Hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis

Highlights

Abstract

Introduction

Hepatic steatosis of nonalcoholic etiology (nonalcoholic fatty liver disease or NAFLD) is an emergent condition that may lead to hepatic cirrhosis and finally to liver cancer. To define NAFLD, there must be evidence of hepatic steatosis and an absence of secondary causes of fat accumulation in the liver (eg, alcohol consumption). In most cases, NAFLD is commonly associated with metabolic comorbidities such as obesity, diabetes mellitus, and dyslipidemia. NAFLD comprises simple steatosis or steatohepatitis (NASH), where steatosis is associated with liver inflammation, with or without liver fibrosis [1]. The global incidence of NAFLD is rising in both Western and Asian countries due to the metabolic increase of etiological factors (eg, diabetes and obesity) [2], [3].

There is no specific therapy for NAFLD or screening method for at-risk patients; general health suggestions (eg, weight loss) are the only possible way to avoid or reduce the risk of NAFLD progression in fibrosis patients. An estimated 20% of patients with NASH will develop cirrhosis, and NASH is predicted to become the leading indication for liver transplants in the United States.

Nonalcoholic fatty liver disease with associated cirrhosis is a risk factor for the development of HCC. In a previous systematic review of 61 studies of patients with steatosis or NASH, the risk of HCC among those without and with cirrhosis ranged from 0.03 to 3.78 × 100 000 person-years [4]. Among subjects without cirrhosis, the risk of mortality from HCC was 0%-3% after longer observation. Furthermore, NASH is associated with liver-associated and overall mortality [5].

We performed an updated meta-analysis to verify the correlation and the prognostic significance of NAFLD in patients with HCC.

Materials and Methods

To comprehensively calculate the cumulative incidence and prognosis of HCC in patients with NAFLD, a systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Results

A total of 1265 citations were identified. Overall, 103 studies were eligible for inclusion in the present meta-analysis (Figure 1; Table 1; Suppl. File 1). Thus, a total of 948 217 participants with NAFLD were evaluated between 1992 and 2021.

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Fig. 1

flow diagram of included studies.

HCC Prognosis According to Steatosis

In total, 14, 8, and 24 studies evaluated HCC prognosis according to NAFLD state in terms of DFS, CSM, and OS, respectively. Overall, no difference was found for recurrence (DFS HR = 0.97 [95% CI, 0.84, 1.13]; = P = .73), CSM (HR = 2.16 [95% CI, 0.85, 5.5]; P = .1; Figure 2), or OS (HR = 1.02 [95% CI, 0.86, 1.21]; P = .84; Figure 3), revealing that outcome of HCC is not more unfavorable in patients with NAFLD.

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Fig. 2

risk of HCC in patients with NAFLD.

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Fig. 3

DFS in patients with HCC and NAFLD.

Discussion

Through a meta-analysis of published literature, we evaluated the risk of HCC in patients with NAFLD in the general population. We confirmed that NAFLD was independently associated with an 88% increased risk of HCC, as compared to no NAFLD, in a series of 103 studies published across 3 decades. In a similar meta-analysis published in 2018, Stine et al. found that the risk of HCC was significantly increased only in patients with noncirrhotic NASH but not in the whole NASH population (with or without cirrhosis) [6]. However, a meta-regression analysis adjusted for the rate of steatosis/NASH and fibrosis did not confirm these findings. Steatohepatitis was also associated with an increased risk of intrahepatic cholangiocarcinoma and colorectal cancer [7],[8]. Similar causative factors such as diabetes, overweight, or hepatitis C may be responsible for this association. In fact, approximately 30% to 40% of incident HCC cases are associated with metabolic syndrome. Type 2 diabetes is also a risk factor for NAFLD and increases HCC incidence [9].

NAFLD mouse models showed altered compositions of their gut microbiome. NAFLD HCC patients had increased levels of IL-13, which can activate myeloid-derived suppressor cells and promote tumor progression by inhibiting cancer immunity [10].

Another mechanism of NAFLD-associated HCC is PNPLA3 polymorphisms, which are associated with general NAFLD progression, by enhancing inflammatory signals, including in the IL-6/STAT3 and CCL5 pathways [11].

Nonalcoholic fatty liver disease (and NASH-related cirrhosis in particular) is an emerging risk factor for HCC in Western countries. However, risk of HCC was increased in Western populations but not Asian populations in subgroup analysis. The indication for liver transplant is increased more than 11-fold worldwide [12]. It is rare, however, to observe HCC in the absence of liver inflammation or cirrhosis [13]. In the present meta-analysis, in fact, the papers included almost all subjects with NASH/cirrhosis, with or without viral hepatitis. We found that steatosis/NASH was an independent risk factor for HCC, as compared to no steatosis/no NASH (more than doubling the risk). Conversely, NAFLD-associated HCC was not linked with a poorer prognosis, as compared to non-NAFLD-related cancers. It appears that steatosis or NASH may exert a somewhat protective effect on the HCC course. Even in the general population, NASH patients without or with minimal fibrosis, but not those with higher levels of fibrosis, have a better prognosis in terms of overall mortality [14], [15]. Even in the NHANES cohort, patients with NASH but not advanced fibrosis had a lower risk of death [16]. However, in our review, HCC-related mortality but not overall mortality was (not significantly) higher in patients with NAFLD. This may be due to the high rates of fibrosis and viral hepatitis C in our cohorts.

These observations highlight that patients with NASH with or without initial fibrosis may need intensive surveillance and treatment to slow or revert fibrosis evolution and cancer transformation. In patients with NAFLD and cirrhosis, in fact, the management is similar to that for cirrhosis due to other causes and includes screening for hepatocellular carcinoma, lifestyle interventions, and evaluation for liver transplantation, for patients with decompensated cirrhosis or HCC.

Treatment of NAFLD-associated HCC is not different from that of HCC related to other causes. Instead, the role of immunotherapy, which provides a better outcome for advanced HCC than antiangiogenetic drugs do, has been questioned in NASH patients. In preclinical models of NASH-induced HCC, the delivery of immunotherapy-targeting programmed death-1 (PD1), in fact, expanded activated CD8+PD1+ T-cells within tumors but did not lead to tumor regression, indicating that tumor immune surveillance was impaired. These observations seem to confirm that NASH-associated HCC might be less responsive to immunotherapy, probably due to NASH-related aberrant T-cell activation causing tissue damage that leads to impaired immune surveillance [17].

Our meta-analysis suffers several limitations, including regarding its inclusion criteria (patients with both steatosis or NASH and various degrees of fibrosis), confounders due to viral hepatitis coinfection, duration of follow-up, race, and NAFLD diagnosis. However, this is the largest meta-analysis to have been performed on studies on how NAFLD affects the risk and prognosis of HCC.

We can conclude that NAFLD, with or without fibrosis, is a major risk factor for the development of HCC. Despite this, overall mortality and CSM are not significantly increased when HCC is diagnosed. Despite the heterogeneity of the included literature and the degree of NAFLD of our populations, these subjects deserve similar follow-up and management like patients with other chronic liver diseases receive.

Figs. 4, ​,55 and Table 2

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Fig. 4

CSM in patients with HCC and NAFLD.

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Fig. 5

OS in patients with HCC and NAFLD.

Declaration of Competing Interest

None to declare

Funding

Footnotes

References