A high-risk methylation signal, months before imaging
Routine surveillance was clean. AFP normal, ultrasound negative, MRI negative. The HelioLiver test was not. Six months later, imaging found a 10 × 9 mm mass.
Can molecular biomarkers identify liver cancer risk before conventional imaging?
In this real-world case, a high-risk cell-free DNA methylation signal was detected by the HelioLiver test at a surveillance visit when AFP, abdominal ultrasound, and multiphasic MRI were all negative. A 10 × 9 mm liver mass was identified approximately six months later, and LI-RADS 5 confirmation of hepatocellular carcinoma followed at approximately nine months.
Case summary
| Setting | Routine HCC surveillance |
|---|---|
| Baseline AFP | Normal |
| Baseline ultrasound | Negative |
| Baseline MRI | Negative |
| HelioLiver® result | High-risk methylation signal detected |
| Lesion size when imaging finally found it | 10 × 9 mm on ultrasound; 1.7 cm LR-4 on MRI |
| Time to imaging confirmation | Approximately 6 months to first mass, 9 months to LR-5 |
| Outcome | SBRT, referred for liver transplant evaluation |
A negative visit is not an absence of disease
Patients with cirrhosis are recommended to undergo surveillance for hepatocellular carcinoma every six months, most commonly with abdominal ultrasound with or without serum alpha-fetoprotein, or AFP. That recommendation is sound in principle. In practice, ultrasound is operator-dependent, its sensitivity for small nodules is limited, and a negative result at a single visit is not the same as an absence of disease.
This case follows one patient through four assessment points across nine months. At the first, every conventional test was negative and HelioLiver® was not. What happened next is the reason we are publishing it.
Timeline
- June 2025 · Routine surveillanceAFP normal. Ultrasound negative. MRI negative. HelioLiver® detected a high-risk methylation signal.
- July 2025 · Additional imagingRepeat ultrasound and magnetic resonance elastography, or MRE, were performed in response to the blood test result. No evidence of HCC was detected.
- December 2025 · Six-month surveillanceUltrasound identified a 10 × 9 mm liver mass. Follow-up MRI demonstrated a 1.7 cm LI-RADS 4 (LR-4) lesion in segment 2, consistent with probable HCC.
- March 2026 · ConfirmationRepeat MRI demonstrated LI-RADS 5 (LR-5), confirming HCC. The patient subsequently underwent stereotactic body radiation therapy, or SBRT, and was referred for liver transplant evaluation.
Because in liver cancer, time matters.
What it means at the point of care
The molecular signal came first, and it came at a point when four separate conventional assessments, AFP, ultrasound, MRI, and later MRE, were all negative. Nine months later the same liver held a confirmed LR-5 lesion.
The appropriate reading of this case is not that the blood test replaced imaging. It is that the blood test changed what the imaging was looking for. Biology precedes anatomy. A test that reads cell-free DNA methylation patterns is measuring a different thing than a test that measures a nodule, and in this patient the two diverged by roughly six months.
That interval matters clinically. Detected at 1.7 cm and LR-4, this patient went on to receive SBRT and a referral for liver transplant evaluation. Treatment options in hepatocellular carcinoma narrow as lesion size and stage increase, which is why the point of detection shapes everything that follows.
Three things to carry forward
- A negative ultrasound, a negative MRI, and a normal AFP at a single surveillance visit did not rule out developing hepatocellular carcinoma in this patient.
- The HelioLiver® methylation signal preceded radiologic detection by approximately six months, and preceded LR-5 confirmation by approximately nine months.
- Molecular diagnostics are best understood here as a complement to conventional surveillance, prompting closer follow-up rather than replacing imaging.
- Taggart DJ, Mahajan S, Gallant MA, et al. A multi-analyte cfDNA-based blood test for early detection of hepatocellular carcinoma. J Hepatol. 2026;1-9. doi:10.1016/j.jhep.2026.04.012
- Marrero JA, Kulik LM, Sirlin CB, et al. Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases. Hepatology. 2018;68:723-750.
About the CLiMB trial
CLiMB was a cross-sectional, prospective, blinded, multicenter validation study conducted across 42 clinical sites in the United States, evaluating the HelioLiver Dx test against abdominal ultrasound for the detection of hepatocellular carcinoma in adults with cirrhosis. Multiphasic MRI served as the reference standard. The HelioLiver Dx test met prespecified co-primary endpoints for superior sensitivity and non-inferior specificity compared to ultrasound.
Enrolled vs. evaluable. A total of 1,556 patients were enrolled in the prospective CLiMB study and assigned to the validation cohort, of whom 1,285 completed the initial visit. At the 6-month follow-up visit, 17 participants were lost to follow-up and were excluded from analysis. Only participants with valid results from the HelioLiver Dx test, ultrasound, and multiphasic MRI were considered evaluable. A total of 1,268 participants (81.5%) were evaluable, including 46 participants with HCC and 1,222 participants without HCC. Every performance figure in this series is calculated on that evaluable population. Published in the Journal of Hepatology, 2026. ClinicalTrials.gov identifier NCT03694600.
Have a case to contribute?
Clinicians using the HelioLiver test can submit de-identified cases for consideration in this series.