Introduction
Alpha-fetoprotein (AFP) is a fetal glycoprotein mainly produced by the yolk sac and fetal liver. Adult serum concentrations are usually low after postnatal repression of AFP gene expression. Clinically, AFP is most often interpreted in the context of hepatocellular carcinoma (HCC), germ-cell tumors, pregnancy, active hepatic inflammation or regeneration, and selected rare hereditary or metabolic disorders.1,2 Current HCC guidance emphasizes that AFP alone is neither sufficiently sensitive nor specific for diagnosis; interpretation requires the clinical context and appropriate imaging.3
Persistent isolated AFP elevation in an otherwise healthy adult is uncommon and may create diagnostic uncertainty, repeated imaging, and patient anxiety. Hereditary persistence of AFP (HPAFP) is a rare benign condition, usually autosomal dominant, in which AFP remains elevated without clinical disease; sporadic or nonhereditary persistent AFP elevation has also been described.4–8 We present a case of marked persistent AFP elevation in a healthy adult after exclusion of malignancy and active liver disease.
Case presentation
Clinical information was obtained from the patient’s medical records, including medical history, serial serum AFP measurements, liver biochemistry, viral serology, additional tumor markers, imaging investigations, and hepatic cyst-fluid analysis. The diagnostic evaluation was directed primarily toward excluding hepatocellular carcinoma, germ-cell tumors, active liver disease, and other potential AFP-producing malignancies. Serial clinical, biochemical, and imaging findings from 2018 to 2024 were reviewed to characterize the longitudinal pattern of AFP elevation.
A 54-year-old man was referred after routine health screening detected a hepatic space-occupying lesion, subsequently characterized on ultrasonography as a simple hepatic cyst, and a concomitant marked elevation in serum AFP. He was asymptomatic and had no abdominal pain, weight loss, anorexia, fever, jaundice, testicular symptoms, or other constitutional symptoms. He reported no history of diabetes, hypertension, chronic liver disease, significant alcohol intake, viral hepatitis risk factors, or prior malignancy. There was no known family history of HCC or testicular cancer.
Liver function tests were within normal limits. Hepatitis B surface antigen, anti-hepatitis C virus antibody, and human immunodeficiency virus (HIV) testing were negative. Serum AFP was persistently elevated, with serial values ranging approximately from 200 to 400 ng/mL during observation. The lectin-reactive AFP fraction (AFP-L3) was less than 10%. Protein induced by vitamin K absence or antagonist-II (PIVKA-II; des-γ-carboxy prothrombin), carcinoembryonic antigen, and carbohydrate antigen 19-9 (CA 19-9) were not elevated. Abdominal ultrasonography showed preserved liver architecture with simple hepatic cysts. Triple-phase contrast-enhanced computed tomography confirmed a few simple hepatic cysts and showed no cirrhosis, suspicious hepatic mass, arterial hyperenhancement with washout, lymphadenopathy, or metastatic disease. Testicular ultrasonography showed no mass or microlithiasis. Whole-body positron emission tomography (PET)/computed tomography (CT) showed no hypermetabolic lesion suggestive of malignancy. Brain and spine magnetic resonance imaging (MRI), performed during the earlier diagnostic work-up, showed no mass lesion. Laboratory investigations and imaging findings are summarized in Table 1.
Table 1Summary of laboratory, imaging, and hepatic cyst fluid investigations
| Test | Result | Reference range |
|---|
| Liver function tests | Within normal limits | — |
| Hepatitis B and C panel | Negative | Negative |
| HIV | Negative | Negative |
| AFP | 258 ng/mL | <10–15 ng/mL |
| AFP-L3 | <10% | <10% |
| CEA | Normal | <5 ng/mL |
| CA 19-9 | Normal | <37 U/mL |
| PIVKA-II | Normal | <7.5 ng/mL |
| Modality | Findings |
|---|
| Abdominal ultrasonography | Normal liver architecture; few simple hepatic cysts; no focal hepatic lesion |
| Contrast-enhanced abdominal CT | A few simple hepatic cysts; no cirrhosis or lymphadenopathy |
| Testicular ultrasonography | Normal testes, no masses or microlithiasis |
| Whole-body PET/CT | No hypermetabolic lesion identified |
| Parameter | Result | Reference/interpretation |
|---|
| Volume | 8.0 mL | — |
| Color | Pale yellow | — |
| Appearance | Clear | — |
| Clot/fibrin web | Absent | — |
| TLC | 1 cell/mm3 | <500 cells/mm3 (normal) |
| Total RBC count | 100 cells/mm3 | Should be minimal |
| Neutrophils | 100% (high) | Normally <25% |
| Lymphocytes, eosinophils, etc | 0% | — |
| Mesothelial cells | 0 | — |
| Macrophages | 0 | — |
| Glucose | 0.80 mg/dL | Reference not established |
| Total protein | 0.10 g/dL | Reference not established |
| Chloride | 126.10 mmol/L | Reference not established |
| AFP (cyst fluid) | 0.97 ng/mL | Within normal limits |
| CEA (cyst fluid) | 0.20 ng/mL | Reference not established |
| Cytology | Negative | No malignant cells seen |
Because the hepatic cysts were initially considered a possible confounder, cyst aspiration was performed before referral. Cyst fluid was clear and pale yellow; cytology was negative for malignant cells; cyst-fluid AFP was 0.97 ng/mL and cyst-fluid carcinoembryonic antigen was 0.20 ng/mL. These findings supported an incidental benign cyst rather than a source of AFP. The patient remained asymptomatic with stable AFP elevation before and after cyst aspiration, with no biochemical or imaging evidence of malignancy or liver disease. Genetic testing for AFP regulatory region variants and family AFP testing could not be performed because testing was unavailable and no first-degree relatives were available. The final clinical impression was probable HPAFP or idiopathic persistent AFP elevation after exclusion of malignant and inflammatory causes. Representative CT images are shown in Figure 1, and cyst-fluid findings are summarized in Table 1. The clinical timeline is presented in Table 2, and serial AFP values are shown in Figure 2.
| Date | Clinical event/investigation | Interpretation/action |
|---|
| May 5, 2018 | Initial documented AFP elevation during health assessment | Marked elevation established; no serial trend yet |
| March 5, 2024 | Abdominal ultrasonography | Avascular cystic lesions in the liver parenchyma measuring 2.13 × 2.09 cm and 1.64 × 1.54 cm |
| March 14, 2024 | Repeat AFP | Persistent but lower than in 2018 |
| April 17, 2024 | Repeat AFP | Persistent fluctuation without a monotonic rise |
| April 23, 2024 | Abdominal MRI | Hepatic cysts seen |
| May 20, 2024 | Repeat AFP | Stable marked elevation |
| June 10, 2024 | Repeat AFP | Stable marked elevation |
| June 23, 2024 | Testicular ultrasonography: no mass or microlithiasis | Targeted germ cell tumor evaluation negative |
| August 29, 2024 | Triple-phase liver CT | Multiple variably sized hepatic cysts in both liver lobes, the largest measuring 2 × 1.4 cm |
| August 30, 2024 | Repeat AFP | Stable marked elevation |
| September 26, 2024 | Whole-body PET/CT | No hypermetabolic lesion identified |
| October 11, 2024 | Whole-body PET/CT repeated at a different center | No hypermetabolic lesion identified |
| October 15, 2024 | Brain and spine MRI | Escalation testing negative |
| October 28, 2024 | Repeat AFP | Lowest documented value; no progressive rise |
| November 20, 2024 | Aspiration of simple hepatic cyst; cyst-fluid AFP 0.97 ng/mL, CEA 0.20 ng/mL, cytology negative | Cyst considered incidental; procedure retrospectively considered low yield |
| December 4, 2024 | First serum AFP measured after cyst aspiration; latest documented AFP and clinical review | Approximately 6 years of marked but nonprogressive elevation |
Focused narrative review
A focused narrative review was undertaken to identify published reports of persistent AFP elevation without demonstrable malignancy or active liver disease. MEDLINE/PubMed, Embase, and Google Scholar were searched from database inception through April 30, 2026. Search terms included “alpha-fetoprotein,” “AFP,” “persistent elevation,” “healthy adult,” “asymptomatic,” “hereditary persistence of alpha-fetoprotein,” “HPAFP,” “idiopathic persistent AFP,” and “without malignancy,” combined using the Boolean operators AND and OR. Reference lists of relevant publications and reviews were additionally screened manually.
Eligible publications included case reports, case series, observational cohorts, and reviews describing persistent AFP elevation in the absence of an AFP-producing malignancy or active hepatic inflammation. Particular attention was given to AFP magnitude, duration of persistence, exclusion of hepatic and germ-cell malignancies, family AFP testing, and molecular analysis of AFP regulatory regions. Reports limited to transient AFP elevation, pregnancy-related elevation, established malignancy, or active hepatitis were excluded from the principal comparison.
A recent comprehensive literature search for HPAFP identified 25 publications describing 30 affected families, illustrating the rarity of the condition. Molecular confirmation was reported in only 9 of these 30 families, while the remainder were supported predominantly by pedigree and persistent AFP measurements.4,6,8,10 The present search updated this evidence base through April 2026 and also included reports of sporadic or idiopathic persistent AFP elevation and clinically relevant reports illustrating diagnostic uncertainty during germ-cell tumor evaluation. Database-specific search terms, eligibility criteria, and the publications included in the comparative synthesis are provided in Supplementary Table 1. Key publications identified in the focused synthesis are summarized in Table 3.
Table 3Key publications on persistent AFP elevation without evident malignancy or active liver disease
| Publication | Design/population | AFP pattern | Diagnosis | Key relevance to present case |
|---|
| Schefer et al.13 | Case report and literature review; healthy adult/familial context | Persistent low-to-moderate elevation | No malignancy identified | Early clinical description of benign persistent AFP elevation |
| Houwert et al.6 | Literature review of HPAFP | Variable persistent elevation | Synthesized genetic and clinical features | Frames HPAFP as benign and often autosomal dominant |
| Jeon et al.4 | Four healthy adults with persistent AFP elevation | Persistent AFP elevation; one hereditary pattern | AFP regulatory regions studied; no malignant disease | Shows persistent AFP elevation can remain unexplained even after regulatory-region testing |
| Jang et al.5 | Retrospective cohort of 137 asymptomatic adults | Mostly mild, stable elevation | No cancer or liver disease during median follow-up | Supports longitudinal follow-up after adequate negative evaluation |
| Saracoglu et al.8 | Case report of HPAFP | High persistent AFP | Imaging workup negative for HCC/germ cell tumor | Highlights avoidance of unnecessary procedures when HPAFP is likely |
Because the objective was a focused clinical synthesis rather than a systematic review or quantitative evidence synthesis, no meta-analysis or formal risk-of-bias assessment was performed.
Discussion
The main clinical challenge in this case was to distinguish a true tumor-marker signal from benign persistent AFP elevation. HCC and germ-cell tumors remain priority diagnoses to exclude when AFP is markedly elevated. However, this patient had normal liver biochemistry, negative viral markers, no cirrhosis or suspicious liver lesion on multiphasic imaging, normal testicular ultrasonography, normal AFP-L3 and PIVKA-II, and no PET-avid lesion. Although no single test completely excludes occult malignancy, the concordance of serial stability, negative multimodality assessment, and absence of clinical progression support a benign explanation.
Simple hepatic cysts are common benign imaging findings, and, in this case, there was no imaging complexity, mural nodule, enhancement, malignant cytology, or cyst-fluid AFP elevation. Therefore, the cysts are best interpreted as incidental rather than causative.
HPAFP is the most clinically relevant benign differential diagnosis. It has been described as an autosomal dominant trait and has been linked in some families to variants in the AFP promoter or enhancer regions, including hepatocyte nuclear factor binding sites.4,6–12 Importantly, not all patients with persistent AFP elevation have an identifiable mutation in routinely studied regulatory regions, and nonhereditary stable AFP elevation in healthy adults has also been reported.4,5 In the series by Jeon et al., four healthy adults had persistent AFP elevation with negative malignancy workup; one family showed a hereditary pattern, but mutations were not found in the studied AFP promoter, enhancer, or silencer regions.4 Similar benign familial persistence of AFP has also been reported in both adults and children.13,14 In a larger observational cohort, Jang et al. reported stable AFP values and no development of cancer or liver disease during follow-up among asymptomatic adults with elevated AFP, suggesting that longitudinal follow-up may be reasonable after adequate initial exclusion of disease.5
The degree of AFP elevation in the present patient was higher than that in many asymptomatic adult cohorts but remains compatible with reported HPAFP cases. Saracoglu et al. described very high AFP concentrations in HPAFP and emphasized that the diagnosis should be considered when imaging evaluation for HCC and germ-cell tumor is negative.8 Such cases are important because failure to recognize benign persistent AFP elevation may lead to repeated radiation exposure, invasive biopsies, unnecessary surgery, chemotherapy, or prolonged psychological distress.7,8
A practical stepwise approach may be useful. First, AFP should be repeated to confirm persistence and exclude analytical or transient causes. Second, history, examination, liver biochemistry, viral hepatitis testing, and targeted tumor-marker assessment should be performed. Third, evaluation should focus on the most probable AFP-producing malignancies, especially HCC and germ-cell tumors, using risk-appropriate imaging. Escalation to whole-body imaging may be considered when diagnostic uncertainty persists, AFP is markedly elevated or rising, symptoms or abnormal examination findings are present, or results are discordant. When AFP is stable, AFP-L3 and PIVKA-II are not suggestive of HCC, imaging remains negative, and the patient is clinically well, HPAFP or idiopathic persistent AFP elevation may be considered, and long-term periodic surveillance may be more appropriate than repeated invasive testing. Common causes of elevated AFP are summarized in Supplementary Table 2, and a proposed diagnostic algorithm is shown in Figure 3.
The patient’s imaging revealed multiple simple hepatic cysts, which are benign developmental lesions lined by cuboidal epithelium and filled with serous fluid. However, distinguishing among hepatic cyst types can be important, especially when AFP is elevated. Selected differential diagnoses for hepatic cysts are summarized in Supplementary Table 3.
Conclusions
Persistent AFP elevation in an otherwise healthy adult may rarely occur without malignancy or active liver disease. In this patient, the most plausible explanation after extensive negative evaluation was probable HPAFP or idiopathic persistent AFP elevation. Recognizing this possibility may help avoid unnecessary procedures while maintaining prudent longitudinal follow-up. Annual clinical review with AFP trend assessment and repeat imaging only if AFP rises substantially, symptoms develop, or liver tests become abnormal may be a reasonable individualized strategy.
Supporting information
Supplementary Table 1
Literature search strategy, eligibility criteria, and study selection for the focused narrative review.
(DOCX)
Supplementary Table 2
Causes of elevated alpha-fetoprotein (AFP).
(DOCX)
Supplementary Table 3
Differential diagnosis of hepatic cysts.
(DOCX)
Declarations
Ethical statement
This manuscript describes a single anonymized clinical case report. Because no experimental intervention was performed and the report is based on routine clinical evaluation and follow-up, formal institutional ethics committee approval was not required for an anonymized case report. The authors confirm that the study was conducted in accordance with the ethical principles of the Declaration of Helsinki (as revised in 2024). Written informed consent was obtained from the patient for publication of this case report and its accompanying clinical details. All identifying information has been removed or anonymized to protect patient confidentiality.
Data sharing statement
All relevant clinical information supporting the conclusions of this case report is included within the article. Additional patient-level data are not publicly available in order to preserve patient confidentiality.
Funding
None to declare.
Conflict of interest
The authors have no conflict of interests related to this publication.
Authors’ contributions
JP and VG contributed substantially to the conception, drafting, critical revision, and final approval of the manuscript. All authors agree to be accountable for the accuracy and integrity of the work.