Systematic Review With Meta-analysis

Risk of Hepatocellular Carcinoma in Non-alcoholic Steatohepatitis Without Cirrhosis Compared to Other Liver Diseases

Jonathan G. Stine; Brian J. Wentworth; Alex Zimmet; Mary E. Rinella; Rohit Loomba; Stephen H. Caldwell; Curtis K. Argo


Aliment Pharmacol Ther. 2018;48(7):696-703. 

In This Article

Abstract and Introduction


Background: Given the lack of long-term prospective studies, it is challenging for clinicians to make informed decisions about screening and treatment decisions regarding the risk of hepatocellular carcinoma (HCC) in patients with non-alcoholic steatohepatitis (NASH) who do not have cirrhosis.

Aim: To characterise the pooled risk of HCC in the non-cirrhosis population.

Methods: Published studies were identified through April 2016 in MEDLINE, Scopus, Science Citation Index, AMED and the Cochrane Library. Two independent reviewers screened citations and extracted data. Random effect odds ratios (OR) were calculated to obtain aggregate estimates of effect size between NASH and non-NASH groups. Between-study variability and heterogeneity were assessed.

Results: Nineteen studies with 168 571 participants were included. Eighty-six per cent of included subjects had cirrhosis. The prevalence of HCC in non-cirrhotic NASH was 38.0%; among other aetiologies in non-cirrhotics, it was 14.2% (P < 0.001). Non-cirrhotic NASH subjects were at greater odds of developing HCC than non-cirrhotic subjects of other aetiologies (OR 2.61, 95% CI 1.27–5.35, P = 0.009). When examining all NASH subjects either with or without cirrhosis, those with NASH as the underlying liver disease did not have a significantly increased risk of HCC (OR 1.43, 95% CI 0.77–2.65, P = 0.250).

Conclusions: In non-cirrhotic subjects, those with NASH have a higher risk of HCC compared to other aetiologies of liver disease. Further study investigating the risk factors of HCC among non-cirrhotic NASH patients is needed.


Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease worldwide.[1–3] Typically associated with the metabolic syndrome (hypertension, hyperglycemia, central obesity and dyslipidemia), the pathogenesis of NAFLD is characterised by a dysfunctional central adipose tissue compartment and insulin resistance leading to the release of inflammatory cytokines, as well as down regulation of adiponectin, an anti-inflammatory molecule.[4,5] The downstream effects of this imbalance lead to lipid deposition in hepatocytes, causing lipotoxicity which interferes with intracellular signaling.[6] In addition, fatty acid oxidation yields free radicals, resulting in oxidative stress.[7] The subsequent hepatic inflammatory response leads to non-alcoholic steatohepatitis (NASH) in 25% of patients.[8] Prolonged damage may ultimately lead to cirrhosis in approximately 20% of NASH patients (about 4%-5% of NAFLD patients).[2,9]

The prevalence of NAFLD has increased dramatically over the past several decades. In the USA, 30%–40% of adults have NAFLD[4] and the prevalence in Japan is between 20% and 35% of the adult population.[1,9,10] These figures are predicted to rise exponentially, as the World Health Organization estimates that the global percentage of overweight adults will increase from 35% to 57.8% by 2030.[11] There is also mounting evidence that the prevalence of NASH is underestimated and that patients with cryptogenic cirrhosis may primarily have underlying NASH.[12,13]

NASH has gained particular attention over the last decade because of its association with hepatocellular carcinoma (HCC). This is largely driven by both lipotoxicity and insulin resistance, ultimately leading to increased fibrogenesis, inflammation and abnormal cellular proliferation in addition to alteration of cell death via apoptosis, necroptosis and autophagy, are associated with HCC.[5] The incidence of HCC has increased by more than threefold over the past 30 years from 1.5 to 4.9 per 100 000, and HCC is now the 5th most common cancer worldwide and 3rd leading cause of cancer-related death.[14] Rates of HCC are also increasing in the USA with nearly a fourfold increase from 1.5 to 6.2 per 100 000 persons since 1973.[15] Notably, there has been a stark increase in the percentage of HCC arising from a nonviral aetiology. The Japanese NOBLESSE study group found that this more than doubled from 10% in 1991 to 24.1% in 2010.[16] While HCC often arises in the presence of cirrhosis (with an exception being chronic hepatitis B given the direct hepatotoxic nature of the virus), NASH-associated HCC may develop in both the presence and absence of cirrhosis.[5,17,18] For this reason, there may be a substantial number of higher risk patients who are not captured by routine HCC screening per current guidelines from the American Association for the Study of Liver Diseases (AASLD).[19]

Given the potential for NASH to become a leading cause of HCC in the future,[20] estimating its substantial morbidity and mortality is important. Tokushige et al[9] demonstrated that 11.3% of patients with NASH cirrhosis developed HCC within 5 years, on par with a 12.5% rate for patients with alcoholic cirrhosis; however, survival is lower.[21] In addition, NASH cirrhosis is currently the second leading indication for liver transplantation (LT) in the USA.[22] However, transplant candidates with NASH cirrhosis and HCC are less likely to undergo LT, perhaps in part because of the more advanced stage of their tumours at the time of diagnosis and an increased burden of medical comorbidity in the setting of advanced age.[23] While the literature clearly demonstrates an association between HCC and NASH on an individual study level, large scale studies are lacking in this patient population as we are aware of only one other meta-analysis investigating this subject incorporating studies from 2012 and before which found that HCC risk was largely limited to NASH cirrhosis patients.[24] This makes informed decisions regarding HCC screening, surveillance and treatment difficult for the clinician. We aimed to determine the pooled risk of HCC in patients with NASH both in the presence and absence of cirrhosis using the available literature.