Neurofibromatosis and Iron Overload/Hepatomegaly
No, neurofibromatosis (NF) is not a recognized cause of iron overload or hepatomegaly related to iron metabolism disorders. The evidence-based diagnostic algorithms for iron overload do not include neurofibromatosis as a differential diagnosis, and the condition is not mentioned in any major guidelines for evaluating hyperferritinemia or hepatic iron deposition 1, 2, 3.
Why NF Is Not the Cause
Neurofibromatosis causes different pathology entirely. When NF affects the gastrointestinal tract or liver, it manifests as:
- Neurofibromas (benign nerve sheath tumors) that can occur in the intestinal wall or hepatic hilum 4, 5
- Chronic iron deficiency anemia from recurrent GI bleeding when intestinal neurofibromas ulcerate and hemorrhage 5
- Hematologic complications requiring bone marrow transplantation in rare cases of xanthogranuloma disseminatum 6
The pattern is opposite to iron overload: NF patients with GI involvement develop iron deficiency from chronic blood loss, not iron accumulation 5.
What Actually Causes Iron Overload and Hepatomegaly
Your diagnostic algorithm should follow this sequence:
Step 1: Measure Transferrin Saturation (TS)
- If TS ≥45%: Suspect primary iron overload and proceed to HFE genetic testing for C282Y and H63D mutations 1, 2
- If TS <45%: Iron overload is unlikely; focus on secondary causes of hyperferritinemia 2, 3
Step 2: Common Causes (>90% of cases)
The following account for over 90% of hyperferritinemia cases 2:
- Chronic alcohol consumption (increases iron absorption and causes hepatocellular injury) 1, 2
- Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome 2, 3
- Inflammation (ferritin is an acute phase reactant) 2, 3
- Cell necrosis (releases ferritin from damaged hepatocytes) 2
- Malignancy (solid tumors, lymphomas, hepatocellular carcinoma) 2
Step 3: If C282Y Homozygous
- Confirms HFE hemochromatosis 1
- Ferritin >1000 μg/L with elevated ALT and platelets <200: 80% risk of cirrhosis, requires liver biopsy 1, 2
- Ferritin <1000 μg/L, normal liver enzymes, age <40: Can proceed to phlebotomy without biopsy 1, 2
Step 4: If Not C282Y Homozygous
- Non-HFE hemochromatosis (TFR2, SLC40A1, HAMP, HJV mutations) 1, 2
- Ferroportin disease (SLC40A1 mutations causing iron retention in macrophages) 1
- Aceruloplasminemia (CP gene defects with hepatic and CNS iron deposition) 1
- Secondary iron overload from:
Critical Diagnostic Pitfalls to Avoid
Never use ferritin alone to diagnose iron overload. Ferritin is an acute phase reactant elevated in inflammation, liver disease, malignancy, and tissue necrosis independent of actual iron stores 1, 2, 3.
Do not overlook liver biopsy when ferritin >1000 μg/L with abnormal liver tests. This combination has 100% sensitivity for cirrhosis in hemochromatosis patients 1, 2.
Do not assume iron overload when TS <45%. In the general population, iron overload is NOT the most common cause of elevated ferritin 2.
Role of MRI in Unclear Cases
MRI R2 quantification should be used when:*
- Diagnosis remains uncertain after genetic testing 7, 8
- Non-C282Y homozygous genotype with biochemical iron overload 7, 8
- Need to quantify hepatic iron concentration and predict phlebotomy requirements 7, 8
- Assessing for cardiac iron deposition in severe cases 7, 8
MRI has replaced liver biopsy as the standard for iron quantification due to superior sensitivity, specificity, and lack of sampling error 7, 8.
Bottom Line
Neurofibromatosis is not part of the differential diagnosis for iron overload. If your patient has both NF and iron overload/hepatomegaly, these are separate, unrelated conditions requiring independent evaluation. Follow the standard iron overload diagnostic algorithm starting with transferrin saturation and HFE genetic testing 1, 2, 3.