With the prevalence of hepatitis C virus expected to decline, the proportion of hepatocellular carcinoma (HCC) related to non-alcoholic steatohepatitis (NASH) is anticipated to increase exponentially due to the growing epidemic of obesity and diabetes. The annual incidence rate of developing HCC in patients with NASH-related cirrhosis is not clearly understood with rates ranging from 2.6%-12.8%. While multiple new mechanisms have been implicated in the development of HCC in NASH; further prospective long-term studies are needed to validate these findings. Recent evidence has shown a significant proportion of patients with non-alcoholic fatty liver disease and NASH progress to HCC in the absence of cirrhosis. Liver resection and transplantation represent curative therapeutic options in select NASH-related HCC patients but have placed a significant burden to our healthcare resources and utilization. Currently NASH-related HCC is the fastest growing indication for liver transplant in HCC candidates. Increased efforts to implement effective screening and preventative strategies, particularly in non-cirrhotic NASH patients, are needed to reduce the future impact imposed by NASH-related HCC.

Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancers Worldwide, HCC being the sixth most common cancer, and is the second leading cause of cancer-related death[1]. HCC largely occurs in the background of chronic liver disease and cirrhosis of the liver[2]. The leading liver disease etiologies for cirrhosis in patients with HCC include but are not limited to chronic hepatitis B, chronic hepatitis C virus (HCV), and alcoholic liver disease. With advent of curative treatments for HCV, the risk of progression to cirrhosis and development of HCC secondary to HCV is anticipated to decline. However, in recent years, non-alcoholic fatty liver disease (NAFLD) has quickly risen as one of leading etiologies for liver disease. NAFLD is a spectrum of chronic liver disease ranging from simple hepatic steatosis to liver cell injury and inflammation known as non-alcoholic steatohepatitis (NASH). The rising incidence of NAFLD/NASH has subsequently led to a dramatic rise in NASH-related HCC incidence[3]. Numerous studies have demonstrated that NASH can lead to advanced fibrosis and cirrhosis, thereby increasing the risk of developing HCC[4-6]. Among patients with NAFLD or NASH, liver disease is the third leading cause of death[4], while HCC represents the main cause of death in this group[7]. The cumulative annual incidence rate for developing HCC in patients with NASH-related cirrhosis is approximately 2.4%-12.8%[8]. In the absence of NASH or cirrhosis, NAFLD can present with HCC. These patients usually present with less aggressive tumors and are less likely to diagnosed by surveillance compared to HCC that develops in the setting of viral hepatitis[9-11]. A similar rising trend has been reported in NASH progressing to HCC in the absence of cirrhosis[12-14]. In NASH, several risk factors for HCC development have been identified including metabolic syndrome and insulin resistance causing changes in serum cytokines, persistent inflammation, and altered gut microflora and bile composition[15].

Currently, NAFLD affects more than 80 million Americans, making it the most common etiology for liver disease in the United States. With the incidence of obesity, diabetes and metabolic syndrome continuing to increase in the United States and Europe, NAFLD/NASH may become the most common cause of HCC in developed countries in the near future[16]. In 2012, primary liver cancer was recognized overall as the second most common cause of cancer-related death in the world. In the United States, HCC is the most rapidly rising cause of cancer and cancer-related deaths with an incidence that has tripled over the last decade. This high likelihood for mortality reflects a poor prognosis without therapeutic intervention[17]. HCC is the most prevalent histological subtype accounting for 70%-85% of primary liver malignancies[18]. Compared to HCC in alcoholic liver disease and viral hepatitis, there is a lack of strong epidemiological data regarding the incidence and prevalence of HCC in NAFLD[19]. While the prevalence of NAFLD is thought to be highest among Hispanics and Caucasians, the ethnic distribution among NAFLD/NASH-related HCC patients has yet to be defined[20]. NASH-related HCC patients are predominantly male; however, gender has not been proven to be a statistical risk factor NASH progression to HCC[21]. Studies analyzing demographic and clinical characteristics of NASH-related HCC patients are outlined in Table 1. Reports indicate that NASH can be verified by histological evaluation in up to 47% of all NAFLD cases among obese individuals[22,23]. Amongst a growing population of diabetes which has surpassed 26 million in the United States, the prevalence of biopsy-proven NAFLD and NASH has been reported to be as high as 74% and 11%, respectively[24,25].

This rise in the incidence of NASH-related HCC has impacted trends in liver transplantation as well. A retrospective cohort study amongst adult liver transplant recipients from 2002-2012 indicated that there was 4-fold increase in patients undergoing liver transplant for NASH-related HCC compared to 2-fold increase in number of patients undergoing transplantation for HCV-related HCC[26]. During this 10-year span, NASH also became the second leading cause of HCC-related liver transplantation in America, steadily increasing from 8.3% in 2002 to 10.3% in 2007 and to 13.5% in 2012[16], and most likely will surpass 15% by 2017.

NAFLD is the hepatic manifestation of metabolic syndrome, with insulin resistance driving the alteration in physiology. As mentioned earlier, it ranges from isolated hepatic steatosis, to NASH with or without cirrhosis, and progression to HCC. The diagnosis of NASH is based on histological evidence of hepatic steatosis or magnetic resonance spectroscopic evidence > 5% fat accumulation of liver weight without the presence of secondary causes such as alcohol abuse, endocrine disorders, chronic HCV infection or familial hypobetalipoproteinemia[27]. Recent evidence has demonstrated an association between NASH and HCC to be exclusive to patients who had progressed to cirrhosis, suggesting causality[8].

Compared to benign course of simple steatosis, patients with NASH are more likely to develop progressive advanced liver disease. Matteoni et al[28] demonstrated increased rates of cirrhosis in patients with NASH compared to those with fatty liver without NASH (25% vs 3%, respectively), and increased risk of liver disease-related death (11% vs 2%, respectively). In a much larger study across the entire spectrum of NAFLD which included 420 patients, Rafiq et al[29] demonstrated a higher mortality in those with NASH/NAFLD when compared to the general population; liver-related deaths occurred in 13% vs < 1% in general population, and 3% of those with NAFLD developed cirrhosis. Another study further confirmed increased rate of liver-related deaths among patients with NASH when compared with those without NASH (17.5% vs 3%, respectively). In patients with compensated cirrhosis, NASH-related cirrhosis patients had better survival outcomes compared to HCV-related cirrhosis patients. However, in decompensated cirrhosis both cohorts had comparable poor outcomes[30,31]. Currently, both the American Association for the Study of Liver Diseases, and the European Association for the Study of Liver Disease recommend screening for HCC in patients with NASH related cirrhosis every 6-12 mo[32].

Emerging evidence suggests that a significant proportion of patients with NAFLD-associated HCC, do not have histologic evidence of cirrhosis. In a study conducted by Kawada et al[13], of 1168 patients who underwent hepatic resection for HCC, 6 of 8 patients with NASH-related HCC did not demonstrate cirrhosis. This study suggested that the presence of cirrhosis in NASH-related HCC was lower compared to HCV-related HCC. These data suggest that compared to patients HCV, HCC may develop at an earlier stage those with NASH. Paradis et al[33] analyzed 128 HCC patients who were recruited over 12 years, and reported significant number of patients with NASH developed HCC in the absence of fibrosis when compared to HCC in the setting of other underlying chronic liver disease (65% with F0-F2 in NASH group vs 26% in chronic liver disease)[33,34]. To explain this phenomenon in non-cirrhotic NAFLD patients, one proposed hypothesis is the malignant transformation of hepatic adenoma. Few published reports have suggested that in the presence of metabolic syndrome, hepatocellular adenoma may incur a malignant transformation[19,35].

During the last two decades, various studies have tried to determine the relationship between NAFLD/NASH, cryptogenic cirrhosis and HCC. A recent meta-analyses by White et al[8] showed that approximately 60% HCC cases attributed to NAFLD/NASH had cirrhosis either before or at the time of diagnosis. This meta analyses also included review of cohort and longitudinal studies which showed that NASH-associated cirrhosis consistently carried an increased HCC risk ranging between 2.4% and 12.8%[8]. Additionally, this study reported the risk of developing HCC is lower in patients with cirrhosis due to NAFLD/NASH when compared to those with chronic HCV (NAFLD/NASH, 26.9% vs HCV, 19.7%).

The true prevalence of NASH and NASH-related HCC is likely underestimated. In up to 6.9%-29% of HCC, the underlying etiology of liver disease is unknown and is considered secondary to cryptogenic cirrhosis[19]. Features suggestive of NASH are more frequently observed in HCC arising in patients with cryptogenic cirrhosis than in age- and sex-matched HCC patients of well-defined viral or alcoholic etiology[36]. Although the prevalence of NAFLD/NASH-related HCC is not well defined, the increasing incidence of obesity and diabetes, suggests the impact of NAFLD/NASH-related HCC will continue to grow.

Long term outcomes in NAFLD and NASH has been evaluated in several studies and distinctive differences between NASH and non-NASH subtypes of NAFLD have been shown[28,29,37-42]. Type 2 diabetes mellitus has been shown to increase the risk of both liver- related mortality and overall mortality in NAFLD patients[43,44]. In light of these findings NAFLD patients with type II diabetes should be prioritized in future treatment protocols[44]. A population-based study published in 1996 followed 153852 subjects and found that diabetic patients had a standardized incidence ratio of 4.1 for HCC[45]. However, another retrospective analysis from United States Veteran Registry noted increased the risk of primary liver cancer in patients with diabetes only in the presence of other risk factors such as hepatitis C or B or alcoholic cirrhosis[46]. These observations were not supported by further analysis that found an incremented HCC risk in diabetic patients independently from alcoholic liver disease and viral hepatitis[47,48]. In a recent meta-analyses, Younossi et al[49] reported that in NAFLD patients, annual incidence of HCC was 0.44 per 1000 person-years (95%CI: 0.29-0.66), whereas for those with NASH, the annual HCC incident rate was 5.29 per 1000 person-years (95%CI: 0.75-37.56). Among NAFLD cohort, the pooled liver-specific and overall mortality incidence rates were 0.77 per 1000 person-years (95%CI: 0.33-1.77 events) and 15.44 per 1000 person-years (95%CI: 11.72-20.34 events), respectively. Among the NASH cohort, the pooled liver-specific and overall mortality incidence rates were 11.77 per 1000 person-years (95%CI: 7.10-19.53 events) and 25.56 per 1000 person-years (95%CI: 6.29-103.8 events), respectively.

Although cardio-vascular (CV) events remain the major cause of death in patients with NAFLD and NASH, the CV mortality rate amongst the NASH and non-NASH subtypes of NAFLD is similar[42,50-52]. Since patients with NASH have significantly higher liver-related mortality than those with non-NASH NAFLD, treatment strategies should be designed to ameliorate the risks for cardiovascular mortality[28,29,38,40-42,49,50]. Further, patients with NASH and type 2 diabetes mellitus, will need increased attention and linkage of care to reduce liver disease-related compliactions and to reduce their risk of HCC[53-55].

Development of HCC in the setting of chronic liver disease is a complex but gradual process that requires transition through a dysplasia-carcinoma sequence. Several putative oncogenic mechanisms has been incriminated that lead to genomic instability, including telomere erosion, chromosome segregation defects and alterations in the DNA-damage-response pathways[56,57]. Obesity and diabetes are involved in the mechanisms involved in the development of HCC in NAFLD. The development of HCC in NAFLD is likely multifactorial; involving low grade chronic systemic inflammatory response, increased lipid storage and lipotoxicity, gut disbiosis with elevated levels of lipopolysaccharide (LPS) and hyperinsulinemia with insulin resistance and increased IGF levels[19]. In addition patients with HCC from NAFLD in general has a distinctive phenotype with presentation in older age, being less aggressive and less likely to be diagnosed by surveillance compared with HCC caused by viral hepatitis[9-11]. Other factors such as genetic polymorphism and, increased iron absorption may also lead to development of HCC in NASH[14]. Proposed mechanisms for NASH-related HCC are depicted in Figure 1.

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Figure 1 Risk factors and proposed mechanisms for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis-related hepatocellular carcinoma. The development of NAFLD and NASH-related HCC is multifactorial. Proposed pathogenic mechanisms include obesity, peripheral and hepatic insulin resistance from type 2 diabetes, increased hepatic lipid storage and lipotoxicity, EMT, genetic mutations and intestinal mibrobiota dysregulation. HCC: Hepatocellular carcinoma; EMT: Epithelial to mesenchymal transition; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis; FFA: Free fatty acid; IGF: Insulin-like growth factor; LPS: Lipopolysaccharide; PNPLA3: Patatin-like phospholipase domain-containing 3; TM6SF2: Transmembrane 6 superfamily member 2.

Cytokines carry out the intercellular communication signals, cellular interactions along with growth and differentiation. Disease states cause imbalances in cytokine levels promoting aberrant signaling and modulating inflammatory responses seen in epithelial to mesenchymal transition pathologic process[15]. Imbalances in the levels of cytokines such as tumor necrosis factor (TNF)-alpha, leptin, adiponectin and interleukin-6 (IL-6) play a pivotal role in NASH[58-60].

With the increasing prevalence of NAFLD/NASH and associated HCC, chemopreventive and perhaps reconsideration of current surveillance guidelines are needed[16]. The current AASLD guidelines recommend screening for HCC every 6 mo in patients with cirrhosis. However, the current guidelines lack recommendations for surveillance of NASH patients without cirrhosis who are at risk for developing HCC. This is further supported by a study performed by Mittal et al[79] in which the data collected on about 1500 HCC patients where HCC related to NASH received less surveillance and treatment compared with HCC arising in underlying etiologies related to HCV and alcohol.

The lack of longitudinal data in the non-cirrhotic NASH population makes it difficult to develop good evidence - based screening guideline. There is a need for studies addressing the screening guidelines for surveillance of HCC in NASH particularly for non-cirrhotic individuals. We suspect that earlier screening may be needed in patients with NASH who have multiple risk factors for HCC[19].

The biological heterogeneity of HCC makes it difficult to clarify the key mechanisms of cancer development and thus to develop and implement effective therapies[80]. A few chemopreventive agents have shown promise in the prevention and treatment of steatohepatitis and fibrosis; however these are small individual studies and thus there is a lack of a general consensus due to paucity of data. There is currently no effective chemoprevention to decrease the incidence of HCC. Exceptions include nucleoside analogues used to reduce viral replication in those with hepatitis B, and DAAs for HCV which have very high cure rates[81].

With the prevalence of HCV expected to decline, NASH is anticipated to account for a greater proportion of HCC incidence in the near future due to the growing epidemic of obesity and diabetes. The annual incidence rate of developing HCC in patients with NASH-related cirrhosis is not clearly understood with rates ranging from 2.6%-12.8%. Recent evidence has shown a significant proportion of patients with NAFLD and NASH progress to HCC in the absence of cirrhosis. While liver resection and transplantation represent curative therapeutic options in select NASH-related HCC candidates, they also have placed a significant burden to our healthcare resources and utilization. Currently NASH-related HCC is the fastest growing indication for liver transplant in HCC candidates. Increased efforts to implement effective screening and preventative strategies, particularly in non-cirrhotic NASH cohort, are needed to reduce the future impact imposed by NASH and NASH-related HCC.