Prevention of NAFLD-Associated Liver Cancer: Role of Lifestyle & Medications

Dr. Khandker Shamsul Arefin, Md.Tourat Hossain, Tania Akter Trishna
Drugs, Genetics, Liver Disease

19

Mar 25

Abstract:

The prevalence of liver cancer, specifically hepatocellular carcinoma (HCC) linked to Non-alcoholic Fatty Liver disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH), is rising in many nations around the world. In Bangladesh, HCC is also the most common primary liver malignancy and 17.51% of HCC patients are associated with NAFLD. To reverse this trend, preventive measures are required. Both HCC and NAFLD/NASH are taken into account, along with the effects of lifestyle factors like weight loss, exercise, quitting smoking, dietary habits, and food items like coffee and alcohol. Additionally, there is strong evidence supporting the use of adjuvant therapy for the tertiary prevention of HCC, including aspirin, anti-diabetic medications, and statins.

Key words: Hepatocellular Carcinoma (HCC); Non-alcoholic Fatty Liver Disease (NAFLD); Non- alcoholic Steatohepatitis (NASH), Lifestyle, Diet, Physical activity, Coffee, Aspirin, Metformin, Statin, Probiotics.

Introduction

Hepatocellular Carcinoma (HCC) is the most common primary liver cancer and cause of cancer related death worldwide and in Bangladesh. It occurs more often in males than females. The incidence of HCC continues to escalate due to HBV, HCV infection, nonalcoholic fatty liver disease (NAFLD). According to an observational study among Bangladeshi 1028 patients, 478 (46.50%) patients were infected with HBV, 56 (5.45%) were infected with HCV, 632 (61.48%) were suffering from CLD, 180 (17.51%) from NAFLD and only 48 (4.46%) had family histories of malignancy.1 NAFLD is a fatty liver disease and the acronym stands for non- alcoholic fatty liver disease. It is a condition in which more than 5% fat is stored in the liver cells due to a combination of eating more calories than the body needs and leading a more sedentary (inactive) lifestyle. 2 When the liver cells containing the fat droplets become inflamed and damaged, it is called non-alcoholic steatohepatitis or NASH (Fig. 1).   Data suggested that, the burden of hepatocellular carcinoma (HCC) associated with nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing. So, Preventive strategies are needed to counteract this trend.  NAFLD-associated HCC may occur without developing cirrhosis. Several risk factors that are associated with HCC in the NAFLD population may be modified by lifestyle intervention or chemo-prevention.3

Fig 1: Evolution of NAFLD; Acknowledge by EASL

Lifestyle factors

An elevated risk of HCC is linked to metabolic disorders, including diabetes and obesity as well as other dysmetabolic characteristics as hypertension and dyslipidemia. Although NAFLD-associated HCC can develop in non-cirrhotic livers, to some extent, this risk may be mediated by a higher rate of progression to NAFLD/NASH cirrhosis, a precancerous state, in the presence of these variables.4-5 Alcohol intake and smoking are linked to carcinogenesis in a variety of tissues, including the liver, while particular foods, dietary habits, and physical activity are associated with a decreased risk of HCC (Fig. 2).

Fig 2: EASL recommended Lifestyle for fatty liver patients

Lifestyle factors: Prospective study:

A study conducted in the prospective, population-based Singapore Chinese Health Study cohort which included a population with high prevalence of viral hepatitis B, found the highest composite score of healthy lifestyle factors, such as a normal body mass index, little alcohol consumption, quitting smoking, adhering to the Mediterranean diet, and getting enough sleep, was discovered in a population with a markedly 87% lower risk of HCC. This implies that the combined modification of these risk variables may lower the risk of HCC.

Weight loss:

Clinical studies have shown beneficial effects of weight loss on NAFLD activity, with some findings indicating the possibility of fibrosis regression.6,7 Recent Cuban study with paired liver biopsies from 261 patients with NAFLD, a 10% reduction in body weight led to- NASH resolution in 90% & Fibrosis regression in 45% after 52 weeks.8

In a large meta-analysis, it was also determined that weight loss following bariatric surgery had a greater impact on individuals with NAFLD and obesity than lifestyle changes. However, 12% of patients showed postoperative worsening of histological disease activity.

Diet:

Various dietary habits, nutrients, and food groups have been studied in relation to NAFLD and HCC, however few research have specifically looked at HCC risk in NAFLD patients.9 A recent comprehensive review found 30 observational studies focusing on the relationship between eating habits and primary liver cancer. High levels of adherence to the Mediterranean diet were among the dietary patterns that were significantly linked to a 48% lower risk of HCC.10-12 The Mediterranean diet is advised by European NAFLD guidelines. Recommended Mediterranean diet includes Vegetables, Wholegrains, fruits, fishes, white meat as poultry, dairy, nuts, tea and coffee (Fig. 3).13-14

Fig. 2 EASL recommended Mediterranean diet

Physical activity

According to the evidence, physical activity lowers the risk of HCC independently of the benefits of weight loss. The enhancement of mitochondrial processes like autophagy and biogenesis, the reduction of NAFLD/NASH activity, and the modification of signaling pathways that promote cancer are possible explanations.15-17 The risk was considerably 25% lower in people who engaged in high physical activity compared to those who did not.

Coffee

Both NAFLD/NASH and HCC exhibit positive effects from coffee use. When compared to non-drinkers, people who drank coffee at least twice a day had a significantly lower risk of liver cancer (HR 0.40; 95% CI 0.20-0.79). A 35% risk decrease was seen with daily consumption of 2 cups, and a risk reduction of 50% was seen with daily consumption of 5 cups. While drinking unfiltered coffee has been linked to higher cholesterol levels.18-20 According to evidence from observational studies, this has overall positive effects on metabolism and the cardiovascular system while lowering the risk of cardiovascular disease. increasing coffee use in those with chronic liver disease, as currently advised by EASL guidelines.

Smoking and alcohol:

According to different studies, smoking and alcohol cessation should be considered important goals in the prevention of NAFLD-HCC.

medicines used for chemoprevention

Several drugs have been shown to modulate risk factors and carcinogenic pathways in NAFLD/ NASH-associated HCC, thereby suggesting potential for use in the development and implementation of prevention strategies. In this section, we review drugs that have demonstrated a preventive effect on HCC.

Aspirin

In a pooled analysis of 2 prospective cohort studies in the USA (N=133,371), Simon et al. (2018) showed that regular use of at least 650 mg aspirin per week was associated with a 50% reduction in HCC risk.21 A Swedish, nationwide registry-based study confirmed that regular intake of less than 160 mg/d aspirin for at least 5 years, lowered 21% risk of HCC without increasing the risk of gastrointestinal bleeding.22

Antidiabetic drugs: Metformin

Several large population-based cohort studies reported that metformin, a first-line drug to treat type 2 diabetes, has a chemo prophylactic effect on HCC. In a sub-analysis of a meta-analysis evaluating 37 trials, the authors found a significant HCC risk reduction in metformin users regarding both HCC incidence (78%) and mortality (77%).23,24 Another meta-analysis of 10 studies, with 22,650 HCC cases among 334,307 diabetic patients, showed that the use of metformin was associated with a 41% reduction in HCC incidence.

Antidiabetic drugs: Pioglitazone

Pioglitazone, an activator of peroxisome proliferator-activated receptor-c (PPAR-c) known for its insulin-sensitizing effects, reduced the incidence of HCC in a hospital-based case-control study and a population-based cohort study.30-31 In vitro studies suggested that the anti-carcinogenic properties of pioglitazone could be the result of suppression of hepatic stellate cell activation. In addition, pioglitazone demonstrated a positive effect on adiponectin levels, which was associated with protection from carcinogenesis. However, serious side effects such as weight gain, bone loss, and fracture risk, increased risk of myocardial infarction (rosiglitazone) and increased risk of bladder cancer (pioglitazone) limit the use of this drug class.32-34

Statins

Several clinical trials have reported that statins are effective in reducing HCC risk. The results of a recent meta-analysis of 24 studies showed a 46% decrease in HCC risk among statin users, suggesting that statins may be an option in chemoprophylaxis.35

According to a sub-analysis of another meta-analysis, the use of lipophilic statins (Atorvastatin) was associated with a significantly reduced risk of HCC compared with hydrophilic statins (Rosuvastatin) (51% vs. 27%). This finding could be explained by the greater lipid solubility and membrane permeability of lipophilic substances, enabling them to exert their cholesterol-dependent effects on HCC development.36

Antifibrotic therapies

Several drugs specifically targeting the pathogenesis of NASH are being tested, but obeticholic acid (OCA), a farnesoid X receptor agonist, is the only drug that has been shown to improve fibrosis without worsening NASH – based on an interim analysis of a phase III trial (REGENERATE). Moreover, OCA has several side effects, including pruritus and elevated LDL cholesterol levels. However, it has been reported that the increase in LDL cholesterol was transient and could be managed with statins.25-26 Thus, LDL cholesterol levels should be followed up regularly and treated as necessary. Long-term safety and efficacy need to be evaluated in real-world populations, particularly with regard to tolerability and cardio-vascular risk.

Pre- and probiotics

A growing body of research indicates that intestinal dysbiosis increases the intestinal barrier’s permeability, which makes it easier for substances like short-chain fatty acids, bile acids, bacterial components, choline, and endogenous ethanol to enter the liver and cause NAFLD and NASH.27 The gut-liver axis is affected by dietary variables, but this ecosystem can also be addressed more precisely using pre- and probiotics. Rats given probiotics were protected from acute hepatic damage, had a noticeably lower rate of cell proliferation, and had less significant intrahepatic leukocyte infiltration in a rat hepatocarcinogenesis model using the diethylnitrosamine (DEN) compound.28-29

Conclusion:

HCC prevention in patients with NAFLD/NASH should embrace a multifactorial approach that includes optimization of lifestyle habits, weight loss, management of metabolic comorbidities and chemoprevention when appropriate. Dietary factors, such as implementation of the Mediterranean diet and regular physical activity remain the mainstays of HCC prevention in the NAFLD/NASH population. In addition, coffee consumption, smoking and alcohol cessation are associated with a reduced risk of HCC. However, achieving more understanding of core pathophysiological mechanisms and disease phenotypes could lead to more targeted preventive strategies in the future.

Authors of this article

  1. Dr. Khandker Shamsul Arefin, MBBS; GM, Specialty Product Department, Jenphar Bangladesh LTD
  2. Md.Tourat Hossain, M.Pharm; Unit Manager, Specialty Product Department, Jenphar Bangladesh LTD
  3. Tania Akter Trishna, B.Pharm; Executive, Medical Department, SPD, Jenphar Bangladesh LTD

References

  1. Epidemiology of HCC in Bangladesh; https://doi.org/10.1016/j.annonc.2020.10.188
  2.  Liver Fat in metabolic syndrome; Kotronen A, Westerbacka J, Bergholm R, Pietiläinen KH, Yki-Järvinen H. J Clin Endocrinol Metab 2007;92:3490–3497. https://doi.org/10.1210/jc.2007-0482.
  3. Systemic Review of HCC 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(7):696–703.
  4. Evolution of NAFLD; Acknowledge by NASH; Singh S, Allen AM, Wang Z, Prokop LJ, Murad MH, Loomba R. Clin Gastroenterol Hepatol 2015;13:643–654. https://doi.org/10.1016/j.cgh. 2014.04.014.
  5. HCC Lifestyle factors; Kanwal F, Kramer JR, Li L, Dai J, Natarajan Y, Yu X, et al. Effect of metabolic traits on the risk of cirrhosis and hepatocellular cancer in nonalcoholic fatty liver disease. Hepatology 2020 Mar;71(3):808–819.
  6. EASL recommended lifestyle advice for fatty liver patients; Howard Bv, Wylie-rosett J. Circulation 2002;106:523–527. https://doi.org/10.1161/01.CIR.0000019552.77778.04.
  7. Weght Loss on NAFLD/NASH; Promrat K, Kleiner DE, Niemeier HM, Jackvony E, Kearns M, Wands JR, et al.Hepatology 2010 Jan;51(1):121–129.
  8. Weight loss through lifestyle modification NASH; Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, et al. Gastroenterology 2015 Aug 1;149(2). 367-378.e5.
  9. Diet factors; Koumbi L. Dietary factors can protect against liver cancer development. World J Hepatol 2017 Jan 28;9(3):119–125.
  10. Diet association levels; George ES, Sood S, Broughton A, Cogan G, Hickey M, Chan WS, et al. Nutrients 2021 Jan;13(1):172.
  11. Dietary Interventions in Liver disease; Vuille-Lessard É, Lange NF, Riebensahm C, Dufour J-F, Berzigotti A. Hepatol Rep 2021 Apr 19. https://doi.org/10.1007/s11901-021-00563-z. https://link.springer.com/article/10.1007/s11901-021-00563-z.
  12. Dietary patterns in CLD; Li W-Q, Park Y, McGlynn KA, Hollenbeck AR, Taylor PR, Goldstein AM, et al. Hepatology 2014 Aug;60(2):588–597.
  13. Mediterranean diet advisement in HCC; Turati F, Trichopoulos D, Polesel J, Bravi F, Rossi M, Talamini R, et al. J Hepatol 2014 Mar;60(3):606–611.
  14. EASL recommended mediterrenean diet; Etemadi A, Sinha R, Ward MH, Graubard BI, Inoue-Choi M, Dawsey SM, et al. BMJ (Online) 2017;357. https://doi.org/10.1136/bmj.j1957.
  15. Mitochondrial dynamics And NAFLD; Longo M, Meroni M, Paolini E, Macchi C, Dongiovanni P. Metabolism 2021 Apr 1;117:154708.
  16. Physical activity risk of HCC; Saran U, Guarino M, Rodríguez S, Simillion C, Montani M, Foti M, et al. Anti-tumoral effects of exercise on hepatocellular carcinoma growth. Hepatol Commun 2018 May;2(5):607–620.
  17. Physical activity systemic review; Baumeister SE, Leitzmann MF, Linseisen J, Schlesinger S. J Natl Canc Inst 2019 Nov 1;111(11):1142–1151.
  18. Coffee, green tea intake and liver cancer; Tamura T,Wada K, Konishi K, Goto Y, Mizuta F, Koda S, et al. Nutr Canc 2018 Dec;70(8):1210–1216.
  19. Coffee consumption in liver cancer; Godos J, Micek A, Marranzano M, Salomone F, Rio DD, Ray S. Coffee consumption and risk of biliary tract cancers and liver cancer: a doseresponse meta-analysis of prospective cohort studies. Nutrients 2017 Aug 28;9(9).
  20. Coffee, including caffeinated and decaffeinated coffee & risk of HCC; Kennedy OJ, Roderick P, Buchanan R, Fallowfield JA, Hayes PC, Parkes J. BMJ Open 2017 May 9;7(5):e013739.
  21. Aspirin use & risk of HCC; Simon TG, Ma Y, Ludvigsson JF, Chong DQ, Giovannucci EL, Fuchs CS, et al. JAMA Oncol 2018 Dec 1;4(12):1683.
  22. Aspirin with HCC and liver-related mortality; Simon TG, Duberg A-S, Aleman S, Chung RT, Chan AT, Ludvigsson JF. N Engl J Med 2020 Mar 12;382(11):1018–1028.
  23. Antidiabetic drugs regimen; Zhang H-L, Yu L-X, Yang W, Tang L, Lin Y,Wu H, et al. J Hepatol 2012 Oct;57(4):803–812.
  24. Antidiabetic drugs and risk of HCC: A systemic review;  Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Am J Gastroenterol 2013 Jun;108(6):881–891.
  25. Antifibrotic therapies (REGENERATE Study) evaluating the safety and efficacy of OCA in patients with fibrosis due to nonalcoholic steatohepatitis; Ratziu V, Sanyal AJ, Loomba R, Rinella M, Harrison S, Anstee QM, et al. Contemp Clin Trials 2019 Sep;84:105803.
  26. OCA approved for NASH; Eslam M, Alvani R, Shiha G. Lancet 2019 Dec 14;394(10215):2131–2133.
  27. Gut microbiota-derived mediators as potential markers in NAFLD; Aragonès G, González-García S, Aguilar C, Richart C, Auguet T. Biomed Res Int 2019 Jan 2;2019:1–10.
  28. Gut microbiome in HCC: Mechanisms, diagnosis; Schwabe RF, Greten TF. J Hepatol 2020 Feb;72(2):230–238.
  29. Risk of HCC in diabetic patients and risk reduction associated with anti-diabetic therapy: a population-based cohort study; Lai S-W, Chen P-C, Liao K-F, Muo C-H, Lin C-C, Sung F-C. Am J Gastroenterol 2012 Jan;107(1):46–52.
  30. Association of diabetes treatment with the risk of HCC; Hassan MM, Curley SA, Li D, Kaseb A, Davila M, Abdalla EK, et al. Cancer 2010 Apr 15;116(8):1938–1946.
  31. Effect of pioglitazone on outcome following curative treatment for hepatocellular carcinoma in patients; Sumie S, Kawaguchi T, Kawaguchi A, Kuromatsu R, Nakano M, Satani M, et al. Mol Clin Oncol 2015 Jan;3(1):115–120.
  32. Pioglitazone reduces HCC development in cirrhosis; Li S, Ghoshal S, Sojoodi M, Arora G, Masia R, Erstad DJ, et al. J Gastrointest Surg 2019 Jan;23(1):101–111.
  33. Pioglitazone and bladder cancer risk: a systematic review; Tang H, Shi W, Fu S, Wang T, Zhai S, Song Y, et al. Canc Med 2018 Apr;7(4):1070–1080.
  34. Statin use decreases the incidence of HCC; Facciorusso A, Abd El Aziz MA, Singh S, Pusceddu S, Milione M, Giacomelli L, et al. Cancer 2020 Apr 3;12(4):874.
  35. Effects of Statins on HCC; Islam MdM, Poly TN, Walther BA, Yang H-C, Li Y-C (Jack). Cancer 2020 Mar 13;12(3):671.
  36. Hydrophilicity/ lipophilicity Statins; Hamelin B. Trends Pharmacol Sci 1998 Jan 1;19(1):26–37.