EASL Five Minutes丨Professor Huiying Rao: Advances in the Application of Non-invasive Diagnostic Prediction Models in the Field of Metabolic-Associated Fatty Liver Disease

Editor’s Note

The recently concluded 2024 European Association for the Study of the Liver (EASL) Annual Meeting provided a platform for hepatology experts and scholars from around the world to exchange and collaborate. This year's meeting brought together top liver disease experts from across the globe to discuss cutting-edge issues and the latest research advances in hepatology. Among the various topics, research on fatty liver disease was particularly noteworthy, not only for its relevance to the health and well-being of a large number of patients but also for its significance in the development of hepatology treatments. To keep our readers updated on the highlights of the conference, the editorial board of "Hepatology Digest" invited Professor Huiying Rao from Peking University People's Hospital to share insights on non-invasive diagnosis and assessment in the field of Metabolic-Associated Fatty Liver Disease (MAFLD), presenting the latest and most authoritative academic information to our readers.

OS-047-YI

Non-invasive Model Predicts Risk of Liver-Related Events in MAFLD cACLD Patients Better than Liver Biopsy

Research Background and Objective

MAFLD is a major cause of chronic liver disease. Liver biopsy is considered the “gold standard” for risk stratification. Non-invasive models have been proven useful in predicting clinically significant portal hypertension (CSPH), a major determinant of decompensation. The ANTICIPATE-NASH model uses liver stiffness measurement (LSM), body mass index (BMI), and platelet count to predict the presence of CSPH in MAFLD. Recent research suggests that this model can be used for individualized risk prediction of liver-related events (LRE) in MAFLD. This study aimed to evaluate whether liver biopsy data can improve the prediction of LRE in patients with compensated advanced chronic liver disease (cACLD) combined with MAFLD compared to using the ANTICIPATE-NASH model alone.

Research Methods

This was a multicenter retrospective cohort study conducted in Europe. The subjects were MAFLD patients with biopsy-proven liver fibrosis stage F3~F4. Baseline data and follow-up LRE (composite events of decompensation, hepatocellular carcinoma, liver transplantation, or liver-related death) incidence were recorded. Researchers estimated the CSPH/LRE risk distribution according to the ANTICIPATE-NASH model. The additional value of histology provided by the ANTICIPATE-NASH model for risk prediction was examined using Cox regression.

Research Results

A total of 699 patients were included, with 52% being male, a median age of 60 years, and a median BMI of 31 kg/m². Among them, 324 patients (46.4%) were F3, and 375 patients (53.6%) were F4. The median follow-up period was 42.8 months. During the follow-up, 56 patients (8.0%) experienced LRE. The median LSM (22.6 vs. 15.8 kPa), LRE rate (13.6% vs. 1.5%), and CSPH probability estimated by the ANTICIPATE-NASH model (26.9% vs. 18.3%) were significantly higher in F4 patients compared to F3 patients (all P values < 0.001). Compared to histology (0.67), the ANTICIPATE-NASH model had a higher discrimination ability for LRE (area under the curve was 0.93) and excellent calibration. Adding histology to the model did not improve prediction accuracy.

Using a threshold value of 0.25 (estimated 3-year LRE risk of 1.6%) based on the ANTICIPATE-NASH model, significant differences in LRE rates were observed: the LRE rate was 0.98% for values below 0.25, and 18.5% for values equal to or above 0.25 (P < 0.001). 61% of patients had a CSPH risk below the 0.25 threshold, while 39% had a risk above it. This dichotomy was more predictive of LRE risk than the F3/F4 classification. In fact, all LREs (5/68) in F3 patients occurred in those with an ANTICIPATE-NASH threshold value ≥ 0.25. Similarly, 30% of F4 patients had a CSPH risk < 12% (the median for F3 patients), with no LREs.

Research Conclusion

The non-invasive ANTICIPATE-NASH model based on LSM, BMI, and platelet count predicted LRE in MAFLD with greater accuracy than histology. Histology did not improve the risk prediction provided by the model.

Expert Commentary

The study focused on compensated chronic fatty liver disease patients, who, despite being in the compensated stage, still have progressing liver disease and may experience liver-related events in the future. Therefore, predicting and assessing these patients to enable early intervention and prevent future liver-related events is crucial.

Although liver biopsy is the “gold standard,” it is an invasive procedure with low patient acceptance. This study used the non-invasive ANTICIPATE-NASH model, utilizing liver stiffness measurement, BMI, and platelet count to assess the risk of future liver-related events and clinically significant portal hypertension in patients with compensated advanced chronic fatty liver disease.

This multicenter cohort study adopted a retrospective design, including patients with advanced liver fibrosis and cirrhosis (F3 and F4) fatty liver disease, collecting their baseline data and defining future liver-related events, such as liver function decompensation, hepatocellular carcinoma, liver-related death, or liver transplantation. The incidence was then assessed. Additionally, the study used Cox regression to evaluate the predictive ability of liver histology for liver-related events.

The study included 699 patients, with 52% being male, a median age of 60 years, and a BMI of 31. F3 patients accounted for 46.4%, and F4 patients accounted for 53.6%, with a median follow-up time of 42.8 months.

During the follow-up period, 8% (56) of the 699 patients experienced severe liver-related events. The results showed that F4 patients had significantly higher rates of liver-related events than F3 patients. According to the non-invasive prediction model, the probability of significant clinical portal hypertension in F4 patients was 26.9%, while it was 18.3% in F3 patients.

Additionally, the study further evaluated using a risk threshold of 0.25. When this value was less than 0.25, the incidence of liver-related events was only 0.98%; however, when this value exceeded 0.25, the incidence of liver-related events rose to 18.5%. This method was more predictive of liver-related events risk than simply classifying as F3 or F4.

Some F3 patients experienced liver-related events, and all these patients had a non-invasive model threshold value exceeding 0.25. This indicates that although F4 patients have a higher risk of liver-related events than F3 patients, F3 patients with a non-invasive model threshold value above 0.25 still have a high risk of liver-related events.

In conclusion, this study utilized non-invasive indicators such as liver stiffness measurement, BMI, and platelet count to establish an effective ANTICIPATE-NASH evaluation model to predict the occurrence of future liver-related events in patients with advanced chronic liver fibrosis and cirrhosis fatty liver disease. The model’s predictive performance surpassed that of standalone liver histology, providing clinicians with a more accurate predictive tool for early intervention and treatment decisions.

OS-051

Relationship Between Advanced Fibrosis and NASH-CRN Activity Score (NAS) Components: Pooled Data from Over 10,000 Patients in Multiple Treatment Trials

Research Background and Objective

Previous studies have reported the relationship between advanced fibrosis and the severity of metabolic dysfunction-associated steatohepatitis (MASH). This study aimed to evaluate the relationship between NAS, NAS components, and advanced fibrosis.

Research Methods

Researchers pooled screening data from 10 Phase II MASH trials and conducted univariate and multivariate logistic regression analyses to evaluate the relationship between NAS, NAS components, and advanced fibrosis (defined as fibrosis stage 3 or 4). They developed an improved version of NAS, termed “lean NAS” (= inflammation grade + ballooning degeneration grade, excluding steatosis), to predict the presence of advanced fibrosis.

Research Results

A total of 4,117 patients who underwent centralized liver biopsy were included. The prevalence of advanced fibrosis in this population was 36%. In univariate analysis, higher NAS, hepatocyte ballooning, and lobular inflammation were associated with advanced fibrosis. Among patients with NAS scores of 0–8, the occurrence of advanced fibrosis was 27%, 19%, 19%, 25%, 34%, 47%, 55%, 66%, and 57%, respectively. The probability of advanced fibrosis increased significantly in patients with NAS ≥5 (P < 0.0001). Among patients with inflammation grades 0–3, the occurrence of advanced fibrosis was 15%, 29%, 51%, and 71%, respectively. The presence of inflammation increased the likelihood of advanced fibrosis by 3.4 times (95% CI: 2.8–4.0, P < 0.0001). Among patients with ballooning grades 0–2, the occurrence of advanced fibrosis was 15%, 37%, and 66%, respectively. The presence of ballooning increased the likelihood of advanced fibrosis by 5.9 times (95% CI: 5.0–6.9, P < 0.0001). Among patients with steatosis grades 0–3, the proportions with advanced fibrosis were 39%, 39%, 36%, and 32%, respectively. The likelihood of advanced fibrosis was lower in patients with steatosis grade 3 (P = 0.048). In a model including “lean NAS” and steatosis grade, patients with high-grade inflammation (grade 3) and ballooning (grade 2) had a 32-fold increased likelihood of advanced fibrosis (95% CI: 16.8–62.1). Conversely, the likelihood of advanced fibrosis was relatively lower in patients with steatosis grades 1, 2, or 3: odds ratios were 0.45 (95% CI: 0.31–0.66), 0.28 (95% CI: 0.19–0.40), and 0.20 (95% CI: 0.13–0.29), respectively.

Research Conclusion

Advanced liver fibrosis is closely associated with the presence and severity of hepatocyte ballooning and, to a lesser extent, inflammation, and is unrelated to NAS. “Lean NAS” can predict the presence of advanced liver fibrosis, while the severity of steatosis is inversely related to the severity of fibrosis.

Expert Commentary

This study mainly observed the relationship between advanced liver fibrosis and the NASH-CRN activity score, or NAS score. The NAS score primarily includes three components: the level of hepatic steatosis, hepatic inflammation, and hepatocyte ballooning.

The study included pooled clinical treatment data from over 10,000 patients, with the main aim of evaluating the relationship between advanced liver fibrosis and NAS scores in these patients. Using the modified NAS score, future risks of advanced liver fibrosis can be predicted.

Researchers adopted a modified NAS score, termed “lean NAS,” which only assesses the level of inflammation and hepatocyte ballooning in fatty liver patients, excluding the steatosis level. This modified lean NAS score can more accurately predict advanced liver fibrosis.

Among multiple clinical trial data, 4,117 patients underwent centralized liver biopsy assessment. Results showed that 36% of these patients had advanced liver fibrosis. The study found that higher NAS scores, hepatocyte ballooning, and lobular inflammation were associated with advanced liver fibrosis. Although the NAS score was not entirely positively correlated with the occurrence of advanced liver fibrosis, when the NAS score reached 5 or higher, the probability of advanced liver fibrosis increased significantly.

Further research found that in patients with ballooning grades 0–2, the risk of advanced liver fibrosis increased with higher ballooning scores to 15%, 37%, and 66%, respectively, indicating a significant correlation between advanced fibrosis and ballooning. Meanwhile, liver inflammation also increased the likelihood of advanced liver fibrosis by 3.4 times, while ballooning increased this likelihood by 5.9 times.

Notably, although steatosis levels in the NAS score were graded 0–3, there was no significant difference in the occurrence rate of advanced liver fibrosis among these grades. Even patients with steatosis grade 3 did not show an increased likelihood of advanced liver fibrosis; in fact, it was lower.

Thus, researchers adopted the lean NAS score, which excludes steatosis grade. Under this scoring system, if high-grade inflammation (grade 3) and ballooning (grade 2) were present, the rate of advanced fibrosis would be 32 times higher. Conversely, the correlation between steatosis and advanced fibrosis was relatively low.

In summary, this study reminds us that in future clinical trials, the lean NAS score may have higher practical value in predicting advanced liver fibrosis. When assessing NAS, liver inflammation, and ballooning scores, whether steatosis scores should be included in the prediction system remains debatable.

EASL Five Minutes丨Professor Huiying Rao: Advances in the Application of Non-invasive Diagnostic Prediction Models in the Field of Metabolic-Associated Fatty Liver Disease

Editor’s Note

The recently concluded 2024 European Association for the Study of the Liver (EASL) Annual Meeting provided a platform for hepatology experts and scholars from around the world to exchange and collaborate. This year’s meeting brought together top liver disease experts from across the globe to discuss cutting-edge issues and the latest research advances in hepatology. Among the various topics, research on fatty liver disease was particularly noteworthy, not only for its relevance to the health and well-being of a large number of patients but also for its significance in the development of hepatology treatments. To keep our readers updated on the highlights of the conference, the editorial board of “Hepatology Digest” invited Professor Huiying Rao from Peking University People’s Hospital to share insights on non-invasive diagnosis and assessment in the field of Metabolic-Associated Fatty Liver Disease (MAFLD), presenting the latest and most authoritative academic information to our readers.

OS-047-YI

Non-invasive Model Predicts Risk of Liver-Related Events in MAFLD cACLD Patients Better than Liver Biopsy

Research Background and Objective

MAFLD is a major cause of chronic liver disease. Liver biopsy is considered the “gold standard” for risk stratification. Non-invasive models have been proven useful in predicting clinically significant portal hypertension (CSPH), a major determinant of decompensation. The ANTICIPATE-NASH model uses liver stiffness measurement (LSM), body mass index (BMI), and platelet count to predict the presence of CSPH in MAFLD. Recent research suggests that this model can be used for individualized risk prediction of liver-related events (LRE) in MAFLD. This study aimed to evaluate whether liver biopsy data can improve the prediction of LRE in patients with compensated advanced chronic liver disease (cACLD) combined with MAFLD compared to using the ANTICIPATE-NASH model alone.

Research Methods

This was a multicenter retrospective cohort study conducted in Europe. The subjects were MAFLD patients with biopsy-proven liver fibrosis stage F3~F4. Baseline data and follow-up LRE (composite events of decompensation, hepatocellular carcinoma, liver transplantation, or liver-related death) incidence were recorded. Researchers estimated the CSPH/LRE risk distribution according to the ANTICIPATE-NASH model. The additional value of histology provided by the ANTICIPATE-NASH model for risk prediction was examined using Cox regression.

Research Results

A total of 699 patients were included, with 52% being male, a median age of 60 years, and a median BMI of 31 kg/m². Among them, 324 patients (46.4%) were F3, and 375 patients (53.6%) were F4. The median follow-up period was 42.8 months. During the follow-up, 56 patients (8.0%) experienced LRE. The median LSM (22.6 vs. 15.8 kPa), LRE rate (13.6% vs. 1.5%), and CSPH probability estimated by the ANTICIPATE-NASH model (26.9% vs. 18.3%) were significantly higher in F4 patients compared to F3 patients (all P values < 0.001). Compared to histology (0.67), the ANTICIPATE-NASH model had a higher discrimination ability for LRE (area under the curve was 0.93) and excellent calibration. Adding histology to the model did not improve prediction accuracy.

Using a threshold value of 0.25 (estimated 3-year LRE risk of 1.6%) based on the ANTICIPATE-NASH model, significant differences in LRE rates were observed: the LRE rate was 0.98% for values below 0.25, and 18.5% for values equal to or above 0.25 (P < 0.001). 61% of patients had a CSPH risk below the 0.25 threshold, while 39% had a risk above it. This dichotomy was more predictive of LRE risk than the F3/F4 classification. In fact, all LREs (5/68) in F3 patients occurred in those with an ANTICIPATE-NASH threshold value ≥ 0.25. Similarly, 30% of F4 patients had a CSPH risk < 12% (the median for F3 patients), with no LREs.

Research Conclusion

The non-invasive ANTICIPATE-NASH model based on LSM, BMI, and platelet count predicted LRE in MAFLD with greater accuracy than histology. Histology did not improve the risk prediction provided by the model.

Expert Commentary

The study focused on compensated chronic fatty liver disease patients, who, despite being in the compensated stage, still have progressing liver disease and may experience liver-related events in the future. Therefore, predicting and assessing these patients to enable early intervention and prevent future liver-related events is crucial.

Although liver biopsy is the “gold standard,” it is an invasive procedure with low patient acceptance. This study used the non-invasive ANTICIPATE-NASH model, utilizing liver stiffness measurement, BMI, and platelet count to assess the risk of future liver-related events and clinically significant portal hypertension in patients with compensated advanced chronic fatty liver disease.

This multicenter cohort study adopted a retrospective design, including patients with advanced liver fibrosis and cirrhosis (F3 and F4) fatty liver disease, collecting their baseline data and defining future liver-related events, such as liver function decompensation, hepatocellular carcinoma, liver-related death, or liver transplantation. The incidence was then assessed. Additionally, the study used Cox regression to evaluate the predictive ability of liver histology for liver-related events.

The study included 699 patients, with 52% being male, a median age of 60 years, and a BMI of 31. F3 patients accounted for 46.4%, and F4 patients accounted for 53.6%, with a median follow-up time of 42.8 months.

During the follow-up period, 8% (56) of the 699 patients experienced severe liver-related events. The results showed that F4 patients had significantly higher rates of liver-related events than F3 patients. According to the non-invasive prediction model, the probability of significant clinical portal hypertension in F4 patients was 26.9%, while it was 18.3% in F3 patients.

Additionally, the study further evaluated using a risk threshold of 0.25. When this value was less than 0.25, the incidence of liver-related events was only 0.98%; however, when this value exceeded 0.25, the incidence of liver-related events rose to 18.5%. This method was more predictive of liver-related events risk than simply classifying as F3 or F4.

Some F3 patients experienced liver-related events, and all these patients had a non-invasive model threshold value exceeding 0.25. This indicates that although F4 patients have a higher risk of liver-related events than F3 patients, F3 patients with a non-invasive model threshold value above 0.25 still have a high risk of liver-related events.

In conclusion, this study utilized non-invasive indicators such as liver stiffness measurement, BMI, and platelet count to establish an effective ANTICIPATE-NASH evaluation model to predict the occurrence of future liver-related events in patients with advanced chronic liver fibrosis and cirrhosis fatty liver disease. The model’s predictive performance surpassed that of standalone liver histology, providing clinicians with a more accurate predictive tool for early intervention and treatment decisions.

OS-051

Relationship Between Advanced Fibrosis and NASH-CRN Activity Score (NAS) Components: Pooled Data from Over 10,000 Patients in Multiple Treatment Trials

Research Background and Objective

Previous studies have reported the relationship between advanced fibrosis and the severity of metabolic dysfunction-associated steatohepatitis (MASH). This study aimed to evaluate the relationship between NAS, NAS components, and advanced fibrosis.

Research Methods

Researchers pooled screening data from 10 Phase II MASH trials and conducted univariate and multivariate logistic regression analyses to evaluate the relationship between NAS, NAS components, and advanced fibrosis (defined as fibrosis stage 3 or 4). They developed an improved version of NAS, termed “lean NAS” (= inflammation grade + ballooning degeneration grade, excluding steatosis), to predict the presence of advanced fibrosis.

Research Results

A total of 4,117 patients who underwent centralized liver biopsy were included. The prevalence of advanced fibrosis in this population was 36%. In univariate analysis, higher NAS, hepatocyte ballooning, and lobular inflammation were associated with advanced fibrosis. Among patients with NAS scores of 0–8, the occurrence of advanced fibrosis was 27%, 19%, 19%, 25%, 34%, 47%, 55%, 66%, and 57%, respectively. The probability of advanced fibrosis increased significantly in patients with NAS ≥5 (P < 0.0001). Among patients with inflammation grades 0–3, the occurrence of advanced fibrosis was 15%, 29%, 51%, and 71%, respectively. The presence of inflammation increased the likelihood of advanced fibrosis by 3.4 times (95% CI: 2.8–4.0, P < 0.0001). Among patients with ballooning grades 0–2, the occurrence of advanced fibrosis was 15%, 37%, and 66%, respectively. The presence of ballooning increased the likelihood of advanced fibrosis by 5.9 times (95% CI: 5.0–6.9, P < 0.0001). Among patients with steatosis grades 0–3, the proportions with advanced fibrosis were 39%, 39%, 36%, and 32%, respectively. The likelihood of advanced fibrosis was lower in patients with steatosis grade 3 (P = 0.048). In a model including “lean NAS” and steatosis grade, patients with high-grade inflammation (grade 3) and ballooning (grade 2) had a 32-fold increased likelihood of advanced fibrosis (95% CI: 16.8–62.1). Conversely, the likelihood of advanced fibrosis was relatively lower in patients with steatosis grades 1, 2, or 3: odds ratios were 0.45 (95% CI: 0.31–0.66), 0.28 (95% CI: 0.19–0.40), and 0.20 (95% CI: 0.13–0.29), respectively.

Research Conclusion

Advanced liver fibrosis is closely associated with the presence and severity of hepatocyte ballooning and, to a lesser extent, inflammation, and is unrelated to NAS. “Lean NAS” can predict the presence of advanced liver fibrosis, while the severity of steatosis is inversely related to the severity of fibrosis.

Expert Commentary

This study mainly observed the relationship between advanced liver fibrosis and the NASH-CRN activity score, or NAS score. The NAS score primarily includes three components: the level of hepatic steatosis, hepatic inflammation, and hepatocyte ballooning.

The study included pooled clinical treatment data from over 10,000 patients, with the main aim of evaluating the relationship between advanced liver fibrosis and NAS scores in these patients. Using the modified NAS score, future risks of advanced liver fibrosis can be predicted.

Researchers adopted a modified NAS score, termed “lean NAS,” which only assesses the level of inflammation and hepatocyte ballooning in fatty liver patients, excluding the steatosis level. This modified lean NAS score can more accurately predict advanced liver fibrosis.

Among multiple clinical trial data, 4,117 patients underwent centralized liver biopsy assessment. Results showed that 36% of these patients had advanced liver fibrosis. The study found that higher NAS scores, hepatocyte ballooning, and lobular inflammation were associated with advanced liver fibrosis. Although the NAS score was not entirely positively correlated with the occurrence of advanced liver fibrosis, when the NAS score reached 5 or higher, the probability of advanced liver fibrosis increased significantly.

Further research found that in patients with ballooning grades 0–2, the risk of advanced liver fibrosis increased with higher ballooning scores to 15%, 37%, and 66%, respectively, indicating a significant correlation between advanced fibrosis and ballooning. Meanwhile, liver inflammation also increased the likelihood of advanced liver fibrosis by 3.4 times, while ballooning increased this likelihood by 5.9 times.

Notably, although steatosis levels in the NAS score were graded 0–3, there was no significant difference in the occurrence rate of advanced liver fibrosis among these grades. Even patients with steatosis grade 3 did not show an increased likelihood of advanced liver fibrosis; in fact, it was lower.

Thus, researchers adopted the lean NAS score, which excludes steatosis grade. Under this scoring system, if high-grade inflammation (grade 3) and ballooning (grade 2) were present, the rate of advanced fibrosis would be 32 times higher. Conversely, the correlation between steatosis and advanced fibrosis was relatively low.

In summary, this study reminds us that in future clinical trials, the lean NAS score may have higher practical value in predicting advanced liver fibrosis. When assessing NAS, liver inflammation, and ballooning scores, whether steatosis scores should be included in the prediction system remains debatable.