Laboratory Medicine & Hematology & Family Medicine
Ferritin
Ferritin is an intracellular iron storage protein - a spherical cage composed of 24 protein subunits (H heavy and L light chains) capable of sequestering up to 4,500 atoms of iron in the form of a non-toxic ferric hydroxyphosphate complex. It is present in virtually all body tissues - mainly the liver (hepatocytes), spleen and bone marrow - and in minute quantities in the bloodstream. It is precisely this circulating fraction, serum ferritin, which is measured in clinical practice as an indirect reflection of the body's total iron stores. Under normal physiological conditions, serum ferritin is proportional to iron reserves: each µg/L of serum ferritin corresponds to approximately 8 to 10 mg of reserve iron. This makes ferritin the most sensitive and earliest marker of iron depletion - it begins to decline long before hemoglobin or mean corpuscular volume are affected. However, its main diagnostic limitation is its behavior as a protein of the acute phase of inflammation: during any inflammatory, infectious, neoplastic or hepatocellular process, ferritin is released from cells in large quantities, irrespective of the actual martial status - high ferritin may therefore mask an underlying iron deficiency (martial deficiency in an inflammatory context), and ferritin in the normal range does not rule out a slight deficiency. This duality - reserve marker and acute-phase reactant - means that serum ferritin must always be interpreted in relation to the clinical context, the complete martial workup (serum iron, transferrin, transferrin saturation coefficient) and inflammatory markers (CRP, VS, CBC).
Reference values, indications and clinical contexts
- Normal values and physiological variations : usual reference values (vary by laboratory): adult men: 30-300 µg/L (ng/mL); adult women (of childbearing age): 13-150 µg/L - lower values due to menstrual losses + pregnancies; post-menopausal women: gradually reach male values (30-200 µg/L); infants (0-5 months): 50-200 µg/L (neonatal peak linked to transplacental reserves - gradual decline thereafter); children 6 months-15 years: 7-140 µg/L (thresholds vary with age); pregnancy: ferritin decreases physiologically in the 2nd and 3rd trimesters (hemodilution + feto-placental transfer) - a threshold of <30 µg/L (and some experts recommend <70 µg/L in the 1st trimester) suggests true deficiency during pregnancy; clinical threshold for martial deficiency: ferritin <30 µg/L in adults is universally accepted as the deficiency threshold - some guidelines (British Committee for Standards in Haematology) use <15 µg/L as the «frank deficiency» threshold - a threshold of <50-70 µg/L is sometimes used for therapeutic decision in the presence of suggestive symptoms (fatigue, restless legs syndrome) even without anemia
- Indications for ferritin measurement : hypochromic microcytic anemia (VGM 75-100 µg/L to optimize response to treatment; chronic heart failure: ferritin <100 µg/L OR 100-299 µg/L with CST <20 % → iron deficiency - indication for IV iron (ferric carboxymaltose - AFFIRM-AHF 2020); pregnancy (systematic 1st trimester if risk factors - history of anemia, vegetarianism, close pregnancies)
- Complete martial assessment - interpret ferritin in context : serum iron (sideremia): concentration of circulating iron bound to transferrin - variable according to time of sampling (morning peak - circadian variation of 30-50 %) + diet + inflammation - unreliable in isolation; transferrin (or TIBC - Total Iron Binding Capacity): iron transport protein - increases in case of deficiency (liver increases production) - decreases in case of inflammation + undernutrition + cirrhosis; transferrin saturation coefficient (TSC) = serum iron / TIBC × 100 : normal value 20-45 % - CST 45 % (female) or >50 % (male) = iron overload (hemochromatosis); soluble transferrin receptor (RsTf): increases in iron deficiency and active erythropoiesis - NOT influenced by inflammation - useful for distinguishing true deficiency from inflammatory anemia - RsTf/log(ferritin) index (Thomas plot): >2 = true martial deficiency even in inflammatory context
Clinical interpretation and treatment
| Clinical situation | Biological results and background | Interpretation and course of action |
|---|---|---|
| Low ferritin - iron deficiency Ferritin <30 µg/L |
Ferritin <30 µg/L (frank deficiency if <15 µg/L) ± hypochromic microcytic anemia (low Hb + VGM <80 fl + low TGMH) + low serum iron + high transferrin + CST <16 %; causes of iron deficiency : inadequate intakes (strict vegan diet, anorexia, infant fed cow's milk before 12 months) + chronic occult or overt blood loss (heavy menstruation - menorrhagia - cause no. 1 in women of childbearing age; digestive bleeding - ulcer, colorectal cancer, polyposis, hiatal hernia, drugs - NSAIDs, aspirin -, symptomatic haemorrhoids; chronic macroscopic haematuria ; repeated blood donation) + malabsorption (celiac disease - a frequent and under-diagnosed cause of unexplained martial deficiency; gastrectomy; duodenal Crohn's disease; achlorhydria - long-term PPI) + increased needs (pregnancy + breast-feeding + pubertal growth + chronic renal failure on EPO) ; symptoms of martial deficiency without anemia (fatigue, exertional dyspnea, palpitations, restless legs syndrome, pica - desire to eat ice cream or dirt -, hair loss, brittle striated nails, perlachia, glossitis) | Systematic search for the cause before starting treatment: in all women >50 years or men of any age → colonoscopy + gastroscopy (digestive cancer screening - unexplained martial deficiency = indication for colonoscopy according to Canadian CPAC recommendations) ; in women of childbearing age with documented menorrhagia → treatment of the cause + martial supplementation without systematic digestive investigation if <50 years of age and fecal test negative; celiac disease serology (anti-transglutaminase IgA + total IgA) systematic in the presence of any unexplained martial deficiency; treatment of oral martial deficiency: ferrous sulfate 300 mg po (60-65 mg elemental iron) × 1/d fasting or between meals - or ferrous gluconate (less digestive disturbance) - or ferrous fumarate - duration : 3 to 6 months after hemoglobin normalization to replenish reserves - CBC check + ferritin at 6-8 weeks; intravenous iron (ferric carboxymaltose - Ferinject, ferric sucrose - Venofer): if digestive intolerance + malabsorption + rapid need (scheduled surgery + advanced pregnancy + heart failure) - dose calculated according to Ganzoni formula or nomogram |
| Low ferritin with high CRP - masked deficiency Inflammatory anemia + concomitant deficiency |
Ferritin in the low normal range (30-100 µg/L) OR even slightly elevated (100-300 µg/L) + elevated CRP + normocytic normochromic anemia (normal GMV) - misleading situation: inflammation artificially elevates ferritin → «normal» ferritin in an inflammatory context may mask a true deficiency; inflammatory anemia (anemia of chronic diseases) : mechanism - hepcidin (hepatic hormone - regulator of iron metabolism) is overexpressed during inflammation → blockage of ferroportin → iron trapping in macrophages + reduced intestinal absorption → functional deficiency in iron available for erythropoiesis; despite potentially sufficient total stores, iron is «blocked» and unavailable for hemoglobin synthesis; commonly associated diseases: rheumatoid arthritis + chronic inflammatory bowel disease (IBD) + cancer + chronic infections + renal failure + heart failure + connectivites | Distinction pure inflammatory anemia vs concomitant true deficiency: CST 2 → true deficiency even in inflammatory context → IV iron recommended (oral iron has 60-80 % reduced absorption by high hepcidin) ; ferritin 30-100 µg/L + high CRP + CST 200 µg/L + normal CST + low RsTf) : treatment of underlying disease + EPO (erythropoietin) if CKD or chemotherapy; in practice: any anemia in a patient with chronic inflammatory disease → complete martial workup + RsTf + CRP - do not conclude purely inflammatory anemia without formally excluding concomitant deficiency; chronic heart failure: iron deficiency (ferritin <100 µg/L OR 100-299 µg/L + CST <20 %) is present in 50 % of patients - IV iron (ferric carboxymaltose 500-1000 mg) → improved exercise capacity, quality of life and reduced hospital admissions (AFFIRM-AHF 2020 - JAMA) |
| Moderately high ferritin (200-1000 µg/L) Inflammation, metabolic syndrome, alcohol |
Moderate hyperferritinemia (200-1000 µg/L): most frequent causes in current practice (account for 90 % of moderate hyperferritinemias): metabolic syndrome (abdominal obesity + dyslipidemia + hyperglycemia + hypertension) → non-alcoholic fatty liver disease (NAFLD/MASLD) → hepatic ferritin release (marker of mild hepatic cytolysis) + insulin resistance → CST generally normal (<45 %) ; chronic alcohol (direct hepatotoxic effect + induction of hepatic ferritin synthesis); systemic inflammatory syndrome (elevated CRP - see cause above); hepatic cytolysis of other cause (viral hepatitis B or C, hepatotoxic drugs, autoimmune hepatitis); repeated transfusions; IMPORTANT: in the vast majority of moderate hyperferritinemias, the CST is NORMAL (45 % + progressively rising ferritin → HFE genotyping | Etiological workup for moderate hyperferritinemia: full liver workup (ALAT, ASAT, GGT, alkaline phosphatases, bilirubin) + fasting blood glucose + lipid workup + TSH + CRP + CBC + hepatitis B and C serologies + CST; if CST <45 % + documented metabolic syndrome → NAFLD/MASLD likely: liver ultrasound + check at 6 months after lifestyle optimization (weight loss 5-10 % → ferritin reduction of 30-50 %); if significant alcohol consumption → reduction or abstinence → ferritin check at 3 months (usual normalization in 4-8 weeks of abstinence) ; if no obvious cause + CST ≥45 % → HFE genotyping (C282Y / H63D); hyperferritinemia-cataract syndrome (ferritin L subunit gene mutation): marked hyperferritinemia (500-5000 µg/L) + normal CST + early bilateral cataract - rare but important diagnosis (no martial treatment required - bloodletting is contraindicated) |
| Very high ferritin (>1000 µg/L) - hemochromatosis and overloads CST ≥45 % - HFE genetic assessment |
Genetic hemochromatosis (HFE): autosomal recessive disease caused by mutation of the HFE gene (chromosome 6) → increased intestinal absorption of iron → progressive accumulation in liver, heart, pancreas, endocrine glands, joints and skin; homozygous C282Y/C282Y mutation: most frequent in Quebec populations of European origin (1/200 to 1/400 - prevalence among the highest in the world in populations of Celtic origin) - variable clinical penetrance (30-50 % of homozygotes develop clinical disease); clinical presentation according to stage: stage 1 (asymptomatic) → ferritin ↑ + CST ↑; stage 2 → fatigue + arthralgias (MCP 2e-3e - painful handshake - quasi-pathognomonic) + impotence + amenorrhea; stage 3 → hepatic cirrhosis + bronze diabetes + cardiomyopathy + hypogonadism + melanoderma (bronze complexion); other overloads: thalassemia major + sideroblastic anemia + iterative transfusions (ferritin 1000-5000 µg/L) + porphyria cutanea tarda; neonatal hemochromatosis (rare - severe from birth) | Diagnostic confirmation of hemochromatosis: HFE genotyping (C282Y / H63D) on blood + quantitative hepatic MRI (non-invasive measurement of hepatic iron stock - hepatic iron content expressed in µmol/g - non-invasive gold standard replacing liver biopsy) + liver biopsy if fibrosis suspected (FIB-4 or hepatic elastography); treatment of hemochromatosis - therapeutic bloodletting (phlebotomy): induction - 400-500 mL of blood / 1 to 2 weeks until ferritin <50 µg/L + CST <30 % (duration: 1 to 2 years depending on initial iron load); maintenance - 3 to 4 bleeds/year for life to maintain ferritin <50-100 µg/L; each 500 mL bleed removes around 200-250 mg of iron; results: normalization of fatigue and dyspnea rapidly (weeks) + improved liver function + stabilization of diabetes (but not reversible if cirrhosis set in) + reduced risk of hepatocellular carcinoma; therapeutic bloodletting program in Quebec: Héma-Québec (blood donation center) - blood donations from patients with hemochromatosis have been accepted and used since 2012 in Canada (under conditions); mandatory family screening: test all siblings and adult children of a C282Y/C282Y patient - ferritin + CST + HFE genotyping |
| Very high ferritin (>500-10,000 µg/L) - macrophagic activation syndrome Extreme hyperferritinemia - diagnostic emergency |
Macrophagic activation syndrome (MAS) or hemophagocytic lymphohistiocytosis (HHL): uncontrolled activation of macrophages and cytotoxic T lymphocytes → hyperphagocytosis of blood cells (erythrophagocytosis + leukophagocytosis) → massive hepatic cytolysis + massive release of intracellular ferritin + cytokines (cytokine storm); ferritin in MAS: often >500 µg/L - diagnostic cut-off value of 10,000 µg/L used (sensitivity 90 %, specificity 96 % for pediatric MAS) - some cases >50,000-100,000 µg/L; HScore diagnostic criteria (secondary adult MAS) or HLH-2004 criteria (pediatric): fever >38.5°C + splenomegaly + cytopenias (≥2 lineages) + hypertriglyceridemia and/or hypofibrinogenemia + hemophagocytosis on myelogram + low NK activity + ferritin >500 µg/L + elevated soluble CD25 (IL-2 receptor); triggering causes: infectious (EBV - #1 cause in children, CMV, HIV, leishmaniasis, tuberculosis) + autoimmune diseases (adult Still's disease - ferritin often 5,000-50,000 µg/L - joints + daily fever + erythema salmonata + arthralgias) + hematological malignancies (T or NK lymphomas - paraneoplastic SAM) + drugs (biological - immunosuppressive) | MAS is a diagnostic and therapeutic emergency - untreated mortality 50-80 %; treatment of MAS: dexamethasone IV 10 mg/m² /d + etoposide (VP-16) IV 150 mg/m² every 2 weeks (HLH-2004 protocol) if primary or severe MAS + ciclosporin A IV 3 mg/kg/d continuous infusion; anakinra (IL-1Ra) IV or SC : increasing 1st-line treatment for MAS secondary to auto-inflammatory diseases (Still's disease) - dose 2-10 mg/kg/d IV; treatment of the cause (eg. rituximab + chemotherapy if EBV-associated lymphoma + HIV antiviral treatment + antiparasitic treatment if leishmaniasis); ferritin in adult Still's disease: ferritin is both a diagnostic marker (>5 × normal - Yamaguchi criterion) and a marker of disease activity - its normalization under treatment (tocilizumab - anti-IL-6 - or anakinra) confirms therapeutic response; any ferritin >10,000 µg/L in a febrile patient with cytopenias → SAM until proven otherwise → emergency myelogram |
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Ferritin and pregnancy - screening is often inadequate : Iron deficiency is the most frequent nutritional deficiency in the world, and pregnancy is one of the main risk factors - iron requirements triple during pregnancy (from 1 to 3 mg/d absorbed, i.e. around 27 mg/d from the diet). A ferritin level <30 µg/L in the 1st trimester (some experts recommend <70 µg/L) justifies preventive oral martial supplementation. In Quebec, the Programme québécois de périnatalité recommends systematic hemoglobin and ferritin determinations in the 1st trimester for women at risk (vegetarians, closely spaced pregnancies, history of anemia). Untreated iron deficiency during pregnancy is associated with an increased risk of prematurity, low birth weight and post-partum depression, as well as consequences for the infant's neurocognitive development.
Signs requiring urgent medical assessment
Consult quickly if : ferritin >1000 µg/L with intense fatigue + arthralgia of the MCP + tanned complexion → advanced hemochromatosis - urgent liver assessment (cirrhosis + hepatocellular carcinoma to be ruled out).
Ferritin >10,000 µg/L + fever + cytopenias (anemia + leukopenia + thrombocytopenia) → macrophagic activation syndrome - hematological emergency - emergency myelogram.
Severe anemia (Hb <70 g/L) + very low ferritin + suspected digestive bleeding → urgent colonoscopy + gastroscopy - martial deficiency by occult bleeding to be ruled out.
Consult at Clinique Omicron
Clinique Omicron's physicians prescribe and interpret ferritin assays as part of the assessment of anemia, chronic fatigue, iron overload or incidentally discovered hyperferritinemia. They coordinate further assessment, referral to haematology or gastroenterology if necessary, and follow-up of martial therapy or therapeutic bloodletting. Consultations are available at our points of service in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.
The contents of this page are provided for information purposes only and do not replace the advice of a qualified healthcare professional. Ferritin must always be interpreted in its clinical context and in relation to the complete martial assessment - an isolated value is not sufficient to make a diagnosis.
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