Nonalcoholic steatohepatitis versus steatosis - Wiley Online Library

7 downloads 186696 Views 806KB Size Report
Nonalcoholic Steatohepatitis Versus Steatosis: ... tosis (SS) to steatosis plus necroinflammation (e.g., ... lowing criteria: persistently (>6 months) elevated liver.
Nonalcoholic Steatohepatitis Versus Steatosis: Adipose Tissue Insulin Resistance and Dysfunctional Response to Fat Ingestion Predict Liver Injury and Altered Glucose and Lipoprotein Metabolism Giovanni Musso,1 Maurizio Cassader,2 Franco De Michieli,2 Floriano Rosina,1 Fabio Orlandi,1 and Roberto Gambino2 Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis (SS) to nonalcoholic steatohepatitis (NASH). Though liver-related risk seems confined to NASH, it is currently unclear whether NASH has a higher risk of cardiovascular disease (CVD) and diabetes than SS as a result of the coexistence of obesity and other cardiometabolic confounders. Adipose tissue is an emerging modulator of liver disease in NAFLD and of cardiometabolic disease in the general population. We evaluated in SS and NASH (1) glucose homeostasis and cardiovascular risk profile and (2) the effect of adipose tissue dysfunction, assessed in fasting conditions and postprandially, on liver injury, glucose and lipoprotein metabolism, and markers of early atherosclerosis. Forty nonobese, nondiabetic, normolipidemic biopsy-proven NAFLD patients (20 with SS and 20 with NASH) and 40 healthy subjects, matched for overall/abdominal adiposity and metabolic syndrome, underwent an oral fat load test, with measurement of plasma triglyceride-rich lipoproteins, oxidized low-density lipoproteins, adipokines, and cytokeratin-18 fragments, and an oral glucose tolerance test with minimal model analysis to yield glucose homeostasis parameters. Circulating endothelial adhesion molecules were measured, and adipose tissue insulin resistance (adipose IR) index and visceral adiposity index were calculated. Despite similar fasting values, compared to SS, NASH showed a more atherogenic postprandial lipoprotein profile, an altered adipokine response (i.e., higher resistin increase and an adiponectin fall), and hepatocyte apoptosis activation after fat ingestion. Adipose IR index, endothelial adhesion molecules, and hepatic insulin resistance progressively increased across NAFLD stages. NASH, but not SS, showed an impaired pancreatic b-cell function. On multiple regression analysis, adipose IR index and postprandial adiponectin independently predicted liver histology and altered cardiometabolic parameters. Conclusion: Adipose tissue dysfunction, including a maladaptive adipokine response to fat ingestion, modulates liver injury and cardiometabolic risk in NAFLD. (HEPATOLOGY 2012;56:933-942)

N

onalcoholic fatty liver disease (NAFLD) affects 30% of the general adult population and up to 80% of obese and diabetic sub1 jects and is considered the hepatic manifestation of

metabolic syndrome. NAFLD ranges from simple steatosis (SS) to steatosis plus necroinflammation (e.g., nonalcoholic steatohepatitis; NASH) with or without fibrosis.2 Emerging evidence suggests that NAFLD is

Abbreviations: adipose IR, adipose tissue insulin resistance; AI, adaptation index; ALT, alanine aminotransferase; ANOVA, analysis of variance; ApoA1, apolipoprotein A1; ApoE, apolipoprotein E; AUC, area under the curve; BMI, body mass index; CGI, CP-genic index; CI, confidence interval; CK-18, cytokeratin-18; CRP, C-reactive protein; CVD, cardiovascular disease; ER, endoplasmic reticulum; FFAs, free fatty acids; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity CRP; iAUC, incremental area under the curve; ICAM-1, intercellular adhesion molecule 1; IR, insulin resistance; IV, intravenous; LDL-C, low-density lipoprotein cholesterol; MTP, microsomal triglyceride transfer protein; NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD activity score; NASH, nonalcoholic steatohepatitis; NT, nitrotyrosine; OGIS, oral glucose insulin sensitivity; OGTT, oral glucose tolerance test; OR, odds ratio; oxLDLs, oxidized low-density lipoproteins; SEM, standard error of the mean; SS, simple steatosis; T2DM, type 2 diabetes mellitus; Tg, triglycerides; TRLPs, triglyceride-rich lipoproteins; VAI, visceral adiposity index; VLDL, very-low-density lipoprotein. From the 1Gradenigo Hospital, Torino, Italy; and 2Department of Internal Medicine, University of Turin, Turin, Italy. Received January 1, 2012; accepted March 19, 2012. This work was funded, in part, by the Piedmont Region Funds Comitato Interministeriale per la Programmazione Economica 2008. 933

934

MUSSO ET AL.

associated with an increased risk of liver-related complications, of type 2 diabetes mellitus (T2DM), and of cardiovascular disease (CVD).3 Though liverrelated risk appears to be confined to NASH, it is currently unclear whether NASH confers a higher risk of CVD and T2DM than SS as a result of the varying epidemiological association of NASH and SS with other cardiometabolic confounders, including obesity and metabolic syndrome, which prevents any inference on the independent effect of NASH/SS on cardiometabolic risk and on mechanisms underlying both liver disease progression and cardiometabolic risk in NAFLD. Adipose tissue is emerging as a key mediator of cardiometabolic disorders in the general population and of liver disease in NAFLD, likely through the modulation of lipotoxic free fatty acid (FFA) metabolism and of pro- and anti-inflammatory cytokine secretion.4-5 Consistently, abdominal adiposity excess, as quantified by magnetic resonance, correlated with liver fat in healthy subjects and with severity of inflammation and fibrosis in NASH.5,6 Among dietary factors, excessive fat ingestion has been consistently linked to the pathogenesis of obesity, CVD, and T2DM in the general population7 and to liver injury in animal models of NASH,8 whereas the evidence connecting dietary fat excess to NAFLD in humans is controversial. We hypothesized that adipose tissue dysfunction may mediate both liver disease progression and cardiometabolic risk in NAFLD, and that a maladaptive adipocyte response to dietary fat modulates liver injury and cardiometabolic risk in NAFLD, even in the absence of overall/abdominal adiposity excess. We therefore assessed the association of adipose tissue dysfunction, evaluated both in fasting conditions through two recently proposed indexes (the adipose tissue insulin resistance [adipose IR] index5 and the visceral adiposity index [VAI]9,10) and dynamically after an oral fat challenge, with liver histology, glucose/ lipoprotein metabolism, and markers of early atherosclerosis in nondiabetic, nonobese patients with biopsy-proven SS or NASH matched for overall/ abdominal adiposity and traditional cardiometabolic risk factors.

HEPATOLOGY, September 2012

Patients and Methods Subjects. Among 85 patients referred by family physicians to our hepato-metabolic clinic for chronic liver enzyme elevations, we selected 40 nonobese, nondiabetic, normolipidemic biopsy-proven NAFLD patients (20 with SS and 20 with NASH) who were matched for age, sex, body mass index (BMI), waist circumference, and metabolic syndrome features without clinical evidence of CVD. NASH was defined according to Brunt’s definition,11 and histological features were scored according to NASH Clinical Research Network criteria.12 Besides histological evidence, the diagnosis of NAFLD required all the following criteria: persistently (>6 months) elevated liver enzymes; ultrasonographic bright liver without any other liver or biliary tract disease; negative viral markers; and a history of alcohol consumption