Dataset Information

Liver Fibrosis and Steatosis in Alstrom Syndrome: A Genetic Model for Metabolic Syndrome.

ABSTRACT: Alström syndrome (ALMS) is an ultra-rare monogenic disease characterized by insulin resistance, multi-organ fibrosis, obesity, type 2 diabetes mellitus (T2DM), and hypertriglyceridemia with high and early incidence of non-alcoholic fatty liver disease (NAFLD). We evaluated liver fibrosis quantifying liver stiffness (LS) by shear wave elastography (SWE) and steatosis using ultrasound sonographic (US) liver/kidney ratios (L/K) in 18 patients with ALMS and 25 controls, and analyzed the contribution of metabolic and genetic alterations in NAFLD progression. We also genetically characterized patients. LS and L/K values were significantly higher in patients compared with in controls (p < 0.001 versus p = 0.013). In patients, LS correlated with the Fibrosis-4 Index and age, while L/K was associated with triglyceride levels. LS showed an increasing trend in patients with metabolic comorbidities and displayed a significant correlation with waist circumference, the homeostasis model assessment, and glycated hemoglobin A1c. SWE and US represent promising tools to accurately evaluate early liver fibrosis and steatosis in adults and children with ALMS during follow-up. We described a new pathogenic variant of exon 8 in ALMS1. Patients with ALMS displayed enhanced steatosis, an early increased age-dependent LS that is associated with obesity and T2DM but also linked to genetic alterations, suggesting that ALMS1 could be involved in liver fibrogenesis.

SUBMITTER: Bettini S

PROVIDER: S-EPMC8170882 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Liver Fibrosis and Steatosis in Alström Syndrome: A Genetic Model for Metabolic Syndrome.

Bettini Silvia S Bombonato Giancarlo G Dassie Francesca F Favaretto Francesca F Piffer Luca L Bizzotto Paola P Busetto Luca L Chemello Liliana L Senzolo Marco M Merkel Carlo C Angeli Paolo P Vettor Roberto R Milan Gabriella G Maffei Pietro P

Diagnostics (Basel, Switzerland) 20210428 5

Alström syndrome (ALMS) is an ultra-rare monogenic disease characterized by insulin resistance, multi-organ fibrosis, obesity, type 2 diabetes mellitus (T2DM), and hypertriglyceridemia with high and early incidence of non-alcoholic fatty liver disease (NAFLD). We evaluated liver fibrosis quantifying liver stiffness (LS) by shear wave elastography (SWE) and steatosis using ultrasound sonographic (US) liver/kidney ratios (L/K) in 18 patients with ALMS and 25 controls, and analyzed the contribution ...[more]

PMID: 33924909

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Project description:BackgroundTo investigate the association of four insulin resistance (IR) indicators with hepatic steatosis and fibrosis in patients with metabolic syndrome (MetS), as well as to compare the diagnostic value of these indicators in identifying hepatic steatosis and fibrosis in individuals with MetS.MethodsThis cross-sectional study used the data from the National Health and Nutrition Examination Survey 2017-2018. IR indicators included homeostasis model assessment of IR (HOMA-IR), triglyceride/glucose (TyG) index, triglyceride glucose-waist-to-height ratio (TyG-WHtR), and metabolic score for IR (METS-IR). The main endpoints of this study were hepatic steatosis and hepatic fibrosis. Weighted univariate and multivariate logistic regression models were employed to evaluate the association between four IR indicators and both hepatic steatosis, hepatic fibrosis. The efficacy of various IR indicators in the detection of hepatic steatosis and hepatic fibrosis were assessed using receiver operating characteristics curve (ROC).ResultsA total of 876 participants with MetS were enrolled. Among the participants, hepatic steatosis was observed in 587 MetS individuals, while hepatic fibrosis was identified in 151 MetS individuals. In multivariate logistic regression model, HOMA-IR, TyG, TyG-WHtR, and METS-IR were related to the increased odd of hepatic steatosis. Additionally, HOMA-IR, TyG-WHtR, and METS-IR were associated with increased odd of hepatic fibrosis. According to the ROC analysis, the area under the curve (AUC) of the TyG-WHtR (AUC = 0.705, 95%CI: 0.668-0.743) was higher than HOMA-IR (AUC = 0.693, 95%CI: 0.656-0.730), TyG (AUC = 0.627, 95%CI: 0.587-0.666), and METS-IR (AUC = 0.685, 95%CI: 0.648-0.722) for identifying hepatic steatosis of MetS patients. Likewise, TyG-WHtR was also higher than HOMA-IR, TyG, and METS-IR for identifying hepatic fibrosis of MetS patients.ConclusionHOMA-IR, TyG-WHtR, and METS-IR may be associated with the risk of hepatic steatosis and fibrosis among the U.S. adult population with MetS. In addition, TyG-WHtR may have a good predictive value for hepatic steatosis and hepatic fibrosis.

Project description:Significant liver fibrosis regression occurs after hepatitis C virus (HCV) therapy. However, the impact of direct-acting antivirals (DAAs) on steatosis is less clear. This study was aimed at evaluating serial fibrosis and steatosis alterations in patients with HCV genotype 1, who achieved sustained virological response (SVR). We enrolled 55 HCV mono-infected and 28 HCV/HIV co-infected patients receiving elbasvir/grazoprevir from a clinical trial. Fibrosis and steatosis were assessed at baseline, follow-up week-24 (FUw24) and week-72 (FUw72) by magnetic resonance elastography (MRE) and proton density fat fraction (PDFF), respectively. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409, transmembrane six superfamily member 2 (TM6SF2) rs58542926 and membrane bound O-acyltransferase domain-containing 7 (MBOAT7) rs641738 polymorphisms were determined by allelic discrimination. Overall, mean MRE decreased significantly from baseline to FUw24 and FUw72. At FUw72, patients with baseline F2-F4 had higher rate of ≥30% MRE decline compared with individuals with baseline F0-F1 (30.2%vs.3.3%, P = 0.004). In multivariate analysis, significant fibrosis was associated with MRE reduction. The prevalence of steatosis (PDFF≥5.2%) at baseline was 21.7%. Compared to baseline, there were 17 (20.5%) patients with decreased PDFF values at FUw72 (<30%), while 23 (27.7%) patients had increased PDFF values (≥30%). Regarding the overall cohort, mean PDFF significantly increased from baseline to FUw72, and displayed positive correlation with body mass index (BMI) alteration. In multivariate analysis, the presence of diabetes, PNPLA3 CG+GG genotypes and increased BMI at FUw72 were significantly associated with progressive steatosis after SVR. Other genetic variants were not related to fibrosis and steatosis alteration. This study concluded that HCV eradication was associated with fibrosis improvement. However, progressive steatosis was observed in a proportion of patients, particularly among individuals with metabolic derangement and PNPLA3 variants. The combined clinical parameters and host genetic factors might allow a better individualized strategy in this sub-group of patients to alleviate progressive steatosis after HCV cure.

Project description:Alström syndrome (ALMS) is an autosomal recessive disease characterized by multiple organ involvement, including neurosensory vision and hearing loss, childhood obesity, diabetes mellitus, cardiomyopathy, hypogonadism, and pulmonary, hepatic, renal failure and systemic fibrosis. Alström Syndrome is caused by mutations in ALMS1, and ALMS1 protein is thought to have a role in microtubule organization, intraflagellar transport, endosome recycling and cell cycle regulation. Here, we report extensive phenotypic and genetic analysis of a large cohort of Turkish patients with ALMS. We evaluated 61 Turkish patients, including 11 previously reported, for both clinical spectrum and mutations in ALMS1. To reveal the molecular diagnosis of the patients, different approaches were used in combination, a cohort of patients were screened by the gene array to detect the common mutations in ALMS1 gene, then in patients having any of the common ALMS1 mutations were subjected to direct DNA sequencing or next-generation sequencing for the screening of mutations in all coding regions of the gene. In total, 20 distinct disease-causing nucleotide changes in ALMS1 have been identified, eight of which are novel, thereby increasing the reported ALMS1 mutations by 6% (8/120). Five disease-causing variants were identified in more than one kindred, but most of the alleles were unique to each single patient and identified only once (16/20). So far, 16 mutations identified were specific to the Turkish population, and four have also been reported in other ethnicities. In addition, 49 variants of uncertain pathogenicity were noted, and four of these were very rare and probably or likely deleterious according to in silico mutation prediction analyses. ALMS has a relatively high incidence in Turkey and the present study shows that the ALMS1 mutations are largely heterogeneous; thus, these data from a particular population may provide a unique source for the identification of additional mutations underlying Alström Syndrome and contribute to genotype-phenotype correlation studies.

Dataset Information

Liver Fibrosis and Steatosis in Alstrom Syndrome: A Genetic Model for Metabolic Syndrome.

Publications

Liver Fibrosis and Steatosis in Alström Syndrome: A Genetic Model for Metabolic Syndrome.

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