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Improvement in liver histology is associated with reduction in dyslipidemia in children with nonalcoholic fatty liver disease.

ABSTRACT: OBJECTIVES:Nonalcoholic fatty liver disease (NAFLD), the most common cause of liver disease among US children, may be associated with cardiovascular disease (CVD) risk. The present study sought to determine the prevalence of dyslipidemia in children with NAFLD and assess dyslipidemia by liver histology and histologic changes. METHODS:Individuals in the Treatment of NAFLD in Children (TONIC) trial were included (N = 173). In the TONIC trial, children with NAFLD were randomized to vitamin E, metformin, or placebo for 96 weeks. Nonalcoholic steatohepatitis (NASH) improved in 56 children. Change in lipid levels from baseline and 96 weeks was compared between patients with and without histologic improvement and with and without NASH. RESULTS:Dyslipidemia was frequent, with low high-density lipoprotein (HDL) (< 40 mg/dL) in 61.8%, hypertriglyceridemia (? 130 mg/dL) in 50.3%, hypercholesterolemia (? 200 mg/dL) in 23.7%, elevated low-density lipoprotein (LDL) (? 130 mg/dL) in 21.5%, elevated non-HDL cholesterol (non-HDL-C) (? 145 mg/dL) in 35.2%, and triglycerides/HDL > 3.0 in 57.2% of patients. Histologic improvement was associated with significant decreases in cholesterol (-11.4 mg/dL vs -1.9 mg/dL, P = 0.04), LDL (-11.2 mg/dL vs -2.1 mg/dL, P = 0.04), and non-HDL-C (-8.8 mg/dL vs 0.5 mg/dL, P = 0.03) compared with those without improvement. Children with NASH resolution had significant decreases in cholesterol (-10.0 mg/dL vs -0.9 mg/dL, P = 0.02) and non-HDL-C (-7.3 mg/dL vs 1.1 mg/dL, P = 0.01) compared with those without NASH resolution. There was no improvement in triglycerides, HDL level, or triglycerides/HDL ratio in either group. CONCLUSIONS:Dyslipidemia is frequent in children with NAFLD. NASH resolution and histologic improvement are associated with improvements in some forms of dyslipidemia.

SUBMITTER: Corey KE

PROVIDER: S-EPMC4341955 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Improvement in liver histology is associated with reduction in dyslipidemia in children with nonalcoholic fatty liver disease.

Corey Kathleen E KE Vuppalanchi Raj R Vos Miriam M Kohli Rohit R Molleston Jean P JP Wilson Laura L Unalp-Arida Aynur A Cummings Oscar W OW Lavine Joel E JE Chalasani Naga N

Journal of pediatric gastroenterology and nutrition 20150301 3

<h4>Objectives</h4>Nonalcoholic fatty liver disease (NAFLD), the most common cause of liver disease among US children, may be associated with cardiovascular disease (CVD) risk. The present study sought to determine the prevalence of dyslipidemia in children with NAFLD and assess dyslipidemia by liver histology and histologic changes.<h4>Methods</h4>Individuals in the Treatment of NAFLD in Children (TONIC) trial were included (N = 173). In the TONIC trial, children with NAFLD were randomized to v ...[more]

PMID: 25714579

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Project description:Nonalcoholic steatohepatitis (NASH) is considered the hepatic manifestation of metabolic syndrome (MetS) among adults. Emerging data suggest that MetS may be associated with nonalcoholic fatty liver disease (NAFLD) in children as well. We sought to determine whether MetS or its component features are associated with specific histological features or severity of NAFLD.Children and adolescents aged 6-17 years enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) with clinical data obtained within 6 months of liver biopsy were included. MetS was defined as the presence of three or more of the following features as determined by application of age-adjusted normative values: central obesity, dyslipidemia, impaired fasting glucose, and elevated blood pressure. Liver biopsies were evaluated by the Pathology Committee of the NASH CRN.Two hundred fifty four children were included in the analysis, of whom 65 (26%) met specified criteria for MetS. Among children with MetS, there is a higher proportion of females who were on average older in age and pubertal. The risk of MetS was greatest among those with severe steatosis (odds ratio (OR)=2.58 for grade 3 vs. grade 1 steatosis, P=0.001). The presence of hepatocellular ballooning was also significantly associated with MetS (OR=2.10, P=0.03). Those with advanced fibrosis (stage 3/4) had an OR for MetS of 3.21 (P=0.04) vs. those without fibrosis (stage 0). Borderline zone 1 or definite NASH patterns compared with "not NASH" were strongly associated with MetS (OR=4.44, P=0.005 and OR=4.07, P=0.002, respectively). The mean NAFLD Activity Score (NAS) was greater among children with MetS vs. those without (4.8 +/- 1.4 vs. 4.3 +/- 1.4, P=0.01). Central obesity was significantly associated with steatosis, fibrosis, hepatocellular ballooning, and NAFLD pattern. Insulin resistance was significantly associated with steatosis, fibrosis, hepatocellular ballooning, NAS, and NAFLD pattern.MetS is common among children with NAFLD and is associated with severity of steatosis, hepatocellular ballooning, NAS, NAFLD pattern, and the presence of advanced fibrosis. Individual MetS features, particularly central obesity and insulin resistance, were also associated with severity of NAFLD. MetS features should be considered in children with NAFLD as individually and collectively they help identify children with more advanced disease.

Project description:IntroductionNonalcoholic fatty liver disease (NAFLD) is one of the most important causes of liver-related morbidity and mortality in children. Recently, we have reported the effects of docosahexaenoic acid (DHA), the major dietary long-chain polyunsaturated fatty acids, in children with NAFLD. DHA exerts a potent anti-inflammatory activity through the G protein-coupled receptor (GPR)120. Our aim was to investigate in pediatric NAFLD the mechanisms underlying the effects of DHA administration on histo-pathological aspects, GPR120 expression, hepatic progenitor cell activation and macrophage pool.Patients and methods20 children with untreated NAFLD were included. Children were treated with DHA for 18 months. Liver biopsies before and after the treatment were analyzed. Hepatic progenitor cell activation, macrophage pool and GPR120 expression were evaluated and correlated with clinical and histo-pathological parameters.ResultsGPR120 was expressed by hepatocytes, liver macrophages, and hepatic progenitor cells. After DHA treatment, the following modifications were present: i) the improvement of histo-pathological parameters such as NAFLD activity score, ballooning, and steatosis; ii) the reduction of hepatic progenitor cell activation in correlation with histo-pathological parameters; iii) the reduction of the number of inflammatory macrophages; iv) the increase of GPR120 expression in hepatocytes; v) the reduction of serine-311-phosphorylated nuclear factor kappa B (NF-κB) nuclear translocation in hepatocytes and macrophages in correlation with serum inflammatory cytokines.ConclusionsDHA could modulate hepatic progenitor cell activation, hepatocyte survival and macrophage polarization through the interaction with GPR120 and NF-κB repression. In this scenario, the modulation of GPR120 exploits a novel crucial role in the regulation of the cell-to-cell cross-talk that drives inflammatory response, hepatic progenitor cell activation and hepatocyte survival.

Project description:Statins, the intestinal cholesterol transporter inhibitor (ezetimibe), and PCSK9 inhibitors can reduce serum LDL-C levels, leading to a significant reduction in cardiovascular events. However, these events cannot be fully prevented even when maintaining very low LDL-C levels. Hypertriglyceridemia and reduced HDL-C are known as residual risk factors for ASCVD. Hypertriglyceridemia and/or low HDL-C can be treated with fibrates, nicotinic acids, and n-3 polyunsaturated fatty acids. Fibrates were demonstrated to be PPARα agonists and can markedly lower serum TG levels, yet were reported to cause some adverse effects, including an increase in the liver enzyme and creatinine levels. Recent megatrials of fibrates have shown negative findings on the prevention of ASCVD, which were supposed to be due to their low selectivity and potency for binding to PPAR α. To overcome the off-target effects of fibrates, the concept of a selective PPARα modulator (SPPARMα) was proposed. Kowa Company, Ltd. (Tokyo, Japan), has developed pemafibrate (K-877). Compared with fenofibrate, pemafibrate showed more favorable effects on the reduction of TG and an increase in HDL-C. Fibrates worsened liver and kidney function test values, although pemafibrate showed a favorable effect on liver function test values and little effect on serum creatinine levels and eGFR. Minimal drug-drug interactions of pemafibrate with statins were observed. While most of the fibrates are mainly excreted from the kidney, pemafibrate is metabolized in the liver and excreted into the bile. It can be used safely even in patients with CKD, without a significant increase in blood concentration. In the megatrial of pemafibrate, PROMINENT, for dyslipidemic patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL-C and LDL-C levels, the incidence of cardiovascular events did not decrease among those receiving pemafibrate compared to those receiving the placebo; however, the incidence of nonalcoholic fatty liver disease was lower. Pemafibrate may be superior to conventional fibrates and applicable to CKD patients. This current review summarizes the recent findings on pemafibrate.

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Improvement in liver histology is associated with reduction in dyslipidemia in children with nonalcoholic fatty liver disease.

Publications

Improvement in liver histology is associated with reduction in dyslipidemia in children with nonalcoholic fatty liver disease.

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