The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis
2015; Elsevier BV; Volume: 5; Issue: 2 Linguagem: Inglês
10.1016/j.jceh.2015.02.002
ISSN2213-3453
AutoresMithun Sharma, Shasikala Mitnala, Ravi K. Vishnubhotla, Rathin Mukherjee, D. Nageshwar Reddy, Padaki Nagaraja Rao,
Tópico(s)Endoplasmic Reticulum Stress and Disease
ResumoNonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed. Nonalcoholic fatty liver (NAFL) is an emerging global epidemic which progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis in a subset of subjects. Various reviews have focused on the etiology, epidemiology, pathogenesis and treatment of NAFLD. This review highlights specifically the triggers implicated in disease progression from NAFL to NASH. The integrating role of genes, dietary factors, innate immunity, cytokines and gut microbiome have been discussed. Non alcoholic fatty liver disease (NAFLD) is an emerging medical problem worldwide which affects a significant proportion of the western population and there is gradual spread of this epidemic to south-east Asian countries. NAFLD encompasses two entities: Non-alcoholic fatty liver (NAFL) and Non-alcoholic steatohepatitis (NASH). NAFL is defined as the evidence of hepatic steatosis without inflammation either by imaging or by histology in individuals without significant alcohol consumption in whom secondary causes of steatosis are absent.1Chalasani N. Younossi Z. Lavine J.E. et al.The diagnosis and management of non-alcoholic fatty liver disease: practice guidelines by the American Association for the study of Liver diseases, American College of Gastroenterology, and the American Gastroenterological Association.Gastroenterology. 2012; 142: 1592-1609Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar NASH on the other hand, is characterized by the presence of both steatosis and inflammation with evidence of hepatocyte injury in the form of ballooning with or without fibrosis.1Chalasani N. Younossi Z. Lavine J.E. et al.The diagnosis and management of non-alcoholic fatty liver disease: practice guidelines by the American Association for the study of Liver diseases, American College of Gastroenterology, and the American Gastroenterological Association.Gastroenterology. 2012; 142: 1592-1609Abstract Full Text Full Text PDF PubMed Scopus (235) Google ScholarThe prevalence of NAFLD has been gradually increasing and one third adult Americans have NAFLD.2Browning J.D. Szczepaniak L.S. Dobbins R. et al.Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity.Hepatology. 2004; 40: 1387-1395Crossref PubMed Scopus (1501) Google Scholar The prevalence in obese population may be as high 57.55–74%.3Bellentani S. Saccoccio G. Masutt F. et al.Prevalence of and risk factors for hepatic steatosis in Northern Italy.Ann Intern Med. 2000; 132: 112-117Crossref PubMed Google Scholar, 4Luyckx F.H. Desaive C. Thiry A. et al.Liver abnormalities in severely obese subjects. Effect of drastic weight loss after gastroplasty.Int J Obes. 1998; 22: 222-226Crossref PubMed Google Scholar The global spread of this epidemic is evidenced by the presence NAFL in 36.8% of Mediterranean, 21.5% of Iranians and 27% of urban Chinese adults.5Chiloiro M. Caruso M.G. Cisternino A.M. et al.Ultrasound evaluation and correlates of fatty liver disease: a population study in a Mediterranean area.Metab Syndr Relat Disord. 2013; 11: 349-358Crossref PubMed Google Scholar, 6Fan J.G. Epidemiology of alcoholic and non-alcoholic fatty liver disease in china.J Gastroenterol Hepatol. 2013; 28: 11-17Crossref PubMed Scopus (22) Google Scholar, 7Lankarani K.B. Ghaffarpasand F. Mahmoodi M. et al.Non alcoholic fatty liver disease in Southern Iran: a population based study.Hepat Mon. 2013; 13: e9248Crossref PubMed Google Scholar However, the prevalence varies between countries and continents. The prevalence in Europe is 20–30% while that in Japan varies between 9 and 30%8Eguchi Y. Hyogo H. Ono M. et al.Prevalence and associated metabolic factors of nonalcoholic fatty liver disease in the general population from 2009 to 2010 in Japan: a muticentre large retrospective study.J Gastroenterol. 2012; 47: 586-595Crossref PubMed Scopus (56) Google Scholar, 9Loomba R. Abraham M. Unalp A. et al.Association between diabetes, family history of diabetes and risk factors of nonalcoholic steatohepatitis and fibrosis.Hepatology. 2012; 56: 943-951Crossref PubMed Scopus (50) Google Scholar and in China between 5 and 24%.10Farrell G.C. Wong V.W. Chitturi S. NAFLD in Asia – as common and important as in West.Nat Rev Gastroenterol Hepatol. 2013; 10: 307-318Crossref PubMed Scopus (38) Google Scholar In India, the prevalence of NAFLD in urban population is 16%–32% while that in rural areas is approximately 9%.11Das K. Das K. Mukherjee P.S. et al.Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease.Hepatology. 2010; 51: 1593-1602Crossref PubMed Scopus (88) Google Scholar, 12Amarapurkar D. Kamani P. Patel N. et al.Prevalence of non-alcoholic fatty liver disease: population based study.Ann Hepatol. 2007; 6: 161-163PubMed Google Scholar, 13Singh S.P. Nayak S. Swain M. et al.Prevalence of nonalcoholic fatty liver disease in costal eastern India: a preliminary ultrasonographic survey.Trop Gastroenterol. 2004; 25: 76-79PubMed Google Scholar Among the Asian countries the lowest prevalence is observed in Singapore at 5%.10Farrell G.C. Wong V.W. Chitturi S. NAFLD in Asia – as common and important as in West.Nat Rev Gastroenterol Hepatol. 2013; 10: 307-318Crossref PubMed Scopus (38) Google Scholar Globally NAFLD has been related to obesity and sedentary lifestyle. Interestingly both NAFL and NASH have been observed in non-obese subjects in Asians, which is referred to as the Asian paradox.11Das K. Das K. Mukherjee P.S. et al.Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease.Hepatology. 2010; 51: 1593-1602Crossref PubMed Scopus (88) Google Scholar, 14Fan J.G. Li F. Cai X.B. Peng Y.D. Ao Q.H. Gao Y. Effects of nonalcoholic fatty liver disease on development of metabolic disorders.J Gastroenterol Hepatol. 2007; 22: 1086-1091Crossref PubMed Scopus (97) Google Scholar, 15Petersen K.F. Dufour S. Feng J. et al.Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian men.Proc Natl Acad Sci U S A. 2006; 103: 18273-18277Crossref PubMed Scopus (143) Google Scholar Mere presence of fat in the hepatocytes is not considered as a disease. As most of the subjects with NAFL do not progress to NASH, differentiation between these two conditions is paramount. Though liver histology is the gold standard in diagnosis of NAFL, the commonest method used is transabdominal ultrasonography which has a sensitivity of 100% and specificity of 90% when fat on liver biopsy exceeds 20%.16Dasarathy S. Dasarathy J. Khiyami A. Joseph R. Lopez R. Mc Cullough A.J. Validity of realtime ultrasound in the diagnosis of hepatic steatosis: a prospective study.J Hepatol. 2009; 51: 1061-1067Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar Other non-invasive modalities used to diagnose NAFL includes transient elastography (Fibroscan) and Acoustic Resonance Magnetic Imaging (ARFI) which measures liver stiffness and corresponds to presence of fibrosis. Magnetic resonance spectroscopy is a quantitative method of measuring liver fat but is limited in clinical use due to lack of widespread availability and cost.17Sczepaniak L.S. Nurenberg P. Leonard D.S. et al.Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in general population.Am J Physiol Endocrinol Metab. 2005; 288: E462-E468Crossref PubMed Scopus (615) Google Scholar However, none of these available noninvasive tests can distinguish simple steatosis from NASH. Although raised aspartate aminotransferase and alanine aminotransferase levels are considered by some as a marker of NASH, yet these enzymes may be normal in many subjects with biopsy proven NASH.18Mofrad P. Contos M.J. Haque M. et al.Clinical and histological spectrum of non-alcoholic fatty liver disease associated with normal ALT values.Hepatology. 2003; 37: 1286-1292Crossref PubMed Scopus (519) Google Scholar A recent study using non-invasive tools have found 81% probability of differentiating NAFL from NASH using Bayesian approach combining clinical, laboratory, and imaging data.19Yilmaz Y. Eren F. A Bayesian approach to an integrated multimodal noninvasive diagnosis of definitive nonalcoholic steatohepatitis in the spectrum of nonalcoholic fatty liver disease.Eur J Gastroenterol Hepatol. 2014; 26: 1292-1295Crossref PubMed Google Scholar Based on the modality used to diagnose NAFL, the detection of disease varies. Ultrasound based study from India has shown the prevalence of NAFLD to be 16.6%12Amarapurkar D. Kamani P. Patel N. et al.Prevalence of non-alcoholic fatty liver disease: population based study.Ann Hepatol. 2007; 6: 161-163PubMed Google Scholar while in a study based on liver biopsy the presence of NASH was 53%.20Duseja A. Das A. Das R. et al.The clinicopathological profile of Indian patients with nonalcoholic fatty liver disease (NAFLD) is different from that in the West.Dig Dis Sci. 2007; 52: 2368-2374Crossref PubMed Scopus (35) Google Scholar In another study from costal eastern India, one fourth of patients had evidence of NASH on liver biopsy on presentation.21Singh S.P. Kar S.K. Panigrahi M.K. et al.Profile of patients with incidentally detected nonalcoholic fatty liver disease (IDNAFLD) in costal eastern India.Trop Gastroenterol. 2013; 34: 144-152Crossref PubMed Google Scholar In another Asian study involving 52 patients, biopsy proven NASH at presentation was found in 32.6% patients while 23% patients with baseline NAFL progressed to NASH.22Wong V.W. Wong G.L. Choi P.C. et al.Disease progression of nonalcoholic fatty liver disease: a prospective study with paired liver biopsy at 3 years.Gut. 2010; 59: 969-974Crossref PubMed Scopus (134) Google Scholar In contrast, a recent study from the West with mean 6.6 years follow up, baseline NASH was found in 75% patients with disease progression from NAFL to NASH in 44% patients. Among those patients with simple steatosis fibrosis progression was observed in follow up liver biopsy which was statistically more in diabetic steatosis thereby suggesting that simple steatosis can progress to clinically significant fibrosis.23Mc Pherson S. Hardy T. Henderson E. Burt A.D. Day C.P. Anstee Q.M. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implication for prognosis and clinical management.J Hepatol. 2014; 29 (S0168–8278(14)00883-6)Google Scholar Similar data from west suggests that among those with NASH only 21–26% progress to cirrhosis over 8.2 years.24Matteoni C.A. Younossi Z.M. Gramlich T. Boparai N. Liu Y.C. McCullough A.J. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity.Gastroenterology. 1999; 116: 1413-1419Abstract Full Text Full Text PDF PubMed Scopus (1818) Google Scholar Meta-analysis have demonstrated that NAFLD increases the risk of all-cause mortality.25Musso G. Gambino R. Cassader M. Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease and diagnostic accuracy of non-invasive tests for liver disease severity.Ann Med. 2011; 43: 617-649Crossref PubMed Scopus (222) Google Scholar Therefore, aggressive management in the form of dietary and lifestyle modification is required in patients who has NASH when compared to those who have simple steatosis. The riddle of progression from NAFL to NASH and subsequently to cirrhosis is poorly understood. In this review, we present new insights into progression of NAFL to NASH, integrating the role of genes, diet, immunological profile, cytokines, liver cell types, and gut microbiota.Journey from nonalcoholic fatty liver disease to nonalcoholic steatohepatitisThe spectrum of NAFLD ranges from simple steatosis to NASH. The accumulation of fat above the physiological level ( G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated with hepatocellular carcinoma.J Hepatol. 2014; 61: 75-81Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar On the other side of the spectrum PNPLA3 S453 polymorphism is associated with lower hepatic fat content in African Americans, making them the group at lowest risk of NAFLD. This protective effect is independent of the presence of PNPLA3—I148M polymorphism.37Stefano R. Julia K. Chao X. et al.Genetic variation in PNPLA3 confers susceptibility to non-alcoholic fatty liver disease.Nat Genet. 2008; 40: 1461-1465Crossref PubMed Scopus (614) Google ScholarOther GWA studies identified common genetic variants in or near LYPLAL1, PPP1R3B, NCAN and GCKR that are associated with steatosis apart from NASH, fibrosis and metabolic traits in patients with European ancestry.30Speliotes E.K. Yerges-Armstrong L.M. Wu J. et al.Genome- wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits.PLoS Genet. 2011; 7: e1001324Crossref PubMed Scopus (181) Google Scholar Importantly, the rs780094 SNP was associated with a higher risk of type2 diabetes, higher levels of triglycerides, reduced fasting plasma glucose levels and lower Homoestatic model assessment–insulin resistance (HOMA-IR) in Japanese population. Furthermore, it was hypothesized that the effect of the SNP on diabetes is probably mediated through impaired beta cell function rather than through obesity.38Onuma H. Tabara Y. Kawamoto R. et al.The GCKR rs780094 polymorphism is associated with susceptibility of type 2 diabetes, reduced fasting plasma glucose levels, increased triglycerides levels and lower HOMA-IR in Japanese population.J Hum Genet. 2010; 55: 600-604Crossref PubMed Scopus (21) Google Scholar Likewise another study in Japanese identified SAMM50, PARVB and PNPLA3 as risk loci associated with NAFLD. A GWA study in Caucasians identified FDFT1, COL13A1, EFCAB4B, PZP as causative loci for steatosis, NAFLD activity score, degree of fibrosis, lobular inflammation and serum levels of alanine amino transferase (ALT). A pooled genetic study that identified SNPs from the above GWA studies and genotyped the same in Indian NAFLD patients identified PNPLA3, SAMM50, PARVB and PZP as risk loci for NAFLD apart from association of variants in NCAN and PZP being associated with higher levels of ALT.39Kanth V.V. Sasikala M. Rao P.N. et al.Pooled genetic analysis in ultrasound measured non-alcoholic fatty liver disease in Indian subjects: a pilot study.World J Hepatol. 2014; 6: 435-442Crossref PubMed Google Scholar Individual hypothesis or candidate gene approach based studies have identified various loci that are either protective, or confer susceptibility to NAFLD, steatosis or faster progression. It was shown that the SCAP rs2101247 “A” allele might decrease the risk of NAFLD especially in females with metabolic syndrome, however the reasons and mechanisms are unclear.40Sun S. Wang M. Song H. et al.SCAP gene polymorphisms decrease the risk of nonalcoholic fatty liver disease in females with metabolic syndrome.J Genet. 2013; 92: 565-570Crossref PubMed Google Scholar SNPs namely rs2276736, rs3772630 and rs3772627 appear to be protective especially in the Indians against NAFLD.41Zain S.M. Mohamed Z. Mahadeva S. et al.Susceptibility and gene interaction study of the angiotensin II type 1 receptor (AGTR1) gene polymorphisms with non-alcoholic fatty liver disease in a multi-ethnic population.PLoS One. 2013; 8: e58538Crossref PubMed Scopus (6) Google Scholar A Val277Ala substitution in the PPAR-α (peroxisome proliferator activated receptor alpha) was associated with NAFLD. However it was associated with decreased waist circumference and waist-to-hip ratio suggesting a protective role in obesity.42Chen S. Li Y. Li S. Yu C.A. Val227Ala substitution in the peroxisome proliferator activated receptor alpha (PPAR alpha) gene associated with non-alcoholic fatty liver disease and decreased waist circumference and waist-to-hip ratio.J Gastroenterol Hepatol. 2008; 23: 1415-1418Crossref PubMed Scopus (30) Google Scholar In contrast, variants in uncoupling protein 3 gene (UCP3),43Xu Y.P. Liang L. Wang C.L. et al.Association between UCP3 gene polymorphisms and nonalcoholic fatty liver disease in Chinese children.World J Gastroenterol. 2013; 19: 5897-5903Crossref PubMed Scopus (2) Google Scholar Sterol Regulatory Element-Binding Protein 1C gene (SREBP-1C),44Musso G. Bo S. Cassader M. DeMichieli F. Gambino R. Impact of sterol regulatory element-binding factor-1c polymorphism on incidence of nonalcoholic fatty liver disease and on the severity of liver disease and of glucose and lipid dysmetabolism.Am J Clin Nutr. 2013; 98: 895-906Crossref PubMed Scopus (8) Google Scholar Adaptor protein (APPL1 and 2),45Barbieri M. Esposito A. Angellotti E. Rizzo M.R. Marfella R. Paolisso G. Association of genetic variation in adaptor protein APPL1/APPL2 loci with non-alcoholic fatty liver disease.PLoS One. 2013; 8: e71391Crossref PubMed Google Scholar Nicotinamide N-methyltransferase gene (NNMT)46Sazci A. Ozel M.D. Ergul E. Aygun C. Association of nicotinamide-N-methyltransferase gene rs694539 variant with patients with nonalcoholic steatohepatitis.Genet Test Mol Biomarkers. 2013; 17: 849-853Crossref PubMed Scopus (4) Google Scholar and mitochondrial superoxide dismutase 2 gene (SOD2)47Namikawa C. Shu-Ping Z. Vyselaar J.R. et al.Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non-alcoholic steatohepatitis.J Hepatol. 2004; 40: 781-786Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar conferred susceptibility.Another gene which has been linked to NAFLD is apolipoprotein 3 (APOC3) gene. Carriers of APOC3 variant alleles (c-482T, T-455C or both) in non-Asian population had increased NAFLD and insulin resistance.48Peterson K.F. Dufour S. Hariri A. et al.Apolipoprotein C3 gene variants in non-alcoholic fatty liver disease.N Eng J Med. 2010; 362: 1082-1089Crossref PubMed Scopus (171) Google Scholar Further studies in Asian Indians has shown varied results. Polymorphism T-455C in APOC3 gene has been associated with NAFLD and higher serum triglyceride levels in Southern Indian population.49Puppala J, Bhrugumalla S, Kumar A, et al Apolipoprotein C3 gene polymorphism in Southern Indian patients with nonalcoholic fatty liver disease. Indian J Gastroenterol [epub] 2014.Oct 17Google Scholar Another study in the same region of India, on the other hand, found that PNPLA3 rs738409 polymorphism to be associated with NAFLD but failed to show any independent association of APOC C3 gene rs2854116 and rs2854117 polymorphism with NAFLD.50Ravikanth V.V. Sasikala M. Urmila S.A. PNPLA3 gene polymorphism but not APOC3 enhances risk for nonalcoholic fatty liver disease in Indian subjects.J Clin Exp Hepatol. 2013; 3: S24Abstract Full Text Full Text PDF PubMed Google ScholarEnvironmental influences on the genotype and the effect they have on the phenotype have been studied to a certain extent in the context of NAFLD. Since identifying disease susceptibility alone would not necessarily aid in disease outcomes, understanding the environmental interactions with the genotype will help in managing the disease in a better way. Recent studies have identified the effect of n3 and n6 poly unsaturated fatty acids (PUFAs) on the genotype. It was seen that there was significantly higher fatty infiltration in individuals who consumed more of n6 versus n3 PUFAs and with GG genotype in the PNPLA3 gene.51Santoro N. Savoye M. Kim G. et al.Hepatic fat accumulation is modulated by the interaction between the rs738409 variant in the PNPLA3 gene and the dietary omega6/omega3 PUFA intake.PLoS One. 2012; 7: e37827Crossref PubMed Scopus (19) Google Scholar Similarly another study which included subjects with both GG and CC genotype, showed that. Individuals in both groups lost 3.1 kg weight on an average. However, individuals in the GG genotype group lost 45% as against only 18% of liver fat in the CC genotype group, suggesting that individuals with the GG genotype may have a better advantage with weight loss and fatty infiltration.52Sevastianova K. Kotronen A. Gastaldelli A. et al.Genetic variation in PNPLA3 (adiponutrin) confers sensitivity to weight loss-induced decrease in liver fat in humans.Am J Clin Nutr. 2011; 94: 104-111Crossref PubMed Scopus (24) Google Scholar In another significant study it was seen that the G allele of the rs738409 in the PNPLA3 gene was associated with both alcoholic and non-alcoholic fatty liver disease, so it is prudent for an individual with the GG genotype to avoid alcohol for an overall better health of the liver.53Stickel F. Buch S. Lau K. et al.Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in Caucasians.Hepatology. 2011; 53: 86-95Crossref PubMed Scopus (100) Google ScholarThe role of hepatic iron in progression of NAFL to NASH is unclear. Dysregulation of iron regulatory molecules or genetic factors may be responsible for iron overload in NAFLD patients. The C282Y mutation (HFE gene) which is common in Europeans are not found in Indian population. However, H63D heterozygosity was found in 16.9% of Asian Indians with NASH when compared to only 12% in controls, suggesting that primary iron overload in Indians is non HFE type.54Dhillon B.K. Das R. Garewal G. et al.Frequency of primary iron overload and HFE gene mutations (C282Y, H63D and S65C0 in chronic liver disease patients in North India.World J Gastroenterol. 2007; 13: 2956-2959PubMed Google Scholar Although genetic susceptibility has been identified for NAFLD, further research should focus on gene–gene and gene–nutrient interactions employing advanced genomic techniques.Obesity, insulin resistance and dietary factors in nonalcoholic fatty liver diseaseLipids and LipotoxicityThe composition of food intake plays an important role in NAFL. Not all lipids are equally harmful. Polyunsaturated fatty acids (PUFAs) are of two type (i) n-6 PUFAs which includes linoleic acid and arachadonic acid and (ii) n-3 PUFAs which includes alpha-linoleic acid, eicosapentanoic acid and docosahxanoic acid. The n-6 PUFAs have the capability of producing proinflammatory eicosanoids55Das U.N. Biological significance of essential fatty acids.J Assoc Physicians India. 2006 Apr; 54: 309-319PubMed Google Scholar and are harmful while the n-3 PUFAs have anti-inflammatory properties leading to decreased lipogenesis and lower hepatic steatosis.56Seki H. Tani Y. Arita M. Omega-3 PUFA derived anti-inflammatory lipid mediator resolving E1.Prostaglandins Other Lipid Mediat. 2009; 89: 126-130Crossref PubMed Scopus (33) Google Scholar, 57Dentin R. Benhamed F. Pégorier J.P. et al.Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through inhibition of ChREBP nuclear protein translocation.J Clin Invest. 2005; 15: 2843-2854Crossref Scopus (126) Google Scholar Studies have shown that a high ratio of n6:n3 PUFA in hepatocytes and circulation is associated with severity of NAFLD.58Araya J. Rodrigo R. Videla L.A. et al.Increase in long chain polyunsaturated fatty acid n6/n3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease.Clin Sci (Lond). 2004; 106: 635-643Crossref PubMed Scopus (240) Google Scholar Based on this, a meta-analysis showed n-3 supplementation may decrease hepatic fat, though herterogenicity of the study population warrants the need of well-designed randomized control trials.59Parker H.M. Johnson N.A. Burdon C.A. Cohn J.S. O'Connor H.T. George J. Omega 3 supplementation and non alcoholic fatty liver disease: a systemic review and meta-analysis.J Hepatol. 2012; 56: 944-951Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar Reducing n-6 intake i
Referência(s)