Non-alcoholic Fatty Liver Disease Associated Hepatocellular Carcinoma

*Kai Sun, Alan Hodges and Maen Abdelrahim*

### **Abstract**

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of diseases ranging from non-alcoholic fatty liver and non-alcoholic steatohepatitis to its more severe forms such as liver fibrosis and cirrhosis. The incidence of hepatocellular carcinoma (HCC) increases as NAFLD progresses to the more severe forms. As prevalence of obesity and metabolic syndrome rising in North America, NAFLD associated HCC is becoming the leading cause of HCC. Different from other causes of HCC, altered metabolic state and its impact on immune response play an important role in the pathogenesis of NAFLD associated HCC. Currently, immune checkpoint inhibitors and combination therapy are first-line treatments of advanced HCC regardless of etiologies. Given the rising incidence of NAFLD associated HCC and its unique pathogenesis, future clinical trials should assess whether HCC etiology—NAFLD in particular—influence the safety and efficacy of a given treatment.

**Keywords:** hepatocellular carcinoma, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, liver cirrhosis, tyrosine kinase inhibitor, immunotherapy

#### **1. Introduction**

Non-alcoholic fatty liver disease (NAFLD) is defined as the presence of >= 5% hepatic fat accumulation of the liver in the absence of other causes of fatty liver disease. NAFLD is a spectrum of diseases. In its mildest form- non-alcoholic fatty liver (NAFL, also known as simple hepatic steatosis)- fat accumulation is seen in the liver but without significant inflammation or hepatocellular injury. The next stage of NAFLD is non-alcoholic steatohepatitis (NASH) which is characterized by histological lobular inflammation and hepatocyte ballooning. The condition then progresses to liver fibrosis and accumulation of fibrosis leads to liver cirrhosis [1]. In studies [2–5] that examined paired liver biopsies in patients with baseline NAFLD, up to 20–40% patients with NAFL can progress to fibrosis over an average follow-up between 2.2 and 13.8 years. In a meta-analysis including 411 patients with NAFLD, 35.8%, 32.5%, 16.7%, 9.3%, and 5.7% patients exhibited stage 0,1,2,3,4 fibrosis, respectively with an average fibrosis progression of 0.07 stages per year [6]. The rate of progression is twice as high in patients with NASH and a subgroup of both NASH and NAFL patients may rapidly progress from no fibrosis to advanced fibrosis over an average of six years [3, 7].

NAFLD is considered the hepatic manifestation of metabolic syndrome and many other manifestations of metabolic syndrome including obesity and type 2 diabetes mellitus (T2DM) are independent risk factors of NAFLD. As metabolic syndrome becomes epidemic, the predicted prevalence of obesity will reach close to 50% by year 2030 [8], and the projected NAFLD prevalence among the adult population (aged ≥15 years) will rise to 33.5% [9]. NAFLD-associated hepatocellular carcinoma (HCC) cases are expected to increase by 146% from 10,100 to 24,900 during 2015–2030 and become the leading cause of HCC.

This chapter summaries the current knowledge on the diagnosis, epidemiology, pathogenesis, and treatment of NAFLD associated HCC. It highlights the unique pathogenesis of NALFD associated HCC and discusses challenges we face with current treatment.

### **2. Definition and diagnosis of NAFLD**

Liver biopsy remains the gold standard of diagnosing NAFL, NASH, liver fibrosis and cirrhosis. However, due to its invasive nature, imaging modalities are commonly utilized for diagnosing different stages of NAFLD. Ultrasound and computed tomography (CT) are the most commonly used fist-line investigation with generally good sensitivity and specificity [10–12]. However, the sensitivity lowers when the level of steatosis is low [13]. Other techniques such as transient elastography MRI, MRI elastography, computer-assisted quantitative techniques have been developed to better assess steatosis and fibrosis [14–17]. These techniques are not widely available and could associate with high cost. Simple biochemical markers such as low albumin, prolonged prothrombin time and thrombocytopenia should be incorporated into the diagnostic algorithm of NAFLD as well [1]. If a diagnosis is uncertain with imaging modalities or if there a high probability of liver fibrosis, a liver biopsy is warranted.

#### **3. Epidemiology of NAFLD-associated HCC**

#### **3.1 Incidence of NAFLD-associated HCC**

NAFLD is the fastest growing cause of HCC in the world. As only a small proportion of patients undergo screening and appropriate surveillance [18], it is extremely difficult to get representative estimates of HCC incidence in the general population with NAFLD. Thus, studies are limited to patients who underwent appropriate workup and surveillance. Given that diagnoses of the exact NAFLD stage can be challenging, the percentage of patients with NAFL, NASH and cirrhosis is unclear without definitive liver biopsy in most published studies. In one large population based study, the incidence of HCC in patients with NAFLD is estimated at 0.51% at year 12 [19]. The incidence of HCC increases as NAFLD progresses from NAFL to cirrhosis with the highest HCC incidence rate seen in those with NAFLD-associated liver cirrhosis. HCC incidence in patients with NAFL is low at 1.2 per 1000 person-years in a population-based study of US Veterans [20] and ranges from 0.3% to 0.43% in other studies that excluded patients with cirrhosis [19, 21, 22]. In contrast, HCC incidence in patients with cirrhosis dramatically rises to about 10 per 1000 person-years in the same US Veterans study [20], and could be up to 12.8% over 3 years in a systemic review [22].

*Non-alcoholic Fatty Liver Disease Associated Hepatocellular Carcinoma DOI: http://dx.doi.org/10.5772/intechopen.106816*

NAFLD-associated HCC is becoming the leading cause of HCC as the prevalence of obesity and metabolic syndrome is rising. The increasing prevalence of NAFLDassociated HCC is reflected in studies utilizing large national transplant registries. Based on the data from the Scientific Registry of Transplant Recipients (SRTR) data system from 2002 to 2017 [23], 17% patients who were listed for liver transplant had a listing diagnosis of HCC. Even though chronic hepatitis C remained the leading cause of HCC in these transplant candidates and had a 6.2-fold increase from 2002 to 2017, NAFLD-associated HCC had an 11.5-fold increase. NAFLD-associated HCC is the most rapidly growing indication for liver transplantation. It comprised of 18% of liver transplant candidates with HCC in 2017 in contrast with that of 2% in 2002, while chronic hepatitis C related HCC decreased to 48% in 2017 from 53% in 2002. According to a predictive model, NAFLD prevalence among the adult population (aged ≥15 years) is projected at 33.5% in 2030; among the NAFLD cases, NASH cases are expected to increase from 20% to 27% by 2030; incidence of decompensated cirrhosis will increase 168% to 105,430 cases by 2030; prevalent HCC cases are expected to increase by 146% from 10,100 to 24,900 during 2015–2030; incident HCC cases are expected to increase by 137% from 5,160 to 12,240 in 2030 [9]. With more curative treatments being developed for chronic hepatitis C, the incidence of chronic hepatitis C related HCC is expected to decrease, while NAFLD-associated HCC is becoming the leading cause of HCC.

#### **3.2 Risk factors of NAFLD-associated HCC**

Many of the NAFLD risk factors including obesity, metabolic syndrome and T2DM are also independent risk factors of HCC. Other demographic risk factors including older age, male sex, Hispanic ethnicity, and genetic predisposition have also been studied as risk factors in HCC, including NAFLD-associated HCC.

#### *3.2.1 Obesity, T2DM and metabolic syndrome*

Obesity is closely related to both NAFLD and HCC. Obesity is the most common metabolic abnormality associated with NAFLD: an estimated 51.3% patients with NAFLD had obesity and up to 81.8% patients with NASH were obese [24]. Obesity is associated with many types of malignancies including HCC. It is assumed that 10% or more liver cancers could be attributable to excess weight [25]. T2DM is found in up to 71% of patients with NASH cirrhosis and is independently associated with increased risk of HCC [26]. A Surveillance, Epidemiology, and End Results (SEER)- Medicare based study from 1993 to 2005 showed that up to 37.1% patients with HCC had metabolic syndrome in contrast with 17.1% of comparison group residing in the same regions as the SEER registries. Among the metabolic conditions, T2DM or impaired fasting glucose has the strongest association with HCC. Metabolic syndrome remained significantly associated with increased risk of HCC even after adjusted multiple logistic regression analyses, suggesting metabolic syndrome as an independent risk factor for developing HCC [27].

#### *3.2.2 Demographic and genetic risk factors*

NAFLD-associated HCC present at a later age and is more prevalent in male. Significant racial and ethnic disparities in NAFLD and NAFLD-associated HCC in the United States are seen. Hispanics have the highest risk of developing NAFLD and NAFLD-associated HCC [28, 29]. Carriage of the PNPLA3 rs738409 C >G polymorphism is not only associated with greater risk of progressive steatohepatitis and fibrosis, but also of HCC with a 2.26-fold increased risk of HCC when carrying one copy of the allele, and 5-fold increased risk in homozygous individuals [30].
