Optimizing hepatocellular carcinoma screening in the era of metabolic dysfunction-associated steatotic liver disease and alcohol-related liver disease: time to lower the alpha-fetoprotein threshold

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Advances in therapies, including surgical, locoregional, and systemic, have improved outcomes for early-stage HCC patients. However, only 30–40% of HCC cases are diagnosed at an early stage.

Cirrhosis is present in over 80% of HCC cases and is the strongest risk factor for the development of HCC. Chronic hepatitis B has a lifetime risk of HCC at 10–25%, and HCC can occur without cirrhosis (1). In the past 20 years, the underlying diseases driving the development of cirrhosis have changed. Hepatitis C virus (HCV) was the leading cause of cirrhosis and liver transplant in the United States of America (USA) from the mid-1990s through the mid-2010s (2). With the development of direct-acting anti-viral therapy for HCV, the rates of HCV-related cirrhosis and HCC have declined. In its place, metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease (ALD) have become the leading causes of cirrhosis in the USA. Hepatitis B-related cirrhosis has also been declining from 2007 to 2016, which is thought to be a reflection of universal infant vaccination, which was introduced in 1991, as well as anti-viral therapy (3).

MASLD is now estimated to affect at least 25% of the worldwide population and accounts for up to 35% of HCC cases (4). MASLD-related HCC is more commonly found in older individuals, more often diagnosed at a later stage, and associated with poorer survival than viral hepatitis related HCC.

Current American Association for the Study of Liver Diseases (AASLD) and European Association for the Study of the Liver (EASL) guidelines recommend the semi-annual surveillance for HCC with ultrasound (US) and alpha-fetoprotein (AFP) in all patients with cirrhosis, no matter the underlying disease. AASLD guidelines recommend an AFP threshold of ≥20 ng/mL or a rising AFP level prior to further diagnostic multiphase imaging with computed tomography (CT) or magnetic resonance imaging (MRI). The recent article by Kim et al. supports lowering the AFP threshold from ≥20 ng/mL to ≥10 ng/mL in those with MASLD, ALD, and cured HCV to increase sensitivity with minimally decreasing specificity in the detection of HCC. However, a change in AFP threshold alone is not sufficient to improve detection of early-stage HCC. The focus needs to be on adherence to recommended screening guidelines and ensuring that the US imaging obtained has adequate visualization of the hepatic parenchyma.

The 2026 American Gastroenterological Association (AGA) Clinical Practice Update highlights that fewer than 1 in 4 patients with cirrhosis receive consistent surveillance, reinforcing that improving adherence to existing guidelines may yield greater gains in early HCC detection than refining biomarker thresholds alone (5). A recent meta-analysis evaluating compliance with recommended HCC surveillance guidelines, which included 48 articles and 1,275,349 patients, indicated that overall utilization of any HCC surveillance was 54%, while less than 10% of the patients received recommended biannual surveillance (6).

With an AFP threshold of ≥20 ng/mL, the sensitivity in cured-HCV, ALD, and MASLD is 15.9–32.5% with a specificity of 99.0–99.4%. When the threshold for AFP is lowered to ≥10 ng/mL, the sensitivity improves to 27.1–41.5% with a specificity that remains high at 94.7–96.7% and the false positive rate increases by 3–4% (7). As the authors note, this would be acceptable given that a positive test would prompt noninvasive cross-sectional imaging rather than an invasive procedure.

In the current AASLD guidelines, it is noted that the optimal AFP cutoff may be lower in those with a nonviral etiology to cirrhosis and gives the caveat that diagnostic imaging can be ordered if the AFP is rising. These guidelines reflect the fact that the AFP limit was set in the era when hepatitis C and B were the leading causes of cirrhosis and HCC. The recent study by Kim et al. shows that, among patients diagnosed with HCC between 2001 and 2021, median AFP at diagnosis was 7.7–9.0 ng/mL in MASLD/ALD and 8.3 ng/mL in cured HCV, vs. 32.7 ng/mL in active HCV (7).

The initial studies that were used to validate semi-annual screening for HCC with US and AFP were conducted in Asian populations where HCC cases were primarily a result of chronic hepatitis B.

AFP levels can fluctuate due to etiologies other than hepatocellular malignancy. Since AFP has a role in liver regeneration, fibrosis, and inflammation, levels may be elevated in such situations as heavy alcohol use. As a result, the AASLD de-emphasized the utilization of AFP in HCC screening in their 2011 guidelines due to poor sensitivity and specificity if utilized independently. In the 2018 guidelines, the AASLD conditionally suggested surveillance using US “with or without” AFP every 6 months (8). Subsequently, a meta-analysis pooling nine studies of US for early HCC detection found that the sensitivity and specificity of US alone was only 53% [95% confidence interval (CI): 35–70%] and 91% (95% CI: 86–94%), respectively, whereas US plus AFP achieves a sensitivity of 63% for early-stage HCC (95% CI: 48–75%) (9). There was a small decrease in specificity that offset the increased sensitivity; however, the diagnostic odds ratio of the combination was higher than US alone. A subsequent cost-effectiveness analysis found that US with AFP was the dominant strategy over both US alone and no surveillance, and was the most cost-effective strategy in 80.1% of simulations at a willingness-to-pay threshold of $100,000 per quality-adjusted life-year (10). Based on these data, the 2023 AASLD Practice Guidance formally recommended the combination of AFP and US for semi-annual HCC surveillance (11), a position reaffirmed by the 2026 AGA Clinical Practice Update (5).

The change in underlying etiology liver disease has also led to further issues with the sensitivity of our screening regimen. It has also been shown that US is less sensitive for MASLD patients in detecting HCC. In a single-center study conducted in the United States screening patients for HCC who were undergoing liver transplant evaluation from 2007 to 2015, it was noted that US missed 41% of patients with HCC and 10% more lesions in patients with a body mass index (BMI) ≥30 kg/m² as compared to those with lower BMIs (12).

The American College of Radiology Liver Imaging Reporting and Data Systems (ACR LI-RADS) US v2017 provided a framework for performing, interpreting, and reporting US studies for HCC surveillance as it had not previously been done (13). This framework was recently updated as ACR LI-RADS US Surveillance v2024. The algorithm consists of an US category (US-1: negative, no US evidence of HCC; US-2: subthreshold, an observation <10 mm that is not definitely benign; and US-3: positive, an observation ≥10 mm that is not definitely benign, or new portal or hepatic venous thrombus, that warrants further evaluation with a diagnostic contrast-enhanced US, CT, or MRI), and an US visualization score (VIS; VIS-A: no or minimal limitations; VIS-B: moderate limitations; and VIS-C: severe limitations) (14). The AASLD notes that visualization limitations (VIS-B or VIS-C) may be observed in approximately 20% of patients, particularly those with obesity and nonviral etiologies of cirrhosis, and that patients with severe limitations may warrant alternative surveillance strategies such as MRI (11).

Given the limited sensitivity of AFP as a biomarker, there have been efforts to improve blood-based biomarkers. The binding capacity of AFP to lens culinaris agglutinin (LCA) can identify three different AFP glycoforms with Western blotting. The AFP-L3, LCA reactive, glycoform is generally more specific to HCC (15). However, it is noted to have insufficient sensitivity alone to detect early-stage HCC.

Some of the more extensively studied approaches are combination scores such as the GALAD score or the HCC early detection screening (HES) algorithm. The GALAD score incorporates age, gender, AFP, AFP-L3, and des-ɣ-carboxyprothrombin (DCP). In case-control studies, GALAD demonstrated sensitivities of 72–82% for the detection of early-stage HCC (16). However, in a phase 3 validation study of 1,558 patients with cirrhosis, GALAD achieved 62% sensitivity with 82% specificity as compared to AFP with a 41% sensitivity at the same specificity (17). Kim et al. note that all of these emerging biomarker panels include AFP as a critical component, and their findings suggest that the algorithms and screening thresholds used in these panels may need to be reassessed and recalibrated using recent cohorts not dominated by active-HCV (7). The HES version 2.0 (V2.0) algorithm incorporates AFP trends, AFP-L3, DCP, alanine aminotransferase (ALT), platelet count, age, and cirrhosis etiology. In a recent phase 3 biomarker study in the USA, the HES V2.0 algorithm had a higher sensitivity than GALAD, although its sensitivity for early-stage HCC remained limited at 47% (18). Notably, performance of these composite scores has been more modest in longitudinal cohort studies than in case-control studies, and currently neither AASLD nor AGA guidelines support their use in routine HCC surveillance citing insufficient evidence (5,11).

There have also been advances in the development of liquid biopsy panels which look at methylated DNA markers or cell-free DNA methylation patterns to try and identify early-stage HCC. One of these tests, the multianalyte HelioLiver Dx blood test, recently completed a phase 3 prospective validation study. While the phase 2 study reported a sensitivity of 76% for early-stage HCC detection, the phase 3 study, which compared HelioLiver Dx to US using MRI as the reference standard, demonstrated a lower overall sensitivity of 47.8%, with sensitivity for lesions ≤2 cm even lower at 28.6% (19). Results from the ALTUS study looking at the methylated DNA markers and AFP as part of the Oncoguard Liver panel have not yet been reported. At this time, even though Oncoguard Liver has received FDA breakthrough device designation, results from the ALTUS phase 3 validation study have not yet been reported, and its role in routine HCC surveillance remains to be defined. Ongoing prospective clinical utility trials, including the TRACER trial comparing US-based vs. GALAD-based screening and the PREMIUM trial evaluating abbreviated MRI, will provide more definitive data on the integration of novel biomarkers and imaging modalities into practice (5).

Abbreviated MRI is an emerging tool to diagnose early-stage HCC. Full contrast-enhanced MRI has demonstrated substantially higher HCC detection rates than US (86.0% vs. 27.9%, P<0.001) with a lower false-positive rate (3.0% vs. 5.6%, P=0.004), and 74.4% of detected HCCs were very early-stage (single lesion <2 cm) (20). Abbreviated MRI protocols, which reduce examination time and cost, may help address practical barriers to MRI-based surveillance, including cost and radiology capacity, particularly for patients with obesity in whom US visualization is limited. A recent cost-effectiveness analysis suggests that HCC surveillance with an US VIS-based approach, using abbreviated MRI for VIS-C, may be the most cost-effective strategy in patients with MASLD cirrhosis (21).

In conclusion, lowering the AFP threshold to ≥10 ng/mL in those with MASLD, alcohol-related disease, and cured HCV may help detect more early HCC cases, but there needs to be more attention paid to screening guideline adherence and the quality of the tests performed. Most specifically, ensuring that US visualization is categorized, and that those studies with poor visualization are followed up on appropriately either with a repeat US or cross-sectional imaging. Importantly, consideration should be given for the use of abbreviated MRI in patients whose BMI is ≥30 kg/m² and those with more significant central adiposity who are more likely to have lesions missed on US. In the near future, we will likely have improved biomarker panels to aid in our detection of early-stage HCC; however, as Kim et al. emphasize, these panels will need to be validated in cohorts enriched for MASLD and ALD, as algorithms that include AFP as a component may need recalibration for non-HCV populations.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0712/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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