Editor's Note: In recent years, the burden of non-alcoholic fatty liver disease (NAFLD) and liver cancer has become increasingly heavy, with a growing incidence of NAFLD-related hepatocellular carcinoma (HCC). Recently, Professor Yutao Zhan from Beijing Tongren Hospital delivered a fascinating presentation titled "Advances in Research on NAFLD-Related Liver Cancer." The presentation comprehensively analyzed the prevention and control strategies for NAFLD-related liver cancer from the perspectives of risk factors, monitoring, and prevention. Here, we summarize the key points from Professor Zhan's report.NAFLD: A Common Chronic Liver Disease
NAFLD is one of the most common chronic liver diseases worldwide. A 2023 meta-analysis covering 92 studies revealed that approximately 30% of the global population suffers from NAFLD. A 2019 meta-analysis encompassing 237 studies indicated that the annual incidence of HCC in NAFLD patients is 1.8‰. A 2022 meta-analysis of 61 studies showed that NAFLD accounts for 15.1% (95% CI: 11.9%-18.9%) of all liver cancer cases. The proportion of NAFLD-related liver cancer is highest in Southeast Asia, followed by the Western Pacific, Europe, and the Americas.
Risk Factors for NAFLD-Related Liver Cancer
01# Liver Cirrhosis
NAFLD-related liver cirrhosis is a major risk factor for NAFLD-related liver cancer. Compared to NAFLD patients without cirrhosis, those with cirrhosis have a tenfold increased risk of developing liver cancer.
02# Metabolic Factors
Hypertension, type 2 diabetes, obesity, and hyperlipidemia are also significant risk factors for NAFLD-related liver cancer. Data show that compared to individuals without metabolic syndrome (MetS), NAFLD patients with MetS have a 2.5-fold increased risk of developing liver cancer. When MetS coexists with type 2 diabetes, the risk increases fivefold. A BMI over 30 kg/m² doubles the risk of liver cancer, and a BMI over 35 kg/m² increases the risk fourfold.
03# Other Risk Factors
Other risk factors include increasing age, male gender, elevated alanine aminotransferase (ALT), genetic susceptibility (PNPLA3 mutation), smoking, and alcohol consumption.
Clinical Characteristics of NAFLD-Related Liver Cancer
A study found that compared to liver cancer from other causes, patients with NAFLD-related liver cancer were on average 5.6 years older, had a BMI that was 3 kg/m² higher, and had an average tumor diameter that was 0.67 cm larger. They also had an increased risk of metabolic and cardiovascular diseases (OR: 2.2-4.3), a higher proportion of non-cirrhotic cases (38.5% vs. 14.6%), and a lower rate of pre-diagnosis cancer surveillance (32.8% vs. 55.7%).
Monitoring and Risk Assessment of NAFLD-Related Liver Cancer
Monitoring and risk assessment of high-risk patients are essential measures to reduce or diagnose liver cancer early. Current guidelines from the American College of Gastroenterology (ACG), the European Association for the Study of the Liver (EASL), and China’s “Guidelines for the Prevention and Treatment of Metabolic (Non-Alcoholic) Fatty Liver Disease (2024 Edition)” all emphasize the need for liver cancer screening in patients with advanced fibrosis due to NAFLD.
How to Determine Advanced Fibrosis in NAFLD Patients
First, identify whether the patient has type 2 diabetes, metabolic risk factors, or elevated transaminase levels. Second, for patients with these risk factors, use non-invasive methods (e.g., FIB-4 score) to assess liver fibrosis. Based on the FIB-4 score results, patients can be categorized as low risk (FIB-4 <1.3), intermediate risk (FIB-4: 1.3-2.67), or high risk (FIB-4 >2.67). Third, use transient elastography to measure liver stiffness (LSM). Based on the LSM results, patients can be categorized as low risk (LSM <8 kPa), intermediate risk (LSM: 8-12 kPa), or high risk (LSM >12 kPa). Finally, for patients with uncertain LSM risk scores, perform a liver biopsy.
Predictive Models for NAFLD-Related Liver Cancer Risk
For the population with a low risk of developing HCC from non-alcoholic steatohepatitis/non-alcoholic fatty liver, how can we further identify high-risk individuals? Many studies have developed predictive models for NAFLD-related liver cancer. Professor Zhan introduced the recently reported HCC-RIFLE model. This model, based on nationwide cohort data, identified male gender (HR 2.43), age >65 (HR 6.46), diabetes (HR 1.41), obesity (HR 1.47), ALT >ULN (HR 1.69), and GGT >ULN (HR 2.07) as independent risk factors for liver cancer. The HCC-RIFLE model categorizes patients into low risk (0-6 points), intermediate risk (7-8 points), and high risk (9-11 points) groups. The study found that patients with a risk score of 0 had a cumulative 5-year and 10-year liver cancer risk of 0.01% and 0.03%, respectively, while patients with a risk score of 11 had a cumulative 5-year and 10-year liver cancer risk of 3.87% and 8.37%, respectively. The HCC-RIFLE model has a certain accuracy in predicting NAFLD-related liver cancer risk (AUC=0.72).
Common Monitoring and Risk Assessment Methods for NAFLD-Related Liver Cancer
Professor Zhan further introduced three commonly used monitoring and risk assessment methods for NAFLD-related liver cancer.
Ultrasound (US) Combined with Alpha-Fetoprotein (AFP)
This combination can be used as a routine method for liver cancer monitoring. However, due to the influence of subcutaneous fat and focal fat infiltration, this combined monitoring method has low sensitivity for early HCC.
CT or MRI
The American College of Gastroenterology recommends considering CT or MRI when US monitoring is insufficient. Both methods have high specificity, reaching 91%-94%, with MRI having higher sensitivity, ranging from 63%-82%.
GALAD Model
The “Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2024 Edition)” state that the GALAD model has a sensitivity and specificity of 85.6% and 93.3% for diagnosing early liver cancer, respectively, and is helpful for the early diagnosis of AFP-negative liver cancer. This model combines several biomarkers, including gender, age, AFP-L3, AFP, and des-gamma-carboxy prothrombin. Phase II studies have shown that when the GALAD model is combined with ultrasound, the AUC reaches 0.98, with similar AUC values for cirrhotic and non-cirrhotic cases, at 0.93 and 0.98, respectively, further demonstrating the stability and reliability of the GALAD model.
Prevention, Treatment, and Prognosis of NAFLD-Related Liver Cancer
Prevention
Studies have confirmed that weight loss of ≥10% helps improve or eliminate liver fibrosis in NAFLD patients. Liver fibrosis, especially advanced fibrosis, is a risk factor for NAFLD-related HCC, making weight loss an important measure for preventing NAFLD-related HCC. Regarding medications, aspirin, metformin, and statins have been shown to have preventive effects against liver cancer, but these drugs are currently considered suitable only for NAFLD patients with appropriate indications, not for all NAFLD patients.
Treatment Options
There are various treatment options for NAFLD-related liver cancer, including surgical resection, radiofrequency ablation, liver transplantation, transarterial chemoembolization, radiotherapy, molecular targeted therapy, and immune checkpoint inhibitor therapy. Professor Zhan emphasized that the choice of treatment method should be based on tumor staging, not etiology. Therefore, the treatment methods for NAFLD-related liver cancer do not differ significantly from those for liver cancer from other causes. However, it is important to note that metabolic diseases often accompany NAFLD-related HCC, which may affect the choice of treatment methods.
Prognosis
Regarding the prognosis of NAFLD-related liver cancer, studies have shown that the mortality rates at 1 year, 3 years, and 5 years after liver cancer diagnosis are 47%, 70%, and 75%, respectively. Over time, the cumulative incidence of HCC and non-HCC deaths increases, with the cumulative incidence of all deaths being higher (Figure 3). Overall, the prognosis for NAFLD-related liver cancer is poor, highlighting the need to strengthen the prevention and treatment of NAFLD-related liver cancer.
Conclusion
In summary, the incidence of NAFLD-related liver cancer is increasing, necessitating enhanced monitoring and prevention. It is crucial to monitor liver cancer in patients with advanced fibrosis due to NAFLD and those at high risk for liver cancer among non-alcoholic steatohepatitis/non-alcoholic fatty liver patients. Active treatment of NAFLD and its risk factors for liver cancer is essential to reduce the occurrence and progression of NAFLD-related liver cancer. The choice of treatment for NAFLD-related liver cancer should be based on liver cancer staging, while also considering the impact of commonly associated metabolic diseases.
