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.

Secular trends of intrahepatic cholangiocarcinoma in a high endemic area: A population-based study.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is one of the most aggressive malignancies. However, because of its scarcity there are limited population-based data available for investigations into its epidemiologic characteristics. In Taiwan, we have a national cancer registry database that can be used to evaluate the secular trends of ICC. AIM: To evaluate secular trends of ICC according to age, sex, and risk factors in Taiwan. METHODS: In this population-based study, we used the national Taiwan Cancer Registry database. Age-standardized and relative percent changes in incidence rates were used to describe secular trends in incidence rates and sex ratios of ICC in Taiwan. RESULTS: The age-standardized ICC incidence rate among males increased from 1.51 per 100000 in 1993-1997 to 4.07 per 100000 in 2013-2017 and among female from 1.73 per 100000 to 2.95 per 100000. The incidence in females tended to plateau after 2008-2012. For males, the ICC incidence increased as age increased. In the long-term incidence trend of ICC in females, the incidence of the four age groups (40-44, 45-49, 50-54 and 55-59 years) remained stable in different years; although, the incidence of the 60-64 group had a peak in 2003-2007, and the peak incidence of the 65-69 and 70-74 groups occurred in 2008-2012. Among males, beginning at the age of 65, there were increases in the incidence of ICC for the period of 2003-2017 as compared with females in the period of 2003-2017. CONCLUSION: Increased incidence of ICC occurred in Taiwan over the past two decades. The increased incidence has progressively shifted toward younger people for both males and females.

Etifoxine, a TSPO Ligand, Worsens Hepatitis C-Related Insulin Resistance but Relieves Lipid Accumulation.

Etifoxine, an 18 kDa translocator protein (TSPO) agonist for the treatment of anxiety disorders in clinic, may be able to cause acute liver injury or cytolytic hepatitis. TSPO has been demonstrated to participate in inflammatory responses in infective diseases as well as to modulate glucose and lipid homeostasis. Hepatitis C virus (HCV) infection disrupts glucose and lipid homoeostasis, leading to insulin resistance (IR). Whether TSPO affects the HCV-induced IR remains unclear. Here, we found that the administration of etifoxine increased the TSPO protein expression and recovered the HCV-mediated lower mitochondrial membrane potential (MMP) without affecting HCV infection. Moreover, etifoxine reversed the HCV-induced lipid accumulation by modulating the expressions of sterol regulatory element-binding protein-1 and apolipoprotein J. On the other hand, in infected cells pretreated with etifoxine, the insulin-mediated insulin receptor substrate-1/Akt signals, forkhead box protein O1 translocation, and glucose uptake were blocked. Taken together, our results pointed out that etifoxine relieved the HCV-retarded MMP and reduced the lipid accumulation but deteriorated the HCV-induced IR by interfering with insulin signal molecules.

Calcitriol Inhibits HCV Infection via Blockade of Activation of PPAR and Interference with Endoplasmic Reticulum-Associated Degradation.

Vitamin D has been identified as an innate anti-hepatitis C virus (HCV) agent but the possible mechanisms for this issue remain unclear. Here, we clarified the mechanisms of calcitriol-mediated inhibition of HCV infection. Calcitriol partially inhibited HCV infection, nitric oxide (NO) release and lipid accumulation in Huh7.5 human hepatoma cells via the activation of vitamin D receptor (VDR). When cells were pretreated with the activators of peroxisome proliferator-activated receptor (PPAR)-α (Wy14643) and -γ (Ly171883), the calcitriol-mediated HCV suppression was reversed. Otherwise, three individual stimulators of PPAR-α/ß/γ blocked the activation of VDR. PPAR-ß (linoleic acid) reversed the inhibition of NO release, whereas PPAR-γ (Ly171883) reversed the inhibitions of NO release and lipid accumulation in the presence of calcitriol. The calcitriol-mediated viral suppression, inhibition of NO release and activation of VDR were partially blocked by an inhibitor of endoplasmic reticulum-associated degradation (ERAD), kifunensine. Furthermore, calcitriol blocked the HCV-induced expressions of apolipoprotein J and 78 kDa glucose-regulated protein, which was restored by pretreatment of kifunensine. These results indicated that the calcitriol-mediated HCV suppression was associated with the activation of VDR, interference with ERAD process, as well as blockades of PPAR, lipid accumulation and nitrative stress.

Cost-effectiveness analysis of population-based screening of hepatocellular carcinoma: Comparing ultrasonography with two-stage screening.

AIM: To assess the cost-effectiveness of two population-based hepatocellular carcinoma (HCC) screening programs, two-stage biomarker-ultrasound method and mass screening using abdominal ultrasonography (AUS). METHODS: In this study, we applied a Markov decision model with a societal perspective and a lifetime horizon for the general population-based cohorts in an area with high HCC incidence, such as Taiwan. The accuracy of biomarkers and ultrasonography was estimated from published meta-analyses. The costs of surveillance, diagnosis, and treatment were based on a combination of published literature, Medicare payments, and medical expenditure at the National Taiwan University Hospital. The main outcome measure was cost per life-year gained with a 3% annual discount rate. RESULTS: The results show that the mass screening using AUS was associated with an incremental cost-effectiveness ratio of USD39825 per life-year gained, whereas two-stage screening was associated with an incremental cost-effectiveness ratio of USD49733 per life-year gained, as compared with no screening. Screening programs with an initial screening age of 50 years old and biennial screening interval were the most cost-effective. These findings were sensitive to the costs of screening tools and the specificity of biomarker screening. CONCLUSION: Mass screening using AUS is more cost effective than two-stage biomarker-ultrasound screening. The most optimal strategy is an initial screening age at 50 years old with a 2-year inter-screening interval.

Durability of Nucleos(t)ide Analogues Treatment in Patients With Chronic Hepatitis B.

Long-term nucleos(t)ide analogues (NUCs) treatment is usually required for patients with chronic hepatitis B (CHB). However, whether discontinuation of NUCs is possible in selected patients remains debated. The aim of this study was to assess the durability of NUCs and predictors of sustained response after cessation of NUCs.Ninety-three CHB patients (29 HBeAg-positive and 64 HBeAg-negative) from 2 medical centers in Taiwan with discontinuation of NUCs after a median of 3 years' treatment were retrospectively reviewed. Fifteen (51.7%) HBeAg-positive and 57 (89.1%) HBeAg-negative patients achieved APASL treatment endpoints. Virological relapse (VR) and clinical relapse (CR) were defined according to APASL guidelines.Achieving APASL endpoint was associated with longer median time to CR in HBeAg-positive patients, but not in HBeAg-negative cases. The cumulative 1-year VR and CR rates were 55.3% and 14.4% in HBeAg-positive patients, and 77.7% and 41.9% in HBeAg-negative patients, respectively. In HBeAg-negative patients, baseline HBV DNA >10 IU/mL was the only predictor of VR (hazard ratio [HR] = 2.277, P = 0.019) and CR (HR = 3.378, P = 0.014). HBsAg >200 IU/mL at the end of treatment (EOT) was associated with CR (HR = 3.573, P = 0.023) in patients developing VR. HBeAg-negative patients with low baseline viral loads and low HBsAg levels at EOT had minimal risk of CR after achieving APASL treatment endpoint (P = 0.016).The VR rate is high, but the risk of CR is low within 1 year with consolidation treatment after HBeAg seroconversion. Longer consolidation treatment to reduce the risk of VR should be considered in HBeAg-positive patients. As high risk of VR and CR, cessation of NUCs therapy could be considered only in selected HBeAg-negative patients.

Application of quantitative estimates of fecal hemoglobin concentration for risk prediction of colorectal neoplasia.

AIM: To determine the role of the fecal immunochemical test (FIT), used to evaluate fecal hemoglobin concentration, in the prediction of histological grade and risk of colorectal tumors. METHODS: We enrolled 17881 individuals who attended the two-step colorectal cancer screening program in a single hospital between January 2010 and October 2011. Colonoscopy was recommended to the participants with an FIT of ≥ 12 ngHb/mL buffer. We classified colorectal lesions as cancer (C), advanced adenoma (AA), adenoma (A), and others (O) by their colonoscopic and histological findings. Multiple linear regression analysis adjusted for age and gender was used to determine the association between the FIT results and colorectal tumor grade. The risk of adenomatous neoplasia was estimated by calculating the positive predictive values for different FIT concentrations. RESULTS: The positive rate of the FIT was 10.9% (1948/17881). The attendance rate for colonoscopy was 63.1% (1229/1948). The number of false positive results was 23. Of these 1229 cases, the numbers of O, A, AA, and C were 759, 221, 201, and 48, respectively. Regression analysis revealed a positive association between histological grade and FIT concentration (ß = 0.088, P < 0.01). A significant log-linear relationship was found between the concentration and positive predictive value of the FIT for predicting colorectal tumors (R(2) > 0.95, P < 0.001). CONCLUSION: Higher FIT concentrations are associated with more advanced histological grades. Risk prediction for colorectal neoplasia based on individual FIT concentrations is significant and may help to improve the performance of screening programs.

Predictors of long-term survival in hepatocellular carcinomas: A longitudinal follow-up of 108 patients with small tumors.

AIM: Locoregional treatment [including percutaneous ethanol injection (PEI) therapy and transcatheter arterial chemoembolization (TACE)] provides an alternative treatment for early-diagnosed hepatocellular carcinoma (HCC). However, the long-term survival of patients after locoregional treatments remains unclear. PATIENTS AND METHODS: A total of 108 patients with small HCC not indicated for surgical hepatic resection were recruited between 1991 and 1999. All patients received first treatment with PEI therapy alone or combined with TACE. We followed-up these patients until the end of 2007. Clinical attributes and biological markers in association with long-term survival were collected. Significant predictors were identified by using proportional hazards regression model. RESULTS: The overall 1-, 3-, 5-, and 10-year cumulative survival of patients with HCC (<5 cm) were 88.8%, 59.4%, 29.4%, and 12.3%, respectively. Child-Pugh status, type of tumor (solitary or multiple), levels of pre-treatment aspartate aminotransferase (AST), and treatment modality were significantly associated with long-term survival after adjustment for age and gender. Child-Pugh B (hazard ration, HR=1.98, 95% confidence interval, CI=1.08-3.60) and higher level of pre-treatment AST (HR=1.91, 95% CI=1.18-3.08) were the two most significant predictors for risk of death from HCC-after adjusting for treatment modality and type of tumor. CONCLUSION: Child-Pugh score and AST level were demonstrated as the two major predictors for long-term survival in patients with small HCC not indicated for surgical treatment who underwent PEI-alone or combined with TACE. Clinical weights from Child-Pugh score and AST level are very informative for risk stratification and clinical surveillance of patients with small HCC treated by PEI-alone or combined with TACE.

Comparing the outcomes of two strategies for colorectal tumor detection: policy-promoted screening program versus health promotion service.

BACKGROUND: The Taiwanese government has proposed a population-based colorectal tumor detection program for the average-risk population. This study's objectives were to understand the outcomes of these screening policies and to evaluate the effectiveness of the program. METHODS: We compared two databases compiled in one medical center. The "policy-promoted cancer screening" (PPS) database was built on the basis of the policy of the Taiwan Bureau of National Health Insurance for cancer screening. The "health promotion service" (HPS) database was built to provide health check-ups for self-paid volunteers. Both the PPS and HPS databases employ the immunochemical fecal occult blood test (iFOBT) and colonoscopy for colorectal tumor screening using different strategies. A comparison of outcomes between the PPS and HPS included: (1) quality indicators-compliance rate, cecum reaching rate, and tumor detection rate; and (2) validity indicators-sensitivity, specificity, positive, and negative predictive values for detecting colorectal neoplasms. RESULTS: A total of 10,563 and 1481 individuals were enrolled in PPS and HPS, respectively. Among quality indicators, there was no statistically significant difference in the cecum reaching rate between PPS and HPS. The compliance rates were 56.1% for PPS and 91.8% for HPS (p < 0.001). The advanced adenoma detection rates of PPS and HPS were 1.0% and 3.6%, respectively (p < 0.01). The carcinoma detection rates were 0.3% and 0.4%, respectively (p = 0.59). For validity indicators, PPS provides only a positive predictive value for colorectal tumor detection. HPS provides additional validity indicators, including sensitivity, specificity, positive predictive value, and negative predictive value, for colorectal tumor screening. CONCLUSION: In comparison with the outcomes of the HPS database, the screening efficacy of the PPS database is even for detecting colorectal carcinoma but is limited in detecting advanced adenoma. HPS may provide comprehensive validity indicators and will be helpful in adjusting current policies for improving screening performance.

Influences of tobacco and alcohol use on hepatocellular carcinoma survival.

Prognosis of hepatocellular carcinoma (HCC) is generally poor. The role of modifiable lifestyle factors on HCC survival has been less studied. To examine whether prediagnosis smoking and alcohol affected HCC survival stratified by viral etiology, we conducted a prospective cohort study of 2,273 (1990 with viral hepatitis and 283 without) incident HCC cases aged 20-75 years who were enrolled between 1997 and 2004 from a Taiwanese multicenter study, and followed up through 2007. Information on habitual smoking and alcohol consumption was obtained at baseline through personal interview. After follow-up to a maximum of 10 years, 1,757 participants died and 1,488 (84.7%) were attributed to HCC. Prediagnosis smoking and alcohol worsened prognosis independent of each other and clinical predictors. The effects of both risky behaviors were limited to viral hepatitis-related HCC and more profound among those with early-stage HCC. Risk for HCC-specific mortality increased with increasing pack-years smoked and ethanol intake (all p < 0.001 for trend), with an additive effect shown for the two habits [hazard ratio (HR) for alcohol ≥ 46.2 g/day and ≥ 10 pack-years = 1.72, 95% confidence interval (CI) = 1.45-2.05]. For either habit, cessation reduced HCC-specific mortality, but a significant mortality benefit occurred 10 years after abstinence (quitting smoking ≥ 10 years vs. continuing smokers: HR = 0.77, 95% CI = 0.61-0.97; quitting drinking ≥ 10 years vs. continuing drinkers: HR = 0.74, 95% CI = 0.56-0.98). In conclusion, among patients with viral hepatitis-related HCC, prediagnosis smoking and alcohol have a deleterious effect on HCC survival. Quitting smoking or drinking alcohol could reduce the excess risk, but only after a long interval of cessation.

Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma.

BACKGROUND & AIMS: It is not clear whether risk for hepatocellular carcinoma can be accurately determined from long-term changes in serum levels of hepatitis B virus (HBV) DNA or alanine aminotransferase (ALT). METHODS: We measured serum levels of HBV DNA and ALT at enrollment and during follow-up analysis of 3160 participants in the REVEAL-HBV study. Development of hepatocellular carcinoma was determined from follow-up examinations and computerized linkage with National Cancer Registry and National Death Certification profiles. Multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models. RESULTS: During 38,330 person-years of follow-up, 81 participants developed hepatocellular carcinoma (incidence rate, 211.3/100,000 person-years). The risk for hepatocellular carcinoma was only slightly higher for participants whose follow-up levels of HBV DNA spontaneously decreased to <10,000 copies/mL compared with those with baseline levels of HBV DNA<10,000 copies/mL (control group; HR, 2.25; 95% CI, 0.68-7.37). Compared with the control group, the HRs (95% CI) for long-term levels of HBV DNA that persisted at 10,000 to 100,000 copies/mL, decreased to/persisted at 100,000 to 1,000,000 copies/mL, or decreased to/persisted at 1,000,000 to 10,000,000 copies/mL were 3.12 (1.09-8.89), 8.85 (3.85-20.35), and 16.78 (7.33-38.39), respectively. A gradient in ALT level was significantly associated with hepatocellular carcinoma risk: from all low-normal, to ever high-normal, to transient abnormal, to persistent abnormal (Ptrend<.001). CONCLUSIONS: Long-term changes in serum levels of HBV DNA and ALT are independent predictors of risk for hepatocellular carcinoma. Regular monitoring of levels of HBV DNA and ALT is important in clinical management of chronic carriers of HBV.

Role of reproductive factors in hepatocellular carcinoma: Impact on hepatitis B- and C-related risk.

Hepatocellular carcinoma (HCC) is more prevalent in men than in women. Estrogen may play some role in the development of HCC. We conducted a multicenter case-control study to evaluate the effects of reproductive factors on HCC risk, and to assess whether the association between each factor and HCC differs between hepatitis B surface antigen (HBsAg)-positive and -negative women, in which hepatitis C virus (HCV) is the major cause of HCC. The study included 218 women with HCC and 729 control women selected from nonbiological and first-degree female relatives of patients with HCC. The risk of HCC was inversely related to the number of full-term pregnancies (FTP) (P(trend) =.0216) and age at natural menopause (P(trend) =.0251 among women aged 45-55 without prior surgical menopause). Oophorectomy at age or=16 years), which increased HCC risk in HBsAg carriers (multivariate-adjusted OR, 6.96; 95% CI, 2.52-19.18) but posed no increased risk in noncarriers (P(interaction) =.0053). In conclusion, increased exposure to estrogen during adulthood may provide a protective effect against HCC. Nevertheless, an early menarche, which results in early estrogen exposure, does not confer protection for HBsAg carriers.

Increased risk for hepatitis B-related liver cirrhosis in relatives of patients with hepatocellular carcinoma in northern Taiwan.

BACKGROUND: There is a tendency for familial aggregation of hepatocellular carcinoma (HCC). The aims of this study were to assess the degree to which familial aggregation of hepatitis B surface antigen (HBsAg) carriers accounts for familiality of HCC in families of hepatitis B-related HCC patients, and whether HCC shares a familial predisposition with liver cirrhosis among HBsAg carriers. METHODS: A total of 671 first-degree relatives of HBsAg-positive HCC cases were recruited using abdominal ultrasonography and tests for HBsAg and serum aminotransferases. They were from 165 simplex families defined as having only one HCC case and 72 multiplex families with more than one case. In analyses of family history of HCC and cirrhosis, the data set consisted of 4,471 unrelated asymptomatic HBsAg carriers recruited in a prospective study. RESULTS: There was no significant difference in the HBsAg-positive rate among relatives between multiplex (55.7%) and simplex (48.1%) families. Sonographic evidence of liver cirrhosis was present in 14.4% of HBsAg-positive relatives from multiplex families but in only 7.8% of HBsAg-positive relatives from simplex families (multiplex versus simplex families: adjusted odds ratio [OR] = 2.29; 95% CI: 1.10-4.77). Among unrelated asymptomatic HBsAg carriers, the adjusted OR of liver cirrhosis associated with a first-degree family history of HCC was 2.80 (95% CI: 1.68-4.66). This association was stronger in HBsAg carriers <50 years. No association was seen between family history of HCC and hepatitis activity based on elevated levels of aminotransferases. CONCLUSIONS: Familial aggregation of HCC in HBsAg carriers is associated with familial clustering of liver cirrhosis.

Androgen receptor exon 1 CAG repeat length and risk of hepatocellular carcinoma in women.

The androgen receptor (AR) gene is localized on chromosome X, and shorter CAG repeats in exon 1 of the AR gene were recently suggested to increase hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) risk among men. To examine whether the relationship between the AR-CAG repeats and HCC was also evident among women, we conducted a case-control study in Taiwan. The number of AR-CAG repeats was determined for 238 women with HCC and 354 unrelated control subjects (comprising 188 first-degree and 166 nonbiological relatives) selected from female relatives of patients with HCC. Women harboring 2 AR alleles with more than 23 CAG repeats had an increased risk of HCC (age-adjusted odds ratio [OR], 1.82; 95% CI, 1.06-3.14), compared with women with only short alleles or a single long allele. The association between harboring 2 AR alleles containing longer CAG repeats and HCC was more striking among HBV carriers (age-adjusted OR for more than 22 repeats, 2.23; 95% CI, 1.14-4.34) and particularly prominent among HBV carriers under age 53 years (age-adjusted OR, 3.16; 95% CI, 1.13-8.82). When CAG repeats were analyzed as a continuous variable, the increase in HCC risk associated with each incremental repeat in the shorter of 2 alleles in a given genotype was statistically significant among women with a first-degree relative with HCC (age-adjusted OR, 1.18; 95% CI, 1.01-1.37). No such relationship was detected among women without the family history. In conclusion, our observations suggest that the AR-CAG alleles may contribute to HCC predisposition among women through a mechanism different from that for men.