The Complete Iron Panel & Anemia Workup

The Goldilocks Problem

Iron is the only nutrient in the body that has no regulated excretion pathway. You absorb it, you use it, and you store it — but you cannot dump it. The body loses iron only through bleeding (menstruation, GI losses, blood donation), skin cell shedding, and trace amounts in sweat and urine. This makes iron a Goldilocks nutrient in the truest sense: too little and your cells suffocate; too much and they rust.

Iron deficiency is the most common nutritional deficiency on Earth, affecting an estimated 2 billion people. Iron overload (hemochromatosis) is the most common genetic disease in people of Northern European descent, affecting 1 in 200-300 individuals. Both conditions are routinely missed because doctors order incomplete panels and accept inadequate reference ranges.

A single ferritin test is not an iron panel. A “normal” ferritin of 15 is not normal. And a high ferritin does not always mean you have too much iron.

The Complete Iron Panel

Ferritin: The Storage Vault

Optimal: Women 50-100 ng/mL, Men 75-150 ng/mL (Standard ranges: women 12-150, men 12-300 — dangerously wide)

Ferritin is the iron storage protein. Each ferritin molecule can hold up to 4,500 iron atoms in its hollow spherical shell. The serum ferritin level reflects total body iron stores, with approximately 1 ng/mL of serum ferritin corresponding to 8-10 mg of stored iron.

But here is the trap: ferritin is also an acute phase reactant. It rises with inflammation, infection, liver disease, malignancy, and metabolic syndrome — independently of iron status. A patient with rheumatoid arthritis can have a ferritin of 200 ng/mL while being profoundly iron deficient. The inflammation inflates the number, masking the depletion.

This dual nature of ferritin — iron storage marker AND inflammation marker — is one of the most clinically important concepts in lab interpretation. Never interpret ferritin without context.

The Ferritin Threshold Cascade:

• Ferritin <15 ng/mL: Absolute iron deficiency. No debate. Even by conventional standards, this is deficient.
• Ferritin <30 ng/mL: Definite iron deficiency, even though many labs call this “normal.” The WHO and multiple hematology guidelines now recognize <30 as the cutoff for iron deficiency, yet the standard lab range persists at 12 as the lower limit.
• Ferritin <50 ng/mL: Hair loss begins. Thyroid conversion from T4 to T3 becomes impaired (thyroid peroxidase is iron-dependent). This is the threshold where chronic fatigue starts to set in, though it is rarely connected to iron by conventional physicians.
• Ferritin <70 ng/mL: Restless legs syndrome threshold. Exercise intolerance begins. Cognitive function suffers — iron is required for dopamine synthesis, myelin formation, and mitochondrial electron transport. Athletes performing below their potential with “normal” labs often have ferritin in the 30-60 range.
• Ferritin 50-100 (women) / 75-150 (men): The functional sweet spot. Energy, cognition, thyroid conversion, and exercise tolerance are optimized.
• Ferritin >150 (women) / >200 (men): Investigate. Rule out inflammation (check hs-CRP, ESR), liver disease (check GGT, ALT), metabolic syndrome, alcohol use, and hemochromatosis (check transferrin saturation and HFE gene).

Serum Iron

Optimal: 85-130 mcg/dL

Serum iron measures iron currently circulating in the blood bound to transferrin. It fluctuates significantly throughout the day (highest in the morning, lowest in the evening), after meals (especially iron-rich meals), and with acute inflammation. Because of this variability, serum iron alone is unreliable. It must be interpreted alongside TIBC and transferrin saturation.

TIBC (Total Iron-Binding Capacity)

Optimal: 250-350 mcg/dL

TIBC measures how much transferrin is available to bind iron — it is an indirect measure of transferrin concentration. Think of transferrin as the taxi fleet and iron as the passengers. TIBC tells you how many taxis are on the road.

• High TIBC (>350): The body is making more taxis because there aren’t enough passengers — this is iron deficiency. The liver ramps up transferrin production to scavenge every available iron atom.
• Low TIBC (<250): Fewer taxis are needed because there are too many passengers — iron overload, chronic inflammation (negative acute phase response), liver disease, or malnutrition.

Transferrin Saturation

Optimal: 25-35%

Transferrin saturation (TSAT) = serum iron / TIBC x 100. This tells you what percentage of the taxi fleet is carrying passengers.

• TSAT <20%: Iron deficiency. Not enough iron to load the available transferrin.
• TSAT 25-35%: Optimal — iron supply meets demand.
• TSAT >45%: Iron overload. Screen for hemochromatosis (HFE gene testing). TSAT is the best screening test for hereditary hemochromatosis — more sensitive than ferritin in early disease.

Soluble Transferrin Receptor (sTfR)

Elevated = iron deficiency

The soluble transferrin receptor is a fragment shed from cell surface transferrin receptors. When cells are iron-hungry, they upregulate transferrin receptors on their surface to grab more iron from circulating transferrin. More surface receptors = more fragments shed into the blood = higher sTfR.

The critical advantage of sTfR: it is NOT affected by inflammation. When CRP is elevated and ferritin is unreliable, sTfR tells the true story of tissue iron status. It rises in genuine iron deficiency and stays normal in anemia of chronic disease.

sTfR/log ferritin index (Thomas plot): A ratio that distinguishes iron deficiency from anemia of chronic disease even in the presence of inflammation. An index >2.0 indicates true iron deficiency; <1.0 indicates adequate iron stores with anemia of chronic disease.

Hepcidin: The Master Regulator

Hepcidin is a peptide hormone produced by the liver that controls iron absorption and recycling. It is the master regulator of iron homeostasis, and understanding it transforms how you think about iron.

Hepcidin blocks ferroportin — the only iron export channel on enterocytes (gut absorptive cells) and macrophages. When hepcidin is high, ferroportin is degraded, iron stays trapped in cells, and absorption from the gut is blocked.

• High hepcidin: Inflammation (IL-6 drives hepcidin production — this is the mechanism behind anemia of chronic disease), iron overload (feedback regulation), infection (iron-withholding defense against pathogens)
• Low hepcidin: Iron deficiency, hypoxia, erythropoietic drive (the bone marrow overrides hepcidin via erythroferrone)

Hepcidin testing is emerging but not yet widely available clinically. Its significance is primarily conceptual for now — but it explains why taking iron supplements during active infection or inflammation is often futile and potentially harmful.

Decoding Ferritin in the Presence of Inflammation

When CRP is elevated and ferritin appears “normal” or even “high,” the clinical algorithm is:

1. Check hs-CRP alongside ferritin. If CRP >3 mg/L, ferritin may be falsely elevated.
2. Order soluble transferrin receptor (sTfR). If elevated, true iron deficiency is present despite the “normal” ferritin.
3. Calculate sTfR/log ferritin index. Values >2.0 confirm iron deficiency with concurrent inflammation.
4. Look at other CBC markers: low MCV, low MCH, high RDW, elevated platelet count — all suggest iron deficiency even when ferritin lies.

This scenario is staggeringly common: a patient with autoimmune disease, chronic infection, or obesity has fatigue attributed to their primary condition, while underlying iron deficiency goes untreated because ferritin looks fine.

Anemia Differential by MCV

When hemoglobin is low, MCV (Mean Corpuscular Volume) guides the differential diagnosis:

Microcytic Anemia (MCV <80 fL)

Small red blood cells. The production line is iron-starved.

• Iron deficiency: Most common cause worldwide. Low ferritin, low serum iron, high TIBC, low TSAT. Causes: blood loss (menstruation, GI bleeding — always scope patients >50 with new iron deficiency), poor intake, malabsorption (celiac disease, low stomach acid, H. pylori, gastric bypass).
• Thalassemia trait: Genetic hemoglobin variant. MCV disproportionately low relative to hemoglobin. Mentzer index (MCV/RBC count): <13 suggests thalassemia, >13 suggests iron deficiency. Confirmed by hemoglobin electrophoresis.
• Anemia of chronic disease: Can be microcytic (usually normocytic). Low serum iron but low TIBC (unlike iron deficiency where TIBC is high).
• Sideroblastic anemia: Defective heme synthesis. Iron is present but cannot be incorporated. Ring sideroblasts on bone marrow biopsy.
• Lead poisoning: Lead inhibits delta-aminolevulinic acid dehydratase and ferrochelatase in heme synthesis. Basophilic stippling on peripheral smear.

Normocytic Anemia (MCV 80-100 fL)

Normal-sized red blood cells, but not enough of them.

• Acute blood loss: The first 24-48 hours before reticulocyte compensation.
• Anemia of chronic disease: The most common anemia in hospitalized patients. Mediated by hepcidin — inflammatory cytokines (IL-6) drive hepcidin production, trapping iron in macrophages and blocking gut absorption.
• Chronic kidney disease: Reduced erythropoietin production.
• Hemolytic anemia: Red blood cells destroyed prematurely. High reticulocytes, high LDH, high indirect bilirubin, low haptoglobin.
• Aplastic anemia: Bone marrow failure. Pancytopenia (low WBC, RBC, and platelets).
• Mixed deficiency: Combined iron + B12 deficiency — small cells and large cells average out to a normal MCV while two deficiencies rage. RDW will be elevated, revealing the variability.

Macrocytic Anemia (MCV >100 fL)

Large red blood cells. The DNA synthesis machinery is impaired.

• Vitamin B12 deficiency: Serum B12 is unreliable — 50% of deficient patients have “normal” serum B12. Check methylmalonic acid (MMA, elevated in B12 deficiency) and homocysteine (elevated in both B12 and folate deficiency). Causes: pernicious anemia (intrinsic factor antibodies), metformin use (depletes B12 via calcium-dependent absorption), vegetarian/vegan diet, atrophic gastritis, H. pylori, gastric bypass, chronic PPI use.
• Folate deficiency: Check RBC folate (more reliable than serum folate). Causes: poor intake, alcohol, medications (methotrexate, trimethoprim, phenytoin), pregnancy, celiac disease, MTHFR polymorphisms.
• Hypothyroidism: Slowed cell division leads to macrocytosis.
• Liver disease and alcohol: Direct toxic effect on bone marrow + folate depletion.
• Myelodysplastic syndrome (MDS): Bone marrow clonal disorder, especially in elderly patients with macrocytosis unresponsive to B12/folate.
• Medications: Metformin, methotrexate, azathioprine, hydroxyurea, antiretrovirals.

Iron Supplementation: The Science of Getting It Right

Forms Matter

Ferrous bisglycinate (iron bisglycinate chelate): The gold standard for oral supplementation. Superior absorption compared to ferrous sulfate, significantly fewer GI side effects (nausea, constipation, cramping). The amino acid chelate protects the iron from binding to phytates and tannins in food. Brands: Thorne Iron Bisglycinate, Pure Encapsulations Iron-C.

Ferrous sulfate: The most prescribed form. Cheap and effective but harsh — up to 40% of patients experience GI side effects leading to non-compliance. Contains 20% elemental iron (325 mg tablet = 65 mg elemental iron).

Iron protein succinylate: Well-tolerated European form with fewer GI effects. Releases iron at intestinal pH, bypassing the stomach.

Heme iron polypeptide (Proferrin): Derived from bovine hemoglobin. Absorbed via a different pathway (HCP1 transporter) than non-heme iron, so it is not blocked by phytates, tannins, or calcium. Useful for patients who cannot tolerate other forms.

IV iron (ferric carboxymaltose — Injectafer, iron sucrose — Venofer): Reserved for severe deficiency, malabsorption, intolerance of oral forms, or when rapid repletion is needed (heavy bleeding, pre-surgical, late pregnancy). Single infusion of Injectafer (750-1000 mg) can replete stores in one session.

Timing and Absorption

The Moretti 2015 study (Lancet Haematology) revolutionized iron dosing: alternate-day dosing is superior to daily dosing. Here is why: each dose of iron triggers a hepcidin surge that peaks at 24 hours and blocks absorption of the next dose. Taking iron every other day results in greater fractional absorption and faster repletion than taking it daily.

Practical protocol: 30-60 mg elemental iron every other day, taken on an empty stomach with 500-1000 mg vitamin C (ascorbic acid enhances non-heme iron absorption by reducing Fe3+ to Fe2+, keeping it soluble in the alkaline duodenum).

Absorption blockers — separate by 2-4 hours:

• Coffee and tea (tannins and polyphenols bind iron)
• Calcium and dairy (calcium competes for DMT-1 transporter)
• Antacids and PPIs (iron requires stomach acid for absorption — Fe3+ needs acid to convert to absorbable Fe2+)
• Phytates (whole grains, legumes, nuts)
• Zinc (competes at high doses)

Absorption enhancers:

• Vitamin C (most important — take simultaneously)
• Meat/fish factor (enhances non-heme iron absorption)
• Fermented foods (reduce phytate content)
• Acidic foods (lemon juice, vinegar)

Monitoring

Recheck ferritin, serum iron, TIBC, and CBC at 8-12 weeks. Ferritin should rise approximately 1 ng/mL per day of effective supplementation. If ferritin is not rising despite compliance, investigate: malabsorption (celiac disease, H. pylori, low stomach acid), ongoing blood loss (GI — check stool for occult blood), or inflammation blocking hepcidin pathway.

Hemochromatosis: The Iron Overload Disease

Screening: Transferrin saturation >45% on fasting morning draw. Confirm with HFE gene testing.

Genetics: C282Y homozygosity (most common, highest penetrance), C282Y/H63D compound heterozygosity (moderate risk), H63D homozygosity (low risk, rarely causes clinical overload).

Clinical manifestations of iron overload: Liver disease (cirrhosis, hepatocellular carcinoma), diabetes (“bronze diabetes” — iron deposits in pancreas destroy beta cells), cardiomyopathy, arthropathy (especially 2nd and 3rd MCP joints), hypogonadism (iron deposits in pituitary), skin hyperpigmentation, fatigue.

Management: Therapeutic phlebotomy — removal of 500 mL whole blood (containing ~250 mg iron) every 1-2 weeks until ferritin reaches 50-100 ng/mL, then maintenance phlebotomy every 2-4 months. Dietary modification: avoid vitamin C supplements with meals (enhances absorption), limit red meat, avoid iron-fortified foods, no alcohol (synergistic liver toxicity).

Iron is the element that makes blood red, that carries oxygen to every cell, that drives the electron transport chain powering mitochondrial ATP production. Without enough of it, you suffocate from the inside out. With too much of it, you rust. The complete iron panel — not a single ferritin test, but the full constellation of ferritin, serum iron, TIBC, transferrin saturation, and when needed sTfR — reveals where you stand on the spectrum between depletion and overload. Both extremes are dangerous. Both are treatable. Both are missed every day by incomplete testing.