What is the appropriate evaluation and workup for an elevated ferritin level?

Evaluation of Elevated Ferritin

Measure fasting transferrin saturation (TS) immediately—this single test determines whether you are dealing with true iron overload (TS ≥45%) requiring genetic testing, or secondary hyperferritinemia (TS <45%) from inflammation, liver disease, or metabolic causes. 1

Initial Diagnostic Algorithm

Step 1: Obtain Transferrin Saturation

• Order fasting transferrin saturation alongside ferritin to distinguish iron overload from inflammatory causes 1, 2
• Morning sample is preferred, though fasting is not strictly required 1
• Never interpret ferritin alone—over 90% of elevated ferritin cases are NOT due to iron overload 1, 2

Step 2: Interpret Based on Transferrin Saturation

If TS ≥45%: Suspect Primary Iron Overload

• Immediately order HFE genetic testing for C282Y and H63D mutations 1, 2
• C282Y homozygosity or C282Y/H63D compound heterozygosity confirms hereditary hemochromatosis 1, 2
• This pathway applies to only ~10% of patients with elevated ferritin 2

If TS <45%: Evaluate Secondary Causes

• Iron overload is excluded with >90% certainty 1, 2
• Do NOT order HFE genetic testing when TS <45% 2
• Focus on identifying the underlying inflammatory, metabolic, or hepatic condition 1, 2

Risk Stratification by Ferritin Level

Ferritin <1,000 μg/L

• Low risk of organ damage 1
• Negative predictive value of 94% for advanced liver fibrosis 1, 2
• If TS ≥45% and C282Y homozygote confirmed, can proceed directly to therapeutic phlebotomy without liver biopsy if age <40 years, normal liver enzymes, and no hepatomegaly 1, 2

Ferritin 1,000–10,000 μg/L

• Critical threshold requiring additional evaluation 1, 2
• In C282Y homozygotes, ferritin >1,000 μg/L with elevated liver enzymes AND platelet count <200,000/μL predicts cirrhosis in 80% of cases 1, 2
• Consider liver biopsy if ferritin >1,000 μg/L with abnormal liver tests or thrombocytopenia 1, 2
• Alternatively, use liver MRI with T2/T2* relaxometry to quantify hepatic iron concentration non-invasively 1, 3

Ferritin >10,000 μg/L

• Rarely represents simple iron overload 1, 2
• Urgent specialist referral required to evaluate for life-threatening conditions 1
• Consider adult-onset Still's disease (glycosylated ferritin <20% is 93% specific) 1, 2
• Consider hemophagocytic lymphohistiocytosis/macrophage activation syndrome 1, 2
• Malignancy is the most common cause in this range 4

Complete Laboratory Workup

Essential Initial Tests

• Fasting transferrin saturation (most critical test) 1, 2
• Complete metabolic panel including ALT, AST to assess hepatocellular injury 1, 2
• Complete blood count with differential 2
• Inflammatory markers: CRP and ESR 1, 2

Additional Tests Based on Clinical Context

• Creatine kinase if muscle injury suspected 2
• Hepatitis B surface antigen and hepatitis C antibody (50% of viral hepatitis patients have abnormal iron studies) 1
• Fasting glucose and lipid panel to assess metabolic syndrome 1
• Abdominal ultrasound to detect fatty liver, hepatomegaly, or cirrhotic morphology 2

Common Secondary Causes (When TS <45%)

Liver Disease (Most Common)

• Chronic alcohol consumption increases iron absorption and causes hepatocellular injury 1, 2
• Non-alcoholic fatty liver disease (NAFLD)/metabolic syndrome—ferritin reflects hepatocellular injury and insulin resistance, not iron overload 1, 2
• Viral hepatitis (B or C)—approximately 50% have abnormal iron studies 1
• Acute hepatitis—ferritin rises with hepatocellular necrosis 2

Inflammatory Conditions

• Chronic rheumatologic diseases (rheumatoid arthritis, inflammatory bowel disease) 1, 2
• Adult-onset Still's disease (ferritin typically 4,000–30,000 ng/mL, can reach 250,000 ng/mL) 2
• Systemic inflammatory response syndrome 2
• Active infection—ferritin rises as acute-phase reactant 1, 2

Malignancy

• Solid tumors 2
• Lymphomas 2
• Hepatocellular carcinoma 2
• Malignancy was the most common cause (24%) in one large series of ferritin >1,000 μg/L 4

Cellular Damage

• Muscle necrosis 2
• Hepatocellular necrosis 2
• Tissue breakdown from any cause 2

Other Conditions

• Chronic kidney disease 1, 2
• Diabetes mellitus 2
• Metabolic syndrome 1, 2

Management Based on Transferrin Saturation

If TS ≥45% (Confirmed Iron Overload)

Therapeutic Phlebotomy Protocol

• Remove 500 mL blood weekly or biweekly as tolerated 1
• Check hemoglobin/hematocrit before each session 1
• Allow hemoglobin to fall no more than 20% from baseline 1
• Check ferritin every 10–12 phlebotomies 1
• Target ferritin 50–100 μg/L for induction phase 1
• Once target achieved, transition to maintenance phlebotomy every 2–4 months 1

Critical Dietary Restrictions

• Avoid iron supplements entirely 1
• Avoid vitamin C supplementation—accelerates iron mobilization and increases oxidative stress 1
• Avoid raw shellfish—risk of Vibrio vulnificus infection in iron-overloaded patients 1

Family Screening

• Screen all first-degree relatives with TS, ferritin, and HFE genetic testing 1, 2
• Penetrance is higher in family members than general population 1

If TS <45% (Secondary Hyperferritinemia)

Treatment Principles

• Treat the underlying condition, NOT the elevated ferritin 1
• Weight loss and metabolic syndrome management for NAFLD patients 2
• Disease-specific anti-inflammatory therapy for inflammatory conditions 2
• Oncologic treatment for malignancy 2
• Do NOT perform phlebotomy when TS <45% 1, 2

Special Clinical Contexts

Chronic Kidney Disease

• Elevated ferritin (500–1,200 μg/L) with low TS (<25%) may represent functional iron deficiency 1, 2
• IV iron may still be beneficial despite elevated ferritin in CKD patients on erythropoiesis-stimulating agents 1, 2
• Withhold iron therapy when ferritin exceeds 1,000 ng/mL or TS exceeds 50% 1

Inflammatory Bowel Disease

• Ferritin <30 μg/L indicates absolute iron deficiency 2
• Ferritin 30–100 μg/L with TS <16% suggests combined iron deficiency and anemia of chronic disease 2
• Ferritin >100 μg/L with TS <16% indicates predominant anemia of chronic disease 2

Chronic Hepatitis C

• Ferritin elevation reflects hepatocellular injury and inflammation, not iron overload 2
• When TS <45%, iron overload is excluded and phlebotomy is not indicated 2

Critical Pitfalls to Avoid

• Never use ferritin alone to diagnose iron overload—TS must be assessed concurrently 1, 2
• Do not order HFE genetic testing when TS <45%—leads to misdiagnosis and unnecessary phlebotomy 2
• Do not overlook liver biopsy in patients with ferritin >1,000 μg/L and abnormal liver tests 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 fail to screen first-degree relatives if HFE-related hemochromatosis is confirmed 1, 2
• Recognize that extremely high ferritin (>10,000 μg/L) rarely represents simple iron overload—urgent evaluation for inflammatory syndromes or malignancy is required 1, 2

Indications for Specialist Referral

Refer to gastroenterology/hepatology or hematology when:

• Ferritin >1,000 μg/L with elevated bilirubin 1
• Ferritin >10,000 μg/L regardless of other findings 1, 2
• Confirmed TS ≥45% on repeat testing 1, 2
• Clinical evidence of cirrhosis (platelet count <200,000/μL, elevated bilirubin, hepatomegaly) 1, 2
• Confirmed C282Y homozygosity requiring therapeutic phlebotomy 1, 2
• Evidence of cardiac involvement (ECG/echocardiography abnormalities) in suspected severe iron overload 1