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BACKGROUND: Metabolic syndrome (MetS) is a cluster of medical conditions and risk factors correlating with insulin resistance that increase the risk of developing cardiometabolic health problems. The specific criteria for diagnosing MetS vary among different medical organizations but are typically based on the evaluation of abdominal obesity, high blood pressure, hyperglycemia, and dyslipidemia. A unique, quantitative and independent estimation of the risk of MetS based only on quantitative biomarkers is highly desirable for the comparison between patients and to study the individual progression of the disease in a quantitative manner. METHODS: We used NMR-based metabolomics on a large cohort of donors (n = 21,323; 37.5% female) to investigate the diagnostic value of serum or serum combined with urine to estimate the MetS risk. Specifically, we have determined 41 circulating metabolites and 112 lipoprotein classes and subclasses in serum samples and this information has been integrated with metabolic profiles extracted from urine samples. RESULTS: We have developed MetSCORE, a metabolic model of MetS that combines serum lipoprotein and metabolite information. MetSCORE discriminate patients with MetS (independently identified using the WHO criterium) from general population, with an AUROC of 0.94 (95% CI 0.920-0.952, p < 0.001). MetSCORE is also able to discriminate the intermediate phenotypes, identifying the early risk of MetS in a quantitative way and ranking individuals according to their risk of undergoing MetS (for general population) or according to the severity of the syndrome (for MetS patients). CONCLUSIONS: We believe that MetSCORE may be an insightful tool for early intervention and lifestyle modifications, potentially preventing the aggravation of metabolic syndrome.
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Biomarcadores , Espectroscopía de Resonancia Magnética , Síndrome Metabólico , Metabolómica , Valor Predictivo de las Pruebas , Humanos , Síndrome Metabólico/diagnóstico , Síndrome Metabólico/sangre , Síndrome Metabólico/epidemiología , Síndrome Metabólico/orina , Femenino , Masculino , Biomarcadores/sangre , Biomarcadores/orina , Persona de Mediana Edad , Medición de Riesgo , Adulto , Anciano , Lipoproteínas/sangre , Pronóstico , Factores de Riesgo , Factores de Riesgo Cardiometabólico , Adulto JovenRESUMEN
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver condition. MASLD is a sexually dimorphic condition, with its development and progression influenced by sex chromosomes and hormones. Estrogens typically protect against, whereas androgens promote, MASLD. Therapeutic approaches for a sex-specific personalized medicine include estrogen replacement, androgen blockers, and novel drugs targeting hormonal pathways. However, the interactions between hormonal factors and inherited genetic variation impacts MASLD risk, necessitating more tailored therapies. Understanding sex disparities and the role of estrogens could improve MASLD interventions and management, whereas clinical trials addressing sex differences are crucial for advancing personalized treatment. This review explores the underappreciated impact of sexual dimorphism in MASLD and discusses the potential therapeutic application of sex-related hormones.
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BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global epidemic and is the most rapidly rising cause of HCC. Clonal hematopoiesis of indeterminate potential (CHIP) contributes to neoplastic and cardiometabolic disorders and is considered a harbinger of tissue inflammation. CHIP was recently associated with increased risk of liver disease. The aim of this study was to examine whether CHIP is associated with HCC development in patients with SLD. APPROACH AND RESULTS: We considered individuals with MASLD-HCC (n=208) and controls with (n =414) and without (n =259) advanced fibrosis who underwent whole exome sequencing. CHIP was diagnosed when ≥2 variant callers identified a known myeloid mutation with variant allele frequency ≥2%. CHIP was observed in 116 participants (13.1%), most frequently in DNMT3A, TET2, TP53 , and ASXL1 , and correlated with age ( p <0.0001) and advanced liver fibrosis (p=0.001). Higher aspartate aminotransferase levels predicted non- DNMT3A -CHIP, in particular with variant allele frequency ≥10% (OR: 1.14, 1.03 -1.28 and OR: 1.30, 1.12 -1.49, respectively, p <0.05). After adjustment for sex, diabetes, and a polygenic risk, a score of inherited MASLD predisposition CHIP was associated with cirrhosis (2.00, 1.30 -3.15, p =0.02), and with HCC even after further adjustment for cirrhosis (OR: 1.81, 1.11 -2.00, 1.30 -3.15, p =0.002). Despite the strong collinearity among aging and development of CHIP and HCC, non- DNTM3A -CHIP, and TET2 lesions remained associated with HCC after full correction for clinical/genetics covariates and age (OR: 2.45, 1.35 -4.53; OR: 4.8, 1.60 -17.0, p =0.02). CONCLUSIONS: We observed an independent association between CHIP, particularly related to non- DNTM3A and TET2 genetic lesions and MASLD-HCC.
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BACKGROUND & AIMS: Metabolic dysfunction associated steatotic liver disease (MASLD) has a strong genetic component. The aim of this study was to examine noninvasively the prevalence of MASLD and of advanced fibrosis in relatives of patients with advanced MASLD and the risk factors for liver involvement, with a focus on the contribution of common genetic risk variants. METHODS: We prospectively enrolled 98 consecutive probands with advanced fibrosis and/or hepatocellular carcinoma caused by MASLD and 160 nontwin first-degree relatives noninvasively screened for MASLD and advanced fibrosis at 4 Italian centers. We evaluated common genetic determinants and polygenic risk scores of liver disease. RESULTS: Among relatives, prevalence of MASLD was 56.8% overall, whereas advanced fibrosis was observed in 14.4%. At multivariable analysis in relatives, MASLD was associated with body mass index (odds ratio [OR], 1.31 [1.18-1.46]) and tended to be associated with diabetes (OR, 5.21 [0.97-28.10]), alcohol intake (OR, 1.32 [0.98-1.78]), and with female sex (OR, 0.54 [0.23-1.15]), whereas advanced fibrosis was associated with diabetes (OR, 3.13 [1.16-8.45]) and nearly with body mass index (OR, 1.09 [1.00-1.19]). Despite that the PNPLA3 risk variant was enriched in probands (P = .003) and overtransmitted to relatives with MASLD (P = .045), evaluation of genetic risk variants and polygenic risk scores was not useful to guide noninvasive screening of advanced fibrosis in relatives. CONCLUSIONS: We confirmed that about 1 in 7 relatives of patients with advanced MASLD has advanced fibrosis, supporting clinical recommendations to perform family screening in this setting. Genetic risk variants contributed to liver disease within families but did not meaningfully improve fibrosis risk stratification.
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Hígado Graso , Humanos , Femenino , Susceptibilidad a Enfermedades , Hígado Graso/genética , Estrógenos/genéticaRESUMEN
BACKGROUND & AIMS: Hepatic fat content can be non-invasively estimated by controlled attenuation parameter (CAP) during transient elastography. The aim of this study was to examine the determinants and predictors of CAP values in individuals with metabolic dysfunction. METHODS: We enrolled 1230 consecutive apparently healthy individuals (Liver-Bible-2022 cohort) with ≥3 metabolic dysfunction features. CAP was measured by Fibroscan. CAP determinants and predictors were identified using backward stepwise analysis and introduced in generalized linear models. RESULTS: Participants were predominantly males (82.9%), mean age was 53.8 ± 6.4 years, 600 (48.8%) had steatosis (CAP ≥ 275 dB/m), and 27 had liver stiffness measurement (LSM) ≥ 8 kPa. CAP values correlated with LSM (p < 10-22). In multivariable analysis, fasting insulin and abdominal circumference (AC) were the main determinants of CAP (p < 10-6), together with body mass index (BMI; p < 10-4), age, diabetes, triglycerides, ferritin, and lower HDL and thyroid stimulating hormone (TSH; p < 0.05 for all). In a subset of 592 participants with thyroid hormone measurement, we found an association between higher free triiodothyronine levels, correlating with lower TSH, and CAP values, independent of TSH and of levothyroxine treatment (p = 0.0025). A clinical CAP score based on age, BMI, AC, HbA1c, ALT, and HDL predicted CAP ≥ 275 dB/m with moderate accuracy (AUROC = 0.73), which was better than that of the Fatty Liver Index and of ALT (AUROC = 0.70/0.61, respectively) and validated it in multiple cohorts. CONCLUSION: Abdominal adiposity and insulin resistance severity were the main determinants of CAP in individuals with metabolic dysfunction and may improve steatotic liver disease risk stratification. CAP values were modulated by the hypophysis-thyroid axis.
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Diagnóstico por Imagen de Elasticidad , Hígado Graso , Masculino , Humanos , Persona de Mediana Edad , Femenino , Índice de Masa Corporal , TirotropinaRESUMEN
Fatty liver disease (FLD) caused by metabolic dysfunction is the leading cause of liver disease and the prevalence is rising, especially in women. Although during reproductive age women are protected against FLD, for still unknown and understudied reasons some develop rapidly progressive disease at the menopause. The patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M variant accounts for the largest fraction of inherited FLD variability. In the present study, we show that there is a specific multiplicative interaction between female sex and PNPLA3 p.I148M in determining FLD in at-risk individuals (steatosis and fibrosis, P < 10-10; advanced fibrosis/hepatocellular carcinoma, P = 0.034) and in the general population (P < 10-7 for alanine transaminase levels). In individuals with obesity, hepatic PNPLA3 expression was higher in women than in men (P = 0.007) and in mice correlated with estrogen levels. In human hepatocytes and liver organoids, PNPLA3 was induced by estrogen receptor-α (ER-α) agonists. By chromatin immunoprecipitation and luciferase assays, we identified and characterized an ER-α-binding site within a PNPLA3 enhancer and demonstrated via CRISPR-Cas9 genome editing that this sequence drives PNPLA3 p.I148M upregulation, leading to lipid droplet accumulation and fibrogenesis in three-dimensional multilineage spheroids with stellate cells. These data suggest that a functional interaction between ER-α and PNPLA3 p.I148M variant contributes to FLD in women.
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Aciltransferasas , Enfermedad del Hígado Graso no Alcohólico , Fosfolipasas A2 Calcio-Independiente , Receptores de Estrógenos , Animales , Femenino , Humanos , Masculino , Ratones , Aciltransferasas/genética , Aciltransferasas/metabolismo , Carcinoma Hepatocelular , Fibrosis , Predisposición Genética a la Enfermedad , Hígado/metabolismo , Neoplasias Hepáticas/patología , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/patología , Fosfolipasas A2 Calcio-Independiente/genética , Fosfolipasas A2 Calcio-Independiente/metabolismo , Receptores de Estrógenos/metabolismoRESUMEN
The membrane-bound O-acyltransferase domain-containing 7 (MBOAT7) protein is an acyltransferase catalyzing arachidonic acid incorporation into lysophosphatidylinositol. Patients with rare, biallelic loss-of-function variants of the MBOAT7 gene display intellectual disability with neurodevelopmental defects. The rs641738 inherited variant associated with reduced hepatic MBOAT7 expression has been linked to steatotic liver disease susceptibility. However, the impact of biallelic loss-of-function MBOAT7 variants on liver disease is not known. We report on a 2-year-old girl with MBOAT7-related intellectual disability and steatotic liver disease, confirming that MBOAT7 loss-of-function predisposes to liver disease.
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Discapacidad Intelectual , Femenino , Humanos , Preescolar , Discapacidad Intelectual/genética , Pacientes , Aciltransferasas/genética , Ácido Araquidónico , Proteínas de la MembranaRESUMEN
Background: The cause of chronic liver diseases (CLD) remains undiagnosed in up to 30% of adult patients. Whole-Exome Sequencing (WES) can improve the diagnostic rate of genetic conditions, but it is not yet widely available, due to the costs and the difficulties in results interpretation. Targeted panel sequencing (TS) represents an alternative more focused diagnostic approach. Aims: To validate a customized TS for hereditary CLD diagnosis. Methods: We designed a customized panel including 82 CLD-associated genes (iron overload, lipid metabolism, cholestatic diseases, storage diseases, specific hereditary CLD and susceptibility to liver diseases). DNA samples from 19 unrelated adult patients with undiagnosed CLD were analyzed by both TS (HaloPlex) and WES (SureSelect Human All Exon kit v5) and the diagnostic performances were compared. Results: The mean depth of coverage of TS-targeted regions was higher with TS than WES (300x vs. 102x; p < 0.0001). Moreover, TS yielded a higher average coverage per gene and lower fraction of exons with low coverage (p < 0.0001). Overall, 374 unique variants were identified across all samples, 98 of which were classified as "Pathogenic" or "Likely Pathogenic" with a high functional impact (HFI). The majority of HFI variants (91%) were detected by both methods; 6 were uniquely identified by TS and 3 by WES. Discrepancies in variant calling were mainly due to variability in read depth and insufficient coverage in the corresponding target regions. All variants were confirmed by Sanger sequencing except two uniquely detected by TS. Detection rate and specificity for variants in TS-targeted regions of TS were 96.9% and 97.9% respectively, whereas those of WES were 95.8% and 100%, respectively. Conclusion: TS was confirmed to be a valid first-tier genetic test, with an average mean depth per gene higher than WES and a comparable detection rate and specificity.
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BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is a complex disease, resulting from the interplay between environmental determinants and genetic variations. Single nucleotide polymorphism rs738409 C>G in the PNPLA3 gene is associated with hepatic fibrosis and with higher risk of developing hepatocellular carcinoma. Here, we analyzed a longitudinal cohort of biopsy-proven NAFLD subjects with the aim to identify individuals in whom genetics may have a stronger impact on disease progression. METHODS: We retrospectively analyzed 756 consecutive, prospectively enrolled biopsy-proven NAFLD subjects from Italy, United Kingdom, and Spain who were followed for a median of 84 months (interquartile range, 65-109 months). We stratified the study cohort according to sex, body mass index (BMI) ≥30 kg/m2) and age (≥50 years). Liver-related events (hepatic decompensation, hepatic encephalopathy, esophageal variceal bleeding, and hepatocellular carcinoma) were recorded during the follow-up and the log-rank test was used to compare groups. RESULTS: Overall, the median age was 48 years and most individuals were men (64.7%). The PNPLA3 rs738409 genotype was CC in 235 (31.1%), CG in 328 (43.4%), and GG in 193 (25.5%) patients. At univariate analysis, the PNPLA3 GG risk genotype was associated with female sex and inversely related to BMI (odds ratio, 1.6; 95% confidence interval, 1.1-2.2; P = .006; and odds ratio, 0.97; 95% confidence interval, 0.94-0.99; P = .043, respectively). Specifically, PNPLA3 GG risk homozygosis was more prevalent in female vs male individuals (31.5% vs 22.3%; P = .006) and in nonobese compared with obese NAFLD subjects (50.0% vs 44.2%; P = .011). Following stratification for age, sex, and BMI, we observed an increased incidence of liver-related events in the subgroup of nonobese women older than 50 years of age carrying the PNPLA3 GG risk genotype (log-rank test, P = .0047). CONCLUSIONS: Nonobese female patients with NAFLD 50 years of age and older, and carrying the PNPLA3 GG risk genotype, are at higher risk of developing liver-related events compared with those with the wild-type allele (CC/CG). This finding may have implications in clinical practice for risk stratification and personalized medicine.
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Carcinoma Hepatocelular , Várices Esofágicas y Gástricas , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Humanos , Femenino , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Carcinoma Hepatocelular/epidemiología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/complicaciones , Estudios Retrospectivos , Várices Esofágicas y Gástricas/complicaciones , Hemorragia Gastrointestinal/complicaciones , Genotipo , Polimorfismo de Nucleótido Simple , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/complicaciones , Predisposición Genética a la EnfermedadRESUMEN
Fatty liver disease is most frequently related to metabolic dysfunction (MAFLD) and associated comorbidities, heightening the risk of cardiovascular disease, and is associated with higher hepatic production of IL32, a cytokine linked with lipotoxicity and endothelial activation. The aim of this study was to examine the relationship between circulating IL32 concentration and blood pressure control in individuals with metabolic dysfunction at high risk of MAFLD. IL32 plasma levels were measured by ELISA in 948 individuals with metabolic dysfunction enrolled in the Liver-Bible-2021 cohort. Higher circulating IL32 levels were independently associated with systolic blood pressure (estimate +0.008 log10 per 1 mmHg increase, 95% c.i. 0.002-0.015; p = 0.016), and inversely correlated with antihypertensive medications (estimate -0.189, 95% c.i. -0.291--0.088, p = 0.0002). Through multivariable analysis, IL32 levels predicted both systolic blood pressure (estimate 0.746, 95% c.i 0.173-1.318; p = 0.010) and impaired blood pressure control (OR 1.22, 95% c.i. 1.09-1.38; p = 0.0009) independently of demographic and metabolic confounders and of treatment. This study reveals that circulating IL32 levels are associated with impaired blood pressure control in individuals at risk of cardiovascular disease.
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Enfermedades Cardiovasculares , Enfermedad del Hígado Graso no Alcohólico , Humanos , Presión Sanguínea , Enfermedades Cardiovasculares/etiología , Presión , Plasma , Antihipertensivos/uso terapéuticoRESUMEN
BACKGROUND AND AIMS: Metabolic dysfunction (MD)-associated fatty liver disease has been proposed to identify individuals at risk of liver events irrespectively of the contemporary presence of other liver diseases. The aim of this study was to examine the impact of MD in patients cured of chronic hepatis C (CHC). PATIENTS AND METHODS: We analysed data from a real-life cohort of 2611 Italian patients cured of CHC with direct antiviral agents and advanced liver fibrosis, without HBV/HIV, transplantation and negative for hepatocellular carcinoma (HCC) history (age 61.4 ± 11.8 years, 63.9% males, median follow-up 34, 24-40 months). Information about ultrasonographic steatosis (US) after sustained virological response was available in 1978. RESULTS: MD affected 58% of patients, diagnosed due to the presence of diabetes (MD-diabetes, 19%), overweight without diabetes (MD-overweight, 37%) or multiple metabolic abnormalities without overweight and diabetes (MD-metabolic, 2%). MD was more frequent than and not coincident with US (32% MD-only, 23% MD-US and 13% US-only). MD was associated with higher liver stiffness (p < 0.05), particularly in patients with MD-diabetes and MD-only subgroups, comprising older individuals with more advanced metabolic and liver disease (p < 0.05). At Cox proportional hazard multivariable analysis, MD was associated with increased risk of HCC (HR 1.97, 95% CI 1.27-3.04; p = 0.0023). Further classification according to diagnostic criteria improved risk stratification (p < 0.0001), with the highest risk observed in patients with MD-diabetes. Patients with MD-only appeared at highest risk since the sustained virological response achievement (p = 0.008), with a later catch-up of those with combined MD-US, whereas US-only was not associated with HCC. CONCLUSIONS: MD is more prevalent than US in patients cured of CHC with advanced fibrosis and identifies more accurately individuals at risk of developing HCC.
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Carcinoma Hepatocelular , Diabetes Mellitus , Hígado Graso , Hepatitis C Crónica , Neoplasias Hepáticas , Masculino , Humanos , Persona de Mediana Edad , Anciano , Femenino , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/epidemiología , Antivirales/uso terapéutico , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/epidemiología , Neoplasias Hepáticas/complicaciones , Sobrepeso/complicaciones , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/diagnóstico , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/tratamiento farmacológico , Hígado Graso/complicaciones , Hígado Graso/diagnóstico por imagen , Hígado Graso/tratamiento farmacológico , Respuesta Virológica Sostenida , HepacivirusRESUMEN
BACKGROUND: The PNPLA3 p.I148M variant is the main genetic determinant of nonalcoholic fatty liver disease, and PNPLA3 silencing is being evaluated to treat this liver condition. Data suggest that the p.I148M variant predisposes to kidney damage, but the relative contribution to kidney function, compared to overall genetic susceptibility, is not defined. AIMS: We aimed to assess the effect of PNPLA3 p.I148M on the estimated glomerular filtration rate (eGFR) in individuals with metabolic dysfunction. METHODS: We included 1144 middle-aged individuals from the Liver-Bible-2022 cohort. Glomerular filtration rate (eGFR) was estimated using the Chronic Kidney Disease Epidemiology Collaboration equation. The effect of PNPLA3 p.I148M on eGFRCKD-EPI levels was tested under additive genetic models adjusted for clinical predictors, ethnicity and a polygenic risk score of chronic kidney disease (PRS-CKD). In a subset of 144 individuals, we examined the effect of PNPLA3 p.I148M on eGFRCKD-EPI over a median follow-up of 17 months. RESULTS: The p.I148M variant was associated with lower eGFRCKD-EPI levels (-1.24 mL/min/1.73 m2 per allele, 95% CI: -2.32 to -0.17; p = 0.023), independent of age, sex, height, waist circumference, systolic blood pressure, LDL-cholesterol, transaminases, fasting insulin, albuminuria, lipid-lowering drugs, ethnicity and PRS-CKD score. In the prospective evaluation, the p.I148M variant was independently associated with faster eGFRCKD-EPI decline (ΔeGFRCKD-EPI -3.57 mL/min/1.73 m2 per allele, 95% CI: -6.94 to -0.21; p = 0.037). CONCLUSIONS: We found a detrimental impact of the PNPLA3 p.I148M variant on eGFRCKD-EPI levels in middle-aged individuals with metabolic dysfunction. This association was independent of established risk factors, ethnicity and genetic predisposition to CKD. PNPLA3 p.I148M silencing may protect against kidney damage progression in carriers.
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Enfermedad del Hígado Graso no Alcohólico , Insuficiencia Renal Crónica , Humanos , Persona de Mediana Edad , Predisposición Genética a la Enfermedad , Riñón , Enfermedad del Hígado Graso no Alcohólico/genética , Factores de RiesgoRESUMEN
Background & Aims: The aim of this study was to examine the determinants of the interplay between liver damage and the coagulation balance in individuals at risk of non-alcoholic fatty liver disease (NAFLD). Methods: We considered 581 healthy participants with ≥3 metabolic alterations undergoing clinical and genomic evaluation, measurement of liver stiffness (LSM) and controlled attenuation parameter (CAP) by Fibroscan, Pro-C3, coagulation balance (von Willebrand factor [vWF], factor VIII/protein C ratio [F8/PC] as the main outcome, D-dimer as marker of coagulation/fibrinolysis activation). Results: Liver fibrosis indices (both Fibrosis-4 [FIB-4] and liver stiffness measurement [LSM]), but not liver fat (CAP), were independently associated with higher F8/PC ratio (p <0.01), triggering D-dimer formation (p = 2E-21). In keeping with a causal role of liver damage in determining a procoagulant status, the main fatty liver inherited risk variant PNPLA3 p.I148M was independently associated with the F8/PC ratio (p = 0.048). Vice versa, the main determinant of the coagulation balance was ABO locus variation (p = 1E-16), through the impact on vWF (p = 8E-26). Both rs687289 ABO and factor V Leiden were independently associated with higher Pro-C3 (p <0.025), with the effect of ABO being mediated by the impact on vWF (p = 5E-10 for association with Pro-C3). Mendelian randomisation analysis was consistent with a causal association of procoagulant imbalance with heightened fibrogenesis (p = 0.001 at robust MR-Egger for Pro-C3), but not with fibrosis (for LSM; p = not significant). Conclusions: In individuals with metabolic dysfunction, liver damage severity and possibly the PNPLA3 p.I148M variant were associated with procoagulant status. Vice versa, evaluation of inherited variants in ABO and other genes influencing coagulation was consistent with a causal role of procoagulant imbalance in activation of early stages of fibrogenesis. Lay summary: In individuals with metabolic alterations at risk of metabolic fatty liver disease, there is a tendency toward heightened blood coagulation (clotting), but the cause and the impact on the progression of liver disease remain unclear. Here we show that liver damage severity and metabolic alterations, but not hepatic fat, are mainly responsible for heightened coagulation in patients with metabolic fatty liver disease. By using genetic approaches, we showed that hepatic inflammation due to lipotoxicity may favour heightened coagulation, which in turn can trigger liver fibrosis, igniting a vicious cycle that leads to progressive liver disease.
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BACKGROUND & AIMS: Non-alcoholic 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 that contribute to severe NAFLD by examining rare variants. METHODS: 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. This was followed by validation at the gene level. RESULTS: In patients with severe NAFLD, we observed an enrichment of the p.P426L variant (rs143545741 C>T; odds ratio [OR] 5.26, 95% CI 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; 95% CI 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; 95% CI 1.1-7.5 and OR 12.30, 95% CI 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; 95% CI 1.2-2.5; p = 0.003), predisposed to hepatocellular ballooning (p = 0.007) evolving to fibrosis in the Liver biopsy cohort (n = 2,268), and was associated with liver injury in the UK Biobank (aspartate aminotransferase levels, p <0.001), with a larger effect in severely obese individuals in whom it was linked to hepatocellular carcinoma (p = 0.009). ATG7 protein localized to periportal hepatocytes, particularly 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. CONCLUSIONS: We identified rare and low-frequency ATG7 loss-of-function variants that promote NAFLD progression by impairing autophagy and facilitating ballooning and inflammation. LAY SUMMARY: We found that rare mutations in a gene called autophagy-related 7 (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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Carcinoma Hepatocelular , Neoplasias Hepáticas , Enfermedad del Hígado Graso no Alcohólico , Proteína 7 Relacionada con la Autofagia/genética , Biopsia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Humanos , Inflamación/patología , Hígado/patología , Cirrosis Hepática/complicaciones , Neoplasias Hepáticas/patología , Enfermedad del Hígado Graso no Alcohólico/complicacionesRESUMEN
Liver diseases remain unexplained in up to 30% of adult patients; genetic analysis could help establish the correct diagnosis. In six adult patients with cryptogenic liver disease, we performed whole-exome sequencing (WES) and evaluated the individual predisposition to progressive fatty liver disease by polygenic risk scores (PRS). In one patient, WES was allowed to diagnose the Hermansky-Pudlak syndrome. In the other two patients, genetic variants in LDLRAP1/MSH6 and ALDOB genes were identified, contributing to explaining the clinical presentation and disease pathogenesis (50% diagnostic uptake). In the other three patients, rare variants with a high likelihood of disrupting protein function in APOB, ATP7B, ABCB4 and ATP8B1 were identified. One patient who developed hepatocellular carcinoma during the follow-up had a high PRS value. The study supports the role of WES, combined with risk stratification by PRS and accurate clinical assessment in improving the diagnosis and informed management in patients with cryptogenic liver disease, a positive family history or severe fatty liver not fully accounted for by environmental triggers.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Adulto , Carcinoma Hepatocelular/genética , Exoma/genética , Humanos , Neoplasias Hepáticas/genética , Mutación , Secuenciación del ExomaRESUMEN
CONTEXT: Guidelines recommend blood-based fibrosis biomarkers to identify advanced nonalcoholic fatty liver disease (NAFLD), which is particularly prevalent in patients with obesity. OBJECTIVE: To study whether the degree of obesity affects the performance of liver fibrosis biomarkers in NAFLD. DESIGN: Cross-sectional cohort study comparing simple fibrosis scores [Fibrosis-4 Index (FIB-4); NAFLD Fibrosis Score (NFS); aspartate aminotransferase to platelet ratio index; BARD (body mass index, aspartate-to-alanine aminotransferase ratio, diabetes); Hepamet Fibrosis Score (HFS)] and newer scores incorporating neo-epitope biomarkers PRO-C3 (ADAPT, FIBC3) or cytokeratin 18 (MACK-3). SETTING: Tertiary referral center. PATIENTS: We recruited overweight/obese patients from endocrinology (nâ =â 307) and hepatology (nâ =â 71) clinics undergoing a liver biopsy [median body mass index (BMI) 40.3 (interquartile range 36.0-44.7) kg/m2]. Additionally, we studied 859 less obese patients with biopsy-proven NAFLD to derive BMI-adjusted cutoffs for NFS. MAIN OUTCOME MEASURES: Biomarker area under the receiver operating characteristic (AUROC), sensitivity, specificity, and predictive values to identify histological stage ≥F3 fibrosis or nonalcoholic steatohepatitis with ≥F2 fibrosis [fibrotic nonalcoholic steatohepatitis (NASH)]. RESULTS: The scores with an AUROCâ ≥0.85 to identify ≥F3 fibrosis were ADAPT, FIB-4, FIBC3, and HFS. For fibrotic NASH, the best predictors were MACK-3 and ADAPT. The specificities of NFS, BARD, and FIBC3 deteriorated as a function of BMI. We derived and validated new cutoffs for NFS to rule in/out ≥F3 fibrosis in groups with BMIs <30.0, 30.0 to 39.9, and ≥40.0 kg/m2. This optimized its performance at all levels of BMI. Sequentially combining FIB-4 with ADAPT or FIBC3 increased specificity to diagnose ≥F3 fibrosis. CONCLUSIONS: In obese patients, the best-performing fibrosis biomarkers are ADAPT and the inexpensive FIB-4, which are unaffected by BMI. The widely used NFS loses specificity in obese individuals, which may be corrected with BMI-adjusted cutoffs.
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Enfermedad del Hígado Graso no Alcohólico , Aspartato Aminotransferasas , Biomarcadores , Biopsia , Estudios Transversales , Fibrosis , Humanos , Hígado/patología , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/etiología , Cirrosis Hepática/patología , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/patología , Obesidad/complicaciones , Obesidad/patologíaRESUMEN
The aim of this study was to examine the impact of features of dysmetabolism on liver disease severity, evolution, and clinical outcomes in a real-life cohort of patients treated with direct acting antivirals for chronic hepatitis C virus (HCV) infection. To this end, we considered 7,007 patients treated between 2014 and 2018, 65.3% with advanced fibrosis, of whom 97.7% achieved viral eradication (NAVIGATORE-Lombardia registry). In a subset (n = 748), liver stiffness measurement (LSM) was available at baseline and follow-up. Higher body mass index (BMI; odds ratio [OR] 1.06 per kg/m2 , 1.03-1.09) and diabetes (OR 2.01 [1.65-2.46]) were independently associated with advanced fibrosis at baseline, whereas statin use was protective (OR 0.46 [0.35-0.60]; P < 0.0001 for all). The impact of BMI was greater in those without diabetes (P = 0.003). Diabetes was independently associated with less pronounced LSM improvement after viral eradication (P = 0.001) and in patients with advanced fibrosis was an independent predictor of the most frequent clinical events, namely de novo hepatocellular carcinoma (HCC; hazard ratio [HR] 2.09 [1.20-3.63]; P = 0.009) and cardiovascular events (HR 2.73 [1.16-6.43]; P = 0.021). Metformin showed a protective association against HCC (HR 0.32 [0.11-0.96]; P = 0.043), which was confirmed after adjustment for propensity score (P = 0.038). Diabetes diagnosis further refined HCC prediction in patients with compensated advanced chronic liver disease at high baseline risk (P = 0.024). Conclusion: Metabolic comorbidities were associated with advanced liver fibrosis at baseline, whereas statins were protective. In patients with advanced fibrosis, diabetes increased the risk of de novo HCC and of cardiovascular events. Optimization of metabolic comorbidities treatment by a multi-disciplinary management approach may improve cardiovascular and possibly liver-related outcomes.
Asunto(s)
Carcinoma Hepatocelular , Enfermedades Cardiovasculares , Diabetes Mellitus , Hepatitis C Crónica , Neoplasias Hepáticas , Antivirales/uso terapéutico , Carcinoma Hepatocelular/epidemiología , Enfermedades Cardiovasculares/complicaciones , Estudios de Cohortes , Diabetes Mellitus/tratamiento farmacológico , Hepatitis C Crónica/complicaciones , Humanos , Cirrosis Hepática/diagnóstico , Neoplasias Hepáticas/epidemiología , Respuesta Virológica SostenidaRESUMEN
BACKGROUND: A large proportion of SARS-CoV-2-infected individuals does not develop severe symptoms. Serological tests help in evaluating the spread of infection and disease immunization. The aim of this study was to prospectively examine the trends and risk factors of SARS-CoV-2 infection in blood donors. STUDY DESIGN AND METHODS: We screened 8798 asymptomatic donors presenting in Milan from July 2020 to February 2021 (10,680 presentations) before the vaccination campaign for anti-nucleoprotein (NP) antibodies, and for anti-spike receptor-binding domain (RBD) antibodies and nasopharyngeal swab PCR in those who tested positive. RESULTS: The prevalence of anti-NP+/RBD+ tests increased progressively with time up to ~15% (p < .0001), preceded by a peak of PCR+ tests. Anti-RBD titers were higher in anti-NP IgG+/IgM+ than in IgG+/IgM- individuals and in those with a history of infection (p < .0001); of these 197/630 (31.2%) displayed high titers (>80 AU/ml). Anti-RBD titers declined during follow-up, depending on baseline titers (p < .0001) and time (p = .025). Risk factors for seroconversion were a later presentation date and non-O ABO blood group (p < .001). A positive PCR was detected in 0.7% of participants in the absence of SARS-CoV-2 viremia. CONCLUSIONS: During the second wave of SARS-CoV-2 infection in Northern Italy, we detected an increase in seroprevalence in healthy blood donors from ~4% to ~15%, with a trend paralleling that observed in the general population. Seroconversion was more frequent in carriers of non-O blood groups. The persistence of anti-RBD antibodies was short-lived.