Genome-Wide Association Study Identifies Loci for Liver Enzyme Concentrations in Mexican Americans: The GUARDIAN Consortium.

ObjectivePopulations of Mexican American ancestry are at an increased risk for nonalcoholic fatty liver disease. The objective of this study was to determine whether loci in known and novel genes were associated with variation in aspartate aminotransferase (AST) (n = 3,644), alanine aminotransferase (ALT) (n = 3,595), and gamma-glutamyl transferase (GGT) (n = 1,577) levels by conducting the first genome-wide association study (GWAS) of liver enzymes, which commonly measure liver function, in individuals of Mexican American ancestry.MethodsLevels of AST, ALT, and GGT were determined by enzymatic colorimetric assays. A multi-cohort GWAS of individuals of Mexican American ancestry was performed. Single-nucleotide polymorphisms (SNP) were tested for association with liver outcomes by multivariable linear regression using an additive genetic model. Association analyses were conducted separately in each cohort, followed by a nonparametric meta-analysis.ResultsIn the PNPLA3 gene, rs4823173 (P = 3.44 × 10-10 ), rs2896019 (P = 7.29 × 10-9 ), and rs2281135 (P = 8.73 × 10-9 ) were significantly associated with AST levels. Although not genome-wide significant, these same SNPs were the top hits for ALT (P = 7.12 × 10-8 , P = 1.98 × 10-7 , and P = 1.81 × 10-7 , respectively). The strong correlation (r2  = 1.0) for these SNPs indicated a single hit in the PNPLA3 gene. No genome-wide significant associations were found for GGT.ConclusionsPNPLA3, a locus previously identified with ALT, AST, and nonalcoholic fatty liver disease in European and Japanese GWAS, is also associated with liver enzymes in populations of Mexican American ancestry

Longitudinal assessment of high blood pressure in children with nonalcoholic fatty liver disease.

ObjectiveNonalcoholic fatty liver disease (NAFLD) affects 9.6% of children and may put these children at elevated risk of high blood pressure and subsequent cardiovascular morbidity and mortality. Therefore, we sought to determine the prevalence of and risk factors for high blood pressure in children with NAFLD.MethodsCohort study performed by the NIDDK NASH Clinical Research Network. There were 484 children with NAFLD ages 2 to 17 at enrollment; 382 children were assessed both at enrollment and 48 weeks afterwards. The main outcomes were high blood pressure at baseline and persistent high blood pressure at both baseline and 48 weeks.ResultsPrevalence of high blood pressure at baseline was 35.8% and prevalence of persistent high blood pressure was 21.4%. Children with high blood pressure were significantly more likely to have worse steatosis than children without high blood pressure (mild 19.8% vs. 34.2%, moderate 35.0% vs. 30.7%, severe 45.2% vs. 35.1%; P = 0.003). Higher body mass index, low-density lipoprotein, and uric acid were independent risk factors for high blood pressure (Odds Ratios: 1.10 per kg/m2, 1.09 per 10 mg/dL, 1.25 per mg/dL, respectively). Compared to boys, girls with NAFLD were significantly more likely to have persistent high blood pressure (28.4% vs.18.9%; P = 0.05).ConclusionsIn conclusion, NAFLD is a common clinical problem that places children at substantial risk for high blood pressure, which may often go undiagnosed. Thus blood pressure evaluation, control, and monitoring should be an integral component of the clinical management of children with NAFLD

Association Between Cytokines and Liver Histology in Children with Nonalcoholic Fatty Liver Disease.

BackgroundReliable non-invasive markers to characterize inflammation, hepatocellular ballooning, and fibrosis in nonalcoholic fatty liver disease (NAFLD) are lacking. We investigated the relationship between plasma cytokine levels and features of NAFLD histology to gain insight into cellular pathways driving NASH and to identify potential non-invasive discriminators of NAFLD severity and pattern.MethodsCytokines were measured from plasma obtained at enrollment in pediatric participants in NASH Clinical Research Network studies with liver biopsy-proven NAFLD. Cytokines were chosen a priori as possible discriminators of NASH and its components. Minimization of Akaike Information Criterion (AIC) was used to determine cytokines retained in multivariable models.ResultsOf 235 subjects, 31% had "Definite NASH" on liver histology, 43% had "Borderline NASH", and 25% had NAFLD but not NASH. Total plasminogen activator inhibitor 1 (PAI1) and activated PAI1 levels were higher in pediatric participants with Definite NASH and with lobular inflammation. Interleukin-8 (IL-8) was higher in those with stage 3-4 fibrosis and lobular inflammation. sIL-2rα was higher in children with stage 3-4 fibrosis and portal inflammation. In multivariable analysis, PAI1 variables were discriminators of Borderline/Definite NASH, definite NASH, lobular inflammation and ballooning. IL-8 increased with steatosis and fibrosis severity; sIL-2rα increased with fibrosis severity and portal inflammation. IL-7 decreased with portal inflammation and fibrosis severity.ConclusionsPlasma cytokines associated with histology varied considerably among NASH features, suggesting promising avenues for investigation. Future, more targeted analysis is needed to identify the role of these markers in NAFLD and to evaluate their potential as non-invasive discriminators of disease severity

Pathogenesis of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of disease ranging from hepatocellular steatosis through steatohepatitis to fibrosis and irreversible cirrhosis. The prevalence of NAFLD has risen rapidly in parallel with the dramatic rise in obesity and diabetes, and is rapidly becoming the most common cause of liver disease in Western countries. Indeed, NAFLD is now recognized to be the aetiology in many cases previously labelled as cryptogenic cirrhosis

Effects of sex and race on the changes in intrahepatic lipid, total and visceral adipose tissue in response to exercise training in obese adolescents

BACKGROUD: Non-alcoholic fatty liver is the most frequent liver abnormality observed in obese children and adolescents. It is has yet to be determined whether sex and race plays a role in the effect of regular exercise without calorie restriction on intrahepatic lipid and regional adiposity in obese adolescent males and females. OBJECTIVE: To examine the effect of sex and race after a 3-month regular exercise regimen alone without calorie restriction on intrahepatic lipid (IHL) and regional adiposity in overweight adolescent males and females. More specifically, we examined the influences of sex and race on the changes in total (TAT) and visceral fat (VAT) and IHL in response to aerobic (AE) versus resistance (RE) exercise in obese adolescents using data published previously. STUDY DESIGN & METHODS: Thirty-one adolescent boys and twenty-eight overweight adolescent females (BMI ≥ 95th percentile, 12-18 years, Tanner stage III-V) were randomly assigned to either: AE (n = 29, 60 min/session, 3 days/week) or RE (n = 30, 60 min/session, 3 days/week). Outcome measurements included IHL by proton magnetic resonance spectroscopy and TAT and VAT assessed by MRI. Cardiorespiratory fitness (CRF) and muscular strength was also assessed. RESULTS: No significant sex differences were seen between obese adolescent males and females for IHL, TAT and VAT after 3 months of exercise regardless of modality. There were no significant race differences between obese black and white adolescents for TAT. White adolescents (Δ -1.46 ± 0.2%) lost significantly more IHL than black adolescents (Δ -0.22 ± 0.1%) after 3 months of exercise regardless of modality. Improvement in CRF was not significantly different in the AE group compared to the RE group. Muscle strength index score significantly increased in the RE (Δ 0.33 ± 0.02) group compared to the AE group (Δ 0.04 ± 0.02). CONCLUSIONS: Our results demonstrate that 3 months of AE versus RE exercise will improve body composition and fitness measurements consistently, with no influence of sex, between obese black and white adolescent males and females. Our observations suggest that regular exercise alone is an effective treatment strategy for the treatment of obesity in overweight black and white adolescents

Non-alcoholic fatty liver disease connections with fat-free tissues: A focus on bone and skeletal muscle

The estimates of global incidence and prevalence of non-alcoholic fatty liver disease (NAFLD) are worrisome, due to the parallel burden of obesity and its metabolic complications. Indeed, excess adiposity and insulin resistance represent two of the major risk factors for NAFLD; interestingly, in the last years a growing body of evidence tended to support a novel mechanistic perspective, in which the liver is at the center of a complex interplay involving organs and systems, other than adipose tissue and glucose homeostasis. Bone and the skeletal muscle are fat- free tissues which appeared to be independently associated with NAFLD in several cross-sectional studies. The deterioration of bone mineral density and lean body mass, leading to osteoporosis and sarcopenia, respectively, are age-related processes. The prevalence of NAFLD also increases with age. Beyond physiological aging, the three conditions share some common underlying mechanisms, and their elucidations could be of paramount importance to design more effective treatment strategies for the management of NAFLD. In this review, we provide an overview on epidemiological data as well as on potential contributors to the connections of NAFLD with bone and skeletal muscle

A Guide to Non-Alcoholic Fatty Liver Disease in Childhood and Adolescence

Non-Alcoholic Fatty Liver Disease (NAFLD) is now the most prevalent form of chronic liver disease, affecting 10%–20% of the general paediatric population. Within the next 10 years it is expected to become the leading cause of liver pathology, liver failure and indication for liver transplantation in childhood and adolescence in the Western world. While our understanding of the pathophysiological mechanisms underlying this disease remains limited, it is thought to be the hepatic manifestation of more widespread metabolic dysfunction and is strongly associated with a number of metabolic risk factors, including insulin resistance, dyslipidaemia, cardiovascular disease and, most significantly, obesity. Despite this, ”paediatric” NAFLD remains under-studied, under-recognised and, potentially, undermanaged. This article will explore and evaluate our current understanding of NAFLD in childhood and adolescence and how it differs from adult NAFLD, in terms of its epidemiology, pathophysiology, natural history, diagnosis and clinical management. Given the current absence of definitive radiological and histopathological diagnostic tests, maintenance of a high clinical suspicion by all members of the multidisciplinary team in primary and specialist care settings remains the most potent of diagnostic tools, enabling early diagnosis and appropriate therapeutic intervention

Pediatric non alcoholic fatty liver disease: old and new concepts on development, progression, metabolic insight and potential treatment targets

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. NAFLD has emerged to be extremely prevalent, and predicted by obesity and male gender. It is defined by hepatic fat infiltration >5% hepatocytes, in the absence of other causes of liver pathology. It includes a spectrum of disease ranging from intrahepatic fat accumulation (steatosis) to various degrees of necrotic inflammation and fibrosis (non-alcoholic steatohepatatis [NASH]). NAFLD is associated, in children as in adults, with severe metabolic impairments, determining an increased risk of developing the metabolic syndrome. It can evolve to cirrhosis and hepatocellular carcinoma, with the consequent need for liver transplantation. Both genetic and environmental factors seem to be involved in the development and progression of the disease, but its physiopathology is not yet entirely clear. In view of this mounting epidemic phenomenon involving the youth, the study of NAFLD should be a priority for all health care systems. This review provides an overview of current and new clinical-histological concepts of pediatric NAFLD, going through possible implications into patho-physiolocical and therapeutic perspectives

When Sugar Reaches the Liver: Phenotypes of Patients with Diabetes and NAFLD

MODY diabetes; Liver fibrosis; Type 2 diabetesDiabetes MODY; Fibrosis hepática; Diabetes tipo 2Diabetis MODY; Fibrosi hepàtica; Diabetis tipus 2Type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) have been traditionally linked to one another. Recent studies suggest that NAFLD may be increasingly common in other types of diabetes such as type 1 diabetes (T1DM) and less frequently ketone-prone and Maturity-onset Diabetes of the Young (MODY) diabetes. In this review, we address the relationship between hyperglycemia and insulin resistance and the onset and progression of NAFLD. In addition, despite the high rate of patients with T2DM and other diabetes phenotypes that can alter liver metabolism and consequently develop steatosis, fibrosis, and cirrhosis, NALFD screening is not still implemented in the daily care routine. Incorporating a clinical algorithm created around a simple, non-invasive, cost-effective model would identify high-risk patients. The principle behind managing these patients is to improve insulin resistance and hyperglycemia states with lifestyle changes, weight loss, and new drug therapies

Noninvasive Screening of Nonalcoholic Fatty Liver Disease Among People Living with HIV

Background: Nonalcoholic fatty liver disease (NAFLD) disproportionately affects up to 75% of people living with HIV (PLWH). Given the high HIV prevalence in Houston and Harris County, knowledge of the prevalence of NAFLD in PLWH is needed to inform prevention efforts. In addition, such knowledge is required to raise awareness among at-risk individuals and healthcare professionals. Specific Aims: This cross-sectional study aimed (1) to examine the demographic, behavioral, clinical, and psychosocial characteristics of PLWH in Houston/Harris County, Texas, and to estimate the prevalence of NAFLD, (2) to determine factors associated with the severity of NAFLD, and (3) to identify specific predictors and their contribution to the severity of the disease in this population. Methods: The Triglyceride Glucose Index with a cutoff value of \u3e 8.38 was applied in a sample of PLWH (N = 601) obtained from the 2015-2019 Houston Medical Monitoring Project. Descriptive statistics and Rao-Scott Chi-Square tests were used to estimate the prevalence of NAFLD. Demographic, behavioral, clinical, and psychosocial characteristics were reported with weighted frequencies, percentages, and 95% confidence interval (CI). Multivariable logistic regression models were utilized to identify predictors. In addition, a recursive partitioning analysis was conducted to determine which predictors contributed to NAFLD severity. Results: Overall, the prevalence of NAFLD was 98.20%. The prevalence was higher among individuals 50 years and older, males, and Black PLWH, but the differences were not statistically significant. In the bivariate analyses, exposure to integrase strand transfer inhibitor was significantly associated with the presence of NAFLD (p = 0.0376). In the multivariable models, PLWH exposed to non-nucleoside reverse transcriptase inhibitors had higher odds, with unreliable confidence intervals (aOR = 15.78; 95% CI: 1.15 – 216.69, p = 0.0392). Time since HIV diagnosis (aOR = 3.64; 95% CI: 1.48 – 8.93, p = 0.0050), and Hispanic ethnicity (aOR = 3.13, 95% CI: 1.21 – 8.13, p = 0.0191), predicted severe NAFLD. In recursive partitioning models, race/ethnicity, exposure to non-nucleoside reverse transcriptase inhibitor, and time since HIV diagnosis contributed 51%, 24%, and 33–49%, respectively, to NAFLD severity. Conclusion: Early and prompt care of NAFLD, particularly liver fibrosis, will reduce the prevalence of the disease and save lives. Providers should, therefore, closely monitor, screen, and counsel PLWH with these identified risk factors and refer them to a liver specialist