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Metabolic dysfunction-associated fatty liver disease (MAFLD) and viral hepatitis due to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are common liver diseases worldwide. Excessive alcohol consumption and alcoholic liver disease (ALD) are also emerging health problems. Therefore, in clinical practice, we may encounter subjects with dual etiology of liver diseases such as coexisting MAFLD/HBV, MAFLD/HCV, and MAFLD/ALD. In this review, we summarize the epidemiology, clinical features, and mutual interactions of MAFLD with coexisting HBV, HCV, or ALD. The impact of MAFLD on the progression of liver diseases and treatment outcomes in patients with chronic viral hepatitis and the clinical questions to be addressed regarding dual MAFLD and ALD are also discussed., (© 2024. Asian Pacific Association for the Study of the Liver.)

Background: With the implementation of the 11th edition of the International Classification of Diseases (ICD-11) and the publication of the metabolic dysfunction-associated fatty liver disease (MAFLD) nomenclature in 2020, it is important to establish consensus for the coding of MAFLD in ICD-11. This will inform subsequent revisions of ICD-11., Methods: Using the Qualtrics XM and WJX platforms, questionnaires were sent online to MAFLD-ICD-11 coding collaborators, authors of papers, and relevant association members., Results: A total of 890 international experts in various fields from 61 countries responded to the survey. We also achieved full coverage of provincial-level administrative regions in China. 77.1% of respondents agreed that MAFLD should be represented in ICD-11 by updating NAFLD, with no significant regional differences (77.3% in Asia and 76.6% in non-Asia, p = 0.819). Over 80% of respondents agreed or somewhat agreed with the need to assign specific codes for progressive stages of MAFLD (i.e. steatohepatitis) (92.2%), MAFLD combined with comorbidities (84.1%), or MAFLD subtypes (i.e., lean, overweight/obese, and diabetic) (86.1%)., Conclusions: This global survey by a collaborative panel of clinical, coding, health management and policy experts, indicates agreement that MAFLD should be coded in ICD-11. The data serves as a foundation for corresponding adjustments in the ICD-11 revision., (© 2024. Asian Pacific Association for the Study of the Liver.)

Background: Magnetic resonance (MR) elastography and proton density fat fraction (PDFF) are emerging techniques for non-invasive assessment of liver stiffness and steatosis, respectively. We investigated the role of MR metrics in pre-treatment prognostication of hepatocellular carcinoma (HCC)., Methods: Patients with newly diagnosed HCC were prospectively recruited. Pre-treatment MR elastography and PDFF were performed on tumor and non-tumor regions. HCC treatment was categorized as potentially curative (resection/ablation) or non-curative (locoregional/systemic therapy). HCC recurrence, liver-related complications (ascites/ variceal bleeding/ hepatic encephalopathy) and mortality were monitored., Results: Of the 158 recruited patients (mean age 62.9 years, 84.2% male, 82.9% viral hepatitis), 58.2% (n = 92) and 41.8% (n = 66) received potentially curative and non-curative therapy, respectively. Pre-treatment non-tumor liver stiffness independently predicted liver-related complications, regardless of treatment type (HR 1.384, 95% CI 1.067-1.796, p = 0.014). In the potentially curative therapy group, non-tumor stiffness and non-tumor PDFF were independently associated with HCC recurrence (HR 1.308, 95% CI 1.022-1.673 & HR 1.080, 95% CI 1.009-1.156 respectively, both p < 0.05); and non-tumor PDFF predicted mortality (HR 1.160, 95% CI 1.038-1.296, p = 0.009). In the non-curative group, tumor stiffness independently predicted liver-related complications (HR 1.299, 95% CI 1.023-1.651, p = 0.032), and a combination of tumor stiffness ≥ 5.7 kPa plus non-tumor stiffness ≥ 3.7 kPa was associated with a two-fold risk of liver-related complications (86.7% vs 40.0%, p < 0.001)., Conclusion: Pre-treatment MR elastography and PDFF over tumor and non-tumor regions demonstrated prognosticating roles in HCC. Simultaneous measurements of both metrics during conventional MR liver should be considered in the diagnostic workup of HCC., (© 2022. Asian Pacific Association for the Study of the Liver.)

Background: Concomitant chronic hepatitis B infection (CHB) and non-alcoholic fatty liver disease (NAFLD) is common, but the implications of NAFLD on clinical outcomes of CHB, including hepatocellular carcinoma (HCC), are not well-investigated., Methods: CHB patients were recruited for transient elastography assessment for liver stiffness (LS), and controlled attenuation parameter (CAP), a non-invasive quantification of hepatic steatosis, and were prospectively followed up for development of HCC. Steatosis and severe steatosis were diagnosed by CAP ≥ 248 dB/m and ≥ 280 dB/m respectively, and advanced fibrosis/cirrhosis was diagnosed by LS ≥ 9 kPa. The independent effect of hepatic steatosis on HCC was examined via propensity score matching (PSM) of LS and other significant clinical variables., Results: Forty-eight patients developed HCC among 2403 CHB patients (55.6% male, median age 55.6 years, 57.1% antiviral-treated, median ALT 26 U/L) during a median follow-up of 46.4 months. Multivariate Cox regression analysis showed age (HR 1.063), male (HR 2.032), Albumin-Bilirubin score (HR 2.393) and CAP (HR 0.993) were associated with HCC development. The cumulative probability of HCC was 2.88%, 1.56% and 0.71%, respectively for patients with no steatosis, mild-to-moderate steatosis, and severe steatosis, respectively (p = 0.01). The risk of HCC increased from 1.56 to 8.89% in patients without severe steatosis if advanced fibrosis/cirrhosis was present (p < 0.001). PSM yielded 957 pairs of CHB patients and hepatic steatosis was independently associated with HCC (HR 0.41)., Conclusion: Reduced hepatic steatosis was significantly associated with a higher risk of incident HCC in CHB infection. Routine CAP and LS measurements are important for risk stratification., (© 2021. Asian Pacific Association for the Study of the Liver.)

Introduction: We aimed to describe long-term clinical outcomes in chronic hepatitis B (CHB) patients after HBsAg seroclearance, and identify factors that modify disease outcomes., Methods: CHB patients with HBsAg seroclearance occurring between 1986 and 2017 were recruited. Primary outcome was cirrhosis/hepatocellular carcinoma (HCC), and secondary outcomes were hepatic decompensation, liver-related death/transplantation, and all-cause mortality. Multivariable Cox model included demographics, prior antivirals, comorbidities, drugs (statins, metformin, proton-pump inhibitors, non-selective beta-blockers), and laboratory parameters (platelet, liver function test, prothrombin time, alpha-fetoprotein [AFP], anti-HBs). Statin users were propensity score matched (PSM) with non-users (1:2 ratio) for survival analysis of all outcomes., Results: Of 913 patients with HBsAg seroclearance (male: 613 [67.1%]; median age: 53.4 years [18.5-87.0]), 129 (14.1%) were statin users. During median follow-up of 7.7 years (up to 29.1 years), 64/833 (7.7%) developed cirrhosis, 25/905 (2.8%) developed HCC, 3/913 (0.3%) underwent transplantation, and 76/913 (8.3%) died. Statins were associated with lower cirrhosis/HCC risk (adjusted hazard ratio [aHR]: 0.44; 95% CI 0.20-0.96; aHR for every 1-year increase in use: 0.85; 95% CI 0.75-0.97). Statin users had no hepatic decompensation or liver-related death/transplantation (vs 18/778 [2.3%] and 18/784 [2.3%] cases in statin non-users, respectively). Statins were also associated with lower all-cause mortality risk (aHR: 0.21; 95% CI 0.08-0.53). PSM yields consistent results for beneficial effects of statins (log-rank p < 0.05 for all outcomes). Other factors for cirrhosis/HCC included increasing age (aHR: 1.06), diabetes (aHR: 2.03), higher creatinine (aHR: 1.008), GGT > 50U/L (aHR: 3.25), and AFP > 9 ng/mL (aHR: 10.14)., Conclusion: Patients with HBsAg seroclearance have favorable long-term survival. However, liver-related adverse outcomes still develop, necessitating further investigations on beneficial effects of statins., (© 2021. Asian Pacific Association for the Study of the Liver.)

In patients with chronic hepatitis B (CHB) infection, it is important to monitor the natural history, assess treatment response, and predict the risk of liver-related complications. Quantification of serum hepatitis B surface antigen (HBsAg) has gained wide interests since the last decade. It is secreted from hepatocytes in both hepatitis B e antigen (HBeAg)-positive and HBeAg-negative phases of the disease, and can be transcribed and translated from different sources of viral genome [ccc DNA or integrated hepatitis B virus (HBV) DNA]. In untreated patients, it declines slowly through the natural course and remains stable for a long time after HBeAg seroconversion. In patients treated with nucleos(t)ide analogues (NA), it also declines very slowly, even though serum hepatitis B DNA has been rendered negative. Low serum HBsAg may predict either spontaneous or treatment-induced HBsAg seroclearance, and potentially selects out HBeAg-negative patients who can safely stop NA. High serum HBsAg is associated with high risk of hepatocellular carcinoma in untreated population, and predicts treatment failure in patients receiving pegylated interferon. These potential roles of HBsAg quantification are applicable to selected populations only. There is also a need for novel markers to study the effect of emerging antiviral therapies targeting various parts of the HBV cycle to reflect their distinct mechanistic effects. Several agents measuring HBsAg levels have shown rapid and significant decline. Ongoing studies are required to demonstrate the sustainability of HBsAg suppression by these novel agents.

Background and Aim: Mac-2-binding protein glycosylation isomer (M2BPGi) is a novel serum diagnostic marker for liver fibrosis in various liver diseases. We aimed to evaluate its role in assessment of liver fibrosis in chronic hepatitis B infection (CHB) with reference to liver stiffness measurement (LSM)., Methods: CHB patients with LSM by transient elastography technology and retrievable serum samples were recruited. Ten-year re-assessments of LSM and M2BPGi were repeated in a patient subgroup., Results: 240 CHB patients (M:F = 116:124; median age 47.5 years) were recruited. The median M2BPGi values for F0/F1/F2, F3 and F4 progressively increased with more advanced stages of liver fibrosis: 0.39, 0.46 and 0.82 COI, respectively (p < 0.01). M2BPGi levels correlated well with liver stiffness (r = 0.611), FIB-4 (r = 0.616), and strongly with APRI (r = 0.825) (all p < 0.001). Using cut-off values of 0.605 and 0.615 COI, the AUROCs were 0.754 and 0.799 for ≥ F3 and F4, respectively. M2BPGi identified one-quarter patients at risk of advanced fibrosis/cirrhosis otherwise classified into 'grey area' by LSM. In 86 patients with reassessment LSM, 21 (24.4%) showed significant fibrosis regression with corresponding decline in median M2BPGi level (- 0.11 COI) compared with the increase of +0.03 COI in patients without significant fibrosis regression (p = 0.011). Male gender, older age, use of potent antiviral therapy and change in serum M2BPGi were independently associated with significant fibrosis regression., Conclusions: Serum M2BPGi can risk-stratify CHB patients whose liver stiffness fell into the 'grey area'. Significant fibrosis regression occurring in one-quarter patients was reflected by a reduction in M2BPGi levels at 10-year interval.

Hepatitis B virus (HBV) reactivation during immunosuppressive therapy is common in patients with solid tumor or hematological malignancies. It is associated with significant morbidity and mortality due to hepatitis flare and/or hepatic decompensation. These consequences arising from HBV reactivation are, however, largely preventable. Routine screening for HBV serologic status is recommended for all cancer patients undergoing chemotherapy or biologics. By recognizing different serological patterns (which represent either overt or occult HBV infection) and the types of immunosuppressive therapies prescribed, a risk-adapted approach can be established. Prophylactic therapy with nucleos(t)ide analogues (prior to or concomitantly with the commencement of immunosuppressive therapies) is more effective than pre-emptive therapy (starting antiviral when HBV DNA level is rising) in high-risk individuals. Entecavir has been proven to be more effective than lamivudine according to recent studies. Close monitoring of serum HBV level is the preferred strategy in low-risk patients. However, the optimal interval of DNA monitoring and the duration of therapy remain unknown.

Introduction: Resistance in nucleoside/nucleotide analog (NA) therapy has always been a challenge in the management of chronic hepatitis B (CHB)., Clinical Studies: Initially developed for the treatment of HIV infection, early in vitro and clinical observational studies had shown tenofovir disoproxil fumarate (TDF) to be also active against CHB. Recent data from various multicenter phase 3 and 4 clinical trials have confirmed TDF being able to achieve a high viral suppression in both NA-naive and -experienced CHB patients. There are also emerging data on the efficacy of TDF in decompensated CHB. Although there are in vitro studies identifying certain mutation loci associated with a reduced susceptibility to TDF, there have so far been no reports of virologic resistance to TDF in clinical studies. TDF has a favorable safety profile, although more long-term data would be needed., Conclusions: TDF has the makings of an "ideal" first-line drug for the treatment of CHB.

Background: We investigated the differences in HBsAg kinetics at different levels of viremia in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB)., Methods: We compared HBsAg levels among HBeAg-negative CHB patients with persistently undetectable HBV DNA (≤20 IU/mL; Group A, n = 100), HBV DNA 20-2,000 IU/mL (Group B, n = 100), and HBV DNA >2,000 IU/mL (Group C, n = 100). HBsAg and HBV DNA levels were measured at three consecutive time points during follow-up (median 21.4 months)., Results: Median HBsAg levels were significantly lower in Group A than in Groups B and C at all time points (p < 0.001). HBV DNA and HBsAg levels were weakly correlated (r = 0.180 and 0.151 for Groups B and C, respectively). Among patients with HBsAg <100 IU/mL, Group A patients had the greatest median serum HBsAg reduction (0.341 log IU/mL/year; Group B, 0.122 log IU/mL/year; Group C, 0.057 log IU/mL/year; p = 0.002). Among Group A patients with HBsAg <100 IU/mL, baseline HBsAg achieved an AUROC of 0.876 in predicting >1 log annual HBsAg reduction; 10-100 IU/mL HBsAg was the optimal level for prediction (sensitivity 90 %; specificity 74.6 %). Serum HBsAg/HBV DNA ratios were significantly higher in Group B than in Groups A and C (p < 0.05)., Conclusions: HBV DNA and HBsAg were weakly correlated. Only patients with undetectable HBV DNA showed decline in HBsAg levels during follow-up. The greatest reduction in HBsAg levels occurred in patients with baseline HBsAg <100 IU/mL.

Background: Possible serologic activity after hepatitis B surface antigen (HBsAg) seroclearance documented by conventional assays in chronic hepatitis B (CHB) has not been thoroughly investigated., Methods: We determined the levels of serum hepatitis B virus (HBV) DNA, hepatitis B core-related antigen (HBcrAg), and linearized HBsAg (CLEIA prototype) in 329 CHB patients (72.0% male) after HBsAg seroclearance was documented by a conventional HBsAg assay., Results: The median interval between presentation and HBsAg seroclearance was 69.4 months. The median age at HBsAg seroclearance was 50 years. Assays for serum HBV DNA, HBcrAg, and linearized HBsAg were performed at a median time interval of 11.2 months after HBsAg loss. Linearized HBsAg and HBcrAg were detectable in 85 (25.8%) and 69 (21%) patients, respectively, and one or both serologic markers were detectable in 133 patients (40.4%). Serum HBV DNA was detectable in only 7 patients (2.1%). There was no correlation between linearized HBsAg and HBcrAg levels (r = 0.095, p = 0.924). The incidences of detectable linearized HBsAg and HBcrAg did not differ between patient samples taken at 6-12 and >12 months after HBsAg seroclearance (p = 0.146 and 0.079, respectively). Among patients with detectable serologic markers, median levels of linearized HBsAg (p = 0.581) and HBcrAg (p = 0.951) did not significantly change with time after HBsAg seroclearance., Conclusion: Using novel HBcrAg and linearized HBsAg assays, viral serologic activity after HBsAg seroclearance was demonstrated in more than 40% of CHB patients. These tests have potential applications in diagnosing and prognosticating CHB patients with HBsAg seroclearance.

The treatment of chronic hepatitis B is in constant evolution. Interferon, the first agent licensed for chronic hepatitis B treatment, has been superseded by the growing popularity of nucleoside/nucleotide analogues (NA). However, resistance to these agents is a major challenge. Newer NAs, such as entecavir and tenofovir dipivoxil fumarate, have very low resistance rates and favorable safety profiles. Long-term use of these agents can effectively suppress hepatitis B virus DNA, leading to decrease in incidence of hepatitic flares, as well as in the development of cirrhosis and hepatocellular carcinoma. The efficacy and safety of various antiviral agents is discussed in this review.

There has been increasing interest in noninvasive methods of assessing liver fibrosis over the last decade. The use of transient elastography in measuring liver stiffness has become the forefront of a wide range of noninvasive tools. Most of the other methods are based on measurements of biomarkers associated with fibrosis. There are several reasons for its wide acceptance, including the ease of performing a scan, the short procedure time, the results being immediately available on completion of the examination, and its reproducibility. For chronic hepatitis B (CHB), the cut-off values for F3 and F4 fibrosis range between 7.5-12.0 and 11.0-13.4 kPa, respectively, although the cut-offs may be slightly lower in those with normal ALT. In addition to measuring liver fibrosis, recent studies have demonstrated several other roles for transient elastography, including selecting patients who will benefit from antiviral therapy, monitoring response to antiviral therapy, and predicting long-term outcomes. However, there are limitations associated with transient elastography, including the confounding effects of inflammatory activity, and to a lesser extent, steatosis, on liver stiffness. There is also reduced accuracy observed in lower fibrosis stages (F0-F2). Furthermore, the incidences of failed and unreliable scan have been reported to be ~ 3 and 16%, respectively. Although liver biopsy can be avoided in an estimated 50-60% using transient elastography, in situations where liver stiffness measurement is nondiagnostic or inconsistent with the clinical picture, a biopsy is still recommended. Further studies are needed to consolidate the role of transient elastography in the management of CHB, and for incorporation of this method into current treatment guidelines.

Background: Measuring liver stiffness is becoming more popular as a non-invasive tool for assessing liver fibrosis., Aim: To assess the effect of severe hepatitis B flare on liver stiffness and determine factors that correlate with liver stiffness measurements., Methods: Twenty-nine patients with severe hepatitis B flare (ALT > 10 × upper limit of normal) were followed up for 1 year. Serial transient elastography was performed at the time of flare, 3-6, and 12 months after flare., Results: At the time of flare, the median liver stiffness was 16.8 kPa, with no patients having normal liver stiffness (<6 kPa). There was a significant decrease in liver stiffness from baseline to 3-6 months (16.8 vs. 7.9 kPa, respectively, P < 0.001), and a further smaller decline from 3-6 to 12 months (7.9 vs. 6.9 kPa, respectively, P = 0.039). By 12 months, 10 (34%) had normalized their liver stiffness. Baseline parameters which correlated with liver stiffness include bilirubin, ALT, albumin, prothrombin time and platelet levels (all P < 0.05)., Conclusion: Liver stiffness was increased in patients with severe hepatitis B flares, with return to near normal levels by 6 months. Transient elastography for proper assessment of liver fibrosis should be performed at least 6 months after flare.