How to diagnose neonatal hemochromatosis?

Diagnosis of Neonatal Hemochromatosis

Neonatal hemochromatosis should be diagnosed by demonstrating extrahepatic siderosis in non-reticuloendothelial organs, most reliably through MRI detection of iron deposition in the pancreas and thyroid, or by minor salivary gland biopsy showing iron accumulation. 1

Clinical Presentation and Initial Recognition

Neonatal hemochromatosis presents as acute liver failure within the first few days of life in term or near-term infants. 1 Key clinical features that should raise suspicion include:

• Severe hepatic dysfunction with coagulopathy, hypoglycemia, and hypoalbuminemia presenting in the first 72 hours of life 1
• Prenatal indicators including oligohydramnios (13% of cases), intrauterine growth restriction (33% of cases), and fetal hydrops (13% of cases) 2, 3
• Family history of prior fetal loss, stillbirth, or neonatal death from liver failure 2

Diagnostic Algorithm

Step 1: Confirm Severe Neonatal Liver Failure

Document hepatic dysfunction through:

• Markedly elevated prothrombin time/INR 4
• Elevated aminotransferases (ALT, AST) 1
• Hyperbilirubinemia, hypoalbuminemia, and hypoglycemia 1

Step 2: Demonstrate Extrahepatic Siderosis (Diagnostic Hallmark)

The critical diagnostic feature is iron deposition in non-reticuloendothelial organs while sparing the reticuloendothelial system (spleen). 1, 5 This distinguishes neonatal hemochromatosis from other causes of neonatal liver failure with secondary hepatic iron overload.

Primary Diagnostic Method: MRI

• Multi-echo gradient recalled echo (GRE) T2-weighted MRI sequences* can detect extrahepatic siderosis within hours of birth 5
• Target organs to evaluate: pancreas, thyroid, myocardium 5
• Key finding: Marked signal loss on T2*-weighted sequences in pancreas and thyroid indicates iron deposition 5
• Spleen sparing: Absence of splenic iron deposition is characteristic and helps differentiate from other conditions 5
• Advantage: Non-invasive, can be performed rapidly, and does not require correction of coagulopathy 5

Alternative Diagnostic Method: Minor Salivary Gland Biopsy

• Lower lip minor salivary gland biopsy demonstrating siderosis is a safe, effective diagnostic method 6
• Procedure: Can be performed under local anesthesia even in severe coagulopathy 6
• Technique: Frozen section analysis should be performed immediately to confirm adequate salivary gland tissue is present 6
• Sensitivity: 86% (6 of 7 cases positive in one series) 6
• Advantage: Can be performed at bedside when MRI is unavailable or infant is too unstable for transport 6

Step 3: Hepatic Iron Assessment (Supportive but Not Diagnostic)

Important caveat: Hepatic siderosis alone is nonspecific and insufficient for diagnosis, as it occurs with any cause of advanced neonatal liver disease. 5 However, marked elevation of hepatic iron can be documented by:

• MRI of the liver showing signal loss on T2*-weighted sequences 1, 5
• Liver biopsy (if coagulopathy can be corrected) showing iron deposition, though this is risky and not specific 6

Prenatal Diagnosis Considerations

When neonatal hemochromatosis is suspected prenatally (based on prior affected pregnancy or concerning ultrasound findings):

• Fetal MRI can detect extrahepatic siderosis prenatally using T2-weighted sequences 3
• Indications for fetal MRI: Unexplained oligohydramnios, fetal hydrops, hepatomegaly, ascites, or growth restriction after excluding more common causes 3
• Timing: Can be performed in second or third trimester when findings become apparent 3

Critical Diagnostic Pitfalls

• Do not rely on hepatic iron alone: Hepatic siderosis without extrahepatic involvement does not establish the diagnosis and may represent secondary iron overload from other causes of liver failure 5
• Reticuloendothelial sparing is essential: Iron deposition in the spleen argues against neonatal hemochromatosis 5
• Serum ferritin is not diagnostic: While often elevated, it is nonspecific in the setting of acute liver failure 1
• Genetic testing for HFE mutations is not indicated: Neonatal hemochromatosis is now understood as gestational alloimmune liver disease (GALD), not hereditary hemochromatosis, and HFE mutations are not causative 2, 5

Urgency of Diagnosis

Diagnosis must be established rapidly because neonatal hemochromatosis is rapidly progressive and fatal without treatment, with mortality exceeding 80% in untreated cases. 1, 2 MRI should be performed within hours of suspicion to allow immediate initiation of exchange transfusion and intravenous immunoglobulin therapy, which improves survival from 17% to 75%. 4