Ferritin

Background

Ferritin is an intracellular protein that stores iron and releases it in a controlled fashion
Serum ferritin reflects total body iron stores but is also an acute phase reactant — it rises with inflammation, infection, malignancy, and liver disease independent of iron status
Normal range: approximately 20-200 ng/mL (women), 20-500 ng/mL (men); varies by lab and age
For the emergency physician, ferritin is most useful as a marker of systemic inflammation and immune activation, not just iron status
The degree of elevation significantly narrows the differential diagnosis

Ferritin Level	Differential Diagnosis
Low (<20 ng/mL)	Iron deficiency anemia (most common cause of low ferritin) Chronic blood loss (GI, menstrual) Malabsorption (celiac disease) Pregnancy
Mildly elevated (200-1,000 ng/mL)	Acute/chronic inflammation (infection, autoimmune disease) Chronic liver disease, hepatitis, steatohepatitis Chronic kidney disease Chronic alcohol use Metabolic syndrome/obesity Malignancy Iron supplementation/transfusion Hyperthyroidism
Markedly elevated (1,000-10,000 ng/mL)	Adult-onset Still's disease (AOSD) / Systemic JIA (sJIA) Hemophagocytic lymphohistiocytosis (HLH) / Macrophage activation syndrome (MAS) Hemochromatosis (hereditary or transfusional iron overload) Hepatocellular injury (acute hepatitis, acetaminophen toxicity, ischemic hepatitis) Hematologic malignancy (leukemia, lymphoma) Sepsis (severe) Renal failure (especially on dialysis with IV iron)
Extremely elevated (>10,000 ng/mL)	Macrophage activation syndrome / HLH — most likely diagnosis Adult-onset Still's disease with MAS Massive hepatocellular necrosis Transfusional iron overload (chronic transfusion-dependent anemias)

Ferritin >5× the upper limit of normal has a limited differential: AOSD/sJIA, MAS/HLH, hemochromatosis, hepatocellular injury, renal failure with iron overload
Ferritin >10,000 ng/mL should be considered MAS/HLH until proven otherwise — this is a medical emergency
A rapidly rising ferritin (doubling over hours to days) is more concerning than a static elevation and should prompt evaluation for MAS/HLH
Ferritin:ESR ratio >21.5 in a patient with known or suspected sJIA is suggestive of MAS (ESR falls as fibrinogen is consumed, while ferritin skyrockets)^[1]
Glycosylated ferritin fraction ≤20% (if available) is relatively specific for AOSD (normal is ~50-80%); not widely available as a stat test^[2]
A normal ferritin does not exclude iron deficiency in the setting of concurrent inflammation (ferritin is an acute phase reactant); a ferritin <100 ng/mL with an elevated CRP may still represent iron deficiency

Suspected MAS/HLH: Any patient (especially children with sJIA or adults with AOSD) with unexplained cytopenias, coagulopathy, hepatitis, and persistent fever
Fever of unknown origin: Ferritin is part of the initial FUO workup — the degree of elevation can rapidly narrow the differential
Suspected Adult-onset Still's disease or Systemic JIA: Quotidian fevers, rash, arthritis, leukocytosis with negative ANA/RF
Undifferentiated sepsis not responding to treatment: Consider MAS/HLH if ferritin returns markedly elevated with falling platelets and falling ESR
Iron deficiency anemia workup: Microcytic anemia, fatigue, pica, heavy menses, GI blood loss
Suspected iron overload: Chronic transfusion patients, suspected hemochromatosis (elevated transferrin saturation + elevated ferritin)

ESR, CRP — interpret ferritin in context of inflammation; a falling ESR with rising ferritin = MAS
CBC with differential and peripheral smear — cytopenias, blasts
LFTs (AST, ALT, LDH) — hepatocellular injury contributes to ferritin elevation
Fibrinogen — low/falling fibrinogen + high ferritin = MAS/DIC
D-dimer, PT/PTT — coagulopathy assessment
Iron studies (serum iron, TIBC, transferrin saturation) — if iron deficiency or overload is the clinical question
Triglycerides — elevated in HLH/MAS

Ferritin is a diagnostic marker, not a condition to treat directly
Management is directed at the underlying cause:
- Iron deficiency: oral or IV iron supplementation
- Iron overload/hemochromatosis: phlebotomy or chelation therapy (hematology referral)
- AOSD/sJIA: corticosteroids, IL-1 or IL-6 inhibitors (rheumatology)
- MAS/HLH: high-dose IV methylprednisolone ± anakinra/cyclosporine (see Macrophage activation syndrome)
- Hepatocellular injury: treat the underlying cause
Serial ferritin trending is valuable for monitoring response to treatment in MAS/HLH and AOSD — falling ferritin indicates therapeutic response

Disposition is determined by the underlying diagnosis, not the ferritin level itself
However, ferritin >10,000 ng/mL should prompt ICU-level evaluation for MAS/HLH regardless of how well the patient appears at that moment
Markedly elevated ferritin (>1,000-5,000 ng/mL) without a clear explanation warrants admission or urgent outpatient follow-up within 24-48 hours

↑ Eloseily EM, Minoia F, Engel B, et al. Ferritin to Erythrocyte Sedimentation Rate Ratio: Simple Measure to Identify Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis. ACR Open Rheumatol. 2019;1(6):345-349.
↑ Fautrel B, Le Moël G, Saint-Marcoux B, et al. Diagnostic value of ferritin and glycosylated ferritin in adult onset Still's disease. J Rheumatol. 2001;28(2):322-9.

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