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• W2979173681 abstract "The risk of incident extrahepatic cancers is higher in non-alcoholic fatty liver disease than obesity – A longitudinal cohort studyJournal of HepatologyVol. 71Issue 6PreviewCancer is a major cause of death in the United States and worldwide.1,2 Numerous meta-analyses support the link between the risk of malignancy and excess body weight.3–5 Some associations are flawed because of bias that exaggerates the effect of obesity on cancer incidence, but strong evidence supports this association with 11 cancers, predominantly among digestive organs and hormone-related malignancies in women.4 Full-Text PDF The association between obesity and cancer risk has been extensively characterized. In a prospective study of more than 900,000 adults free of cancer at enrollment and observed during a 16-year follow-up, Calle et al. were able to calculate the risk of mortality for cancer at different sites in relation to body mass index (BMI), as well as the proportion of all deaths from cancer attributable to overweight and obesity.[1]Calle E.E. Rodriguez C. Walker-Thurmond K. Thun M.J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults.N Engl J Med. 2003; 348: 1625-1638Crossref PubMed Scopus (5938) Google Scholar In both men and women, a high BMI increased the risk of cancer, and for several cancers the risk appeared to increase in a BMI-dependent manner. The authors concluded that overweight and obesity in the adult US population could account for 14% of all cancer deaths in men and 20% of those in women. Notably, cancer at liver site was recorded as one of the sites at higher risk, particularly in men. These data were confirmed by analysis of cancer incidence rates in 221 databases, including nearly 300,000 cases of cancer at different sites, with obesity accounting for a variable population attributable fraction of all cancers.[2]Renehan A.G. Tyson M. Egger M. Heller R.F. Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies.Lancet. 2008; 371: 569-578Abstract Full Text Full Text PDF PubMed Scopus (3701) Google Scholar But “not all fat is alike”;[3]Arner P. Not all fat is alike.Lancet. 1998; 351: 1301-1302Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar we now know that a) visceral fat carries a much higher risk of cardiovascular and metabolic complications compared with total body fat, mediated by inflammatory adipokines, and b) BMI is an inaccurate measure of central obesity, as different ethnicities experience central obesity at a lower BMI than Caucasians. More limited data are available on the risk of cancer based on anthropometric parameters of visceral adiposity. Zhang et al.,[4]Zhang C. Rexrode K.M. van Dam R.M. Li T.Y. Hu F.B. Abdominal obesity and the risk of all-cause, cardiovascular, and cancer mortality: sixteen years of follow-up in US women.Circulation. 2008; 117: 1658-1667Crossref PubMed Scopus (597) Google Scholar in a prospective cohort of the Nurses Health study, showed that the risks of overall mortality, cardiovascular disease-related mortality and cancer-related mortality were all increased in relation to both BMI and waist circumference, but the risks associated with quintiles of waist circumference remained statistically significant after adjustment for BMI (1.00, 1.18, 1.20, 1.34, and 1.63; 95% CI 1.32–2.01; p for trend <0.001). In a systematic review of the association of anthropometric markers of visceral adiposity with malignancy,[5]De Ridder J. Julian-Almarcegui C. Mullee A. Rinaldi S. Van Herck K. Vicente-Rodriguez G. et al.Comparison of anthropometric measurements of adiposity in relation to cancer risk: a systematic review of prospective studies.Cancer Causes Control. 2016; 27: 291-300Crossref PubMed Scopus (21) Google Scholar abdominal adiposity was identified as a stronger predictor than whole body adiposity for cancer at gastro-esophageal and colorectal sites, with differences between gender. Abdominal adiposity was also a stronger predictor of liver cancer, as well as breast and endometrial cancers in post-menopausal women. In the presence of visceral obesity, fatty liver is nearly the rule – the products of the visceral fat are drained by the portal vein into the liver – contributing to alterations in lipid and glucose homeostasis and to diabetes development, fulfilling the criteria that link non-alcoholic fatty liver disease (NAFLD) to the metabolic syndrome. Therefore, it is no surprise that fatty liver is also associated with the risk of extrahepatic malignancy. In an adult Korean population with steatosis diagnosed by ultrasonography, the risk of colorectal cancer in males and breast cancer in females was approximately doubled, with some relation with advanced NAFLD progression.[6]Kim G.A. Lee H.C. Choe J. Kim M.J. Lee M.J. Chang H.S. et al.Association between non-alcoholic fatty liver disease and cancer incidence rate.J Hepatol. 2018; 68: 140-146Abstract Full Text Full Text PDF Scopus (144) Google Scholar In the present issue of Journal of Hepatology, Allen et al.[7]Allen A.M. Hicks S.B. Mara K.C. Larson J.J. Therneau T.M. The risk of incident extrahepatic cancers is higher in nonalcoholic fatty liver disease than obesity – a longitudinal cohort study.J Hepatol. 2019; 71: 1229-1236Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar move one step further and propose that liver fat is primarily involved in the association between obesity and incident hepatic and extrahepatic cancer. Inside the medical record linkage system of the Olmsted County, they identified all individuals with NAFLD on the basis of Mayo Clinic-specific and internationally-validated ICD codes, observed in the period 1997–2016. This cohort was compared with those living in the same area who did not have a NAFLD diagnosis, individually matched by age and sex; both cohorts were followed until death, last visit, or June 2018 for incident cancer diagnosis. Cancers of interest were grouped as gastrointestinal, hormone-sensitive and lung cancers (total, 656 in NAFLD and 1,568 in controls). After adjustment for possible confounders (follow-up of less than 1 year, immortal time bias) and covariates, NAFLD diagnosis conferred a 90% higher risk of overall malignancy (incidence rate ratio [IRR] 1.9, 95% CI 1.3–2.7), with the expected highest excess for liver cancers (IRR 2.8; 95% CI, 1.6–5.1), followed by uterine cancers and gastrointestinal cancers, with gender-specific differences. In the whole setting, obesity was only associated with a trend towards significant malignancy risk (IRR 1.2; 95% CI 0.9–1.6), whereas the risk associated with NAFLD was highly significant (IRR 2.0; 95% CI 1.5–2.9), with no independent effect of obesity. Of note, the risk associated with NAFLD was also present when compared with obese controls, whereas obesity alone, in the absence of NAFLD, did not increase the risk in comparison to non-obese controls (IRR 1.0; 95% CI 0.4–1.4). How can we explain these intriguing results? The authors themselves are very careful in defining the results as evidence that NAFLD is directly responsible for cancer risk, and indicate that liver fat may be a possible mediator on the causal pathway linking fat accumulation to cancer. The metabolic effects of visceral and hepatic fat are well established, and include high insulin levels, insulin resistance and a different response in terms of lipolysis and lipogenesis compared with total body fat (Fig. 1). Visceral fat is directly involved in the development of cardiovascular risk and extensively associated with the metabolic syndrome, whereas liver fat represents a good example of fatty acid spillover out of the adipose tissue, originally described by Unger as lipotoxicity and implicated in the pathogenesis of diabetes.[8]Unger R.H. Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genet clinical implications.Diabetes. 1995; 44: 863-870Crossref PubMed Google Scholar Some differences have been described between liver fat and visceral adipose tissue in studies carried out by tracer techniques,[9]Gastaldelli A. Cusi K. Pettiti M. Hardies J. Miyazaki Y. Berria R. et al.Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects.Gastroenterology. 2007; 133: 496-506Abstract Full Text Full Text PDF PubMed Scopus (435) Google Scholar and the presence of diabetes might be a confounder. Whereas high insulin levels are likely to exert a proliferative action via MAP-kinase stimulation in the presence of both liver and visceral fat, the role of insulin-like growth factor 1 (IGF-1) deserves attention. IGF-1 is produced in the liver and specific changes in individuals with established liver disease are possible. The adipose tissue microenvironment undergoes important changes during fat accumulation, and these changes might promote cancer initiation and progression in target organs.[10]Quail D.F. Dannenberg A.J. The obese adipose tissue microenvironment in cancer development and progression.Nat Rev Endocrinol. 2019; 15: 139-154Crossref PubMed Scopus (241) Google Scholar It was hypothesized that the major tumor-promoting mechanism associated with obesity, could be the indolent inflammation that takes place at particular organ sites, including the liver, pancreas, and gastrointestinal tract,[11]Font-Burgada J. Sun B. Karin M. Obesity and cancer: the oil that feeds the flame.Cell Metab. 2016; 23: 48-62Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar where pro-inflammatory M1 macrophages become more abundant, producing multiple pro-inflammatory cytokines.[12]McNelis J.C. Olefsky J.M. Macrophages, immunity, and metabolic disease.Immunity. 2014; 41: 36-48Abstract Full Text Full Text PDF PubMed Scopus (524) Google Scholar Diabetes might be an additional factor associated with cancer development; the presence of fatty liver has been reported to increase the risk of incident type 2 diabetes, after adjustment for obesity,[13]Sung K.C. Wild S.H. Kwag H.J. Byrne C.D. Fatty liver, insulin resistance, and features of metabolic syndrome: relationships with coronary artery calcium in 10,153 people.Diabetes Care. 2012; 35: 2359-2364Crossref PubMed Scopus (107) Google Scholar and in the same Korean population the resolution of NAFLD in a 5-year follow-up prevented the development of type 2 diabetes.[14]Sung K.C. Wild S.H. Byrne C.D. Resolution of fatty liver and risk of incident diabetes.J Clin Endocrinol Metab. 2013; 98: 3637-3643Crossref PubMed Scopus (109) Google Scholar The possibility that the association of diabetes with cancer (namely, colorectal cancer) might be mediated by IGF-1 has long been postulated; a very recent study explored the effects of genetic variants in the IGF pathway on the risk of colorectal cancer in individuals with diabetes and concluded that unfavorable alleles might be involved.[15]de Kort S. Simons C.C.J.M. van den Brandt P.A. Janssen-Heijnen M.L.G. Sanduleanu S. Masclee A.A.M. et al.Diabetes mellitus, genetic variants in the insulin-like growth factor pathway and colorectal cancer risk.Int J Cancer. 2019; 145: 1774-1781Crossref PubMed Scopus (17) Google Scholar Modulation of IGF might open a totally new area of pharmacologic intervention for cancer prevention. The IGF pathway is effectively modulated by dietary restriction;[16]Lashinger L.M. Malone L.M. McArthur M.J. Goldberg J.A. Daniels E.A. Pavone A. et al.Genetic reduction of insulin-like growth factor-1 mimics the anticancer effects of calorie restriction on cyclooxygenase-2-driven pancreatic neoplasia.Cancer Prev Res (Phila). 2011; 4: 1030-1040Crossref PubMed Scopus (47) Google Scholar weight gain in adulthood is associated with a remarkable increase in the risk of incident adiposity-associated cancers,[17]Keum N. Greenwood D.C. Lee D.H. Kim R. Aune D. Ju W. et al.Adult weight gain and adiposity-related cancers: a dose-response meta-analysis of prospective observational studies.J Natl Cancer Inst. 2015; 107: djv088Crossref PubMed Scopus (185) Google Scholar whereas intentional weight loss results in decreased cancer incidence, particularly in female obesity-related cancers fuelled by liver fat.[18]Birks S. Peeters A. Backholer K. O'Brien P. Brown W. A systematic review of the impact of weight loss on cancer incidence and mortality.Obes Rev. 2012; 13: 868-891Crossref PubMed Scopus (64) Google Scholar Finally, bariatric (metabolic) surgery effectively reduces liver fat and promotes regression of non-alcoholic steatohepatitis ;[19]Lassailly G. Caiazzo R. Buob D. Pigeyre M. Verkindt H. Labreuche J. et al.Bariatric surgery reduces features of nonalcoholic steatohepatitis in morbidly obese patients.Gastroenterology. 2015; 149 (quiz e315-376): 379-388Abstract Full Text Full Text PDF PubMed Scopus (485) Google Scholar accordingly, the large Swedish Obese Subjects study confirmed a reduction of incident cancers in the intervention arm, again in the female obesity-related cancers.[20]Sjostrom L. Gummesson A. Sjostrom C.D. Narbro K. Peltonen M. Wedel H. et al.Effects of bariatric surgery on cancer incidence in obese patients in Sweden (Swedish Obese Subjects Study): a prospective, controlled intervention trial.Lancet Oncol. 2009; 10: 653-662Abstract Full Text Full Text PDF PubMed Scopus (551) Google Scholar Similarly, in a group of overweight post-menopausal women, loss of fat at different body locations was associated with changes in variable biomarkers, related to the risk of breast cancer.[21]van Gemert W.A. Monninkhof E.M. May A.M. Elias S.G. van der Palen J. Veldhuis W. et al.Association between changes in fat distribution and biomarkers for breast cancer.Endocr Relat Cancer. 2017; 24: 297-305Crossref PubMed Scopus (16) Google Scholar In conclusion, the study is definitely provocative and, as usual, it raises many more questions than it answers. Not all data may be explained on the basis of evidence from the literature – as an example, the association of liver fat with cancer incidence appears to be independent of coexisting diabetes – but it opens a clinically relevant area of research. The authors extensively discuss the limits of their investigation and the possible pitfalls – the effect of liver fat on cancer risk might even be underestimated considering that controls might have undiagnosed NAFLD. These results definitely need extensive external validation. The most plausible explanation for Allen et al.’s findings is that the presence of NAFLD works as a reliable marker of predominantly visceral obesity, that associates with indolent inflammation and related pro-carcinogenic hormones, thus increasing the risk of cancer. If confirmed by studies evaluating the predominance of visceral or sub-cutaneous fat, these results will have consequences for the identification of patients at the highest risk of obesity-promoted malignancy. The authors declare no conflicts of interest in relation to this work. Please refer to the accompanying ICMJE disclosure forms for further details. The following are the Supplementary data to this article: Download .pdf (.24 MB) Help with pdf files Supplementary Data 1" @default.
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• W2979173681 title "Adipose tissue-associated cancer risk: Is it the fat around the liver, or the fat inside the liver?" @default.
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