Association of liver fibrosis with extrahepatic cancer in steatotic liver disease patients with PNPLA3 I148M GG genotype.

The impacts of patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M-rs738409, methylenetetrahydrofolate reductase (MTHFR) Ala222Val-rs1801133, and aldehyde dehydrogenase 2 (ALDH2) Glu504Lys-rs671 on the outcomes of Taiwanese patients with steatotic liver disease (SLD) have remained elusive. An 8-year prospective cohort study of patients with (n = 546) and without (n = 580) SLD (controls) was undertaken in a Taiwanese tertiary care center. The 546 SLD patients comprised 306 (56.0%) men and 240 (44.0%) women with mean ages of 53.3 and 56.4 years, respectively. Compared with the controls, SLD patients had an increased frequency of the PNPLA3 I148M-rs738409 GG genotype (25.5 vs. 5.9%, p = 0.001). Among the SLD patients, 236 (43.1%) suffered cardiovascular events, 52 (9.5%) showed extrahepatic cancers, 13 (2.38%) experienced hepatic events, including hepatocellular carcinoma (n = 3, 0.5%) and liver cirrhosis (n = 8, 1.47%), and none died. The Fibrosis-4 (FIB-4) scores were associated with extrahepatic cancer (hazard ratio [HR] 1.325; 95% confidence interval [CI], 1.038-1.691) and cirrhosis development (HR 1.532; 95% CI, 1.055-2.224), and the PNPLA3 I148M-rs738409 G allele (ß = 0.158, 95% CI, 0.054-0.325) was associated with the FIB-4 score. Stratified analyses showed that the impact of the FIB-4 score on extrahepatic cancer development was evident only in SLD patients with the PNPLA3 I148M-rs738409 GG genotype (HR 1.543; 95% CI, 1.195-1.993) and not in patients with the GC or CC genotype. Moreover, the ALDH2 Glu504Lys-rs671 G allele had a dose-dependent effect on alcoholism, and the MTHFR and ALDH2 genotypes were not significantly associated with SLD patient outcomes. In conclusion, special vigilance should be exercised for emerging extrahepatic cancer in SLD patients with the PNPLA3 I148M-rs738409 GG genotype and high FIB-4 scores.

Factors associated with treatment responses to pioglitazone in patients with steatotic liver disease: A 3-year prospective cohort study.

AIM: The response rate to pioglitazone and the predictive factors for its effects on improving liver biochemistry in patients with steatotic liver disease (SLD) remain elusive, so we aimed to investigate these issues. METHODS: A 3-year prospective cohort study of 126 Taiwanese patients with SLD treated with pioglitazone (15-30 mg/day) was conducted. Phospholipase domain-containing protein 3 I148M rs738409, methylenetetrahydrofolate reductase rs1801133, aldehyde dehydrogenase 2 (ALDH2) rs671 and lipoprotein lipase rs10099160 single nucleotide polymorphisms were assessed in the patients. RESULTS: Of 126 patients, 78 (61.9%) were men, and the mean and median ages were 54.3 and 56.5 years, respectively. Pioglitazone responders were defined as those with decreased alanine aminotransferase (ALT) levels at 6 months post-treatment, and 105 (83.3%) patients were responders. Compared with non-responders, responders were more frequently women and had higher baseline ALT levels. The proportion of patients with the ALDH2 rs671 GG genotype was lower among responders (38.6% vs. 66.6%, p = .028). Female sex [odds ratio (OR): 4.514, p = .023] and baseline ALT level (OR: 1.015, p = .046; cut-off level: ≥82 U/L) were associated with pioglitazone response. Among responders, the liver biochemistry and homeostasis model assessment of insulin resistance improved from 6 to 24 months post-treatment. The total cholesterol levels decreased within 6 months, while increases in high-density lipoprotein cholesterol levels and decreases in triglyceride levels and fibrosis-4 scores were noted only at 24 months post-treatment. The 2-year cumulative incidences of cardiovascular events, cancers and hepatic events were similar between responders and non-responders. CONCLUSIONS: Regarding liver biochemistry, over 80% of Taiwanese patients with SLD had a pioglitazone response, which was positively associated with female sex and baseline ALT levels. Insulin resistance improved as early as 6 months post-treatment, while liver fibrosis improvement was not observed until 24 months post-treatment. The link between the pioglitazone response and the ALDH2 genotype warrants further investigation.

Hepatic and Extrahepatic Characteristics of Autoimmune Hepatitis: A 23-year Hospital-Based Cohort Study.

BACKGROUND: The characteristics of autoimmune hepatitis (AIH) in Asia mostly remain elusive. METHODS: A cohort study of liver biopsy-proven AIH patients was conducted in a tertiary care cancer of Taiwan. RESULTS: From 1999 to 2022, of 13,766 patients who underwent liver biopsy, 150 patients with AIH were enrolled. The female-to-male ratio was 2.26. At baseline, the mean age was 51.09 years, mean alanine aminotransferase level was 494.11 U/L, and 17 (11.3%) had cirrhosis. All except one patient had AIH type 1. The females were older and had higher baseline cirrhosis rates than did the males. The 23-year cumulative incidences of cirrhosis, hepatocellular carcinoma (HCC), mortality/liver transplantation, autoimmune diseases and extrahepatic cancer were 64.2%, 13.3%, 23.4%, 30.7% and 21.2%, respectively. The 1-year, 2-year, 3-year, 5-year, 10-year and 20-year postimmunosuppressive therapy relapse rates were 60%, 78.2%, 81.8%, 89.1%, 94.5% and 100%, respectively. Baseline associations were as follows: alkaline phosphatase (Alk-p) levels with postimmunosuppressive therapy flare [hazard ratio (HR): 1.003; 95% CI HR: 1.000-1.005]; age with HCC (1.072; 1.010-1.138) and all-cause cancer (1.041;1.005-1.079); cirrhosis with mortality/liver transplantation (11.933;1.984-71.787); and antinuclear antibody (ANA) titers with mortality/liver transplantation (1.001;1.000-1.003), cirrhosis (1.001;1.000-1.002), and autoimmune diseases (1.001; 1.000-1.002). CONCLUSION: In an Asian country endemic for viral hepatitis, the female-to-male and baseline cirrhosis rates of AIH patients were lower than expected, while over 60% of the patients eventually developed cirrhosis. The high posttherapy relapse rate warrants cautious monitoring, particularly for patients with high baseline Alk-p levels. Baseline age, cirrhosis status and ANA titers are crucial for outcomes.

Temporal Trends of Inflammatory Bowel Diseases in Taiwan from 2016 to 2020: A Population-Based Study.

BACKGROUND: There are scanty population-based studies investigating the incidence and prevalence rates of inflammatory bowel disease (IBD) in Taiwan. AIMS: This study aimed to estimate the nationwide prevalence and incidence of IBD and identify its noticeable trends in Taiwan between 2016 and 2020. METHODS: A retrospective study by analyzing the data from the National Health Insurance Research Database of Taiwan. RESULTS: A total of 2595 patients with catastrophic IBD illness were registered from 2016 to 2020 in Taiwan (CD, 880; UC, 1715). The male-to-female ratio in the study sample was 1.83:1 for CD and 1.69:1 for UC. The median age of those registered with CD and UC was 37 and 47 years, respectively. The incidence rate of CD was 0.65 per 100,000 persons in 2016 and it was increased to 0.81 per 100,000 persons in 2020. The incidence rate of UC was 1.16 per 100,000 persons in 2016 and it was increased to 1.53 in 2020. Overall, the incidence of IBD was increase from 1.81 per 100,000 persons to 2.34 per 100,000 persons between 2016 and 2020. Overall, the prevalence rates of IBD was increase from 14.95 per 100,000 persons to 20.02 per 100,000 persons between 2016 and 2020. CONCLUSION: The epidemiological stages of IBD in Taiwan was considered in the acceleration in incidence stage, during which incidence rises and prevalence is relatively low. Understanding these geographical differences is important for the rising global burden of IBD.

An SNP Marker Predicts Colorectal Cancer Outcomes with 5-Fluorouracil-Based Adjuvant Chemotherapy Post-Resection.

Colorectal cancer (CRC) is a global health concern, necessitating adjuvant chemotherapy post-curative surgery to mitigate recurrence and enhance survival, particularly in intermediate-stage patients. However, existing therapeutic disparities highlight the need for biomarker-guided adjuvant chemotherapy to achieve better CRC inhibition. This study explores the molecular mechanisms underlying the inhibition of CRC through a genome-wide association study (GWAS) focused on 5-fluorouracil (5-FU)-based adjuvant therapy in intermediate-stage CRC patients, a domain previously unexplored. We retrospectively included 226 intermediate-stage CRC patients undergoing surgical resection followed by 5-FU-based adjuvant chemotherapy. The exploration cohort comprised 31 patients, and the validation cohort included 195 individuals. Genotyping was carried out using either Axiom Genome-Wide TWB 2.0 Array Plate-based or polymerase chain reaction-based methods on genomic DNA derived from collected tissue samples. Statistical analyses involved descriptive statistics, Kaplan-Meier analyses, and Cox proportional hazard analyses. From the GWAS, potential genetic predictors, GALNT14-rs62139523 and DNMBP-rs10786578 genotypes, of 5-FU-based adjuvant therapy following surgery in intermediate-stage CRC patients were identified. Validation in a larger cohort of 195 patients emphasized the predictive significance of GALNT14-rs62139523 genotypes, especially the "A/G" genotype, for improved overall and progression-free survival. This predictive association remained robust across various subgroups, with exceptions for specific demographic and clinical parameters such as age < 58 years old, CEA ≤ 2.5 ng/mL, tumor diameter > 44.0 mm, and tumor-free margin ≥ 50 mm. This study identifies that the GALNT14-rs62139523 "A/G" genotype modulates therapeutic outcomes, establishing it as a promising biomarker for predicting favorable responses to 5-FU-based adjuvant chemotherapy in intermediate-stage CRC patients, although further investigations are needed to detail these mechanisms.

Hepatitis C micro-elimination through the retrieval strategy of patients lost to follow-up.

BACKGROUND AND AIM: World Health Organization sets up an ambitious and attainable goal to eliminate hepatitis C (HCV) by 2030. The previous diagnosed HCV patients lost to follow-up were considered as an important target group for HCV elimination. We conducted a call back program to retrieve the lost to follow-up HCV patients and link them to care in our hospital. By analyzing and comparing our result with that from other studies, we wish to improve our retrieval strategy and provide our experience to the general communities. METHODS: A list of the patients with a medical record showing seropositive for antibody to HCV (anti-HCV Ab) from 2004 to 2017 was retrieved by the department of intelligent technology of our hospital. Three dedicated staff members reviewed the patients' electronic medical records (EMRs) and recruited the patient lost follow-up to the call back program. The staff members contacted the qualified patients by telephone and inquired about their opinions for treating their chronic HCV infection. We also informed the patients about the retrieval strategy and why we contact them. As our National Health Insurance request, we gave all patient one informed consent for hepatitis C treatment. Informed consents have been obtained from all patients. Referrals to our gastroenterology unit (GU) were arranged for the patients who would like to continue their chronic HCV care in our hospital. RESULTS: There were 31,275 anti-HCV positive patients. We included 11,934 patients (38.2%) into the call back system and contacted them by telephone. Based on the response to our call, we ascertained 1277 eligible cases (10.7%) for retrieval. The patients who were younger (< 55), lived in Taoyaun City or had tested positive for anti-HCV Ab at the department of internal medicine department had an increased rate of successful call back. There were 563 patients (44.1%) returning to our GU. Of them, 354 patients (62.9%) were positive for HCV viremia. 323 patients (91.2%) received the DAAs treatment. The SVR12 with Grazoprevir + elbasvir, Glecaprevir + pibrentasvir, Sofosbuvir + ledipasvir and Sofosbuvir + velpatasvir were 97.9%, 98.8%, 100% and 97.5%, respectively. CONCLUSIONS: Call back system can expand our reach to those unaware or ignoring chronic HCV infection patients and link them to treatment.

Characteristic geoepidemiology of primary biliary cholangitis in Taiwan: A nationwide population-based study.

AIM: Data on the geoepidemiology and outcomes of primary biliary cholangitis (PBC) in Asia are limited; thus, we aimed to collect and assess this information for Taiwan. METHODS: A nationwide population-based cohort study was undertaken using data from the Taiwan National Health Insurance Research Database. Primary biliary cholangitis was defined by the International Classification of Diseases, Ninth Revision, Clinical Modification code 571.6 based on alkaline phosphatase and antimitochondrial antibody measurements and ursodeoxycholic acid treatment. RESULTS: During 2002-2015, 2737 patients (2137 female patients; mean age, 57.78 years) had PBC. The average annual age- and sex-adjusted prevalence and incidence rates of PBC were 8.092/105 and 1.148/105 , respectively. Prevalent cases peaked in patients aged 50-59 years; the female-to-male ratio was 4.21. Annual prevalence rates increased with time (average percentage change, 12.03%; p < 0.0001). The annual incidence rates decreased with time (-7.39%; p = 0.000011) in female patients (-8.94%; p = 0.000003) but remained steady in male patients. Female-to-male and northern-to-southern relative risks of PBC incidence rates ranged from 2.2675 to 4.3318 and from 1.5707 to 3.1725, respectively. The 14-year hepatocellular carcinoma (HCC) cumulative incidence was 9.11%, and the mortality rate was 32.44%; the cumulative incidences of dyslipidemia, thyroid disease, and extrahepatic cancers were 65.13%, 24.40%, and 12.79%, respectively. Higher cumulative incidences of HCC (p = 0.0064) and mortality (p < 0.0001) were noted in male than female PBC patients; southern Taiwan PBC patients had higher cumulative incidences of mortality (p < 0.0001) than their northern counterparts. CONCLUSION: In Taiwan, decreasing trends in incidence rates and the female-to-male ratio of PBC patients and specific sex and geographic impacts on the incidence rates and outcomes of PBC demand further investigation.

Robust antiviral responses in severe hepatitis flare persist after early retreatment cessation and lead toward hepatitis B surface antigen loss: A proof-of-concept study.

AIM: Hepatitis B flare has been interpreted as result of immune response against upsurging hepatitis B virus (HBV) and its antigen(s) that may lead to HBV decline/clearance spontaneously. It has been speculated that antiviral therapy could halt the effective immune response with viral persistent as a consequence. A proof-of-concept study was conducted to investigate this issue. METHODS: Serial biochemical, quantitative hepatitis B surface antigen (HBsAg), interferon-γ (IFN-γ) and tumor-necrosis factor-α (TNF-α) assays were performed in four patients with severe hepatitis flare who had achieved precipitous HBsAg decline within 4 weeks of antiviral therapy. RESULTS: TNF-α and IFN-γ were found to be elevated in parallel to upsurging HBV DNA and HBsAg levels in all patients. Higher levels of TNF-α and IFN-γ and levels relative to qHBsAg were observed during and after early termination of therapy within 4 weeks in two patients and were followed by further HBsAg decline to <5 IU/ml and even achieved HBsAg loss in one patient. The patient who had stopped therapy on day 44 showed minimal HBsAg decline afterward and the patient who continued therapy showed a 10-fold rebound of qHBsAg from its nadir. The subsequent IFN-γ and TNF-α activity of these two patients was minimal. CONCLUSIONS: The results suggest that patients with severe hepatitis flare who achieved precipitous HBsAg decline may have robust immune response to clear the virus, and early termination of antiviral therapy may allow the protective immune response to continue and accelerate HBV decline toward HBsAg loss.

Hepatitis B Flare in Hepatitis B e Antigen-Negative Patients: A Complicated Cascade of Innate and Adaptive Immune Responses.

Chronic hepatitis B virus (HBV) infection is a dynamic process involving interactions among HBV, hepatocytes, and the host immune system. The natural course of chronic hepatitis B (CHB) is divided into four chronological phases, including the hepatitis B e antigen (HBeAg)-positive and HBeAg-negative phases. During HBV flare, alanine aminotransferase (ALT) levels abruptly rise to >5× the upper limit of normal; this is thought to occur due to the immune response against an upsurge in serum HBV DNA and antigen levels. Hepatitis flares may occur spontaneously, during or after antiviral therapy, or upon immunosuppression or chemotherapy in both HBeAg-positive and HBeAg-negative patients. The clinical spectrum of HBV flares varies from asymptomatic to hepatic decompensation or failure. HBeAg seroconversion with ≥ 1 year of consolidation therapy is accepted as an endpoint of oral antiviral therapy in HBeAg-positive patients, but recommendations for treating HBeAg-negative patients differ. Thus, the management of HBeAg-negative patients has attracted increasing interest. In the current review, we summarize various types of HBV flares and the associated complex cascade of innate and adaptive immune responses, with a focus on HBeAg-negative CHB patients. Hopefully, this review will provide insight into immunopathogenesis to improve the management of HBV flares in HBeAg-negative CHB patients.

Thrombin-Activated Platelets Protect Vascular Endothelium against Tumor Cell Extravasation by Targeting Endothelial VCAM-1.

When activated by thrombin, the platelets release their granular store of factors. These thrombin-activated platelets (TAPLT) have been shown to be capable of ameliorating pro-inflammatory processes. In this study, we tested if TAPLT could also protect the endothelium against tumor-related pro-inflammatory changes that promote angiogenesis and metastasis. Using endothelial cell (EC) models in vitro, we demonstrated that TAPLT protected EC against tumor conditioned medium (TCM)-induced increases of reactive oxygen species (ROS) production, EC permeability and angiogenesis, and inhibited transendothelial migration that was critical for cancer cell extravasation and metastasis. In vivo observations of TAPLT-mediated inhibition of angiogenesis and pulmonary colonization in a BALB/c nude mouse model were consistent with the in vitro findings. Neutralization of vascular cell adhesion molecule-1 (VCAM-1) binding significantly inhibited the ability of TAPLT to interact with EC and abrogated the TAPLT-mediated protection of EC against tumor angiogenesis and metastasis. Taken together, these findings suggest that VCAM-1-mediated linkage to EC is required for TAPLT to confer protection of EC against tumor-induced permeation and angiogenesis, thereby resisting tumor extravasation and metastasis.

Critical role of triglycerides for adiponectin levels in hepatitis C: a joint study of human and HCV core transgenic mice.

BACKGROUND: Both hepatitis C virus (HCV) infection and adiponectin are critically involved in metabolism. The reversal and associations of altering adiponectin levels after sustained virological responses (SVRs) following direct-acting antivirals (DAA) in HCV-infected patients remained elusive. METHODS: A joint study was conducted in a prospective cohort of 427 HCV-infected patients and a line of HCV core transgenic mice. RESULTS: Of 427, 358 had completed a course of DAA therapy and 353 had SVRs. At baseline, male sex (95% CI ß: - 1.44 to - 0.417), estimated glomerular filtration rate (eGFR) (- 0.025 to - 0.008), triglycerides (- 0.015 to - 0.005), and fibrosis-4 levels (0.08-0.297) were associated with adiponectin levels; BMI (0.029-0.327) and triglycerides levels (0.01-0.03) were associated with homeostatic model assessment for insulin resistance (HOMA-IR) in HCV-infected patients. At 24-week post-therapy, in SVR patients, male sex (- 1.89 to - 0.5) and eGFR (- 0.02 to - 0.001) levels were associated with adiponectin levels, levels of BMI (0.094-0.335) and alanine transaminase (0.018-0.078) were associated with HOMA-IR; compared with baseline levels, adiponectin levels decreased (6.53 ± 2.77 vs. 5.45 ± 2.56 µg/mL, p < 0.001). In 12-month-old HCV core transgenic mice with hepatic steatosis, triglyceride levels (0.021-0.111) were associated with adiponectin levels, and hepatic adipopnectin expression was comparable with that of control mice. CONCLUSIONS: Triglycerides and hepatic fibrosis are associated with HCV-specific alteration of adiponectin levels, and adiponectin may affect insulin sensitivity through triglycerides during HCV infection. In DAA-treated patients, after SVR, adiponectin levels decreased and the linking function of triglycerides between adiponectin and insulin sensitivity vanished. Moreover, HCV core with hepatic steatosis might affect extrahepatic adiponectin expression through triglycerides.

Hepatitis C-associated late-onset schizophrenia: a nationwide, population-based cohort study.

BACKGROUND: Whether infection with the hepatitis C virus (HCV) causes schizophrenia - and whether the associated risk reverses after anti-HCV therapy - is unknown; we aimed to investigate these topics. METHODS: We conducted a nationwide, population-based cohort study using the Taiwan National Health Insurance Research Database (TNHIRD). A diagnosis of schizophrenia was based on criteria from the International Classification of Diseases, 9th revision (295.xx). RESULTS: From 2003 to 2012, from a total population of 19 298 735, we enrolled 3 propensity-score-matched cohorts (1:2:2): HCV-treated (8931 HCV-infected patients who had received interferon-based therapy for ≥ 6 months); HCV-untreated (17 862); and HCV-uninfected (17 862) from the TNHIRD. Of the total sample (44 655), 82.81% (36 980) were 40 years of age or older. Of the 3 cohorts, the HCV-untreated group had the highest 9-year cumulative incidence of schizophrenia (0.870%, 95% confidence interval [CI] 0.556%-1.311%; p < 0.001); the HCV-treated (0.251%, 95% CI 0.091%-0.599%) and HCV-uninfected (0.118%, 95% CI 0.062%-0.213%) cohorts showed similar cumulative incidence of schizophrenia (p = 0.33). Multivariate Cox analyses showed that HCV positivity (hazard ratio [HR] 3.469, 95% CI 2.168-5.551) was independently associated with the development of schizophrenia. The HCV-untreated cohort also had the highest cumulative incidence of overall mortality (20.799%, 95% CI 18.739%-22.936%; p < 0.001); the HCV-treated (12.518%, 95% CI 8.707%-17.052%) and HCV uninfected (6.707%, 95% CI 5.533%-8.026%) cohorts showed similar cumulative incidence of mortality (p = 0.12). LIMITATIONS: We were unable to determine the precise mechanism of the increased risk of schizophrenia in patients with HCV infection. CONCLUSION: In a population-based cohort (most aged ≥ 40 years), HCV positivity was a potential risk factor for the development of schizophrenia; the HCV-associated risk of schizophrenia might be reversed by interferon-based antiviral therapy.

Interactive Impacts from Hepatitis C Virus Infection and Mixed Cryoglobulinemia on Complement Levels.

BACKGROUND/AIM: How hepatitis C virus (HCV) infection and mixed cryoglobulinemia interactively affect complement levels remains elusive, and we aimed to elucidate it. METHODS: A prospective cohort study of 678 consecutive chronic HCV-infected (CHC) patients was conducted. Of 678, 438 had completed a course of anti-HCV therapy and 362 had achieved a sustained virological response (SVR). The baseline and 24-week post-therapy variables including complement levels and mixed cryoglobulinemia status were surveyed. RESULTS: At baseline, lower complement component 3 (C3) and component 4 (C4) levels were noted in patients with than those without mixed cryoglobulinemia. The differences between pre-therapy (in 678 CHC patients) and 24-week post-therapy (in 362 SVR patients) factors associated with C3 levels were interferon λ3 (IFNL3) genotype, triglycerides, cirrhosis, and estimated glomerular filtration rate; the different associations with C4 levels were cirrhosis, sex and high sensitivity C-reactive protein. Compared with baseline, SVR patients without pre- and post-therapy mixed cryoglobulinemia had increased C3 levels, and SVR patients with pre-therapy mixed cryoglobulinemia had increased C4 levels. Lower C3 levels were noted in SVR patients with than those without post-therapy mixed cryoglobulinemia. CONCLUSIONS: HCV might affect C3 levels through IFNL3 genotype, triglycerides, cirrhosis, and renal function; and affect C4 with a link to sex, inflammation, and cirrhosis. That C3 levels decreased in CHC patients without mixed cryoglobulinemia or in SVR patients with post-therapy mixed cryoglobulinemia, and C4 levels decreased in CHC patients with mixed cryoglobulinemia, suggested that mixed cryoglobulinemia and HCV infection antagonistically and synergistically decrease C3 and C4 levels, respectively.

Hepatitis Flares Are Associated With Better Outcomes Than No Flare in Patients With Decompensated Cirrhosis and Chronic Hepatitis B Virus Infection.

BACKGROUND & AIMS: Little is known about the effects of baseline hepatitis flares (level of alanine aminotransferase ≥5-fold above the upper limit of normal) on the outcomes of patients with chronic hepatitis B virus (HBV) infection with decompensated cirrhosis treated with nucleos(t)ide analogues. We aimed to investigate these effects. METHODS: We performed a cohort study of 511 consecutive patients (78.1% men; 58.7% with flares at baseline) with chronic HBV infection and decompensated cirrhosis who were treated with nucleos(t)ide analogues as soon as decompensation was noted. Patients were enrolled from January 2002 to March 2018 at a tertiary care center in Taiwan and followed up for 16 years. RESULTS: Patients with hepatitis flares had higher mean baseline levels of HBV DNA (6.44 ± 1.52 vs 6.08 ± 1.46 log10 IU/mL; P = .003), hepatitis B surface antigen, and total bilirubin; prolonged prothrombin time; higher platelet counts (108.0 ± 42.9 vs 83.6 ± 44.7 103/µL; P < .001); and a higher proportion were infected with HBV genotype B, compared with patients without flares. Patients with flares had lower ratios of neutrophils to lymphocytes than patients with flares (6.14 ± 9.18 vs 9.12 ± 1.36; P = .019); were less likely than patients without flares to be positive for hepatitis B e antigen, ascites, esophageal varices, or splenomegaly; and a lower proportion died or underwent liver transplantation (46.5% vs 73.2% of patients without flares; P < .001), even though the patients without flares had similar short-term (<3 mo) outcomes. Factors associated independently with baseline flares were esophageal varices (odds ratio [OR], 0.165; 95% CI, 0.067-0.406), ascites (OR, 0.415; 95% CI, 0.178-0.969), levels of total bilirubin (OR, 1.158; 95% CI, 1.041-1.269), prolonged prothrombin time (OR, 1.095; 95% CI, 1.033-1.168), and higher platelet counts (OR, 1.009; 95% CI, 1.00-1.018). After we used propensity score matching to match patients with and without baseline flares, factors associated with the cumulative incidence of death or liver transplantation were flares (hazard ratio [HR], 0.491; 95% CI, 0.317-0.76), ratio of neutrophils to lymphocytes (HR, 1.278; 95% CI, 1.027-1.591), and prolonged prothrombin time (HR, 1.223; 95% CI, 1.052-1.423). CONCLUSIONS: In a 16-year study of patients with chronic HBV infection and decompensated cirrhosis treated with nucleos(t)ide analogues, a baseline flare of hepatitis was associated independently with better long-term (≥3 mo) outcomes than no flare.

A GALNT14 rs9679162 genotype-guided therapeutic strategy for advanced hepatocellular carcinoma: systemic or hepatic arterial infusion chemotherapy.

Although targeted agents are recommended as the first-line treatments for advanced hepatocellular carcinoma (aHCC), systemic chemotherapy or hepatic arterial infusion chemotherapy (HAIC) are still being used in Asian countries. Beside economic considerations, it was found that targeted drugs could not significantly prolong overall survival in aHCC patients with distant metastasis. In addition, chemotherapy could achieve complete response in a small proportion of patients. Here, we aimed to investigate whether combination of three previously identified single nucleotide polymorphism (SNP) predictors (GALNT14-rs9679162, WWOX-rs13338697, and rs6025211) could guide our choice between systemic chemotherapy, HAIC, and targeted agents in aHCC patients. A cohort of 237 real-world aHCC patients (171 receiving systemic chemotherapy followed by various anticancer treatments including sorafenib; 66 receiving HAIC) were included for outcome analysis. By combining the three SNP markers with or without addition of two clinical criteria (tumor diameter <8 cm, neutrophils <80%), small groups of patients were found to harbor high complete response rates to systemic chemotherapy (35.3% if the 3-SNP signature alone matched; 60.0% if clinical criteria also matched). Subsequent sorafenib treatment for chemotherapy non-responders was associated with longer overall survival (P < 0.001). In HAIC-treated patients, GALNT14-rs9679162 genotype "GG" was associated with longer overall survival (P = 0.019, median survival > 10.5 months). In conclusion, pre-test for the 3-SNP signature in aHCC patients could identify potential systemic chemotherapy or HAIC responders. Chemotherapy non-responders still benefited from subsequent sorafenib treatment. Accordingly, we propose a roadmap for aHCC patients when chemotherapy or HAIC is to be used.

Decreasing seroprevalence of anti-hepatitis D virus antibodies in the antiviral era with inverse association with hepatitis B virus DNA, Taiwan, 2006 to 2019.

We examined the seroprevalence change of anti-hepatitis D virus (HDV) antibodies in Taiwan from 2006 to 2019. A total of 1147 patients who had chronic hepatitis B virus (HBV) infection were assessed. Of them, 51 (4.4%) were positive for anti-HDV antibodies. Comparison between anti-HDV-positive and negative groups was performed to examine clinical and virological factors related to anti-HDV positivity. It was found that the median HBV-DNA concentration was 1.6 × 105 IU/mL (range, <20-4.5 × 1010 IU/mL) and <20 IU/mL (range, <20-2.0 × 109 IU/mL) for patients with negative and positive anti-HDV antibodies, respectively (P < .001). In addition, a progressive year-to-year decrease of anti-HDV seroprevalence was unveiled. For patients who had HBV-DNA >15 000 IU/mL, the year-to-year (calculated every 2 years) seropositive rates of anti-HDV were 10.0%, 7.9%, 0.7%, 0.3%, 0%, 0%, and 0% (P < .001). For patients who had HBV-DNA <15 000 IU/mL, the year-to-year seropositive rates were 18.6%, 12.8%, 7.8%, 5.0%, 7.3%, 8.0%, and 3.7% (P < .001). In conclusion, seropositive of anti-HDV was inversely associated with HBV-DNA levels. A progressive decrease of anti-HDV seroprevalence was found with no anti-HDV-positive cases detected in high HBV-DNA patient group after 2014.

Impact of mixed cryoglobulinemia on patients with spontaneous hepatitis C virus clearance: A 13-year prospective cohort study.

BACKGROUND: The prevalence and associations of mixed cryoglobulinemia (MC) in patients with spontaneous clearance of hepatitis C virus (HCV) remain elusive. MATERIALS AND METHODS: A 13-year prospective cohort study of patients with spontaneous HCV clearance was conducted in a tertiary care centre. Baseline characteristics, incident cardiovascular and neurologic events and cancers were analysed. RESULTS: Of 104 consecutive patients (mean age: 54.08 years old; females: 71 [68%]), 37 (34.6%) had MC and 6 (5.8%) had cirrhosis. MC (+) patients were more female (86% vs 58%, P = .002), had higher rate of cirrhosis (14% vs 1.5%, P = .012), higher levels of Immunoglobulin G (IgG; P = .001), IgM (P = .002) and fibrosis-4 (FIB-4) (P = .004), but lower levels of complement C4 (P = .034) than the MC (-) patients. Female gender (95% confidence interval [CI] of odds ratio: 1.402-26.715), levels of IgG (1.000-1.004), IgM (1.009-1.037) and FIB-4 (1.217-3.966) were independently associated with MC. Baseline rheumatoid factor (RF) levels were independently associated with incident cancer (95% CI hazard ratio [HR]: 1.001-1.030 [HR: 1.015], P = .039). With a cut-off value of 11.3 IU/mL, RF levels significantly predicted incident cancer (area under curve: 0.865, P = .002). No different cumulative incidences of cardiovascular and neurologic events, cancers or mortalities were identified between MC (+) and MC (-) patient. CONCLUSIONS: Approximately 1/3 of patients with spontaneous HCV clearance yielded MC, which harboured similar characteristics of MC in patients with chronic hepatitis C. Despite the negligible role of MC in the prognosis of patients with spontaneous HCV clearance, the connection between RF and incident cancer demands further investigation.

Rescue therapy with rifabutin regimen for refractory Helicobacter pylori infection with dual drug-resistant strains.

BACKGROUND: There is no current standard rescue treatment for dual drug-resistant strains of Helicobacter pylori (H. pylori). This aim of this study was to investigate the efficacy of rifabutin-based triple therapy for patients infected with dual drug-resistant strains to clarithromycin and levofloxacin. METHODS: After 2 or 3 H. pylori treatment failures, patients underwent upper endoscopy with tissue biopsies. Phenotypic and genotypic resistances were determined using agar dilution test and polymerase chain reaction with direct sequencing, respectively. Patients infected with dual drug-resistant (clarithromycin and levofloxacin) strains and receiving rifabutin-based triple therapy (rifabutin 150 mg bid, amoxicillin 1 g bid and esomeprazole 40 mg bid for 10 days) were enrolled. Eradication status was determined by 13C-urea breath test 4 weeks after treatment completion. RESULTS: A total of 39 patients infected with dual drug-resistant strains were enrolled in this study, with a mean age of 55.9 years. The eradication rate was 79.5% (31/39) (95% confidence intervals: 54.96% ~ 111.40%). Adverse event was reported in 23.1% (9/39) of patients but they were mild and tolerable. In univariate analysis, no factor was identified as an independent predictor of eradication failure. CONCLUSIONS: Our current study demonstrated that rifabutin-based triple therapy was well tolerated and yielded an acceptable eradication rate for patients infected with dual drug-resistant strains of H. pylori.

Roles of Adipokines in Digestive Diseases: Markers of Inflammation, Metabolic Alteration and Disease Progression.

Adipose tissue is a highly dynamic endocrine tissue and constitutes a central node in the interorgan crosstalk network through adipokines, which cause pleiotropic effects, including the modulation of angiogenesis, metabolism, and inflammation. Specifically, digestive cancers grow anatomically near adipose tissue. During their interaction with cancer cells, adipocytes are reprogrammed into cancer-associated adipocytes and secrete adipokines to affect tumor cells. Moreover, the liver is the central metabolic hub. Adipose tissue and the liver cooperatively regulate whole-body energy homeostasis via adipokines. Obesity, the excessive accumulation of adipose tissue due to hyperplasia and hypertrophy, is currently considered a global epidemic and is related to low-grade systemic inflammation characterized by altered adipokine regulation. Obesity-related digestive diseases, including gastroesophageal reflux disease, Barrett's esophagus, esophageal cancer, colon polyps and cancer, non-alcoholic fatty liver disease, viral hepatitis-related diseases, cholelithiasis, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, and diabetes, might cause specific alterations in adipokine profiles. These patterns and associated bases potentially contribute to the identification of prognostic biomarkers and therapeutic approaches for the associated digestive diseases. This review highlights important findings about altered adipokine profiles relevant to digestive diseases, including hepatic, pancreatic, gastrointestinal, and biliary tract diseases, with a perspective on clinical implications and mechanistic explorations.

Off-therapy precipitous HBsAg decline predicts HBsAg loss after finite entecavir therapy in HBeAg-negative patients.

Cessation of nucleos(t)ide analogue (Nuc) therapy in HBeAg-negative patients may increase HBsAg loss rate in patients with sustained remission (SR) and non-retreated clinical relapsers (CR). To investigate and compare the HBsAg kinetics from end of treatment (EOT) to HBsAg loss in these patients, serial serum samples after EOT from 36 SR and 12 CR with HBsAg loss (study group) and an 1:1 matched control who remained HBsAg-seropositive (control group) were assayed retrospectively for quantitative HBsAg (qHBsAg). The results showed that study group SR and CR had comparable EOT features except SR had lower EOT qHBsAg (67.5 vs 350.5 IU/mL; P = 0.02; < 100 IU/mL: 58.3% vs 25%; P = 0.09). All showed gradual qHBsAg decrease then "precipitous HBsAg decline" (>0.5 log10 IU/mL in 1 year) prior to HBsAg loss. Patients with EOT qHBsAg <100 showed earlier (<12 months) "precipitous HBsAg decline" (91.7% vs 58.3%; P = 0.017) and sooner HBsAg loss (5.5 vs 21.9 months; P = 0.026). The control group also showed gradual qHBsAg decrease but less frequent "precipitous HBsAg decline" (39.6% vs 100%; P < 0.001) which occurred later (15.1 vs 5.7 months; P = 0.003) and was less steep (slope -0.6 vs -1.65 log10 IU/mL/year; P < 0.001). HBsAg loss was achieved in 92.9% of the patients with "precipitous HBsAg decline" >0.76 log10 IU/mL in 1 year. In conclusion, both the SR and CR groups showed gradual HBsAg decrease followed by a "precipitous HBsAg decline", which is a prerequisite for HBsAg loss. Lower EOT HBsAg in the SR group and qHBsAg <100 IU/mL may reflect better immune control hence followed by sooner HBsAg loss.