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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.
Houston Methodist Neal Cancer Center, United States
Alan Hodges
Houston Methodist Research Institute, Center for Immunotherapy Research, United States
Texas A&M College of Medicine, United States
Maen Abdelrahim*
Houston Methodist Neal Cancer Center, United States
*Address all correspondence to: mabdelrahim@houstonmethodist.org
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, 3, 4, 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.
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, 11, 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, 15, 16, 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.
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].
NAFLD-associated HCC is becoming the leading cause of HCC as the prevalence of obesity and metabolic syndrome is rising. The increasing prevalence of NAFLD-associated 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].
NAFLD associated HCC is similar to many chronic liver disease related hepatocellular carcinomas, where hepatocellular injury and subsequent necroinflammation drive the formation of a protumorigenic microenvironment in the liver [31, 32, 33]. This microenvironment consists of a complex chronic inflammatory state with increased metabolic, oxidative, and mutagenic cellular stress, ultimately driving hepatocarcinogenesis (Figure 1) [31, 34, 35]. Different from other causes of HCC, e.g., viral or alcohol, an altered metabolomic state is the driver of hepatocellular injury in NAFLD associated HCC, playing an important role throughout the pathogenic process, and culminating in unique alterations of the molecular phenotype of the resulting tumor. The precise pathogenic mechanisms of NAFLD associated HCC continue to evolve, as the complex interplay of environmental factors, genetic susceptibility, and intricate inflammatory conditions further unfold.
Figure 1.
Stepwise pathogenesis of NAFLD associated HCC. In the setting of environmental and genetic predisposition, the sequalae of metabolic reprograming and hepatocellular injury in NAFLD lead to the creation of a protumorigenic microenvironment and ultimately hepatocarcinogenesis. Created with BioRender.com.
4.1 Hepatocellular injury and the production of a protumorigenic microenvironment
The original model of hepatocellular injury in NASH was described as a “two-hit” hypothesis, where the first hit, steatosis, sensitizes the hepatocyte to injury and cell death resulting from the “second-hit” of oxidative stress [36]. Although this model is largely seen as overly reductive, it does provide a conceptual framework for hepatocellular injury in NAFLD associated HCC. Lipotoxicity, a state of lipid dysregulation leading to organelle dysfunction and cell death, is often-considered the initial metabolic insult that causes hepatocellular injury in NAFLD [32]. Increased hepatic lipid deposits are a hallmark of NAFLD. Multiple features of metabolic syndrome, including excess dietary free fatty acids (FFAs), excess FFA release from adipose tissue, increased insulin resistance, upregulated de-novo lipogenesis and alterations of the gut microbiota all contribute to a lipid-rich hepatic metabolic state [37]. At increased concentrations in the liver, lipids are directly and indirectly hepatotoxic, promoting proapoptotic and ER-stress pathways, while inducing mitochondrial dysfunction and reactive oxygen species (ROS) production [38]. In addition to lipid induced hepatocellular injury, derangements in other metabolic pathways seen in NAFLD, including bile acid metabolism and iron storage, likely contribute to hepatocyte damage and hepatocarcinogenesis as well [39, 40].
As in many cancers, the innate and adaptive immune system play a Janus-faced role in tumor development: both promoting necroinflammation and therefore carcinogenesis, while also performing antitumor cell killing and immune surveillance [41]. Hepatocellular injury in NAFLD plays a central role in disrupting this balancing act, skewing the immune response to favor tumorigenesis. Hepatocyte death stimulates the immune response through exposure of immune cells to damage associated molecular patterns (DAMPS). Additionally, microbiome changes in NAFLD patients likely contribute to the inflammatory immune phenotype, with the increased “leakiness” gut leading to increased translocation of lipopolysaccharide (LPS) and other pathogen associated molecular patterns (PAMPS) into the portal circulation [42]. Both DAMPS and PAMPS act through Toll-like receptors (TLR) and other pattern recognition receptors to activate liver resident macrophages (Kupffer cells). Activated Kupffer cells (KCs) recruit and stimulate other innate and adaptive immune cell subsets which secrete proinflammatory factors including IL-1β, IL-2, IL-7, IL-12, IL-15, TNFα, and IFNγ, further promoting an immunostimulatory and cytotoxic environment. A major consequence of the immunostimulatory environment is the activation of non-parenchymal hepatic cells including hepatic stellate cells, which increase extracellular matrix deposition and fibrosis. Moreover, stimulated innate cells directly contribute to the abundance of ROS and therefore oxidative DNA damage in the liver due to increased respiratory burst activity [41]. Together these immunostimulatory processes perpetuate hepatic cell death, promote hepatic stellate cell mediated fibrosis, and contribute genotoxic metabolites to the microenvironment, all key drivers of hepatocarcinogenesis. In response to these chronic inflammatory conditions, many immune exhaustion responses are induced, including the expression of immunosuppressive factors (IL-10, TGFβ) and the immune checkpoint PD-L1. While this immunosuppressive response contributes to the reduction of detrimental inflammation, antitumor cytotoxic immune response is inhibited as well, contributing to tumor growth.
In addition to the directly cytotoxic and genotoxic mechanisms described above, the positive feedback loop of hepatocellular injury, necroinflammation and fibrosis indirectly promote tumor progression through induction of angiogenesis. In response to inflammatory stimuli, activated monocytes increase production of VEGF and MMP9, promoting tumor neovascularization, growth, and metastasis [43]. Notably even prior to HCC development, NAFLD patients exhibit increased serologic markers of angiogenesis and increased neovascularization in biopsy samples [44], further contributing to the confluence of protumorigenic factors ultimately leading to tumorigenesis in NAFLD.
The influence of metabolic syndrome can be observed in each of these protumorigenic mechanisms, hepatocellular injury, chronic inflammation, immune exhaustion, and increased neovascularization. Many features of metabolic syndrome including hyperlipidemia, hyperglyceridemia, and obesity directly contribute to steatosis and lipotoxic hepatocellular injury. Adipocytes directly produce multiple inflammatory cytokines (TNFα, IL-6) and proangiogenic factors (VEGF, FDGF), likely contributing to oncogenic chronic inflammation, immune exhaustion, and angiogenesis [45]. Mouse models of NAFLD induced HCC highlight the importance of metabolic syndrome in HCC pathogenesis. In mice with diet ± activity modifications designed to recapitulate conditions common metabolic syndrome, the vast majority (60–89%) of mice develop HCC [46], suggesting a potent role of metabolic syndrome in HCC development.
4.2 Hepatocarcinogenesis and disease progression
Ultimately the protumorigenic microenvironment results in DNA damage and subsequent mutagenesis. DNA oxidative damage is a major contributor to mutagenesis in NAFLD associated HCC. The DNA oxidative stress marker 8-hydroxy-2′-deoxyguanosine (8-OHdG) in NAFLD associated HCC is increased compared to that of healthy patient livers or tumors from patients with viral and alcohol associated HCC [47]. 8-OHdG is an independent risk factor for hepatocarcinogenesis and therefore highlights the role of oxidative damage in HCC pathogenesis. In addition to genotoxic alterations from DNA oxidative damage, oxidative damage can cause epigenetic changes, which may play a role in HCC carcinogenesis. Epigenetic inactivation of tumor suppressor genes consistent with oxidative DNA damage response have been observed in NAFLD induced HCC patients [48]. Furthermore, alterations in DNA repair pathways may also contribute to genomic instability. Upregulation of DNA-dependent protein kinase, a central member of the error prone DNA repair mechanism non-homologous end joining (NHEJ), has been observed in NAFLD associated HCC [49]. Together these mechanisms lead to an increased mutagenic state in NAFLD associated HCC.
Although a wide variety of mutations have been documented in NAFLD associated HCC, hotspot genes and mutational signatures have been described. In a cohort of 80 patients with NAFLD associated HCC, the most frequently mutated genes were the telomerase (TERT) promoter (56%); the gene encoding beta-catenin, CTNNB1 (28%); the tumor suppressor, TP53 (18%); and the activin receptor, ACVR2A (10%) [35]. Notably, TERT promotor, CTNNB1 and TP53 are mutated at similar rates in HCC patients en masse regardless of etiology; however, mutations in ACVR2A are more enriched in patients with NAFLD associated HCC compared with that in other etiologies [50]. Transcriptionally, the majority of NAFLD-associated HCC tumors demonstrated upregulation of either the WNT–TGFβ or WNT–β-catenin oncogenic signaling pathways, highlighting the importance of both non-canonical and canonical WNT signaling in NAFLD associated HCC carcinogenesis [35]. Moreover, other transcriptional signatures consistent with underlying pathogenic features of NAFLD associated HCC are enriched in these patients including bile acid metabolism, oxidative stress, and inflammation-related gene signatures. Together these genomic and transcriptomic alterations drive malignant transformation and disease progression.
Current HCC treatment recommendations incorporate Barcelona Clinic Liver Cancer (BCLC) stage, liver lesion number and size, liver function and patient performance status [51]. Treatment modalities for localized disease include hepatic resection, ablation, and liver transplant for single or small lesions; chemoembolization and stereotactic radiation for larger, multiple unresectable lesions. These locoregional treatments seem to be equally effective regardless of HCC etiology. A comprehensive review on different locoregional treatment modalities in NAFLD-associated HCC has been published recently [52]. This chapter will focus on systemic therapies, especially immune checkpoint inhibitors in NAFLD-associated HCC.
5.1 Tyrosine kinase inhibitor (TKI)
5.1.1 Sorafenib
The Phase III SHARP trial established the efficacy of sorafenib, a multikinase inhibitor, which prolonged the median survival and median time to radiographic progression for patients with locally advanced or metastatic HCC [53]. A similar Phase III trial that was conducted in Asian-Pacific region observed similar results [54]. In the SHARP study, 48% patients had viral hepatitis as an etiology of HCC and the percentage of NAFLD-associated HCC is unknown. The subsequent published subgroup analysis of SHARP study patients and combined analysis of SHARP study and Asian-Pacific study patients didn’t include NAFLD-associated HCC as a subgroup either [55, 56]. A recent presented study of 5201 patients with HCC treated with sorafenib found that there is no overall survival or adverse event difference between NAFLD-associated HCC and other etiology related HCC. However, patients with NAFLD-associated HCC were significantly older and sorafenib was commenced at more advanced stages. There were only 3.6% patients with NAFLD-associated HCC in the study, limiting the ability of drawing definite conclusions [57].
5.1.2 Lenvatinib
Lenvatinib, another multikinase inhibitor, showed non-inferiority to sorafenib in the Phase III REFLECT study [58]. Similar to SHARP study, patients in REFLECT study was characterized as having viral etiologic HCC or alcohol related HCC. The percentage of NALFD-associated HCC is unknown. A recently published multi-center retrospective study from Japan included 530 HCC patients treated with Lenvatinib [59]. The study compared the survival of 103 patients with NAFLD-associated HCC with that of 427 patients with HCC from other etiologies and revealed that progression free survival was statistically better in patients with NAFLD-associated HCC (9.3 vs. 7.5 months, P = 0.012), and overall survival was numerically better even though not statistically significant (20.5 vs. 16.9 months, P = 0.057).
5.1.3 Other TKIs
Regorafenib was approved as a second-line treatment for advanced HCC after progressing on sorafenib based on the Phase III RESORCE study [60]. Ramucirumab was also approved for the same indication after showing overall survival and progression free survival benefit in patients with advanced HCC in REACH-2 study [61]. Multikinase inhibitor cabozantinib improved survival and PFS in patients who have failed one or two lines of treatment in the study CELESTIAL and cabozantinib was the first approved third-line treatment for advanced HCC [62]. In these three studies, subgroup analysis didn’t show different response to these TKIs according to HCC etiology. In a retrospective study that included 23.5% NAFLD-associated HCC also showed similar responses to regorafenib regardless of HCC etiologies. However, there were less than 10% of NAFLD-associated HCC patients included in RESORCE, REACH-2 and CELESTIAL studies. And there were less than 25 patients in the retrospective study mentioned above. The small number of patients enrolled in the studies limit definitive conclusions.
5.2 Immune checkpoint inhibitors
Checkpoint inhibitor single agent was first studied in the second line settings. Both nivolumab and pembrolizumab showed improved response rate in the early phase clinical trials [63, 64]. Based on the results from these studies, FDA granted accelerated approval for advanced HCC. Pembrolizumab was further tested in the second line setting in KEYNOTE 240 study. However, the study didn’t meet the primary endpoint of superior combined OS and PFS [65]. Similarly, Phase III CheckMate 459 study comparing nivolumab with sorafenib in the first line setting didn’t show superiority of nivolumab [66]. Combing nivolumab and ipilimumab at different dose and schedule was explored and doublet regimen has shown improved response rate up to 30% in the second line setting [67]. Phase III HIMALAYA study added tremelimumab to durvalumab and compared this regimen with sorafenib. The combination treatment improved overall survival compared to sorafenib and the final results are eagerly anticipated [68].
As with studies of TKIs in HCC, most studies of immune checkpoint inhibitors stratified patients to groups of HBV related, HCV related and uninfected, and the percentage of NAFLD-associated HCC in the uninfected group is unknown. Nevertheless, subgroup analysis in most of these studies showed comparable efficacy of immune checkpoint inhibitors in uninfected and overall population (Table 1).
Overview of outcomes of checkpoint inhibitor studies in patients with locally advanced or metastatic hepatocellular carcinoma.
OS hazard ratios in patients with HBV, HCV and uninfected were 0.57 (0.35–0.94), 0.96 (0.48–1.92) and 0.88 (0.64–1.20) respectively. PFS hazard ratios in patients with HBV, HCV and uninfected were 0.70 (0.44–1.13), 0.46 (0.24–0.90), 0.75 (0.56–1.01).
Arm A: nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks; Arm B: nivolumab 3 mg/kg plus ipilimumab 1 mg/kg, administered every 3 weeks (4 doses), followed by nivolumab 240 mg every 2 weeks; Arm C: nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (arm C).
Median overall survival of patients who were HBV/HCV uninfected, HBV infected, or HCV infected in arm A was 22.2 months, 22.8 months, and 14.9 months; in arm B, 11.8 months, 12.1 months, and 16.1 months; and in arm C, 7.4 months, 9.6 months, and 33.0 months, respectively.
5.3 Immune checkpoint inhibitor and VGEF inhibitor
The combination of immune checkpoint inhibitor atezolizumab and VEGF inhibitor bevacizumab in patients with locally advanced or metastatic HCC in the first setting has shown superior OS and PFS compared to sorafenib in IMbrave150 trial [69]. The median OS was 19.2 months with atezolizumab plus bevacizumab and 13.4 months with sorafenib (hazard ratio 0.66; 95% CI 0.52–0.85; p <0.001). The median PFS was 6.9 and 4.3 months in the respective treatment groups (HR 0.65; 95% CI 0.53–0.81; p < 0.001). The combination was approved by FDA as first line treatment for HCC in 2020 and is the preferred first line treatment over single agent immune checkpoint inhibitor or TKIs in eligible patients.
The percentage of NAFLD-associated HCC is unknown in this study but 30% of the patients had no viral infection. In the subgroup analysis, uninfected patients with HCC seemed to have derived less benefit from the combination treatment compared to patients with viral hepatitis (HR for death 1.05; 95% CI 0.68–1.63) [70]. A previous animal study has demonstrated the existence of a CD8+PD-1+ subset of protumorigenic cells in NASH that favor the development of HCC and hamper response to immune checkpoint inhibitors. The authors also performed meta-analysis using data from CheckMate 459, IMbrave150 and KEYNOTE240, and revealed that patients with non-viral etiology had inferior survival when treated with immune checkpoint inhibitors. They then performed a cohort study of 130 patients with HCC from various etiologies and patients with NAFLD associated HCC had shorter overall survival of 5.4 months vs. 11 months in patients with HCC from other etiologies.
The better response to immunotherapy in patients with viral-induced HCC than in patients with NAFLD associated HCC might be due to the amount or quality of viral antigens or to a different liver micro-environment, possibly one that does not impair immune surveillance. Stratifying clinical trials according to HCC etiology for prospective validation in future clinical trials is warranted.
As incidence of HBV and HCV associated HCC continues to decrease with effective antiviral treatment, NAFLD associated HCC is becoming the leading cause of HCC. In light of the rising prevalence of NAFLD associated HCC, its unique pathogenesis and findings suggestive inferior response to immune checkpoint inhibitors, future clinical trials should assess whether HCC etiology influence the efficacy of a given treatment.
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Written By
Kai Sun, Alan Hodges and Maen Abdelrahim
Submitted: 26 June 2022Reviewed: 27 July 2022Published: 13 April 2023
Open access peer-reviewed chapter
