What lab work is indicated for elevated ferritin (iron) levels?

Laboratory Workup for Elevated Ferritin

The initial laboratory evaluation for elevated ferritin must include fasting transferrin saturation (TS) and serum ferritin measured simultaneously, as TS ≥45% distinguishes primary iron overload from the 90% of cases caused by inflammation, liver disease, malignancy, or metabolic conditions. 1, 2

Step 1: Initial Iron Studies

• Fasting transferrin saturation (TS) is the single most important test to determine if true iron overload exists 1
• Measure serum ferritin simultaneously with TS to increase diagnostic accuracy 1
• Obtain morning blood sample (fasting preferred but not absolutely required) 2
• Calculate TS from serum iron and total iron binding capacity (TIBC) or transferrin 1

Critical interpretation thresholds:

• TS ≥45% suggests primary iron overload and requires genetic testing 1, 2
• TS <45% indicates secondary hyperferritinemia (inflammation, liver disease, malignancy) in >90% of cases 1, 2

Step 2: Screen for Common Secondary Causes

Before pursuing genetic testing, evaluate for the conditions that cause >90% of elevated ferritin in outpatients 1, 2:

Inflammatory Markers

• C-reactive protein (CRP) to detect occult inflammation 1, 2
• Erythrocyte sedimentation rate (ESR) if malignancy suspected 1
• White blood cell count with differential 1

Liver Function Tests

• AST and ALT to assess hepatocellular injury 1, 2
• Bilirubin to evaluate liver function 1
• Albumin for synthetic liver function 2

Metabolic Syndrome Screening

• Fasting glucose or hemoglobin A1c for diabetes 1, 2
• Lipid panel (cholesterol, triglycerides) 1
• Blood pressure and BMI documentation 1

Additional Tests Based on Clinical Context

• Creatine kinase (CK) if muscle injury suspected (cell necrosis releases ferritin) 1
• Alcohol consumption history (chronic alcohol increases iron absorption and causes hepatocellular injury) 1, 2

Step 3: Genetic Testing (If TS ≥45%)

HFE gene testing for C282Y and H63D mutations should be performed when TS ≥45% with elevated ferritin 1, 2:

• C282Y homozygosity confirms HFE hemochromatosis 1
• C282Y/H63D compound heterozygosity may cause mild iron overload with additional risk factors 1
• H63D homozygosity alone rarely causes significant iron overload without other factors 1

Step 4: Risk Stratification by Ferritin Level

Ferritin <1000 µg/L

• Low risk of organ damage (94% negative predictive value for advanced fibrosis) 2
• If C282Y homozygote with TS ≥45%, can initiate phlebotomy without liver biopsy if age <40, normal liver enzymes, and no hepatomegaly 1

Ferritin 1000-10,000 µg/L

• Platelet count (count <200 × 10⁹/L predicts cirrhosis in 80% of C282Y homozygotes when combined with ferritin >1000 µg/L and elevated ALT) 2
• Consider liver biopsy if ferritin >1000 µg/L with elevated transaminases, hepatomegaly, or age >40 years 1, 2
• Liver MRI with T2 or R2 relaxometry* can quantify hepatic iron concentration non-invasively 1, 3

Ferritin >10,000 µg/L

• Rarely represents simple iron overload 2
• Urgent evaluation for life-threatening conditions: adult-onset Still's disease (check glycosylated ferritin fraction <20%), hemophagocytic lymphohistiocytosis, severe infection, or malignancy 2, 4

Step 5: Additional Testing for Non-HFE Iron Overload

If iron overload confirmed (TS ≥45%, elevated ferritin, liver MRI or biopsy showing increased iron) but not C282Y homozygous, consider 1:

• Genetic testing for non-HFE hemochromatosis genes: TFR2, SLC40A1, HAMP, HJV 1, 2
• Referral to specialist (gastroenterologist, hematologist, or iron overload expert) if ferritin >1000 µg/L or diagnosis unclear 5

Step 6: Baseline Assessments Before Treatment

If hereditary hemochromatosis confirmed and phlebotomy planned 1:

• Serum creatinine in duplicate (due to measurement variation) and calculate eGFR 1
• Urinalysis and serum electrolytes to evaluate renal tubular function 1
• Complete blood count to assess for cytopenias 1
• Baseline auditory and ophthalmic examinations 1

Critical Pitfalls to Avoid

• Never diagnose iron overload based on ferritin alone without measuring TS - ferritin is an acute phase reactant elevated in inflammation, infection, liver disease, and malignancy independent of iron stores 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 1, 2
• Do not overlook liver biopsy in patients with ferritin >1000 µg/L and abnormal liver tests - this combination warrants histologic assessment for cirrhosis 1, 2
• Screen first-degree relatives if HFE-related hemochromatosis confirmed (C282Y homozygote with iron overload) 1
• Recognize that extremely high ferritin (>10,000 µg/L) rarely represents simple iron overload and requires urgent evaluation for inflammatory/rheumatologic conditions or malignancy 2, 4