What causes elevated alpha-fetoprotein (AFP) levels in adult men, outside of testicular cancer and hepatocellular carcinoma (HCC)?

Causes of Elevated AFP in Men (Excluding Testicular Cancer and HCC)

Benign Liver Disease

The most common non-malignant cause of elevated AFP in adult men is benign liver disease, including hepatitis, hepatic toxicity from chemotherapy, and other liver disorders. 1

• Acute exacerbation of chronic hepatitis B can cause extremely elevated AFP levels (>2000 ng/mL) without any malignancy present, with AFP levels decreasing in parallel with viral load reduction during antiviral treatment 2
• Chronic liver disease and cirrhosis commonly elevate AFP levels even without HCC development 3
• Active hepatitis B or C infection can elevate AFP, and in the presence of active hepatitis B, the diagnostic cut-off for HCC should be raised to at least 1,000-4,000 ng/mL rather than the standard 400 ng/mL 4
• Hepatic steatosis (fatty liver disease) may cause persistently elevated AFP levels in some patients 5

Other Malignancies

• Intrahepatic cholangiocarcinoma can produce elevated AFP levels 1
• Metastatic colon cancer to the liver may elevate AFP 1
• Lymphoma, small-cell lung cancer, Ewing sarcoma, and osteogenic sarcoma can all cause AFP elevation 1
• Sertoli-Leydig cell tumors of the testis (non-germ cell testicular tumors) can release AFP, though this is rare 4

Constitutively Elevated AFP

• Some individuals have chronically mildly elevated AFP in the 15-30 ng/mL range without any pathology, representing a benign variant 1
• Hereditary persistence of AFP (HPAFP) is an extremely rare autosomal dominant condition where genetically predisposed individuals have persistently elevated AFP without underlying disease; this can be confirmed by measuring AFP levels in family members 6

Tumor Lysis During Treatment

• Serum AFP levels may rise during the first week of chemotherapy due to tumor lysis; if AFP rises between day 1 of cycle 1 and day 1 of cycle 2, repeat testing midway through cycle 2 to determine if levels have begun to decline 1

Critical Diagnostic Algorithm

When evaluating elevated AFP in a man without known testicular cancer or HCC:

1. Measure concurrent β-hCG and LDH to evaluate for occult germ cell tumor 7
2. Obtain testicular ultrasound even if physical examination is normal, as occult testicular tumors can present with only marker elevation 7
3. Perform CT chest, abdomen, and pelvis to identify retroperitoneal or mediastinal primary tumors 7
4. Check liver function tests (ALT, AST, bilirubin) and hepatitis B/C serologies to assess for benign liver disease 7, 2
5. Obtain serial AFP measurements over 2-4 weeks: cancer-associated AFP shows a consistent rising pattern, while constitutively elevated AFP remains stable 1, 7
6. If no mass is identified and AFP is stable or mildly elevated (15-30 ng/mL), consider constitutive elevation or benign liver disease 1
7. If AFP is markedly elevated (>400 ng/mL) without identified malignancy, strongly consider acute hepatitis exacerbation and check hepatitis B viral load 2, 4

Important Caveats

• Pure seminoma never produces AFP; if a patient with "pure seminoma" histology has elevated AFP, assume undetected nonseminomatous elements are present 1, 7
• AFP elevation is only present in 40-60% of HCC cases, so normal AFP does not exclude HCC 1
• Laboratory artifact from hemolysis does not typically affect AFP (unlike LDH), but should be considered if results are inconsistent 1
• Upper limit of normal for AFP is 9 ng/mL if <40 years old and 13 ng/mL if ≥40 years old 7