Hepatocellular carcinoma (HCC) incidence is increasing worldwide in recent years. Most HCC cases develop in the presence of advanced chronic liver disease related to chronic hepatitis C virus (HCV) infection, chronic hepatitis B (HBV) infection, and alcohol abuse. Approximately 15–50% of HCC cases are classified as idiopathic, suggesting that other risk factors are responsible for its rising incidence. Recent studies suggest that nonalcoholic fatty liver disease (NAFLD) can be associated with these “idiopathic” cases. NAFLD progresses slowly and can develop into liver cirrhosis, liver failure, and HCC. In the last few years, NAFLD has received more attention because of its high prevalence worldwide.
Hepatocellular carcinoma (HCC) is considered the 5th most common cancer in the world and is responsible for 5% of all malignant tumors in humans [
In a retrospective case-control study, the prevalence of CC in 641 patients with HCC was 6.9%. Risk factors for NAFLD, mainly obesity and diabetes, were more common in patients with CC when compared to patients with chronic hepatitis and alcoholic liver cirrhosis. The prevalence of obesity before the onset of cirrhosis was 41% in CC compared to 16% in the control group (
In a cohort of 105 HCC patients, CC was the second etiology (29%), only after HCV (51%). Compared to others etiologies, the majority of CC patients were female (60% versus 28%,
Between January 2010 and December 2012, 42 patients with HCC related to either NAFLD or CC were retrieved retrospectively from 2 centers in Brazil (Instituto do Câncer do Estado de São Paulo and Universidade Federal do Rio Grande do Sul). This included patients from an observation study of HCC in NAFLD of the FLIP consortium. The median age of the patients was 66.5 years (range of 25–80 years) and male gender predominated (
Clinical and histological characteristics of 16 HCC cases associated with NAFLD, reported until 2007, were described in a review study from Bugianesi [
Case reports of HCC associated with NAFLD [
Case number | Age (years) | Sex | Comorbidity | Interval between liver disease and HCC (years) | Number/size (cm) HCC | Liver histology | Treatment | Survival |
---|---|---|---|---|---|---|---|---|
1 | 52 | F | DM | 4 | Mult/— | Cirrhosis | Resection | Dead |
2 | 62 | M | DM, Ob | 4 | 1/3 | Cirrhosis | PEI | Dead |
3 | 72 | F | DM | 10 | 3/1.4 | Cirrhosis | NR | NR |
4 | 67 | F | DM | 0 | 1/2.6 | Fibrosis | Resection | NR |
5 | 66 | F | DM | 2.5 | 1/1.5 | Cirrhosis | Resection | Recurrence |
6 | 68 | F | NR | 2 | 1/2 | Cirrhosis | TAE | Alive |
7 | 69 | F | DM, Ob | 0.5 | 1/2.5 | Cirrhosis | TAI | Recurrence |
8 | 72 | M | Ob | 0 | 1/3 | Cirrhosis | TAE, PEI | Recurrence |
9 | 63 | M | DLP, Ob | 0 | 1/2 | Cirrhosis | Resection | Alive |
10 | 56 | M | DM | 0 | Mult/6 | Cirrhosis | TAE | Dead |
11 | 76 | M | DM, Ob | 10 | 1/1.9 | Cirrhosis | RFA | Alive |
12 | 74 | M | DM, Ob | 0 | 1/4 | Fibrosis | Resection | NR |
13 | 64 | M | DM, Ob | 0 | 1/— | Steatosis | TAE, resection | Alive |
14 | 67 | F | Res. Ins | 2 | 2/1.5 | Cirrhosis | TAE | Dead |
15 | 64 | M | Ob, DLP | 0 | Mult/13 | Fibrosis | NR | Dead |
16 | 70 | M | DM, Ob | 0 | 1/4.5 | Cirrhosis | TAE, resection | NR |
M: male, F: female, DM: diabetes mellitus, Ob: obese, DLP: dyslipidemia, Mult: multinodular, PEI: percutaneous ethanol injection, TAE: transarterial embolization, TAI: transarterial chemotherapy infusion, RFA: radiofrequency ablation, and NR: not reported.
In 2009, our group reported 7 cases of HCC in patients with NAFLD confirmed by histology. Four patients were male and the median age was 63 years. Obesity and diabetes were observed in 57% of patients and one patient was noncirrhotic. Among cirrhotic patients, most of them (71%) had a Child-Pugh score of A. Four patients presented with multifocal HCC and the tumor size varied from 10 to 52 mm with 57% of cases having a tumor smaller than 30 mm. All patients had alpha-fetoprotein levels less than 100 ng/mL at diagnosis. For HCC therapy, liver resection was performed in 2 patients, transarterial chemoembolization in 3 patients, percutaneous ethanol injection in 2 patients, and liver transplant in 1 patient [
The natural history of NASH has been evaluated in cohort studies and liver biopsy sequential studies to analyze the clinical outcome and progression to cirrhosis and HCC. The main limitations of these studies are the reduced number of patients and short follow-up periods. There are few studies that correlate HCC development in patients with NAFLD, probably due to the low rate of fibrosis progression [
A study that evaluated 420 patients with NAFLD identified cirrhosis in 5% after a follow-up period of 7 years. Only 3% of patients progressed to cirrhosis, including 2 cases of HCC. Survival was shorter than in the general population and liver disease was the third cause of death in this group of patients (after cancer and cardiovascular disease). Only 2 out of 420 patients developed HCC (0.5%), but this rate was 10% in patients with liver cirrhosis (2 out of 21 patients). Results from this study confirmed the bad prognosis in patients with NAFLD-related cirrhosis; 33% of patients died from complications of liver disease, suggesting that surveillance may be helpful in this subgroup [
Risk factors for HCC were evaluated in another prospective study that followed 137 Japanese patients with NAFLD since 1990. The median age was 70 years and around 88% of patients with HCC had advanced liver fibrosis. Other risk factors for HCC were lower aminotransferases levels and histological activity. The cumulative incidence of HCC was 7% in 5 years and it was the main cause of death. Surveillance for early detection of HCC in patients with NAFLD and advanced fibrosis was highly recommended in this study [
One study compared the risk of developing HCC in NASH- to HCV-cirrhotic patients. Yearly cumulative incidence of HCC was found to be 2.6% in patients with NASH-cirrhosis, compared with 4.0% in patients with HCV-cirrhosis (
HCC can be considered a rare complication in patients with NAFLD, but it should not be underestimated. First, HCC is a common complication after the establishment of cirrhosis, with an approximately 7 to 21% prevalence, mainly in obese and overweight patients, and an incidence of 10% during follow-up (7 years) [
The mechanisms of hepatocarcinogenesis in NAFLD patients are related to cirrhosis and underlying disease (e.g., carcinogenic potential of steatosis and metabolic dysregulation). In obese and diabetic patients, HCC development can be attributed to the presence of NAFLD. Evidence suggests that adiposity and diabetes can increase the incidence, death rate, or both in a variety of malignant neoplasms in human beings [
Obesity is recognized as an important risk factor for carcinogenesis in many malignant neoplasms. A National Cancer Institute study followed 900,000 adults from 1982 to 1998 and registered more than 57,000 cancer-related deaths [
Obesity also represents a risk factor for HCC in patients with cirrhosis from other etiologies. In liver transplant patients in the USA, the HCC incidence was a little higher in obese patients (4% versus 3%,
Epidemiologic studies demonstrated an increased risk for HCC in patients with diabetes mellitus type 2 (DM2). In cohort studies, patients with DM2 presented with a 3-fold increased risk of developing HCC and, in the presence of hepatitis, cirrhosis, and alcohol abuse, this risk increased 4-fold [
The incidence of HCC among patients with (
The absolute risk for HCC development in patients with DM2 and obesity can be considered low; however, the pandemic of these two diseases can transform this small number into a great number of HCC cases. In fact, almost 35% of the adult population in the USA and a great proportion of the worldwide population are overweight or obese, including children [
Most HCC cases are diagnosed in patients with cirrhosis after long term follow-up. It is not clear, however, if the neoplastic process begins after the establishment of cirrhosis or in earlier stages of liver disease. Steatosis
Most molecular events that lead to HCC need better clarification, but the main steps to cancer development (initiation, promotion, and progression) present a clear correlation with the NAFLD physiopathology [
Mechanisms of carcinogenesis in NAFLD adapted from: Sun & Karin, Journal of Hepatology, 2011; Toffanin, Friedman, Llovet, Cancer Cell, 2010.
Proliferation of oval cells (progenitor cells of hepatocytes, which have been implicated as the origin of many liver tumors) has been observed in many patients with NAFLD in experimental studies [
Recently, our group published a tissue microarray study that demonstrated, in all spectrums of NAFLD, that Survivin, an antiapoptotic protein, was expressed differently in NASH-HCC related tissues compared with HCV-HCC related tissues [
Several small animal models of nonviral HCC have been characterized and demonstrated that carcinogenesis in NAFLD has peculiar aspects. The liver-specific Pten deficient mouse is a transgenic mouse that develops NASH, adenomas, and HCC and is bred by mating Ptenflox/flox mice with Alb-Cre transgenic mice. These animals develop steatohepatitis associated with cancer cell expression of PPAR
Fatty change, cirrhosis, and HCC have also been described in Sprague Dawley and Fisher rats exposed to diethylnitrosamine, administered either weekly by intraperitoneal injection for 3 weeks or daily in the drinking water (110 mg/L) for 10 weeks. Following exposure, 94% (68 of 72 animals) developed HCC by 37 weeks [
Studies about HCC in NAFLD are scarce and are mostly from retrospective studies and case series. The long and indolent progression of the disease limits prospective studies. HCC seems to be a rare but disturbing complication of NAFLD that is related to the higher incidence of metabolic syndrome. Cirrhotic patients with NAFLD show important risk factors for HCC development and have a worse prognosis because they are older and present with other comorbidities. The role of cirrhosis, steatosis, and metabolic derangement in hepatocarcinogenesis needs to be elucidated. A better understanding of genetic and metabolic determinants of hepatocyte growth and differentiation can lead to the development of new pharmacological therapies. The main efforts must be directed to NAFLD prevention through promotion of healthy measures.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors would like to thank Alves de Queiroz Family Fund for Research for their support of our continued work.