Liver transplantation for alcoholic liver disease: a retrospective analysis of recidivism, survival and risk factors predisposing to alcohol relapse

Background and study aims : Alcoholic liver disease (ALD) is the second most common indication for liver transplantation. The aim of this study was to evaluate the alcohol relapse rate and long-term survival after liver transplantation for ALD and to identify risk factors predisposing to alcohol relapse. Patients and methods : Between 2000 and 2007, 108 patients transplanted for ALD in the Ghent University Hospital were included in this retrospective analysis. Relapse was defined as any drinking after transplantation, problem drinking as more than 2 units/day for women and 3 units/day for men. A wide range of variables was obtained from a questionnaire and medical records. Results : The mean follow-up was 55 months. Relapse was observed in 29%, 16% in problem drinking. The one-and five-year survival was 87% and 74% respectively. No significant difference in survival was found between non-relapsers, occasional drinkers and problem drinkers. The following risk factors were found to be significantly associated with relapse into problem drinking in an univariate analysis : a shorter pre-transplant abstinence period, the presence of a first degree relative with alcohol abuse and a higher number of prior attempts to quit. In multivariable analysis, the presence of a first degree relative with alcohol abuse was found associated with relapse into problem drinking. Conclusions : The presence of a first degree relative with alcohol abuse is a valuable pre-transplant variable evaluating an ALD patient's eligibility for liver transplantation. Other variables are also helpful to outline the broader context of the drinking behavior of the patient

Rôle des facteurs génétiques dans l'évolution de la fibrose des hépatopathies chroniques alcooliques et virales C

La maladie alcoolique du foie (MAF) et l’hépatite C chronique (HCC) sont les causes les plus fréquentes de cirrhose, carcinome hépatocellulaire (CHC) et transplantation hépatique dans les pays industrialisés. La fibrose hépatique est le stigmate lésionnel de la progression de la maladie vers la cirrhose comme dans toutes les hépatopathies chroniques. Certains facteurs de risque cliniques environnementaux ont été identifiés. Toutefois, ils n’expliquent pas l’extrême variabilité individuelle de la progression de la fibrose. L’influence ethnique à développer une maladie plus sévère ainsi que les études de concordance des jumeaux mono- et di-zygotiques sur la prévalence de la cirrhose alcoolique ont suggéré l’existence de facteurs génétiques associés. Les nombreuses études de gènes candidats réalisées n’ont identifié que très peu de variants associés de manière reproductible. Pour l’HCC par exemple, le score de risque de cirrhose ou « CRS » a montré sa capacité à prédire une fibrose avancée dans diverses cohortes caucasiennes. Récemment, une étude d’association pangénomique (GWAS) dans la stéatohépatopathie non-alcoolique (NAFLD) a mis en évidence un singleton (single nucleotide polymorphism [SNP]) particulier (rs738409 C>G) dans le gène PNPLA3. Ce dernier s’est révélé être, dans diverses études, le SNP ayant l’impact le plus robuste et le plus reproductible dans cette maladie. Par ailleurs, ce même variant a également été significativement associé à la cirrhose alcoolique chez les hispaniques.Les travaux réalisés dans le cadre de cette thèse ont permis de montrer que :1) Le CRS avait la capacité de prédire la progression de la fibrose chez des patients caucasiens ayant une HCC dans 2 cohortes européennes indépendantes.2) Par ailleurs, dans la MAF, nous avons répliqué chez des patients caucasiens l’association entre le SNP rs738409 dans le gène PNPLA3 et la cirrhose. Nous avons également montré pour la première fois, que l’expression de PNPLA3 était significativement diminuée chez les patients avec une fibrose plus avancée. De plus, nous avons observé dans 2 cohortes européennes que rs738409 était également associé à la prévalence du CHC.3) Enfin, nous avons également mis en évidence l’impact de ce même SNP sur la stéatose hépatique et la fibrose dans l’HCC sans toutefois qu’il influence la réponse à la thérapie antivirale dans 3 cohortes caucasiennes indépendantes.Ainsi de manière remarquable, un même SNP (rs738409) apparait associé à des lésions hépatiques sévères dans les trois pathologies hépatiques chroniques les plus fréquentes (la MAF, l’HCC et la NAFLD). Ceci suggère des voies pathogéniques communes de la fibrogénèse hépatique. Par ailleurs, ces travaux soulignent indirectement que les GWAS ont la capacité d’ouvrir de nouvelles voies physiopathologiques et d’identifier de nouveaux variants, gènes ou région génétiques capables de constituer de nouveaux biomarqueurs et cibles thérapeutiques dans l’HCC et la MAF.Doctorat en Sciences médicalesinfo:eu-repo/semantics/nonPublishe

Contribution of PNPLA3 gene to the natural history of liver diseases

In 2008, a genome-wide association studies (GWAS) showed a strong association between a variant (rs738409 C>G p.I148M) in the PNPLA3 and nonalcoholic fatty liver disease. Further replication studies have shown robust associations between PNPLA3 and steatosis, fibrosis/cirrhosis, and hepatocellular carcinoma on a background of metabolic, alcoholic, and viral insults. The PNPLA3 protein has lipase activity towards triglycerides in hepatocytes and retinyl esters in hepatic stellate cells. The I148M substitution leads to a loss of function promoting triglyceride accumulation in hepatocytes. Although PNPLA3 function has been extensively studied, the molecular mechanisms leading to hepatic fibrosis and carcinogenesis remain unclear. This unsuspected association has highlighted the fact that liver fat metabolism may have a major impact on the pathophysiology of liver disease. Conversely, alone, this locus may have limited predictive value with regard to liver disease outcomes in clinical practice. Additional studies at the genome-wide level will be required to identify new variants associated with liver damage and cancer to explain a greater proportion of the heritability of these phenotypes. Thus, incorporating PNPLA3 and other genetic variants in combination with clinical data will allow for the development of tailored predictive models. This attractive approach should be evaluated in prospective cohorts.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Vitamin D deficiency and liver disease

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Association of PNPLA3 (rs738409 C>G) with liver damage in liver diseases: One step closer to personalized medicine?

info:eu-repo/semantics/publishe

Role of the cirrhosis risk score for the prediction of fibrosis progression in hepatitis C patients with minimal liver disease

info:eu-repo/semantics/publishe

Fibrosis progression and gender – an age-dependent interaction in patients with chronic hepatitis C

info:eu-repo/semantics/nonPublishe

Progressive cholangiopathy in COVID-19 patients: Other possible diagnoses than ketamine-induced cholangiopathy should be considered

SCOPUS: le.jinfo:eu-repo/semantics/publishe

Genetics of alcohol-related hepatocellular carcinoma - its role in risk prediction

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy, with increasing incidence worldwide. Alcohol-related cirrhosis (AC) accounts for 30% of the global incidence of HCC and HCC-related deaths. With the decline of hepatitis C virus (HCV) and decreasing HCV-related HCC, AC will soon become the leading cause of HCC. Excess alcohol consumption (> 80 g per day for > 10 years) increases the risk of HCC by 5-fold. However, only up to 35% of excessive drinkers develop cirrhosis and its associated HCC risk. Individual variation in susceptibility to HCC is known, but there is limited information to predict who among the patients is at high risk of progressing to HCC. Clinical risk factors for HCC include male gender, older age, severity of cirrhosis, obesity and presence of type 2 diabetes. In addition to ethnic variability in HCC risk, genetic variants are known to alter the risk of alcohol-related HCC. For example, single nucleotide polymorphisms in PNPLA3 (rs738409, C>G) and TM6SF2 (rs58542926, C>T) increase the risk of AC-related HCC, whereas HSD17B13 (T>A) reduces the risk for HCC. Studies have also confirmed PNPLA3 and TM6SF2 to be independent risk factors for AC-related (but not HCV-related) HCC. Combining genetic risk factors with phenotypic/clinical risk factors has been explored for stratification of patients for HCC development. Risk allele rs378409-G in PNPLA3 when combined with phenotypic/clinical risk factors (BMI, age, sex) has enabled HCC risk stratification of AC patients into low-, intermediate- and high-risk subgroups. Similarly, a combination of the two genetic variants PNPLA3-G and TM6SF2-T has been independently associated with risk of HCC onset. Using a polygenic risk score approach of incorporating several genetic variants, prognostic performance of polygenic risk score that included PNPLA3 rs378409 and TM6SF2 rs58542926 improved HCC prediction better than with either variant alone. Incorporating new variants and risk factors has the potential to build better algorithms/models to predict onset, early diagnosis and treatments for AC-related HCC. However, clinical usefulness of these approaches is yet to be determined

Noninvasive diagnosis in alcohol-related liver disease

Background: Alcohol-related liver disease (ALD) represents a major cause of death worldwide, and unfortunately, most patients are diagnosed at an advanced stage of the disease, which is related to poorer outcomes. Liver biopsy has historically been the gold standard for identifying advanced hepatic fibrosis, but this approach has several limitations, including invasiveness, low applicability, sampling variability, and cost. Main Text: In order to detect earlier features of advanced liver fibrosis, surrogate biomarkers and techniques have been developed. While these were initially developed for chronic liver diseases such as viral hepatitis and nonalcoholic fatty liver disease (NAFLD), their performance in ALD has also been recently studied. Among the noninvasive surrogate markers and techniques used to detect liver fibrosis, the Enhanced Liver Fibrosis test, FibroTest, and Transient Elastography are the most accurate and validated techniques. In this review, we summarize the current status of the noninvasive assessment of liver disease in ALD and provide a synthesis of how these noninvasive tools can be used in clinical practice. Finally, we briefly outline novel biomarkers that are currently being investigated and discuss future directions and new opportunities in the noninvasive diagnosis of ALD.SCOPUS: re.jinfo:eu-repo/semantics/publishe