Molecular Mechanisms of Pathogenesis of Acute and Chronic Liver Diseases

National Institute Of Allergy And Infectious Diseases

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Abstract

The Hepatic Pathogenesis Section has developed an extensive program involving basic and clinical research to study the pathogenesis of acute and chronic liver disease, with a major focus on viral hepatitis and its long-term sequelae, cirrhosis and HCC, which contribute to a huge burden of disease worldwide. 1. Pathogenesis of Acute Liver Failure (ALF) and Acute Viral Hepatitis A. Role of viral and host factors in determining the outcome of acute HBV infection The mechanisms dictating the 3 main outcomes of acute HBV infection, acute self-limited hepatitis (AHB), acute liver failure (ALF), and HBV reactivation with acute-on-chronic ALF (CHB ALF), are poorly understood. Access to serial serum samples from the US Acute Liver Failure Study Group and the Hepatitis B Research Network allowed us to study the complex interplay between virus and host and to perform comparative studies between the 3 phenotypes. ALF was characterized by the highest titer of IgM anti-HBcAg and by a pro-inflammatory cytokine profile compared to AHB and CHB ALF. When we separated the HBV ALF group into early (<10 days from the onset to the development of encephalopathy) and late (> 10 days), we found distinct signatures. Over 90% of HBV ALF late presenters died or required liver transplantation compared to 40% of the early presenters. This study provides evidence that there are distinct serologic, virologic and cytokine profiles differentiating classic acute hepatitis B from HBV ALF and CHB ALF. Moreover, it provides the first evidence that early and late ALF differ in their profiles and outcomes suggesting different mechanisms of pathogenesis. The differences documented among the 3 groups of patients may help to identify early biomarkers that predict the different clinical outcomes. B. Prevalence of Hepatitis E Virus (HEV) in Drug-Induced Liver Injury (DILI) and in Solid-Organ Transplant Recipients in the United States The diagnosis of idiosyncratic DILI is difficult because of the diverse clinical presentations that mimic other, more common, causes of liver injury. We recently showed that acute HEV infection accounts for less than 1% of suspected DILI cases in the US and is more frequent in older men (Fontana et al. 2022). Thus, clinicians should consider testing for unsuspected acute HEV infection in older adult patients with acute hepatocellular DILI and jaundice. In a more recent prospective, U.S., multicenter study conducted in the solid-organ transplant population, we found that the HEV seroprevalence was significantly higher among transplant-recipients (24%) than waitlist patients (16%) (Samala et al. 2022). Conversely, detection of HEV RNA was rare, suggesting that progression to chronic HEV infection is uncommon in transplant-recipients in the U.S. Older age, history of graft hepatitis and kidney transplantation were the most important risk factors. Thus, this study indicates that HEV should be considered in transplant-recipients presenting with graft hepatitis. C. Pathogenesis of Acute and Chronic HEV Infection in Immunocompetent and Immunosuppressed Mongolian Gerbils. Infection with HEV usually induces acute self-limited hepatitis, but it may also cause chronic hepatitis in immunosuppressed patients, such as solid-organ transplant-recipients. The lack of a small animal model of HEV infection has hampered our understanding of pathogenesis in chronic infection. In collaboration with Dr. McGivern, we compared HEV kinetics, antibody responses, and liver disease in Mongolian gerbils with or without immunosuppression induced by the drug tacrolimus. Immunocompetent gerbils develop signs of acute hepatitis whereas immunosuppressed gerbils, despite persistent viremia and fecal shedding, showed no signs of inflammation, consistent with the hypothesis that liver damage in acute hepatitis E is immune-mediated. Thus, this study suggests that progression to fibrosis in immunosuppressed patients is due to underlying factors other than HEV. 2. Pathogenesis of Liver Fibrosis Progression, Cirrhosis, and Hepatocellular Carcinoma (HCC): Role of Viral and Host factors HCC is the third leading cause of cancer-related death worldwide, and chronic infection with hepatitis viruses accounts for more than 70% of all cases. Cirrhosis is the single most important risk factor for HCC being present in 80-90% of the cases. Although the major etiologic agents and risk factors for HCC are well-defined, the molecular mechanisms of hepatocarcinogenesis remain unclear. A) Role of Age in Liver Fibrosis Progression Older age at the time of infection with hepatitis viruses is associated with an increased risk of fibrosis progression, but the mechanisms remain unclear. We identified a gene, chitinase 3-like 1 (CHI3L1), as having the greatest age-dependent increase in expression and as being overexpressed in cirrhotic livers. In vitro studies demonstrated that CHI3L1 promotes liver fibrogenesis through a direct effect on HSCs and support a role for CHI3L1 in the increased susceptibility of aging livers to fibrosis progression (Nishimura et al. 2021). Preliminary data suggest that CHI3L1 has a major role in the rapid progression of chronic hepatitis D, which progresses to cirrhosis in up to 80% of cases within 5 to 10 years and in 15% of them within 1-2 years. B. Immune Profiling of HBV-Associated Hepatocellular Carcinoma (HCC) Identifies Two Distinct Immune Subtypes Chronic infection with HBV is the leading cause of HCC worldwide. Despite significant advances in immunotherapy, there is limited information on the HBV HCC microenvironment. Taking advantage of a unique series of paired liver specimens from well-characterized Caucasian patients with HBV HCC, we characterized the tumor microenvironment that may provide important clues to identify patients who could benefit from immunotherapy. An extensive immunohistochemistry analysis of immune cells combined with RNAseq identified two distinct tumor subtypes: immune-high and immune-low. Half of the tumors were immune-high. They were characterized by clusters of infiltrating B cells and T cells expressing PD1. Outside the tumors, the distribution of the immunologic markers was similar in the 2 subtypes. Immune-high was characterized by an enrichment of upregulated genes involved in anti-inflammatory pathways and downregulated genes involved in pro-inflammatory pathways. Thus, this study identifies two subtypes in HBV HCC with distinct molecular signatures. Immune-high tumors are characterized by abundant tumor-infiltrating immune cells, but upregulation of genes related to anti-inflammatory pathways. C. Role of HDV in Hepatocellular Carcinoma The mechanisms whereby HDV promotes liver cancer remain elusive. We demonstrated that the molecular profile of HCC HDV is unique and distinct from that of HBV HCC (Diaz et al. 2018), which suggests that HBV and HDV promote carcinogenesis by distinct molecular mechanisms (Farci et al. 2021). There is limited information on the molecular characteristics of HDV strains associated with HCC and on the role of edited genomes, which encode large (L)-HDAg, versus unedited genomes, which encode small (S)-HDAg, in pathogenesis. In this study, we investigated the HDV heterogeneity and the abundance of edited and unedited genomes by next-generation sequencing in liver specimens obtained from well-characterized patients with HDV HCC and non-HCC HDV cirrhosis. Our study demonstrates an abundance of unedited HDV genomes in livers containing HCC compared to non-HCC cirrhosis, suggesting that S- and L-HDAg play a differential role not only in the biology of the virus but also in HCC pathogenesis. Since HDV HCC is characterized by genomic instability, our data raise the possibility that nuclear accumulation of S-HDAg may lead to somatic mutations and genome instability.