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

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

Risk factors for hospitalizations among patients with cirrhosis: A prospective cohort study

<div><p>This study was designed to assess unique baseline factors associated with subsequent hospitalizations in a cohort of outpatients with cirrhosis. A cohort of 193 patients with cirrhosis was recruited from an outpatient liver disease clinic at a single, tertiary medical center. Comorbidities, prescription medications, liver disease symptoms and severity, and psychiatric and pain symptoms were assessed at baseline using validated instruments. Inflammatory markers were measured using standardized Luminex assays. Subsequent hospitalizations and the primary admission diagnoses were collected via chart review. Multivariable models were used to evaluate which baseline factors were associated with time to hospitalization and number of hospitalizations. The cohort consisted of 193 outpatients, with an average age of 58±9 and model for end-stage liver disease (MELD) score of 12±5. Over follow-up, 57 (30%) were admitted to the hospital. The factors associated with time to hospitalization included the severity of liver disease (HR/MELD point:1.10, 95% CI:1.04,1.16), ascites (HR: 1.90, 95% CI: 1.01, 3.58), baseline symptoms of depression (HR:2.34, 95% CI:1.28,4.25), sleep medications (HR:1.81, 95% CI:1.01, 3.22) and IL-6 (HR:1.43, 95% CI: 1.10, 1.84). Similarly the number admissions was significantly associated with MELD (IIR: 1.08, CI: 1.07,1.09), ascites (IIR: 4.15, CI:3.89, 4.43), depressive symptoms (IIR:1.54, CI:1.44,1.64), IL-6 (IIR:1.26, CI:1.23,1.30), sleep medications (IIR:2.74, CI:2.57, 2.93), and widespread pain (IIR: 1.61, CI: 1.50, 1.73). In conclusion, consistent with prior studies, MELD and ascites were associated with subsequent hospitalization. However, this study also identified other factors associated with hospitalization including inflammation, depressive symptoms, sleep medication use, and pain.</p></div