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.

Evolutionary relationship between antimitochondrial antibody positivity and primary biliary cholangitis in Taiwan: a 16-year hospital cohort study.

Background: How antimitochondrial antibody (AMA)-positive patients evolve to have primary biliary cholangitis (PBC) in viral hepatitis-endemic areas is unknown. Objectives: We aimed to investigate this evolution in Taiwan. Design/methods: A 16-year medical center-based cohort study of 2,095,628 subjects was conducted in Taiwan, an Asian country endemic to viral hepatitis. AMA-positive subjects were those with positive AMA with alkaline phosphatase (ALP) ⩽1.5 times the upper limit of normal (ULN), and PBC was defined as positive AMA with ALP >1.5 × ULN. Results: AMA-positive subjects had a lower average age- and sex-adjusted prevalence than PBC patients (4.68/105 versus 11.61/105, p = 0.0002), but their incidence was comparable (0.99/105 versus 1.12/105, p = 0.36). The former group had a borderline significantly lower mean age (56.59 years versus 58.10 years, p = 0.06) and a lower female-to-male ratio (2.85:1 versus 5.44:1, p < 0.0001). Both AMA-positive subjects (prevalence change: 20.0%, p < 0.01; incidence change: -9.2%, p < 0.01) and PBC patients (prevalence change: 14.6%, p < 0.01; incidence change: -4.7%, p < 0.01) prevalence rate increased but the incidence rate decreased. Among the 423 AMA-positive subjects, 77 (18.2%) developed PBC, for a mean duration of 1.757 years. Compared with AMA-positive subjects, PBC patients had similar concurrent chronic hepatitis B (CHB) rates (2.7% versus 4.3%, p = 0.197) but lower chronic hepatitis C (CHC) rates (3.69% versus 15.60%, p < 0.01). Conclusion: PBC was more prevalent than AMA-positive subjects, and PBC patients had a higher female-to-male ratio than AMA-positive subjects, of whom 18.2% developed PBC (mean lag: 1.757 years). Upward trends in prevalence rates and downward trends in incidence rates were noted for both AMA-positive subjects and PBC. CHB was rare, CHC was more prevalent among PBC patients than the general population, and CHC was less prevalent among PBC than among AMA-positive subjects.

Evolutionary relationship between AMA positivity and PBC in Taiwan PBC was more prevalent than AMA-positive subjects, and PBC patients had a higher female-to-male ratio than AMA-positive subjects, of whom 18.2% developed PBC (mean lag: 1.757 years). Upward trends in prevalence rates and downward trends in incidence rates were noted for both AMA-positive subjects and PBC. CHB was rare, CHC was more prevalent among PBC patients than the general population, and CHC was less prevalent among PBC than among AMA-positive subjects.

Hepatocellular Carcinoma with Gastric Metastasis Mimicking a 4 cm Gastrointestinal Stromal Tumor After a 3-year Disease-free Interval.

Hepatocellular carcinoma (HCC) is an aggressive tumor that usually occurs in patients with chronic liver disease and cirrhosis. Surgical resection is an optimal treatment for HCC, but the 5-year recurrence rates are significantly high. The majority of recurrent HCCs occur through intrahepatic metastasis with local tumor progression, and less than 20% of recurrences are extrahepatic metastases. HCC with gastric metastasis is extremely rare, and it is easily misdiagnosed as primary gastric cancer with liver metastasis. An 80-year-old male chronic hepatitis B virus carrier had received lamivudine and entecavir for years and was regularly followed up in the clinic. He had a 3.5 cm solitary HCC with microvascular invasion and received curative surgical resection in 2009. In 2013, he developed a 1.3 cm solitary HCC again and was treated with combination therapy with radiofrequency ablation and pure ethanol injection. Afterwards, he was followed every 3-6 months and was HCC-free. Three years later, in 2016, endoscopy for intermittent epigastralgia showed a solitary 4 cm intraluminal gastric subepithelial tumor without mucosal ulcers or erosions over the gastric fundus. All imaging studies, including computed tomography, favored the diagnosis of gastrointestinal stromal tumor (GIST), but the pathology of the tumor proved to be HCC. The patient did not receive any systemic anticancer therapy but only wedge resection of the stomach and remained tumor- and HCC-free until his latest clinic visit in 2023. The current case is unique and indicates the possibility of HCC with late solitary gastric metastasis mimicking GIST. Complete gastric tumor resection ensured an extremely good outcome for the patient, which is different from the devastating prognosis of most cases of HCC with gastric metastasis.

Long-term renal function alterations in hepatitis C patients with SVRs: Impacts of therapies and mixed cryoglobulinemia.

BACKGROUND / AIMS: Effects of anti-hepatitis C virus (HCV) therapeutic regimens and mixed cryoglobulinemia on long-term renal function of HCV-infected patients with viral clearance have not been determined. METHODS/MATERIALS: A prospective 10-year cohort study of 1212 HCV-infected patients (interferon-based therapy, n = 615; direct-acting antiviral (DAA) therapy, n = 434) was conducted. RESULTS: At baseline, age, body mass index (BMI), hemoglobin (Hb) and uric acid (UA) levels, and fibrosis-4 score were associated with estimated glomerular filtration rates (eGFRs) in HCV-infected patients. At 24 weeks posttherapy, age, BMI, and Hb and UA levels were associated with eGFRs in patients with a sustained virological response (SVR) (n = 930). Compared with those at baseline, the eGFRs were lower in SVR patients at 24 weeks posttherapy, regardless of the therapeutic regimen. The eGFRs reverted to baseline levels in interferon-treated SVR patients up to 10 years posttherapy but remained decreased in DAA-treated SVR patients up to 4 years posttherapy. Longitudinally, repeated measures analyses with generalized estimating equations showed that the interactions between DAA-based therapy and mixed cryoglobulinemia (OR: 3.291) and Hb levels (1.778) were positively, while DAA-based therapy (0.442), age (0.956), UA levels (0.698), homeostasis model assessment-insulin resistance index (0.961) and complement 4 levels (0.9395) were negatively associated with the eGFR. Among DAA-treated SVR patients, the baseline eGFR (OR: 1.014; 95%CI OR: 1.004-1.023) and high-sensitivity C-reactive protein (HR: 1.082; 95%CI HR: 1.018-1.15) were associated with eGFR reduction at 24 weeks and 4 years posttherapy, respectively. CONCLUSIONS: Hepatic fibrosis was an HCV-related factor for renal function. Longitudinally, DAA therapy was negatively, while the interaction between DAA therapy and mixed cryoglobulinemia was positively associated with renal function in SVR patients; deteriorated renal function was recovered in interferon-treated SVR patients. Particularly in DAA-treated SVR patients, baseline renal function and systemic inflammation were associated with short- and long-term reductions in renal function, respectively.

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.

Molecular characterization of rifabutin-resistance in refractory Helicobacter pylori infection in Taiwan.

OBJECTIVES: To explore the molecular characteristics of rpoB, encoding ß-subunit of DNA-directed RNA polymerase, and unravel the link to rifabutin-resistance in patients with refractory Helicobacter pylori infection. METHODS: From January 2018-March 2021, a total of 1590 patients were screened for eligibility to participate in the study. Patients with refractory H. pylori infection were confirmed by using the (13C)-urea breath assay. All enrolled patients underwent esophagogastroduodenoscopy, and biopsies were taken for H. pylori culture and antibacterial susceptibility testing. Sequence analysis of rpoB was conducted for all rifabutin-resistant isolates. RESULTS: In total, 70 patients were diagnosed with refractory H. pylori infection, and 39 isolates were successfully cultured. Amongst, 10 isolates were identified as rifabutin-resistance and nine isolates exhibited at least one amino acid substitution in RpoB. Isolates with a minimal inhibitory concentration >32 mg/l displayed a higher number of mutational changes in RpoB than the others. Additionally, more amino acid substitutions in RpoB correlated with developing a higher minimal inhibitory concentration for H. pylori rifabutin-resistance. CONCLUSION: Our findings highlight the relationship between rifabutin-resistance in refractory H. pylori infection and specific mutations in RpoB, which will aid the clinical selection of appropriate antibacterial agents with better therapeutic effects.

Taiwan Association for the Study of the Liver-Taiwan Society of Cardiology Taiwan position statement for the management of metabolic dysfunction- associated fatty liver disease and cardiovascular diseases.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is an increasingly common liver disease worldwide. MAFLD is diagnosed based on the presence of steatosis on images, histological findings, or serum marker levels as well as the presence of at least one of the three metabolic features: overweight/obesity, type 2 diabetes mellitus, and metabolic risk factors. MAFLD is not only a liver disease but also a factor contributing to or related to cardiovascular diseases (CVD), which is the major etiology responsible for morbidity and mortality in patients with MAFLD. Hence, understanding the association between MAFLD and CVD, surveillance and risk stratification of MAFLD in patients with CVD, and assessment of the current status of MAFLD management are urgent requirements for both hepatologists and cardiologists. This Taiwan position statement reviews the literature and provides suggestions regarding the epidemiology, etiology, risk factors, risk stratification, nonpharmacological interventions, and potential drug treatments of MAFLD, focusing on its association with CVD.

Hepatitis C accelerates extrahepatic cholangiocarcinoma risk: a joint study of hospital-based cases and nationwide population-based cohorts in a viral hepatitis-endemic area.

Hepatitis C virus (HCV) infection causes many cancers, including intrahepatic cholangiocarcinoma. Whether it increases the risk of extrahepatic cholangiocarcinoma (ECC) is unknown. A 10-year nationwide population-based cohort study of the Taiwan National Health Insurance Research Database (TNHIRD) was conducted. ECC was defined by ICD-9-CM code 156 or ICD-O-3 code C23-24. Risk factors and HCV core protein expression were surveyed in patients with ECC from a tertiary-care center. Out of 11,892,067 patients, three propensity score-matched TNHIRD cohorts were matched at a 1:4:4 ratio: HCV-treated (8,331 patients with interferon-based therapy >6 months), HCV-untreated (n=33,324), and HCV-uninfected cohorts (n=33,324). The cumulative incidence of ECC [HCV-treated: 0.088%, 95% confidence interval (CI): 0.035-0.198%; HCV-untreated: 0.095%, 0.047-0.179%; HCV-uninfected: 0.048%, 0.017-0.119%] was lowest in the HCV-uninfected cohort (P=0.0285) but was not different between the treated and untreated cohorts (P=0.5436). HCV infection [HCV-treated cohort: hazard ratio (HR): 3.618, 95% CI HR: 1.253-10.451; HCV-untreated cohort: 2.593, 95% CI HR: 1.077-6.241; reference: HCV-uninfected cohort] and age ≥49 years (HR: 5.139, 95% CI HR: 1.613-16.369) were associated with ECC development. Among the 855 hospitalized ECC patients (males: 57%; baseline age: 63.09±11.75 years, 2008-2018), the HCV Ab-positive rate was 8.4%. The HCV Ab-positive patients were more frequently female than their counterparts (66.7% vs. 40.8%, P=0.009). No HCV core-positive cells were found in the ECC tissues. In conclusion, HCV infection and age ≥49 years are potential risk factors for ECC. The HCV-associated ECC risk might not be reversed by interferon-based anti-HCV therapy nor associated with in situ HCV core-related carcinogenesis.

Acoustic radiation force impulse predicts long-term outcomes in a large-scale cohort: High liver cancer, low comorbidity in hepatitis B virus.

BACKGROUND: Acoustic radiation force impulse (ARFI) is used to measure liver fibrosis and predict outcomes. The performance of elastography in assessment of fibrosis is poorer in hepatitis B virus (HBV) than in other etiologies of chronic liver disease. AIM: To evaluate the performance of ARFI in long-term outcome prediction among different etiologies of chronic liver disease. METHODS: Consecutive patients who received an ARFI study between 2011 and 2018 were enrolled. After excluding dual infection, alcoholism, autoimmune hepatitis, and others with incomplete data, this retrospective cohort were divided into hepatitis B (HBV, n = 1064), hepatitis C (HCV, n = 507), and non-HBV, non-HCV (NBNC, n = 391) groups. The indexed cases were linked to cancer registration (1987-2020) and national mortality databases. The differences in morbidity and mortality among the groups were analyzed. RESULTS: At the enrollment, the HBV group showed more males (77.5%), a higher prevalence of pre-diagnosed hepatocellular carcinoma (HCC), and a lower prevalence of comorbidities than the other groups (P < 0.001). The HCV group was older and had a lower platelet count and higher ARFI score than the other groups (P < 0.001). The NBNC group showed a higher body mass index and platelet count, a higher prevalence of pre-diagnosed non-HCC cancers (P < 0.001), especially breast cancer, and a lower prevalence of cirrhosis. Male gender, ARFI score, and HBV were independent predictors of HCC. The 5-year risk of HCC was 5.9% and 9.8% for those ARFI-graded with severe fibrosis and cirrhosis. ARFI alone had an area under the receiver operating characteristic curve (AUROC) of 0.742 for prediction of HCC in 5 years. AUROC increased to 0.828 after adding etiology, gender, age, and platelet score. No difference was found in mortality rate among the groups. CONCLUSION: The HBV group showed a higher prevalence of HCC but lower comorbidity that made mortality similar among the groups. Those patients with ARFI-graded severe fibrosis or cirrhosis should receive regular surveillance.

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.

Case report: Unusual viral evolutions following antiviral therapies in a patient with concurrent hepatitis B virus and hepatitis C virus infection.

Concurrent hepatitis B virus (HBV) and hepatitis C virus (HCV) infection is not uncommon as the two viruses shared the similar transmission routes. HCV is usually the dominant virus to suppress HBV, and HBV reactivation may occur during or after the course of anti-HCV treatment. By contrast, HCV reactivation after anti-HBV therapy in the concurrent HBV- and HCV-infected patients was rarely noted. Here, we reported the unusual viral evolutions of a patient with concurrent HBV and HCV infection, in whom HCV reactivation occurred during the entecavir therapy to rescue the severe HBV flare, while the following anti-HCV combination therapy with pegylated interferon and ribavirin elicited the second HBV flare despite sustained virological response to HCV infection, and further entecavir therapy healed the flare.

Extracellular Nicotinamide Phosphoribosyltransferase as a Surrogate Marker of Prominent Malignant Potential in Colonic Polyps: A 2-Year Prospective Study.

BACKGROUND/AIMS: The implications of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), a cancer metabokine, in colonic polyps remain uncertain. METHODS: A 2-year prospective cohort study of patients who underwent colonoscopy was conducted. Biochemical parameters and serum eNAMPT levels were analyzed at baseline and every 24 weeks postpolypectomy. NAMPT-associated single-nucleotide polymorphisms (SNPs), including rs61330082, rs2302559, rs10953502, and rs23058539, were assayed. RESULTS: Of 532 patients, 80 (15%) had prominent malignant potential (PMP) in colonic polyps, including villous adenomas (n = 18, 3.3%), adenomas with high-grade dysplasia (n = 33, 6.2%), and adenocarcinomas (n = 29, 5.5%). Baseline associations were as follows: colonic polyp pathology (p < 0.001), total cholesterol (p = 0.019), and neutrophil-to-lymphocyte ratio (p = 0.023) with eNAMPT levels; and age (p < 0.001), polyp size (p < 0.001), and eNAMPT levels (p < 0.001) with polyp pathology. Higher baseline eNAMPT levels were noted in patients harboring polyps with PMP than in patients without PMP (p < 0.001), and baseline eNAMPT levels significantly predicted PMP (cutoff: >4.238 ng/mL, p < 0.001). Proportions of eNAMPT-positive glandular and stromal cells were higher in polyps with PMP than in polyps without PMP (64.55 ± 11.94 vs. 14.82 ± 11.45%, p = 0.025). eNAMPT levels decreased within 48 weeks postpolypectomy (p = 0.01) and remained stable afterward regardless of PMP until 96 weeks postpolypectomy. However, those with PMP had a higher degree of eNAMPT decline within 24 weeks (p = 0.046). All investigated SNPs were in linkage disequilibrium with each other but were not associated with eNAMPT levels. CONCLUSION: With a link to inflammation and lipid metabolism, along with its decreasing trend after polypectomy, serum eNAMPT may serve as a surrogate marker of PMP in colonic polyps. In situ probing of the NAMPT-associated pathway holds promise in attenuating PMP, as much of the eNAMPT likely originates from colonic polyps.

Emerging Therapies for Chronic Hepatitis B and the Potential for a Functional Cure.

Worldwide, an estimated 296 million people are living with chronic hepatitis B virus (HBV) infection, with a significant risk of morbidity and mortality. Current therapy with pegylated interferon (Peg-IFN) and indefinite or finite therapy with nucleoside/nucleotide analogues (Nucs) are effective in HBV suppression, hepatitis resolution, and prevention of disease progression. However, few achieve hepatitis B surface antigen (HBsAg) loss (functional cure), and relapse often occurs after the end of therapy (EOT) because these agents have no direct effect on durable template: covalently closed circular DNA (cccDNA) and integrated HBV DNA. Hepatitis B surface antigen loss rate increases slightly by adding or switching to Peg-IFN in Nuc-treated patients and this loss rate greatly increases up to 39% in 5 years with finite Nuc therapy with currently available Nuc(s). For this, great effort has been made to develop novel direct-acting antivirals (DAAs) and immunomodulators. Among the DAAs, entry inhibitors and capsid assembly modulators have little effect on reducing HBsAg levels; small interfering RNA, antisense oligonucleotides, and nucleic acid polymers in combination with Peg-IFN and Nuc may reduce HBsAg levels significantly, even a rate of HBsAg loss sustained for > 24 weeks after EOT up to 40%. Novel immunomodulators, including T-cell receptor agonists, check-point inhibitors, therapeutic vaccines, and monoclonal antibodies may restore HBV-specific T-cell response but not sustained HBsAg loss. The safety issues and the durability of HBsAg loss warrant further investigation. Combining agents of different classes has the potential to enhance HBsAg loss. Compounds directly targeting cccDNA would be more effective but are still in the early stage of development. More effort is required to achieve this goal.

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.

Association between viral hepatitis and metabolic syndrome in lung function impairment: A Taiwan community-based study.

OBJECTIVES: Metabolic syndrome (MetS) and hepatitis C virus (HCV) are associated with a higher risk of impaired pulmonary function (iPF). This study aimed to investigate the relationships among MetS, iPF, and viral hepatitis. METHODS: This community-based study enrolled participants undergoing annual health check-ups in southern Taiwan between March and December 2019. We performed multivariable logistic regression analyses adjusted for demographics and characteristics to identify the factors associated with iPF. RESULTS: A total of 2337 participants completed examinations, of whom 928 (39.7%) had iPF. The participants with iPF were elderly (68.8 ± 12.8 years old) and predominately female (63%). MetS increased the risk of iPF (odds ratio (OR) 1.51, 95% confidence interval (CI) 1.27-1.81, p < 0.001). Beyond age (OR 1.03, 95% CI 1.02-1.04) and smoking (OR 1.309, 95% CI 1.004-1.705), female sex (OR 0.74, 95% CI 0.59-0.93) and high education level (OR 0.96, 95% CI 0.94-0.98, p < 0.001) protected against iPF. HCV was not significantly associated with iPF (OR 1.17, 95% CI 0.90-1.52, p = 0.235) in multivariable analysis. MetS was associated with a higher risk of iPF in the non-HBV/HCV group (OR 1.86, 95% CI 1.54-2.26) and HBV alone group (OR 3.44, 95% CI 1.89-6.28), but not in the HCV alone group (OR 1.02, 95% CI 0.64-1.62). DISCUSSION: MetS was an independent predictor of iPF, especially the restrictive type, and had different effects in the HBV/non-viral hepatitis and HCV groups. Female sex and education were inversely associated with iPF.

Comparison of Clinical Manifestations and Pathology between Kimura Disease and IgG4-Related Disease: A Report of Two Cases and Literature Review.

Kimura disease (KD) is a rare, chronic proliferative condition presenting as a subcutaneous mass predominantly located in the head and neck region; it is characterized by eosinophilia and elevated serum IgE levels. IgG4-related disease (IgG4RD) is a fibroinflammatory condition characterized by swelling in single or multiple organs and the infiltration of IgG4 plasma cells. Herein, we presented two cases. Case 1 is a 38-year-old man with a painless mass in his right postauricular region, and Case 2 is a 36-year-old man with painless lymphadenopathy in his bilateral postauricular region. After surgical excision, they showed good recovery with no relapse. Although Cases 1 and 2 shared several overlapping pathological manifestations, there were a few differences that allowed the differentiation of KD and IgG4RD.

Hepatitis C Virus Reactivation in Anti-HCV Antibody-Positive Patients with Chronic Hepatitis B Following Anti-HBV Therapies.

Background and Aims: Whether hepatitis C virus (HCV) reactivation occurs and how the viral load evolves in anti-HCV antibody-positive chronic hepatitis B (CHB) patients who underwent nucleos(t)ide analogue (Nuc) therapies remain unsolved. Methods: A cohort of 66 such patients was studied. Results: At the start of Nuc treatment (baseline), all patients had detectable hepatitis B virus (HBV) DNA levels (6.05 ± 1.88 log IU/mL), while HCV RNA levels (3.79 ± 1.43 log IU/mL) were detected (i.e., chronic hepatitis C (CHC)) in only 13 patients (19.7%). Following Nuc therapies, HBV DNA levels reached the nadirs at end of therapy (EOT) (6.05 ± 1.88 vs. 0.25 ± 0.99 log IU/mL, p < 0.0001) and relapsed at 6 months after EOT (6mEOT) at a level of 3.45 ± 2.64 log IU/mL compared with EOT (p < 0.0001). Among the 13 CHC patients, a non-significant decrease in HCV RNA was noted at EOT (3.52 ± 1.71 vs. 2.77 ± 2.63 log IU/mL, p = 0.166) but tended to decrease further at 6mEOT (2.77 ± 2.63 vs. 1.89 ± 2.06 log IU/mL, p = 0.063). Two of the thirteen CHC patients showed an increase in HCV-RNA ≥ 1 log10 IU/mL at EOT, and one of the fifty-three patients with undetectable HCV RNA at baseline (i.e., resolved past HCV infection) showed detectable HCV RNA at year 1 (3200 IU/mL) and year 2 (1240 IU/mL) following entecavir therapy. Conclusions: HCV reactivation did occur during HBV suppression, and the rate was 4.5% (3/66), 15.4% (2/13), and 1.9% (1/53), for all patients, CHC patients, and patients with resolved past HCV infection, respectively. The reverse HBV and HCV viral evolutions at 6mEOT indicate that HBV relapse may suppress HCV replication again.

Alanine aminotransferase to aspartate aminotransferase ratio and hepatitis B virus on metabolic syndrome: a community-based study.

Background: The serum aminotransferase elevation in metabolic syndrome (MetS) reflected hepatosteatosis, but there is a conflict with the coexistence of viral hepatitis, especially for the hepatitis B virus (HBV). Thus, this study aimed to investigate the relationship between the alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ratio, MetS, and HBV infection in a rural Taiwanese population. Methods: We conducted a cross-sectional analysis in southern Taiwan between March and December 2019. Multivariable logistic regression analyses adjusted for demographics, education, dietary behaviors, irregular exercise, substance use, and viral markers were performed to investigate the association between the ALT/AST ratio and MetS. Results: Altogether, 2,416 participants (891 men and 1,525 women; mean age, 64.1 ± 14.9 years) were enrolled. Of the participants, 22.7% (n = 519) were seropositive for viral hepatitis. In the multivariable analysis, age [odds ratio (OR) 1.02, 95% CI 1.01-1.03, p < 0.001], ALT/AST ratio >1 (OR 2.63, 95% CI 2.15-3.21, p < 0.001), education (OR 0.96, 95% CI 0.94-0.98, p < 0.001), and HBV seropositivity (OR 0.70, 95% CI 0.52-0.95, p = 0.021) were associated with the risk of MetS. The area under the curve of the ALT/AST ratio was 0.62 (95% CI 0.60-0.64, p < 0.001), and the cutoff value was >0.852 for the Youden index. Conclusion: An ALT/AST ratio >1 could be a simple index for MetS prediction during community checkups. In contrast to age and betel nut chewing, HBV seropositivity and higher education might be inversely associated with MetS. Aggressive health promotion for MetS prevention has emerged as essential in participants without HBV and with lower education levels. Further large-scale, longitudinal studies are needed to unlink these correlations.