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- 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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- 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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| 5. |
- 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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| 8. |
- 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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| 10. |
- 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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