Background
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide [
1]. Globally the majority of HCC are associated with chronic viral hepatitis with a high prevalence in less industrialized countries mainly East Asia and sub-Saharan Africa. Over the last years, the incidence of HCC in these countries is decreasing while the incidence of HCC in developed countries has increased [
1,
2]. This trend is likely related to the increasing prevalence of the metabolic syndrome and the associated risk factors including insulin resistance and obesity [
3]. These risk factors contribute to the development of non-alcoholic fatty liver disease (NAFLD) which has become the most prevalent liver disease world-wide [
4]. The clinical spectrum of NAFLD ranges from isolated hepatic steatosis to non-alcoholic steatohepatitis (NASH), which is characterized by hepatic necroinflammation and varying degrees of fibrosis [
5]. The estimated prevalence of NAFLD in the adult population ranges from 9-37% with strong cultural and geographic differences and the prevalence of NASH is estimated at 3-5% [
6]. Although epidemiological studies have to determine the risk of disease progression, it has become obvious that chronic inflammation in NASH is a trigger that can lead to the development of HCC – even in the absence of cirrhosis in a yet poorly defined subset of patients [
7]. Despite advances in screening and therapy for HCC the overall prognosis is poor with a 5-year-survival rate of 15% [
8]. Treatment decisions for HCC are commonly based on the Barcelona Clinic Liver Cancer (BCLC) staging system which considers performance status, tumour size and location, extra hepatic spread and the underlying liver function [
9]. For the multimodal treatment of HCC different surgical, interventional (radiological/sonographical) and non-interventional procedures have been established. Curative treatment options include resection, orthotopic liver transplantation (OLT) or locoregional therapies and are available for early tumour stages. For intermediate tumour stages (BCLC B), transarterial chemoembolization (TACE) with or without drug-eluting beads (DEB-TACE) and selective internal radiation therapy (SIRT) are used. In advanced tumour stages (BCLC C) systemic therapy with the multikinase inhibitor sorafenib represents the current standard in patients with compensated cirrhosis [
10]. Best supportive care is recommended for end-stage HCC patients (BCLC D) [
11].
The global increase of metabolic risk factors including diabetes and obesity will lead to an increasing prevalence of NASH and complications including cirrhosis and HCC [
7]. Currently only few studies have explored disease characteristics, treatment and outcome of NASH-related HCC. The aim of this retrospective analysis was to evaluate differences in the epidemiology, risk factors, tumour characteristics, therapy and overall survival in patients with NASH-HCC in contrast to non-NASH aetiologies in a European cohort over a period of 11 years.
Discussion
NAFLD – beeing the most prevalent liver disease in industrialized countries – can lead to NASH, where the emergence of HCC – even in the absence of cirrhosis – has been described [
1]. Among all patients with NAFLD, the third leading cause of death is related to liver-specific causes [
17] and HCC contributes significantly to this mortality [
18]. Still, the underlying pathomechanism, the associated risk factors and incidence of NASH-HCC are poorly understood. In the current retrospective analysis, epidemiology, risk factors, tumour characteristics, therapy and overall survival in patients with NASH-HCC were evaluated in a large single-centre cohort consisting of 1119 HCC patients in Germany, which represents one of the most comprehensive cohorts in Germany [
19]. In accordance to the literature, patients with NASH-HCC were significantly older compared to HCC of other aetiology [
7]. However, the predominance of male gender commonly observed in HCC was less pronounced in the NASH-HCC group [
20].
Since the definition of NASH-HCC included metabolic risk factors, the frequency of metabolic features and the frequency of obesity (BMI > 30 kg/m
2) were significantly higher in this group. Recent studies have shown that a body mass index above 30 kg/m
2 and the presence of type 2 diabetes are associated with an increased risk of HCC development [
21,
22]. In our analysis the prevalence of type 2 diabetes mellitus was almost two fold higher in NASH-HCC, comparable to the findings of Davila et al. [
23]. Likewise, the prevalence of hypertension, as a common co-morbidity, was increased in NASH-HCC and a significant higher rate of myocardial infarction and apoplectic stroke was detected among NASH-HCC patients.
Recent studies showed an increasing number of patients with NASH-associated HCC in comparison to other underlying aetiologies and it has been suggested that NASH may become the most frequent cause of HCC in an era with improving therapeutic options for chronic viral hepatitis [
1]. In the current analysis alcoholic liver disease (36%) was the most frequent cause of HCC, comparable to other investigations in Germany [
24,
25]. Interestingly, NASH-HCC accounted for only 4% of all HCC cases. The frequency of NASH-related HCC is likely influenced by the retrospective analysis which excluded all patients with any reported alcohol consumption. Thus this analysis likely excludes patients with NASH and a regular but low consumption of alcoholic beverages. Additionally, NASH as a cofactor in other underlying disease was not considered in this analysis. Several studies suggested that undiagnosed NASH is existent in patients with idiopathic or cryptogenic cirrhosis [
2,
7]. In the current cohort, cryptogenic cirrhosis accounted for 17% of cases, in analogy to findings in the literature, where a range between 6.9 up to 50% has been described in industrialized countries [
7]. The prevalence of cryptogenic cirrhosis is clearly related to the quality of the data acquisition and handling and is also a potential confounder.
Superior hepatic function in NASH-HCC patients compared to other HCC is among the most relevant findings of the current analysis. Although there was no difference with regards to the prevalence of hepatic cirrhosis, more NASH-HCC patients presented in early CTP stage A or B and the MELD score was significantly lower. The difference between the two groups regarding the absolute MELD score with 9 vs. 10 seems low, but with regard to the range, the highest MELD score in NASH-HCC patients was 21 while in the other group it was 40. These findings are in accordance with data in the United States that found a lower MELD score in NASH-HCC patients [
20].
The majority of HCC in this cohort was confirmed by histology. Although EASL and AASLD guidelines do not require a biopsy for diagnosis, these were frequently obtained following patient consent to (1) differentiate regenerative nodules from HCC and (2) to develop and identify prognostic marker. Thus we were able to assess tumour grading, where no significant difference between the two groups was observed. Interestingly, HCC was larger in the NASH-HCC group and we observed a trend towards multifocality and a higher rate of distant metastases at the time of diagnosis. In the literature, NASH-HCC has been typically described as large and well-differentiated at the time of presentation [
7]. In HCC, curative treatment is only available in early stages, in which liver transplantation or resection is feasible. In the current analysis liver transplantation was not performed as primary therapy in any of the 45 cases of NASH-HCC. This might be related to the tendency of NASH-HCC to have a larger tumour size and a higher rate of multifocality at the time of diagnosis, possibly restricting surgical therapy. As discussed above, hepatic function was significantly better in these patients, and thus it is conceivable that the detection of cirrhosis and its complications were delayed. Other studies have made similar observations and suggested that NASH-related HCC may be diagnosed at a later time point and more advanced stage [
26]. The differences in hepatic function also influenced the decision to initiate systemic treatment with sorafenib, which was significantly more frequently applied as primary treatment in our NASH-HCC patients. Sorafenib and transarterial chemoembolization are currently the only non-curative treatments that improve survival [
27].
The results regarding the overall survival in NASH-HCC are inconsistent. In a recent study the overall survival following curative treatment approaches for HCC was increased in NASH compared to patients with HCV and/or alcoholic liver disease [
20]. Wong et al. found that patients with NASH in the absence of HCC exhibited a better survival following OLT compared to patients with HCV or HCC of non-NASH origin [
28], while Dyson and colleagues reported similar survival of NAFLD and other aetiologies for HCC [
29]. In the current cohort, overall survival was shorter in NASH-HCC and a significant difference existed in the subgroup of patients with CTP B. It can be speculated that this decrease in survival is related to a delay in detection of the disease. Alternatively, these differences could be explained by different treatment strategies, since systemic therapy with sorafenib is currently only recommended for CTP A. Other explanations include the existence of co-morbidities and the higher age in NASH-associated HCC. A second central observation with regards to overall survival was the differences in patients with a higher BMI, which was protective. These observations are in contrast to several other studies, which reported a negative correlation of BMI and mortality in HCC [
30,
31]. Limitations of this analysis are related to the retrospective nature of the clinical cohort. Also, follow-up data regarding the cause of death was not completed available. In cases with complete death records mortality was related to complications of the underlying liver disease and tumour progression, rather than co-morbidities or cardiovascular disease.
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Competing interests
The authors declare that they have no competing interests.
Authors' contributions
AW analysed and interpreted data, obtained administrative, technical and material support and supervised the study. YA made acquisition of data, analysed and interpreted the data, performed statistical analysis and drafted the manuscript. SK participated in the design of the study, contributed to the acquisition of data, analysed the data and performed statistical analysis. CN contributed to data acquisition, analysed and interpreted the data. The analysis are parts of the doctoral thesis of CN at the Johannes Gutenberg University Mainz. CD and HL obtained administrative, technical or material support. GO analysed and interpreted the data and obtained administrative and material support. TZ and JUM analysed and interpreted the data. PRG obtained administrative support and supervised the study. MAW participated in the design of the study, supervised the study and critically revised the manuscript. JMS conceived of the study, participated in its design, analysed and interpreted the data, drafted the manuscript, obtained funding support and supervised the study. All authors read and approved the final manuscript.
Arndt Weinmann and Yvonne Alt contributed equally as first authors to this work.