Clin Mol Hepatol > Volume 29(Suppl); 2023 > Article
Cho, Kim, and Park: Preventive strategy for nonalcoholic fatty liver disease-related hepatocellular carcinoma

ABSTRACT

The incidence of hepatocellular carcinoma (HCC) associated with nonalcoholic fatty liver disease (NAFLD) has been increasing worldwide, including Asia. Most patients with NAFLD-related HCC are at a much-advanced stage and older age at the time of diagnosis than those with virus-related HCC because they have not undergone HCC surveillance. This review provides an overview of the mechanism of hepatocarcinogenesis in NAFLD, preventive strategies for NAFLDrelated HCC, and strategies for the surveillance of patients with NAFLD.

INTRODUCTION

Nonalcoholic fatty liver disease (NAFLD) is currently the leading cause of chronic liver disease in Korea, with an estimated prevalence of 20–30% among general population [1]. NAFLD is regarded as the hepatic manifestation of the metabolic syndrome and is also closely associated with diabetes, hyperlipidemia, obesity, and hypertension. Considering the trend of obesity in Korea [2], NAFLD may become more prevalent in the near future and may become an important etiology of chronic liver disease and liver cancer. As the prevalence of metabolic syndrome has notably increased [3], the prevalence of NAFLD has doubled in the last two decades to 30%. Although simple steatosis is often regarded as a non-progressive condition, 20–30% of patients with nonalcoholic fatty liver progress to chronic liver disease (nonalcoholic steatohepatitis [NASH]), which is characterized by hepatocyte injury, lobular inflammation, and fibrosis, and can result in liver cirrhosis (LC) (F4) in 20% of NASH patients with advanced fibrosis (F3) over 2 years [4,5]. NAFLD and NAFLD-related hepatocellular carcinoma (HCC) have received relatively little attention because cardiovascular events are the most common cause of death among patients with NAFLD. However, with the increase in the prevalence of metabolic syndrome and the decrease in the population with chronic hepatitis B or C worldwide, NAFLD, especially NASH, has increasingly become an important etiology of HCC [6].
Hepatocarcinogenesis in patients with NAFLD and NASH is complex and not fully understood. Although the progression to cirrhosis occurs before the development of HCC in the majority of chronic liver diseases, this is not always the case with NAFLD-related HCC, because HCC may develop even if cirrhosis is not definitively present [7]. The rate of NASH-associated hepatocarcinogenesis is approximately 1.5–2.6% per year [6].

PATHOGENESIS: PROPOSED MECHANISMS

Obesity and diabetes, which are two important risk factors for NAFLD, increase the risk of HCC [8]. The pathogenesis of HCC in patients with NAFLD (Fig. 1) is also independent of the presence of liver cirrhosis. Among patients with NAFLD, HCC may develop even in the absence of advanced hepatic fibrosis and histological inflammation.
The association between obesity and HCC among patients with NAFLD has also been proven for HCC in a previous study in the United States, which included more than 900,000 persons. The individuals were stratified according to their body mass index (BMI). The relative risk of mortality of HCC was 4.52 and 1.90 in patients with obesity grade II and I, respectively [9]. A study from Korea with 700,000 participants also confirmed an increased risk (relative risk, 1.56) of HCC in patients with BMI >30 kg/m2 [10]. A persistent, low-grade inflammatory response due to obesity and an abundance of adipose tisssue are thought to be key factors in hepatocarcinogenesis [11]. Increased levels of leptin, a proinflammatory, proangiogenic, and profibrogenic cytokine that promotes growth by activating the Janus kinase pathway [12], are a result of obesity. Adiponectin, an anti-inflammatory cytokine, is decreased in obesity [13-15]. Lipotoxicity, which results from lipid accumulation in the liver, causes the development of reactive oxygen species, endothelial reticulum stress, and saturated and monounsaturated free fatty acids. Free fatty acids can disrupt cellular signaling pathways causing changes in gene transcription [16]. By activating numerous carcinogenic pathways, insulin and insulin-like growth factor may aid in the development of primary liver cancer [17].
Insulin resistance and hyperinsulinemia also increase toxic metabolites in hepatocytes [18]. Hyperglycemia modifies the cell vasculature, leading to defects in endothelial cells. Endothelial damage leads to impaired fibrinolytic capacity, increased growth factor production, increased levels of adhesion molecules and inflammatory cytokines, increased reactive oxygen species, and enhanced cellular permeability [19]. Insulin resistance also leads to hyperinsulinemia, which triggers the production of free fatty acids and reactive carbonyl compounds in adipose tissue [20]. Advanced glycation end-products in hepatocytes aggravate oxidative stress and DNA damage, which are the probable consequences of hepatocarcinogenesis [21].
The alteration of the gut microbiota in patients with NAFLD also leads to hepatocarcinogenesis [22]. The level of lipopolysaccharide, which is the main component of the outer membrane of gram-negative bacteria, increases with obesity. Interestingly, further evidence of the role of lipopolysaccharide in hepatocarcinogenesis is derived from the finding that gut sterilization and lipopolysaccharide removal reduce HCC development in the chronically damaged liver [23,24].
The development of HCC in NAFLD may also be influenced by genetic variation. The minor allele of PNPLA3 rs738409 c.444C>G (encoding the I148M variant) has been linked to hepatocarcinogenesis. This polymorphism provides an elevated risk in the absence of potentially confounding covariates such as age, sex, coexisting diabetes, obesity, and cirrhosis [25,26].

PREVENTION OF NAFLD-RELATED HCC

Several risk factors associated with hepatocarcinogenesis in the NAFLD population may be reduced by lifestyle interventions or chemoprevention; however, the benefits of these approaches are likely to extend beyond risk factor modification. Changes in lifestyle and management of metabolic risk factors may help prevent HCC. Further epidemiological studies are required to tailor screening strategies, particularly in noncirrhotic populations with NAFLD.

Weight reduction

The primary treatment for the majority of patients with NAFLD is weight reduction. However, weight loss has not been directly proven to reduce the incidence of NAFLD-related HCC. Previous clinical studies have demonstrated that weight loss positively influences NAFLD activity, with some data indicating the possibility of hepatic fibrosis regression. Weight reduction for all patients with NAFLD is recommended, especially those who are overweight (BMI >25 kg/m2) or obese (BMI >30 kg/m2), because weight loss at a rate of 0.5–1.0 kg/week can lead to improvement in biochemical tests, serum insulin levels, and liver histology [27-30]. Weight reduction of 5–7% leads to lower intrahepatic fat content in NAFLD patients, and weight loss of 7–10% is necessary to ameliorate hepatic inflammation and fibrosis [1].
The following are the behavioral adjustments for obese patients: (1) consuming a low-calorie, low-fat diet; (2) regular participation in moderate physical activity; and (3) regular checking of body weight and abdominal circumference.

Physical activity

HCC risk reduction has recently been found in the European Prospective Investigation into Cancer and Nutrition cohort study among subjects who engaged in at least 2 hours of intense exercise each week with a hazard ratio (HR) of 0.5, independent of body weight and other common risk factors for HCC [31]. A meta-analysis of 14 prospective studies also indicated a considerably decreased risk of liver cancer in those with high physical activity compared to those with low physical activity (HR, 0.75; 95% confidence interval [CI], 0.63– 0.89) [32].

Dietary modification

Among dietary patterns, higher adherence to the Mediterranean diet substantially lowered the risk of HCC (odds ratio, 0.51 [33]; HRs, 0.62 [34] and 0.68 [35]). The Mediterranean diet is also recommended by European and Korean guidelines for NAFLD [1,36].
Coffee is a dietary component that has shown potential for the treatment of both NAFLD and HCC. People who drank coffee at least twice a day had a considerably decreased incidence of HCC than non-drinkers (HR, 0.40; 95% CI, 0.20–0.79) [37]. A meta-analysis of six Japanese cohort studies corroborated this finding, with a pooled relative risk estimate of 0.50 (95% CI, 0.38–0.66) for frequent coffee drinking vs. no coffee consumption [38].
It has also been proposed that dietary antioxidants (vitamins C and E, as well as selenium) may help reduce hepatocarcinogenesis [39]. This may particularly important given that patients with NASH have been shown to have vitamin E and D insufficiency [40], and that vitamin D deficiency may play a role in hepatocarcinogenesis [41].

PHARMACOLOGIC PREVENTION

Several pharmacological treatments have been reported to modify risk variables and carcinogenic pathways in NAFLD-associated HCC, indicating their potential use in preventive pharmacological strategies. In this section, the pharmacological treatments that have been shown to prevent HCC are reviewed. There are few studies that have verified the chemopreventive effect only on NAFLD patients. Therefore, clinicians should be careful in interpreting the routine use of drugs such as metformin and statin as prophylactic therapy in patients with NAFLD.

Aspirin

In large prospective population-based observational studies, aspirin and other antiplatelet medications have been shown to lower the risk of HCC [42-44]. Most studies have found that aspirin might exert a hepatitis B virus (HBV)-specific chemopreventive effect on HCC development. However, recent studies have also suggested that aspirin might have a preventive effect on NAFLD-related HCC.
A recent pooled analysis of two prospective United States cohort studies (the Nurses’ Health Study and the Health Professionals Follow-up Study) analyzed 133,371 participants. This study reported that regular, long-term aspirin use was associated with a reduction in HCC risk in a dose-dependent manner, which was apparent after ≥5 years of use. Interestingly, similar associations were not found with non-aspirin nonsteroidal anti-inflammatory drugs [43]. The analysis of this study was not limited to those with NAFLD, but considering that one dominant HCC risk factor in the Unites States is NAFLD, it can be accepted as a significant result. A prospective study of 361 patients with biopsy-proven NAFLD also reported that daily aspirin use was associated with a significantly lower risk of advanced fibrosis compared to non-regular aspirin use (adjusted HR, 0.63; 95% CI, 0.43–0.85) [45]. A recent systematic review and meta-analysis analyzing 19 observational studies also supported the preventive effect of aspirin on HCC development [46].
The ideal dose and duration of aspirin for preventing HCC incidence are still uncertain, and the chemopreventive impact of other nonsteroidal anti-inflammatory medications other than aspirin on HCC is unknown. Future studies are needed to determine the chemopreventive effects of aspirin in NAFLD and NASH patients.

Metformin

Metformin suppresses hepatic fat formation and glucose excretion by activating adenosine monophosphate-activated protein kinase; it also reduces tumor necrosis factor expression. In a subanalysis of a meta-analysis [47] analyzing 37 studies, a substantial decrease in HCC risk in diabetic patients was observed among metformin users in terms of HCC incidence (78%) and death (77%). Another meta-analysis of 10 studies that included 22,650 HCC cases among 334,307 diabetic individuals found that metformin treatment was associated with a 41% decrease in HCC incidence [48]. Metformin appears to have antitumoral effects via several pathways by decreasing the level of insulin-like growth factor-1, suppressing c-Jun N-terminal kinase/p38 mitogen-activated protein kinase, human epidermal growth factor receptor-2, and nuclear factor-κB pathways, activating AMP-activated protein kinase, inhibiting the mammalian target of rapamycin pathway, and decreasing the endogenous production of reactive oxygen species.

Statins

The protective impact of statins on HCC development is most likely due to their anti-inflammatory characteristics, which are mediated through Janus kinase inhibition [49]. Several clinical studies have found that statins are useful in lowering the risk of HCC [50-52]. A recent meta-analysis of 24 studies found that statin users had a 46% lower risk of HCC, indicating that statins might be used in chemoprophylaxis [53]. A subanalysis of another meta-analysis found that using lipophilic statins (atorvastatin, pitavastatin, lovastatin, fluvastatin, simvastatin) was linked with a considerably lower risk of HCC when compared to hydrophilic statins (rosuvastatin, pravastatin) (27% vs. 51%) [54]. Lipophilic statins have higher lipid solubility and membrane permeability, allowing them to have cholesterol-dependent effects on HCC development [55].

SURVEILLANCE STRATEGY FOR NAFLD

The annual incidence of HCC in individuals with NAFLD-related cirrhosis is greater than 1.5% [56,57]. If liver cirrhosis is clinically suspected among patients with NAFLD, HCC surveillance is recommended [58-60]. Since NAFLD-related LC patients may lose weight when they progress to LC, the etiology of cryptogenic LC should not be judged based on BMI alone. Non-invasive modalities to diagnose advanced fibrosis such as transient elastography might be a good tool to discriminate those high-risk population [1]. As shown in the previous systemic review [61], the incidence of HCC was quite low in subjects with early liver fibrosis (F0–2), 2.7% at 10 years and 23 per 100,000 person-years. However, patients with early liver fibrosis are more prone to develop HCC if they have other risk factors (obesity, metabolic syndrome, diabetes, etc.) and also HBV or hepatitis C virus infection in terms of metabolic-associated fatty liver disease. Therefore, a surveillance strategy for NAFLD patients should be individualized [58,62].
Although some evidence suggests that HCC can develop in livers without cirrhosis or steatohepatitis, surveillance should be carefully planned. Owing to the lack of robust data on the noncirrhotic population, it is difficult to develop evidence-based, cost-effective surveillance strategies for the NAFLD population. Clinical trials are needed to address the issue of surveillance in NAFLD, particularly in noncirrhotic persons [63].
Abdominal ultrasonography is the primary tool used for HCC surveillance. However, it might be difficult to accurately execute this procedure in overweight or obese patients [64,65]. Computed tomography or magnetic resonance imaging can be used instead.

CONCLUSION

Weight loss, dietary changes, and increased physical activity continue to be the cornerstones of HCC prevention in patients with NAFLD. The impact of lifestyle factors and chemopreventive agents may differ between NAFLD-associated hepatocarcinogenesis and hepatocarcinogenesis due to other etiologies, taking into account the heterogeneity of the NAFLD and NASH populations. A better understanding of the underlying pathophysiological mechanisms and disease phenotypes may enable focused preventive interventions for NAFLD-associated HCC in the future. New insights into the etiology, pathogenesis, and surveillance of HCC in patients with NAFLD may enable the development of therapeutic and preventive strategies.

ACKNOWLEDGMENTS

This work has supported by grants from the National Research Foundation of Korea grant funded by the Korea government (2021R1A2C4001401), the National Cancer Center, Korea (NCC-2210420-1), and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health & Welfare, Republic of Korea (HI21C0240).

FOOTNOTES

Authors’ contribution
Study conceptualization: YC and JWP; Drafting of the manuscript: YC; Critical revision of the manuscript: BHK, YC, and JWP
Conflicts of Interest
The authors have no conflicts to disclose.

Figure 1.
Pathogenesis of hepatocellular carcinoma in patients with nonalcoholic fatty liver disease. NAFLD, nonalcoholic fatty liver disease; HCC, hepatocellular carcinoma; LPS, lipopolysaccharide; ROS, reactive oxygen species.

cmh-2022-0360f1.jpg

Abbreviations

BMI
body mass index
CI
confidence interval
HCC
hepatocellular carcinoma
HR
hazard ratio
LC
liver cirrhosis
NAFLD
nonalcoholic fatty liver disease
NASH
nonalcoholic steatohepatitis

REFERENCES

1. Kang SH, Lee HW, Yoo JJ, Cho Y, Kim SU, Lee TH, et al. KASL clinical practice guidelines: management of nonalcoholic fatty liver disease. Clin Mol Hepatol 2021;27:363-401.
crossref pmid pmc pdf
2. Ministry of Health and Welfare. The National Health and Nutrition Survey, South Korea, 2020. Statistics Korea. < https://www.index.go.kr/unify/idx-info.do?idxCd=8021>. 22 Jul 2022.

3. Kang SH, Cho Y, Jeong SW, Kim SU, Lee JW; Korean NSG. From nonalcoholic fatty liver disease to metabolic-associated fatty liver disease: big wave or ripple? Clin Mol Hepatol 2021;27:257-269.
crossref pmid pmc pdf
4. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999;116:1413-1419.
crossref pmid
5. Loomba R, Adams LA. The 20% rule of NASH progression: the natural history of advanced fibrosis and cirrhosis caused by NASH. Hepatology 2019;70:1885-1888.
crossref pmid pmc pdf
6. Nakade Y, Sato K, Nakao H, Yoneda M. [Hepatocarcinogenesis in NASH]. Gan To Kagaku Ryoho 2012;39:693-697.
pmid
7. Stine JG, Wentworth BJ, Zimmet A, Rinella ME, Loomba R, Caldwell SH, et al. Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases. Aliment Pharmacol Ther 2018;48:696-703.
crossref pmid pmc pdf
8. Margini C, Dufour JF. The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment. Liver Int 2016;36:317-324.
crossref pmid pdf
9. 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;348:1625-1638.
crossref pmid
10. Oh SW, Yoon YS, Shin SA. Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea national health insurance corporation study. J Clin Oncol 2005;23:4742-4754.
crossref pmid
11. Stickel F, Hellerbrand C. Non-alcoholic fatty liver disease as a risk factor for hepatocellular carcinoma: mechanisms and implications. Gut 2010;59:1303-1307.
crossref pmid
12. Auwerx J, Staels B. Leptin. Lancet 1998;351:737-742.
crossref pmid
13. Ikejima K, Takei Y, Honda H, Hirose M, Yoshikawa M, Zhang YJ, et al. Leptin receptor-mediated signaling regulates hepatic fibrogenesis and remodeling of extracellular matrix in the rat. Gastroenterology 2002;122:1399-1410.
crossref pmid
14. Dalamaga M, Diakopoulos KN, Mantzoros CS. The role of adiponectin in cancer: a review of current evidence. Endocr Rev 2012;33:547-594.
crossref pmid pmc pdf
15. Saxena NK, Sharma D, Ding X, Lin S, Marra F, Merlin D, et al. Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res 2007;67:2497-2507.
crossref pmid pmc pdf
16. Vinciguerra M, Carrozzino F, Peyrou M, Carlone S, Montesano R, Benelli R, et al. Unsaturated fatty acids promote hepatoma proliferation and progression through downregulation of the tumor suppressor PTEN. J Hepatol 2009;50:1132-1141.
crossref pmid
17. Chettouh H, Lequoy M, Fartoux L, Vigouroux C, DesboisMouthon C. Hyperinsulinaemia and insulin signalling in the pathogenesis and the clinical course of hepatocellular carcinoma. Liver Int 2015;35:2203-2217.
crossref pmid pdf
18. Singh MK, Das BK, Choudhary S, Gupta D, Patil UK. Diabetes and hepatocellular carcinoma: a pathophysiological link and pharmacological management. Biomed Pharmacother 2018;106:991-1002.
crossref pmid
19. Capone F, Guerriero E, Colonna G, Maio P, Mangia A, Marfella R, et al. The cytokinome profile in patients with hepatocellular carcinoma and type 2 diabetes. PLoS One 2015;10:e0134594.
crossref pmid pmc
20. Hay N. Reprogramming glucose metabolism in cancer: can it be exploited for cancer therapy? Nat Rev Cancer 2016;16:635-649.
crossref pmid pmc pdf
21. Hollenbach M. The role of Glyoxalase-I (Glo-I), advanced glycation endproducts (AGEs), and their receptor (RAGE) in chronic liver disease and hepatocellular carcinoma (HCC). Int J Mol Sci 2017;18:2466.
crossref pmid pmc
22. Zhao L. The gut microbiota and obesity: from correlation to causality. Nat Rev Microbiol 2013;11:639-647.
crossref pmid pdf
23. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, Oyadomari S, et al. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 2013;499:97-101.
crossref pmid pdf
24. Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK, Mederacke I, et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 2012;21:504-516.
crossref pmid pmc
25. Burza MA, Pirazzi C, Maglio C, Sjoholm K, Mancina RM, Svensson PA, et al. PNPLA3 I148M (rs738409) genetic variant is associated with hepatocellular carcinoma in obese individuals. Dig Liver Dis 2012;44:1037-1041.
crossref pmid
26. Liu YL, Patman GL, Leathart JB, Piguet AC, Burt AD, Dufour JF, et al. Carriage of the PNPLA3 rs738409 C >G polymorphism confers an increased risk of non-alcoholic fatty liver disease associated hepatocellular carcinoma. J Hepatol 2014;61:75-81.
crossref pmid
27. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 2005;54:603-608.
crossref pmid pmc pdf
28. Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology 2010;51:121-129.
crossref pmid pmc
29. Keating SE, Hackett DA, George J, Johnson NA. Exercise and non-alcoholic fatty liver disease: a systematic review and metaanalysis. J Hepatol 2012;57:157-166.
crossref pmid
30. Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, TorresGonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology 2015;149:367-378 e5; quiz e314-315.
crossref pmid
31. Baumeister SE, Schlesinger S, Aleksandrova K, Jochem C, Jenab M, Gunter MJ, et al. Association between physical activity and risk of hepatobiliary cancers: a multinational cohort study. J Hepatol 2019;70:885-892.
crossref pmid
32. Baumeister SE, Leitzmann MF, Linseisen J, Schlesinger S. Physical activity and the risk of liver cancer: a systematic review and meta-analysis of prospective studies and a bias analysis. J Natl Cancer Inst 2019;111:1142-1151.
crossref pmid pmc pdf
33. Turati F, Trichopoulos D, Polesel J, Bravi F, Rossi M, Talamini R, et al. Mediterranean diet and hepatocellular carcinoma. J Hepatol 2014;60:606-611.
crossref pmid
34. Li WQ, Park Y, McGlynn KA, Hollenbeck AR, Taylor PR, Goldstein AM, et al. Index-based dietary patterns and risk of incident hepatocellular carcinoma and mortality from chronic liver disease in a prospective study. Hepatology 2014;60:588-597.
crossref pmid pmc
35. Bogumil D, Park SY, Le Marchand L, Haiman CA, Wilkens LR, Boushey CJ, et al. High-quality diets are associated with reduced risk of hepatocellular carcinoma and chronic liver disease: the multiethnic cohort. Hepatol Commun 2019;3:437-447.
crossref pmid pmc pdf
36. European Association for the Study of the Liver; European Association for the Study of Diabetes; European Association for the Study of Obesity. EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64:1388-1402.
crossref pmid
37. Tamura T, Wada K, Konishi K, Goto Y, Mizuta F, Koda S, et al. Coffee, green tea, and caffeine intake and liver cancer risk: a prospective cohort study. Nutr Cancer 2018;70:1210-1216.
crossref pmid
38. Tamura T, Hishida A, Wakai K. Coffee consumption and liver cancer risk in Japan: a meta-analysis of six prospective cohort studies. Nagoya J Med Sci 2019;81:143-150.
pmid pmc
39. Montella M, Crispo A, Giudice A. HCC, diet and metabolic factors: diet and HCC. Hepat Mon 2011;11:159-162.
pmid pmc
40. Erhardt A, Stahl W, Sies H, Lirussi F, Donner A, Haussinger D. Plasma levels of vitamin E and carotenoids are decreased in patients with nonalcoholic steatohepatitis (NASH). Eur J Med Res 2011;16:76-78.
crossref pmid pmc
41. Fedirko V, Duarte-Salles T, Bamia C, Trichopoulou A, Aleksandrova K, Trichopoulos D, et al. Prediagnostic circulating vitamin D levels and risk of hepatocellular carcinoma in European populations: a nested case-control study. Hepatology 2014;60:1222-1230.
crossref pmid pdf
42. Sahasrabuddhe VV, Gunja MZ, Graubard BI, Trabert B, Schwartz LM, Park Y, et al. Nonsteroidal anti-inflammatory drug use, chronic liver disease, and hepatocellular carcinoma. J Natl Cancer Inst 2012;104:1808-1814.
crossref pmid pmc
43. Simon TG, Ma Y, Ludvigsson JF, Chong DQ, Giovannucci EL, Fuchs CS, et al. Association between aspirin use and risk of hepatocellular carcinoma. JAMA Oncol 2018;4:1683-1690.
crossref pmid pmc
44. Goh MJ, Sinn DH. Statin and aspirin for chemoprevention of hepatocellular carcinoma: time to use or wait further? Clin Mol Hepatol 2022;28:380-395.
crossref pmid pmc pdf
45. Simon TG, Henson J, Osganian S, Masia R, Chan AT, Chung RT, et al. Daily aspirin use associated with reduced risk for fibrosis progression in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2019;17:2776-2784 e4.
crossref pmid pmc
46. Memel ZN, Arvind A, Moninuola O, Philpotts L, Chung RT, Corey KE, et al. Aspirin use is associated with a reduced incidence of hepatocellular carcinoma: a systematic review and metaanalysis. Hepatol Commun 2021;5:133-143.
crossref pmid pmc pdf
47. Zhang HL, Yu LX, Yang W, Tang L, Lin Y, Wu H, et al. Profound impact of gut homeostasis on chemically-induced pro-tumorigenic inflammation and hepatocarcinogenesis in rats. J Hepatol 2012;57:803-812.
crossref pmid
48. Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Antidiabetic medications and the risk of hepatocellular cancer: a systematic review and meta-analysis. Am J Gastroenterol 2013;108:881-891 quiz 892.
crossref pmid pdf
49. El-Serag HB, Johnson ML, Hachem C, Morgana RO. Statins are associated with a reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes. Gastroenterology 2009;136:1601-1608.
crossref pmid pmc
50. Chiu HF, Ho SC, Chen CC, Yang CY. Statin use and the risk of liver cancer: a population-based case-control study. Am J Gastroenterol 2011;106:894-898.
crossref pmid pdf
51. McGlynn KA, Divine GW, Sahasrabuddhe VV, Engel LS, VanSlooten A, Wells K, et al. Statin use and risk of hepatocellular carcinoma in a U.S. population. Cancer Epidemiol 2014;38:523-527.
crossref pmid pmc
52. Kim G, Jang SY, Han E, Lee YH, Park SY, Nam CM, et al. Effect of statin on hepatocellular carcinoma in patients with type 2 diabetes: a nationwide nested case-control study. Int J Cancer 2017;140:798-806.
crossref pmid pdf
53. Islam MM, Poly TN, Walther BA, Yang HC, Jack Li YC. Statin use and the risk of hepatocellular carcinoma: a meta-analysis of observational studies. Cancers (Basel) 2020;12:671.
crossref pmid pmc
54. Facciorusso A, Abd El Aziz MA, Singh S, Pusceddu S, Milione M, Giacomelli L, et al. Statin use decreases the incidence of hepatocellular carcinoma: an updated meta-analysis. Cancers (Basel) 2020;12:874.
crossref pmid pmc
55. Hamelin BA, Turgeon J. Hydrophilicity/lipophilicity: relevance for the pharmacology and clinical effects of HMG-CoA reductase inhibitors. Trends Pharmacol Sci 1998;19:26-37.
crossref pmid
56. Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010;51:1972-1978.
crossref pmid
57. Yatsuji S, Hashimoto E, Tobari M, Taniai M, Tokushige K, Shiratori K. Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C. J Gastroenterol Hepatol 2009;24:248-254.
crossref pmid
58. White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 2012;10:1342-1359 e2.
crossref pmid pmc
59. Castera L, Friedrich-Rust M, Loomba R. Noninvasive assessment of liver disease in patients with nonalcoholic fatty liver disease. Gastroenterology 2019;156:1264-1281 e4.
crossref pmid pmc
60. Tapper EB, Lok ASF. Use of liver imaging and biopsy in clinical practice. N Engl J Med 2017;377:2296-2297.
crossref pmid
61. Reig M, Gambato M, Man NK, Roberts JP, Victor D, Orci LA, et al. Should patients with NAFLD/NASH be surveyed for HCC? Transplantation 2019;103:39-44.
crossref pmid
62. Kanwal F, Kramer JR, Mapakshi S, Natarajan Y, Chayanupatkul M, Richardson PA, et al. Risk of hepatocellular cancer in patients with non-alcoholic fatty liver disease. Gastroenterology 2018;155:1828-1837 e2.
crossref pmid pmc
63. Mittal S, Sada YH, El-Serag HB, Kanwal F, Duan Z, Temple S, et al. Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population. Clin Gastroenterol Hepatol 2015;13:594-601 e1.
crossref pmid pmc
64. Del Poggio P, Olmi S, Ciccarese F, Di Marco M, Rapaccini GL, Benvegnu L, et al. Factors that affect efficacy of ultrasound surveillance for early stage hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol 2014;12:1927-1933 e.2.
crossref pmid
65. Simmons O, Fetzer DT, Yokoo T, Marrero JA, Yopp A, Kono Y, et al. Predictors of adequate ultrasound quality for hepatocellular carcinoma surveillance in patients with cirrhosis. Aliment Pharmacol Ther 2017;45:169-177.
crossref pmid pmc pdf

Editorial Office
The Korean Association for the Study of the Liver
Room A1210, 53 Mapo-daero(MapoTrapalace, Dowha-dong), Mapo-gu, Seoul, 04158, Korea
TEL: +82-2-703-0051   FAX: +82-2-703-0071    E-mail: kasl@kams.or.kr
Copyright © The Korean Association for the Study of the Liver.         
COUNTER
TODAY : 2310
TOTAL : 1766649
Close layer