Intrahepatic and extrahepatic clinical manifestations and treatment progress for hepatitis type E / 中华肝脏病杂志

Hepatitis type E virus (HEV) is one of the main causes of acute hepatitis globally and has thus gained attention as a public health issue. The diverse clinical manifestations of hepatitis type E are typically acute and self-limiting with mild symptoms, but populations with underlying liver disease or immunocompromised patients can have severe and chronic symptoms. Severity and chronicity can arise and manifest as fulminant hepatitis, chronic hepatitis, or even hepatic failure. HEV infection-induced hepatic failure (acute-on-chronic liver failure), based on the different backgrounds of chronic liver disease, is a clinical phenotype of severe HEV infection that requires attention. In addition, HEV infection can exhibit extrahepatic clinical manifestations of multi-system and organ involvement like neurological diseases (Guillain-Barré syndrome), renal diseases (membranous/membranous proliferative glomerulonephritis, cryoglobulinemia), and blood diseases (thrombocytopenia). At home or abroad, there are no antiviral drugs approved, particularly for HE treatment. Since most acute HE can resolve spontaneously, no special treatment is required clinically. However, in patients with severe or chronic HE, ribavirin (RBV) monotherapy and/or pegylated interferon-combination therapy have achieved certain antiviral effects. Combined small-molecule drugs and RBV have been attempted to treat HEV, but high-level evidence-based treatment is still lacking. Thus, new, highly effective anti-HEV drugs are clinical priorities to address these concerns. Severe and chronic HEV infections' clinical phenotype, early detection, mechanism, intervention, and outcome need additional study.

Strengthening the study of chronic hepatitis E / 中华肝脏病杂志

This paper summarizes the incidence, modes of transmission, diagnosis, treatment and prevention of chronic hepatitis E.

Falla hepática aguda sobre crónica por exacerbación de hepatitis B asociada a suspensión de la terapia antiviral: reporte de caso / Acute-on-chronic liver failure caused by hepatitis B flare associated with stopping antiviral therapy: case report

El principal objetivo del tratamiento de la infección por virus de la hepatitis B es prevenir la replicación viral, con el fin de evitar las posibles complicaciones asociadas a la infección, como son las exacerbaciones o flares, las cuales pueden llegar a ser tan severas que causan una falla hepática aguda sobre crónica (ACLF). La ACLF se asocia con falla multiorgánica y una alta mortalidad, y puede ser desencadenada por la reactivación de hepatitis virales, infecciones bacterianas y consumo de alcohol, entre otros factores. Aunque la fisiopatología de la ACLF no es clara aún, parece haber una respuesta inflamatoria excesiva asociada con esta condición. El uso de análogos de nucleótidos/nucleósidos en el tratamiento de la hepatitis B crónica reduce el riesgo de morbilidad y mortalidad asociadas a la progresión de la enfermedad hepática, pero la terapia a largo plazo tiene sus limitaciones por el alto costo y por el riesgo asociado al uso indefinido. Debido a esto, en los últimos años se ha venido considerando la interrupción de la terapia en algunos pacientes por parte de las diferentes asociaciones; no obstante, aún no hay consenso en cuanto al mejor momento para hacerlo. Se describe el caso clínico de un paciente con cirrosis compensada por hepatitis B, con HBsAg positivo y HBeAg inicialmente negativo, a quien se le suspendió el tratamiento con entecavir por decisión médica, presentando una ACLF por exacerbación de la hepatitis B, con posterior deterioro y muerte del paciente. Se debe realizar una caracterización adecuada de cada paciente antes de suspender el tratamiento.

The main objective of treating hepatitis B virus infection is to prevent viral replication in order to avoid possible complications, including flares which can become so severe that can cause an acute over chronic liver failure (ACLF). ACLF is associated with multiple organ failure and high mortality, and can be triggered by reactivation of viral hepatitis, bacterial infections and alcohol consumption, among other factors. Although the pathophysiology of ACLF is not yet clear, there appears to be an excessive inflammatory response associated with this condition. The use of nucleotide/nucleoside analogs in chronic hepatitis B reduces the risk of morbidity and mortality related to the progression of the disease, but long-term treatment has its limitations due to the high cost and the risk of indefinite therapy. Due to this, in recent years the stopping of therapy in some patients has been considered by the different associations; however, there is currently no consensus as to the best time to do it. We present a clinical report of a patient with compensated hepatitis B cirrhosis, with positive HBsAg and initially negative HBeAg, who stopped treatment with entecavir by medical instruction, developing ACLF due to exacerbation of hepatitis B, with subsequent deterioration of the patient condition and ultimately death. An adequate characterization of each patient must be carried out before stopping treatment.

Refractory Hepatic Hydrothorax in Chronic Hepatitis C Controlled by Direct-acting Antivirals / 대한소화기학회지

Hepatic hydrothorax is a transudative pleural effusion that complicates advanced liver cirrhosis. Patients refractory to medical treatment plus salt restriction and diuretics are considered to have refractory hepatic hydrothorax and may require transjugular intrahepatic portosystemic shunt (TIPS) or liver transplant. Successful antiviral therapy reduces the incidence of some complications of cirrhosis secondary to HCV infection. We report a case of hepatic hydrothorax in a 55-year-old female patient with HCV cirrhosis, which exhibited a spontaneous decrease in pleural effusion after direct antiviral agent (DAA) therapy. In cases of HCV cirrhosis, DAAs are worth administering before treatment by TIPS or liver transplantation.

Liver Involvement in Children with Alpha-1 Antitrypsin Deficiency: A Multicenter Study / 대한소아소화기영양학회지

PURPOSE: Alpha-1 antitrypsin deficiency (A1ATD) in one of the most common genetic causes of liver disease in children. We aimed to analyze the clinical characteristics and outcomes of patients with A1ATD.METHODS: This study included patients with A1ATD from five pediatric hepatology units. Demographics, clinical findings, genetics, and outcome of the patients were recorded (n=25).RESULTS: Eight patients (32.0%) had homozygous PiZZ genotype while 17 (68.0%) had heterozygous genotype. Patients with PiZZ genotype had lower alpha-1 antitrypsin levels than patients with PiMZ genotype (37.6±7.7 mg/dL vs. 66.5±22.7 mg/dL, p=0.0001). Patients with PiZZ genotype were diagnosed earlier than patients with PiMZ genotype, but this was not significant (13±6.8 months vs. 23.7±30.1 months, p=0.192). Follow-up revealed the death of one patient (12.5%) with a homozygous mutation, and revealed that one patient had child A cirrhosis, five patients (62.5%) had chronic hepatitis, and one patient (12.5%) was asymptomatic. Nine of the 17 patients with a heterozygous mutation had chronic hepatitis (52.9%), two (11.7%) had child A cirrhosis, and six (35.2%) were asymptomatic. Overall, 18 (72%) of the 25 children had liver pathology in the long-term.CONCLUSION: Although prevalence is rare, patients with liver disorders should be checked for alpha-1 antitrypsin levels. Moreover, long-term follow-up is essential because most patients have a liver pathology.

New Biomarkers of Chronic Hepatitis B

Chronic hepatitis B (CHB) infection leads to clinically heterogeneous disease outcomes. Different viral markers are utilized to monitor treatment effects and predict risk of complications in patients with CHB. Hepatitis B core-related antigen (HBcrAg) is a novel serum composite viral protein whose performance has been proven to be superior to that of existing viral markers. It showed good correlation with intrahepatic covalently closed-circular DNA. Its profile differs drastically in patients in different disease phases, and the level declines with antiviral therapies. HBcrAg may be helpful for predicting hepatocellular carcinoma development and hepatitis B virus (HBV) reactivation in immunosuppressed patients. Another emerging measurable serum marker, HBV RNA, exists in the form of pregenomic RNA-containing virions. Its profile differs between patients in different disease phases in a similar manner to that of HBcrAg. HBV RNA is present in serum at lower levels than HBV DNA in treatment-naive patients by 1–2 logs. In contrast, its level is higher than HBV DNA in patients receiving nucleos(t)ide analogues (NAs). A significant decline in serum RNA was observed in patients receiving novel antiviral therapies, including core protein allosteric modulators and RIG-1/NOD2 agonists. Both HBcrAg and HBV RNA may be helpful for predicting off-therapy sustained virological control in patients who stop long-term NA treatment.

Comparison of the Clinical Characteristics and Outcomes between Leprosy-Affected Persons in Sorokdo and the General Population Affected by Chronic Hepatitis C in Korea

BACKGROUND/AIMS: Patients with Hansen’s disease are the most vulnerable to hepatitis C. However, no data on the treatment efficacy of direct-acting antiviral agents (DAAs) are available in this group. Therefore, we elucidated the prevalence and clinical outcomes of hepatitis C in persons affected by leprosy in Sorokdo, Jeollanam-do, Korea. METHODS: We retrospectively included 50 leprosy patients with positive hepatitis C virus (HCV) RNA test results (group A) hospitalized at the Sorokdo National Hospital from May 2016 to March 2018 and 73 patients with chronic hepatitis C who were treated with DAAs at the Chonnam National University Hospital (group B) from May 2016 to December 2017. RESULTS: Overall, at the Sorokdo National Hospital, positive HCV antibody and HCV RNA rates were 18.4% and 11.0%, respectively. The mean participant age was 76.5±7 years, and 58% of participants were men. The genotypes were type 1b in 44% (22 out of 50) and type 2 in 56% (28 out of 50). Sustained virologic response was achieved at a rate of 95.5% (21/22) in genotype 1b and 92.9% (26/28) in genotype 2 patients. Ribavirin-induced hemolytic anemia occurred in 57.1% (16/28) of patients with genotype 2. Among these, 28.5% (8/28) received blood transfusions. CONCLUSIONS: Treatment efficacy was not different between the leprosy-affected population and the general population. However, severe ribavirin-induced hemolytic anemia requiring transfusion was present in 28.5% of genotype 2 patients. Therefore, we suggest ribavirin-free DAAs for the treatment of genotype 2 hepatitis C in leprosy-affected persons in the future.

Development and surveillance of hepatocellular carcinoma in patients with sustained virologic response after antiviral therapy for chronic hepatitis C

Hepatitis C virus (HCV) infection is a major risk factor for liver cirrhosis and hepatocellular carcinoma (HCC), and is a leading cause of liver-related deaths worldwide. Recently available direct-acting antiviral agent is very safe and highly effective (>95% sustained virologic response, SVR) against all genotypes of HCV. Achievement of SVR has been associated with a significant reduction of hepatic decompensation, development of HCC, and liver-related mortality. However, HCC risk is not eliminated even after SVR. The annual incidences of HCC in advanced fibrosis or cirrhosis have been estimated to be up to 2.5–4.5% even in patients with SVR. Therefore, surveillance for HCC is recommended in this high-risk patients. In this review, we will describe the clinical outcomes and the risk of HCC in patients with SVR and suggest who should receive surveillance for HCC.

How does hepatic steatosis affect the outcome of patients with chronic hepatitis B?

No abstract available.

Influence of hepatic steatosis on the outcomes of patients with chronic hepatitis B treated with entecavir and tenofovir

BACKGROUND/AIMS: The influence of hepatic steatosis (HS) on chronic hepatitis B (CHB) is unclear. We evaluated the influence of the degree of HS, assessed using the controlled attenuation parameter (CAP) of transient elastography (TE), on treatment outcomes in CHB patients initiated on antiviral therapy. METHODS: A total of 334 patients who were initiated on entecavir or tenofovir between 2007 and 2016 with available TE results were recruited. RESULTS: Of the total study population, 146 (43.7%) patients had HS (CAP > 238 dB/m). Three-hundred-three patients (90.7%) achieved complete virological response (CVR) (hepatitis B virus DNA<12 IU/L), and 25 patients (7.5%) developed hepatocellular carcinoma (HCC). Among hepatitis B e antigen (HBeAg)-positive patients (n=172, 51.5%), 37 (21.5%) experienced HBeAg loss. On univariate analysis, CAP value was not associated with the probability of HCC development (P=0.380). However, lower CAP value was independently associated with higher probability of HBeAg loss among HBeAg-positive patients (hazard ratio [HR]=0.991, P=0.026) and with CVR achievement in the entire study population (HR=0.996, P=0.004). The cumulative incidence of HBeAg loss among HBeAg-positive patients was significantly higher in patients without HS than in those with HS (log-rank, P=0.022). CONCLUSIONS: CAP values were not correlated with HCC development in patients initiated on entecavir and tenofovir. However, CAP values were negatively correlated with the probability of HBeAg loss among HBeAg-positive patients and with CVR achievement.

Unmet need in chronic hepatitis B management

Despite all these exciting developments, there remain some unmet needs in the management for patients with chronic hepatitis B (CHB). As majority of CHB patients are going to use oral nucleos(t)ide analogues (NAs) for decades, Safety profile of NAs is of no doubt an important issue. The newest nucleotide analogue tenofovir alafenamide is potent in terms of viral suppression, together with favourable renal and bone safety profile. Biochemical response as reflected by alanine aminotransferase (ALT) normalization is recently found to be prognostically important. Patients who achieved ALT normalization have reduced the risk of hepatic events by 49%. Functional cure as reflected by hepatitis B surface antigen seroclearance not only implies patients may stop NA treatment, it also confers to a reduced risk of hepatocellular carcinoma and other hepatic events. Hence functional cure should be the ultimate treatment goal in CHB patients. Preemptive antiviral treatment may reduce mother-to-child transmission of hepatitis B virus, especially if birth dose of vaccination cannot be given in the first two hours after delivery. Lastly, despite the currently first-line NAs have high-genetic barrier to drug resistance mutations, there are still are many patients who were previously treated with low barrier of resistance including lamivudine, telbivudine or adefovir dipivoxil which could lead to antiviral resistance and affecting the choice of NAs.

Association between hepatic steatosis and the development of hepatocellular carcinoma in patients with chronic hepatitis B

BACKGROUND/AIMS: Nonalcoholic fatty liver disease (NAFLD) is becoming a worldwide epidemic, and is frequently found in patients with chronic hepatitis B (CHB). We investigated the impact of histologically proven hepatic steatosis on the risk for hepatocellular carcinoma (HCC) in CHB patients without excessive alcohol intake. METHODS: Consecutive CHB patients who underwent liver biopsy from January 2007 to December 2015 were included. The association between hepatic steatosis (≥ 5%) and subsequent HCC risk was analyzed. Inverse probability weighting (IPW) using the propensity score was applied to adjust for differences in patient characteristics, including metabolic factors. RESULTS: Fatty liver was histologically proven in 70 patients (21.8%) among a total of 321 patients. During the median (interquartile range) follow-up of 5.3 (2.9–8.3) years, 17 of 321 patients (5.3%) developed HCC: 8 of 70 patients (11.4%) with fatty liver and 9 of 251 patients (3.6%) without fatty liver. The five-year cumulative incidences of HCC among patients without and with fatty liver were 1.9% and 8.2%, respectively (P=0.004). Coexisting fatty liver was associated with a higher risk for HCC (adjusted hazards ratio [HR], 3.005; 95% confidence interval [CI], 1.122–8.051; P=0.03). After balancing with IPW, HCC incidences were not significantly different between the groups (P=0.19), and the association between fatty liver and HCC was not significant (adjusted HR, 1.709; 95% CI, 0.404–7.228; P=0.47). CONCLUSIONS: Superimposed NAFLD was associated with a higher HCC risk in CHB patients. However, the association between steatosis per se and HCC risk was not evident after adjustment for metabolic factors.

Efficacy of L-carnitine on ribavirin-induced hemolytic anemia in patients with hepatitis C virus infection

BACKGROUND/AIMS: L-carnitine not only alleviates hyperammonemia and reduces muscle cramps in patients with liver cirrhosis, but also improves anemia in patients with chronic hepatitis and renal dysfunction. This study prospectively evaluated the preventative efficacy of L-carnitine supplementation against hemolytic anemia during antiviral treatment using ribavirin in patients with hepatitis C virus (HCV)-related chronic liver disease. METHODS: A total of 41 patients with chronic hepatitis were consecutively enrolled in this study. Group A (n=22) received sofosbuvir plus ribavirin for 3 months, whereas group B (n=19) was treated with sofosbuvir, ribavirin, and L-carnitine. Hemoglobin concentration changes, the effects of antiviral treatment, and the health status of patients were analyzed using short form-8 questionnaires. RESULTS: A significantly smaller decrease in hemoglobin concentration was observed in group B compared to group A at every time point. Moreover, the prescribed dose intensity of ribavirin in group B was higher than that of group A, resulting in a higher ratio of sustained virological response (SVR) 24 in group B compared with group A. The physical function of patients in group B was also significantly improved compared to group A at the end of antiviral treatment. CONCLUSIONS: L-carnitine supplementation alleviates ribavirin-induced hemolytic anemia in patients with HCV and helps relieve the physical burden of treatment with ribavirin-containing regimens. These advantages significantly increase the likelihood of achieving SVR.

Result Patterns and Characteristics of HBeAg and HBV DNA in Patients with Chronic Hepatitis B

BACKGROUND: Discrepancies in the results between hepatitis B e-antigen (HBeAg) and hepatitis B virus (HBV) DNA levels pose difficulties in the management of chronic hepatitis B (CHB). This study aims to better understand the different phases of CHB and to detect additional meaningful parameters for CHB patients. METHODS: We collected datasets of HBeAg and HBV DNA levels measured during 2016 and the follow-up results for CHB patients for past 3 years. We analyzed the collected data by applying the definitions of CHB clinical phase and compared the results of semi-quantitative and quantitative HBeAg assays. RESULTS: About 55% of 2,291 result pairs from CHB patients showed qualitative agreement between HBeAg and HBV DNA results. HBeAg (−) CHB was reported in 16.49%, while hepatitis B surface antigen (HBsAg) loss occurred in 0.18% among 1,146 patients annually. HBeAg reversion occurred in 2.74% of 839 patients that experienced HBeAg seroconversion. Patients with HBeAg (+) and HBV DNA (−) showed statistically significant differences in the levels and percentage abnormality of alanine aminotransferase (ALT) based on whether HBV DNA was ‘Target not detected’ or ‘Detected,

Evaluation of Noninvasive Liver Fibrosis Blood Markers in Patients with Chronic Hepatitis B and Hepatitis C

BACKGROUND: Liver fibrosis evaluation is an important issue in chronic liver disease patients. We aimed to develop noninvasive liver fibrosis biomarkers based on transient elastography (TE, FibroScan®) through retrospective review of clinicopathological data. METHODS: We recruited 278 chronic hepatitis B patients who underwent Fibroscan and HBV DNA testing. A total of 115 HBeAg-positive and 159 HBeAg-negative chronic hepatitis B patients were analyzed. A total of 100 hepatitis C patients were analyzed. Successful fibroscan data, gamma-glutamyl transferase (GGT) to platelet ratio (GPR), platelet count, AST, ALT, international normalized ratio of prothrombin time, total cholesterol, triglycerides, bilirubin, mean platelet volume, AST to platelet ratio index, fibrosis index based on four factors (FIB-4), neutrophil to lymphocyte ratio (NLR), and NLR to platelet ratio were analyzed to determine the new noninvasive markers for assessing liver fibrosis. RESULTS: Elevated GPR (OR=9.1, P=0.011) and FIB-4 (OR=2.3, P=0.01) were associated with greater risk of liver fibrosis in chronic hepatitis B patients. FIB-4 (OR=6.04, P=0.005) was a risk factor for liver fibrosis in HBeAg-positive patients. FIB-4 (OR=2.371, P=0.015) and GPR (OR=33.78, P=0.003) were liver fibrosis risk factor in HBeAg-negative patients. In chronic hepatitis C patients, GGT (OR=1.033, P=0.002), triglyceride (OR=−0.990, P=0.038) and FIB-4 (OR=3.499, P=0.006) showed statistical significances. The AUCs were 0.816 in FIB-4 (P<0.001) and 0.849 in GPR (P<0.001). CONCLUSIONS: FIB-4 and GPR may be useful blood markers for assessing liver fibrosis in chronic hepatitis B and hepatitis C patients. Further well-designed prospective study is required to validate these noninvasive blood markers in clinical practice.

Updated Treatment of Chronic Hepatitis B / 대한내과학회지

Chronic hepatitis B virus (HBV) infection is a major cause of liver cirrhosis and hepatocellular carcinoma in Korea. The prevalence of HBV infection is gradually decreasing in Korea, but 3.0% of the total population still suffers from HBV- related chronic liver diseases. In this review, we summarize the updated clinical practice guideline for management of chronic hepatitis B, as revised by the Korean Association for the Study of the Liver in 2018.

2018 Korean Association for the Study of the Liver (KASL) Clinical Practice Guidelines of Chronic Hepatitis B: What's Different? / 대한소화기학회지

The clinical practice guideline for the management of chronic hepatitis B (CHB) was originally enacted in 2004 by the Korean Association for the Study of the Liver in order to provide medical practitioners with specific medical information regarding CHB to help them facilitate their understanding of the disease and treatment of the infected patients. Other than an update on the treatment of antiviral resistance in 2014, which is a partial revision, the guidelines for the treatment of chronic hepatitis B have been revised entirely three times in 2007, 2011, and 2015. Although several major international liver association have established and revised clinical practice guidelines, since the medical environment in each country is somewhat different depending on race, region, institution, and economic conditions, it is necessary to revise the Korean guidelines to that reflect our medical environment and own research results. In this review, major change and its background will be summarized about 2018 updated clinical practice guidelines for the management of CHB.

Effect of Statin Use on Liver Cancer Mortality Considering Hypercholesterolemia and Obesity in Patients with Non-Cirrhotic Chronic Hepatitis B

Little is known about the benefits of statin use on liver cancer mortality among patients with chronic hepatitis B (CHB) considering hypercholesterolemia and obesity. A nationwide retrospective cohort study was conducted using data from a Health Examination Cohort of the National Health Insurance Service of Korea. Data on CHB patients with no other concurrent liver disease were acquired, and statin use was defined as a cumulative daily dose ≥28. A 3-year landmark analysis was performed to avoid immortal time bias. Patients who started statin therapy within the landmark date were considered statin users. A Cox regression analysis was applied to assess associations between statin use and liver cancer mortality considering hypercholesterolemia and obesity. Among 13063 patients, 193 (1.5%) died of liver cancer during the mean follow-up period of 10.6 years. After adjusting for demographic and metabolic factors, statin use [hazard ratio (HR), 0.17; 95% confidence interval (CI), 0.04–0.70] and hypercholesterolemia (HR, 0.46; 95% CI, 0.24–0.88 for total cholesterol ≥240 mg/dL) were associated with a decreased risk of liver cancer mortality, whereas body mass index (BMI) ≥30 kg/m² was associated with an increased risk of liver cancer mortality (HR, 2.46; 95% CI, 1.20–5.06). This study showed that statin use was associated with decreased liver cancer mortality when adjusting for cholesterol levels and BMI. This study found that hypercholesterolemia was independently associated with decreased liver cancer mortality regardless of statin use.

Patchy echogenicity of the liver in patients with chronic hepatitis B does not indicate poorer elasticity

PURPOSE: This study was conducted to investigate whether the presence of patchy echogenicity in the liver of patients with chronic hepatitis B (CHB) is predictive of liver stiffness. METHODS: A total of 200 CHB patients with and without patchy echogenicity of the liver were assigned to two groups, with 100 patients in each group, and 32 of them underwent liver biopsy. Additionally, 80 healthy subjects, 100 inactive HBV carriers, and 100 patients with decompensated hepatic cirrhosis were assigned to the control groups. Laboratory tests and clinical data were collected, and shear wave velocity (SWV) of the liver was measured for all 480 subjects. RESULTS: The median SWV in patients with a normal liver, inactive hepatitis B virus carriers, CHB patients with and without patchy echogenicity, and decompensated hepatic cirrhosis were 1.07 m/sec, 1.08 m/sec, 1.16 m/sec, 1.16 m/sec, and 2.02 m/sec, respectively; there was no significant difference in SWV values between CHB patients with patchy echogenicity and those without patchy echogenicity. Furthermore, among CHB patients with and without patchy echogenicity, no significant difference in SWV was found according to fibrosis stage. CONCLUSION: The presence of patchy echogenicity of the liver does not indicate a higher degree of liver stiffness.