NAFLD is a wide spectrum disease ranging from simple steatosis, NASH to liver cirrhosis and is the most common type of CLD in the Western world. Many studies showed increased incidence of T2 DM in patients with NAFLD independently of ordinary risk factors. The risk of T2 DM ranged from 33% to 55% in patients with NAFLD [1].

A meta-analysis of 20 observational studies, involving more than 115 000 individuals, demonstrated that NAFLD was associated with an almost two-fold increased risk of T2 DM over a median period of 5 years [2]. The prevalence of NAFLD is estimated to be about 25% in the general population, and even higher in certain parts of the world and in some patient populations, such as among the obese and patients with diabetes. This high prevalence is closely associated with the rise in the rates of obesity and MS. Components of MS include increased fasting plasma glucose or T2DM, hypertriglyceridemia, low high density lipoprotein level, increased waist circumference, and hypertension [3].

Bidirectional relation between NAFLD and MS component was documented recently, most important is T2DM. This association carries more burdens to CVD, also cancer including HCC [1,4]. Observational studies have shown that older age, too much fibrosis, diabetes, obesity, MetS, high iron, much alcohol consumption, and menopause are further risk factors for HCC development in NAFLD/NASH [3]. HCC is rare among adolescents and accounts for less than 1% of all malignant neoplasms among children younger than 20 years [5].

The progression to HCC in NAFLD happens particularly in those with NASH and exacerbated by metabolic syndrome (Table 1), or PNPLA3 gene polymorphism [6].

RR, Risk Ratio

The pathophysiology of NAFLD involves many factors, and the intestinal microbiota plays an important role in the pathogenesis of both NAFLD and HCC. NAFLD and NASH are associated with alterations in the gut microbial population through various routes, such as alterations in gut epithelial permeability, choline metabolism, endogenous alcohol production, release of inflammatory cytokines, regulation of hepatic TLR, and bile acid metabolism. In addition, altered bile acid metabolism, release of inflammatory cytokines, and TLR-4 expression may promote NAFLD/NASH-associated HCC [8] (Figure 1).

Role of Obesity and MS in HCC Pathogenesis

Obesity and metabolic syndrome lead the oncogenesis in the setting of abnormal hepatic morphology, and hepatic steatosis may provide the appropriate microenvironment for the development of cancer. Insulin resistance leads to fat accumulation in the hepatocytes by lipolysis and hyperinsulinemia. Obesity may lead to release of pro-inflammatory cytokines, inhibition of anti -inflammatory cytokines, and lipotoxicity.

Abbreviations: DAMP, damage-associated molecular pattern; LPS, lipopolysaccharide; PAMP, pathogen-associated molecular pattern. Adapted from [9].

Although the RRs of DM, obesity, and metabolic syndrome do not approach those of HCV or HBV (table 2), they are far more prevalent conditions than HCV and HBV in developed countries. Given the increasing prevalence of these conditions, the proportion of HCC related to obesity, DM, and metabolic syndrome will likely increase in the future [10].

HCC in NAFLD Non-cirrhosis

Has usually large measurements, is partially or well differentiated, and generally lacks encapsulation. HCC in NAFLD may arise in the absence of histologically definite or evident inflammation. Dysregulated hepatic and circulating pro-inflammatory cytokines and adipokines, oxidative and endoplasmic reticulum stress, and dysbiosis are likely associated with obesity-related Hepatocarcinogenesis [12].

 An interesting possibility is the malignant transformation of hepatocellular adenoma, associated with obesity in non-cirrhotic patients with NAFLD [3]. Currently, there is a lack of recommendations for surveillance of patients with NASH and without cirrhosis, probably because of the difficulty of identifying patients with NASH without a liver biopsy. However, recent blood-based biomarkers could be an affordable

alternative for identification of patients at high risk of NASH and advanced fibrosis [13].

The incidence and prevalence of HCC in NAFLD depend on the stage of underlying fatty liver disease. While the epidemiological data in relation to HCC in viral hepatitis and alcoholic hepatitis are consistent, there is a lack of strong epidemiological data concerning the incidence and prevalence of HCC in NAFLD. A few longitudinal outcome studies explored the prevalence of HCC in NASH, reporting a prevalence varying from 0 to 3% on a follow-up period between 5.6 and 21 years. The percentage was increased if the incidence of HCC in NAFLD cirrhosis was considered, with a cumulative HCC incidence ranging between 2.4% with a median follow-up of 7.2 years and 12.8% with a 3.2-year median follow-up [14].

Is That Possible to Stop or Cease the NASH to Turn into HCC and increase its incidence?

We do not exactly know this because the etiopathogenesis of NASH is not completely known. Primary prevention, which is our aim focuses on risk factors for HCC and their treatment, secondary prevention concentrates on the treatment of underlying liver diseases in patients with HCC aiming at a prevention of disease progression, and tertiary prevention aims at a reduction of recurrence after successful curative treatment of HCC [15].

A few chemo preventive agents have shown promise in the prevention and treatment of steatohepatitis and fibrosis (small individual studies); thus there is a lack of a general consensus due to paucity of data. Exceptions include nucleoside analogues used to reduce hepatitis B viral replication, and DAAs for HCV which have very high cure rates [16].

Preventions and Treatment in NAFLD-Related HCC

Lifestyle changes

Considering the pathogenesis of HCC in NAFLD, one has to face the burden of obesity and diabetes, lifestyle changes is the cornerstone for primary prevention and has been shown to reduce incident NAFLD and the related metabolic disorders and also may reverse NASH and liver fibrosis. It has been reported to have a preventive effect on the development of HCC. A protective effect in the development of HCC has been attributed in general to the Mediterranean diet. Bariatric surgery could be recommended for patients with morbid obesity, it may reduce Liver fibrosis but carries a risk of decompensation in advanced cirrhotics. Observational studies and animal work suggest that exercise can prevent HCC development (inhibition of mTOR and the activation of AMPK, which are both involved in cell growth and proliferation). In a prospective cohort Study on 507,897 subjects followed up for 10 years: a RR of 0.56 for HCC was found in vigorously active (≥5 days/week) compared to sedentary subjects (independent of BMI) [3,10].

Dietary Supplements, Role and Mechanism: Tables 3,4 and Figure 2

Chemoprevention, Role and Mechanism: Tables 5 and Table 6

So, lack of a general consensus due to paucity of data makes us still do not know if it is Possible to Stop or Cease the NASH to Turn into HCC and increase its incidence. However, Exercise, especially vigorous (RR of 0.56), Metformin (Reduced incidence 50% in diabetics) and Statins (In NAFLD without cirrhosis HR 0.29) may be helpful. Obeticholic acid, Elafibranor, Selonsertib and Cenicriviroc, the new drugs for NAFLD/NASH treatment we are waiting for, may carry more hope to decrease HCC.

Figure 1: Role of Obesity and MS in HCC Pathogenesis.

Figure 2: showed [19].

Table 1: Association Between Metabolic Syndrome and HCC: Systemic Review and Meta-Analysis- modified from [7].

Table 2: Modified from [11].

Table 3: Adapted from [3,12,17,18].

Table 4: Adapted from [12,19].

Table 5: Adapted from [3,6,12,17,19].

Table 6: Adapted from [12,15].

1.       Hamed AE, Elsahar M, Elwan NM, El-Nakeep S, Naguib M, et al. (2018) Managing diabetes and liver disease association. Arab Journal of Gastroenterology 19: 166-179.

2.       Ballestri S, Zona S, Targher G, Romagnoli D, Baldelli E, et al. (2016) Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol 31: 936-944.

3.       Uygun A (2017) Is That Possible to Stop or Cease the NASH to Turn into HCC?: J Gastrointest Canc 48: 250-255.

4.       Wainwright P, Byrne CD (2016) Bidirectional Relationships and Disconnects between NAFLD and Features of the Metabolic Syndrome. Int. J. Mol. Sci 17: 367.

5.       Moore SW, Davidson A, Hadley GP, Kruger M, Poole J, et al. (2008) Malignant liver tumors in South African children: a national audit. World J Surg 32: 1389-1395.

6.       Mak LY, Cruz-Ramón V, Chinchilla-López P, Torres HA, LoConte NK, et al. (2018) Global Epidemiology, Prevention, and Management of Hepatocellular Carcinoma: 2018 Asco Educational Book.

7.       Jinjuvadia R, Patel S, Liangpunsakul S (2014) The association between metabolic syndrome and hepatocellular carcinoma: systemic review and meta-analysis. J Clin Gastroenterol 48: 172-177.

8.       Huikuan Chu, Brandon Williams, Bernd Schnabl (2018) Gut microbiota, fatty liver disease, and hepatocellular carcinoma: Liver Research 2: 43-51.

9.       Paradis V, Zalinski S, Chelbi E, et al. (2009) Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 49: 851-859.

10.    Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, et al. (2017) Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update: Hepatol Int: 11.

11.    Donadon V, Balbi M, Casarin P, Vario A, Alberti A (2008) Association between hepatocellular carcinoma and type 2 diabetes mellitus in Italy: Potential role of insulin: World J Gastroenterol 14: 5695-5700.

12.    Fujiwara N, Friedman SL, Goossens N, Hoshida Y (2018) Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine: Journal of Hepatology 68: 526-549.

13.    Vilar-Gomez E, Chalasani N (2018) Non-invasive assessment of nonalcoholic fatty liver disease: clinical prediction rules and blood-based biomarkers. J Hepatol 68: 305-315.

14.    White DL, Kanwal F, El-Serag HB (2012) Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 10: 1342-1359.

15.    Schütte K, Balbisi F, Malfertheiner P (2016) Prevention of Hepatocellular Carcinoma: Gastrointest Tumors 3: 37-43.

16.    Hosaka T, Suzuki F, Kobayashi M, Seko Y, Kawamura Y, et al. (2013) Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection. Hepatology 58: 98-107.

17.    Cholankeril G, Patel R, Khurana S, Satapathy SK (2017) Hepatocellular carcinoma in non-alcoholic steatohepatitis: World J Hepatol 9: 533-543.

18.    Said A, Ghufran A (2017) Epidemic of non-alcoholic fatty liver disease and hepatocellular carcinoma: World J Clin Oncol 8: 429-436.

19.    Uchida D, Takaki A, Adachi T, Okada H (2018) Beneficial and Paradoxical Roles of Anti-Oxidative Nutritional Support for Non-Alcoholic Fatty Liver Disease: Nutrients 10: 977.