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Page 2 of 11 Raza et al. Hepatoma Res 2019;5:42 I http://dx.doi.org/10.20517/2394-5079.2019.014

recognised as the major causes of HCC; however, the incidence of virus-associated HCC is expected to
decrease in the near future due to the development of effective and inexpensive vaccines for HBV and
[1,2]
potent anti-HCV drugs . In contrast, the prevalence of non-viral hepatitis continues to rise and has
[3]
become the major cause for liver transplantation in Europe and the USA . The increased prevalence of
metabolic disorders, particularly diabetes, NAFLD and obesity, have led to changes in the epidemiology
[4]
and aetiology of HCC . Obesity is considered a risk factor for hepatic complications such as NAFLD and
[5-9]
HCC . Although 17%-33% of the general population is estimated to be affected by NAFLD, it reaches 75%
in obese individuals and is even higher in patients with type II diabetes mellitus (T2DM) [10,11] . Moreover,
[12]
T2DM itself is associated with an increased risk of liver damage , including HCC [13-15] . Chronic damage to
liver metabolism caused by alcohol and poor nutrition leads to alcoholic liver disease that can co-exist with
NAFLD/non-alcoholic steatohepatistis (NASH), and thereby increases both the progression of NAFLD and
[2,3]
the risk for NAFLD/NASH-associated HCC .
This review focuses on NAFLD-associated HCC, and describes its epidemiology and the clinical, cellular,
metabolic, microbiome and endocrine factors that promote the development of HCC from NAFLD.
We also examine the molecular pathways that lead to progression from NAFLD to HCC as well as the
challenges and future directions for its treatment and prevention.

NAFLD INCREASES THE RISK OF LIVER CANCER
NAFLD encompasses a spectrum of liver pathologies which involve an accumulation of triglycerides in the
hepatocytes, hepatocyte apoptosis, liver inflammation and fibrosis termed as NASH, and, in extreme cases,
[16]
it can progress to cirrhosis and HCC . NAFLD is the most common cause of HCC across the globe [16-28] .
Although the progression of NAFLD to HCC involves NASH and cirrhosis, the direct development of
HCC from benign steatosis or non-cirrhotic NASH has also been reported [29,30] . The increased prevalence
of the underlying liver disease in the general population has led to an increase of 9% in the annual rates of
[31]
incidence of NAFLD-associated HCC . Interestingly, HCC can progress from NASH as well as cirrhosis.
[32]
In a study cohort based on 756 patients, Piscaglia et al. reported that 46.2% of the NAFLD associated
HCC cases occurred without cirrhosis. Similar results were reported by a Japanese study, in which 49%
[33]
of NAFLD associated HCC cases arose without cirrhosis , and a German study where 41.7% of the cases
[34]
arose without cirrhosis . Furthermore, in animal models, diet-induced NAFLD leads to spontaneous
[35]
HCC .

CELLULAR MECHANISMS INVOLVED IN NAFLD PATHOGENESIS
NAFLD is a complex disease with multiple modifiers such as diet, lifestyle and gut microbiota which act
in a susceptible genetic/epigenetic environment and modulate response to calorific excess [36,37] . The role
of insulin resistance is central to this pathophysiological process and causes an increase in hepatic fat
[38]
accumulation by increased deposition of free fatty acids (FFAs) . This leads to oxidative stress, protein
[38]
misfolding, autophagy inhibition and mitochondrial damage within hepatocytes, termed as “lipotoxicity” .
Chronic lipotoxicity challenges hepatocytes with both oxidative and endoplasmic reticulum (ER) stress.
Oxidative stress mediated by reactive oxygen/nitrogen species (ROS/RNS) play a major role in NAFLD/
NASH pathogenesis and complications. The high production of ROS causes mitochondrial damage, lipid
peroxidation and low-density lipoprotein oxidation culminating into inflammation, activation of hepatic
[39]
stellate cells (HSCs) leading to fibrogenesis, necrosis, cirrhosis and HCC .

ER stress is cell activated to regulate protein synthesis and restore homeostatic equilibrium in response
to accumulation of unfolded or misfolded proteins. However, deregulated or insufficient responses to ER
stress in liver may lead to lipid accumulation, insulin resistance, inflammation and apoptosis, all of which
[40]
play important roles in the pathogenesis of NAFLD . These events lead to inflammation and fibrosis as
macrophage infiltration, hepatic progenitor cell activation and fibrogenesis ensue [41,42] . There are multiple