Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis of the biliary tree leading to biliary strictures, cholangitis, and cirrhosis. Early in p...Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis of the biliary tree leading to biliary strictures, cholangitis, and cirrhosis. Early in presentation, patients may have normal liver tests, though over time develop a cholestatic pattern of liver injury. Diagnosis is made radiographically with magnetic resonance or endoscopic cholangiography. While several autoantibodies are associated with PSC, none have proven to have adequate diagnostic utility. Liver biopsy is rarely recommended unless to evaluate for small-duct PSC or overlap syndrome. Elastography, in various forms, is an effective, non-invasive modality to evaluate liver fibrosis in PSC.
Genome-wide association analyses suggest that HLA genes including HLA-DRB*0301, HLA-DRB*0401, and HLA-B*3501 as well as non-HLA genes including CD28/CTLA4/ICOS and SYNPR increased AIH susceptibility. The destruction of h...Genome-wide association analyses suggest that HLA genes including HLA-DRB*0301, HLA-DRB*0401, and HLA-B*3501 as well as non-HLA genes including CD28/CTLA4/ICOS and SYNPR increased AIH susceptibility. The destruction of hepatocytes is the result of the imbalance between proinflammatory cells and immunosuppressive cells, especially the imbalance between Tregs and Th17 cells. The microbiome in patients with AIH is decreased in diversity with a specific decline in Bifidobacterium and enrichment in Veillonella and Faecalibacterium. Recent evidence has demonstrated the pathogenic role of E. gallinarum and L.reuteri in inducing autoimmunity in the liver.
Primary sclerosing cholangitis is a heterogenous immune-mediated disorder characterized by chronic inflammation and stricturing of the bile ducts. Though the driving pathophysiologic mechanisms remain elusive, there are...Primary sclerosing cholangitis is a heterogenous immune-mediated disorder characterized by chronic inflammation and stricturing of the bile ducts. Though the driving pathophysiologic mechanisms remain elusive, there are several observed clinical phenotypes of the disease. The distribution of bile duct involvement, presence of concomitant inflammatory bowel disease, significant infiltration of IgG4-positive plasma cells, and overlapping features with other autoimmune disease has significant implications for prognosis and treatment. As there remains no pathognomonic finding for primary sclerosing cholangitis, a broad differential diagnosis and extensive evaluation of other underlying causes is critical to appropriate management.
Primary sclerosing cholangitis (PSC) is considered an immunologically mediated disease. However, some of its features are not consistent with the typical profile of autoimmune conditions. PSC is characterized by progress...Primary sclerosing cholangitis (PSC) is considered an immunologically mediated disease. However, some of its features are not consistent with the typical profile of autoimmune conditions. PSC is characterized by progressive biliary fibrosis that may ultimately result in the eventual development of cirrhosis. In recent years, multiple studies have reported that the incidence and prevalence of this disease are on the rise. Consequently, patients are often diagnosed without symptoms or signs of advanced liver disease, although many still present with signs of decompensated liver disease. This article discusses the epidemiology, clinical presentation, and diagnostic workup in patients with PSC.
Chronic cholestasis is the hallmark clinical feature of primary biliary cholangitis. In addition to progressive liver damage, chronic cholestasis can lead to serious complications, many of which occur outside the liver....Chronic cholestasis is the hallmark clinical feature of primary biliary cholangitis. In addition to progressive liver damage, chronic cholestasis can lead to serious complications, many of which occur outside the liver. Bile acids are ligands for nuclear hormone receptors, and alterations in their concentration disrupt normal functioning of numerous different cell types. This article discusses the clinical presentation, pathophysiology, and management of pruritus (itching), fatigue, osteoporosis, hyperlipidemia, fat-soluble vitamin deficiencies, malignancies, cardiac dysfunction, bacterial cholangitis, cholemic (bile cast) nephropathy, and Sicca syndrome.
Ursodeoxycholic acid (UDCA) is the first-line treatment of primary biliary cholangitis (PBC). Long-term UDCA use significantly reduces progression to cirrhosis. UDCA improves liver enzymes and transplant-free survival ra...Ursodeoxycholic acid (UDCA) is the first-line treatment of primary biliary cholangitis (PBC). Long-term UDCA use significantly reduces progression to cirrhosis. UDCA improves liver enzymes and transplant-free survival rates. Despite the association between PBC and hyperlipidemia, treatment is indicated under specific circumstances with statins and fibrates being safe options. Osteoporosis, which is frequently seen, is usually managed based on data from postmenopausal women. Sicca syndrome is treated similarly to its standalone condition with the use of hydroxypropyl methylcellulose eye drops and anticholinergic drugs.
Autoimmune hepatitis (AIH) is a chronic immunologic disorder in which the immune system targets the liver. The disease has a genetic basis and this accounts for the epidemiologic variation observed in serologic testing a...Autoimmune hepatitis (AIH) is a chronic immunologic disorder in which the immune system targets the liver. The disease has a genetic basis and this accounts for the epidemiologic variation observed in serologic testing and clinical presentation across different populations. The incidence of AIH increases with age into the 70s and seems to be increasing in prevalence. Most patients test positive for antinuclear antibody, ASMA, or anti-LKM but about 20% of patients do not have these serologic markers. At clinical presentation, patients may be asymptomatic, symptomatic, have acute liver failure, or decompensated cirrhosis.
Hepatitis B infection affects approximately 262 million people worldwide and is responsible for 900,000 deaths annually. This article reviews the major factors limiting HBV elimination, which includes limited linkage to...Hepatitis B infection affects approximately 262 million people worldwide and is responsible for 900,000 deaths annually. This article reviews the major factors limiting HBV elimination, which includes limited linkage to care and complicated HBV testing and treatment guidelines. The article then provides solutions to these pressing issues.
HDV use the cell enzymes for its own replication, and the HBsAg as an envelope. There is an urgent need to develop new drugs for chronic hepatitis D (CHD). Pegylated interferon alpha (PEG-IFNα) (direct-antiviral and immu...HDV use the cell enzymes for its own replication, and the HBsAg as an envelope. There is an urgent need to develop new drugs for chronic hepatitis D (CHD). Pegylated interferon alpha (PEG-IFNα) (direct-antiviral and immune modulator) has been used and recommended by scientific guidelines, although not approved, with moderate efficacy and poor tolerability. There are several drugs in development which target the host: bulevirtide (BLV), lonafarnib (LNF), nucleic acid polymer, and others.
The disease burden of HDV is poorly understood. Our review identified multiple reasons: (1) HDV infection rates are overestimated in the general population due to limited sample sizes, sampling high-risk populations, and...The disease burden of HDV is poorly understood. Our review identified multiple reasons: (1) HDV infection rates are overestimated in the general population due to limited sample sizes, sampling high-risk populations, and significant regional variations, (2) estimates are based on chronic HBV populations, but HBV burden itself is uncertain, (3) there is a lack of testing in at-risk populations, (4) prevalence testing is based on HDV antibody testing and not HDV RNA, which distinguishes between active infection versus prior exposure, (5) older studies used less reliable testing and (6) HBV vaccination programs have affected HDV prevalence, but is often not accounted for.
Hepatitis delta virus (HDV) only infects patients with hepatitis B virus (HBV) due to its reliance on HBV surface proteins to form its envelope. With shared routes of transmission, HDV coinfection is estimated to occur i...Hepatitis delta virus (HDV) only infects patients with hepatitis B virus (HBV) due to its reliance on HBV surface proteins to form its envelope. With shared routes of transmission, HDV coinfection is estimated to occur in 15% of patients with HIV and HBV. However, HDV is often underdiagnosed and may be missed particularly in people living with HIV (PLWH) who are already on antiretroviral therapy with anti-HBV activity and coincidental HBV suppression. At the same time, HDV causes the most severe form of chronic viral hepatitis and leads to faster progression of liver disease and hepatocellular carcinoma. Thus, increased recognition and effective treatment are paramount, and as novel treatment options approach global markets, the study of their efficacy in PLWH should be pursued.
Diagnosis of HDV exposure is based on clinical assays of anti-hepatitis D antibody and current infection with hepatitis D RNA PCR. The role of hepatitis D antigen testing is not yet defined. RT-qPCR is the gold standard...Diagnosis of HDV exposure is based on clinical assays of anti-hepatitis D antibody and current infection with hepatitis D RNA PCR. The role of hepatitis D antigen testing is not yet defined. RT-qPCR is the gold standard for measuring HDV RNA viral load, which is used to assess response to the treatment of HDV infection. Gaps in testing include poor sensitivity of antigen testing and quantitative HDV RNA accuracy can be affected by the genotypic variability of the virus and variation in laboratory techniques. There is also a limitation in HDV testing due to access, cost, and limited knowledge of testing indications. Droplet digital PCR promises to be a more accurate method to quantify HDV RNA. Also, the recent development of a rapid HDV detection test could prove useful in resource-limited areas.
Maternal-to-child transmission of hepatitis B virus (HBV) and hepatitis delta virus (HDV) can lead to the risk of progressive liver disease in infants, but fortunately effective interventions exist to decrease transmissi...Maternal-to-child transmission of hepatitis B virus (HBV) and hepatitis delta virus (HDV) can lead to the risk of progressive liver disease in infants, but fortunately effective interventions exist to decrease transmission. Counseling on the risk of maternal-to-child transmission, care pathways to decrease transmission, and the implications of HBV and HDV on pregnancy outcomes are the key components of caring for pregnant people living with HBV and HDV.
Chronic hepatitis B virus (HBV) infection is a serious disease that currently has no cure. Key forms of HBV include covalently closed circular DNA, which mediates chronic persistence, and integrated DNA, which contribute...Chronic hepatitis B virus (HBV) infection is a serious disease that currently has no cure. Key forms of HBV include covalently closed circular DNA, which mediates chronic persistence, and integrated DNA, which contributes to immune evasion and carcinogenesis. These forms are not targeted by current therapies; however, gene editing technologies have emerged as promising tools for disrupting HBV DNA. Gene editor-induced double-stranded breaks at precise locations within the HBV genome can induce effects ranging from inactivation of target genes to complete degradation of the target genome. Although promising, several challenges remain in efficacy and safety that require solutions.
Currently approved treatment of patients with chronic hepatitis B infection is insufficient to achieve functional cure. Numerous new compounds are identified, and among many, capsid assembly modulators (CAMs) and nucleic...Currently approved treatment of patients with chronic hepatitis B infection is insufficient to achieve functional cure. Numerous new compounds are identified, and among many, capsid assembly modulators (CAMs) and nucleic acid polymers (NAPs) are 2 classes of virus-directing agents in clinical development. CAMs interfere with viral pregenomic RNA encapsidation and are effective in viral load reduction but have limited effects on hepatitis B surface antigen (HBsAg). NAPs prevent HBsAg release from hepatocytes and induce intracellular degradation, leading to potent suppression of serum HBsAg when combined with nucleoside analogues and pegylated interferon demonstrated by initial data, but awaiting further confirmation studies.
Nucleos(t)ide analogs are the cornerstone of treatment against hepatitis B virus; however, they have no direct effect on its transcriptional template (ie, covalently closed circular DNA) and so functional cure is rarely...Nucleos(t)ide analogs are the cornerstone of treatment against hepatitis B virus; however, they have no direct effect on its transcriptional template (ie, covalently closed circular DNA) and so functional cure is rarely achieved. Over recent years, there has been a significant improvement in our understanding of the viral life cycle and its mechanisms of immune evasion. In this review article, we will explore novel therapeutic targets, discuss the latest data from clinical trials, and highlight future research priorities.
Chronic infection with Hepatitis B is a common, incurable, and deadly infection. Despite inexpensive laboratory tests for diagnosis and management that have been established for decades, the worldwide rate of diagnosis i...Chronic infection with Hepatitis B is a common, incurable, and deadly infection. Despite inexpensive laboratory tests for diagnosis and management that have been established for decades, the worldwide rate of diagnosis is only ∼10%, and ∼5% of people are under treatment. Novel assays have been developed to improve linkage to care by providing more flexible approaches to determine a patient's health status. Other assays have been established to better investigate intrahepatic host-virus interactions to support clinical trials for cure research. This review outlines the clinical and scientific challenges still to be solved and the upcoming methods used to address them.
The natural history of hepatitis B virus (HBV) infection is closely dependent on the dynamic interplay between the host immune response and viral replication. Spontaneous HBV clearance in acute self-limited infection is...The natural history of hepatitis B virus (HBV) infection is closely dependent on the dynamic interplay between the host immune response and viral replication. Spontaneous HBV clearance in acute self-limited infection is the result of an adequate and efficient antiviral immune response. Instead, it is widely recognized that in chronic HBV infection, immunologic dysfunction contributes to viral persistence. Long-lasting exposure to high viral antigens, upregulation of multiple co-inhibitory receptors, dysfunctional intracellular signaling pathways and metabolic alterations, and intrahepatic regulatory mechanisms have been described as features ultimately leading to a hierarchical loss of effector functions up to full T-cell exhaustion.
In treatment-naïve patients with chronic hepatitis B virus (HBV) infection, entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide have a minimal or no risk of drug-resistance. These 3 nucleos(t)...In treatment-naïve patients with chronic hepatitis B virus (HBV) infection, entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide have a minimal or no risk of drug-resistance. These 3 nucleos(t)ide analog agents are highly potent inducing high rate of virologic response (reducing serum HBV DNA to levels undetectable by polymerase chain reaction assays) in most treatment-naïve patients. Our randomized trials have demonstrated that monotherapy with TDF can provide a successful virological response in most of the heavily pretreated patients with multidrug resistance to ETV or adefovir.