Laboratory Medicine & Hematology & Family Medicine
Serum iron
Serum iron refers to the concentration of circulating iron in plasma, bound almost exclusively to transferrin (the specific iron transport protein). It is one of the parameters of the martial (or iron) balance, which also includes serum ferritin, transferrin, total iron-binding capacity (TIB) and transferrin saturation coefficient (TSC). Iron is a trace element essential to life: it is indispensable for oxygen transport by hemoglobin (2/3 of the body's iron) and for muscle myoglobin, a component of mitochondrial cytochromes (cellular respiration), numerous enzymes (catalase, peroxidases, ribonucleotide reductase) and aconitase (Krebs cycle). The adult body contains around 3.5 to 4 g of total iron, divided between the functional compartment (hemoglobin + myoglobin + enzymes = 70 %) and the reserve compartment (hepatic + splenic + medullary ferritin + hemosiderin = 30 %). Iron metabolism is mainly regulated by hepcidin, a hepatic peptide that inhibits ferroportin (cellular iron exporter) in response to martial overload or inflammation - the central mechanism of iron retention in macrophages and enterocytes during chronic inflammatory diseases. Serum iron exhibits significant biological variability: circadian variations (morning peak 8-10am, nadir late afternoon - variation of 30-40 % over the course of the day), variation according to recent nutritional status, stress and the menstrual cycle. This variability means that serum iron should always be interpreted as part of a complete iron workup (ferritin + transferrin + CST), and not in isolation - ferritin being the most reliable parameter of iron stores in the vast majority of clinical situations.
Martial Balance Settings — Reference Values and Integrated Interpretation
- Reference values for iron studies: serum iron: men 11-28 µmol/L (60-160 µg/dL) + women 9-26 µmol/L (50-145 µg/dL) - to be taken in the morning on an empty stomach to limit circadian variability - values vary slightly between laboratories and assay methods; serum ferritin: man 20-300 µg/L (ng/mL) + premenopausal woman 12-150 µg/L + postmenopausal woman 20-200 µg/L - most reliable parameter of iron reserves - 1 µg/L ferritin corresponds to approx. 8-10 mg iron reserve - true martial deficiency threshold : ferritin 30-50 µg/L (WHO 2020 recommendation); transferrin (siderophilin): 2.0-3.6 g/L - hepatic iron transport protein - increases in response to martial deficiency (increased hepatic synthesis - inverse response of ferritin) - decreases in inflammation + hepatopathies + protein malnutrition + nephrotic syndrome; total iron binding capacity (TIBC or TIBC): 45-72 µmol/L (250-400 µg/dL) - direct or calculated measure of transferrin's maximum capacity to bind iron - increased in deficiency + decreased in inflammation and overload; transferrin saturation coefficient (TSC): CST = serum iron / CTF × 100 - normal values: 20-45 % - low CST 45-55 % = martial overload (hemochromatosis); soluble transferrin receptor (RsTf): 0.8-1.7 mg/L - reflects iron demand at cellular level - elevated in true martial deficiency (even in the presence of inflammation - unlike ferritin) - normal in anemia of chronic diseases - useful for distinguishing true deficiency vs. inflammatory anemia when ferritin is normal or elevated
- Preanalytical Conditions and Factors Affecting Serum Iron: essential preanalytical conditions: sampling in the morning (8-10 a.m.) on an empty stomach or at least 2 hours after a meal - avoid sampling after a meal (iron-rich meals transiently increase serum iron levels)prandial (iron-rich meal transiently increases serum iron by 10-30 µmol/L) - avoid sampling after oral iron supplementation (oral iron transiently increases serum iron for 4-6h) - dry tube or gel tube - no contamination by traces of iron (clean needles + tubes) - hemolysis of sample → false increase in serum iron (erythrocyte iron contaminates serum) ; factors raising serum iron (beyond true overload): intravascular hemolysis (release of iron from hemoglobin) + multiple transfusions + acute hepatic necrosis (release of hepatic storage iron - serum iron very high in fulminant hepatitis) + tumor lysis syndrome + recent IV iron supplementation + post-prandial or post-supplementation sampling; factors decreasing serum iron (beyond true deficiency): acute or chronic inflammation (elevated hepcidin → iron sequestration in macrophages) + pregnancy (hemodilution + increased fetal demand) + chronic renal failure (hemodialysis - losses + EPO deficiency) + hypothyroidism + hypopituitarism + drugs (cholestyramine + iron chelators); drugs interfering with martial balance: oral contraceptives (increase transferrin and serum iron) + erythropoietin (uses stored iron → rapid decline in reserves) + corticosteroids (slightly increase serum iron)
- Characteristic Biological Profiles of Iron Balance Testing - Integrated Reading: true martial deficiency profile: low serum iron + low ferritin (<15-20 µg/L) + high transferrin + high CTF + low CST (2 = probable true deficiency + 300 µg/L male + >200 µg/L female) + low or normal transferrin + low or normal CTF + very high CST >45-55 % (most sensitive early sign of hemochromatosis - may be elevated before ferritin is frankly abnormal); transfusion overload profile (hemosiderosis): high serum iron + very high ferritin + high CST + context: multiple transfusions + sickle cell disease + thalassemia major + bone marrow aplasia.
Major pathologies of iron metabolism
| Pathology | Mechanism, biological profile, and clinical presentation | Diagnosis, treatment and follow-up |
|---|---|---|
| Iron deficiency and iron-deficiency anemia The most common cause of anemia in the world |
Iron deficiency is the most widespread nutritional deficiency in the world - it affects around 2 billion people according to the WHO - and iron deficiency anemia is the most frequent form of anemia, all causes combined; stages of martial deficiency: stage 1 (depletion of reserves): low ferritin <15 µg/L + normal serum iron + normal CST + normal Hb - no anemia yet but possible symptoms (fatigue + cognitive impairment); stage 2 (iron-deficient erythropoiesis): low ferritin + low serum iron + low CST + high transferrin + normal or slightly low Hb + incipient microcytosis; stage 3 (established iron-deficiency anemia): low ferritin + low serum iron + CST <15 % + low Hb + microcytosis + hypochromia + elevated IDR + anisocytosis on smear; symptoms of martial deficiency (with or without frank anemia): fatigue + asthenia + dyspnea on exertion + palpitations + pallor + headache + irritability + difficulty concentrating (cognitive deficit) + restless legs syndrome (RLS - strong association with martial deficiency + low ferritin low <50 µg/L) + pica (compulsive desire to ingest non-food substances - ice = pagophagia + clay + earth = geophagia) + koilonychia (spoon-shaped nails) + atrophic glossitis + angular cheilitis + diffuse alopecia; main causes of martial deficiency : chronic blood loss (most frequent cause in developed countries): menorrhagia (women of childbearing age) + chronic occulted rectorrhagia (colorectal cancer + polyps + angiodysplasia + IBD + peptic ulcer - obligatory digestive check-up in adult men + postmenopausal women with unexplained martial deficiency) + chronic haematuria + chronic intravascular haemolysis (haemoglobinuria - HPN); inadequate intakes: strict veganism + unbalanced diet + undernutrition; malabsorption: celiac disease (important cause always to be excluded in the face of unexplained martial deficiency - IgA anti-transglutaminase + total IgA antibodies) + gastrectomy + bariatric surgery (gastric bypass - duodenal short-circuit - iron is absorbed in the duodenum) + long-term PPIs (reduction of acidity → reduction of Fe³⁺ conversion to absorbable Fe²⁺) | Etiological work-up for martial deficiency: in women of childbearing age: menorrhagia (most frequent cause - gynecological work-up + PBAC score) + pregnancy + breastfeeding; in all adults with no obvious cause or in adult men + postmenopausal women: compulsory digestive work-up - faecal immunoassay (FIT - search for occult bleeding) + colonoscopy if FIT positive or symptoms + gastroscopy if high digestive symptoms or normal colonoscopy; celiac disease: anti-transglutaminase IgA + total IgA antibodies + gastroscopy + duodenal biopsies (villous atrophy); Helicobacter pylori: serology + urea-13C breath test (H. pylori can cause martial deficiency through chronic gastritis + competition for iron absorption); treatment of martial deficiency - oral iron: ferrous salt (ferrous fumarate + ferrous gluconate + ferrous sulfate) : 150-200 mg elemental iron/d - take on an empty stomach or 30 min before meals (maximum absorption in acidic environment) - concomitant vitamin C 200 mg improves absorption - separate antacids + PPIs + calcium + tea + coffee (absorption inhibitors) by 2h - diarrhea + constipation + nausea + black stools (normal) - in case of intolerance : reduce dose or alternate every other day (comparable absorption + better tolerance); response monitoring: reticulocytosis at D7-J10 (early response criterion) + Hb normalization in 4-8 weeks + continue 3-6 months after Hb normalization to replenish reserves (target ferritin >50 µg/L); IV iron : ferric carboxymaltose (Ferinject 500-1,000 mg IV in a single infusion) or iron sucrose (Venofer 200 mg IV): indicated if intolerant to oral iron + malabsorption + bariatric surgery + CKD + severe symptomatic deficiency (Hb <90 g/L) + 2nd-3rd trimester pregnancy - superior efficacy in terms of speed of correction |
| Anemia of chronic disease Low serum iron — normal or high ferritin |
Anemia of chronic diseases - also known as inflammatory anemia or anemia of chronic diseases (ACD) - is the 2nd leading cause of anemia worldwide after iron-deficiency anemia, and the 1st leading cause of anemia in hospitalized patients; pathophysiology of ACD - central role of hepcidin: systemic inflammation (pro-inflammatory cytokines: IL-6 + IL-1β + TNF-α) → stimulation of hepatic hepcidin synthesis → hepcidin inhibits ferroportin in enterocytes and macrophages → blockage of iron export → iron sequestration in splenic and hepatic macrophages + reduced intestinal iron absorption → low serum iron despite normal or increased reserves + inhibition of erythropoiesis (direct effect of cytokines on erythroblasts + relative erythropoietin) → normochromic normocytic anemia (sometimes slightly microcytic in prolonged forms) ; main diseases causing ACD : chronic infections (tuberculosis + HIV + chronic hepatitis + recurrent bacterial infections) + chronic inflammatory diseases (rheumatoid arthritis + SLE + IBD + psoriasis + inflammatory bowel disease) + neoplasia (carcinoma + lymphoma + leukemia - ACD is the most frequent type of anemia in oncology) + chronic renal failure (CKD - endogenous erythropoietin deficiency + inflammation + iron losses through hemodialysis - mixed mechanism) + chronic heart failure (inflammation + hemodilution + ACD) ; characteristic biological profile : low serum iron + normal or high ferritin (>100-200 µg/L - positive reactant of inflammation) + low transferrin + low CTF + low or normal CST + normal RsTf (in contrast to true deficiency) + CBC: mild to moderate normochromic normocytic anemia (Hb 90-115 g/L usually) | Distinction ACD vs martial deficiency - major practical issue: treatment differs radically (treat cause of ACD vs iron supplementation in deficiency) - differential diagnosis can be difficult in presence of concomitant inflammation masking ferritin; distinction algorithm: ferritin 2 → added deficiency → treat both + if 100 µg/L + inflammation + low serum iron → ACD very likely → no indication for systematic oral iron supplementation (sequestered iron will not be used and excess free iron promotes oxidation and infections); ACD treatment: treatment of the underlying disease (1st measure - the only one that treats the cause) + erythropoietin (EPO) and erythropoiesis-stimulating agents (ESAs) in CKD: recombinant EPO (epoetin alfa + darbepoetin) → dose according to dialysis protocol → target Hb 100-115 g/L (avoid Hb >130 g/L - thrombo-embolic risk) → always check iron stores before and during EPO (IV iron if ferritin <200 µg/L or CST <20 % under EPO); erythrocyte transfusion: reserved for severe symptomatic anemias (Hb <70-80 g/L depending on clinical context) + surgical emergencies + symptomatic patients despite EPO; place of IV iron in DKA: systematic IV iron in CKD on dialysis if CST <20 % + ferritin <200 µg/L - proven efficacy in CHF (chronic heart failure) with iron deficiency (CST <20 % or ferritin <100 µg/L): IV iron carboxymaltose reduces hospitalizations + improves quality of life and dyspnea (FAIR-HF + CONFIRM-HF + AFFIRM-AHF) |
| Hereditary hemochromatosis Elevated CST — very high ferritin — HFE mutation |
Hereditary hemochromatosis is the most common genetic disease in populations of Northern European origin - prevalence of C282Y homozygotes: 1/200 to 1/400 in populations of Celtic ancestry (Ireland + Brittany + Quebec - at-risk populations) - autosomal recessive disease linked to mutations in the HFE gene (chromosome 6p); pathophysiology : HFE mutation (C282Y/C282Y most frequent - accounts for 85-90 % of type 1 hereditary hemochromatoses) → reduced hepcidin synthesis → persistent increase in intestinal iron absorption + reduced macrophagic retention → progressive accumulation of iron in parenchymal organs (liver + pancreas + heart + pituitary + joints + skin) over several decades; clinical stages: stage 1: genetic predisposition without biological abnormalities (normal CST + ferritin); stage 2: biological abnormalities without symptoms (CST >45 % + elevated ferritin); stage 3: biological abnormalities + fatigue + arthralgias; stage 4: target organs affected (cirrhosis + diabetes + cardiomyopathy + hypogonadism + arthropathy); clinical manifestations of advanced forms (often diagnosed late): asthenia + arthralgias (2nd and 3rd metacarpophalangeal - almost pathognomonic sign + chondrocytes)pathognomonic sign + chondrocalcinosis - calcium pyrophosphate) + melanoderma (tanned skin hyperpigmentation = «tan diabetes») + liver cirrhosis (risk of hepatocellular carcinoma × 200 even after treatment) + secondary diabetes (destruction of pancreatic β-cells) + hypogonadism (pituitary depot → gonadotropic deficit → impotence + amenorrhea) + restrictive cardiomyopathy + rhythm disorders ; HFE mutations: C282Y/C282Y (homozygous - variable penetrance: 28 % of homozygotes develop clinical disease according to the HEmochromatosis and IRon Overload Screening - HEIRS study) + C282Y/H63D (composite heterozygote - mild to moderate overload) + H63D/H63D (homozygous H63D - rarely significant overload) | Diagnosis of hereditary hemochromatosis: biological screening: fasting CST ≥45 % (male) or ≥40 % (female) → the earliest and most sensitive sign + high ferritin (>300 µg/L male + >200 µg/L female) - repeat fasting if CST limit + confirm on two samples; HFE genetic test: C282Y + H63D by PCR on blood (EDTA tube) - available in Québec (CHU genetic laboratories + Génome Québec) - confirms diagnosis without liver biopsy if C282Y/C282Y + ferritin 1,000 µg/L + elevated AST + suspected cirrhosis (to quantify fibrosis and iron deposition - Metavir score) - hepatic MRI (T2*): non-invasive alternative to quantify hepatic iron overload; family screening: HFE genotype assay in 1st degree relatives of any diagnosed C282Y homozygote; treatment of hereditary hemochromatosis: phlebotomies (therapeutic bloodletting): reference treatment - elimination of 250 mL blood = approx. 250 mg iron - induction phase: 1 phlebotomy/week (500 mL blood = 200-250 mg iron) until ferritin 120 g/L (maintenance criterion) - duration of induction phase: 1-3 years depending on initial load - maintenance phase: 1 phlebotomy/2-4 months for life to maintain ferritin 50-100 µg/L + CST <45 % - monitoring: ferritin + CBC before each session → Hb <120 g/L → postpone session - prognosis: early phlebotomies (before cirrhosis) → normal life expectancy - cirrhosis already established → HCC risk persists (biannual monitoring by ultrasound + AFP); iron chelators (deferoxamine + deferasirox): reserved for contraindications to phlebotomies (pre-existing anemia) or transfusion overload (thalassemia + sickle cell anemia) |
| Transfusion surcharge Hemosiderosis — chronic hematologic diseases |
Transfusional martial overload (post-transfusion hemosiderosis) is an unavoidable complication of repeated erythrocyte transfusions in patients with chronic hematological diseases requiring long-term transfusion support; mechanism: each packed red blood cell (PRBC) provides around 200-250 mg of iron - the body has no active iron elimination mechanism (physiological losses are 1-2 mg/d) → progressive accumulation after 10-20 transfusions → parenchymal overload analogous to hemochromatosis; pathologies concerned: thalassemia major (transfusion-dependent β-thalassemia - up to 200 transfusions in a lifetime) + severe sickle cell anemia (transfusion exchange program) + bone marrow aplasia (support transfusions) + myelodysplasia (transfusion-dependent MDS) + other severe chronic hemolytic anemias; biological profile: very high ferritin (often >2,000-5,000 µg/L) + CST >55 % + high serum iron - CBC: depending on underlying disease - liver work-up: abnormalities if hepatic overload; target organs of transfusion overload: liver (siderotic hepatitis → fibrosis → cirrhosis) + heart (restrictive cardiomyopathy + rhythm disorders - main cause of death in unchelated thalassemia major) + endocrine glands (diabetes + hypogonadism + hypothyroidism + hypoparathyroidism) + skin (melanoderma); quantification of overload: serum ferritin (imperfect but practical reflection) + T2* liver MRI (quantification of hepatic iron - LIC: liver iron content - >7 mg Fe/g dry tissue = significant overload) + T2* cardiac MRI (T2* <20 ms = significant cardiac overload) - gold standard for chelation monitoring. | Treatment of transfusion overload - iron chelation: deferasirox (Exjade + Jadenu) : selective oral inhibitor of trivalent iron (Fe³⁺) - 14-28 mg/kg/d PO (Exjade dispersible suspension) or 7-21 mg/kg/d (Jadenu film-coated tablet - bioavailability 30 % higher) - taken once daily on an empty stomach (Exjade) or with a light meal (Jadenu) - indications: transfusion overload in children >2 years + adults - efficacy: reduction in ferritin by 15-25 % per year + improvement in cardiac T2* if treated early + reduction in cardiovascular mortality in thalassemia (ESCALATOR trial) - side effects : elevated creatinine + proteinuria (monthly monitoring of creatinine + proteinuria) + hepatic cytolysis + diarrhea + skin rash + rare agranulocytosis - contraindication if GFR <40 mL/min + nephrotoxic concomitant treatment + severe thrombocytopenia; deferiprone (Ferriprox) : oral bidentate chelator - 75-100 mg/kg/d in 3 doses - particularly effective for cardiac chelation (cardiomyocyte penetration superior to deferoxamine) - agranulocytosis in 1 % (weekly CBC mandatory throughout treatment - fatal risk if not monitored) + arthropathy + nausea; deferoxamine (Desferal) : hexadentate SC or IV chelator (SC infusion night × 8-12h per day 5-7 d/wk) - historical gold standard - abandoned for oral chelators in usual indications except emergencies (symptomatic severe cardiac overload → continuous IV deferoxamine + deferiprone); chelation targets: ferritin <1,000 µg/L + LIC 20 ms - annual hepatic + cardiac MRI monitoring |
| Hyperferritinemia — Diagnostic Approach High ferritin - various causes |
Hyperferritinemia (ferritin >200 µg/L female + >300 µg/L male) is a frequent finding during a routine biological workup - its cause is often benign (metabolic syndrome + alcoholism) but may reveal hemochromatosis or severe disease; causes of hyperferritinemia according to level: moderate hyperferritinemia (300-1,000 µg/L) - frequent and benign causes: metabolic syndrome (obesity + insulin resistance + dyslipidemia + NAFLD/NASH - mechanism: hepatocyte oxidative stress + low-grade inflammation → elevated ferritin as inflammatory reactant without actual martial overload - normal or low CST) + alcoholism (alcoholic hepatitis + hepatic cytolysis → hepatic ferritin release - normal or slightly elevated CST) + acute or chronic inflammatory syndrome (positive ferritin reactant of the acute phase) + chronic hepatitis B and C + hypothyroidism + hyperthyroidism + intense physical activity ; intermediate hyperferritinemia (1,000-5,000 µg/L) - causes not to be missed : C282Y/C282Y hemochromatosis with organic damage (high CST >45 %) + transfusion overload + severe alcoholic hepatitis + severe metabolic syndrome + advanced liver disease + neoplasia (non-specific marker); major hyperferritinemia (>5,000-10,000 µg/L) - severe causes: hemophagocytic syndrome (HLH): ferritin often >10,000-50,000 µg/L + pancytopenia + splenomegaly + hypofibrinogenemia + hemolysis → emergency + HLH-94 protocol; adult Still's disease: >3,000-10,000 µg/L + glycosylated fraction of ferritin <20 % (normal ≥50 %) → very specific; fulminant hepatitis (massive hepatic necrosis); massive transfusion syndrome; aggressive T lymphoma | Diagnostic approach to hyperferritinemia: step 1 - obvious clinical context (metabolic syndrome + alcoholism + known inflammation) → no immediate in-depth exploration + treatment of the cause + check-up at 3-6 months after correction of the triggering factor; step 2 - persistent ferritin >300 µg/L with no obvious cause → complete martial workup: fasting CST (key parameter) → CST >45 % → probable hereditary hemochromatosis → HFE genotyping → if C282Y/C282Y confirmed → phlebotomies → if CST normal or low → causes not related to martial overload (inflammation + metabolic syndrome + alcoholism) → treat cause + control ; step 3 - ferritin >1,000 µg/L + high CST + doubt about hepatic fibrosis → hepatic workup + FibroTest or hepatic elastometry (Fibroscan) + T2* hepatic MRI if necessary → hepatic biopsy if advanced fibrosis suspected ; stage 4 - massive hyperferritinemia >5,000-10,000 µg/L → HLH and Still's disease to be excluded urgently → glycosylated ferritin fraction + CBC + fibrinogen + LDH + haptoglobin + myelogram; hyperferritinemia-cataract syndrome (HHCS): rare genetic cause of benign hyperferritinemia - FTL (ferritin light chain) gene mutation → constitutional hyperferritinemia without martial overload (normal CST + normal serum iron) + early bilateral crystalline cataract (20-40 years) - diagnosis: FTL genotyping - no treatment necessary (phlebotomies are contraindicated and worsen anemia) |
ℹ️
Ferritin or serum iron — which to choose? In the vast majority of clinical situations, the ferritin is the parameter of choice for assessing iron stores—it is more stable (no marked circadian variation), less influenced by recent diet, and a more reliable marker of stores than serum iron. serum iron It is mainly used to calculate the TSAT (transferrin saturation coefficient), an essential parameter for screening hereditary hemochromatosis. A complete iron panel (serum iron + ferritin + transferrin + TSAT) is recommended for any suspected iron metabolism abnormality, avoiding isolated serum iron testing, the interpretation of which is unreliable without context.
Results of martial balance requiring rapid medical action
Ferritin >10,000 µg/L + pancytopenia + splenomegaly → Hemophagocytic lymphohistiocytosis (HLH) → urgent hospitalization in hematology — life-threatening prognosis without immediate treatment.
CST >55 % + ferritin >1000 µg/L + elevated transaminases → Advanced hemochromatosis with liver involvement → Urgent HFE genotyping + comprehensive liver assessment + elastography → Phlebotomy to be started promptly.
Severe iron deficiency anemia (Hb <80 g/L) + collapsed serum iron in an adult man or postmenopausal woman occult gastrointestinal bleeding must be ruled out → FIT + colonoscopy + gastroscopy depending on symptoms.
Consult at Clinique Omicron
Clinique Omicron physicians prescribe and interpret the complete iron panel as part of health checkups, the investigation of anemia, unexplained fatigue, or high ferritin levels. Screening and monitoring of hereditary hemochromatosis, prescribing oral iron or requesting IV iron, and referrals to specialists (hematologist, gastroenterologist, geneticist) are part of the care offered. Consultations are available at several service points in Quebec and via telemedicine. To make an appointment, visit cliniqueomicron.ca.
The content of this page is for informational purposes only and does not substitute for a physician's interpretation. Serum iron and iron studies should always be interpreted within the overall clinical context.
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