CIRRHOSIS, the final stage of chronic liver disease, is a global health concern affecting 1%–2% of the population and causing 1.32 million deaths annually. The prevalence of chronic liver disease has risen by 15% over the past decade, largely due to increasing obesity and metabolic disorders. Hepatocellular carcinoma (HCC), a major complication of cirrhosis, is the fastest-growing cause of cancer-related death in the United States. Late-stage diagnosis often precludes curative treatment, prompting professional societies to recommend semi-annual ultrasound screening for all cirrhotic patients. However, this broad screening approach is neither feasible nor cost-effective due to the expanding at-risk population with metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and cured hepatitis C virus (HCV) infection.
To improve screening efficiency, it is crucial to identify patients with elevated HCC risk while sparing low-risk individuals from unnecessary procedures. A prior simulation model demonstrated that risk-stratified screening would be cost-effective if a biomarker could distinguish at least a two-fold difference in HCC incidence between patient groups. The 8-protein prognostic liver secretome signature (PLSec), combined with α-fetoprotein (PLSec-AFP), has shown promise in long-term HCC risk prediction. However, there remained a need for improved identification of low-risk patients.
The newly developed PAaM score integrates PLSec-AFP with clinical variables, refining risk stratification. Validated in two large multicenter cohorts, PAaM successfully identified high-risk patients (15%–20% of the cohort) with an annual HCC incidence exceeding 5%, a threshold at which MRI-based screening becomes cost-effective. Conversely, PAaM identified approximately 40% of patients as low-risk, a significant improvement over previous clinical scores. These individuals may forgo semi-annual ultrasound screening or adopt a less intensive monitoring approach.
PAaM’s general applicability was confirmed across diverse patient demographics, with variations in HCC risk by etiology and ethnicity. Furthermore, PLSec, a key component of PAaM, is modifiable through medical interventions, making it a potential companion biomarker for HCC chemoprevention. While limitations remain, PAaM represents a significant advancement in personalised HCC risk assessment, paving the way for more targeted and effective screening strategies to reduce HCC mortality.
Katie Wright, EMJ
Reference
Fujiwara N et al. Phase 3 validation of PAaM for hepatocellular carcinoma risk stratification in cirrhosis. Gastroenterology. 2024;DOI:10.1053/j.gastro.2024.10.035.
