What is the recommended workup for a child with an elevated alpha‑fetoprotein level?

Approach for Elevated Alpha-Fetoprotein in Children

In children with elevated AFP, immediately obtain serial measurements every 2-4 weeks to distinguish physiological decline from pathological elevation, while simultaneously performing comprehensive liver function tests and abdominal ultrasound to identify underlying causes such as hepatoblastoma, hepatocellular carcinoma, tyrosinemia type 1, or overgrowth syndromes. 1

Initial Interpretation: Age-Dependent Physiological Context

• AFP is the main circulating protein in fetal blood and remains physiologically elevated in infants under 1 month of age, declining rapidly after birth. 2, 1
• Normal reference intervals at birth (≥34 weeks gestation) range from 15.7-146.5 μg/ml (median 48.3 μg/ml), dropping to 9.7-111.9 μg/ml (median 34.2 μg/ml) by 60 hours of life. 3
• AFP typically falls to adult values (<10-20 ng/ml) by 8-12 months of age. 2, 4
• Pathological AFP elevations in conditions like tyrosinemia type 1 or hepatoblastoma are typically 10-fold higher than normal neonatal values. 2, 1

Mandatory Serial Monitoring Protocol

• Measure AFP every 2-4 weeks to establish a trend—physiological AFP should consistently decrease, while pathological elevations persist or rise. 1
• If AFP does not consistently decrease or increases at any point, immediate investigation with imaging is required. 2, 1
• In overgrowth syndromes (Beckwith-Wiedemann, Trisomy 18, Simpson-Golabi-Behmel), AFP levels tend to be elevated above normal pediatric values during the first years of life, requiring syndrome-specific interpretation. 2, 1

Essential Laboratory Workup

• Complete liver function tests: AST, ALT, alkaline phosphatase, GGT, direct and indirect bilirubin. 2, 1
• Synthetic liver function tests: Prothrombin time (PT), partial thromboplastin time (PTT), albumin. 2, 1
• Succinylacetone in blood and urine: This is the specific diagnostic test for tyrosinemia type 1, which presents with elevated AFP and acute liver failure in early infancy. 2, 1
• Coagulopathy (elevated PT/PTT) may be the earliest sign of hepatic dysfunction in tyrosinemia type 1, even before other liver abnormalities appear. 2

Imaging Strategy

• Perform complete abdominal ultrasound (not just renal) to evaluate for hepatomegaly, liver masses, hepatoblastoma, and abdominal anatomy. 2, 1
• Ultrasound is optimal for initial screening—widely available, no radiation, no sedation required. 2
• If ultrasound shows abnormal findings or AFP continues to rise despite serial monitoring, proceed immediately to MRI with hepatobiliary contrast. 2, 1
• For large AFP rises (>1000 ng/ml), validate with repeat testing and proceed directly to additional imaging if confirmed. 2

Syndrome-Specific Surveillance Protocols

For Beckwith-Wiedemann Syndrome, Trisomy 18, Simpson-Golabi-Behmel Syndrome:

• Perform full abdominal ultrasound AND serum AFP screening every 3 months starting at birth through the 4th birthday for hepatoblastoma surveillance. 2
• After the 4th birthday, continue renal ultrasound every 3 months until the 7th birthday for Wilms tumor surveillance. 2
• Interpret AFP values in the context of syndrome-specific reference ranges, which are elevated compared to normal pediatric values. 2, 1
• Small rises within reference ranges should not trigger additional testing (can be due to intercurrent illness, teething), but rises >50-100 ng/ml warrant repeat AFP in 6 weeks and re-examination of recent imaging. 2
• If two successive increases occur, proceed to MRI. 2

For Tyrosinemia Type 1 (if succinylacetone is elevated):

• Start NTBC therapy immediately and restrict dietary phenylalanine and tyrosine. 2, 1
• AFP should decrease continuously throughout the first year of treatment—if it does not decrease consistently or increases, perform imaging immediately to rule out hepatocellular carcinoma. 2, 1
• Monitor succinylacetone levels—they should return to undetectable levels with NTBC therapy as evidence of compliance. 2
• A sudden appearance of succinylacetone is a sign of noncompliance with NTBC, not emergence of HCC. 2
• Ongoing normal AFP values do NOT guarantee absence of HCC—continuous surveillance with periodic imaging is crucial. 2, 1, 5

Critical Pitfalls to Avoid

• Never assume normal AFP excludes malignancy—up to 35% of hepatocellular carcinoma cases have normal AFP levels, even with large tumors. 5
• Do not interpret isolated AFP values without considering the trend over time and clinical context. 2, 1
• Hyperbilirubinemia alone in the absence of other abnormal hepatic studies is NOT helpful in diagnosing tyrosinemia type 1 and may suggest another liver problem. 2
• Do not delay imaging if AFP is rising—hepatoblastoma can grow rapidly, and early detection at lower stages has better prognosis. 2
• Avoid using adult AFP reference ranges in children—this leads to misinterpretation of physiologically elevated values. 6, 3

Indications for Urgent Specialist Referral

• Any neonate with acute liver failure requires urgent referral to a pediatric liver transplant center. 1
• Coagulopathy (elevated PT/INR, PTT), hypoalbuminemia, hard hepatomegaly, and elevated bilirubin are red flags requiring urgent action. 2, 1
• Physical examination by a specialist (geneticist or pediatric oncologist) twice yearly is recommended for children with overgrowth syndromes, including ongoing education about tumor manifestations and screening compliance. 2

Differential Diagnosis Considerations

• Malignant causes: Hepatoblastoma, hepatocellular carcinoma, germ cell tumors (yolk sac tumor, teratoma). 2, 6
• Metabolic causes: Tyrosinemia type 1 (elevated succinylacetone is diagnostic). 2, 1
• Genetic syndromes: Beckwith-Wiedemann, Trisomy 18, Simpson-Golabi-Behmel. 2
• Neurological causes: Ataxia-telangiectasia and other autosomal recessive neurodegenerative disorders with cerebellar ataxia. 7
• Benign causes: Hereditary persistence of AFP (autosomal dominant, clinically benign, confirmed by testing family members). 8
• Liver disease: Active hepatitis, cirrhosis, regenerating nodules. 5

Interpretation Requires Expert Consultation

• AFP interpretation should be done by or in consultation with physicians familiar with AFP monitoring in children, particularly geneticists and oncologists in cancer predisposition programs. 2, 1
• AFP values must be interpreted in the context of clinical picture, patient age, most recent imaging, and syndrome-specific reference ranges. 2, 1