Liquid Biopsy for Hepatocellular Carcinoma

Abstract

Purpose of Review

Clinically available biomarkers for hepatocellular carcinoma (HCC) early diagnosis and prognostication have limited utility. Further lack of routine biopsy in hepatocellular carcinoma limits the availability of molecular information to guide drug development. Recent studies investigating liquid biopsy using circulating tumor cells (CTCs) and cell-free deoxyribonucleic acid (cfDNA) have yielded promising data that could address both of these limitations.

Recent Findings

For early HCC diagnosis, CTCs have modest sensitivity but high specificity. CfDNA methylation scores have shown high sensitivity and specificity in two large phase II studies. Presence of CTCs has been associated with poorer prognosis in numerous studies, particularly increased cancer recurrence following curative therapy, while the literature on cfDNA and prognosis is less robust.

Summary

Liquid biopsy using CTCs and cfDNA has shown promise in prognostication and early diagnosis in HCC. Further robust validation of this liquid biopsy is required for routine clinical use.

Screening Indications and Treatments for Cholangiocarcinoma

Abstract

Purpose of Review

The goal of this review paper is to provide a comprehensive overview of cholangiocarcinoma (CCA) including its classification, epidemiology, risk factors, surveillance, diagnosis, and treatment.

Recent Findings

Guidelines recommend CCA surveillance in PSC patients with MRI/MRCP or ultrasound and CA 19-9 every 6–12 months. Fluorescience in situ hybridization and next-generation sequencing improve the poor sensitivity of biliary brushings. Surgical resection with negative margins gives the best chance of survival, and liver transplantation is an option for patients with very early intrahepatic CCA and perihilar CCA.

Summary

CCA is a deadly epithelial malignancy of the biliary-ductal system and is the second most common primary liver cancer. Surveillance should be offered to all patients with PSC. CCA carries poor prognosis, especially if resection or liver transplantion is not feasible. Novel biomarkers and therapeutic options such as molecularly targeted therapy and immunotherapy hold promise to improve the detection and outcome of CCA patients.

Update in Drug Development for Chronic HBV/HDV Infection

Abstract

Purpose of Review

Chronic hepatitis D is the most severe form of viral hepatitis. Currently, no drug has been approved for its treatment and pegylated interferon alpha remains the only recommended therapy, with dismal efficiency and important side effects. This review summarizes the recent advances in drug development for chronic hepatitis D.

Recent Findings

A better knowledge of virology of hepatitis D virus has led to the development of several drugs targeting different steps of the viral life cycle. Among them, bulevirtide (a viral entry inhibitor, formerly denominated as Myrcludex B), lonafarnib (a viral assembly inhibitor), REP-2139-Ca (an inhibitor of HBsAg secretion), and pegylated interferon lambda have shown promising results in phase II clinical trials.

Summary

In the near future, new therapeutic options will be available for the treatment of chronic hepatitis D. However, no drug is currently under development targeting viral replication and an effective treatment strategy may require combination of several drugs.

Future Therapies for Functional Cure of Chronic HBV: Review of Investigational Drugs in Phase 1 and 2 Development

Abstract

Purpose of Review

Treating patients with chronic hepatitis B (CHB) infection with long-term oral antiviral therapy or pegylated interferon is the current standard of care (SOC). However, functional cure, defined as sustained hepatitis B surface antigen (HBsAg) seroclearance that is associated with favorable clinical outcomes, is a rarely achieved treatment endpoint with the SOC.

Recent Findings

Remarkable advances in CHB therapy have been made in the recent years. This review was aimed to describe the different new treatment agents that are in the clinical phase of development. These include two main groups of agents that either target the viral replication cycle or enhance host immune control on the hepatitis B virus (HBV). The former group includes viral entry inhibitor, RNA gene silencers, core protein inhibitors, nucleic acid polymer, and monoclonal antibodies. The latter group includes toll-like receptor agonists, RIG-1/NOD2 agonist, therapeutic vaccines, and apoptosis inducer.

Summary

While some agents show promise in reduction of HBsAg levels and even HBsAg seroclearance, others are relatively modest in term of additional virological control effected by their different modes of action against HBV. These agents are in general well tolerated. Many upcoming new drugs against HBV are expected to enter phase II clinical trials. New challenge ahead would be the choice and duration of combination therapy to achieve a satisfactory rate of HBsAg seroclearance.

HIV-Associated NAFLD: Disease Burden and Management

Abstract

Purpose of Review

Highly potent anti-retroviral therapy (ART) for the treatment of human immunodeficiency virus (HIV) has led to dramatic improvements in quality of life and lifespan in persons living with HIV (PLWH). PLWH, however, are suffering from other comorbid conditions, including non-alcoholic fatty liver disease (NAFLD). This review summarizes the epidemiology and pathophysiology of NAFLD in PLWH and explores unique diagnostic and treatment considerations in this population.

Recent Findings

Though it is well established that there is a high prevalence of NAFLD in PLWH, the mechanisms underlying NAFLD in this population are just beginning to be explored. Traditional NAFLD risk factors, including insulin resistance, visceral adiposity, and genetics, have been consistently linked with NAFLD in PLWH. In addition, HIV-related factors including mitochondrial dysfunction, microbiome alterations, and direct effects of the virus and of ART may play a role.

Summary

Given the burden of NAFLD in PLWH, further studies are necessary to investigate mechanisms specific to HIV with which to target therapies.

Extrahepatic Malignancies in Nonalcoholic Fatty Liver Disease

Abstract

Purpose of Review

Malignancy is the second most common cause of death in individuals with nonalcoholic fatty liver disease (NAFLD). Understanding unique characteristics of malignancy risk beyond hepatocellular carcinoma in NAFLD has significant implications in counseling and personalized preventative measures in this high-risk population. Herein, we systematically review the literature reporting extra-hepatic malignancies in NAFLD and discuss the key biological mechanisms underpinning the association between excess adiposity and cancer risk.

Recent Findings

Several studies have shown significant associations between NAFLD and extrahepatic malignancies. The strongest association was found with cancers of the gastrointestinal tract and hormone-sensitive cancers. Recent data support sex-specific differences in cancer risk increase in NAFLD: colorectal cancer in men and uterine cancer in women. The risk of cancer development is higher in NAFLD than obesity alone.

Summary

A growing body of observational evidence over the last decade supports the association between NAFLD and extrahepatic malignancies. This association requires further studies, ideally designed to include more detailed measures of body fat deposition beyond BMI in well-characterized, large cohorts of NAFLD patients, to determine if screening policies should be individualized in this group.

Downstaging and Expanded Criteria Hepatocellular Carcinoma Liver Transplantation

Abstract

Purpose of Review

Liver transplantation (LT) has been utilized in the last two decades for the treatment of selected patients with hepatocellular carcinoma (HCC). Currently, in most jurisdictions worldwide, only tumor size and number determine transplant candidacy, which may not sufficiently predict tumor behavior. Both tumor downstaging and expanding transplant criteria play an important role in expanding access to LT for HCC patients.

Recent Findings

New downstaging protocols are emerging that incorporate response to locoregional therapies (LRT) among those that initially present beyond the accepted Milan criteria. In parallel, new serologic, histologic, and radiographic tools are being identified that may better predict outcomes after LT for HCC, in so-called extended criteria. The efforts of different jurisdictions worldwide in creating new treatment protocols have made it possible to evaluate and compare outcomes of patients over time.

Summary

Improvements of LRT and expansion of the criteria for LT for HCC will both play a role in optimizing outcomes for patients with HCC.

Should We Screen High-Risk Populations for NAFLD?

Abstract

Purpose of review

Nonalcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide and yet remains largely underdiagnosed. However, whether a systematic screening in high-risk population for NAFLD should be performed remains debated.

Recent findings

Over the past decade, a better knowledge of the natural history and epidemiology of NAFLD has identified high-risk population for NAFLD including obese and type 2 diabetes patients. Moreover, the presence of advanced fibrosis has been identified as the major determinant of overall and liver-related mortality. Moreover, several non-invasive biomarkers have been developed for the screening of advanced fibrosis while therapeutic clinical trials are intensive field of research.

Summary

Screening for advanced fibrosis in high-risk population for NAFLD should be performed as it would benefit to the patients. However further studies are needed to determine the optimal strategy and cost-effectiveness of such screening.

Spectrum of Drug Induced Liver Injury Caused by Anabolic Androgenic Steroids Abuse

Abstract

Purpose of Review

Potent anabolic androgenic steroids (AAS) are often illegally present in commercially available body building supplements (BBS) and may cause drug induced liver injury (DILI) with different phenotypes.

Recent Findings

AAS induced DILI typically presents with a prolonged cholestatic liver injury with pruritus and a typical enzyme pattern of elevated transaminases that rapidly fall as alkaline phosphatase slowly increases. Liver biopsy reveals bland cholestasis that usually does not have chronic sequalae. Pathophysiology is unknown and genetic variants in genes associated with cholestatic syndromes were observed in a minority of patients. Chemical analysis of BBS have identified controlled AAS, which were not documented on the label.

Summary

More frequent use of BBS in males to enhance physical performance is predicted to increase the incidence of cholestatic DILI. The typical presentation of AAS induced liver injury in an at risk populations should prompt careful assessment of BBS exposure.