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- Duberg, Ann-Sofi, Docent, 1957-, et al.
(författare)
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The incidence of hepatocellular carcinoma in hepatitis B virus infected persons of different origins, living in Sweden
- 2018
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 68:Suppl. 1, s. S488-S488
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and Aims: Chronic hepatitis B (CHB) is associated with an increased risk of hepatocellular carcinoma (HCC) in both cirrhotic and non-cirrhotic persons. CHB patients with high risk for HCC are therefore recommended to undergo surveillance for HCC, with an estimated cut-off for surveillance in non-cirrhotic patients at incidence rate (IR) of 0.2% per year. People originating from Asia and men from Africa are estimated to have particularly high risks, but the IR for HCC when living in the Western world has not been fully estimated. Therefore, our aim was to study the incidence of HCC by age and origin in persons with CHB who are living in Sweden.Method: In this national population-based study all persons diagnosed with CHB in Sweden during 1990–2015, their country of birth, co-infections, antiviral therapy, liver cancer or death/emigration were identified retrospectively, using the national HBV-surveil-lance register and other national registers. Those co-infected with hepatitis C were excluded. Observation time started at date of reported CHB diagnosis. The IR was calculated for different age groups and by region of birth.Results: In total 16,410 persons (47% women) with CHB were studied. The number of persons and observation time (person-years) by origin were: Western Europe 2,316 (25,415); Eastern Europe 2,349 (26,237); Middle East/North Africa 4,402 (47,320); Sub-Saharan Africa 3,677 (30,565), Asia 3,537 (35,358) and other 129 (1,277). Those from Sub-Saharan Africa were youngest and had the shortest mean time in Sweden, 11.6 years. There were in total 232 diagnosed HCCs (82% in men); 23, 54 and 58 in people from Sub-Saharan Africa ,Asia and Middle East/North Africa, respectively. The corresponding mean ages at HCC diagnoses were 45, 51 and 59 years, respectively. The IRexceeded 0.2% for men from Asia from age-group≥40–49 years (IR 0.63, 95%CI 0.39–1.00), and for men of all other origins from age-group≥50–59 years. Among African men aged <40 yearstherewere 7 HCC, with incidence rate 0.05 and 0.11 in age groups 20–29 and 30–39 years, respectively. In women, HCC was rare but exceeded 0.2% among those aged≥60 years with origins from East Europe, Asia and Middle East/North Africa.Conclusion: In this study only men of Asian origin exceeded the cut-off for HCC surveillance by ages 40–49 years. African men had a few HCCs at youngerages, but did not exceed the cut-off before age 50–59 years. This study confirms the high risk for HCC in especially Asian men living in the Western world, but questions the benefit of surveillance at younger ages for men with African origin who live in a Northern European country
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| 11. |
- Lybeck, Charlotte, 1979-, et al.
(författare)
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A national study of risk for non-liver cancer in people with hepatitis C treated with direct acting antivirals or an interferon-based regimen
- 2018
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 68:Suppl. 1, s. S263-S264
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and Aims: Direct acting antivirals (DAA) against hepatitis C virus (HCV) have been shown to have an immune modulatory effect, with a possibly decreased tumour specific CD8 T cell response. Reports indicative of a high risk for hepatocellular carcinoma or advanced tumours early after DAA treatment, have raised concerns about whether the risk for non-liver cancer could be increased. Therefore, our aim was to study the early incidence of non-liver cancer after initiation of DAA or interferon (IFN-based) therapy in a national HCV cohort.Method: All diagnosed HCV-infected persons in Sweden, their antiviral treatments, non-liver cancer or death/emigration were identified retrospectively, using the national HCV-surveillance register and other national registers. Cox regression was used to compare persons treated with DAAs (n = 1,920), IFN-based therapy(n = 2,586) or no HCV therapy (n = 13,872) between 2009 and 2015. Persons with a previous cancer diagnosis (5.7%) were studied separately. Age was used as the time-scale, and the analyses were stratified by sex and adjusted for the Charlson comorbidity index.Results: In total 492 non-liver cancers were diagnosed, with 222 among persons with no previous cancer and 270 new cancer diagnoses among those with previous cancer. Among persons with no previous cancer, 21, 24 and 177 developed non-liver cancer following DAA, IFN-based and no treatment, respectively. The corresponding numbers for those with previous cancer were 25, 20 and 225, respectively. The hazard ratios (and 95% confidence intervals) for non-liver cancer in the no previous cancer group are 1.35 (0.66–2.76; p = 0.41) for men and 1.75 (0.59–5.18; p = 0.31) for women with DAA treatment, compared with IFN treatment. For those with previous cancer, the corresponding hazard ratios are 1.03 (0.41–2.57; p = 0.95) for men and 0.86 (0.35–2.13; p = 0.75) for women with DAA treatment.Conclusion: This study did not demonstrate any significantly increased risk for non-liver cancer early after DAA therapy initiation. The hazard ratio was slightly increased among those with outprevious cancer, but the cancers were few and the results were not statistically significant. Further studies with higher numbers of DAA treated patients and longer follow-up are needed to fully explore thisissue.
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| 13. |
- Nasr, Patrik, et al.
(författare)
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Incidence, prevalence and mortality of chronic liver diseases in Sweden between 2005 and 2019
- 2022
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 77:Suppl. 1, s. S82-S82
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: Chronic liver diseases affects approximately 844 million individuals and causes an estimated two million deaths per year. The most common causes are chronic viral hepatitis, alcohol-related liver disease and non-alcoholic fatty liver disease. With the availability of curative treatments and effective vaccines for viral hepatitis and increasing prevalence of metabolic syndrome-thel andscape of liver diseases is shifting. In this study, we aimed to describe the incidence and prevalence of a wide range of chronic liver diseases as well as their role in mortality in Sweden.Method: In this register-based, nationwide cohort study, aggregated statistics, stratified on categories of age, sex and geographic allocations, on all adult Swedish inhabitants with a diagnosis of liver disease during 2005 to 2019 were obtained from National registers.Results: During 2005 to 2019, there were substantial changes in the epidemiology of liver diseases in Sweden. The incidence of alcohol-related cirrhosis increased by 18% annually (incidence rate 13.1/100, 000 in 2019). The incidence rate of non-alcoholic fatty liver diseasea nd cirrhosis with unspecified etiology increased by 14% and 20% annually respectively (incidence rate 15.2 and 18.7/100, 000). Furthermore, incidence rates of chronic hepatitis C steeply declined, while autoimmune hepatitis increased (3.4/100, 000). In parallel with the increasing incidence of liver cirrhosis, liver malignancies have become more common.The most common causes of liver related mortality were alcohol-related disease without a code for cirrhosis, alcohol-related cirrhosis, and unspecified liver disease with mortality rates of 4.1, 2.9, and 2.8/100, 000. Most liver diseases were more frequent amongst men. Furthermore, varying differences was seen in the incidence ratebetween regions, with some etiologies (e.g. autoimmune liver diseases) being more common in rural areas.Conclusion: The incidence rates of non-alcoholic fatty liver disease, alcohol-related cirrhosis, unspecified liver cirrhosis has increased during the last 15 years, in parallel with a decreasing incidence of viral hepatitis. The incidence of AIH and hepatobiliary malignancies is also increasing. Worryingly, mortality in several liver diseases increased, likely reflecting the increasing incidence of cirrhosis. Significant disparities of liver diseases exist across sex and geographical regions, which needs to be considered when allocating healthcare resources.
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- Qadri, Sami, et al.
(författare)
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Hepatic insulin resistance is the basis of bile acid dysmetabolism in non-alcoholic fatty liver disease
- 2022
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 77:Suppl. 1, s. S694-S695
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: Non-alcoholic fatty liver disease (NAFLD) is associated with increased circulating bile acids (BAs). It is unknown whether this reflects altered intrahepatic BA metabolism due to NAFLD or the associated insulin resistance (IR). To dissociate steatosis from IR, we compared BA metabolism in NAFLD associated with either IR or high genetic risk.Method: In 106 patients undergoing a liver biopsy, we analysed serum/liver BAs, the hepatic transcriptome (RNA-seq), and concentrations of plasma FGF-19 (marker of intestinal BA metabolism). Using HOMA-IR and a validated weighted Polygenic Risk Score (PRS) for NAFLD, we divided the patients into matched groups to compare the effects of NAFLD associated with IR (‘High HOMA-IR’ vs. ‘LowHOMA-IR’) or with high genetic risk (‘High PRS’ vs. ‘Low PRS’) on BA metabolism.Results: An untargeted analysis identified distinct clusters of patients with simultaneously increased BAs, HOMA-IR, and liver fat content. Compared to ‘Low HOMA-IR’, patients with ‘High HOMA-IR’ had significantly higher total (+57%, P = 0.011) and especially conjugated (+82%, P = 0.002) serum BAs, but unchanged hepatic BAs. Expression of the primary hepatic BA uptake transporter NTCP was down-regulated, while plasma FGF-19 was unchanged. Despite having the same degree of steatosis and NASH compared to the ‘High HOMA-IR’ group, patients with ‘High PRS’ had similar serum/liver BAs compared to those with ‘Low PRS’. Stage F3-F4 liver fibrosis independently predicted higher serum BAs.Conclusion: In NAFLD without advanced fibrosis, serum BAs are increased due to IR, which may impair hepatocellular BA uptake. Intrahepatic BAs are unchanged in NAFLD.
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| 16. |
- Qadri, Sami, et al.
(författare)
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Heterogeneity of phosphatidylcholine metabolism in nonalcoholic fatty liver disease
- 2022
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 77:Suppl. 1, s. S111-S111
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: In murine models of non-alcoholic fatty liver disease (NAFLD), liver damage associates with a deficiency of phosphatidylcholines (PCs), particularly polyunsaturated PCs (PUFA-PCs). We studied whether human PC metabolism is altered by NAFLD or by the protective genetic variant in HSD17B13 (rs72613567 T > TA).Method: In 143 obese patients with a liver biopsy and genotyping for HSD17B13 rs72613567, we analysed the hepatic lipidome (UPLC-MS). As the hepatic parenchymal fat fraction (HPFF) affects apparent concentrations of amphiphilic lipids, we normalised hepatic phospholipid concentrations to fat-free liver mass. To this end, we employed a state-of-the-art deep learning image analysis method (Aiforia Technologies) to accurately quantify HPFF in liver biopsies.Results: Total unadjusted hepatic PCs correlated negatively with HPFF (rs = −0.26, P < 0.01), but this association disappeared after normalising to fat-free liver mass (rs = 0.02, P = 0.81). With increasing HPFF, concentrations of especially saturated and monounsaturated PCs significantly increased, whereas concentrations of PUFA-PCs decreased. Accordingly, the hepatic triacylglycerol composition significantly correlated with that of hepatic PCs. In carriers of the protective variant in HSD17B13, as compared to non-carriers, the hepatic lipidome was enriched in especially PUFA-PCs.Conclusion: Patients with NAFLD have a deficiency of PUFA-PCs. The protective HSD17B13 rs72613567 variant opposes these changes, increasing intrahepatic PC concentrations.
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| 20. |
- Lazarus, J.V., et al.
(författare)
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A cross-sectional study of the public health response to non-alcoholic fatty liver disease in Europe
- 2020
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 72:1, s. 14-24
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Tidskriftsartikel (refereegranskat)abstract
- Background & AimsNon-alcoholic fatty liver disease (NAFLD) is a growing public health problem worldwide and has become an important field of biomedical inquiry. We aimed to determine whether European countries have mounted an adequate public health response to NAFLD and non-alcoholic steatohepatitis (NASH).MethodsIn 2018 and 2019, NAFLD experts in 29 European countries completed an English-language survey on policies, guidelines, awareness, monitoring, diagnosis and clinical assessment in their country. The data were compiled, quality checked against existing official documents and reported descriptively.ResultsNone of the 29 participating countries had written strategies or action plans for NAFLD. Two countries (7%) had mentions of NAFLD or NASH in related existing strategies (obesity and alcohol). Ten (34%) reported having national clinical guidelines specifically addressing NAFLD and, upon diagnosis, all included recommendations for the assessment of diabetes and liver cirrhosis. Eleven countries (38%) recommended screening for NAFLD in all patients with either diabetes, obesity and/or metabolic syndrome. Five countries (17%) had referral algorithms for follow-up and specialist referral in primary care, and 7 (24%) reported structured lifestyle programmes aimed at NAFLD. Seven (24%) had funded awareness campaigns that specifically included prevention of liver disease. Four countries (14%) reported having civil society groups which address NAFLD and 3 countries (10%) had national registries that include NAFLD.ConclusionsWe found that a comprehensive public health response to NAFLD is lacking in the surveyed European countries. This includes policy in the form of a strategy, clinical guidelines, awareness campaigns, civil society involvement, and health systems organisation, including registries.Lay summaryWe conducted a survey on non-alcoholic fatty liver disease with experts in European countries, coupled with data extracted from official documents on policies, clinical guidelines, awareness, and monitoring. We found a general lack of national policies, awareness campaigns and civil society involvement, and few epidemiological registries.
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| 21. |
- Bureau, Christophe, et al.
(författare)
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Alfapump® system vs. large volume paracentesis for refractory ascites : a multicenter randomized controlled study
- 2017
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 67:5, s. 940-949
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Patients with refractory ascites (RA) require repeated large volume paracenteses (LVP), which involves frequent hospital visits and is associated with a poor quality-of-life. This study assessed safety and efficacy of an automated, low-flow pump (alfapump® [AP]) compared with LVP standard of care [SoC].Methods: A randomized controlled trial, in seven centers, with six month patient observation was conducted. Primary outcome was time to first LVP. Secondary outcomes included paracentesis requirement, safety, health-related quality-of-life (HRQoL), and survival. Nutrition, hemodynamics, and renal injury biomarkers were assessed in a sub-study at three months.Results: Sixty patients were randomized and 58 were analyzed (27 AP, 31 SoC, mean age 61.9years, mean MELD 11.7). Eighteen patients were included in the sub-study. Compared with SoC, median time to first LVP was not reached after six months in the AP group, meaning a significant reduction in LVP requirement for the AP patients (AP, median not reached; SoC, 15.0days (HR 0.13; 95%CI 13.0-22.0; p<0.001), and AP patients also showed significantly improved Chronic Liver Disease Questionnaire (CLDQ) scores compared with SoC patients (p<0.05 between treatment arms). Improvements in nutritional parameters were observed for hand-grip strength (p=0.044) and body mass index (p<0.001) in the sub-study. Compared with SoC, more AP patients reported adverse events (AEs; 96.3% vs. 77.4%, p=0.057) and serious AEs (85.2 vs. 45.2%, p=0.002). AEs consisted predominantly of acute kidney injury in the immediate post-operative period, and re-intervention for pump related issues, and were treatable in most cases. Survival was similar in AP and SoC.Conclusions: The AP system is effective for reducing the need for paracentesis and improving quality of life in cirrhotic patients with RA. Although the frequency of SAEs (and by inference hospitalizations) was significantly higher in the AP group, they were generally limited and did not impact survival.Lay summary: The alfapump® moves abdominal fluid into the bladder from where it is then removed by urination. Compared with standard treatment, the alfapump reduces the need for large volume paracentesis (manual fluid removal by needle) in patients with medically untreatable ascites. This can improve life quality for these patients.
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| 22. |
- Al-Dury, Samer, et al.
(författare)
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Obeticholic acid may increase the risk of gallstone formation in susceptible patients.
- 2019
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Ingår i: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 71:5, s. 986-991
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Tidskriftsartikel (refereegranskat)abstract
- The nuclear farnesoid X receptor (FXR) agonist obeticholic acid (OCA) has been developed for the treatment of liver diseases. We aimed to determine whether OCA treatment increases the risk of gallstone formation.Twenty patients awaiting laparoscopic cholecystectomy were randomized to treatment with OCA (25 mg/day) or placebo for three weeks before surgery. Serum bile acids (BAs), the BA synthesis marker C4 (7α-hydroxy-cholest-4-ene-3-one), and fibroblast growth factor 19 (FGF19) were measured before and after treatment. During surgery, biopsies from the liver and the whole bile-filled gallbladder were collected for analyses of gene expression, biliary lipids and FGF19.In serum, OCA increased FGF19 (from 95.0±8.5 to 234.4±35.6 ng/L) and decreased C4 (from 31.4±22.8 to 2.8±4.0 nmol/L) and endogenous BAs (from 1312.2±236.2 to 517.7±178.9 nmol/L; all p<0.05). At surgery, BAs in gallbladder bile were lower in OCA patients than controls (OCA, 77.9±53.6 mmol/L; placebo, 196.4±99.3 mmol/L; p<0.01), resulting in a higher cholesterol saturation index (OCA, 2.8±1.1; placebo, 1.8±0.8; p < 0.05). In addition, hydrophobic OCA conjugates accounted for 13.6±5.0% of gallbladder BAs after OCA treatment, resulting in a higher hydrophobicity index (OCA, 0.43±0.09; placebo, 0.34±0.07, p<0.05). Gallbladder FGF19 was three-fold higher in OCA patients than in controls (OCA, 40.3±16.5 ng/L; placebo, 13.5±13.1 ng/mL; p<0.005). Gene expression analysis indicated a mainly gallbladder epithelial origin of FGF19.Our results show for the first time an enrichment of FGF19 in human bile after OCA treatment. In accordance with its murine homolog FGF15, FGF19 might trigger relaxation and filling of the gallbladder which, in combination with increased cholesterol saturation and BA hydrophobicity, would enhance the risk for gallstone development.Obeticholic acid increased human gallbladder cholesterol saturation and bile acid hydrophobicity, both decreasing cholesterol solubility in bile. Together with increased hepatobiliary FGF19, our findings suggest that pharmacological FXR activation increases the risk of gallstone formation.
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| 26. |
- Anstee, Quentin M., et al.
(författare)
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Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically-characterised cohort
- 2020
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 73:3, s. 505-515
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Genetic factors associated with non-alcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most GWAS studies have adopted radiologically assessed hepatic triglyceride content as reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a genome-wide association study (GWAS) encompassing the full spectrum of histologically characterized NAFLD.METHODS: The GWAS involved 1483 European NAFLD cases and 17781 genetically-matched population controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance.RESULTS: Case-control analysis identified signals showing p-values ≤ 5 x 10-8 at four locations (chromosome (chr) 2 GCKR/C2ORF16; chr4 HSD17B13; chr19 TM6SF2; chr22 PNPLA3) together with two other signals with p<1 x10-7 (chr1 near LEPR and chr8 near IDO2/TC1). Case-only analysis of quantitative traits steatosis, disease activity score, NAS and fibrosis showed that the PNPLA3 signal (rs738409) was genome-wide significantly associated with steatosis, fibrosis and NAS score and identified a new signal (PYGO1 rs62021874) with close to genome-wide significance for steatosis (p=8.2 x 10-8). Subgroup case-control analysis for NASH confirmed the PNPLA3 signal. The chr1 LEPR SNP also showed genome-wide significance for this phenotype. Considering the subgroup with advanced fibrosis (≥F3), the signals on chromosomes 2, 19 and 22 remained genome-wide significant. With the exception of GCKR/C2ORF16, the genome-wide significant signals replicated.CONCLUSIONS: This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome-wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting relevance of Wnt signalling pathways in NAFLD pathogenesis.
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| 28. |
- Baselli, Guido A, et al.
(författare)
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Rare ATG7 genetic variants predispose patients to severe fatty liver disease.
- 2022
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Ingår i: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 77:3, s. 596-606
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Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver disorders and has a strong heritable component. The aim of this study was to identify new loci contributing to severe NAFLD by examining rare variants.We performed whole-exome sequencing in individuals with NAFLD and advanced fibrosis or hepatocellular carcinoma (n=301) and examined the enrichment of likely pathogenic rare variants vs. the general population, followed by validation at gene level.In patients with severe NAFLD, we observed an enrichment of the p.P426L variant (rs143545741 C>T; OR 5.26, 2.1-12.6; p=0.003) of autophagy-related 7 (ATG7), which we characterized as a loss-of-function, vs. the general population, and an enrichment in rare variants affecting the catalytic domain (OR 13.9, 1.9-612; p=0.002). In the UK Biobank cohort, loss-of-function ATG7 variants increased the risk of cirrhosis and hepatocellular carcinoma (OR 3.30, 1.1-7.5 and OR 12.30, 2.6-36, respectively; p<0.001 for both). The low-frequency loss-of-function p.V471A variant (rs36117895 T>C) was also associated with severe NAFLD in the clinical cohort (OR=1.7, 1.2-2.5; p=0.003), predisposed to hepatocellular ballooning (p=0.007) evolving to fibrosis in a Liver biopsy cohort (n=2268), and was associated with liver injury in the UK Biobank (AST levels, p<0.001), with a larger effect in severely obese individuals where it was linked to hepatocellular carcinoma (p=0.009). ATG7 protein localized to periportal hepatocytes, more so in the presence of ballooning. In the Liver Transcriptomic cohort (n=125) ATG7 expression correlated with suppression of the TNFα pathway, which was conversely upregulated in p.V471A carriers.We identified rare and low-frequency ATG7 loss-of-function variants as modifiers of NAFLD progression by impairing autophagy and facilitating ballooning and inflammation.•We found that rare mutations in a gene called autophagy related (ATG7) increase the risk of developing severe liver disease in individuals with dysmetabolism. •These mutations cause an alteration in protein function and impairment of self-renewal of cellular content, leading to liver damage and inflammation.
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| 31. |
- Baumeister, Sebastian E., et al.
(författare)
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Association between physical activity and risk of hepatobiliary cancers : A multinational cohort study
- 2019
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Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 70:5, s. 885-892
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: To date, evidence on the association between physical activity and risk of hepatobiliary cancers has been inconclusive. We examined this association in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC).Methods: We identified 275 hepatocellular carcinoma (HCC) cases, 93 intrahepatic bile duct cancers (IHBCs), and 164 non-gallbladder extrahepatic bile duct cancers (NGBCs) among 467,336 EPIC participants (median follow-up 14.9 years). We estimated cause-specific hazard ratios (HRs) for total physical activity and vigorous physical activity and performed mediation analysis and secondary analyses to assess robustness to confounding (e.g. due to hepatitis virus infection).Results: In the EPIC cohort, the multivariable-adjusted HR of HCC was 0.55 (95% CI 0.38–0.80) comparing active and inactive individuals. Regarding vigorous physical activity, for those reporting >2 hours/week compared to those with no vigorous activity, the HR for HCC was 0.50 (95% CI 0.33–0.76). Estimates were similar in sensitivity analyses for confounding. Total and vigorous physical activity were unrelated to IHBC and NGBC. In mediation analysis, waist circumference explained about 40% and body mass index 30% of the overall association of total physical activity and HCC.Conclusions: These findings suggest an inverse association between physical activity and risk of HCC, which is potentially mediated by obesity.Lay summary: In a pan-European study of 467,336 men and women, we found that physical activity is associated with a reduced risk of developing liver cancers over the next decade. This risk was independent of other liver cancer risk factors, and did not vary by age, gender, smoking status, body weight, and alcohol consumption.
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| 32. |
- Bergquist, Annika M., et al.
(författare)
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Hepatobiliary malignancy surveillance strategies in primary sclerosing cholangitis associate with reduced mortality
- 2021
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 75:Suppl. 2, s. S227-S228
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background and aims: Patients with primary sclerosing cholangitis (PSC) are at increased risk for hepatobiliary malignancies, especially cholangiocarcinoma. Although many recommend surveillance for malignancy in PSC, different strategies are used by various centers and countries. We aimed to evaluate different surveillance strategies and their effectiveness in PSC with the hypothesis that surveillance imaging improves survival.Method: We queried centers about surveillance practices and retrospectively collected imaging surveillance data for hepatobiliary cancer in 2, 975 patients with PSC from 28 centers within the International PSC Study Group (IPSCSG). Surveillance strategies were grouped in (i) non-surveillance (no imaging in asymptomatic patients), (ii) magnetic resonance imaging (MRI) and/or ultrasound (US) surveillance (regular imaging regardless of symptoms/labs) and (iii) surveillance including endoscopic retrograde cholangiopancreatography (ERCP)-based (imaging and/or ERCP regardless of symptoms/labs). The primary end point was all-cause mortality. Cox-proportional hazard regression models were used to estimate hazard ratios (HRs).Results: 65.6% (1953/2975) of patients were male, mean age (SD) at diagnosis of PSC was 35.6 (14.2) years, with concomitant IBD in 71.5% (2127/2973). Hepatobiliary malignancy was found in 175 (5.9%) patients at 7.9 years of follow-up (Figure). Surveillance strategies differed significantly between centers. Of patients undergoing surveillance, 83% were subjected to MRI/MRCP, 49% to US and 28% to ERCP. Deaths were more frequent in the non-surveillance group 23.4% (82/350) than in the surveillance group 8.3% (218/2625). Mortality rate (95% CI) per 1000 person-years was 23.1 (18.1–28.1) inthe non-surveillance group (n = 350), 12.5 (10.6–14.5) in imaging surveillance with MRI and/or US (n = 1897) and 8.4 (6.3–10.5) in surveillance that included ERCP (n = 728). The risk of dying wasr educed in patients undergoing any type of surveillance (HR 0.53; 95% CI: 0.41–0.68) and the reduced risk remained after adjusting for sex, age and start year of follow-up (HR 0.61; 95% CI: 0.47–0.80).Conclusion: A broad variety of surveillance strategies across centers are used. Regular sur veillance for hepatobiliary malignancy in patients with PSC is associated with improved survival.
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| 33. |
- Bianco, Cristina, et al.
(författare)
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Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores.
- 2021
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Ingår i: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 74:4, s. 775-782
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Tidskriftsartikel (refereegranskat)abstract
- Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into the causal relationship between NAFLD and HCC, and to improve HCC risk stratification.We examined at-risk individuals (NAFLD cohort, n=2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD) and the general population (UK Biobank [UKBB] cohort, n=364,048; 202 with HCC). Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS (PRS-HFC), and then adjusted for HSD17B13 (PRS-5).In the NAFLD cohort, the adjusted impact of genetic risk variants on HCC was proportional to the predisposition to fatty liver (p=0.002) with some heterogeneity in the effect. PRS predicted HCC more robustly than single variants (p<10-13). The association between PRS and HCC was mainly mediated through severe fibrosis, but was independent of fibrosis in clinically relevant subgroups, and was also observed in those without severe fibrosis (p<0.05). In the UKBB cohort, PRS predicted HCC independently of classical risk factors and cirrhosis (p<10-7). In the NAFLD cohort, we identified high PRS cut-offs (≥0.532/0.495 for PRS-HFC/PRS-5) that in the UKBB cohort detected HCC with ∼90% specificity but limited sensitivity; PRS predicted HCC both in individuals with (p<10-5) and without cirrhosis (p<0.05).Our results are consistent with a causal relationship between hepatic fat and HCC. PRS improved the accuracy to detect HCC and may help stratify HCC risk in individuals with dysmetabolism, including those without severe liver fibrosis. Further studies are needed to validate our findings.
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| 34. |
- Bjorkstrom, NK
(författare)
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Immunobiology of the biliary tract system
- 2022
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Ingår i: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 77:6, s. 1657-1669
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Tidskriftsartikel (refereegranskat)
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| 35. |
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| 36. |
- Boesch, Markus, et al.
(författare)
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Adipose tissue macrophage dysfunction is associated with a breach of vascular integrity in NASH
- 2024
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Ingår i: Journal of Hepatology. - 0168-8278 .- 1600-0641. ; 80:3, s. 397-408
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: In non-alcoholic fatty liver disease (NAFLD), monocytes infiltrate visceral adipose tissue promoting local and hepatic inflammation. However, it remains unclear what drives inflammation and how the immune landscape in adipose tissue differs across the NAFLD severity spectrum. We aimed to assess adipose tissue macrophage (ATM) heterogeneity in a NAFLD cohort. Methods: Visceral adipose tissue macrophages from lean and obese patients, stratified by NAFLD phenotypes, underwent single-cell RNA sequencing. Adipose tissue vascular integrity and breaching was assessed on a protein level via immunohistochemistry and immunofluorescence to determine targets of interest. Results: We discovered multiple ATM populations, including resident vasculature-associated macrophages (ResVAMs) and distinct metabolically active macrophages (MMacs). Using trajectory analysis, we show that ResVAMs and MMacs are replenished by a common transitional macrophage (TransMac) subtype and that, during NASH, MMacs are not effectively replenished by TransMac precursors. We postulate an accessory role for MMacs and ResVAMs in protecting the adipose tissue vascular barrier, since they both interact with endothelial cells and localize around the vasculature. However, across the NAFLD severity spectrum, alterations occur in these subsets that parallel an adipose tissue vasculature breach characterized by albumin extravasation into the perivascular tissue. Conclusions: NAFLD-related macrophage dysfunction coincides with a loss of adipose tissue vascular integrity, providing a plausible mechanism by which tissue inflammation is perpetuated in adipose tissue and downstream in the liver. Impact and implications: Our study describes for the first time the myeloid cell landscape in human visceral adipose tissue at single-cell level within a cohort of well-characterized patients with non-alcoholic fatty liver disease. We report unique non-alcoholic steatohepatitis-specific transcriptional changes within metabolically active macrophages (MMacs) and resident vasculature-associated macrophages (ResVAMs) and we demonstrate their spatial location surrounding the vasculature. These dysfunctional transcriptional macrophage states coincided with the loss of adipose tissue vascular integrity, providing a plausible mechanism by which tissue inflammation is perpetuated in adipose tissue and downstream in the liver. Our study provides a theoretical basis for new therapeutic strategies to be directed towards reinstating the endogenous metabolic, homeostatic and cytoprotective functions of ResVAMs and MMacs, including their role in protecting vascular integrity.
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| 37. |
- Boursier, Jerome, et al.
(författare)
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Non-invasive tests accurately stratify patients with NAFLD based on their risk of liver-related events
- 2022
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Ingår i: Journal of Hepatology. - : ELSEVIER. - 0168-8278 .- 1600-0641. ; 76:5, s. 1013-1020
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Tidskriftsartikel (refereegranskat)abstract
- Background & Aims: Previous studies on the prognostic significance of non-invasive liver fibrosis tests in non-alcoholic fatty liver disease (NAFLD) lack direct comparison to liver biopsy. We aimed to evaluate the prognostic accuracy of fibrosis-4 (FIB4) and vibration-controlled transient elastography (VCTE), compared to liver biopsy, for the prediction of liver-related events (LREs) in NAFLD. Methods: A total of 1,057 patients with NAFLD and baseline FIB4 and VCTE were included in a multicenter cohort. Of these patients, 594 also had a baseline liver biopsy. The main study outcome during follow-up was occurrence of LREs, a composite endpoint combining cirrhosis complications and/or hepatocellular carcinoma. Discriminative ability was evaluated using Harrells C-index. Results: FIB4 and VCTE showed good accuracy for the prediction of LREs, with Harrells C-indexes >0.80 (0.817 [0.768-0.866] vs. 0.878 [0.835-0.921], respectively, p = 0.059). In the biopsy subgroup, Harrells C-indexes of histological fibrosis staging and VCTE were not significantly different (0.932 [0.910-0.955] vs. 0.881 [0.832-0.931], respectively, p = 0.164), while both significantly outperformed FIB4 for the prediction of LREs. FIB4 and VCTE were independent predictors of LREs in the whole study cohort. The stepwise FIB4-VCTE algorithm accurately stratified the risk of LREs: compared to patients with "FIB4 <1.30", those with "FIB4 >- 1.30 then VCTE <8.0 kPa" had similar risk of LREs (adjusted hazard ratio [aHR] 1.3; 95% CI 0.3-6.8), whereas the risk of LREs significantly increased in patients with "FIB4 >1.30 then VCTE 8.0-12.0 kPa" (aHR 3.8; 95% CI 1.3-10.9), and even more for those with "FIB4 >-1.30 then VCTE >12.0 kPa" (aHR 12.4; 95% CI 5.1- 30.2). Conclusion: VCTE and FIB4 accurately stratify patients with NAFLD based on their risk of LREs. These non-invasive tests are alternatives to liver biopsy for the identification of patients in need of specialized management. Lay summary: The amount of fibrosis in the liver is closely associated with the risk of liver-related complications in nonalcoholic fatty liver disease (NAFLD). Liver biopsy currently remains the reference standard for the evaluation of fibrosis, but its application is limited by its invasiveness. Therefore, we evaluated the ability of non-invasive liver fibrosis tests to predict liver-related complications in NAFLD. Our results show that the blood test FIB4 and transient elastography stratify the risk of liver-related complications in NAFLD, and that transient elastography has similar prognostic accuracy as liver biopsy. These results support the use of non-invasive liver fibrosis tests instead of liver biopsy for the management of patients with NAFLD.(C) 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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| 38. |
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| 39. |
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| 40. |
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| 41. |
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| 42. |
- Caja, Laia, et al.
(författare)
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Dissecting the effect of targeting the epidermal growth factor receptor on TGF-β-induced-apoptosis in human hepatocellular carcinoma cells.
- 2011
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Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 55:2, s. 351-358
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Transforming growth factor-beta (TGF-β) induces apoptosis in hepatocytes, a process that is inhibited by the epidermal growth factor receptor (EGFR) pathway. The aim of this work was to ablate EGFR in hepatocellular carcinoma (HCC) cells to understand its role in impairing TGF-β-induced cell death.METHODS: Response to TGF-β in terms of apoptosis was analyzed in different HCC cell lines and the effect of canceling EGFR expression was evaluated.RESULTS: TGF-β induces apoptosis in some HCC cells (such as Hep3B, PLC/PRF/5, Huh7, or SNU449), but it also mediates survival signals, coincident with the up-regulation of EGFR ligands. Inhibition of the EGFR, either by targeted knock-down with specific siRNA or by pharmacological inhibition, significantly enhances apoptotic response. TGF-β treatment in EGFR targeted knock-down cells correlates with higher levels of the NADPH oxidase NOX4 and changes in the expression profile of BCL-2 and IAP families. However, other HCC cells, such as HepG2, which show over activation of the Ras/ERKs pathway, SK-Hep1, with an endothelial phenotype, or SNU398, where the TGF-β-Smad signaling is altered, show apoptosis resistance that is not restored through EGFR blockade.CONCLUSIONS: The inhibition of EGFR in HCC may enhance TGF-β-induced pro-apoptotic signaling. However, this effect may only concern those tumors with an epithelial phenotype which do not bear alterations in TGF-β signaling nor exhibit an over-activation of the survival pathways downstream of the EGFR.
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| 43. |
- Carmona-Cuenca, Irene, et al.
(författare)
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Upregulation of the NADPH oxidase NOX4 by TGF-beta in hepatocytes is required for its pro-apoptotic activity
- 2008
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Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 49:6, s. 965-76
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND/AIMS: The transforming growth factor-beta (TGF-beta) induces apoptosis in hepatocytes through an oxidative stress process. Here, we have analyzed the role of different NADPH oxidase isoforms in the intracellular signalling induced by TGF-beta in hepatocytes, to later explore whether this mechanism is altered in liver tumor cells.METHODS: Primary cultures of rat and human hepatocytes, HepG2 and Hep3B cells were used in in vitro studies to analyze the TGF-beta response.RESULTS: TGF-beta-induced apoptosis in rat hepatocytes does not require Rac-dependent NADPH oxidases. TGF-beta upregulates the Rac-independent Nox4, which correlates with its pro-apoptotic activity. Regulation of Nox4 occurs at the transcriptional level and is counteracted by intracellular survival signals. siRNA targeted knock-down of Nox4 attenuates NADPH oxidase activity, caspase activation and cell death in rat hepatocytes. NOX4 upregulation by TGF-beta is also observed in human hepatocytes, coincident with apoptosis. In human hepatocellular carcinoma (HCC) cell lines, NOX4 upregulation by TGF-beta is only observed in cells that are sensitive to its cytotoxic effect, such as Hep3B cells. siRNA targeted knock-down of NOX4 in these cells impairs TGF-beta-induced apoptosis.CONCLUSIONS: Upregulation of NOX4 by TGF-beta is required for its pro-apoptotic activity in hepatocytes. Impairment of this TGF-beta-induced response might confer apoptosis resistance in HCC cells.
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| 44. |
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| 45. |
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| 46. |
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| 47. |
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| 48. |
- Dongiovanni, Paola, et al.
(författare)
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Statin use and nonalcoholic steatohepatitis in at risk individuals.
- 2015
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Ingår i: Journal of hepatology. - : Elsevier BV. - 1600-0641 .- 0168-8278. ; 63:3, s. 705-712
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Tidskriftsartikel (refereegranskat)abstract
- Excess hepatic free cholesterol contributes to the pathogenesis of nonalcoholic steatohepatitis, and statins reduce cholesterol synthesis. Aim of this study was to assess whether statin use is associated with histological liver damage related to steatohepatitis.
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| 49. |
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| 50. |
- Ekstedt, Mattias, et al.
(författare)
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Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes : a histopathological follow-up study.
- 2007
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Ingår i: Journal of Hepatology. - : Elsevier BV. - 0168-8278 .- 1600-0641. ; 47:1, s. 135-141
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aims: The effect of statins on hepatic histology in non-alcoholic fatty liver disease (NAFLD) is not known. This study explores hepatic histology in NAFLD patients before and after initiation of statin therapy and compares histological outcome with NAFLD patients who had not been prescribed statins. Methods: Sixty-eight NAFLD patients were re-evaluated. Follow-up ranged from 10.3 to 16.3 years. Subjects were clinically investigated and a repeat liver biopsy was obtained. No patient was taking statins at baseline while 17 patients were treated with statins at follow-up. Results: At baseline, patients that later were prescribed statins had significantly higher BMI and more pronounced hepatic steatosis. At follow-up patients on medication with statins continued to have significantly higher BMI. Diabetes was significantly more common among patients on medication with statins and they had significantly more pronounced insulin resistance. However, they exhibited a significant reduction of liver steatosis at follow-up as opposed to patients not taking statins. Despite exhibiting a high risk profile for progression of liver fibrosis, only four patients on statin treatment progressed in fibrosis stage. Conclusions: Statins can be prescribed in patients with elevated liver enzymes because of NAFLD.
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