Summary
Background
Data reporting the heritability of non‐alcoholic fatty liver disease (NAFLD) are highly variable.
Aims
To investigate the association of NAFLD between parents and their adolescent ...children using a nationwide, population‐based cohort.
Methods
We analysed 1737 families with both parents and adolescent children aged 12–18 who participated in Korean National Health and Nutrition Examination Surveys (KNHANES) between 2010 and 2019. NAFLD was defined by body mass index and elevated alanine aminotransferase levels in children and by the hepatic steatosis index in parents.
Results
The prevalence of NAFLD in adolescent children with either parent with NAFLD was higher than that in those without a parent with NAFLD (10.2% vs. 3.1%, p < 0.001). In a model fully adjusted for demographic, nutritional, behavioural and metabolic risk factors, children with either parent with NAFLD had a higher odds ratio (OR) for NAFLD (OR = 1.75, 95% CI: 1.02–3.00) than those without a parent with NAFLD. Compared to those without a parent with NAFLD, the fully adjusted ORs of NAFLD in children with paternal NAFLD, maternal NAFLD and NAFLD in both parents were 1.80 (95% CI: 1.01–3.20), 2.21 (95% CI: 1.11–4.42) and 2.60 (95% CI: 1.03–6.54), respectively.
Conclusion
Adolescent children with a parent with NAFLD were at increased risk of NAFLD; risk was higher when both parents had NAFLD. Further studies are needed to explore the benefit of NAFLD screening in children who have a parent with NAFLD.
Adolescent children with a parent with NAFLD were at increased risk of NAFLD. NAFLD screening might be needed for children who have a parent with NAFLD.
The long‐term clinical impact of low‐level viremia (LLV; <2,000 IU/mL) is not well understood. As a result, it is unclear whether the development of LLV during entecavir monotherapy requires a change ...in therapy. A retrospective cohort of 875 treatment‐naive chronic hepatitis B virus (HBV) monoinfected patients (mean age 47.7 years, male = 564 65.5%, cirrhosis = 443 50.6%) who received entecavir monotherapy were analyzed for the development of hepatocellular carcinoma (HCC). The HCC risk was compared between patients who maintained virological response (MVR), defined by persistently undetectable HBV DNA (<12 IU/mL), and patients who experienced LLV, defined by either persistent or intermittent episodes of <2,000 IU/mL detectable HBV DNA. During a median 4.5 years of follow‐up (range 1.0‐8.7 years), HCC was diagnosed in 85 patients (9.7%). HCC developed more frequently in patients who experienced LLV than MVR (14.3% versus 7.5% at 5 years, P = 0.015). The hazard ratio comparing those with LLV to MVR was 1.98 (95% confidence interval = 1.28‐3.06, P = 0.002, adjusted for age, sex, hepatitis B e antigen, baseline HBV DNA levels, and cirrhosis). Among patients with cirrhosis, those with LLV exhibited a significantly higher HCC risk than those with MVR (HCC incidence rate at 5 years 23.4% versus 10.3%, adjusted hazard ratio = 2.20, 95% confidence interval 1.34‐3.60; P = 0.002). However, for patients without cirrhosis, there was no significant difference in the HCC risk between LLV and MVR. Conclusion: LLV observed during entecavir monotherapy was associated with a higher risk of HCC, especially for those with cirrhosis, indicating that LLV during potent antiviral therapy is consequential. (Hepatology 2017;66:335–343).
LINKED CONTENT
This article is linked to Park et al papers. To view these articles, visit https://doi.org/10.1111/apt.17257 and https://doi.org/10.1111/apt.17390
Background and Aims
Statins have pleiotropic effects that may include chemoprevention. Several observational studies have suggested that statins may prevent hepatocellular carcinoma (HCC), but they ...have not yet been fully studied in patients with chronic hepatitis B virus (HBV) infections.
Approach and Results
A hospital‐based retrospective cohort of 7,713 chronic HBV‐infected individuals between January 2008 and December 2012 were analyzed. The primary outcome was the development of HCC. Patients who used statins for at least 28 cumulative defined daily doses during the follow‐up period were defined as statin users (n = 713). The association between the use of statin and the incidence of HCC was analyzed using the multivariable Cox regression model with time‐dependent covariates. During a median follow‐up of 7.2 years (min‐max: 0.5‐9.9), HCC newly developed in 702 patients (9.1%). Statin use was associated with a lower risk of HCC (adjusted hazard ratio = 0.36, 95% confidence interval: 0.19‐0.68, adjusted for age, sex, cirrhosis, diabetes, hypertension, serum alanine aminotransferase, cholesterol, HBV DNA level, antiviral treatment, and antiplatelet therapy). The observed benefit of the statin use was dose‐dependent (adjusted hazard ratio 95% confidence interval, 0.63 0.31‐1.29; 0.51 0.21‐1.25; 0.32 0.07,1.36; and 0.17 0.06, 0.48 for patients with statin use of 28‐365, 366‐730, 731‐1095, and more than 1,095 cumulative defined daily doses, respectively). In subgroup analysis, the association between statin use and reduced risk of HCC was observed in all prespecified subgroups analyzed.
Conclusion
Statin use was associated with a reduced risk of HCC development in chronic HBV‐infected patients, suggesting that statins may have a chemopreventive role in this population. These findings warrant a prospective evaluation.
LINKED CONTENT
This article is linked to Park et al papers. To view these articles, visit https://doi.org/10.1111/apt.17257 and https://doi.org/10.1111/apt.17317
Background and Aim
Non‐alcoholic fatty liver disease (NAFLD) is a multisystem disease associated with an increased risk of cardiovascular disease (CVD), diabetes, and chronic kidney disease. Indeed, ...CVD is the most common cause of death in NAFLD patients. This study aimed to evaluate the association between NAFLD and the risk of incident myocardial infarction.
Methods
This is a retrospective cohort study involving 111 492 adults over 40 years old without history of CVD, liver disease, or cancer at baseline who participated in a regular health screening exam between 2003 and 2013. Fatty liver was diagnosed by ultrasonography.
Results
During 725 706.9 person‐years of follow‐up, 183 participants developed myocardial infarction (incidence rate 0.3 cases per 1000 person‐years). The age, sex, and year of visit‐adjusted hazard ratio (HR) for incident myocardial infarction comparing participants with NAFLD with those without it was 2.14 (95% confidence interval 1.59, 2.89). This association remained significant in fully adjusted models (HR 1.54; 95% confidence interval 1.11, 2.14). Compared with participants without NAFLD, in participants with low NAFLD fibrosis score (NFS) (< −1.455) and with intermediate‐to‐high NFS (≥ −1.455), the fully adjusted HRs for incident myocardial infarction were 1.70 (1.22, 2.36) and 1.88 (1.24, 2.87), respectively.
Conclusion
In this large cohort study, NAFLD was associated with an increased incidence of myocardial infarction independently of established risk factors. In addition, this association was similar in participants with and without evidence of more advanced NAFLD as indicated by the NFS. NAFLD patients may need to be carefully monitored and managed early to prevent myocardial infarction.
Background & Aims Activated hepatic stellate cells (HSCs), the main fibrogenic cell type in the liver, undergo apoptosis after cessation of liver injury, which contributes to resolution of fibrosis. ...In this study, we investigated whether HSC deactivation constitutes an additional mechanism of liver fibrosis resolution. Methods HSC activation and deactivation were investigated by single-cell PCR and genetic tracking in transgenic mice that expressed a tamoxifen-inducible CreER under control of the endogenous vimentin promoter (Vimentin-CreER). Results Single-cell quantitative polymerase chain reaction demonstrated activation of almost the entire HSC population in fibrotic livers, and a gradual decrease of HSC activation during fibrosis resolution, indicating deactivation of HSCs. Vimentin-CreER marked activated HSCs, demonstrated by a 6- to 16-fold induction of a membrane-bound green fluorescent protein (mGFP) Cre-reporter after injection of carbon tetrachloride, in liver and isolated HSCs, and a shift in localization of mGFP-marked HSCs from peri-sinusoidal to fibrotic septa. Tracking of mGFP-positive HSCs revealed the persistence of 40%–45% of mGFP expression in livers and isolated HSCs 30–45 days after carbon tetrachloride was no longer administered, despite normalization of fibrogenesis parameters; these findings confirm reversal of HSC activation. After fibrosis resolution, mGFP expression was observed again in desmin-positive peri-sinusoidal HSCs; no mGFP expression was detected in hepatocytes or cholangiocytes, excluding mesenchymal-epithelial transition. Notably, reverted HSCs remained in a primed state, with higher levels of responsiveness to fibrogenic stimuli. Conclusions In mice, reversal of HSC activation contributes to termination of fibrogenesis during fibrosis resolution, but results in higher responsiveness of reverted HSCs to recurring fibrogenic stimulation.
Fibrosis and cancer represent two major complications of chronic liver disease. MicroRNAs have been implicated in the development of fibrosis and cancer, thus constituting potential therapeutic ...targets. Here, we investigated the role of microRNA‐21 (miR‐21), a microRNA that has been implicated in the development of fibrosis in multiple organs and has also been suggested to act as an “oncomir.” Accordingly, miR‐21 was the microRNA that showed the strongest up‐regulation in activated hepatic stellate cells (HSCs) in multiple models of fibrogenesis, with an 8‐fold to 24‐fold induction compared to quiescent HSCs. However, miR‐21 antisense inhibition did not suppress the activation of murine or human HSCs in culture or in liver slices. Moreover, genetic deletion of miR‐21 in two independently generated knockout mice or miR‐21 antisense inhibition did not alter HSC activation or liver fibrosis in models of toxic and biliary liver injury. Despite a strong up‐regulation of miR‐21 in injury‐associated hepatocellular carcinoma and in cholangiocarcinoma, miR‐21 deletion or antisense inhibition did not reduce the development of liver tumors. As inhibition of the most up‐regulated microRNA did not affect HSC activation, liver fibrosis, or fibrosis‐associated liver cancer, we additionally tested the role of microRNAs in HSCs by HSC‐specific Dicer deletion. Although Dicer deletion decreased microRNA expression in HSCs and altered the expression of select genes, it only exerted negligible effects on HSC activation and liver fibrosis. Conclusion: Genetic and pharmacologic manipulation of miR‐21 does not inhibit the development of liver fibrosis and liver cancer. Moreover, suppression of microRNA synthesis does not significantly affect HSC phenotype and activation. (Hepatology 2018;67:2414‐2429).
Although it is well established that hepatic macrophages play a crucial role in the development of liver fibrosis, the underlying mechanisms remain largely elusive. Moreover, it is not known whether ...other mononuclear phagocytes such as dendritic cells (DCs) contribute to hepatic stellate cell (HSC) activation and liver fibrosis. We show for the first time that hepatic macrophages enhance myofibroblast survival in a nuclear factor kappa B (NF‐κB)–dependent manner and thereby promote liver fibrosis. Microarray and pathway analysis revealed no induction of HSC activation pathways by hepatic macrophages but a profound activation of the NF‐κB pathway in HSCs. Conversely, depletion of mononuclear phagocytes during fibrogenesis in vivo resulted in suppressed NF‐κB activation in HSCs. Macrophage‐induced activation of NF‐κB in HSCs in vitro and in vivo was mediated by interleukin (IL)−1 and tumor necrosis factor (TNF). Notably, IL‐1 and TNF did not promote HSC activation but promoted survival of activated HSCs in vitro and in vivo and thereby increased liver fibrosis, as demonstrated by neutralization in coculture experiments and genetic ablation of IL‐1 and TNF receptor in vivo. Coculture and in vivo ablation experiments revealed only a minor contribution to NF‐κB activation in HSCs by DCs, and no contribution of DCs to liver fibrosis development, respectively. Conclusion: Promotion of NF‐κB–dependent myofibroblast survival by macrophages but not DCs provides a novel link between inflammation and fibrosis. (Hepatology 2013;58:1461–1473)
This study examined the association between chronic HBV or HCV infection and the risk of extrahepatic cancers. A total of 537 103 adults aged ≥20 years without history of cancer were identified from ...the Korean National Health Insurance Service‐National Sample Cohort between 2003 and 2013. The difference in cancer incidence was compared between those with and without chronic HBV or HCV infection. During 3 854 130 person‐years of follow‐up (median follow‐up: 8.0 years), 19 089 participants developed cancer. After adjusting for sex, body mass index, smoking, drinking, income percentile, residential area and comorbidities, hazard ratios (HRs) for incident extrahepatic cancer were significantly higher in participants with chronic HBV infection (HR: 1.27, 95% confidence interval CI: 1.20‐1.35), HCV infection (HR: 1.31, 95% CI: 1.16‐1.48) or HBV/HCV dual infection (HR: 1.41, 95% CI: 1.31‐1.72) compared to participants without HBV or HCV infection. In chronic HBV infection, the cancer risk was higher for haematologic malignancy HR (95% CI) = 2.46 (1.92‐3.15), gallbladder 1.55 (1.05‐2.29), pancreas 1.52 (1.07‐2.15), stomach 1.39 (1.22‐1.58), lung 1.27 (1.04‐1.55), colorectum 1.21 (1.03‐1.42) and thyroid cancer 1.20 (1.05‐1.36). In chronic HCV infection, the cancer risk was higher for testis 10.34 (1.35‐79.78), gallbladder 2.90 (1.62‐5.18), prostate 2.51 (1.65‐3.82) and thyroid cancer 1.46 (1.10‐1.93). In conclusion, chronic HBV or HCV infection was not only associated with an increased risk of liver cancer, but also associated with an increased risk of multiple extrahepatic cancers.
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