Nonalcoholic steatohepatitis is associated with an atherogenic lipoprotein subfraction profile

Lipids in Health and Disease, Jun 2014

Background Nonalcoholic steatohepatitis (NASH) carries an increased risk of cardiovascular disease (CVD) relative to the general population. We sought to evaluate whether differences in lipoprotein subfractions in obese patients with and without NASH contributes to this difference in CVD risk. Findings Ion mobility analysis was performed on 78 individuals with obesity undergoing weight loss surgery. All individuals had standard of care liver biopsies performed during surgery. Patients with NASH had significantly smaller peak LDL diameter (P = 0.02, 219.0 Å vs. 222.6 Å), and levels of IDL2 (P = 0.01, 104. nmol/L vs. 133.4 nmol/L) and HDL2b (P = 0.05, 676.7 nmol/L vs. 880.1 nmol/L) compared to those without NASH. NASH patients had significantly higher LDL-IVb levels than those without NASH (P = 0.02, 49.0 nmol/L vs. 37.1 nmol/L). The inverse association of LDL peak diameter with NASH remained significant after adjustment for diabetes (P = 0.02). HDL2b levels were inversely correlated with hepatocyte ballooning and NASH and these remained significant after adjustment for diabetes (P = 0.0017 and P = 0.007, respectively). IDL2 levels were inversely correlated with NASH, hepatocyte ballooning and fibrosis stage but these were not significant after adjustment for diabetes. Conclusions The lipoprotein subfraction profile in subjects with NASH is characterized by small peak LDL diameter, reduced HDL2b levels and elevated LDL-IVb levels. These changes may contribute to the increased CVD seen in patients with NASH.

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Nonalcoholic steatohepatitis is associated with an atherogenic lipoprotein subfraction profile

Lipids in Health and Disease Nonalcoholic steatohepatitis is associated with an atherogenic lipoprotein subfraction profile Kathleen E Corey 0 1 4 Joseph Misdraji 2 4 Lou Gelrud 4 Hui Zheng 4 5 Raymond T Chung 1 4 Ronald M Krauss 3 0 Department of Internal Medicine, Bon Secours Richmond Health System , Richmond, VA , USA 1 Gastrointestinal Unit, Massachusetts General Hospital , Boston, MA , USA 2 Department of Pathology, Massachusetts General Hospital , Boston, MA , USA 3 Children's Hospital Oakland Research Institute , Oakland , USA 4 Harvard Medical School , Boston, MA , USA 5 MGH Biostatistics Center, Massachusetts General Hospital , Boston, MA , USA Background: Nonalcoholic steatohepatitis (NASH) carries an increased risk of cardiovascular disease (CVD) relative to the general population. We sought to evaluate whether differences in lipoprotein subfractions in obese patients with and without NASH contributes to this difference in CVD risk. Findings: Ion mobility analysis was performed on 78 individuals with obesity undergoing weight loss surgery. All individuals had standard of care liver biopsies performed during surgery. Patients with NASH had significantly smaller peak LDL diameter (P = 0.02, 219.0 vs. 222.6 ), and levels of IDL2 (P = 0.01, 104. nmol/L vs. 133.4 nmol/L) and HDL2b (P = 0.05, 676.7 nmol/L vs. 880.1 nmol/L) compared to those without NASH. NASH patients had significantly higher LDL-IVb levels than those without NASH (P = 0.02, 49.0 nmol/L vs. 37.1 nmol/L). The inverse association of LDL peak diameter with NASH remained significant after adjustment for diabetes (P = 0.02). HDL2b levels were inversely correlated with hepatocyte ballooning and NASH and these remained significant after adjustment for diabetes (P = 0.0017 and P = 0.007, respectively). IDL2 levels were inversely correlated with NASH, hepatocyte ballooning and fibrosis stage but these were not significant after adjustment for diabetes. Conclusions: The lipoprotein subfraction profile in subjects with NASH is characterized by small peak LDL diameter, reduced HDL2b levels and elevated LDL-IVb levels. These changes may contribute to the increased CVD seen in patients with NASH. Ion mobility analysis; Lipid subfractions; Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis - Introduction Cardiovascular disease (CVD) is prevalent in individuals with nonalcoholic fatty liver disease (NAFLD). Three community-based studies from the United States and Japan have demonstrated an increased CVD risk in individuals with radiographic evidence of NAFLD when compared to those without NAFLD [1-3]. Individuals with histologically defined nonalcoholic steatohepatitis (NASH) have also been shown to have an increased CVD mortality when compared to the general population [4,5]. Thus, individuals with both radiographic NAFLD and histologically defined NASH are at increased risk for CVD and CVD-related mortality. Multiple factors likely contribute to the increased CVD risk seen in those with NASH including hyperinsulinemia, impaired thrombolysis and alterations in lipid and lipoprotein metabolism. To date studies of lipids in NASH have been largely limited to standard lipid profiles which include total cholesterol, triglycerides, high density lipoproteins (HDL) cholesterol and a calculated, rather than direct, measurement of low density lipoprotein (LDL) cholesterol. While these parameters are accepted markers of CVD risk, it has long been recognized that these measures provide only a crude index of disease pathophysiology and recent evidence shows that additional information can be gained from measurements of lipoprotein particles and their subfractions [6-8]. Ion Mobility (IM) is an innovative method that uses gas-phase differential electrophoretic macromolecular mobility to distinguish lipoprotein particles as a function of their size and to directly and rapidly quantify their plasma levels [9,10]. We hypothesized that IM would reveal important differences in the lipoprotein subfraction profiles of individuals with obesity with and without NASH that may contribute to the increased CVD seen in NASH. Methods This cohort study included consecutively enrolled patients who underwent weight loss surgery (WLS) at the Bon Secours Health System between 2010 and 2012. Subjects were assessed by a treating clinician for weight, height, BMI and co-morbidities. Diabetes mellitus was defined by a fasting glucose 126 mg/dL, HbA1C >6.5% or known diagnosis of diabetes. Hypertension was defined by a blood pressure 135/85 or undergoing treatment for hypertension. Individuals on lipid lowering therapy were excluded. No individual experienced significant weight loss prior to surgery. All subjects undergoing WLS had a standard of care liver biopsy at the time of surgery. Liver biopsies were reviewed by single blinded hepatopathologist (JM) and assigned a score for grade of steatosis (grade 0 = <5% steatosis; 1 = 5-33%; 2 = 33-66%; 3 = >66%), hepatocyt (...truncated)


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Kathleen E Corey, Joseph Misdraji, Lou Gelrud, Hui Zheng, Raymond T Chung, Ronald M Krauss. Nonalcoholic steatohepatitis is associated with an atherogenic lipoprotein subfraction profile, Lipids in Health and Disease, 2014, pp. 100, 13, DOI: 10.1186/1476-511X-13-100