The global prevalence of MAFLD has risen from 15–25% over the past 10 years, and this trend is expected to continue10. The risk of HCC, the most serious complication of MAFLD, is also increasing. At present, MAFLD is considered as the most common risk factor for liver cancer in the United States and Japan, and MAFLD-HCC is considered an emerging indication for liver transplantation11,12. However, data from large-scale studies of the incidence and risk of MAFLD-HCC in China are lacking. MAFLD is the manifestation of metabolic syndrome in the liver. Numerous studies have confirmed that metabolic characteristics are closely related to the development of HCC. Particularly patients without cirrhosis, obesity and T2 DM are considered independent risk factors for the development of HCC13,14. In this study, we found that prediabetes, obesity, hypertension, and hyperlipidemia are all individually or in combination associated with an increased risk of HCC, and this risk is positively correlated with the number of metabolic characteristics.
As there was no statistically significant difference in the prevalence of T2 DM in the two study cohorts in the independent and joint correlation analyses of metabolic characteristics, we selected prediabetes as an alternative metabolic characteristic based on the diagnostic criteria of MAFLD and confirmed that it has a strong correlation with HCC risk. In the multivariate model, obesity was the factor most strongly associated with risk of HCC progression; this risk was 3.1 times that of non-obese individuals. Several studies have noted that although obesity is associated with increased risk of many cancers, it has the strongest correlation with increased risk of HCC, which is consistent with our results15,16. Dyslipidemia is a key risk factor for MAFLD-related HCC17. Our study confirmed that dyslipidemia is associated with the risk of MAFLD-HCC, and we therefore analyzed the associations between hypertriglyceridemia and low HDL and HCC separately. Although both factors exhibited independent effects, in the multivariate model, only hypertriglyceridemia was associated with risk of HCC (adjusted OR = 2.40, 95% CI = 1.36–4.22).
In the joint correlation analysis of metabolic characteristics, patients with two metabolic characteristics only exhibited obesity and dyslipidemia or obesity and hypertension, which are related to the risk of HCC, which to some extent demonstrates that obesity has a strong impact. Patients with three metabolic characteristics had a significantly higher correlation with the risk of HCC, demonstrating that the number of metabolic characteristics is positively correlated with disease risk. Among these patients, obesity, prediabetes, and hypertension had the highest correlation with MAFLD-HCC risk (adjusted OR = 5.7, 95% CI = 1.47–21.78). Our results are basically consistent with those of previous studies in which obesity, T2 DM, and hypertension exhibited the highest combined correlation with HCC risk18.
The results of the current study indicate that a considerable proportion of MAFLD-HCC appears in patients without cirrhosis19,20. In our study, this proportion was 80%, slightly higher than that reported from studies in other parts of the world. In the correlation analysis of metabolic characteristics in this group of patients, the correlation between obesity and prediabetes and HCC risk was slightly higher than that in the overall analysis, whereas the correlation between hypertension and dyslipidemia and HCC risk was slightly lower, with obesity remaining the most strongly correlated risk factor (adjusted OR = 3.14, 95% CI = 1.62–6.08).
Surveillance of MAFLD-HCC is very challenging. The current guidelines of European Association for the Study of the Liver only recommend monitoring patients with MAFLD-cirrhosis. It is recommended that abdominal ultrasound and serum alpha-fetoprotein examinations be performed every 6 months21. However, the guidelines ignore the occurrence of HCC in patients without cirrhosis, and there is no precise screening recommendation. Our research provides a basis for accurate screening and risk stratification of MAFLD-HCC. According to our research results, HCC surveillance is critical for patients with obesity, prediabetes, and hypertension. In addition, data regarding related metabolic factors such as obesity, prediabetes, dyslipidemia, and hypertension, as confirmed by our research, are objective and easy to obtain, which can provide a scientific basis for the establishment of a cost-effective accurate surveillance tool for HCC. Simultaneously, these metabolic factors could also be used as an important target of secondary prevention to delay the progress of MAFLD-HCC.
This study has several limitations. First, this was a retrospective analysis, and the retrospective, non-randomized design could introduce selection bias. Second, there may be problems with the selection of the patient metabolic factors. For example, we only selected biochemical indicators when a patient was first diagnosed with HCC, which could have introduced errors, and there are obesity markers that are more sensitive than BMI. Third, considering that patients in the control group also have risk factors of HCC, a long-term follow-up is needed to observe the prognosis and outcome of these patients. Finally, our research did not involve treatment methods or patient prognosis. Our proposed strategy for secondary prevention goals thus requires prospective risk reduction trials to demonstrate its effectiveness.
In summary, our study found that metabolic characteristics increase the risk of MAFLD-HCC, and this risk is positively correlated with the number of metabolic characteristics. Regardless of the presence or absence of cirrhosis, obesity has the strongest correlation with risk of HCC. Our results indicate that monitoring of prediabetes, hypertension, dyslipidemia, and obesity can be used to comprehensively assess the risk of HCC, which can in turn facilitate the establishment of reasonable, cost-effective risk stratification and precise screening strategies.