Metabolic and Genetic Risk Factors Are the Strongest Predictors of Severity of Alcohol-Related Liver Fibrosis

Israelsen, Mads; Juel, Helene Bæk; Detlefsen, Sönke; Madsen, Bjørn Stæhr; Rasmussen, Ditlev Nytoft; Larsen, Trine Rennebod; Kjærgaard, Maria; Jensen, Mary Jo Fernandes; Stender, Stefan; Hansen, Torben; Krag, Aleksander; Thiele, Maja

doi:10.1016/j.cgh.2020.11.038

Cited by 54 publications

(41 citation statements)

References 31 publications

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“…Finally, alcohol and abstinence did not clearly affect the ECM dysbalance, except for higher levels of PRO‐C3 in the 5% heaviest drinking ALD patients, suggesting that other factors such as genetics and metabolic comorbidity may be important additional regulators of collagen turnover. In support of this hypothesis, we have previously shown that the majority of ALD patients exhibit several metabolic comorbidities, and that glucose intolerance is a stronger predictor of fibrosis severity than the magnitude of prior or ongoing drinking 19 . We also found elevated PRO‐C3 collagen formation in ALD patients without liver fibrosis on biopsy, compared to controls, suggesting a heightened damage‐repair process in the liver before histological evidence of harm.…”

Section: Discussionsupporting

confidence: 73%

Progressive alcohol‐related liver fibrosis is characterised by imbalanced collagen formation and degradation

Thiele

Johansen

Gudmann

et al. 2021

Aliment Pharmacol Ther

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Summary Background Liver fibrosis accumulation is considered a turnover disease, with formation exceeding degradation, although this hypothesis has never been tested in humans. Aims To investigate extracellular matrix (ECM) remodelling in a biopsy‐controlled study of alcohol‐related liver disease (ALD) patients. Methods We evaluated the relationship between formation and degradation of four collagens as a function of histological fibrosis, inflammation and steatosis in 281 patients with ALD and 50 matched healthy controls. Post hoc, we tested the findings in a cohort of patients with alcohol‐related cirrhosis and assessed the collagens' prognostic accuracy. We assessed the fibrillar collagens type III (PRO‐C3/C3M) and V (PRO‐C5/C5M), the basement membrane collagen IV (PRO‐C4/C4M), and the microfilament interface collagen VI (PRO‐C6/C6M). Results Mean age was 54 ± 6 years, 74% male, fibrosis stage F0/1/2/3/4 = 33/98/84/18/48. Compared to controls, patients with ALD had higher levels of type III collagen formation and degradation, with the highest concentrations in those with cirrhosis (PRO‐C3 = 8.2 ± 1.7 ng/mL in controls, 14.6 ± 13.5 in ALD, 34.8 ± 23.1 in cirrhosis; C3M 7.4 ± 1.9 in controls, 9.3 ± 4.4 in ALD, 14.0 ± 5 in cirrhosis). ECM remodelling became increasingly imbalanced in higher stages of liver fibrosis, with formation progressively superseding degradation. This was particularly pronounced for type III collagen. We observed similar imbalance for inflammatory severity, but not steatosis. Conclusions ALD is characterised by both elevated collagen formation and degradation, which becomes increasingly imbalanced with more severe disease. Net increase in fibrillar collagens contributes to fibrosis progression. This has important implications for monitoring and very early identification of patients at highest risk of progressing to cirrhosis.

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Section: Discussionsupporting

confidence: 73%

Progressive alcohol‐related liver fibrosis is characterised by imbalanced collagen formation and degradation

Thiele

Johansen

Gudmann

et al. 2021

Aliment Pharmacol Ther

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“… 6 This mechanism may help explain why metabolic risk factors and alcohol have synergistic effect on liver disease. 7 , 12 , 35 …”

Section: Discussionmentioning

confidence: 99%

“…[6] This mechanism may help explain why metabolic risk factors and alcohol have synergistic effect on liver disease. [7,12,35] The pathogenesis of NAFLD is closely related to dyslipidemia. [36] In line with that, the NAFLD phenotype was significantly different to the ALD and healthy control phenotypes with respect to fasting levels of TG and LPC.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

Comprehensive lipidomics reveals phenotypic differences in hepatic lipid turnover in ALD and NAFLD during alcohol intoxication

et al. 2021

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“…More recently, AMC have been the target of gene identification efforts. These efforts have largely been restricted to candidate genes (Beaudoin et al, 2021; Israelsen et al, 2020), which are not reflective of the likely polygenicity of AMC. However, several genome‐wide association studies, which employed different methods to account for the contingency of AMC on alcohol problems, identified a limited number of loci associated with alcoholic chronic pancreatitis (Derikx et al, 2015) and alcohol‐related cirrhosis (Innes et al, 2020; Schwantes‐An et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Genetic and environmental influences on the progression from alcohol use disorder to alcohol‐related medical conditions

Edwards

Sundquist

et al. 2021

Alcoholism Clin & Exp Res

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Background: Medical conditions related to alcohol use disorders (AUD) represent a substantial public health concern. However, only a subset of individuals with AUD develop these conditions and the extent to which genetic and environmental factors that are shared with AUD, versus those distinct from it, contribute to this progressionhas not yet been determined. Methods:Using data from Swedish national registries for a cohort born from 1932 to 1970 (N = 1,319,214, 48.9% women), we conducted twin-sibling biometric model fitting to examine the genetic and environmental sources of variance that contribute to the liability to alcohol-related medical conditions (AMC). Progression to AMC, determined using medical registry data, was contingent on an AUD registration, which was determined using medical and criminal registry data. Results:We identified AUD registrations in 3.2% of women and 9.2% of men. Among individuals with an AUD registration, 14.4% of women and 15.4% of men had an AMC registration. In the final models, we constrained the beta pathway from AUD to AMC and the genetic and unique environmental paths to be equal across sexes. The beta path was estimated at 0.59. AMC was modestly heritable in women (A = 0.32) and men (A = 0.30). The proportion of total heritability unique to AMC was 39.6% among women and 41.3% among men. A higher proportion of total environmental variance was unique to AMC: 76.7% for women and 77.2% for men. In a sensitivity analysis limited to liver-related AMC, we observed similar results, with a slightly lower beta path from AUD to AMC (0.46) and higher proportions of AMC-specific genetic (70.0% in women; 71.7% in men) and environmental (84.5% in both sexes) variance. Conclusions:A moderate-to-substantial proportion of genetic and environmental variance that contributes to AMC risk is not shared with AUD, underscoring the need for additional gene identification efforts for AMC. Furthermore, the prominent influence of environmental factors specific to AMC provides a promising area for the identification of prevention targets. We did not observe significant sex differences in the etiology of AMC, although follow-up is warranted in other well-powered studies.

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Metabolic and Genetic Risk Factors Are the Strongest Predictors of Severity of Alcohol-Related Liver Fibrosis

Cited by 54 publications

References 31 publications

Progressive alcohol‐related liver fibrosis is characterised by imbalanced collagen formation and degradation

Progressive alcohol‐related liver fibrosis is characterised by imbalanced collagen formation and degradation

Comprehensive lipidomics reveals phenotypic differences in hepatic lipid turnover in ALD and NAFLD during alcohol intoxication

Genetic and environmental influences on the progression from alcohol use disorder to alcohol‐related medical conditions

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