Trajectories of hepatic steatosis and incidence of cardiovascular disease over a 29-year follow-up.

AIM: To examine the dynamic change in hepatic steatosis status during repeated assessments over time, and its potential impact on the risk of developing cardiovascular disease (CVD). METHODS: We assessed trajectories of hepatic steatosis and other metabolic disorders in 3134 middle-aged adults undergoing longitudinal assessment of ultrasonography during a pre-baseline period (1993-2009) in a population-based cohort study of liver health. Subsequently, we determined the association of hepatic steatosis trajectories with the incidence of CVD among 2185 CVD-free individuals, followed until 2021. Metabolic risk factors and cardiovascular events (including coronary heart disease and stroke) were determined through medical examination and linkage with nationwide health databases. RESULTS: We identified three discrete trajectories of hepatic steatosis according to changing pattern over time through group-based trajectory modeling: "stable, non-steatosis" (n = 1298), "intermittent" (n = 921), and "persistent steatosis" (n = 915). During the pre-baseline period, hepatic steatosis trajectories were associated with trajectories of developing diabetes and hypertension, and persistent steatosis (vs. other trajectories) was associated with higher risks and rapidly progressive disease patterns. At a median 13.6 years of follow-up, 629 CVD events occurred. A persistent (vs. non-steatosis: HR 1.44, 95% CI 1.17-1.76), but not intermittent, steatosis pattern predicted the future risk of CVD, after adjustment for age, sex, smoking, and obesity. This association was independent of genetic background, and remained after accounting for pre-baseline body-mass index, other cardiometabolic risk factors, Framingham risk score, medications, and hepatic fibrosis score. CONCLUSIONS: The persistence of hepatic steatosis is associated with trajectories of metabolic disorder development and increased risk of CVD. These data have important implications for practice and further research.

Benefits of Hepatitis C Viral Eradication: A Real-World Nationwide Cohort Study in Taiwan.

BACKGROUND: Chronic hepatitis C (CHC) increases the risk of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). This nationwide cohort study assessed the effectiveness of viral eradication of CHC. METHODS: The Taiwanese chronic hepatitis C cohort and Taiwan hepatitis C virus (HCV) registry are nationwide HCV registry cohorts incorporating data from 23 and 53 hospitals in Taiwan, respectively. This study included 27,577 individuals from these cohorts that were given a diagnosis of CHC and with data linked to the Taiwan National Health Insurance Research Database. Patients received either pegylated interferon and ribavirin or direct-acting antiviral agent therapy for > 4 weeks for new-onset LC and liver-related events. RESULTS: Among the 27,577 analyzed patients, 25,461 (92.3%) achieved sustained virologic response (SVR). The mean follow-up duration was 51.2 ± 48.4 months, totaling 118,567 person-years. In the multivariable Cox proportional hazard analysis, the hazard ratio (HR) for incident HCC was 1.39 (95% confidence interval [CI]: 1.00-1.95, p = 0.052) among noncirrhotic patients without SVR compared with those with SVR and 1.82 (95% CI 1.34-2.48) among cirrhotic patients without SVR. The HR for liver-related events, including HCC and decompensated LC, was 1.70 (95% CI 1.30-2.24) among cirrhotic patients without SVR. Patients with SVR had a lower 10-year cumulative incidence of new-onset HCC than those without SVR did (21.7 vs. 38.7% in patients with LC, p < 0.001; 6.0 vs. 18.4% in patients without LC, p < 0.001). CONCLUSION: HCV eradication reduced the incidence of HCC in patients with and without LC and reduced the incidence of liver-related events in patients with LC.

Impact of HCV eradication by directly acting antivirals on glycemic indices in chronic hepatitis C patients -a nationwide Taiwan HCV registry.

BACKGROUND/AIMS: Hepatitis C virus (HCV) eradication using antiviral agents augments the metabolic profile. Changes in glycated hemoglobin (HbA1c) levels in chronic hepatitis C patients who receive glecaprevir/pibrentasvir (GLE/PIB) remain elusive. METHODS: Data from 2417 patients treated with GLE/PIB from the Taiwan HCV Registry were analyzed, and pretreatment HbA1c levels were compared with 3-months after the-end-of treatment levels. A sustained virological response (SVR) was defined as undetectable HCV RNA at 12 weeks after the end of treatment. A significant change in HbA1c level was defined as the 75th percentile of the change in the HbA1c level before and after treatment (decrement >0.2%). RESULTS: Serum HbA1c levels decreased significantly (6.0 vs 5.9%, P < 0.001). Post-treatment HbA1c levels decreased in all subgroups, except in non-SVR patients (5.7 vs 5.7%, P = 0.79). Compared to patients without significant HbA1c improvement (decrement >0.2%), those with HbA1c improvement were older (60.2 vs 58.6 years, P < 0.001), had higher serum creatinine levels (1.9 vs 1.6 mg/dL, P < 0.001), triglycerides (129.8 vs 106.2 mg/dL, P < 0.001), fasting glucose (135.8 vs 104.0 mg/dL, P < 0.001), and pretreatment HbA1c (7.1 vs 5.7%, P < 0.001) and had a higher proportion of male sex (57.9% vs 50.9%, P = 0.003), diabetes (84.3 vs 16.8%, P < 0.001), more advanced stages of chronic kidney disease (CKD) (15.7 vs 11.1 %, P < 0.001), anti-diabetic medication use (47.3 vs 16.4%, P < 0.001) and fatty liver (49.6 vs 38.3 %, P < 0.001). Multivariate analysis revealed that the factors associated with significant HbA1c improvement were age (odds ratio [OR]/95% confidence intervals [CI]: 1.01/1.00-1.02, P = 0.01), HbA1c level (OR/CI: 2.83/2.48-3.24, P < 0.001) and advanced CKD stages (OR/CI: 1.16/1.05-1.28, P = 0.004). If the HbA1c variable was not considered, the factors associated with significant HbA1c improvement included alanine aminotransferase level (OR/CI, 1.002/1.000-1.004, P = 0.01), fasting glucose level (OR/CI: 1.010/1.006-1.013, P < 0.001), and diabetes (OR/CI: 3.35/2.52-4.45, P < 0.001). CONCLUSIONS: The HbA1c levels improved shortly after HCV eradication using GLE/PIB. The improvement in glycemic control can be generalized to all subpopulations, particularly in patients with a higher baseline HbA1c level or diabetes.

Lifetime risk of liver-related outcomes and determinants in male inactive carriers of chronic hepatitis B.

The full spectrum of risks for the life course of inactive hepatitis B virus (HBV) carriers remains unclear. In this study, 995 untreated HBV carriers (median age: 42.8 years; median follow-up: 30.2 years) were included. Their data were sourced from a population-based cohort study of male civil servants recruited in 1989-1992. Outcomes were identified by active follow-up examinations and linkage with national health insurance research database. At baseline, 483 subjects were inactive carriers, 385 with indeterminate phase, and 127 with other phases. The joint lifetime risk for incident cirrhosis, decompensation, hepatocellular carcinoma, and liver-related deaths was lower for inactive carriers compared to subjects in other phases (p < 0.0001). There was a trend of increase in incidence among inactive carriers; the 5-, 10-, and 20-year cumulative incidences were 1.86%, 6.03%, and 10.07%, respectively. Of the inactive carriers, 37.7% cleared HBsAg and 36.6% had biochemical relapse during the study. Biochemical relapse, obesity, and advanced age were predictors for disease progression in inactive carriers. Virological relapse was the predominant cause of biochemical relapse. Higher HBV-DNA levels (≥1000 copies/mL or 200 IU/mL) and HBV genotype B (vs. C) were associated with higher virological relapse rate. After 30 years, we found that one-time measure of inactive carrier state continued to have the lowest risk compared with other infection phases. Despite a more favorable prognosis, inactive carriers had a non-negligible risk. Our findings of lifetime risk may provide important clues for the management of such patients and consideration of therapeutic strategies aiming to achieve functional cure.

Impact of Sofosbuvir-Based Direct-Acting Antivirals on Renal Function in Chronic Hepatitis C Patients With Impaired Renal Function: A Large Cohort Study From the Nationwide HCV Registry Program (TACR).

BACKGROUND & AIMS: Sofosbuvir is approved for chronic hepatitis C (CHC) patients with severe chronic kidney disease (CKD). The impact of sofosbuvir-based therapy on renal function augmentation on a real-world nationwide basis is elusive. METHODS: The 12,995 CHC patients treated with sofosbuvir-based (n = 6802) or non-sofosbuvir-based (n = 6193) regimens were retrieved from the Taiwan nationwide real-world HCV Registry Program. Serial estimated glomerular filtration rate (eGFR) levels were measured at baseline, end of treatment (EOT), and end of follow-up (EOF) (3 months after EOT). RESULTS: The eGFR decreased from baseline (91.4 mL/min/1.73 m2) to EOT (88.4 mL/min/1.73 m2; P < .001) and substantially recovered at EOF (88.8 mL/min/1.73 m2) but did not return to pretreatment levels (P < .001). Notably, a significant decrease in eGFR was observed only in patients with baseline eGFR ≥90 mL/min/1.73 m2 (from 112.9 to 106.4 mL/min/1.73 m2; P < .001). In contrast, eGFR increased progressively in patients whose baseline eGFR was <90 mL/min/1.73 m2 (from 70.0 to 71.5 mL/min/1.73 m2; P < .001), and this increase was generalized across different stages of CKD. The trend of eGFR amelioration was consistent irrespective of sofosbuvir usage. Multivariate adjusted analysis demonstrated that baseline eGFR >90 mL/min/1.73 m2 was the only factor independently associated with significant slope coefficient differences of eGFR (-1.98 mL/min/1.73 m2; 95% confidence interval, -2.24 to -1.72; P < .001). The use of sofosbuvir was not an independent factor associated with eGFR change. CONCLUSIONS: Both sofosbuvir and non-sofosbuvir-based regimens restored renal function in CHC patients with CKD, especially in those with significant renal function impairment.

Hepatic steatosis and development of type 2 diabetes: Impact of chronic hepatitis B and viral specific factors.

BACKGROUND: Chronic hepatitis B (CHB) was associated with a lower prevalence of nonalcoholic fatty liver disease (NAFLD). The impact of CHB on the link between NAFLD and type 2 diabetes (T2D) and related virological implications remain unclear. METHODS: We recruited 2255 middle-to older-aged individuals who were examined serially for hepatic steatosis by ultrasonography and blood biochemistry as part of a population-based hepatocellular-carcinoma cohort study. In CHB patients, hepatitis B surface antigen (HBsAg) seroclearance and variation in viral load trajectory were also evaluated. RESULTS: During the average follow-up of 6 years, 168 participants developed T2D. CHB, as compared with uninfected subjects, was associated with lower risks for both new development and persistence of hepatic steatosis. Furthermore, the risk of steatosis decreased with higher levels of past viral load trajectories (p for trend = 0.0002). However, concomitant steatosis at baseline in CHB patients was still significantly associated with a 1.98-fold increased risk for T2D after multivariate adjustment including age, impaired fasting glucose, cirrhosis, and time-varying body mass index, although CHB reduced the propensity of hepatic steatosis to develop diabetes, especially for patients with high levels of past viral-load trajectory. In CHB, the functional cure of HBV infection, as indicated by HBsAg seroclearance, was associated with a 1.41-fold (95% CI 1.12-1.79) increased risk of steatosis. In addition, the increased risk for progressive impairment of glucose metabolism due to steatosis was especially prominent after HBsAg seroclearance. CONCLUSION: The data showed that HBV interferes with fatty liver disease and modulates its related T2D risk, offering additional insight into the interplay between NAFLD and CHB.

Reappraisal of the roles of alpha-fetoprotein in hepatocellular carcinoma surveillance using large-scale nationwide database and hospital-based information.

BACKGROUND/PURPOSE: Controversies over the use of alpha-fetoprotein (AFP) for detection of hepatocellular carcinoma (HCC) existed from guidelines. Using large-scale database and hospital-based information, we aimed to reappraise the role of AFP in HCC surveillance, including proportion of AFP elevation by stage of HCC, additional benefit of AFP in combination of ultrasonography (US) in the detection of early HCC, and survival in early HCC with high AFP levels. METHODS: This retrospective study enrolled 43,437 patients from database of the Taiwan Cancer Registry (TCR) and 4250 patients from Kaohsiung Chang Gung Memorial Hospital (KCGMH) between January 2011 and December 2017. RESULTS: The HCC cases in KCGMH accounted for 9.8% of the total cases in the TCR. Among both nationwide database and hospital-based information, the proportion of early HCC patients with an AFP level of ≥20 ng/mL was approximately 40%. In KCGMH, the proportion of patients with an AFP level of ≥20 ng/mL and a virus-related (hepatitis B and C) etiology was around 41.7%; furthermore, among patients with early HCC, those with an AFP level of ≥20 ng/mL had 4.7 years of median survival and 48.3% of the 5-year overall survival rate. By hospital electronic medical records review of early HCC cohort in KCGMH, approximately 10.9% of patients with AFP levels ≥20 ng/mL had US-undetectable early HCC. CONCLUSION: This study suggested that AFP in combination with US would add an additional benefit as being a prompted role for detection of early HCC in patients with US-undetectable HCC.

Ledipasvir/sofosbuvir for HCV genotype 1, 2, 4-6 infection: Real-world evidence from a nationwide registry in Taiwan.

BACKGROUND/PURPOSE: The Taiwan Association for the Study of the Liver (TASL) HCV Registry (TACR) is a nationwide registry of chronic hepatitis C patients in Taiwan. This study evaluated antiviral effectiveness of ledipasvir (LDV)/sofosbuvir (SOF) in patients in the TACR. METHODS: Patients enrolled in TACR from 2017-2020 treated with LDV/SOF were eligible. The primary outcome was the proportion of patients with sustained virologic response 12 weeks after end of treatment (SVR12). RESULTS: 5644 LDV/SOF ± ribavirin-treated patients were included (mean age: 61.4 years; 54.4% female). Dominant viral genotypes were GT1 (50.8%) and GT2 (39.3%). 1529 (27.1%) patients had liver cirrhosis, including 201 (3.6%) with liver decompensation; 686 (12.2%) had chronic kidney disease. SVR12 was achieved in 98.6% of the overall population and in 98.2% and 98.7% of patients with and without cirrhosis, respectively. SVR12 rates in patients with compensated cirrhosis treated with LDV/SOF without RBV were >98%, regardless of prior treatment experience. SVR12 was 98.6%, 98.4%, 100%, 100%, and 98.7% among those with GT1, GT2, GT4, GT5, and GT6 infections, respectively. Although patient numbers were relatively small, SVR12 rates of 100% were reported in patients infected with HCV GT2, GT5, and GT6 with decompensated cirrhosis and 98% in patients with severely compromised renal function. LDV/SOF adherence ≤60% (P < 0.001) was the most important factor associated with treatment failure. Incidence of adverse events was 15.8%, with fatigue being the most common. CONCLUSION: LDV/SOF is effective and well tolerated in routine clinical practice in Taiwan. Cure rates were high across patient populations.

Factors associated with treatment failure of direct-acting antivirals for chronic hepatitis C: A real-world nationwide hepatitis C virus registry programme in Taiwan.

BACKGROUND/AIMS: Direct-acting antivirals (DAAs) are highly effective in treating chronic hepatitis C virus (HCV)-infected patients. The real-world treatment outcome in Taiwanese patients on a nationwide basis is elusive. METHODS: The Taiwan HCV Registry (TACR) programme is a nationwide registry platform including 48 study sites, which is organized and supervised by the Taiwan Association for the Study of the Liver. The primary endpoint was sustained virological response (SVR12, undetectable HCV RNA 12 weeks after end-of-treatment). RESULTS: A total of 13 951 registered patients with SVR12 data available were analysed (mean age, 63.0 years; female, 55.9%; HCV genotype-1 [GT1], 57.9%; cirrhosis, 38.4%; preexisting hepatocellular carcinoma [HCC], 10.6%; and hepatitis B virus coinfection, 7.7%). The overall SVR12 rate was 98.3%, with 98.7%, 98.0%, 98.4% and 97.4% in treatment-naïve noncirrhotic, treatment-naïve cirrhotic, treatment-experienced noncirrhotic and treatment-experienced cirrhotic patients, respectively. The SVR12 rate was > 95% across all subgroups except treatment-experienced cirrhotic patients who received sofosbuvir/ribavirin (88.7%), treatment-naïve noncirrhotic patients (94.8%) and treatment-experienced cirrhotic (94.8%) patients who received daclatasvir/asunaprevir. The most important factor associated with treatment failure was DAA adherence < 60% ( adjusted odds ratio [aOR]/95% confidence interval [CI]: 117.1/52.4-261.3, P < .001), followed by GT3/GT2 (aOR/CI: 5.78/2.25-14.9, P = .0003 and aOR/CI: 1.55/1.05-2.29, P = .03, compared with GT1), active hepatocellular carcinoma (aOR/CI: 4.29/2.57-7.16, P < .001), the use of sofosbuvir/ribavirin (aOR/CI: 2.51/1.67-3.77, P < .001) and daclatasvir/asunaprevir (aOR/CI: 3.29/1.94-5.58, P < .001), decompensated liver cirrhosis (aOR/CI: 2.50/1.20-5.22, P = .02) and high HCV viral loads (aOR/CI: 2.16/1.57-2.97, P < .001). CONCLUSIONS: DAAs are highly effective in treating Taiwanese HCV patients in the real-world setting. Maintaining DAA adherence and selecting highly efficacious regimens are keys to ensure treatment success.

Longitudinal change of metabolite profile and its relation to multiple risk factors for the risk of developing hepatitis B-related hepatocellular carcinoma.

Despite considerable knowledge of viral pathogenesis, the pathophysiological changes related to the multifactorial, multistep process of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) development remains unclear. Longitudinal metabolomics study can reveal biological process for disease progression. We performed metabolite profiling with longitudinal prediagnostic plasma samples from two nested case-control studies of hepatitis B surface antigen carriers participating in ultrasound screening for HCC, one within a government employee cohort (870 samples from 109 HCC cases and 107 controls) and the other within a hospital-based cohort (266 samples from 63 HCC cases and 114 controls). Of the 34 measured metabolites, tyrosine, isoleucine, and glutamine were consistently associated with HCC. In analyses combining longitudinal data, a high metabolic risk score based on the three amino acids was robustly associated with increased risk of HCC (OR = 3.71, 95% confidence interval: 2.53-5.42), even after adjustment for clinical factors, or when assessed for different times up to ≥8 years before diagnosis. Similar association was observed in an independent, prospective analysis comprising 633 randomly selected individuals of the government employee cohort. More importantly, this metabolite signature was longitudinally influenced by HBV-infection phase and involved in gradual progression to liver fibrosis and cirrhosis. Furthermore, mediation analysis showed that the score mediated substantial proportions of the associations of key viral factors, insulin resistance, and diabetes status with HCC risk. Our results suggest that an amino-acid dysregulation metabotype may play a role in HBV-related HCC development, and may also be linked to common pathways that mediate increased HCC risks.

Triple-negative breast cancer with calcified metastases of hepatic, portal vein and inferior vena cava: Report of a case and review of the literature.

Breast cancer frequently metastasizes to the liver and this usually bears a poor prognosis. Complete calcifications of hepatic, portal vein and inferior vena cava (IVC) metastases from breast cancer after systemic chemotherapy is extremely rare and to our knowledge, has never been reported. It is important for physicians to recognize the pattern and the formation of calcified liver metastases because the radiographic features of calcifications may assist in differentiating the etiologies of underlying malignancies and provide prognostic significance. We here presented such a case of triple negative breast cancer (TNBC) with calcified liver, portal vein and IVC metastases, and reviewed the literature.

Safety of Perfluorobutane (Sonazoid) in Characterizing Focal Liver Lesions.

BACKGROUND: The purpose of this study was to report the safety of perfluorobutane (Sonazoid) as a vascular-phase imaging agent in characterizing focal liver lesions (FLLs). MATERIALS AND METHODS: From May 2014 to April 2015, a total of 54 individuals who received Sonazoid contrast-enhanced ultrasound (CEUS) were enrolled at 5 hospitals of 4 medical centers. All individuals were included in safety evaluation. A prospective study to evaluate the adverse effect (AE) incidences after intravenous administration of Sonazoid. RESULTS: Sonazoid was well tolerated. Treatment-emergent adverse events (TEAEs) representing AE were recorded for 13 (24.1%) patients. The most common AE was abdominal pain (9.3%), followed by heart rate irregularity (5.6%). The majority of these patients (69.2%) experienced TEAEs that were mild in intensity. Sonazoid causes no significant AEs after intravenous injection. The only noteworthy AEs are related to tolerable myalgia (3.7%), abdominal pain (1.9%), and headache (1.9%). None of the 54 patients showed serious adverse effects. CONCLUSION: Sonazoid shows good safety and tolerance of intravenous use during CEUS of the liver for evaluation of FLLs.

Corrigendum: Statins Reduce the Risk of Cirrhosis and Its Decompensation in Chronic Hepatitis B Patients: A Nationwide Cohort Study.

This corrects the article DOI: 10.1038/ajg.2017.494.

Statins Reduce the Risk of Cirrhosis and Its Decompensation in Chronic Hepatitis B Patients: A Nationwide Cohort Study.

OBJECTIVES: The protective effect of statins in cirrhosis and its decompensation in chronic hepatitis B (CHB) patients remains unknown. METHODS: We conducted a population-based cohort study using data from the Taiwanese National Health Insurance Research Database from 1997 to 2009. A total of 298,761 CHB patients were identified. CHB patients using statins (n=6,543; defined as ≥28 cumulative defined daily doses (cDDD)) and a 1:1 ratio propensity score and inception point (the date of first use of statins)-matched non-statins (<28 cDDD) were followed up from the inception point until the development of cirrhosis or its decompensation or until withdrawal from insurance or December 2009. RESULTS: After adjustment for competing mortality, CHB patients using statins had a significantly lower cumulative incidence of cirrhosis (relative risk)=0.433; 95% confidence interval (CI)=0.344-0.515; modified log-rank test, P<0.001) and decompensated cirrhosis (relative risk=0.468; 95% CI=0.344-0.637; P<0.001) compared with patients not using statins. After adjustment for age, gender, comorbidity index, hypertension, diabetes, hyperlipidemia, hepatocellular carcinoma, obesity, non-alcoholic fatty liver disease, aspirin use, diabetes medication, CHB treatment, non-statin lipid-lowering drugs, and triglyceride lipid-lowering drugs using the Cox proportional hazard model, statins were still an independent protector against cirrhosis (adjusted hazard ratio (AHR)=0.512; 95% CI=0.413-0.634; P<0.001) and its decompensation (AHR=0.534; 95% CI=0.433-0.659; P<0.001). The AHRs for cirrhosis were 0.467 and 0.200, and the AHRs for decompensated cirrhosis were 0.611 and 0.231 with 91-365 and >365 cDDD of statins, respectively. CONCLUSIONS: CHB patients who receive statin therapy have a dose-dependent reduction in the risk of cirrhosis and its decompensation.

Increased risk of cirrhosis and its decompensation in chronic hepatitis C patients with new-onset diabetes: a nationwide cohort study.

UNLABELLED: The effect of diabetes on cirrhosis, its decompensation, and their time relationship in chronic hepatitis C (CHC) patients remains unclear. We conducted a nation-wide cohort study by using the Taiwanese National Health Insurance Research Database, which is comprised of data from >99% of the entire population. Among having randomly sampled 1 million enrollees, 6,251 adult CHC patients were identified from 1997 to 2009. Diabetes was defined as new onset in CHC patients who were given the diagnosis in the years 1999-2003, but not in 1997-1998. The cohorts of CHC with new-onset diabetes (n=424) and nondiabetes (n=1,708) were followed up from inception point in diabetes and from year 1999 in the nondiabetes cohort until development of cirrhosis or its decompensation, withdrawal from insurance, or December 2009. Kaplan-Meier's survival analysis showed a significantly higher cumulative incidence of cirrhosis (relative risk [RR]=1.53; 95% confidence interval [CI]=1.11-2.11; log-rank test; P<0.001) and decompensated cirrhosis (RR=2.01; 95% CI=1.07-3.79; log-rank test; P<0.001) among patients with new-onset diabetes, as compared to those without. After adjustment for age, gender, CHC treatment, diabetes treatment, hepatocellular carcinoma, comorbidity index, hypertension, hyperlipidemia, and obesity by Cox's proportional hazard model, diabetes was still an independent predictor for cirrhosis (hazard ratio [HR]=2.505; 95% CI=1.609-3.897; P<0.001) and its decompensation (HR=3.560; 95% CI=1.526-8.307; P=0.003). CONCLUSION: CHC patients who develop diabetes are at an increased risk of liver cirrhosis and its decompensation over time.

Runx1-deficient afferents impair visceral nociception, exacerbating dextran sodium sulfate-induced colitis.

Colitis is a group of inflammatory and auto-immune disorders that affect the tissue lining of the gastrointestinal (GI) system. Studies of chemically-induced animal models of colitis have indicated that nociceptive afferents or neuropeptides have differing effects on GI inflammation. However, the molecular mechanisms involved in visceral pain and the role of visceral sensory afferents involved in the modulation of colitis remains unclear. A previous study demonstrated that Runx1, a Runt domain transcription factor, is restricted to nociceptors. In these neurons, Runx1 regulates the expression of numerous ion channels and receptors, controlling the lamina-specific innervation patterns of nociceptive afferents in the spinal cord. Moreover, mice that lack Runx1 exhibit specific defects in thermal and neuropathic pain. To examine the function of Runx1 in visceral nociception, we employed double-transgenic mice (WntCre: Runx1(F/F)), in which the expression of Runx1 was specifically disrupted in the sensory neurons. To determine the role of Runx1 in visceral pain sensation, the WntCre: Runx1(F/F) mice and their control littermates (Runx1(F/F)) were treated using dextran sodium sulfate (DSS) to induce colitis. The results indicated that disrupted Runx1 in the sensory afferents resulted in: (1) impairment of the visceral pain sensation in murine DSS-induced colitis; (2) exacerbating the phenotypes in murine DSS-induced colitis; (3) a differential effect on the production of pro- and anti-inflammatory cytokines in the colon tissues isolated from mice treated using DSS and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis; and (4) alteration of the distribution of lymphocytes and mast cells in mucosa. These results show that the function of Runx1 in sensory afferents is vital for modulating visceral pain and the neuro-immune axis.

An algorithm for simplified hepatitis C virus treatment with non-specialist care based on nation-wide data from Taiwan.

BACKGROUND: Both European Association for the Study of the Liver (EASL) and American Association for the Study of Liver Diseases and the Infectious Diseases Society of America (AASLD-IDSA) guidelines recommend simplified hepatitis C virus (HCV) treatment with pan-genotypic sofosbuvir/velpatasvir or glecaprevir/pibrentasvir for eligible patients. This observational study used real-world data to assess these regimens' safety in eligible patients and develop an algorithm to identify patients suitable for simplified treatment by non-specialists. METHODS: 7,677 HCV-infected patients from Taiwan Hepatitis C Registry (TACR) who received at least one dose of sofosbuvir/velpatasvir or glecaprevir/pibrentasvir, and fulfilled the EASL/AASLD-IDSA criteria for simplified treatment were analyzed. Multivariate analysis was conducted on patient characteristics and safety data. RESULTS: Overall, 92.8% (7,128/7,677) of patients achieved sustained virological response and only 1.9% (146/7,677) experienced Grades 2-4 laboratory abnormalities in key liver function parameters (alanine aminotransferase, aspartate aminotransferase, and total bilirubin), with only 18 patients (0.23%) experiencing Grades 3-4 abnormalities. Age > 70 years old, presence of hepatocellular carcinoma, total bilirubin > 1.2 mg/dL, estimated glomerular filtration rate < 60 mL/min/1.73 m2, and Fibrosis-4 > 3.25 were associated with higher risks of Grades 2-4 abnormalities. Patients with any of these had an odds of 4.53 times than that of those without in developing Grades 2-4 abnormalities (p < 0.01). CONCLUSIONS: Real-world data from Taiwan confirmed that simplified HCV treatment for eligible patients with pan-genotypic regimens is effective and well tolerated. The TACR algorithm, developed based on this study's results, can further identify patients who can be safely managed by non-specialist care.

Artificial intelligence predicts direct-acting antivirals failure among hepatitis C virus patients: A nationwide hepatitis C virus registry program.

BACKGROUND/AIMS: Despite the high efficacy of direct-acting antivirals (DAAs), approximately 1-3% of hepatitis C virus (HCV) patients fail to achieve a sustained virological response. We conducted a nationwide study to investigate risk factors associated with DAA treatment failure. Machine-learning algorithms have been applied to discriminate subjects who may fail to respond to DAA therapy. METHODS: We analyzed the Taiwan HCV Registry Program database to explore predictors of DAA failure in HCV patients. Fifty-five host and virological features were assessed using multivariate logistic regression, decision tree, random forest, eXtreme Gradient Boosting (XGBoost), and artificial neural network. The primary outcome was undetectable HCV RNA at 12 weeks after the end of treatment. RESULTS: The training (n=23,955) and validation (n=10,346) datasets had similar baseline demographics, with an overall DAA failure rate of 1.6% (n=538). Multivariate logistic regression analysis revealed that liver cirrhosis, hepatocellular carcinoma, poor DAA adherence, and higher hemoglobin A1c were significantly associated with virological failure. XGBoost outperformed the other algorithms and logistic regression models, with an area under the receiver operating characteristic curve of 1.000 in the training dataset and 0.803 in the validation dataset. The top five predictors of treatment failure were HCV RNA, body mass index, α-fetoprotein, platelets, and FIB-4 index. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of the XGBoost model (cutoff value=0.5) were 99.5%, 69.7%, 99.9%, 97.4%, and 99.5%, respectively, for the entire dataset. CONCLUSION: Machine learning algorithms effectively provide risk stratification for DAA failure and additional information on the factors associated with DAA failure.

Real-World Efficacy and Safety of Universal 8-Week Glecaprevir/Pibrentasvir for Treatment-Naïve Patients from a Nationwide HCV Registry in Taiwan.

INTRODUCTION: Eight-week glecaprevir/pibrentasvir (GLE/PIB) is indicated for treatment-naïve (TN) patients with chronic hepatitis C (CHC), with or without compensated cirrhosis. Given that the Taiwanese government is committed to eliminating hepatitis C virus (HCV) by 2025, this study aimed to measure real-world evidence for TN patients using 8-week GLE/PIB in the Taiwan HCV Registry (TACR). METHODS: The data of patients with CHC treated with 8-week GLE/PIB were retrieved from TACR, a nationwide registry program organized by the Taiwan Association for the Study of the Liver (TASL). Treatment efficacy, defined as a sustained virologic response at posttreatment week 12 (SVR12), was assessed in the modified intention-to-treat (mITT) population, which excluded patients who were lost to follow-up or lacked SVR12 data. The safety profile of the ITT population was assessed. RESULTS: A total of 7246 (6897 without cirrhosis; 349 with cirrhosis) patients received at least one dose of GLE/PIB (ITT), 7204 of whom had SVR12 data available (mITT). The overall SVR12 rate was 98.9% (7122/7204) among all patients, 98.9% (6780/6856) and 98.3% (342/348) among patients without and with cirrhosis, respectively. For the selected subgroups, which included patients with genotype 3 infection, diabetes, chronic kidney disease, people who injected drugs, and those with human immunodeficiency virus coinfection, the SVR12 rates were 95.1% (272/286), 98.9% (1084/1096), 99.0% (1171/1183), 97.4% (566/581), and 96.1% (248/258), respectively. Overall, 14.1% (1021/7246) of the patients experienced adverse events (AEs). Twenty-two patients (0.3%) experienced serious AEs, and 15 events (0.2%) resulted in permanent drug discontinuation. Only one event was considered treatment drug related. CONCLUSION: Eight-week GLE/PIB therapy was effective and well tolerated in all TN patients, regardless of cirrhosis status.

Increased risk of cirrhosis and its decompensation in chronic hepatitis B patients with newly diagnosed diabetes: a nationwide cohort study.

BACKGROUND: The impact of diabetes on cirrhosis, its decompensation, and their time relationship in patients with chronic hepatitis B (CHB) remain unclear. METHODS: We conducted a nationwide cohort study by using the Taiwanese National Health Insurance Research Database, which was comprised of data from >99% of the entire population. Among 1 million randomly sampled enrollees, 14 523 adult CHB patients were identified from 1997 to 2009. Diabetes was defined as newly diagnosed in CHB patients who were given the diagnosis in the years 1998-2001 but not in 1996-1997 and with physician visits of at least twice per year. The cohorts of CHB with newly diagnosed diabetes (n = 351) and without diabetes (n = 7886) were followed up from the diagnosis of diabetes and from 2000 in the patients without diabetes until development of cirrhosis or its decompensation, withdrawal from insurance, or December 2009. RESULTS: Kaplan-Meier survival analysis showed a significantly higher cumulative incidence of cirrhosis (relative risk [RR] = 3.43; 95% confidence interval [CI], 2.62-4.49; P < .001, log-rank test) and decompensated cirrhosis (RR = 4.11; 95% CI, 2.95-5.70; P < .001, log-rank test) among patients with newly developed diabetes compared with those without diabetes. After adjustment for age, sex, CHB treatment, hepatocellular carcinoma, and comorbidity index by Cox proportional hazards model, diabetes was still an independent predictor for cirrhosis (hazard ratio [HR] = 2.015; 95% CI, 1.393-2.915; P < .001) and its decompensation (HR = 1.792; 95% CI, 1.192-2.695; P = .005). CONCLUSIONS: Patients with CHB who develop diabetes are at an increased risk of liver cirrhosis and its decompensation over time.