Role of physical activity in non-alcoholic fatty liver disease (NAFLD): A population based study
S. Zelber Sagi1, 3; D. Nitzan-Kaluski2, 3; R. Goldsmith2; M. Webb1; L. M. Blendis1; Z. Halpern1, 3; R. Oren1, 3
1. Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv , Israel.
2. The Food and Nutrition Administration, Ministry of Health, Tel Aviv , Israel.
3. The Sackler Faculty of Medicine , Tel-Aviv University, Tel Aviv , Israel.
Background and aims: Physical activity (PA) is commonly recommended for patients with NAFLD. However, evidence that PA is effective in NAFLD prevention and treatment is scarce.
Aims: To examine the association between self-reported PA and NAFLD.
Methods: A cross-sectional study of a sub-sample (n=375) of the Israeli National Health and Nutrition Survey. Exclusion criteria were any known etiology for secondary NAFLD. Participants underwent an abdominal ultrasound, biochemical tests and anthropometric evaluations (abdominal obesity defined as waist circumference >88 cm in women and >102 cm in men). During a face-to-face interview a detailed PA (leisure and occupational) questionnaire was administered including the name of the PA, its frequency and duration and how long did the subject engaged in the PA (multiplication of all categories was defined as "score").
Results: After exclusion 349 subjects (52.7% male, mean age 50.7±10.4, 30.9% primary NAFLD) were included in the analysis. No association was found with occupational PA. The NAFLD group as compared to subjects with normal liver performed less than half the amount of all kind of sports (32.1 minutes/week vs. 67.3, P=0.001), almost half the amount of aerobic exercise (23.2 minutes/week vs. 42.3, P= 0.03) and only one third the amount of anaerobic exercise (8.9 minutes/week vs. 25.0, P <0.001). Adjusting for age and gender, performance of all kind of sports (OR=0.66, 0.44-0.96 95% CI per 413.2 increment in score units [1 SD]) and anaerobic exercise (OR=0.61, 0.38-0.85 95% CI per 162.5 increment in score units [1 SD]) were inversely associated with NAFLD. The association with anaerobic exercise remained significant with further adjustment for BMI (OR=0.61, 0.44-0.85 95% CI). Only anaerobic exercise was associated with a lower rate of abdominal obesity irrespective of BMI, gender and age (P=0.03).
Among NAFLD patients, performance of PA was associated with lower fasting serum insulin levels (25.7 vs. 32.0, P=0.03) and waist circumference (99.8 vs. 104.7, P=0.04) though BMI was similar. Moreover, performance of PA was associated with a lower rate of abdominal obesity irrespective of BMI, gender and age (OR=0.25, 0.07-0.93 95% CI).
Conclusions: Higher leisure-time PA may protect against NAFLD. The protective role of anaerobic exercise can stem from its independent association with a lower rate of abdominal obesity. NAFLD patients that perform PA benefit lower insulin levels irrespective of BMI, probably mediated by a lower rate of abdominal obesity.
Nutritional Assessment of Patients with Non-alcoholic Fatty Liver Disease (NAFLD) and Chronic Viral Hepatitis
Z. M. Younossi1; C. Kim1; J. B. Kallman1; R. Srivastava1; R. Gupta1; A. Murthy1; M. Sabatella1; L. Pawloski1
1. Outcomes Research Program and the Center for Liver Disease, Inova Health System, Annandale, VA, USA.
NAFLD is a common liver disease in the U.S. Obesity is a complex disease affected by both genetic and environmental factors, with dietary intake being one of the most important components. Obesity, found in the majority of patients with NAFLD, is a primary risk factor. Additionally, obesity may also impact other liver diseases such as HCV. Aim: Nutritional assessment of patients with chronic liver disease, specifically NAFLD, HCV, and HBV. Design: A nutrition questionnaire was mailed to 1853 patients with chronic liver diseases. The nutrition survey contained 13 indices measuring dietary choices and frequency of consumption for a wide variety of foods. Demographic and clinical data were available. Results: Three-hundred forty four patients returned completed questionnaires, age 52.3 years +/- 11.4 years, HCV (29.9%), NAFLD (18.9%), HBV (12.5%), other liver diseases (38.7%), 54.9% Female, 66.7% White, 10.2% Black, 2.5% Hispanic, 18.2% Asian, 2.5% other. Overall, 16.3% have been diagnosed with diabetes mellitus, 29.4% with hypertension, and 36.6% with hyperlipidemia. Kruskal-Wallis, followed by Mann-Whitney analysis tests were completed to compare diagnosis groups across 13 nutrition category variables. Diagnosis groups differed significantly on 7 of 13 nutrition categories. The NAFLD group consumed significantly more high sodium foods (p=.036) and low nutrient dense foods/baking products, fats, oils, and sweets (p=.028), and high fat sources of meat/protein (p=.022) than the HBV group. HBV group also consumed significantly more fruit (p=.005), cereals and grains (p=.007) and vegetables (p=.043) than the NAFLD group. The HCV group consumed significantly more fruits (p=.001) and bread and starchy foods (p=.033) than the NAFLD group. The HCV group consumed significantly more high sodium foods (p=.012) and low nutrient dense foods/baking products, fats, oils, and sweets consumption (p=.001) than the HBV group. The HBV group consumed significantly more lean sources of protein (p=.014), cereals and grains (p=.023) than the HCV group. Conclusions: Dietary habits appear to differ significantly between groups, with NAFLD patients overall consuming more high sodium foods and high fat protein sources, and significantly less consumption of fruit. The HBV group appeared to have the healthiest dietary habits with highest overall lean sources of protein, total fruit and vegetable consumption, and highest intake of cereals and grains.
Alcohol Consumption in Severely Obese Patients with Nonalcoholic Fatty Liver Disease: Relationship with Hepatic Fibrosis
H. P. Cotrim1; A. Almeida1; E. Alves1; D. May1; A. Ferraz1; S. H. Caldwell3; L. Freitas2
1. Medicine, Universidade Federal da Bahia, Salvador, Bahia, Brazil.
2. CPqGM - FIOCRUZ - BAHIA, Salvador, Bahia, Brazil.
3. Virginia University, CharlloteVille , VA, USA.
BACKGROUND: Moderate alcohol consumption has been associated with improved insulin activity, a lower prevalence of type II diabetes and a favorable vascular risk in severely obese. This study aimed to examine the association between light-to-moderate alcohol consumption and severity of nonalcoholic fatty liver disease (NAFLD) in the obese patient. METHOD: A cross-sectional study was performed in severely obese subjects, who underwent liver biopsy during bariatric surgery from October 2004 to April 2005. The patients were classified into 3 groups according to alcohol consumption: G1: alcohol intake > 20g/day and < 40g/day; G2: alcohol intake 3. Biopsies were scored and classified as isolated steatosis (Type I); steatosis + inflammation (Type II); steatohepatitis (steatosis, ballooning of hepatocytes and inflammation) (Type III); and steatohepatitis with fibrosis and cirrhosis (Type IV). The study was approved by the Ethics Committee for Medical Research (CPqGM- FIOCRUZ, Bahia). RESULTS: There were 132 subjects (83 female and 49 male) mean age 37.27 +/- 11.06 (18 to 65) years) with a body mass index of 43.9 +/- 5.6 kg/m2. G1, G2 and G3 included 19, 56 and 57 patients respectively. Histological diagnoses by levels of alcohol consumption were: G1 (moderate alcohol): 2 (10.5%) had normal liver and 89.5% (17) had NAFLD, Type III or IV, G2 (light alcohol): 6 (10.7%) had normal liver and 1.8% (1) had Type 1 or 2 and 87.5% (49) had Type III or IV of NAFLD, and G3 (no alcohol intake): 6 (10.5%) had normal liver, 3.5 % (2) had Type 1 or 2 and 86% (49) had Type III or IV. One of these had cirrhosis. IR was evaluated in 102 patients. It was correlated with moderate and no alcohol intake in 81.3% and 78.7% cases respectively (p<0.05). In patients with light alcohol intake 54.8% did not presented IR. CONCLUSIONS: Light-to-moderate alcohol consumption was not associated with the severity of NAFLD in obese patients. Steatohepatitis with fibrosis had a similar prevalence in patients with or without history of alcohol intake. However, light alcohol intake may protect the severely obese patients from insulin resistance. Dissociation of the effect on IR versus liver histology is consistent with a complex and as yet incompletely understood interaction between alcohol and obesity-related liver disease.
Advanced Fibrosis in NAFLD is Associated with Lifetime Alcohol Use, Diabetes, and Age but not with Lifetime Cigarette Smoking
C. O. Zein1; A. Unalp3; R. Colvin3; A. J. McCullough2, 3; .. for the NASH CRN Research Group3
1. Gastroenterology and Hepatology, Case Western Reserve University, Cleveland, OH, USA.
2. Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA.
3. NASH CRN Research Group, Baltimore, MD, USA.
Background: Cigarette smoking, alcohol use, diabetes (DM) and older age have all been linked with histological severity in certain chronic liver conditions. Associations between older age and DM with advanced histological stage in nonalcoholic fatty liver disease (NAFLD) have been suggested however, possible links between cigarette smoking or alcohol history with advanced liver fibrosis have not been studied in NAFLD. Aim: To study the associations between cigarette smoking history, alcohol use, DM and age with advanced fibrosis in patients with NAFLD, controlling for other patient characteristics. Methods: All adult patients enrolled in the NASH Clinical Research Network (NASH CRN) studies between February 2005 and December 2006 who had centrally read liver biopsies were included. Advanced fibrosis was defined as stage 3 or 4 by the validated NASH CRN Histological Scoring System for NAFLD. Significant smoking history was defined as a history of smoking >=10 pack-years. Alcohol consumption (abstinent or not) was derived from the Lifetime Drinking History (LDH) questionnaire based on reported history of lifetime abstinence (referent) or not, without quantification of exposure. Bivariate and multivariate logistic regression analyses were performed. Results: 666 subjects were included; 417 were female. Mean age was 48.5. Advanced fibrosis was present in 29.4%. Smoking history >=10 pk-yrs was reported 23% subjects. DM was present in 27% of subjects. Lifetime abstinence was reported by 50.2% of subjects. Significant bivariate associations were demonstrated between advanced fibrosis and age, significant smoking history, alcohol usage (versus lifetime abstinence), and DM. Alcohol use, DM, and age were independently associated with advanced fibrosis in the multivariate analysis (see Table); however, the association between >=10 pk-yrs smoking history and advanced fibrosis was not significant. Conclusions: Although a link between smoking and liver fibrosis has been demonstrated in some chronic liver diseases, this link was not found in NAFLD. Advanced fibrosis in NAFLD was linked to alcohol use, DM, and age. The possible association between lifetime abstinence or not and advanced fibrosis in NAFLD is an interesting observation that will be investigated further specifically regarding more detailed lifetime drinking histories.
Logistic regression model for advanced fibrosis and smoking, alcohol, DM, and age
OR 95% CI p
>=10 pack-year history 1.24 0.82, 1.88 0.31
Alcohol, not abstinent vs. abstinent 0.59 0.41, 0.85 0.005
Diabetes, yes vs. no 2.33 1.59, 3.40 <0.0001
The traditional Japanese Kampo formula keishibukuryogan ameliorates steatosis, reduces oxidative stress and inflammation, and ultimately prevents liver fibrosis in a rabbit model of non alcoholic steatohepatitis
M. Fujimoto1, 2; K. Tsuneyama2, 3; M. Kainuma4; N. Sekiya5; Y. Takano2; K. Terasawa3, 6; C. Selmi7, 8; M. Gershwin7; Y. Shimada1, 3
1. Japanese Oriental Medicine, University of Toyama, Toyama, Japan.
2. Diagnostic Pathology, University of Toyama, Toyama, Japan.
3. 21st Century COE Program, University of Toyama, Toyama, Japan.
4. Environmental Medicine and Infectious Diseases, Kyushu University, Fukuoka, Japan.
5. Frontier Japanese Oriental Medicine, Chiba University, Chiba, Japan.
6. Japanese Oriental Medicine, Chiba University, Chiba, Japan.
7. Internal Medicine, University of California, Davis, Davis, CA, USA.
8. Clinical Sciences 'Luigi Sacco', University of Milan, Milan, Italy.
The mechanisms responsible for the progression of non alcoholic fatty liver disease (NAFLD) to steatohepatitis (NASH) remain unknown although oxidative stress and inflammation appear to play a crucial role. Although traditional Chinese and Japanese medicine has been advocated for a variety of human diseases, the vast majority of such studies lack the appropriate quality controls, standardization, and evidence-based blind evaluation. We have been intrigued with specific Japanese herbal compounds (Kampo formulas) alleged to have significant antioxidant activity. We studied the effects of 12-week supplementations with three Kampo formulas [keishibukuryogan (1% KBG, TJ-25), orengedokuto (1% OGT, TJ-15) and shosaikoto (1% SST, TJ-9)] or two proposed NASH treatments [i.e. vitamin E (VE) and pioglitazone (PG)] on a cholesterol-fed rabbit model of NAFLD/NASH. Control groups were fed with standard rabbit chow and SRC containing only 1% cholesterol (C). Our readouts included (i) markers of liver function, lipid and glucose metabolism; (ii) liver histology and tissue lipid contents; (iii) oxidative stress; and (iv) plasma mediators of inflammation and fibrosis. Results demonstrate that (i) total cholesterol levels in group C were significantly higher compared to each of the other supplemented groups (P<0.01 for all comparisons) and the KBG group had the lowest total cholesterol levels with the expected exception of the group not receiving cholesterol nor treatments while no significant differences were observed between treatment groups in fasting glucose, insulin levels, or transaminase activities. (ii) KBG treatment led to significantly lower levels of total cholesterol (P<0.01), free cholesterol (P<0.01), and triglycerides (P<0.05) in the liver tissues. KBG treatment was associated with significantly higher adiponectin levels. (iii) KBG treatment was associated with significantly lower levels of plasma lipid peroxide compared to group C; urinary amounts of 8-OHdG were significantly reduced in all 5 supplement groups. (iv) KBG treatment was characterized by significantly reduced proportions of α-SMA positive areas and hepatic stellate cells at immunohistochemistry. Plasma levels of hyaluronic acid and TGF-β1 were significantly lower in groups KBG, OGT, and VE compared to group C. In conclusion, Kampo formulas (KBG in particular) exert a significant protective effect in a dietary rabbit model of NAFLD/NASH through several mechanisms that ultimately prevent the progression to liver fibrosis. We should also emphasize the rigor of these data and the need not only for further observations but also for the evaluation of cellular and molecular mechanisms.
Green Tea Polyphenols Improve Liver Injury of Nonalcoholic Steatohepatitis (NASH) Model Mice Expressing Nuclear Sterol Regulatory Element-Binding Protein 1C (nSREBP-1c) in Adipose Tissue
T. Ueno1, 2; T. Nakamura2, 1; R. Sakata2, 1; O. Hashimoto2, 1; K. Inoue2, 1; H. Koga2, 1; T. Torimura2, 1; M. Shinkawa1; H. Nakayama3; S. Otabe3; N. Hirota3; K. Yamada3; M. Sata2, 1
1. Research Center for Innvative Cancer Therapy and Center of the 21st Century COE Program for Medical Science, kurume University, Kurume, Japan.
2. Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
3. Division of Endocrinology and Metabolism, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
Background/Aim: Part of patients with NASH progress to end-stage liver disease such as cirrhosis and hepatocellular carcinoma, and the therapy of NASH is very important. In the present study, we examined whether green tea polyphenols (GTPs) including catechins improve liver injury of NASH model mice expressing nuclear sterol regulatory element-binding protein 1c (nSREBP-1c) in adipose tissue. Materials and Methods: nSREBP-1c transgenic C57BL6 male mice aged 30 weeks, that show the typical NASH in liver histology at this age, were prepared in this study. These mice were shared three groups (Group 1; mice given water containing high dose GTPs (0.1%), Group 2; mice given water containing low dose GTPs (0.01%), and Group 3; control mice given water without GTPs). After treatment for 12 weeks, these mice were bled, humanely killed and examined as follows. 1) Ratio of liver weight to body weight, 2) Biochemical assays containing serum AST and ALT. 3) Morphometry of liver specimens according to the grading and staging of NASH proposed by Brunt et al., 4) Immunohistochemistry using antibody of 8-hydro-2’-deoxyguanosine (8OhdG) to estimate oxidative stress, 5) Western blotting using antibodies of insulin receptor (IR), insulin receptor substrate (IRS)-1 and phosphorylated IRS-1 (pIRS-1) for insulin signaling, and using antibodies of Akt, pAkt, pIKKβ, NFκB and pNFκB for TNFα signaling. Results: 1) Ratio of liver weight to body weight in the high dose GTPs -treated group (group 1) was significantly lower than those of the groups 2 and 3 (p<0.05, respectively). 2) Blood AST, ALT, glucose, total cholesterol, and triglyceride levels of the group 1 were significantly low compared with that of the GTPs -no treated group (group 3) (p<0.05, respectively). 3) The degrees of steatosis, inflammation, ballooning hepatocytes, Mallory bodies, lipogranuloma and fibrosis in the group 1 significantly improved compared with those in the group 3 (p<0.01, respectively). 4) 8OhdG immunolocalization in liver tissues of the group 1 obviously decreased compared with those of the groups 2 and 3. 5) In Western blotting, the expressions of IR and pIRS-1 in liver tissues of the group 1 increased compared with those of the groups 2 and 3. On the other hands, the expressions of pAkt, pIKKβ and pNFκB decreased compared with those of the groups 2 and 3. Conclusions: These results indicate that GTPs have the effects of anti-inflammation, anti-insulin resistance and anti-oxidative stress, and improve the liver injury of the transgenic mice expressing nSREBP-1c in the adipose tissue. Moreover, GTPs containing catechins are suggested to be useful for the therapy of patients with NASH
(Dr. D. talked made a point on the dangers of Fructose in his video)
Fructose Induced Hyperuricemia as a Causal Mechanism for Nonalcoholic Fatty Liver Disease.
M. F. Abdelmalek1; A. Suzuki1; C. Guy1; R. J. Johnson2; A. Diehl1; . for the NASH Clinical Research Group3
1. Division of Gastroenterology, Duke University, Durham, NC, USA.
2. Divison of Nephrology, University of Florida, Gainesville, FL, USA.
3. NIDDK, National Institutes of Health, Baltimore, MD, USA.
The rise in obesity coincides with an increase in total fructose (FRU) intake. Excess FRU intake leads to hepatic increases in pyruvate and lactate production and a shift in balance from oxidation to esterification of fatty acids. Acute FRU loading of the liver causes sequestration of inorganic phosphate in FRU-1-phosphate and diminished ATP synthesis. Hepatic ATP depletion increases uric acid formation. FRU-induced hyperuricemia results in endothelial dysfunction and insulin resistance (IR) and may be a novel mechanism underlying NAFLD. Methods: We studied 341 adults enrolled in the NASH Clinical Research Network for whom dietary data using the Block Food Questionaire was collected within 6 months of a liver biopsy. Total FRU consumption was estimated based on reporting (frequency x amount) of kool-aid, fruit juices, and non-dietary soda intake and expressed as servings per wk and classified into none, occasional (=7 servings/wk). Multiple linear and logistic regression analyses were used to analyze the association between FRU intake, hyperuricemia [serum uric acid (SUA) >5.5 mg/dl], HOMA-IR and the histologic features of NAFLD. Results: Of the 341 pts, 40% were male and 80% were Caucasian. The mean ± SD of age, BMI and caloric intake was 47 ± 12 yrs, 34 ± 6.3 and 1896 ± 957 kcal /day respectively. Overall, mean SUA was 6.2 ± 1.5 mg/dl, triglycerides (TG) was 196 ± 42 mg/dl, and total, HDL and LDL cholesterol was 196 ± 42 mg/dl, 44 ± 11 mg/dl and 120 ± 35 mg/dl respectively. Daily FRU intake was dose-dependently associated with hyperuricemia compared to non-consumers of FRU (p<0.002), even after controlling for total calorie intake and BMI: OR [95% CI] vs non-consumer was 2.4[1.1, 5.6], p=0.036. Elevated SUA was associated with high TG (p=0.0175), total cholesterol (p=0.008), and a trend towards low HDL cholesterol (p=0.06) which did not alter after controlling for HOMA-IR. On the other hand, even after controlling for other confounders, increased FRU intake was significantly associated with lower steatosis score but higher ballooning, inflammation, and fibrosis score (p<0.05 for each). However, SUA did not correlate with NAFLD Activity Score or fibrosis stage. Conclusions: Increased FRU intake is significantly associated with SUA. Elevated SUA is associated with altered lipid profiles independent of the severity of IR but not with histologic liver damage. However, increased FRU intake correlated negatively with steatosis and positively with ballooning and fibrosis stage. Whether increased FRU intake promotes NAFLD progression via the esterification of fatty acids and hepatic ATP depletion warrants further investigation.
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Hepatitis C and NAFLD are both common liver diseases. The concomitant presence of both conditions frequently indicates the presence of underlying metabolic syndrome especially in those with genotype 1 infection. HCV genotype 3 is independently associated with the presence of hepatic steatosis. The concomitant presence of NAFLD increases the risk of having advanced hepatic fibrosis and failure of antiviral therapy in subjects with HCV. Clinical trials of weight loss to improve hepatic steatosis are currently underway to see if this will improve the response rates to antiviral therapy and improve hepatic fibrosis."
Non-alcoholic Fatty Liver Disease and Hepatitis C
Hepatitis C and non-alcoholic fatty liver disease (NAFLD) are the two most common liver diseases in the Western hemisphere. It is therefore natural that these conditions often co-exist in the same individual.
Hepatitis C, especially genotype 3, is often associated with hepatic steatosis. In subjects with genotype 3 infection, a sustained virologic response to treatment is associated with improvement in hepatic steatosis.
The diagnosis of NAFLD in a subject with hepatitis C infection is based on the presence of hepatic steatosis. Most investigators require the presence of at least grade II steatosis to warrant a diagnosis of concomitant NAFLD because the significance of minimal steatosis is uncertain.
The presence of steatohepatitis is surmised by the additional presence of Mallory bodies, cytologic ballooning and pericellular fibrosis.
It is of paramount importance to exclude alcohol as a cause of these histologic findings in this population before a diagnosis of NAFLD is made.
The presence of NAFLD in subjects with hepatitis C genotype 1 infection is most strongly associated with the presence of the metabolic syndrome and insulin resistance.
The degree of hepatic steatosis correlates with the degree of hepatic fibrosis and the presence of concomitant steatosis is associated with more advanced fibrosis.
The presence of cytologic ballooning confers an additional risk for increased fibrosis.
Insulin resistance and hyperinsulinemia have been associated with increased collagen production by hepatic stellate cells.
Subjects with hepatitis C and NAFLD are more likely to be virologic nonresponders following anti-HCV therapy.
The value of treating insulin resistance and NAFLD prior to antiviral therapy remains to be verified.
Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University, Health System, Richmond, VA, USA.
A J Sanjal. Review article: non-alcoholic fatty liver disease and hepatitis C - risk factors and clinical implications. Alimentary Pharmacology and ��� Therapeutics 22 (Suppl 2):48-51. November 2005.
Probably should mention that all of the above abstracts -- with the exception of the last two -- are advanced abstracts from the AASLD 2007 Liver Conference in Boston that is starting November 2nd. You can register here and examine all the abstracts as well as other events: