Disease Progression In Chronic Hepatitis Research Articles

Machine-learning methodologies to predict disease progression in chronic hepatitis B in Africa

Background: Little is known about the determinants of disease progression among African patients with chronic HBV infection. Methods: We used machine-learning models with longitudinal data to establish predictive algorithms in a well-characterized cohort of Ethiopian HBV-infected patients without baseline liver fibrosis. Disease progression was defined as an increase in liver stiffness to >7.9 kPa or initiation of treatment based on meeting the eligibility criteria. Results: Twenty-four of 551 patients (4.4%) experienced disease progression after a median follow-up time of 69 months. A random forest model based on a combination of available laboratory tests (standard hematology and biochemistry) demonstrated the best predictive properties with the AUROC ranging from 0.82 to 0.88. Conclusion: We conclude that combined metrics based on simple and available laboratory tests had good predictive properties and should be explored further in larger HBV cohorts.

Interrelationships among MTHFR gene polymorphisms, MTRR gene polymorphisms, and HBV gene BCP 1762/1764 mutations with disease progression in Chronic hepatitis B virus infection patients

Objective Chronic hepatitis B virus (HBV) infection is a major disease that seriously affects the health of patients. In this paper, the relationship among MTHFR gene polymorphism, MTRR gene polymorphism and 1762/1764 mutation in the BCP region of HBV gene with disease progression in chronic HBV patients was studied. Methods A total of 144 chronic HBV infection patients from January 2021 to June 2022 in the Third People’s Hospital of Zigong City, were included as the study subjects. These patients were divided into hepatitis B primary liver cancer patients group (PLC) in 51 cases, Non-primary liver cancer patients group (Non-PLC) in 93 cases, Non-PLC is also divided into chronic hepatitis B virus carriers (CHC) in 49 cases, hepatitis B Live cirrhosis(LC) in 44 cases. MTHFR (C677T), MTRR (A66G) and MTHFR (A1298C) genes polymorphisms were detected by PCR-dissolution curve. The level of HBV-DNA was quantified by real-time PCR, and the 1762/1764 mutation site in the BCP region of the HBV gene were detected by ARMS-PCR. Data were statistically analyzed using the SPSS statistical software. Results The proportion of HBV mutations in BCP region 1762/1764 in PLC group was 82.4%, which was higher than that in LC group (63.6%) and CHC group (51.0%), and the differences were statistically significant (p < 0.05). There were no significant differences in the distribution of MTHFR C677T, MTHFR A1298C and MTRR A66G polymorphisms among CHC, LC and PLC (p > 0.05). The polymorphism distribution of MTHFR C677T, MTRR A66G and MTHFR A1298C genes in patients with chronic hepatitis B virus infection at different stages (CHC, LC and PLC) showed no gender or age differences between and within groups (p > 0.05). Among the patients with MTHFR 677CT + TT, MTRR 66AG + GG and MTHFR 1298AA genotype, the proportion of HBV mutation in BCP region 1762/1764 in PLC group was higher than that in CHC group and LC group, and the differences were statistically significant (p < 0.05). Folate levels in the PLC group were lower than those in the non-PLC group (CHC and LC patients), and the difference was statistically significant compared with the CHC group (p < 0.05). In different MTHFR C677T and MTRR A66G genotypes, the serum GGT activity were statistically significant between mutant PLC and mutant Non-PLC (p < 0.05). Conclusion MTHFR C677T, MTRR A66G and MTHFR A1298C gene polymorphisms distribution have no gender and age differences in chronic hepatitis B virus infection patients. The mutation of HBV gene BCP region 1762/1764 may be associated with the occurrence and development of liver cancer in patients with chronic HBV infection. Single difference of MTHFR C677T, MTHFR A1298C and MTRR A66G gene polymorphisms may have little effect on the disease progression in patients with chronic HBV infection. MTHFR 677CT + TT, MTRR 66AG + GG and MTHFR 1298AA genotype combined with HBV gene BCP region 1762/1764 mutation may be closely related to the occurrence and development of hepatitis B liver cancer.

The Relationship between Viral Replication and the Severity of Hepatic Necroinflammatory Damage Changed before HBeAg Loss in Patients with Chronic Hepatitis B Virus Infection.

Disease progression of chronic hepatitis B virus (HBV) infection is driven by the interactions between viral replication and the host immune response against the infection. This study aimed to clarify the relationship between HBV replication and hepatic inflammation during disease progression. Two cross-sectional, one validation cohort, and meta-analyses were used to explore the relationship between HBV replication and liver inflammation. Spearman analysis, multiple linear regression, and logistic regression were used to explore the relationship between variables. In the cross-sectional cohorts A and B including 1,350 chronic hepatitis B patients, Spearman analysis revealed a negative relationship between HBV replication (such as HBV DNA) and liver inflammation (such as ALT) in HBeAg-positive patients with higher HBV DNA >2×106 IU/mL (rho=-0.160 and -0.042) which turned to be positive in HBeAg-positive patients with HBV DNA ≤2×106 IU/mL (rho=0.278 and 0.260) and HBeAg-negative patients (rho=0.450 and 0.363). After adjustment for sex, age, and anti-HBe, results from logistic regression and multiple linear regression showed the opposite relationship still existed in HBeAg-positive patients with different DNA levels; the opposite relationship in HBeAg-positive patients with different DNA levels was validated in a third cohort; the opposite relationship in patients with different HBeAg status was partially confirmed by meta-analysis (overall R: -0.004 vs 0.481). These results suggested a negative relationship between viral replication and liver inflammation in HBeAg-positive patients with high HBV DNA, which changed to a positive relationship for those HBeAg-positive patients with DNA less than 2×106 IU/mL and HBeAg-negative patients.

Serum hepatitis B virus spliced RNA proportion increases with liver disease progression in patients with chronic hepatitis B.

Serum hepatitis B virus (HBV) spliced RNAs (spRNAs) are ubiquitous in HBV-infected patients; however, their clinical significance remains unknown. Therefore, we aimed to explore the relationship between HBV spRNAs and liver disease progression in chronic hepatitis B (CHB) patients; in vitro cell line assessment was also performed. The serum HBV wild-type RNA (wtRNA) and spRNA levels were individually quantified in a cohort of 279 treatment-naïve, hepatitis B e antigenpositive CHB patients with or without cirrhosis. The spRNA proportion was determined as (spRNA × 100%)/(spRNAs + wtRNA). 20 patients'serum samples underwent spRNA species profiling using next-generation sequencing. Serum spRNA species 1, 2, 3, 4, and 5 were the most common variants. The spRNA proportion varied from 0.00% to 19.02%, with higher levels in HBV genotype C patients than in those with genotype B (1.76% vs. 0.84%, p < 0.001). The spRNA proportion was positively associated with the alanine aminotransferase levels (r = 0.144, p = 0.053) and significantly higher in cirrhotic than in non-cirrhotic patients (1.69% vs. 1.04%, p = 0.001). Multivariate analysis revealed a 2.566-fold higher risk of cirrhosis in patients with elevated spRNA proportion (p = 0.024). In vitro experiments confirmed that spRNAs contributed to hepatic stellate cell activation, which is critical in liver fibrosis development. Therefore, increased HBV spRNA expression poses a risk for liver disease progression. Quantifying serum HBV spRNAs can aid in monitoring liver disease progression. Furthermore, the therapeutic targeting of spRNAs may improve the prognosis of patients with CHB.

Polymorphisms within DIO2 and GADD45A genes increase the risk of liver disease progression in chronic hepatitis b carriers

The study enrolled 284 patients with chronic hepatitis B virus infection. Participants included people with mild fibrotic lesions (32.5%), moderate to severe fibrotic lesions (27.5%), cirrhotic lesions (22%), hepatocellular carcinoma (HCC) in 5%, and people with no fibrotic lesions in 13%. Eleven SNPs within DIO2, PPARG, ATF3, AKT, GADD45A, and TBX21 were genotyped by mass spectrometry. The rs225014 TT (DIO2) and rs10865710 CC (PPARG) genotypes were independently associated with susceptibility to advanced liver fibrosis. However, cirrhosis was more prevalent in individuals with the GADD45A rs532446 TT and ATF3 rs11119982 TT genotypes. In addition, the rs225014 CC variant of DIO2 was more frequently found in patients with a diagnosis of HCC. These findings suggest that the above SNPs may play a role in HBV-induced liver damage in a Caucasian population.

Studying T Cell Responses to Hepatotropic Viruses in the Liver Microenvironment.

T cells play an important role in the clearance of hepatotropic viruses but may also cause liver injury and contribute to disease progression in chronic hepatitis B and C virus infections which affect millions of people worldwide. The liver provides a unique microenvironment of immunological tolerance and hepatic immune regulation can modulate the functional properties of T cell subsets and influence the outcome of a virus infection. Extensive research over the last years has advanced our understanding of hepatic conventional CD4+ and CD8+ T cells and unconventional T cell subsets and their functions in the liver environment during acute and chronic viral infections. The recent development of new small animal models and technological advances should further increase our knowledge of hepatic immunological mechanisms. Here we provide an overview of the existing models to study hepatic T cells and review the current knowledge about the distinct roles of heterogeneous T cell populations during acute and chronic viral hepatitis.

Serum total IgE as immunological marker in patients with chronic hepatitis B Virus infection, and hepatitis B related hepatocellular carcinoma

This study evaluated the efficacy of IgE in predicting disease progression in chronic hepatitis B virus (HBV) and HBV related hepatocellular carcinoma (HCC) compared to normal controls. The study included 60 HBV-infected patients. Of these, 30 patients with chronic hepatitis B but not related to HCC and 30 patients with related HCC. Serum level of IgE was measured by ELISA. Serum level of IgE was higher in HCC patients than non-HCC patients (p < 0.005). Significant correlations were detected between IgE, transaminases (ALT, AST), alpha-fetoprotein and severity scores in chronic hepatitis B (CHB) patients. The level of IgE was correlated with HB viral load. Stronger correlations were evident between IgE, prothrombin time and total bilirubin. In conclusion, IgE levels may be considered as non-invasive markers for monitoring liver disease progression in CHB.

Association Between Serum Cytotoxic T Lymphocyte Antigen (CTLA)-4 Level and Disease Progression in Patients With Chronic Hepatitis B.

Immune impairment, marked by increased expression of cytotoxic T lymphocyte antigen (CTLA)-4, promotes the disease progression of chronic hepatitis B. This study aimed to determine the association between serum CTLA-4 level and disease progression in patients with chronic hepatitis B. A cross-sectional study was conducted at Haji Adam Malik General Hospital Medan, Indonesia between October 2021 to September 2022. A total of 150 participants were enrolled. Patients aged 18 years or older with evidence of chronic hepatitis B, HBV-related liver cirrhosis, and HBV-related hepatocellular carcinoma (HCC) were enrolled. Exclusion criteria were history of chronic hepatotoxic drug consumption, underlying liver abnormalities other than HBV infection, and liver injury due to metastasized malignancy from other sites. Serum CTLA-4 level was determined from serum using human CTLA-4 enzyme linked immunosorbent assay kit. Most participants were males and aged between 40 and 60 years. Serum CTLA-4 level was positively associated with chronic hepatitis B progression (P<0.001). Serum CTLA-4 level was negatively correlated with serum platelet (P<0.001) and albumin levels (P<0.001) but positively correlated with serum ALT (P=0.045) and total bilirubin levels (P<0.001). Serum CTLA-4 level is associated with disease progression in patients with chronic hepatitis B.

Hepatitis C virus replication requires integrity of mitochondria-associated ER membranes

Chronic HCV infection causes cellular stress, fibrosis and predisposes to hepatocarcinogenesis. Mitochondria play key roles in orchestrating stress responses by regulating bioenergetics, inflammation and apoptosis. To better understand the role of mitochondria in the viral life cycle and disease progression of chronic hepatitis C, we studied morphological and functional mitochondrial alterations induced by HCV using productively infected hepatoma cells and patient livers. Biochemical and imaging assays were used to assess localization of cellular and viral proteins and mitochondrial functions in cell cultures and liver biopsies. Cyclophilin D (CypD) knockout was performed using CRISPR/Cas9 technology. Viral replication was quantified by quantitative reverse-transcription PCR and western blotting. Several HCV proteins were found to associate with mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), the points of contact between the ER and mitochondria. Downregulation of CypD, which is known to disrupt MAM integrity, reduced viral replication, suggesting that MAMs play an important role in the viral life cycle. This process was rescued by ectopic CypD expression. Furthermore, HCV proteins were found to associate with voltage dependent anion channel 1 (VDAC1) at MAMs and to reduce VDAC1 protein levels at MAMs invitro and in patient biopsies. This association did not affect MAM-associated functions in glucose homeostasis and Ca2+ signaling. HCV proteins associate specifically with MAMs and MAMs play an important role in viral replication. The association between viral proteins and MAMs did not impact Ca2+ signaling between the ER and mitochondria or glucose homeostasis. Whether additional functions of MAMs and/or VDAC are impacted by HCV and contribute to the associated pathology remains to be assessed. Hepatitis C virus infects the liver, where it causes inflammation, cell damage and increases the long-term risk of liver cancer. We show that several HCV proteins interact with mitochondria in liver cells and alter the composition of mitochondrial subdomains. Importantly, HCV requires the architecture of these mitochondrial subdomains to remain intact for efficient viral replication.

Effect of microbiota metabolites on the progression of chronic hepatitis B virus infection.

Accumulating evidence shows that the intestinal microbiota is closely related to the pathophysiology and the disease progression of chronic hepatitis B virus (HBV) infection. The intestinal microbiota acts on the host through its metabolites. This review aimed to discuss the effects of gut microbiota metabolites on the disease progression of chronic HBV infection. A literature search on PubMed database and Wiley Online Library with pre-specified criteria yielded 96 unique results. After consensus by all authors, the contents from 86 original publications were extracted and included in this review. In liver disease with HBV infection, the intestinal microbiota changed in different stages and affected the production of bacterial metabolites. The abundance of bacteria producing short-chain fatty acids such as butyrate reduced, which was associated with bacterial translocation and the progression of liver disease. The intestinal microbiota-bile acid-host axis was destroyed, affecting the progression of the disease. Under the control of intestinal microbiota, tryptophan affected the gut-liver axis through three main metabolic pathways, among which the kynurenine pathway was closely related to the immune response of hepatitis B. The level of trimethylamine-N-oxide decreased in liver cancer with HBV infection and were used as a potential biomarker of liver cancer. Vitamin deficiencies, including those of vitamin D and vitamin A related to microbiota, were common and associated with survival. Hydrogen sulfide regulated by the intestinal microbiota was also closely related to the gut-liver axis. In liver disease with hepatitis B infection, the intestinal microbiota is imbalanced, and a variety of intestinal microbiota metabolites participate in the occurrence and development of the disease.

High Rates of Liver Cirrhosis and Hepatocellular Carcinoma in Chronic Hepatitis B Patients with Metabolic and Cardiovascular Comorbidities

Background: The prevalence of metabolic and cardiovascular diseases is rising worldwide. However, little is known about the impact of such disorders on hepatic disease progression in chronic hepatitis B (CHB) during the era of potent nucleo(s)tide analogues (NAs). Methods: We retrospectively analyzed a single-center cohort of 602 CHB patients, comparing the frequency of liver cirrhosis at baseline and incidences of liver-related events during follow-up (hepatocellular carcinoma, liver transplantation and liver-related death) between CHB patients with a history of diabetes, obesity, hypertension or coronary heart disease (CHD). Results: Rates of cirrhosis at baseline and liver-related events during follow-up (median follow-up time: 2.51 years; NA-treated: 37%) were substantially higher in CHB patients with diabetes (11/23; 3/23), obesity (6/13; 2/13), CHD (7/11; 2/11) or hypertension (15/43; 4/43) compared to CHB patients without the indicated comorbidities (26/509; 6/509). Multivariate analysis identified diabetes as the most significant predictor for cirrhosis (p = 0.0105), while comorbidities did not correlate with liver-related events in pre-existing cirrhosis. Conclusion: The combination of metabolic diseases and CHB is associated with substantially increased rates of liver cirrhosis and secondary liver-related events compared to CHB alone, indicating that hepatitis B patients with metabolic comorbidities warrant particular attention in disease surveillance and evaluation of treatment indication.

Clinical course and outcomes of chronic viral hepatitis D in patients from Republic of Tuva as endemic region

Hepatitis D (delta, 5) is caused by an RNA virus (hepatitis D virus, HDV) from genus Deltavirus, and is the most severe and difficult to treat disease among both viral hepatitis and infectious diseases in general. The development of HDV infection in the host organism is possible only in the presence of hepatitis B virus (HBV). Coinfection with HBV and HDV is associated with a more rapid progression of chronic viral hepatitis (CVH) to liver cirrhosis (LC) and an unfavorable outcome in comparison with HBV monoinfection. Data on the influence of clinical, biochemical and virological factors on the infectious process in patients with hepatitis D are limited due to the insufficient amount of research on this theme.The study aimed to determine demographic, clinical, biochemical, and virological factors influencing the course and progression of CVH D in patients followed during 10 years, residing in the territory of the Tuva Republic, one of the endemic regions of the Russian Federation. Changes in clinical and laboratory parameters were analyzed in dynamics in 121 HDV infected patients with a different course of the disease, who were under observation from 2009 to 2019. Three groups of patients were identified: group 1 - 61 patients with disease progression of chronic hepatitis to LC (Child-Pugh class B-C), group 2 - 49 patients with non-progressive chronic hepatitis, and group 3 - 11 patients with slowly progressive LC (class A). Demographic data, the presence of detectable HBV DNA, indicators of the functional state of the liver: alanine aminotransferase (ALT/GPT), aspartate aminotransferase (AST/GOT), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), and total bilirubin content were analyzed. The severity of hepatic encephalopathy was assessed by the duration of the numbers connection test (NCT). All patients belonged to the same ethnic group (Tuvinians), were infected with HDV genotype 1 and were positive for HDV RNA throughout the entire follow-up period. There were no significant differences in sex ratio and mean age at the time of inclusion in the study between the groups. In group 1, the average number of years from inclusion in the study to the formation of LC was 3.65 ± 2.3 years, years to the lethal outcome: 4.5 ± 3 years. Significantly higher levels of AST/GOT, ALP, GGT, total bilirubin (TB) and NCT grade were found in group 1 compared to group 2. ALT/GPT levels did not differ significantly in these groups. When comparing groups with disease progression and slowly progressive LC (groups 1 and 3), no significant differences were found in any of the clinical and biochemical parameters. ALT/GPT, GGT, TB and NCT values were significantly higher in patients with slowly progressive LC (group 3) compared to group 2. No differences in AST/GOT and ALP levels were found between these groups. Detectable HBV DNA was significantly more frequent in patients with progressive disease and with chronic viral hepatitis than in patients with slowly progressive LC. There were no significant differences in the frequency of HBV DNA detection in patients from groups 1 and 2. The results obtained on a relatively homogeneous cohort demonstrated that age and gender are not the factors influencing the progression of chronic viral hepatitis D to cirrhosis. The lack of detectable HBV DNA is associated with the slow progression of LC. The revealed differences in clinical and biochemical parameters reflect the degree of functional liver damage in chronic viral hepatitis D and HDV-associated cirrhosis.

Serum hepatitis B core-related antigen level stratifies risk of disease progression in chronic hepatitis B patients with intermediate viral load.

Patients with chronic hepatitis B virus (HBV) infection are at risk of developing liver disease. Serum hepatitis B core-related antigen (HBcrAg) is a new biomarker for intrahepatic templates for HBV replication. To explore whether a high HBcrAg level is associated with increased risk of cirrhosis, especially in patients with intermediate viral load (HBV DNA 2000-19999IU/mL) due to their moderate risk of disease progression. A total of 1673 treatment-naïve, non-cirrhotic patients with negative hepatitis B e antigen (HBeAg) and alanine aminotransferase (ALT) level <40U/L at baseline were enrolled. We explored the relationship between baseline levels of HBcrAg and cirrhosis development in all patients, and whether a higher HBcrAg level (<10 vs ≥10KU/mL) was associated with an increased risk of disease progression in those with intermediate viral load. Of the 1673 patients, 104 developed cirrhosis after a mean follow-up of 15.9years. Higher HBcrAg levels were associated with increased incidence of cirrhosis, cirrhosis-related complications, and liver-related death. In 445 patients with intermediate viral load, the cirrhosis risk stratified by HBcrAg level of 10 KU/mL yielded a hazard ratio of 3.22 (95% CI: 1.61-6.47). The risk stratification remained significant when exploring other pre-cirrhosis endpoints, including HBeAg-negative hepatitis, hepatitis flare, and HBV DNA >20000IU/mL after 3years of follow-up. In HBeAg-negative patients with normal ALT levels, higher HBcrAg levels are associated with increased risk of cirrhosis. Among those with intermediate viral load, HBcrAg <10KU/mL defines a low-risk group for disease progression.

Impact of deranged B cell subsets distribution in the development of HCV-related cirrhosis and HCC in type two diabetes mellitus

Type II diabetes (T2D) may worsen the course of hepatitis C virus infection with a greater risk of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). In chronic viral infections, the deranged B cell subset signifies uncontrolled disease. The study aimed to verify the relation between B cell subsets’ distribution and liver disease progression in chronic hepatitis C (CHC) patients with T2D. A total of 67 CHC patients were divided into two groups; 33 non-diabetic and 34 with T2D. Each group was subdivided into CHC-without LC or HCC (N-CHC), CHC-with LC (CHC-LC), and CHC-with HCC (CHC-HCC). Twenty-seven healthy individuals also participated as controls. Flow cytometry was used to analyze CD19+ B cell subsets based on the expression of CD24 and CD38. CD19+CD24hiCD38hi Immature/transitional B cells elevated in diabetic than non-diabetic patients. In diabetic patients, while CD19+CD24+CD38− primarily memory B cells were higher in CHC-N and CHC-HCC groups than LC with a good predictive accuracy of LC, the opposite was observed for CD19+CD24−CD38− new memory B cells. Only in diabetic patients, the CD19+CD24intCD38int naïve mature B cells were high in CHC-HCC patients with good prognostic accuracy of HCC. Merely in diabetic patients, several correlations were observed between B cell subsets and liver function. Immature/transitional B cells increase remarkably in diabetic CHCpatients and might have a role in liver disease progression. Memory and Naïve B cells are good potential predictors of LC and HCCin diabetic CHCpatients, respectively. Further studies are needed to investigate the role of the CD19+CD24−CD38− new memory B cells in disease progression in CHC patients.

Sustained off therapy response after peglyated interferon favours functional cure and no disease progression in chronic hepatitis B.

Nucleos(t)ide analogue (NA) therapy in chronic hepatitis B (CHB) patients reduces liver-related mortality. However, long-term outcomes after pegylated interferon (PEG-IFN) therapy remain to be elucidated. Therefore, we aimed to investigate the long-term effectiveness and clinical outcomes of PEG-IFN therapy. A total of 190 patients treated with PEG-IFN for CHB or compensated cirrhosis were consecutively enrolled between 2005 and 2014, and 122 patients who completed the treatment were analysed. The initial response was assessed at 6months post-treatment and defined as achieving both <2000IU/mL HBV DNA and HBeAg loss or seroconversion in the HBeAg-positive group, and <2000IU/mL HBV DNA in the HBeAg-negative group. The rates of HBsAg loss, disease progression to cirrhosis or HCC, and sustained off-therapy response, defined as not requiring further NAs because of low viremia and liver enzymes, were analysed. The median follow-up period was 7.2years. Forty-three (35.2%) patients achieved an initial response and 53 patients (43.4%) achieved a sustained response. Initial responders displayed higher rates of sustained response than noninitial responders (69.6% vs 32.5%, P<.001). A higher rate of HBsAg loss was observed in patients who achieved a sustained response than in non-sustained responders (16.2% vs 2.5%, P=.01). Disease progression to cirrhosis or HCC was observed in eight patients (6.6%) who were nonsustained responders. During long-term follow-up after PEG-IFN treatment, nearly half of patients achieved sustained response without the need of further NA and these patients displayed favourable outcomes, including HBsAg loss and no disease progression.

Circulating vascular adhesion protein-1(VAP-1): a possible biomarker for liver fibrosis associated with chronic hepatitis B and C.

Vascular adhesion protein-1 (VAP-1) is a multifunctional protein that plays a role in chronic liver diseases and fibrogenesis. The present study aimed to investigate the possible association of VAP-1 levels with the severity of disease progression in chronic hepatitis (CH) B and C patients with differing stages of fibrosis (F0-4), CHB/CHC-related cirrhosis, and hepatocellular carcinoma (HCC). The VAP-1 concentration in patient sera was determined by ELISA. The VAP-1 levels were compared between the F0 group and the F1, F2, F3, F4, cirrhosis, and HCC groups of CHB patients and between the F1 group and the F2, F3, F4, cirrhosis, and HCC groups of CHC patients. The levels of VAP-1 were significantly increased in CHB patients with progressive stages of fibrosis, with the highest concentration being found in those with stage F4 (severe fibrosis). A statistically significant difference was found between F0 and F4 in patients with CHB, but no statistically significant difference was observed between F1 and F4 in patients with CHC. Interestingly, there was no statistically significant difference in VAP-1 levels between patients with cirrhosis and HCC (either CHB or CHC, independently). Moreover, no relationship was found between VAP-1 and ALT levels in either CHC or CHB patients. In general, the VAP-1 levels were significantly higher in CHB than in CHC patients (P < 0.01). In conclusion, we suggest that the VAP-1 level may be a noninvasive biomarker for monitoring the severity of fibrogenesis in patients with hepatitis B infection.

Nucleos(t)ide analogue continuous therapy associated with reduced adverse outcomes of chronic hepatitis B.

Nucleos(t)ide analogue (NA) therapy reduces the risk of disease progression in chronic hepatitis B virus-infected patients. However, the risk of liver decompensation, hepatic failure, and mortality after discontinuation of NA therapy remains unknown. Among 51,574 chronic hepatitis B patients who received NAs in the Taiwan National Health Insurance Research Database, we identified 8,631 patients who continued NA therapy (treatment cohort) and 8,631 propensity-score matched patients who stopped NA therapy after their initial 1.5 years treatment (off-therapy cohort) between October 1, 2003 and December 31, 2011. All study subjects were followed up from the index date, that is, the date 1.5 years after the first prescription of NA, until development of liver decompensation and hepatic failure, death or end of 18-month follow-up period. Treatment cohort had significantly lower risks of liver decompensation (1.05%; 95% confidence interval [CI], 0.81%-1.30% vs 2.13%; 95% CI, 1.82%-2.45%; p < 0.001), hepatic failure (0.35%; 95% CI, 0.21%-0.49% vs 0.63%; 95% CI, 0.46%-0.80%; p = 0.008) and overall mortality (1.67%; 1.37%-1.98% vs 2.44%; 95% CI, 2.10%-2.77%; p < 0.001) during the 18-month follow-up period. After adjusting for potential confounders, NA continuous therapy was associated with reduced risks of liver decompensation (hazard ratio [HR]: 0.47; 95% CI, 0.36-0.62, p < 0.001), hepatic failure (HR: 0.53; 95% CI, 0.33-0.86, p = 0.01) and overall mortality (HR: 0.67; 95% CI, 0.53-0.84, p = 0.001). The number needed to reduce one less disease progression and mortality was 47. The protective effect of NA continuous therapy was found in nearly all subgroups. NA continuous therapy is associated with reduced risks of liver decompensation, hepatic failure, and overall mortality.

Hepatitis B Virus: From Diagnosis to Treatment.

Hepatitis B infection is still a global concern progressing as acute-chronic hepatitis, severe liver failure, and death. The infection is most widely transmitted from the infected mother to a child, with infected blood and body fluids. Pregnant women, adolescents, and all adults at high risk of chronic infection are recommended to be screened for hepatitis B infection. The initial analysis includes serological tests that allow differentiation of acute and chronic hepatitis. Molecular assays performed provide detection and quantification of viral DNA, genotyping, drug resistance, and precore/core mutation analysis to confirm infection and monitor disease progression in chronic hepatitis B patients. All patients with chronic hepatitis B should be treated with antiviral medications and regularly monitored for efficient treatment. The current treatment is based on nucleos(t)ide analogs and pegylated interferons that save lives by decreasing liver cancer death, liver transplant, slow or reverse the progression of liver disease as well as the virus infectivity.

Tumor necrosis factor-\u03b1-induced protein 8-like 2 mRNA in peripheral blood mononuclear cells is associated with the disease progression of chronic hepatitis B virus infection

BackgroundTumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) is a novel target and molecule in the negative regulation of immune homeostasis. The present study aimed to investigate the dynamic expression of TIPE2 mRNA during the progression of chronic hepatitis B virus (HBV) infection.MethodsA total of 193 patients with chronic HBV infection were retrospectively recruited into this cross-sectional study, including 97 patients with chronic hepatitis B (CHB), 55 with liver cirrhosis and 41 with HBV-related hepatocellular carcinoma (HCC). TIPE2 mRNA was determined using real-time quantitative polymerase chain reaction.ResultsThe expression of TIPE2 levels in patients with HCC was significantly decreased compared with expression in patients with liver cirrhosis, CHB and healthy controls (P < 0.05); meanwhile, the TIPE2 mRNA levels in patients with CHB and liver cirrhosis were significantly increased compared with levels in healthy controls (P < 0.01). In liver cirrhosis, the TIPE2 mRNA level in the decompensated state was significantly higher than that in the compensated state (P < 0.05). In HCC patients, TIPE2 mRNA was significantly associated with venous invasion, tumor size and tumor node metastasis stage. Furthermore, the optimal cutoff of 0.78 for the level of TIPE2 mRNA has a sensitivity of 97.56% and a specificity of 88.16% for discriminating HCC from patients with CHB and liver cirrhosis.ConclusionsTIPE2 mRNA was associated with various stages of chronic HBV infection, ranging from CHB to liver cirrhosis and HCC. Furthermore, TIPE2 mRNA with an optional cutoff value of 0.78 might serve as a promising biomarker to discriminate HBV-associated HCC from CHB and LC patients.

Association of adipokines with hepatic steatosis and fibrosis in chronic hepatitis B patients on long-term nucleoside analogue.

It is unknown how concomitant hepatic steatosis affects disease progression in chronic hepatitis B (CHB). Adipokines such as fibroblast growth factor 21 (FGF21) and adipocyte fatty acid-binding protein (AFABP) have been associated with non-alcoholic fatty liver disease. We determined the significance of these metabolic markers in CHB-related liver injury. We recruited CHB patients on antiviral treatment for transient elastography assessment to determine liver stiffness (advanced fibrosis/cirrhosis, F3/F4, defined by EASL-ALEH criteria) and controlled attenuation parameter (hepatic steatosis, defined as≥248dB/m). Plasma FGF-21, AFABP and adiponectin levels were measured. A total of 415 patients [mean age 59.6years, 71.6% male, median treatment duration 6.2years] were recruited. Patients with F3/F4 (N=151) had lower FGF-21 (11.7 vs 13.6pg/mL, P=0.055), higher AFABP (126.8 vs 84.1pg/mL, P<0.001) and HOMA-IR (7.1 vs 5.1, P=0.004) levels compared to those without F3/F4 (N=264). Multivariate analysis showed that FGF-21 level was associated with hepatic steatosis (OR 1.005, 95% CI 1.001-1.009) and F3/F4 (OR 0.993, 95% CI 0.989-0.998), while AFABP level (OR 1.001, 95% CI 1-1.002), body mass index (BMI) (OR 1.107, 95% CI 1.037-1.182) and presence of diabetes mellitus (OR 2.059, 95% CI 1.206-3.516) were associated with F3/F4. With the combined presence of BMI≥25kg/m2 , diabetes and AFABP>105.9pg/mL, the odds ratio for F3/F4 was 3.712 (95% CI 1.364-10.105, P=0.010). Low FGF-21 and high AFABP levels were associated with advanced fibrosis/cirrhosis in CHB patients on antiviral treatment. Plasma AFABP, together with other metabolic risk factors, may aid identification of patients lacking fibrosis improvement during antiviral treatment.