Non-alcoholic fatty liver disease (NAFLD) is a

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1 Original Article / Liver Hepatobiliary & Pancreatic Diseases International The association of non-alcoholic fatty liver disease and metabolic syndrome in a Chinese population Shou-Wu Lee, Teng-Yu Lee, Sheng-Shun Yang, Yen-Chun Peng, Hong-Zen Yeh and Chi-Sen Chang Taichung, Taiwan, China BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is associated with features of metabolic syndrome. The aim of this study was to investigate the association between NAFLD and metabolic syndrome in a Chinese population. METHODS: Data from subjects were retrospectively collected from 2006 to The exclusion criteria included significant consumption of alcohol and chronic hepatitis B and C. The patients were assigned to two groups according to ultrasound findings: normal group and fatty liver group. The liver function of patients was determined by assessing serum alanine aminotransferase (ALT). Metabolic syndrome was diagnosed based on the 2005 International Diabetes Federation criteria. RESULTS: A total of 7568 subjects were enrolled and 5736 (75.8%) and 1832 (24.2%) patients were assigned to the normal and fatty liver groups, respectively. The fatty liver group had significant male predominance (69.7% vs 56.0%), higher body mass index (mean, vs kg/m 2 ) compared with the normal group. There were 441 (7.7%) and 377 (20.6%) cases with metabolic syndrome in the normal and fatty liver groups, respectively, with significant difference (P=0.001), and the subgroup of 385 cases with fatty liver and elevated ALT had higher prevalence (28.8%) of metabolic syndrome. The strongest association of an individual component of metabolic syndrome with NAFLD was hyperlipidemia (adjusted OR=2.55, 95% CI: ). Author Affiliations: Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan, China (Lee SW, Lee TY, Yang SS, Peng YC, Yeh HZ and Chang CS) Corresponding Author: Shou-Wu Lee, MD, Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan, China (Tel: ext3306; Fax: ; ericest@vghtc.gov.tw) 2017, Hepatobiliary Pancreat Dis Int. All rights reserved. doi: /S (16) Published online September 16, Hepatobiliary Pancreat Dis Int,Vol 16,No 2 April 15, CONCLUSION: The individuals with NAFLD had a higher ratio of metabolic syndrome. Hyperlipidemia had the strongest positive association with NAFLD. (Hepatobiliary Pancreat Dis Int 2017;16: ) KEY WORDS: fatty liver; hyperlipidemia; metabolic syndrome Introduction Non-alcoholic fatty liver disease (NAFLD) is a clinicopathologic condition characterized by abnormal lipid deposition in hepatocytes (steatosis) in the absence of excess alcohol intake, and it comprises a spectrum of diseases, ranging from simple hepatic steatosis to steatosis in association with necroinflammation and fibrosis (non-alcoholic steatohepatitis, NASH) to cirrhosis. [1] The reported prevalence of NAFLD when defined by liver ultrasound ranged between 17% and 46% depending on the population. [2] Metabolic syndrome describes a spectrum of disorders that may contribute to visceral obesity, insulin resistance, hyperglycemia, dyslipidemia, and hypertension. [3] Data indicate that the metabolic syndrome prevalence varies widely across populations. According to the National Health and Examination Survey (NHANES) III and the NHANES , the age-adjusted prevalence rates of metabolic syndrome were 24.1% and 27%, respectively. [4] NAFLD has been reported to be associated with several features of metabolic syndrome including obesity, type 2 diabetes, atherogenic dyslipidemia, and hypertension, and is characterized by insulin resistance. Furthermore, it has been suggested that NAFLD may be a hepatic manifestation of [5, 6] metabolic syndrome. The aim of our study was to determine the association between NAFLD and metabolic syndrome in a Chinese population.

2 and metabolic syndrome Methods Data from subjects who visited the Medical Screening Center at Taichung Veterans General Hospital were retrospectively collected from January 2006 to December The general data of enrolled patients, including age, gender, body mass index (BMI), waist circumference, blood pressure, fasting glucose, triglyceride (TG), and high-density lipoprotein (HDL) were recorded. All patients underwent a liver ultrasound which was conducted by experienced radiologists, and the findings of each case were collected. The exclusion criteria included significant consumption of alcohol (>40 g/day for males or >20 g/day for females) and chronic hepatitis B and C. These patients were assigned to two groups according to whether they had a normal liver appearance (normal group) or a fatty liver (fatty liver group). Liver function was determined by assessing levels of serum alanine aminotransferase (ALT). The definition of upper normal limit (UNL) of ALT was 50 U/L in men and 35 U/L in women. Metabolic syndrome was diagnosed based on the 2005 International Diabetes Federation criteria with ethnicity-specific values: central obesity (waist circumference 90 cm for men and 80 cm for women), combined with any two of the following four conditions: (1) TG levels 150 mg/dl; (2) HDL levels <40 mg/dl for men and <50 mg/dl for women; (3) fasting glucose levels >100 mg/dl; and (4) systolic blood pressure 130 mmhg or diastolic blood pressure 85 mmhg. Statistical analysis Data are expressed as mean±sd for each of the measured parameters. Gender, positive ratio of metabolic syndrome, and its associated components are expressed as a percentage of the total patient number. Statistical comparisons were made using Pearson s Chi-square test to compare the effects of gender and positive ratio of metabolic syndrome and individual components. Independent t test was used to analyze age and BMI. A P value below 0.05 was considered statistically significant. Multivariate Cox s regression was used to examine the strength of association between metabolic syndrome and fatty liver, as shown by odds ratios (ORs) with 95% confidence interval (CI). Results Table 1. The characteristics of enrolled cases Age (yr) 52.20± ± * BMI (kg/m 2 ) 23.55± ± * Waist (cm) 79.63± ± * Gender (male) (n, %) 3215 (56.0) 1277 (69.7) # *: s were analyzed with independent t test; #: Pearson s Chisquare test. BMI: body mass index. Table 2. The characteristics of enrolled cases in each subgroup (n, %) Metabolic syndrome 441 (7.7) 377 (20.6) Waist 705 (12.3) 534 (29.1) TG 3040 (53.0) 1505 (82.2) HDL 638 (11.1) 339 (18.5) Glucose 1215 (21.2) 758 (41.4) BP 169 (2.9) 72 (3.9) All s were analyzed with Pearson s Chi-square test. TG: triglyceride; HDL: high-density lipoprotein; BP: blood pressure. Among the 7568 subjects enrolled in our study, 5736 (75.8%) and 1832 (24.2%) were in the normal and fatty liver groups, respectively. Among the subjects wih fatty liver, 868 (47.4%), 622 (34.0%) and 342 (18.7%) belonged to mild, moderate and severe fatty liver respectively. Patients characteristics are summarized in Table 1. The mean age of the cases with fatty liver was older than that without (53.66 vs years). The individuals in the fatty liver group had significantly higher BMI than those in the normal group (26.67 vs kg/m 2 ). Furthermore, there was significant male predominance in the fatty liver group (69.7%). Among the 1832 individuals with fatty liver, 385 (21%) had elevated serum ALT. The cases with fatty liver and elevated ALT were significantly younger (mean vs years), had higher BMI (mean vs kg/m 2 ), and were more likely to be male (79.5% vs 67.1%) than those with fatty liver and normal ALT. Associations between normal liver or fatty liver and metabolic syndrome are displayed in Table 2. There were 441 (7.7%) and 377 (20.6%) cases with metabolic syndrome in the normal and fatty liver groups, respectively (P=0.001). Among the cases in the fatty liver group, an extremely large portion of cases had hypertriglyceridemia (82.2%) and hyperglycemia (41.4%). All components of metabolic syndrome were significantly elevated in the cases with fatty liver than in those without, except HDL (18.5% vs 11.1%, P=0.086). The strengths of associations between individual components of metabolic syndrome and fatty liver are shown in Table 3. After adjustment for measured potential confounders, including age, gender, and BMI, there were significant positive associations between all com- Hepatobiliary Pancreat Dis Int,Vol 16,No 2 April 15,

3 Hepatobiliary & Pancreatic Diseases International Table 3. Odds ratios and 95% confidence interval of associated fatty liver with metabolic syndrome items Endoscopic findings OR * 95% CI 1.00 [reference] Waist 1.49 [ ] TG 2.55 [ ] HDL 1.39 [ ] Glucose 1.84 [ ] BP 0.87 [ ] *: Adjusted for age, gender and BMI. Analyzed with multivariate Cox s regression. TG: triglyceride; HDL: high-density lipoprotein; BP: blood pressure; OR: odds ratio; CI: confidence interval. Table 4. The strengths of associations between metabolic syndrome and fatty liver in cases with elevated ALT (n, %) with normal ALT (n=1447) with elevated ALT (n=385) Metabolic syndrome 266 (18.4) 111 (28.8) Waist 398 (27.5) 136 (35.3) TG 1159 (80.1) 346 (89.9) HDL 250 (17.3) 89 (23.1) Glucose 574 (39.7) 184 (47.8) BP 55 (3.8) 17 (4.4) The definition of normal limit of ALT was below 50 U/L in men and 35 U/L in women. All s were analyzed with Pearson s Chi-square test. TG: triglyceride; HDL: high-density lipoprotein; BP: blood pressure; ALT: serum alanine aminotransferase. ponents of metabolic syndrome and fatty liver, except blood pressure (adjusted OR=0.87; 95% CI: ). The metabolic syndrome component with the strongest correlation with fatty liver was hyperlipidemia (adjusted OR=2.55; 95% CI: ). As shown in Table 4, among the individuals with fatty liver and elevated ALT, there was a significantly higher portion (28.8%) with metabolic syndrome compared with those with fatty liver and normal ALT (18.4%). All components of metabolic syndrome were significantly elevated in the cases with fatty liver and elevated ALT, except blood pressure (4.4% vs 3.8%, P=0.581). As shown in Table 5, the strengths of associations between metabolic syndrome items and fatty liver in patients with elevated ALT were all strongly positive, except blood pressure (adjusted OR=1.11; 95% CI: ) and waist circumference (adjusted OR=1.25; 95% CI: ). The items that correlated most strongly with fatty liver in patients with elevated ALT were hyperlipidemia (adjusted OR=4.49; 95% CI: ) and hyperglycemia (adjusted OR=2.74; 95% CI: ). The positive numbers of metabolic syndrome items in the normal liver group and fatty liver group were Table 5. Odds ratios and 95% confidence interval of associated fatty liver with elevated ALT and metabolic syndrome items Endoscopic findings OR * 95% CI 1.00 [reference] Waist 1.25 [ ] TG 4.49 [ ] HDL 1.84 [ ] Glucose 2.74 [ ] BP 1.11 [ ] The definition of normal limit of ALT was below 50 U/L in men and 35 U/L in women. *: Adjusted for age, gender and BMI. Analyzed with multivariate Cox s regression. ALT: alanine aminotransferase; TG: triglyceride; HDL: high-density lipoprotein; BP: blood pressure; OR: odds ratio; CI: confidence interval. Table 6. Positve numbers of metabolic syndrome items in the normal liver group and fatty liver group (n, %) Number (35.4) 144 (7.9) No (37.9) 655 (35.8) No (19.0) 660 (36.0) No (6.3) 283 (15.4) Yes 4 78 (1.4) 86 (4.7) Yes 5 5 (0.1) 8 (0.4) Yes Metabolic syndrome shown in Table 6. To the individuals in the fatty liver group without metabolic syndrome, most cases owned two criteria (36.0%). On the contrary, the most cases had no (35.4%) or only one criteria (37.9%) in the normal liver group without metabolic syndrome. Discussion According to the previous studies, male gender and obesity are risk factors for NAFLD. [2, 7] Moreover, aging tends to be accompanied with reduced physical mobility, which contributes to worsening of the components of metabolic syndrome, including abdominal obesity, hyperglycemia, hyperlipidemia, and hypertension. [8] Our results are consistent with these findings, which showed that the fatty liver group was older, male predominance, and had a greater prevalence of obesity. Metabolic syndrome is considered to be an insulin resistance syndrome comprising glucose intolerance, insulin resistance, central obesity, dyslipidemia, and hypertension, all of which are well-established risk factors for cardiovascular disease. [9] NAFLD is thought to be closely related to insulin resistance, and might play a role in the hepatic manifestation of metabolic syndrome. [6] The primary laboratory abnormality of NAFLD is an 178 Hepatobiliary Pancreat Dis Int,Vol 16,No 2 April 15,2017

4 and metabolic syndrome elevated serum ALT level, although many individuals whose entire histological spectrum of NAFLD is evaluated have normal ALT values. [10] One study reported that improvement in ALT levels appears to indicate improvement in steatosis, [11] suggesting that individuals with fatty liver and elevated ALT have greater severity of hepatic steatosis than those with fatty liver and normal ALT level. In our study, there was a higher prevalence of metabolic syndrome in the individuals with fatty liver (20.6%) than those without (7.7%), especially in the cases with fatty liver and high ALT (28.8%). These differences might reflect the degree of insulin resistance of individual cases. Numerous studies have been conducted on the association between NAFLD and individual components of metabolic syndrome. Steatohepatitis can be found in 40% to 100% of obese adults, [12] and waist circumference was found to be an independent determinant of the degree of hepatic necro-inflammation. [13] One Japanese study showed that prevalence of NAFLD increased to 43% in individuals with impaired fasting glucose and rose to 62% in individuals with type 2 diabetes mellitus. [14] An Italian study reported hypertriglyceridemia and low HDL-cholesterol level in 64% and 30%-42% of NAFLD patients, respectively. [15] A study conducted in Canada found the prevalence of NAFLD in individuals with dyslipidemia attending lipid clinics was estimated to be 50%. [16] In 55 non-obese, non-diabetic Italian patients with primary hypertension, there was a two-fold prevalence of fatty liver compared with that of the control group. [17] In our cases, the components of metabolic syndrome which correlated most strongly with NAFLD were hyperlipidemia and hyperglycemia. Interestingly, these variables are considered to be direct manifestations of insulin resistance. In contrast, hypertension had no association with NAFLD, which may be explained by other confounding factors that impact blood pressure. To our enrolled cases with fatty liver but not belonged to metabolic syndrome, a large portion of individuals had at least one or two criteria of metabolic syndromes. According to previous studies, the predisposing factors accounting to fatty liver, but independent of metabolic syndrome, were abnormal diet lifestyle, such as a large soft drink consumption, [18] or gene alternation, for example, PNPLA3 gene polymorphism. [19] The pathogenesis in this subgroup should need further investigation. There were some limitations in our study. Firstly, ultrasound was utilized to detect fatty liver disease, rather than liver biopsy. There was no precise quantitative information about the degree of fat accumulation, and inflammation and fibrosis were not evaluated. Secondly, we did not determine if subjects were on medications to control blood pressure, lipids, or glucose, which might have led to an underestimation of the prevalence of metabolic syndrome. Thirdly, our study was hospital-based and the all participants were enrolled from a self-paid health check-up. Selection bias might have existed due to the relatively high socioeconomic status of the studied population. Fourthly, there might be intra and inter operators variability of imaging of liver ultrasound determinations. Lastly, diet or lifestyle characteristics, such as healthy diet and exercise performance, which are considered to be protective factors in NAFLD or metabolic syndrome, [20] were not analyzed in our study. Further prospective community-based research using data that includes a more comprehensive range of basic characteristics is needed. In conclusion, our findings demonstrated that individuals with NAFLD had a higher prevalence rate of metabolic syndrome. Hyperlipidemia and hyperglycemia showed the strongest positive associations with NAFLD. Contributors: LSW and LTY proposed the study. LSW, YSS and PYC performed the research and wrote the first draft. LSW, YHZ and CCS collected and analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. LSW is the guarantor. Funding: None. Ethical approval: This study was approved by the Ethics Committee of the Taichung Veterans General Hospital (No. CF14040). Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. References 1 Brunt EM. Nonalcoholic steatohepatitis: definition and pathology. Semin Liver Dis 2001;21: Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. 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5 Hepatobiliary & Pancreatic Diseases International Lung, and Blood Institute Scientific Statement. Circulation 2005;112: Penninx BW, Nicklas BJ, Newman AB, Harris TB, Goodpaster BH, Satterfield S, et al. Metabolic syndrome and physical decline in older persons: results from the Health, Aging And Body Composition Study. J Gerontol A Biol Sci Med Sci 2009;64: Expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285: Mofrad P, Contos MJ, Haque M, Sargeant C, Fisher RA, Luketic VA, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology 2003;37: Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol 2005;42: Tarantino G, Saldalamacchia G, Conca P, Arena A. Non-alcoholic fatty liver disease: further expression of the metabolic syndrome. J Gastroenterol Hepatol 2007;22: Singh DK, Sakhuja P, Malhotra V, Gondal R, Sarin SK. Independent predictors of steatohepatitis and fibrosis in Asian Indian patients with non-alcoholic steatohepatitis. Dig Dis Sci 2008;53: Jimba S, Nakagami T, Takahashi M, Wakamatsu T, Hirota Y, Iwamoto Y, et al. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet Med 2005;22: Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 2003;37: Assy N, Kaita K, Mymin D, Levy C, Rosser B, Minuk G. Fatty infiltration of liver in hyperlipidemic patients. Dig Dis Sci 2000;45: Donati G, Stagni B, Piscaglia F, Venturoli N, Morselli-Labate AM, Rasciti L, et al. Increased prevalence of fatty liver in arterial hypertensive patients with normal liver enzymes: role of insulin resistance. Gut 2004;53: Abid A, Taha O, Nseir W, Farah R, Grosovski M, Assy N. Soft drink consumption is associated with fatty liver disease independent of metabolic syndrome. J Hepatol 2009;51: Shen J, Wong GL, Chan HL, Chan HY, Yeung DK, Chan RS, et al. PNPLA3 gene polymorphism accounts for fatty liver in community subjects without metabolic syndrome. Aliment Pharmacol Ther 2014;39: Finelli C, Tarantino G. Is there any consensus as to what diet or lifestyle approach is the right one for NAFLD patients? J Gastrointestin Liver Dis 2012;21: Received January 19, 2016 Accepted after revision August 10, Hepatobiliary Pancreat Dis Int,Vol 16,No 2 April 15,2017