The Weight of Risk: Exploring the Link Between Obesity and Liver Cancer
Main Article Content
Abstract
Obesity is a chronic, preventable condition, and has a significant public health concern. Its implications extend beyond metabolic syndrome, casting a shadow over the development and prognosis of various cancers, with a particularly strong tie to hepatocellular carcinoma (HCC) among all cancer types. Non-Alcoholic Fatty Liver Disease (NAFLD) is now a leading cause of liver cancer, along with the treatment of hepatitis B and C. Liver cancer is the fourth most common cause of cancer related deaths worldwide, with obesity, exacerbating the risk especially two times higher in Body Mass Index (BMI) above 30 and four times higher in BMI above 35. Visceral adiposity, measured by waist circumference, is considered more important risk factor than general adiposity. Several mechanisms have been proposed to explain the pathophysiology of how obesity can trigger HCC, but the precise mechanisms that control the progression from steatosis to steatohepatitis and tumor initiation remain unclear. Hepatocellular cancer may occur in patients with NAFLD without cirrhosis. The diagnosis of HCC in NAFLD can be challenging due to an increase in poor-quality ultrasound in obese individuals, which necessitates a more accurate and cost-effective surveillance strategy for early detection. The delay in diagnosis, older age, and the presence of relevant comorbidities limit the possibility of therapeutic intervention. Weight management through lifestyle changes and surgical interventions like bariatric surgery offers promise in mitigating both metabolic syndrome and the risk of HCC. Diagnosis hinges on advanced imaging techniques like multiphase Magnetic Resonance Imaging or Computed Tomography scan using specific criteria. Treatment modalities for HCC are multifaceted, depends upon tumor characteristics, metastasis, cirrhosis, and overall liver function. However, despite advancements, there remains a pressing need for more efficacious interventions to combat obesity and curb the trajectory of HCC, given its persistently high mortality rate. Surveillance protocols for HCC in cirrhotic patients entail regular abdominal ultrasounds with or without Alpha Fetoprotein testing at six-month intervals. However, there is a need for cost effective surveillance strategies for HCC in non-cirrhotic NAFLD.
Keywords:
Obesity, Liver Cancer, Hepatocellular Carcinoma, Carcinoma, HCC, NAFLD, NASH, Lean NASH, Cirrhosis, HCC surveillance, Risk, Prognosis, Mortality
Article Details
How to Cite
GURALA, Dhineshreddy; NISHAL, Ravindran; PHILIPOSE, Jobin.
The Weight of Risk: Exploring the Link Between Obesity and Liver Cancer.
Medical Research Archives, [S.l.], v. 12, n. 8, aug. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5568>. Date accessed: 06 sep. 2024.
doi: https://doi.org/10.18103/mra.v12i8.5568.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Haslam DW, James WP. Obesity. Lancet. 2005;366(9492):1197-1209. doi:10.1016/S0140-6736(05)67483-
2. Nimptsch K, Pischon T. Body fatness, related biomarkers and cancer risk: an epidemiological perspective. Horm Mol Biol Clin Investig. 2015;22(2):39-51. doi:10.1515/hmbci-2014-0043
3. Seyfried TN, Flores RE, Poff AM, D'Agostino DP. Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis. 2014;35(3):515-527. doi:10.1093/carcin/bgt480
4. Coller HA. Is cancer a metabolic disease?. Am J Pathol. 2014;184(1):4-17. doi:10.1016/j.ajpath.2013.07.035
5. Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33(7):1674-1685. doi:10.2337/dc10-0666
6. Wiseman M. The second World Cancer Research Fund/American Institute for Cancer Research expert report. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Proc Nutr Soc. 2008;67(3):253-256. doi:10.1017/S002966510800712X
7. World Cancer Research Fund International/American Institute for Cancer Research (2015) Continuous update project report: diet, nutrition, physical activity and liver cancer. https://www.wcrf.org/wp-content/uploads/2021/02/liver-cancer-report.pdf
8. World Cancer Research Fund International/American Institute for Cancer Research (2014) Continuous update project report: diet, nutrition, physical activity and ovarian cancer. https://www.wcrf.org/wp-content/uploads/2021/02/ovarian-cancer-report.pdf
9. World Cancer Research Fund International/American Institute for Cancer Research (2015) Continuous update project report: diet, nutrition, physical activity and gallbladder cancer. https://www.wcrf.org/wp-content/uploads/2021/02/gallbladder-cancer-report.pdf
10. World Cancer Research Fund International/American Institute for Cancer Research (2014) Continuous update project report: diet, nutrition, physical activity and prostate cancer. https://www.wcrf.org/wp-content/uploads/2021/02/prostate-cancer-report.pdf
11. World Cancer Research Fund International/American Institute for Cancer Research (2016) Continuous update project report: diet, nutrition, physical activity and stomach cancer. https://www.wcrf.org/wp-content/uploads/2021/02/stomach-cancer-report.pdf
12. Sun B, Karin M. Obesity, inflammation, and liver cancer. J Hepatol. 2012;56(3):704-713. doi:10.1016/j.jhep.2011.09.020
13. Villanueva A. Hepatocellular Carcinoma. N Engl J Med. 2019;380(15):1450-1462. doi:10.1056/NEJMra1713263
14. Zhang C, Liu S, Yang M. Hepatocellular Carcinoma and Obesity, Type 2 Diabetes Mellitus, Cardiovascular Disease: Causing Factors, Molecular Links, and Treatment Options. Front Endocrinol (Lausanne). 2021;12:808526. Published 2021 Dec 23. doi:10.3389/fendo.2021.808526
15. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16(10):589-604. doi:10.1038/s41575-019-0186-y
16. Saitta C, Pollicino T, Raimondo G. Obesity and liver cancer. Ann Hepatol. 2019;18(6):810-815. doi:10.1016/j.aohep.2019.07.004
17. Definition & facts of NAFLD & NASH. National Institute of Diabetes and Digestive and Kidney Diseases website. https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash/definition-facts
18. Jukaku SA, Williams SRP. The cause of obesity is multifactorial but GPs can do more. BMJ. 2021;373:n956. Published 2021 Apr 13. doi:10.1136/bmj.n956
19. Suresh D, Srinivas AN, Kumar DP. Etiology of Hepatocellular Carcinoma: Special Focus on Fatty Liver Disease. Front Oncol. 2020;10:601710. Published 2020 Nov 30. doi:10.3389/fonc.2020.601710
20. Zhu RX, Seto WK, Lai CL, Yuen MF. Epidemiology of Hepatocellular Carcinoma in the Asia-Pacific Region. Gut Liver. 2016;10(3):332-339. doi:10.5009/gnl15257
21. Diehl AM. Hepatic complications of obesity. Gastroenterol Clin North Am. 2010;39(1):57-68. doi:10.1016/j.gtc.2009.12.001
22. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84. doi:10.1002/hep.28431
23. Larsson SC, Wolk A. Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer. 2007;97(7):1005-1008. doi:10.1038/sj.bjc.6603932
24. Moore LL, Bradlee ML, Singer MR, et al. BMI and waist circumference as predictors of lifetime colon cancer risk in Framingham Study adults. Int J Obes Relat Metab Disord. 2004;28(4):559-567. doi:10.1038/sj.ijo.0802606
25. Donohoe CL, O'Farrell NJ, Doyle SL, Reynolds JV. The role of obesity in gastrointestinal cancer: evidence and opinion. Therap Adv Gastroenterol. 2014;7(1):38-50. doi:10.1177/1756283X13501786
26. Wang Y, Jacobs EJ, Patel AV, et al. A prospective study of waist circumference and body mass index in relation to colorectal cancer incidence. Cancer Causes Control. 2008;19(7):783-792. doi:10.1007/s10552-008-9141-x
27. Steffen A, Schulze MB, Pischon T, et al. Anthropometry and esophageal cancer risk in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev. 2009;18(7):2079-2089.
doi:10.1158/1055-9965.EPI-09-0265
28. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371(9612):569-578. doi:10.1016/S0140-6736(08)60269-X
29. Wang Y, Wang B, Shen F, Fan J, Cao H. Body mass index and risk of primary liver cancer: a meta-analysis of prospective studies. Oncologist. 2012;17(11):1461-1468. doi:10.1634/theoncologist.2012-0066
30. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625-1638. doi:10.1056/NEJMoa021423
31. Sohn W, Lee HW, Lee S, et al. Obesity and the risk of primary liver cancer: A systematic review and meta-analysis. Clin Mol Hepatol. 2021;27(1):157-174. doi:10.3350/cmh.2020.0176
32. Younes R, Bugianesi E. NASH in Lean Individuals. Semin Liver Dis. 2019;39(1):86-95. doi:10.1055/s-0038-1677517
33. Singh SP, Kar SK. The Lean NASH Conundrum. J Diabetes Metab. 2016;7: 642. doi:10.4172/2155-6156.1000642
34. Albhaisi S, Chowdhury A, Sanyal AJ. Non-alcoholic fatty liver disease in lean individuals. JHEP Rep. 2019;1(4):329-341. Published 2019 Aug 30. doi:10.1016/j.jhepr.2019.08.002
35. Younes R, Bugianesi E. NASH in Lean Individuals. Semin Liver Dis. 2019;39(1):86-95. doi:10.1055/s-0038-1677517
36. Albhaisi S, Chowdhury A, Sanyal AJ. Non-alcoholic fatty liver disease in lean individuals. JHEP Rep. 2019;1(4):329-341. Published 2019 Aug 30. doi:10.1016/j.jhepr.2019.08.002
37. Younossi ZM, Otgonsuren M, Henry L, et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology. 2015;62(6):1723-1730. doi:10.1002/hep.28123
38. Rajesh Y, Sarkar D. Association of Adipose Tissue and Adipokines with Development of Obesity-Induced Liver Cancer. Int J Mol Sci. 2021;22(4):2163. Published 2021 Feb 22. doi:10.3390/ijms22042163
39. Adamek A, Kasprzak A. Insulin-Like Growth Factor (IGF) System in Liver Diseases. Int J Mol Sci. 2018;19(5):1308. Published 2018 Apr 27. doi:10.3390/ijms19051308
40. Nishikawa H, Enomoto H, Ishii A, et al. Elevated serum myostatin level is associated with worse survival in patients with liver cirrhosis. J Cachexia Sarcopenia Muscle. 2017;8(6):915-925. doi:10.1002/jcsm.12212
41. Yoshimoto S, Loo TM, Atarashi K, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome [published correction appears in Nature. 2014 Feb 20;506(7488):396. Hattori, Masahisa [corrected to Hattori, Masahira]]. Nature. 2013;499(7456):97-101. doi:10.1038/nature12347
42. Hashimoto E, Taniai M, Tokushige K. Characteristics and diagnosis of NAFLD/NASH. J Gastroenterol Hepatol. 2013;28 Suppl 4:64-70. doi:10.1111/jgh.12271
43. Nalbantoglu IL, Brunt EM. Role of liver biopsy in nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20(27):9026-9037. doi:10.3748/wjg.v20.i27.9026
44. Nalbantoglu IL, Brunt EM. Role of liver biopsy in nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20(27):9026-9037. doi:10.3748/wjg.v20.i27.9026
45. Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol. 2010;53(2):372-384. doi:10.1016/j.jhep.2010.04.008
46. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55(6):2005-2023. doi:10.1002/hep.25762
47. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328-357. doi:10.1002/hep.29367
48. Hernaez R, Lazo M, Bonekamp S, et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology. 2011;54(3):1082-1090. doi:10.1002/hep.24452
49. Idilman IS, Keskin O, Celik A, et al. A comparison of liver fat content as determined by magnetic resonance imaging-proton density fat fraction and MRS versus liver histology in non-alcoholic fatty liver disease. Acta Radiol. 2016;57(3):271-278. doi:10.1177/0284185115580488
50. Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S. Nonalcoholic Steatohepatitis: A Review [published correction appears in JAMA. 2020 Apr 28;323(16):1619. doi:10.1001/jama.2020.5249]. JAMA. 2020;323(12):1175-1183. doi:10.1001/jama.2020.2298
51. Cefalu WT, Bray GA, Home PD, et al. Advances in the Science, Treatment, and Prevention of the Disease of Obesity: Reflections From a Diabetes Care Editors' Expert Forum. Diabetes Care. 2015;38(8):1567-1582. doi:10.2337/dc15-1081
52. Turati F, Trichopoulos D, Polesel J, et al. Mediterranean diet and hepatocellular carcinoma. J Hepatol. 2014;60(3):606-611. doi:10.1016/j.jhep.2013.10.034
53. Piercy KL, Troiano RP, Ballard RM, et al. The Physical Activity Guidelines for Americans. JAMA. 2018;320(19):2020-2028. doi:10.1001/jama.2018.14854
54. Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study [published correction appears in Int J Obes (Lond). 2013 Nov;37(11):1514] [published correction appears in Int J Obes (Lond). 2015 Jan;39(1):187. doi: 10.1038/ijo.2014.88]. Int J Obes (Lond). 2013;37(11):1443-1451. doi:10.1038/ijo.2013.120
55. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183
56. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216. doi:10.1056/NEJMoa2206038
57. Caiazzo R, Lassailly G, Leteurtre E, et al. Roux-en-Y gastric bypass versus adjustable gastric banding to reduce nonalcoholic fatty liver disease: a 5-year controlled longitudinal study. Ann Surg. 2014;260(5): 893-899. doi:10.1097/SLA.0000000000000945
58. Tang A, Bashir MR, Corwin MT, et al. Evidence Supporting LI-RADS Major Features for CT- and MR Imaging-based Diagnosis of Hepatocellular Carcinoma: A Systematic Review. Radiology. 2018; 286(1):29-48. doi:10.1148/radiol.2017170554
59. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390. doi:10.1056/NEJMoa0708857
60. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745
61. Kudo M. Durvalumab plus tremelimumab in unresectable hepatocellular carcinoma. Hepatobiliary Surg Nutr. 2022;11(4):592-596. doi:10.21037/ hbsn-22-143
62. European Association for the Study of the Liver. Electronic address: [email protected]; European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma [published correction appears in J Hepatol. 2019 Apr;70(4):817. doi: 10.1016/j.jhep.2019.01.020]. J Hepatol. 2018;69 (1):182-236. doi:10.1016/j.jhep.2018.03.019
63. Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: An update. Hepatology.
2011;53(3):1020-1022. doi:10.1002/hep.24199
64. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301-1314. doi:10.1016/S0140-6736(18)30010-2
65. Piscaglia F, Svegliati-Baroni G, Barchetti A, et al. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective study. Hepatology. 2016;63(3):827-838. doi:10.1002/hep.28368
66. Paradis V, Zalinski S, Chelbi E, et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology. 2009;49(3):851-859. doi:10.1002/hep.22734
67. Kim CK, Lim JH, Lee WJ. Detection of hepatocellular carcinomas and dysplastic nodules in cirrhotic liver: accuracy of ultrasonography in transplant patients. J Ultrasound Med. 2001;20(2):99-104. doi:10.7863/jum.2001.20.2.99
68. Gupta P, Soundararajan R, Patel A, Kumar-M P, Sharma V, Kalra N. Abbreviated MRI for hepatocellular carcinoma screening: A systematic review and meta-analysis. J Hepatol. 2021;75(1):108-119. doi:10.1016/j.jhep.2021.01.041
69. Kanwal F, Singal AG. Surveillance for Hepatocellular Carcinoma: Current Best Practice and Future Direction. Gastroenterology. 2019;157(1):54-64. doi:10.1053/j.gastro.2019.02.049
70. Chan SL, Mo F, Johnson PJ, et al. Performance of serum α-fetoprotein levels in the diagnosis of hepatocellular carcinoma in patients with a hepatic mass. HPB (Oxford). 2014;16(4):366-372. doi:10.1111/hpb.12146
71. Farinati F, Marino D, De Giorgio M, et al. Diagnostic and prognostic role of alpha-fetoprotein in hepatocellular carcinoma: both or neither?. Am J Gastroenterol. 2006;101(3):524-532. doi:10.1111/j.1572-0241.2006.00443.x
72. Li D, Mallory T, Satomura S. AFP-L3: a new generation of tumor marker for hepatocellular carcinoma. Clin Chim Acta. 2001;313(1-2):15-19. doi:10.1016/ s0009-8981(01)00644-1
2. Nimptsch K, Pischon T. Body fatness, related biomarkers and cancer risk: an epidemiological perspective. Horm Mol Biol Clin Investig. 2015;22(2):39-51. doi:10.1515/hmbci-2014-0043
3. Seyfried TN, Flores RE, Poff AM, D'Agostino DP. Cancer as a metabolic disease: implications for novel therapeutics. Carcinogenesis. 2014;35(3):515-527. doi:10.1093/carcin/bgt480
4. Coller HA. Is cancer a metabolic disease?. Am J Pathol. 2014;184(1):4-17. doi:10.1016/j.ajpath.2013.07.035
5. Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer: a consensus report. Diabetes Care. 2010;33(7):1674-1685. doi:10.2337/dc10-0666
6. Wiseman M. The second World Cancer Research Fund/American Institute for Cancer Research expert report. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Proc Nutr Soc. 2008;67(3):253-256. doi:10.1017/S002966510800712X
7. World Cancer Research Fund International/American Institute for Cancer Research (2015) Continuous update project report: diet, nutrition, physical activity and liver cancer. https://www.wcrf.org/wp-content/uploads/2021/02/liver-cancer-report.pdf
8. World Cancer Research Fund International/American Institute for Cancer Research (2014) Continuous update project report: diet, nutrition, physical activity and ovarian cancer. https://www.wcrf.org/wp-content/uploads/2021/02/ovarian-cancer-report.pdf
9. World Cancer Research Fund International/American Institute for Cancer Research (2015) Continuous update project report: diet, nutrition, physical activity and gallbladder cancer. https://www.wcrf.org/wp-content/uploads/2021/02/gallbladder-cancer-report.pdf
10. World Cancer Research Fund International/American Institute for Cancer Research (2014) Continuous update project report: diet, nutrition, physical activity and prostate cancer. https://www.wcrf.org/wp-content/uploads/2021/02/prostate-cancer-report.pdf
11. World Cancer Research Fund International/American Institute for Cancer Research (2016) Continuous update project report: diet, nutrition, physical activity and stomach cancer. https://www.wcrf.org/wp-content/uploads/2021/02/stomach-cancer-report.pdf
12. Sun B, Karin M. Obesity, inflammation, and liver cancer. J Hepatol. 2012;56(3):704-713. doi:10.1016/j.jhep.2011.09.020
13. Villanueva A. Hepatocellular Carcinoma. N Engl J Med. 2019;380(15):1450-1462. doi:10.1056/NEJMra1713263
14. Zhang C, Liu S, Yang M. Hepatocellular Carcinoma and Obesity, Type 2 Diabetes Mellitus, Cardiovascular Disease: Causing Factors, Molecular Links, and Treatment Options. Front Endocrinol (Lausanne). 2021;12:808526. Published 2021 Dec 23. doi:10.3389/fendo.2021.808526
15. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16(10):589-604. doi:10.1038/s41575-019-0186-y
16. Saitta C, Pollicino T, Raimondo G. Obesity and liver cancer. Ann Hepatol. 2019;18(6):810-815. doi:10.1016/j.aohep.2019.07.004
17. Definition & facts of NAFLD & NASH. National Institute of Diabetes and Digestive and Kidney Diseases website. https://www.niddk.nih.gov/health-information/liver-disease/nafld-nash/definition-facts
18. Jukaku SA, Williams SRP. The cause of obesity is multifactorial but GPs can do more. BMJ. 2021;373:n956. Published 2021 Apr 13. doi:10.1136/bmj.n956
19. Suresh D, Srinivas AN, Kumar DP. Etiology of Hepatocellular Carcinoma: Special Focus on Fatty Liver Disease. Front Oncol. 2020;10:601710. Published 2020 Nov 30. doi:10.3389/fonc.2020.601710
20. Zhu RX, Seto WK, Lai CL, Yuen MF. Epidemiology of Hepatocellular Carcinoma in the Asia-Pacific Region. Gut Liver. 2016;10(3):332-339. doi:10.5009/gnl15257
21. Diehl AM. Hepatic complications of obesity. Gastroenterol Clin North Am. 2010;39(1):57-68. doi:10.1016/j.gtc.2009.12.001
22. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73-84. doi:10.1002/hep.28431
23. Larsson SC, Wolk A. Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer. 2007;97(7):1005-1008. doi:10.1038/sj.bjc.6603932
24. Moore LL, Bradlee ML, Singer MR, et al. BMI and waist circumference as predictors of lifetime colon cancer risk in Framingham Study adults. Int J Obes Relat Metab Disord. 2004;28(4):559-567. doi:10.1038/sj.ijo.0802606
25. Donohoe CL, O'Farrell NJ, Doyle SL, Reynolds JV. The role of obesity in gastrointestinal cancer: evidence and opinion. Therap Adv Gastroenterol. 2014;7(1):38-50. doi:10.1177/1756283X13501786
26. Wang Y, Jacobs EJ, Patel AV, et al. A prospective study of waist circumference and body mass index in relation to colorectal cancer incidence. Cancer Causes Control. 2008;19(7):783-792. doi:10.1007/s10552-008-9141-x
27. Steffen A, Schulze MB, Pischon T, et al. Anthropometry and esophageal cancer risk in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev. 2009;18(7):2079-2089.
doi:10.1158/1055-9965.EPI-09-0265
28. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371(9612):569-578. doi:10.1016/S0140-6736(08)60269-X
29. Wang Y, Wang B, Shen F, Fan J, Cao H. Body mass index and risk of primary liver cancer: a meta-analysis of prospective studies. Oncologist. 2012;17(11):1461-1468. doi:10.1634/theoncologist.2012-0066
30. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625-1638. doi:10.1056/NEJMoa021423
31. Sohn W, Lee HW, Lee S, et al. Obesity and the risk of primary liver cancer: A systematic review and meta-analysis. Clin Mol Hepatol. 2021;27(1):157-174. doi:10.3350/cmh.2020.0176
32. Younes R, Bugianesi E. NASH in Lean Individuals. Semin Liver Dis. 2019;39(1):86-95. doi:10.1055/s-0038-1677517
33. Singh SP, Kar SK. The Lean NASH Conundrum. J Diabetes Metab. 2016;7: 642. doi:10.4172/2155-6156.1000642
34. Albhaisi S, Chowdhury A, Sanyal AJ. Non-alcoholic fatty liver disease in lean individuals. JHEP Rep. 2019;1(4):329-341. Published 2019 Aug 30. doi:10.1016/j.jhepr.2019.08.002
35. Younes R, Bugianesi E. NASH in Lean Individuals. Semin Liver Dis. 2019;39(1):86-95. doi:10.1055/s-0038-1677517
36. Albhaisi S, Chowdhury A, Sanyal AJ. Non-alcoholic fatty liver disease in lean individuals. JHEP Rep. 2019;1(4):329-341. Published 2019 Aug 30. doi:10.1016/j.jhepr.2019.08.002
37. Younossi ZM, Otgonsuren M, Henry L, et al. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to 2009. Hepatology. 2015;62(6):1723-1730. doi:10.1002/hep.28123
38. Rajesh Y, Sarkar D. Association of Adipose Tissue and Adipokines with Development of Obesity-Induced Liver Cancer. Int J Mol Sci. 2021;22(4):2163. Published 2021 Feb 22. doi:10.3390/ijms22042163
39. Adamek A, Kasprzak A. Insulin-Like Growth Factor (IGF) System in Liver Diseases. Int J Mol Sci. 2018;19(5):1308. Published 2018 Apr 27. doi:10.3390/ijms19051308
40. Nishikawa H, Enomoto H, Ishii A, et al. Elevated serum myostatin level is associated with worse survival in patients with liver cirrhosis. J Cachexia Sarcopenia Muscle. 2017;8(6):915-925. doi:10.1002/jcsm.12212
41. Yoshimoto S, Loo TM, Atarashi K, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome [published correction appears in Nature. 2014 Feb 20;506(7488):396. Hattori, Masahisa [corrected to Hattori, Masahira]]. Nature. 2013;499(7456):97-101. doi:10.1038/nature12347
42. Hashimoto E, Taniai M, Tokushige K. Characteristics and diagnosis of NAFLD/NASH. J Gastroenterol Hepatol. 2013;28 Suppl 4:64-70. doi:10.1111/jgh.12271
43. Nalbantoglu IL, Brunt EM. Role of liver biopsy in nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20(27):9026-9037. doi:10.3748/wjg.v20.i27.9026
44. Nalbantoglu IL, Brunt EM. Role of liver biopsy in nonalcoholic fatty liver disease. World J Gastroenterol. 2014;20(27):9026-9037. doi:10.3748/wjg.v20.i27.9026
45. Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol. 2010;53(2):372-384. doi:10.1016/j.jhep.2010.04.008
46. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology. 2012;55(6):2005-2023. doi:10.1002/hep.25762
47. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328-357. doi:10.1002/hep.29367
48. Hernaez R, Lazo M, Bonekamp S, et al. Diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver: a meta-analysis. Hepatology. 2011;54(3):1082-1090. doi:10.1002/hep.24452
49. Idilman IS, Keskin O, Celik A, et al. A comparison of liver fat content as determined by magnetic resonance imaging-proton density fat fraction and MRS versus liver histology in non-alcoholic fatty liver disease. Acta Radiol. 2016;57(3):271-278. doi:10.1177/0284185115580488
50. Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S. Nonalcoholic Steatohepatitis: A Review [published correction appears in JAMA. 2020 Apr 28;323(16):1619. doi:10.1001/jama.2020.5249]. JAMA. 2020;323(12):1175-1183. doi:10.1001/jama.2020.2298
51. Cefalu WT, Bray GA, Home PD, et al. Advances in the Science, Treatment, and Prevention of the Disease of Obesity: Reflections From a Diabetes Care Editors' Expert Forum. Diabetes Care. 2015;38(8):1567-1582. doi:10.2337/dc15-1081
52. Turati F, Trichopoulos D, Polesel J, et al. Mediterranean diet and hepatocellular carcinoma. J Hepatol. 2014;60(3):606-611. doi:10.1016/j.jhep.2013.10.034
53. Piercy KL, Troiano RP, Ballard RM, et al. The Physical Activity Guidelines for Americans. JAMA. 2018;320(19):2020-2028. doi:10.1001/jama.2018.14854
54. Wadden TA, Hollander P, Klein S, et al. Weight maintenance and additional weight loss with liraglutide after low-calorie-diet-induced weight loss: the SCALE Maintenance randomized study [published correction appears in Int J Obes (Lond). 2013 Nov;37(11):1514] [published correction appears in Int J Obes (Lond). 2015 Jan;39(1):187. doi: 10.1038/ijo.2014.88]. Int J Obes (Lond). 2013;37(11):1443-1451. doi:10.1038/ijo.2013.120
55. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183
56. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022;387(3):205-216. doi:10.1056/NEJMoa2206038
57. Caiazzo R, Lassailly G, Leteurtre E, et al. Roux-en-Y gastric bypass versus adjustable gastric banding to reduce nonalcoholic fatty liver disease: a 5-year controlled longitudinal study. Ann Surg. 2014;260(5): 893-899. doi:10.1097/SLA.0000000000000945
58. Tang A, Bashir MR, Corwin MT, et al. Evidence Supporting LI-RADS Major Features for CT- and MR Imaging-based Diagnosis of Hepatocellular Carcinoma: A Systematic Review. Radiology. 2018; 286(1):29-48. doi:10.1148/radiol.2017170554
59. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378-390. doi:10.1056/NEJMoa0708857
60. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745
61. Kudo M. Durvalumab plus tremelimumab in unresectable hepatocellular carcinoma. Hepatobiliary Surg Nutr. 2022;11(4):592-596. doi:10.21037/ hbsn-22-143
62. European Association for the Study of the Liver. Electronic address: [email protected]; European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma [published correction appears in J Hepatol. 2019 Apr;70(4):817. doi: 10.1016/j.jhep.2019.01.020]. J Hepatol. 2018;69 (1):182-236. doi:10.1016/j.jhep.2018.03.019
63. Bruix J, Sherman M; American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma: An update. Hepatology.
2011;53(3):1020-1022. doi:10.1002/hep.24199
64. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391(10127):1301-1314. doi:10.1016/S0140-6736(18)30010-2
65. Piscaglia F, Svegliati-Baroni G, Barchetti A, et al. Clinical patterns of hepatocellular carcinoma in nonalcoholic fatty liver disease: A multicenter prospective study. Hepatology. 2016;63(3):827-838. doi:10.1002/hep.28368
66. Paradis V, Zalinski S, Chelbi E, et al. Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology. 2009;49(3):851-859. doi:10.1002/hep.22734
67. Kim CK, Lim JH, Lee WJ. Detection of hepatocellular carcinomas and dysplastic nodules in cirrhotic liver: accuracy of ultrasonography in transplant patients. J Ultrasound Med. 2001;20(2):99-104. doi:10.7863/jum.2001.20.2.99
68. Gupta P, Soundararajan R, Patel A, Kumar-M P, Sharma V, Kalra N. Abbreviated MRI for hepatocellular carcinoma screening: A systematic review and meta-analysis. J Hepatol. 2021;75(1):108-119. doi:10.1016/j.jhep.2021.01.041
69. Kanwal F, Singal AG. Surveillance for Hepatocellular Carcinoma: Current Best Practice and Future Direction. Gastroenterology. 2019;157(1):54-64. doi:10.1053/j.gastro.2019.02.049
70. Chan SL, Mo F, Johnson PJ, et al. Performance of serum α-fetoprotein levels in the diagnosis of hepatocellular carcinoma in patients with a hepatic mass. HPB (Oxford). 2014;16(4):366-372. doi:10.1111/hpb.12146
71. Farinati F, Marino D, De Giorgio M, et al. Diagnostic and prognostic role of alpha-fetoprotein in hepatocellular carcinoma: both or neither?. Am J Gastroenterol. 2006;101(3):524-532. doi:10.1111/j.1572-0241.2006.00443.x
72. Li D, Mallory T, Satomura S. AFP-L3: a new generation of tumor marker for hepatocellular carcinoma. Clin Chim Acta. 2001;313(1-2):15-19. doi:10.1016/ s0009-8981(01)00644-1