Which specialist should I refer a patient with normal liver enzymes, normal transferrin saturation, normal inflammatory markers, and an elevated ferritin greater than 600 µg/L to?

Referral for Elevated Ferritin >600 with Normal Transferrin Saturation and Normal Inflammatory Markers

You should order HFE genetic testing yourself first, and if negative or if the patient has additional risk factors (age >40, elevated liver enzymes, hepatomegaly), refer to a hepatologist or gastroenterologist for further evaluation of potential non-HFE iron overload or metabolic liver disease. 1

Diagnostic Algorithm Before Referral

Your patient's presentation—elevated ferritin >600 with normal transferrin saturation and normal inflammatory markers—suggests this is not classic HFE hemochromatosis, which typically presents with elevated transferrin saturation (≥45%) 1. However, you need to complete initial workup before referral:

Step 1: Order HFE Genetic Testing

• Test for C282Y and H63D mutations 1
• This is appropriate when ferritin is above the upper limit of normal, even with normal transferrin saturation
• Iron overload can occur with normal transferrin saturation in non-HFE hemochromatosis or C282Y/H63D compound heterozygotes 1

Step 2: Assess for Secondary Causes You May Have Missed

Even with "normal" inflammatory markers, verify:

• Metabolic syndrome components: Check fasting glucose/HbA1c, lipid panel, blood pressure, BMI 2, 3
• Alcohol consumption history: Chronic alcohol use is a leading cause of hyperferritinemia with normal transferrin saturation 4, 2
• Fatty liver disease (MASLD): Obtain liver ultrasound or elastography 2, 3
• Medications: SGLT2 inhibitors and GLP-1 receptor agonists can alter ferritin levels 5

When and Where to Refer

Refer to Hepatology/Gastroenterology if:

1. HFE testing is negative AND ferritin remains elevated—to evaluate for:

   • Non-HFE hemochromatosis (TFR2, SLC40A1, HAMP, HJV mutations) 4, 2
   • Metabolic dysfunction-associated steatotic liver disease (MASLD) 2, 3
   • Other liver pathology

2. Ferritin >1000 µg/L with any of the following 1:

   • Elevated ALT or AST
   • Age >40 years
   • Hepatomegaly
   • These factors predict cirrhosis risk in 80% of cases and warrant liver biopsy consideration

3. Evidence of liver disease on imaging or clinical examination 1, 2

4. Compound heterozygote (C282Y/H63D) or other non-classic genotypes with persistent hyperferritinemia 1, 4

Consider Hematology referral if:

• Unexplained cytopenias develop (concern for hemophagocytic syndrome, though your inflammatory markers are normal) 6
• Ferritin >10,000 µg/L (suggests hemophagocytic lymphohistiocytosis, though unlikely with normal inflammatory markers) 5

Critical Pitfalls to Avoid

Do not assume normal transferrin saturation excludes iron overload. The guidelines explicitly state that "iron overload may be present in a patient with an elevated ferritin and a normal TS, particularly in non-HFE-related iron overload" 1. This pattern occurs in:

• Ferroportin disease
• Dysmetabolic hyperferritinemia (metabolic syndrome-related) 7
• Aceruloplasminemia
• Secondary iron overload from other causes

The hepatologist can order MRI-based liver iron quantification (R2 sequence)* to definitively determine if true iron overload exists 2, 8. This is the gold standard for distinguishing inflammatory hyperferritinemia from actual tissue iron accumulation and will guide whether phlebotomy therapy is needed 2, 3.

In 40-70% of hyperferritinemia cases, multiple etiologies coexist 9, so the hepatologist will systematically exclude metabolic syndrome, alcohol use, and fatty liver disease while quantifying actual iron burden 10, 8.