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)