Hepatocellular carcinoma: Advances in systemic therapies.

Advanced hepatocellular carcinoma (HCC) is traditionally associated with limited treatment options and a poor prognosis. Sorafenib, a multiple tyrosine kinase inhibitor, was introduced in 2007 as a first-in-class systemic agent for advanced HCC. After sorafenib, a range of targeted therapies and immunotherapies have demonstrated survival benefits in the past 5 years, revolutionizing the treatment landscape of advanced HCC. More recently, evidence of novel combinations of systemic agents with distinct mechanisms has emerged. In particular, combination trials on atezolizumab plus bevacizumab and durvalumab plus tremelimumab have shown encouraging efficacy. Hence, international societies have revamped their guidelines to incorporate new recommendations for these novel systemic agents. Aside from treatment in advanced HCC, the indications for systemic therapy are expanding. For example, the combination of systemic therapeutics with locoregional therapy (trans-arterial chemoembolization or stereotactic body radiation therapy) has demonstrated promising early results in downstaging HCC. Recent trials have also explored the role of systemic therapy as neoadjuvant treatment for borderline-resectable HCC or as adjuvant treatment to reduce recurrence risk after curative resection. Despite encouraging results from clinical trials, the real-world efficacy of systemic agents in specific patient subgroups (such as patients with advanced cirrhosis, high bleeding risk, renal impairment, or cardiometabolic diseases) remains uncertain. The effect of liver disease etiology on systemic treatment efficacy warrants further research. With an increased understanding of the pathophysiological pathways and accumulation of clinical data, personalized treatment decisions will be possible, and the field of systemic treatment for HCC will continue to evolve.

Optimal glycaemic control and the reduced risk of colorectal adenoma and cancer in patients with diabetes: a population-based cohort study.

OBJECTIVE: Whether varying degrees of glycaemic control impact colonic neoplasm risk in patients with diabetes mellitus (DM) remains uncertain. DESIGN: Patients with newly diagnosed DM were retrieved from 2005 to 2013. Optimal glycaemic control at baseline was defined as mean haemoglobin A1c (HbA1c)<7%. Outcomes of interest included colorectal cancer (CRC) and colonic adenoma development. We used propensity score (PS) matching with competing risk models to estimate subdistribution HRs (SHRs). We further analysed the combined effect of baseline and postbaseline glycaemic control based on time-weighted mean HbA1c during follow-up. RESULTS: Of 88 468 PS-matched patients with DM (mean (SD) age: 61.5 (±11.7) years; male: 47 127 (53.3%)), 1229 (1.4%) patients developed CRC during a median follow-up of 7.2 (IQR: 5.5-9.4) years. Optimal glycaemic control was associated with lower CRC risk (SHR 0.72; 95% CI 0.65 to 0.81). The beneficial effect was limited to left-sided colon (SHR 0.71; 95% CI 0.59 to 0.85) and rectum (SHR 0.71; 95% CI 0.57 to 0.89), but not right-sided colon (SHR 0.86; 95% CI 0.67 to 1.10). Setting suboptimal glycaemic control at baseline/postbaseline as a reference, a decreased CRC risk was found in optimal control at postbaseline (SHR 0.79), baseline (SHR 0.71) and both time periods (SHR 0.61). Similar associations were demonstrated using glycaemic control as a time-varying covariate (HR 0.75). A stepwise greater risk of CRC was found (Ptrend<0.001) with increasing HbA1c (SHRs 1.34, 1.30, 1.44, 1.58 for HbA1c 7.0% to <7.5%, 7.5% to <8.0%, 8.0% to <8.5% and ≥8.5%, respectively). Optimal glycaemic control was associated with a lower risk of any, non-advanced and advanced colonic adenoma (SHRs 0.73-0.87). CONCLUSION: Glycaemic control in patients with DM was independently associated with the risk of colonic adenoma and CRC development with a biological gradient.

Endocuff With or Without Artificial Intelligence-Assisted Colonoscopy in Detection of Colorectal Adenoma: A Randomized Colonoscopy Trial.

INTRODUCTION: Both artificial intelligence (AI) and distal attachment devices have been shown to improve adenoma detection rate and reduce miss rate during colonoscopy. We studied the combined effect of Endocuff and AI on enhancing detection rates of various colonic lesions. METHODS: This was a 3-arm prospective randomized colonoscopy study involving patients aged 40 years or older. Participants were randomly assigned in a 1:1:1 ratio to undergo Endocuff with AI, AI alone, or standard high-definition (HD) colonoscopy. The primary outcome was adenoma detection rate (ADR) between the Endocuff-AI and AI groups while secondary outcomes included detection rates of polyp (PDR), sessile serrated lesion (sessile detection rate [SDR]), and advanced adenoma (advanced adenoma detection rate) between the 2 groups. RESULTS: A total of 682 patients were included (mean age 65.4 years, 52.3% male), with 53.7% undergoing diagnostic colonoscopy. The ADR for the Endocuff-AI, AI, and HD groups was 58.7%, 53.8%, and 46.3%, respectively, while the corresponding PDR was 77.0%, 74.0%, and 61.2%. A significant increase in ADR, PDR, and SDR was observed between the Endocuff-AI and AI groups (ADR difference: 4.9%, 95% CI: 1.4%-8.2%, P = 0.03; PDR difference: 3.0%, 95% CI: 0.4%-5.8%, P = 0.04; SDR difference: 6.4%, 95% CI: 3.4%-9.7%, P < 0.01). Both Endocuff-AI and AI groups had a higher ADR, PDR, SDR, and advanced adenoma detection rate than the HD group (all P < 0.01). DISCUSSION: Endocuff in combination with AI further improves various colonic lesion detection rates when compared with AI alone.

FAT4 loss initiates hepatocarcinogenesis through the switching of canonical to noncanonical WNT signaling pathways.

BACKGROUND: Mutation and downregulation of FAT atypical cadherin 4 (FAT4) are frequently detected in HCC, suggesting a tumor suppressor role of FAT4. However, the underlying molecular mechanism remains elusive. METHODS: CRISPR-Cas9 system was used to knockout FAT4 (FAT4-KO) in a normal human hepatic cell line L02 to investigate the impact of FAT4 loss on the development of HCC. RNA-sequencing and xenograft mouse model were used to study gene expression and tumorigenesis, respectively. The mechanistic basis of FAT4 loss on hepatocarcinogenesis was elucidated using in vitro experiments. RESULTS: We found that FAT4-KO disrupted cell-cell adhesion, induced epithelial-mesenchymal transition, and increased expression of extracellular matrix components. FAT4-KO is sufficient for tumor initiation in a xenograft mouse model. RNA-sequencing of FAT4-KO cells identified PAK6-mediated WNT/ß-catenin signaling to promote tumor growth. Suppression of PAK6 led to ß-catenin shuttling out of the nucleus for ubiquitin-dependent degradation and constrained tumor growth. Further, RNA-sequencing of amassed FAT4-KO cells identified activation of WNT5A and ROR2. The noncanonical WNT5A/ROR2 signaling has no effect on ß-catenin and its target genes (CCND1 and c-Myc) expression. Instead, we observed downregulation of receptors for WNT/ß-catenin signaling, suggesting the shifting of ß-catenin-dependent to ß-catenin-independent pathways as tumor progression depends on its receptor expression. Both PAK6 and WNT5A could induce the expression of extracellular matrix glycoprotein, laminin subunit alpha 4. Laminin subunit alpha 4 upregulation in HCC correlated with poor patient survival. CONCLUSIONS: Our data show that FAT4 loss is sufficient to drive HCC development through the switching of canonical to noncanonical Wingless-type signaling pathways. The findings may provide a mechanistic basis for an in-depth study of the two pathways in the early and late stages of HCC for precise treatment.

Comparing general anaesthesia versus sedation for endoscopic submucosal dissection: results from a systematic review and meta-analysis.

Endoscopic submucosal dissection (ESD) is an advanced endoscopic procedure for management of gastrointestinal tumours. ESD is usually performed under sedation. However, the use of general anaesthesia (GA) has been hypothesised to improve ESD outcomes. We performed a systematic review and meta-analysis to compare GA against sedation in ESD. A systematic literature search was performed on Cochrane Library, EMBASE and MEDLINE using the terms "General Anaesthesia", "Sedation" and "Endoscopic submucosal dissection". Original articles comparing GA versus sedation in ESD were included. The risk of bias and level of evidence were assessed by validated methods. This review is registered in PROSPERO (CRD42021275813). 176 articles were found in the initial literature search, and 7 articles (comprising 518 patients receiving GA and 495 receiving sedation) were included. Compared with sedation, GA was associated with higher en-bloc resection rates in oesophageal ESD (RR 1.05; 95% CI: 1.00-1.10; I 2 = 65%; P = 0.05). GA patients also trended towards lower rates of gastrointestinal perforation in all ESD procedures (RR 0.62; 95% CI: 0.21-1.82; I 2 = 52%; P = 0.06). Rates of intra- procedural desaturation and post-procedural aspiration pneumonia were lower in GA patients than in patients under sedation. The included studies had a moderate to high risk of bias, and the overall level of evidence was low. GA appears safe and feasible for ESD, yet high-quality trials will be required before GA can be regularly implemented for ESD.

The role of different viral biomarkers on the management of chronic hepatitis B.

Chronic hepatitis B infection is a major public health challenge. With the advancement in technology, various components of the viral cycle can now be measured in the blood to assess viral activity. In this review article, we summarize the relevant data of how antiviral therapies impact viral biomarkers, and discuss their potential implications. Viral nucleic acids including hepatitis B virus (HBV) double-stranded deoxy-ribonucleic acid (DNA) and to a lesser extent, pre-genomic RNA, are readily suppressed by nucleos(t)ide analogues (NUCs). The primary role of these markers include risk prediction for hepatocellular carcinoma (HCC) and risk stratification for partial cure, defined as off-therapy virological control, or functional cure, defined as hepatitis B surface antigen (HBsAg) seroclearance plus undetectable serum HBV DNA for ≥6 months. Viral translational products including hepatitis e antigen, quantitative HBsAg and hepatitis B core-related antigen can be reduced by NUCs and pegylated interferon a. They are important in defining disease phase, delineating treatment endpoints, and predicting clinical outcomes including HCC risk and partial/ functional cure. As the primary outcome of phase III trials in chronic hepatitis B is set as HBsAg seroclearance, appropriate viral biomarkers can potentially inform the efficacy of novel compounds. Early viral biomarker response can help with prioritization of subjects into clinical trials. However, standardization and validation studies would be crucial before viral biomarkers can be broadly implemented in clinical use.

Clinical practice guidelines and real-life practice on hepatocellular carcinoma: the Hong Kong perspective.

Hepatocellular carcinoma (HCC) is a major public health burden in Hong Kong, and chronic hepatitis B is the most common HCC etiology in our region. With the high case load, extensive local expertise on HCC has been accumulated. This article summarized local guidelines and real-life practice on HCC management in Hong Kong. For HCC surveillance, liver ultrasound and serum alpha-fetoprotein for periodic screening is recommended in viral hepatitis or cirrhotic patients, and this is adhered to in clinical practice. HCC diagnosis is not covered in local guidelines, yet our practice is in-line with regional guidelines, where diagnosis is usually achieved by cross-sectional imaging and without the need for histology. Our guidelines recommend using the Hong Kong Liver Cancer Staging for pre-treatment staging, yet we routinely use other widely-adopted systems such as the Barcelona Clinic Liver Cancer Staging and the Tumor-Node-Metastasis Staging as well. Our local guidelines have provided clear treatment algorithms for the whole range of HCC therapies, including resection, ablation, transplant, transarterial chemoembolization, transarterial radioembolization, stereotactic body radiation therapy, targeted therapy, and immunotherapy. Real-life treatment choices are largely in line with the guidelines, although treatment protocols are individualized, and availability of specific therapies can vary between centers. Overall, HCC guidelines in Hong Kong are tailored based on local expertise and our unique patient population. The guidelines are up-to-date and provide practical pathways to assist our routine practice. Regular updates of local guidelines are warranted to account for the rapidly evolving paradigm of HCC management.

Glycemic burden and the risk of adverse hepatic outcomes in patients with chronic hepatitis B with type 2 diabetes.

BACKGROUND AND AIMS: Type 2 diabetes (T2D) is common among patients with chronic hepatitis B infection (CHB) and has been associated with increased risk of carcinogenesis, including HCC. We investigated factors associated with HCC and fibrosis progression among patients with CHB with T2D (CHB+T2D). APPROACH AND RESULTS: Chinese patients with CHB were prospectively recruited for the incidence of HCC and fibrosis progression defined by transient elastography. Among patients with CHB+T2D, glycemic control was assessed by mean glycated hemoglobin (HbA1c) and HbA1c variability determined using HbA1c measurements in the 5 years preceding recruitment. A total of 2330 patients with CHB were recruited (mean age 54.6 ±11.8 years old, 55.5% male, 57.9% antiviral-treated), with 671 (28.8%) having CHB+T2D (mean T2D duration 7.2 ± 4.6 years, mean HbA1c 7.2 ± 0.9%). T2D was independently associated with HCC (HR 2.080, 95% CI 1.343-3.222) and fibrosis progression (OR 4.305, 95% CI 3.416-5.424) in the overall cohort. In patients with CHB+T2D, factors reflecting glycemic burden (T2D duration [HR 1.107, 95% CI 1.023-1.198]), mean HbA1c (HR 1.851, 95% CI 1.026-3.339), time reaching target HbA1c (HbA1c-TRT; HR 0.978, 95% CI 0.957-0.999), liver stiffness (HR 1.041-1.043), and smoking (HR 2.726-3.344) were independently associated with HCC (all p < 0.05), but not HbA1c variability or controlled attenuation parameter. The same glycemic burden-related factors (T2D duration, mean HbA1c, and HbA1c-TRT), in addition to baseline fasting glucose, baseline HbA1c, AST and antiviral therapy, were independently associated with fibrosis progression at 3 years. CONCLUSIONS: High glycemic burden was associated with HCC development and fibrosis progression among patients with CHB+T2D, highlighting the importance of glycemic control in reducing liver-related complications.

Enhanced Liver Fibrosis Score Stratifies Hepatocellular Carcinoma Risk in Patients With Hepatitis B Surface Antigen Seroclearance.

In this prospective study involving 337 chronic hepatitis B patients who achieved spontaneous hepatitis B surface antigen (HBsAg) seroclearance (SC), serum enhanced liver fibrosis (ELF) before SC was associated with hepatocellular carcinoma (HCC) (hazard ratio 2.588), and ELF <10.8 was associated with >97% reduction in risk of HCC development in patients with age SC ≥ 50 (n = 190).

Magnetic resonance imaging metrics and the predictability of adverse outcomes in on-treatment Asian chronic hepatitis B.

BACKGROUND AND AIM: Liver fibrosis and steatosis are important factors affecting chronic hepatitis B (CHB) disease outcome. Multiparametric magnetic resonance (MR) imaging of the liver measures fibroinflammation, fat, and iron through iron-corrected T1 relaxation time (cT1), proton density fat fraction (PDFF), and T2*-weighted imaging, respectively. We assessed the utility of MR metrics for prognostication in CHB. METHODS: Chronic hepatitis B patients receiving nucleos(t)ide analogs with advanced fibrosis documented by vibration-controlled transient elastography were recruited. Paired multiparametric MR liver and transient elastography were performed at baseline and after at least 2 years. Adverse outcomes including death, hepatocellular carcinoma (HCC), and liver decompensation were monitored. RESULTS: One hundred and ninety-two patients (mean age 60.3 ± 8.5 years; 76.0% male) were recruited. Eight patients (4.2%) developed HCC after 11.6 (8.8-22.8) months, and increased baseline liver iron independently predicted HCC (hazard ratio 2.329 [1.030-5.266]; P = 0.042). Liver MR metrics were not predictive of death or hepatic decompensation. Among 150 patients with follow-up liver MR at 30.3 (25.2-35.6) months, longitudinal liver PDFF increase was associated with liver cT1 increase (odds ratio 1.571 [1.217-2.029]; P = 0.001). Ninety patients received simultaneous multiparametric MR pancreas during the follow-up MR. Pancreatic PDFF correlated with liver PDFF (r = 0.501, P < 0.001), while pancreatic T1 had no correlation with liver cT1 (r = -0.092, P = 0.479). Pancreatic T1 and PDFF were not associated with adverse outcomes. CONCLUSION: Among CHB patients with advanced disease, liver iron level on MR predicts HCC. Multiparametric MR can also simultaneously assess the pancreas and the liver. Multiparametric MR should be further studied as a one-stop option for monitoring and prognosticating CHB.

Magnetic resonance elastography and proton density fat fraction predict adverse outcomes in hepatocellular carcinoma.

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.

Role of Serum M2BPGi Levels in Predicting Persistence of Advanced Fibrosis in Chronic Hepatitis B Virus Infection.

BACKGROUND: Serum mac-2-binding protein glycosylation isomer (M2BPGi) is a novel marker for liver fibrosis assessment in patients with different liver diseases. For chronic hepatitis B infection (CHB), advanced fibrosis or cirrhosis is a risk factor for liver cancer and hepatic decompensation. We aimed to assess the role of serum M2BPGi in prediction of persistence of advanced fibrosis in CHB patients despite potent antiviral therapy. METHODS: CHB patients with advanced fibrosis or cirrhosis who were put on nucleos(t)ide analogs for ≥ 3 years with normal alanine aminotransferase and undetectable serum HBV DNA were prospectively recruited. Assessment of liver fibrosis with transient elastography (TE) and M2BPGi measurements were performed at baseline and repeated at 3 years. Advanced fibrosis and cirrhosis were defined by liver stiffness (LS) ≥ 9.0 kPa and ≥ 12.0 kPa, respectively. RESULTS: A total of 143 patients (M:F = 101:42; median age 58.7 years; 53.8% cirrhotic) were recruited and completed paired assessment. The median value of baseline LS and M2BPGi were 12.0 (IQR: 10.5-18.2) kPa and 0.99 cut-off-index (IQR: 0.75-1.74) (COI), respectively, with 96% concordance for diagnosing F3/F4. Ninety-six (67.1%) patients had persistent advanced fibrosis or cirrhosis at 3 years despite continuation of long-term antiviral treatment. Upon multivariate analysis, baseline M2BPGi (OR 2.128, 95% CI 1.037-4.366) and presence of central obesity (OR 4.648, 95% CI 1.742-12.402) were significantly associated with persistent advanced fibrosis or cirrhosis at 3 years. Baseline M2BPGi ≥ 1.265 COI has 50.6% sensitivity and 79.4% specificity for predicting persistent advanced fibrosis or cirrhosis at 3 years (area under the receiver-operating characteristic curve: 0.695). The presence of central obesity in combination with baseline M2BPGi ≥ 1.265 COI was associated with 95.7% patients having persistent advanced fibrosis or cirrhosis at 3 years. HCC development was observed in five patients during follow-up and was associated with bigger median increase in the level of serum M2BPGi compared to patients without HCC (46% vs 6.2%, P = 0.038). CONCLUSION: Persistent advanced fibrosis or cirrhosis was observed in two-thirds of CHB patients despite potent antiviral therapy. High serum M2BPGi and central obesity were associated with more than twofold and fourfold increase in risk of persistent advanced fibrosis or cirrhosis, respectively.

Reduced hepatic steatosis is associated with higher risk of hepatocellular carcinoma in chronic hepatitis B infection.

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.

Burnout in orthopaedic surgeons: A systematic review.

Occupational burnout is a syndrome composing of emotional exhaustion, depersonalisation and low sense of personal accomplishment. Burnout has been shown to negatively affect both the personal lives and professional performance of doctors. Orthopaedic surgery is a challenging specialty, and while burnout has been studied in orthopaedic surgeons, a comprehensive review article in this area is lacking. Hence we performed a systematic review to summarise the evidence regarding burnout in orthopaedic surgeons. We conducted a systematic literature review using the terms "orthopaedic surgeons" and "burnout" and related terms. Studies were reviewed by two independent reviewers. English articles that were (a) peer-reviewed original research articles; (b) measures burnout directly in study participants; (c) uses validated scales for burnout assessment; and (d) on orthopaedic surgeons, were included. Discrepancies between reviewers were resolved by panel discussion. 216 papers were identified and 14 papers were selected for qualitative synthesis. The prevalence of burnout varied considerably between orthopaedic surgeons from different centres and of different seniority. There is insufficient evidence to suggest that the burnout rate in orthopaedic surgeons is different from doctors in other specialties. A range of risk factors and protective factors associated with burnout were identified. Similar to prior studies in the general medical population, key determinants of burnout included personal, family, working environment and career factors. One paper identified an association between burnout and irritable behaviour during operation, yet no studies have assessed the effect of burnout on orthopaedic patient outcomes. We did not identify papers on the management of burnout in orthopaedic surgeons. To conclude, the evidence on burnout in orthopaedic surgeons is preliminary and key methodological limitations have been noted in the current studies. Large-scale prospective studies are warranted to better understand the determinants and effects of burnout in orthopaedic surgeons, in order to guide appropriate interventions against this occupational mental health hazard.

Fibrosis evolution in chronic hepatitis B e antigen-negative patients across a 10-year interval.

The degree of liver fibrosis in chronic hepatitis B (CHB) infection influences outcome and management. Existing data describing the long-term dynamic changes of liver fibrosis are limited. This study aimed to evaluate the evolution of liver fibrosis in CHB across a 10-year period. CHB patients with liver stiffness measurement (LSM) by transient elastography 10 years ago were recruited for follow-up LSM. Fibrosis stages were classified according to EASL-ALEH guidelines. Fibrosis progression/regression was arbitrarily defined as ≥1 fibrosis stage change from baseline. A total of 459 hepatitis B e antigen (HBeAg)-negative patients (224 untreated, 235 treated with nucleos(t)ide analogues [NAs]) were recruited. The mean age at baseline LSM was 41.7 ± 9.0 years (56.2% male). Over 10 years, the proportion of patients with advanced fibrosis/cirrhosis significantly reduced from 16.3% to 5.7% (P < 0.001). Fibrosis progression and regression were observed in 8.7% and 37.5%, respectively. No treatment with NAs (OR 2.259, 95% confidence interval [CI]: 1.032-4.945), metabolic syndrome (OR 4.379, 95% CI: 1.128-16.999) and hepatic steatosis (OR 7.799, 95% CI: 2.271-26.776) was associated with fibrosis progression. Liver stiffness decline demonstrated positive correlation with the time after HBsAg seroclearance (r = -0.50, P < 0.001). Median liver stiffness was higher both at baseline (14.0 vs 6 kPa, P < 0.001) and 10 years (9.1 vs 4.9 kPa, P < 0.001) in patients with cirrhosis-related complications/hepatocellular carcinoma compared with those without. In conclusion, CHB-related liver fibrosis changed dynamically across 10 years. Metabolic syndrome and hepatic steatosis were associated with fibrosis progression, while antiviral therapy was associated with fibrosis regression. Patients with HBsAg seroclearance demonstrated time-dependent decline in liver stiffness.

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

BACKGROUND & AIMS: 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. METHODS: 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 ≥ 248 dB/m). Plasma FGF-21, AFABP and adiponectin levels were measured. RESULTS: A total of 415 patients [mean age 59.6 years, 71.6% male, median treatment duration 6.2 years] were recruited. Patients with F3/F4 (N = 151) had lower FGF-21 (11.7 vs 13.6 pg/mL, P = 0.055), higher AFABP (126.8 vs 84.1 pg/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 ≥ 25 kg/m2 , diabetes and AFABP > 105.9 pg/mL, the odds ratio for F3/F4 was 3.712 (95% CI 1.364-10.105, P = 0.010). CONCLUSIONS: 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.