expression during disease pathogenesis. Notably, modifications of core histones in the nucleosome regulate chromatin structure and DNA methylation, and control gene transcription. This review highlights the role of nutrient disturbances brought about during alcohol metabolism and their impact on epigenetic histone modifications that may contribute to ALD. The review is focused on four critical metabolites, namely, acetate, S-adenosylmethionine, nicotinamide adenine dinucleotide and zinc that are particularly relevant to alcohol metabolism and ALD

Donor hepatitis C status is not associated with an increased risk of acute rejection in kidney transplantation

Introduction: In renal transplantation, donor hepatitis C virus (HCV) status is crucial to consider when selecting a recipient given the high likelihood of transmission. We analyzed the effect of donor HCV status on post-renal transplant rejection and virologic infectious outcomes using electronic health record data from multiple US health care organizations. Methods: Using real world data from electronic health records of renal transplant recipients, a propensity score-matched case-control study of one-year renal transplant outcomes was conducted on cohorts of HCV-negative recipients who received an organ from an HCV-positive donor (HCV D+/R-) versus from an HCV-negative donor (HCV D-/R-). Donor HCV positivity was defined as new recipient HCV positivity within 30 days post-transplant. Cohorts were matched by major risk factors for rejection including age, gender, race, etiologies of end-stage renal disease, dialysis dependence, donor type, induction immunosuppression, and virologic lab studies. The primary outcome was one-year incidence of rejection. Secondary outcomes included longitudinal measures of liver and kidney function, incidence of non-HCV viremia, and DAA treatment pathways and responses. Results: Data from 900 renal transplant recipients were analyzed, 450 subjects per group (D+/R-, D-/R-). Mean age at transplant was 57.1 ± 11.9 years, 60 % were male, and 38 % were African American. Kaplan-Meier analysis showed a significantly increased incidence of one-year rejection for HCV D-/R- compared to HCV D+/R- (16.6% vs 22.8 %, p = 0.02). This difference did not persist on a sub-analysis excluding subjects with delayed graft function (DGF) (16.3% vs 19.2 %, p = 0.25). Although mean eGFR was initially higher in HCV D+/R-, there were no significant differences in liver or kidney allograft function at 12 months. There was no significant difference for composite viremia (CMV/EBV/BK; 37.66% vs 31.60 %, p = 0.07). The most common DAA regimen was glecaprevir/pibrentasvir (52.8 %). DAA treatment responses were excellent, with most subjects having a negative viral load by 90 days (mean: 1.7 ± 1.9 log units/mL). Conclusion: Donor HCV positivity did not negatively impact one-year rejection outcomes post-renal transplantation. Importantly, this effect was not biased by age. Anti-HCV treatment was effective and liver and kidney function were excellent at one-year post-transplant. These data support the continued expansion of the donor pool by utilizing organs from HCV-positive donors in the era of anti-HCV direct-acting antiviral therapies

Sarcopenia Predicts Post-transplant Mortality in Acutely Ill Men Undergoing Urgent Evaluation and Liver Transplantation.

BackgroundWe examined the association between sarcopenia and post-transplant mortality in acutely ill inpatients with cirrhosis who underwent urgent liver transplantation.MethodsIncluded were inpatients at 4 centers who were urgently listed as nonstatus 1 and transplanted from 2005 to 2017 with an abdominal computed tomography scan <90 days before transplantation. Skeletal muscle index (SMI) = total skeletal muscle cross-sectional area at the L3 vertebral level, normalized to height. Cox regression associated SMI with post-transplant mortality. Optimal search identified SMI cutoffs to detect survival.ResultsOf 126 inpatients, 63% were male patients, model for end-stage liver disease (MELDNa) was 32, and follow up was 5.1 years. Among men, 23% died. Median SMI was lower in men who died versus survived (45 versus 51 cm/m). SMI was associated with post-transplant mortality (hazard ratio [HR] = 0.96 per cm/m, 95% CI 0.92-0.99). Patients with SMI ≤ 48 cm/m versus >48 cm/m experienced higher rates of death at 1 year (86% versus 95%) and 3 years (73% versus 95%) (Log-rank P = 0.01). In MELD-adjusted analysis, sarcopenia was strongly associated with post-transplant mortality (HR = 4.39, 95% CI 1.49-12.97). Among women, 35% died. Median SMI was similar in women who died versus survived (45 versus 44 cm/m). SMI was not associated with post-transplant mortality (HR = 1.02, 95% CI 0.96-1.09). Optimal search did not identify any SMI cutoff that predicted post-transplant mortality.ConclusionsAmong patients who underwent urgent inpatient evaluation and liver transplantation, we identified an SMI cutoff value of 48 cm/m to predict post-transplant mortality in men. Our data support the use of SMI as a tool to capture the impact of muscle depletion on post-transplant mortality in acutely ill men with cirrhosis undergoing urgent liver transplantation