Internal and Emergency Medicine Official Journal of the Italian Society of Internal Medicine. ISSN Volume 8 Number 3

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1 Hepatic Steatosis Index and Lipid Accumulation Product as middle-term predictors of incident metabolic syndrome in a large population sample: data from the Brisighella Heart Study Arrigo F. G. Cicero, Sergio D Addato, Alessandra Reggi, Giulio Marchesini Reggiani & Claudio Borghi Internal and Emergency Medicine Official Journal of the Italian Society of Internal Medicine ISSN Volume 8 Number 3 Intern Emerg Med (2013) 8: DOI /s

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3 Intern Emerg Med (2013) 8: DOI /s CE - LETTER TO THE EDITOR Hepatic Steatosis Index and Lipid Accumulation Product as middle-term predictors of incident metabolic syndrome in a large population sample: data from the Brisighella Heart Study Arrigo F. G. Cicero Sergio D Addato Alessandra Reggi Giulio Marchesini Reggiani Claudio Borghi Received: 4 October 2012 / Accepted: 8 November 2012 / Published online: 25 November 2012 Ó SIMI 2012 Dear Editor, Non-alcoholic fatty liver disease (NAFLD) is a pathologic condition characterized by the deposition of triglycerides (TG) in the liver [5 % of the total liver weight, in the presence of alcohol consumption \10 g daily, involving % of the adult population in Western countries [1]. Progression of fatty liver to necroinflammation and fibrosis stages is not only a common cause of chronic liver disease but also a risk factor for increased all-cause mortality, type 2 diabetes and cardiovascular disease. The pathophysiological link among NAFLD, type 2 diabetes, and cardiovascular diseases seems to be insulin-resistance, which induces pathological ectopic fat accumulation combined with a low-grade chronic inflammatory state, in turn, resulting in abnormal glucose, altered fatty acid and lipoprotein metabolism, increased oxidative stress, deranged adipokine profile, hypercoagulability, endothelial dysfunction, and accelerated progression of atherosclerosis. This makes NAFLD the hepatic expression of the On behalf of the Brisighella Heart Study. A. F. G. Cicero Internal Medicine, Aging and Kidney diseases Department, Sant Orsola-Malpighi University Hospital, Poliambulatorio Pad. 2, Via Albertoni, 15, Bologna, Italy afgcicero@cardionet.it S. D Addato A. Reggi (&) G. M. Reggiani C. Borghi Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy alereggi@hotmail.it metabolic syndrome (MS). Epidemiological data support the hypothesis that MS is an independent risk factor for NAFLD, although it is difficult to distinguish which is the cause and which the effect. The main risk factors for NAFLD are also the components of MS, and a few observations suggest that NAFLD may develop independently of MS or also predict it [2]. The aim of our study is to evaluate if two inexpensive NAFLD indices are able to predict the 4-year MS incidence in a large population sample of pharmacologically untreated subjects. The Brisighella Heart Study (BHS) is a prospective, population-based longitudinal epidemiological investigation involving 2,939 randomly selected subjects (1,491 men and 1,448 women), aged years, free of cardiovascular disease at enrollment, who live in the northern Italian rural town of Brisighella. A detailed description of the BHS has been largely described elsewhere [3]. For the purpose of the present study, we considered a subsample of 824 pharmacologically untreated participants without MS, type 2 diabetes, cardiovascular disease, history of alcohol abuse, or known liver diseases (evaluated on the basis of patient reported history cross-matched with GPs databases, and on liver enzymes) in the 2004 population survey who were re-examined during the 2008 survey. We calculated, for all the subjects, the Hepatic Steatosis Index (HSI) [calculated as 8 9 (ALT/AST ratio)? body mass index (BMI) (?2 if woman;?2 if diabetes)] [4] and the Lipid Accumulation Product (LAP) {calculated as [waist circumference, WC (cm) - 65] 9 triglycerides, TG (mmol/l) for men and [WC (cm) - 58] 9 TG (mmol/l) for women} [5]. The main anthropometric, clinical and laboratory characteristics of the selected population during the 2004 and 2008 BHS surveys are summarized in Table 1: from 2004 to

4 266 Intern Emerg Med (2013) 8: Table 1 Descriptive analysis of available anthropometric, clinical, and laboratory data at 2004 and 2008 population surveys for the selected subjects (N = 824) Mean SD Mean SD Mean SD Mean SD Age (years) TC (mg/dl) Body mass index (kg/m 2 ) TG (mg/dl) Waist circumference (cm) HDL-C (mg/dl) Hip circumference (cm) LDL-C (mg/dl) Waist/hip ratio Non-HDL-C (mg/dl) Waist/height ratio ApoA1 (mg/dl) Pulse circumference (cm) ApoB (mg/dl) Arm circumference (cm) FPG (mg/dl) SBP (mmhg) SUA (mg/dl) DBP (mmhg) Creatinine (mg/dl) PP (mmhg) AST (U/L) MAP (mmhg) ALT (U/L) Heart rate (ppm) CPK (U/L) Breath rate (bpm) HSI LAP SBP systolic blood pressure, DBP diastolic blood pressure, PP pulse pressure, MAP mean arterial pressure, TC total cholesterol, LDL-C low density lipoprotein cholesterol, TG triglycerides, HDL-C high density lipoprotein cholesterol, Apo apolipoprotein, FPG fasting plasma glucose, SUA serum uric acid, AST aspartate aminotransferase, ALT alanine aminotransferase, CPK creatinine phospho-kinase, HSI Hepatic Steatosis Index, LAP Lipid Accumulation Product 2008, a non-significant trend to an increase in the levels of all the MS components, as defined by the third Adult Treatment Panel of the National Cholesterol Education Program, was observed. The predicting role of LSI and lnlap for MS was tested by a Cox-regression analysis adjusted for the components of the MS, also including age, BMI, alcohol intake, and physical activity (estimated by validated questionnaires [3]), ALT, AST, serum uric acid, HIS, and lnlap. The analysis was later repeated according to gender, because both indices are gender-related (Fig. 1). A level of p=0.05 was considered significant for all the tests. We observed 46 new cases of MS (M: 25, F: 21) with an incidence of 1.4 % per year. Considering the whole population, in a model adjusted for the baseline MS components, the predictors of MS (R 2 = 0.59) were age (OR 1.13, 95 % CI , p \ 0.001), HSI (OR 1.17, 95 % CI , p \ 0.001), and lnlap (OR 1.16, 95 % CI , p \ 0.001). When repeating the prediction analysis by gender, in men the MS predictors (R 2 = 0.55) were age (OR 1.13, 95 % CI ), and lnlap (OR 1.17, 95 % CI ). In women the MS predictors (R 2 = 0.680) were age (OR 1.13, 95 % CI ), LSI (OR 1.20, 95 % CI ), and lnlap (OR 1.16, 95 % CI ). A liver biopsy and histological diagnosis using Kleiner s histological NAFLD activity score is the gold standard to ascertain the stage of the disease. The invasive nature of Fig. 1 Hepatic Steatosis Index (HSI) and Lipid Accumulation Product (LAP) level by gender at the study baseline liver biopsy inevitably limits this diagnosis; thus, noninvasive methods have been developed to diagnose NA- FLD. Such methods include the combination of clinical data with ultrasound, CT-scan, and magnetic resonance imaging. However, the screening of asymptomatic individuals using imaging techniques does not appear to be cost-effective, due to the high cost for mass screening and the need of trained professionals. Therefore, simple, noninvasive tests would be welcome to identify patients at high risk of NAFLD and to establish an appropriate NAFLD screening program.

5 Intern Emerg Med (2013) 8: The LAP and the HSI are two of such tests. The HSI contains heterogeneous components linked to liver fat, able to rule out NAFLD with a sensitivity of 93.1 %, or detect NAFLD with a specificity of 92.4 %, respectively [4]. LAP includes a measure of intra-abdominal fat depot (WC) and a measure of long-chain fatty acids that circulate in blood inside lipoproteins, thus combining anatomic and physiologic changes associated with over-accumulation of lipids in adults [5]. We find that the scores of the two algorithms predicting the presence of fat in the liver (HSI) and fat accumulation (LAP) with time also predict the development of MS in subjects free of MS at baseline. Among the limitations of our study, we did not evaluate the prevalence of NAFLD by ultrasonography or by more sophisticated techniques. However, we have used validated NAFLD indices, useful for screening purposes in the general population. In our large population sample of healthy subjects more expensive or invasive diagnostic tests would be a priori neither ethical nor cost-effective. Finally, other confounding variables might have influenced our results, but the regression analyses were adjusted for a large number of parameters, so we trust our observation. In conclusion, both LAP and HSI, as correlates of NAFLD, are significant middle-term predictors of incident MS in a large sample of general population. Acknowledgments This study was supported by institutional funding of the University of Bologna, Italy. Conflict of interest References None. 1. Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S (2005) Prevalence of and risk factors for nonalcoholic fatty liver disease: the nutrition and liver study. Hepatology 42: Vanni E, Bugianesi E, Kotronen A, De Minicis S, Yki-Järvinen H, Svegliati-Baroni G (2010) From the metabolic syndrome to NAFLD or vice versa? Dig Liver Dis 42: Cicero AFG, Dormi A, D Addato S, Borghi C, On behalf of the Brisighella Heart Study Staff (2011) From risk factor assessment to cardiovascular disease risk and mortality modification: the first 40 years of the. Clin Lipidol 6: Lee JH, Kim D, Kim HJ, Lee CH, Yang JI, Kim W, Kim YJ, Yoon JH, Cho SH, Sung MW, Lee HS (2010) Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease. Dig Liver Dis 42: Bedogni G, Kahn HS, Bellentani S, Tiribelli C (2010) A simple index of lipid overaccumulation is a good marker of liver steatosis. BMC Gastroenterol 10:98