The development and appraisal of MELD 3.0 in liver diseases: Good things never come easy

The Model for End-Stage Liver Disease (MELD) score has played a pivotal role in assessing the severity of liver disease and prioritizing liver transplant candidates since its development by Kamath et al. in 2000. Initially designed to predict short-term mortality in patients undergoing transjugular intrahepatic portosystemic shunt (TIPS) procedures, it has since become a standard tool in clinical hepatology. By incorporating serum creatinine, bilirubin, and the international normalized ratio (INR), the MELD score provided an objective, reliable measure for determining disease severity and transplant urgency. However, as the epidemiology of liver diseases and transplantation practices evolved, significant limitations in the MELD score emerged, including its inability to account for sex-based disparities, advanced complications, and changing demographic profiles of liver disease patients. This review explores the development and clinical application of MELD 3.0, the latest iteration aimed at overcoming these challenges.

Evolution of MELD and Its Variants

Since its inception, the MELD score has undergone numerous modifications to address its inherent limitations. Early concerns included its susceptibility to extrahepatic influences, the underestimation of renal dysfunction in women due to differences in muscle mass, and its inability to fully capture pathophysiological changes in advanced liver diseases.

One significant adaptation was the MELD-Na score, which incorporated serum sodium levels to improve the prediction of short-term mortality in liver transplant candidates. Its implementation by the Organ Procurement and Transplantation Network (OPTN) in 2016 led to a notable reduction in waitlist mortality. Other variants include delta MELD, which monitors changes in MELD over time, and iMELD, which adds age and sodium to enhance prognostication in cirrhosis. For specific subgroups, like anticoagulated patients, the MELD-XI variant excludes INR, while MELD-LA incorporates lactate to predict outcomes in critically ill patients. For pediatric populations, the PELD score uses age-specific indicators such as growth failure and albumin levels to prioritize liver transplants.

These adaptations have collectively broadened the scope of the MELD system, yet each variant has limitations, necessitating a more comprehensive model to address the complexities of liver disease.

Development of MELD 3.0

MELD 3.0, developed by Stanford University and the Mayo Clinic, represents a significant step forward in addressing the limitations of earlier models. This version builds upon MELD-Na by including serum albumin and gender as variables, aiming to correct disparities in organ allocation, particularly for women, who often faced disadvantages under previous systems.

Albumin, an indicator of nutritional and liver synthetic function, adds depth to the score’s predictive accuracy. Furthermore, MELD 3.0 introduces interaction terms between variables like bilirubin and sodium, creatinine and albumin, reflecting complex relationships within liver disease pathophysiology. Adjustments to the creatinine ceiling mitigate gender biases and account for comorbidities. Validation studies demonstrated MELD 3.0’s ability to reclassify high-risk patients more effectively, reducing mortality on transplant waiting lists and addressing gender inequities in organ allocation.

Applications in Liver Transplantation

A central goal of organ allocation is to balance urgency, utility, and transplant benefit. MELD 3.0 enhances this balance by prioritizing patients based on biological predictors of mortality, ensuring equitable access to transplants. For example, MELD 3.0 demonstrated an increased likelihood of transplantation for women compared to MELD-Na, addressing longstanding inequities in liver allocation.

However, its performance varies across different liver disease etiologies. In alcohol-associated liver disease (ALD) and metabolic dysfunction-associated steatotic liver disease (MASLD), MELD 3.0 improves prognostication but may underperform in certain contexts like alcoholic hepatitis (AH). Additionally, regional differences in practice, such as the prevalence of living donor liver transplantation in Asia, highlight the need for further regional validations of MELD 3.0.

Use in Chronic Liver Disease

MELD 3.0 shows promise in predicting outcomes for various chronic liver diseases. It outperforms MELD-Na in forecasting three- and six-month mortality for cirrhosis patients and offers more precise risk stratification for complications like refractory ascites and spontaneous bacterial peritonitis. For hepatocellular carcinoma (HCC), MELD 3.0 provides superior mortality predictions compared to albumin-bilirubin scores, though its utility is limited in patients with renal insufficiency. In acute-on-chronic liver failure (ACLF), where rapid prognostic changes occur, alternative models like the CLIF-C ACLF may offer better predictive performance.

Challenges and Future Directions

Despite its advancements, MELD 3.0 is not without limitations. It struggles to predict long-term outcomes in specific scenarios like ACLF and alcohol-associated hepatitis. Additionally, its predictive accuracy can be influenced by regional, demographic, and etiological factors. For instance, the score’s performance in Asian cohorts differs due to variations in disease profiles and transplant practices.

Future research should focus on eliminating score ceilings and integrating MELD 3.0 with emerging technologies like artificial intelligence (AI) and electronic health records. These tools could enable real-time data analysis, enhancing predictive accuracy and tailoring interventions to individual patient needs.

Conclusions

MELD 3.0 represents a significant evolution in the management of liver diseases, offering improved predictive accuracy and equity in organ allocation. Its incorporation of gender and albumin addresses critical disparities, ensuring fairer prioritization of transplant candidates. While further refinements and regional validations are needed, MELD 3.0 sets a robust foundation for future advancements in liver disease management, paving the way for personalized, data-driven approaches to transplantation and chronic liver disease care.

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https://www.xiahepublishing.com/2310-8819/JCTH-2024-00303

 

The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

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