Important environmental risk factors for HCC include chronic hepatitis virus infections, alcohol abuse, and non-alcoholic steatohepatitis (NASH). These risk factors are also relevant aetiologic factors for cirrhosis[4]. In Eastern Asia and sub-Saharan Africa the main risk factors for HCC are chronic hepatitis B infection and exposure to aflatoxin B1. In North America, Europe, and Japan, the main risk factors are chronic hepatitis C (CHC) infection and alcohol consumption[5]. HCV increases HCC risk by promoting cirrhosis and causing specific genetic lesions to the infected liver cells[6]. Clinically relevant hepatitis viral infections has been shown to predispose individuals to HCC, similarly, occult hepatitis B infection has been associated with the development of HCC[7].

Higher viral loads with prolonged infections have been correlated with the occurrence of HCC and may be due to accumulated risks from chronic oncogenic damage[8]. Daily alcohol consumption and Aflatoxin food contamination have been associated with increased risks of HCC[9,10]. Patients with CHC, increased insulin resistance and high serum adiponectin levels are more likely to develop liver cancer[11]. Metabolic syndrome, a combination of phenomena, including obesity, dyslipidaemia, insulin resistance and type 2 diabetes mellitus (DM), is a known potential risk factor for HCC. Due to obesity or other causes, NASH has been associated with increased risks of HCC[12,13]. DM has been associated with a two to three fold increased risk of HCC. Additionally, DM has been shown to affect the prognosis of HCC after curative therapies[14]. Furthermore, DM type 2 can lead to HCC caused by carcinogenic effects on the liver and other tissues from insulin-like growth factor-1 (IGF-1) due to hyperinsulinaemia and insulin-resistance (Figure ​(Figure11)[15,16]. The risk for HCC was particularly higher in diabetic patients treated with insulin[17]. However, Yamamoto et al[18], 2012, reported a case in which a dramatic regression of HCC was observed after four weeks of treatment with a dipeptidyl peptidase-4 enzyme (DPP-4) inhibitor in a patient with HCV-related chronic hepatitis. CD8+ T-cells were shown to accumulate around the HCC tissue, indicating that a DPP-4 inhibitor may safely exert beneficial effects on HCV-related HCC through immunity modulation[19]. A 1.7-fold increase in the incidence rates of HCC was reported for individuals with hereditary haemochromatosis confirming preliminary observations in smaller studies in related populations[20]. A correlation was also observed for alcoholics presenting with liver iron overload for increased risks of HCC and C282Y mutation in haemochromatosis[21].

Insulin resistance and the development of hepatocellular carcinoma (cited from Eslam et al[16], 2011). HCC: Hepatocellular carcinoma; HOMA-IR: Homeostasis model of insulin resistance; IRS: Insulin receptor; MAPK: Mitogen-activated protein kinase; IGF1: Insulin like growth factor 1; CTGF: Connective tissue growth factor.