Characterization of Nonalcoholic Fatty Liver Disease Unrelated to the Metabolic Syndrome

BMI; body mass index, DM; diabetes, Tu1923

AASLD Abstracts

Components of Metabolic Syndrome and the Rising Prevalence of NonAlcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) in the United States Maria Stepanova, Mariam Afendy, Gregory C. Vernon, Fatema Nader, Zobair M. Younossi The recent epidemic of obesity and other components of metabolic syndrome are expected to contribute to the prevalence of NAFLD and NASH in the United States. METHODS: In this study, we used two cycles of the National Health and Nutrition Examination Survey (NHANES) which were conducted approximately 20 years apart (1988-1994 and 20052008). For the purpose of this study, diagnoses of NAFLD was established as abnormal ALT and AST (ALT >40 U/L, AST >37 U/L in men and ALT, AST >31 U/L in women.) in the absence of all other types of chronic liver diseases (HCV antibody and HCV RNA negative, HBV surface antigen negative, normal transferrin saturation and alcohol consumption less than 10 grams per day in women or <20g/day in men). For the purpose of this study, NASH was defined as individuals without any evidence for chronic liver disease other than elevated aminotransferases (defined as above) who also had type 2 diabetes. This definition was based on extremely high prevalence of NASH in patients with DM and elevated liver enzymes. Logistic regression was used to identify independent predictors of both NAFLD and NASH. Statistical analyses were performed using SUDAAN 10.0 (SAS Institute, Cary, NC).RESULTS: In this study, a total of 25,536 adults were included from two NHANES cycles (1988-1994, N=15,866 and 2005-2008, N=9,670). Over this period of time, the prevalence of NAFLD doubled from the initial rate of 5.51±0.31% (1988-1994) to 11.01±0.51% (2005-2008) (p<0.0001). During the same period of time, the prevalence of NASH also doubled from 0.65±0.07% (1988-1994) to 1.10±0.14% (2005-2008) (p=0.0055). Furthermore, the prevalence of obesity (defined as BMI>30) raised from 21.74±0.65% to 33.22±1.08% (p<0.0001), as well as the prevalence of visceral obesity (defined using ATP-III threshold) [35.2±0.5% to 51.4±1.3%, p<0.0001], type 2 diabetes (DM) [5.55±0.29% to 9.11±0.47%, p<0.0001], insulin resistance (defined as HOMA>3.0) [23.29± 0.80% to 35.00±1.41%, p<0.0001] and hypertension [22.68±0.80% to 34.08±1.05%, p<0.0001]. In the multivariate analysis, obesity and DM remained independent predictors of NAFLD and NASH over the past two decades. If the current increases in rate of obesity and DM continue, the prevalence of NAFLD and NASH in the United States is expected to increase by at least 50% over the next two decades. CONCLUSIONS: In parallel to the increase in the prevalence of components of metabolic syndrome, the prevalence of NAFLD and NASH are steadily rising in the United States. This increase will probably make NAFLD/NASH the most important future cause of liver disease contributing significantly to the burden of chronic diseases in the United States.

NAFLD with or without T2DM and mortality Tu1925 Validity of the Non-Alcoholic Fatty Liver Disease Activity Score (NAS): Comparing the Nas With Pathology Diagnosis Michael Hjelkrem, Chris Stauch, Stephen Harrison, Janet Shaw PURPOSE: The NAS is a scoring system, developed by the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network, used to evaluate histological changes in research trials involving a therapeutic intervention, in order to provide a method to compare disease activity between patients. However, the NAS had not been validated outside of the NASH Clinical Research Network. METHODS: This study retrospectively examined adult patients from a tertiary medical center hepatology clinic undergoing liver biopsy to evaluate suspected NAFLD or NASH from January 2003 to May 2010. Patients with a diagnosis of liver disease other than NAFLD or NASH were excluded. The biopsy specimens were evaluated twice in a blinded manner by a single expert hepatopathologist, one time to determine a biopsy diagnosis (NASH, Steatosis, or normal) and separate, second time to determine the NAS. RESULTS: Three-hundred and Eighty-six biopsy specimens were analyzed. Area under the Receiver Operating Characteristic (ROC) curve was 0.900 (P < 0.001) (excellent agreement). A diagnosis of NASH was determined in 50.8% of the biopsies, steatosis in 43.5%, and indeterminate in 5.7%. For a NAS ≥ 5 as a diagnosis of NASH and a NAS <5 for not NASH the sensitivity was 57.1% and the specificity was 95.3% with negative predictive value (NPV) of 68.3% and positive predictive value (PPV) of 92.6%. Lowering the NAS to ≥ 4 as a diagnosis of NASH and < 4 as not NASH increased the sensitivity to 85.2% with a decrease in specificity to 80.5%, with NPV of 84.0% and PPV of 81.9%. CONCLUSION: The NAS is a valid scoring system with an excellent level of agreement between the histologic diagnosis and the NAS. An NAS ≥ 4 has optimal balance between sensitivity and specificity for a diagnosis of NASH.

Tu1924 Type 2 Diabetes Increases the Mortality Among Patients With Non Alcoholic Fatty Liver Disease Sombat Treeprasertsuk, Felicity Enders, Keith D. Lindor BACKGROUND: Type2 diabetes has been demonstrated to be one of important risk factors for advanced liver fibrosis in patients with non alcoholic fatty liver disease (NAFLD). However, there is limited information of long-term outcomes for the effect of type 2 diabetes (T2DM) on the mortality rate of patients with NAFLD. We aimed to compare the mortality rate between NAFLD patients with and without T2DM. METHODS: We identified and analyzed the existing data from a cohort study of 479 NAFLD patients diagnosed during 1980 and 2000 drawn from the Rochester Epidemiology Project. We excluded 177 patients due to incomplete data, known coronary heart disease (CHD) or known liver complications. The remaining 302 NAFLD patients with mean age of 47.3±12.9 years were followed-up for an average of 11.9 ± 3.9 years. Survival analysis were used to estimate the association of mortality and T2DM. RESULTS: T2DM was present in 48 patients (16%) at the time of NAFLD diagnosis. By univariate analysis, NAFLD patients with T2DM were older, had more female, more patients with hypertension, more patients with higher liver fibrosis score, higher triglyceride and glucose levels, and more patients with higher AST and ALT ratio(p<0.05). At the end of follow up 39 patients (12.9%) died. Of 246 NAFLD patients without T2DM at baseline, 86 of them (34%) developed diabetes during the follow-up. NAFLD patients with T2DM had significantly higher mortality rate than those without T2DM (23% vs. 11%). Survival analysis showed that NAFLD patients with T2DM had a significantly higher mortality rate then those without T2DM ((log-rank test statistics =35.5 ; P= 0.003; figure1). CONCLUSIONS: Type 2 diabetes is associated with a higher mortality rate among those patients with NAFLD. Clinical parameters, laboratory features at baseline of NAFLD patients grouped by status of T2DM.

AASLD Abstracts

Tu1926 Characterization of Nonalcoholic Fatty Liver Disease Unrelated to the Metabolic Syndrome Yusuf Yilmaz, Ebubekir Senates, Talat Ayyildiz, Yasar Colak, Ilyas Tuncer, Ayse O. Kurdas Ovunc, Enver Dolar, Cem Kalayci Nonalcoholic fatty liver disease (NAFLD) is currently considered as the hepatic manifestation of the metabolic syndrome (MS). However, not all patients with MS will develop NAFLD and not all patients with NAFLD have MS. The aim of this multicenter cross-sectional study was to determine the differences between patients with biopsy-proven NAFLD with and without a diagnosis of the MS. Our hypothesis was that a detailed characterization of NAFLD patients who do not meet the criteria for the MS would shed more light on the pathophysiological relevance of novel mechanisms related to liver fat accumulation. We enrolled 357 consecutive patients with biopsy-proven NAFLD (190 males and 167 females; mean age: 45.6 ± 10.2 years). The MS was defined as ≥3 of the ATP-III criteria. Two separate logistic regression analyses were constructed to assess the variables independently associated with the presence of NASH and the presence of advanced fibrosis (≥2). A total of 214 patients (59.9%) met the criteria for the MS, while the remaining 143 (40.1%) did

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not. compared with NAFLD patients with the MS - those who did not met the criteria for MS were younger, had a lower BMI and CRP levels, a higher prevalence of male subjects, a lower prevalence of gallstone disease, and higher levels of hemoglobin. In patients with the MS, HOMA-IR (P = 0.03; OR, 1.06; 95% CI, 1.023-1.25 per unit increase) and diabetes (P = 0.01; OR, 1.2; 95% CI, 1.1-2.4) were independent predictors of NASH, whereas in patients without the MS the only variable independently associated with NASH was serum hemoglobin (P = 0.007; OR, 1.9; 95% CI, 1.4-3.6 per 5 g/dL increase). ALT (P = 0.03; OR, 1.04; 95% CI, 1.006-1.11 per 10 U/L increase) was an independent predictor of fibrosis ≥ 2 in patients with the MS, while hemoglobin (P = 0.02; OR, 1.4; 95% CI, 1.2-1.9 per 5 g/ dL increase) was the only variable significantly associated with fibrosis ≥ 2 in patients without the MS. This study, performed in a large series of subjects who underwent liver biopsy, shows for the first time that advanced liver disease in NAFLD subjects without the MS was strongly and independently associated with serum hemoglobin levels. Increased serum hemoglobin in subjects without a diagnosis of the MS should be considered in the selection of NAFLD cases for histological assessment of disease severity and progression. For patients with NAFLD, a goal must be the prevention of end-stage liver disease even in the absence of the MS. Our data should be used to increase awareness of this subset of NAFLD patients and to guide future studies aimed at elucidating natural history and treatment of this condition even in the absence of the MS.

index was superior to other tested noninvasive markers of fibrosis in Japanese patients with NAFLD, with a high NPV for excluding advanced fibrosis. The small number of cases of advanced fibrosis in this cohort meant that this study had limited power for validating the high cut-off point. Tu1929

Background and Aim Recent studies suggest an association between non-alcoholic fatty liver disease (NAFLD) and the development and progression of cardiovascular disease. (Diabetologia 2008;51:1947-53) There are not studies investigating the association between cellular component of the endothelium and NAFLD. Circulating endothelial progenitor cells (EPCs) (characterized by the presence of CD34+, KDR+ and CD133+ surface markers) correlate with cardiovascular disease (NEJM 2009 3;361:2286-8.) The aim of this study was to investigate the association between NAFLD and levels of EPCs. Methods A cross-sectional pilot study was carried out at the University Hospital in Mexico City, inviting patients form the check-up unit without known chronic diseases. Two groups were formed, based on the presence of NAFLD which was established through ultrasonography. Anthropometric, dietary, biochemical variables and levels of circulating EPCs (using the modified ISHAGE protocol) were measured and compared between the groups. Results Forty subjects were included, 20 presented NAFLD and 20 controls. Thirty one were male and nine female. Overall prevalence of insulin resistance was 25% and metabolic syndrome 17.5%. Subjects with NAFLD were more obese and had significantly higher prevalence of metabolic syndrome and insulin resistance (Table 1). EPCs levels were significantly higher on NAFLD subjects than in controls, increasing along with the severity of steatosis. In the same way EPCs levels were higher in subjects with insulin resistance and metabolic syndrome (Table 2). Conclusions NAFLD subjects have higher EPCs levels, and it is proportional with the severity of NAFLD. This finding suggests that these cells may have an important role on the early natural history of NAFLD and also on its contribution to the increased cardiovascular risk in these patients. The EPCs may be increased as an attempt to repair and to compensate the endothelial damage as a consequence of metabolic alteration that NAFLD implies. Further studies are needed to establish the dynamics of these cells in NAFLD. Table 1. Significant anthropometric, biochemical and dietary variables

Tu1927 The Role of Dyslipidemia and Hyperglycemia in the Individuals With Nonalcoholic Fatty Liver Disease in the General Population in Japan Yuichiro Eguchi, Hideyuki Hyogo, Masafumi Ono, Toshihiko Mizuta, Kazuaki Chayama, Toshiji Saibara, Kazuma Fujimoto Background: Nonalcoholic fatty liver disease (NAFLD) is present in 20 to 40% in the general population of industrialized countries. Due to the dramatic increase in obesity in many industrialized countries, there is also a dramatic increase in the prevalence of NAFLD and nonalcoholic steatohepatitis (NASH). Although there is a relationship between metabolic disorder and pathogenesis of NAFLD, the role of dyslipidemia and hyperglycemia in the pathogenesis of NAFLD remains unclear. Aim: The aim of this study is to define the prevalence of ultrasound-diagnosed NAFLD in large adult general population and to clarify the role and relationship between dyslipidemia and hyperglycemia in the individuals with NAFLD utilizing the database of a large proportion of general population in Japan. Methods: We studied 9923 individuals (66.1% males) aged 21 to 86 (mean, 49.9) years, who were received health-check up from 2009 to 2010 in three health centers in Japan. Fatty liver was detected by ultrasound. The presence of fatty liver was recognized as a marked increase in hepatic echogenicity compared with the normal renal cortex. Individuals with intake over 20-gram alcohol/day or with other chronic liver disease were excluded. Each individual underwent a standard ultrasound, anthropometric and biochemical examination. Variables including sex, age, body mass index (BMI), blood count, alanine transaminase (AST), aspartate transaminase (ALT), gammaglutamyl-transferase (GGT), fasting plasma glucose (FPG), triglycerides, and HDL, LDL-cholesterol were analyzed. Results: The prevalence of NAFLD was 30.1%. There was a significant three-fold difference in the average prevalence between in males (40.4%) and females (15.3%). The prevalence was equally higher in males than in females in all ages except above the 7th decade, and showed a linear increase with BMI (BMI<23, 12.1%; 23= =28, 78.4%), serum level of triglyceride and LDL-cholesterol, respectively. On the other hand, the prevalence showed a linear increase with serum level of glucose (<120 mg/dL), and the prevalence achieved about 60% and reached a plateau with glucose >=120 mg/dL. An algorithm based on BMI, AST/ALT, GGT, FPG, hemoglobin, triglycerides, and HDL-cholesterol had an accuracy of 79.9% in detecting NAFLD. Conclusions: This study revealed that the prevalence of NAFLD was high in general population, especially in males, even though individuals were not obesity in Japan. The development of dyslipidemia and hyperglycemia might have different metabolic roles in the pathogenesis of NAFLD. Tu1928 Validation of the FIB4 Index in a Japanese Nonalcoholic Fatty Liver Disease Population Yoshio Sumida, Masato Yoneda, Hideyuki Hyogo, Yoshito Itoh, Masafumi Ono, Hideki Fujii, Yuichiro Eguchi, Yasuaki Suzuki, Noriaki Aoki, Kazuyuki Kanemasa, Koji Fujita, Kazuaki Chayama, Toshiji Saibara, Norifumi Kawada, Kazuma Fujimoto, Yutaka Kohgo, Toshikazu Yoshikawa, Takeshi Okanoue

BMI Body mass index; HDL-c High density lipoprotein-cholesterol; ALT Alanine-aminotransferase; AST Aspartate-aminotransferase. Table 2. Relationship of EPCs with the presence and severity of NAFLD, metabolic syndrome and insulin resistance.

BACKGORUND and AIMS: A reliable and inexpensive noninvasive marker of hepatic fibrosis is required in patients with nonalcoholic fatty liver disease (NAFLD). FIB4 index (based on age, aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels, and platelet counts) is expected to be useful for evaluating hepatic fibrosis. We validated the performance of FIB4 index in a Japanese cohort with NAFLD. METHODS: The areas under the receiver operating characteristic curves (AUROC) for FIB4 and six other markers were compared, based on data from 576 biopsy-proven NAFLD patients between 2002 and 2008, who were enrolled from the Japan Study Group of NAFLD (JSG-NAFLD) which includes nine hepatology centers in Japan Advanced fibrosis was defined as stage 3-4 fibrosis. FIB4 index was assessed as: age (yr) × AST (IU/L)/(platelet count (109/L) × √ALT (IU/L)). The following scores were also calculated for each patient: AST/ALT ratio, AST to platelet ratio index, ageplatelet index, BARD score, Nippon score, and NAFLD fibrosis score. Written informed consent was obtained from all patients at the time of liver biopsy, and the study was conducted in accordance with the Helsinki Declaration. RESULTS: Advanced fibrosis was found in 64 (11%) patients. The AUROC for FIB4 index (0.87) was superior to those for the other scoring systems for differentiating between advanced and mild fibrosis. Only six of 308 patients with a FIB4 index below the proposed low cut-off point (<1.45) were understaged, giving a high negative predictive value (NPV) of 98%. Twenty-eight of 59 patients with a FIB4 index above the high cut-off point (>3.25) were over-staged, giving a low positive predictive value of 53%. Using these cutoffs, 91% of the 395 patients with FIB-4 values outside 1.45-3.25 would be correctly classified. Implementation of the FIB4 index in the Japanese population would avoid 58% of liver biopsies.CONCLUSIONS: The FIB4

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AASLD Abstracts

AASLD Abstracts

The Role of Endothelial Progenitor Cells in Non-Alcoholic Fatty Liver Disease Nahum Mendez-Sanchez, Ylse Gutierrez-Grobe, Ramón A. Kobashi-Margáin, Juan G. Gavilanes-Espinar, Angel A. Gutiérrez-Jiménez, Vicente Sánchez-Valle, Felipe A. MassoRojas, Araceli Paez-Arenas, Norberto C. Chavez-Tapia, Martha H. Ramos, Misael Uribe