Iron Status Beyond Haemoglobin: Ferritin, Transferrin Saturation and Context

Iron is one of the most commonly measured nutrients and one of the most commonly misinterpreted. A normal haemoglobin is often taken as reassurance that iron status is fine, when iron stores may have been depleted for months. A ferritin in the normal range may conceal deficiency in someone with inflammation. A high ferritin may be read as iron overload when it actually reflects fatty liver or infection. Interpreting iron studies well requires understanding what each marker measures and what else changes it.

How the body handles iron

The body has no active way to excrete iron, so iron balance is controlled at the point of absorption. The central regulator is hepcidin, a hormone made by the liver. When iron stores are adequate or inflammation is present, hepcidin rises and blocks iron absorption from the gut and release from stores. When iron is needed, hepcidin falls. This explains 2 important clinical facts: inflammation reduces iron absorption and availability even when stores are adequate, and oral iron raises hepcidin for about a day, which is why alternate day dosing can improve absorption.

Most of the body’s iron is in haemoglobin. Smaller amounts are in muscle myoglobin and enzymes, including those in mitochondria. Stores are held as ferritin, mainly in the liver, spleen and bone marrow. Iron travels in the blood bound to transferrin.

What each marker tells you

Thresholds for iron deficiency

A ferritin below 15 micrograms per litre is widely accepted as diagnostic of absent iron stores. Many guidelines, including those of the British Society of Gastroenterology, use a threshold of around 30 micrograms per litre, below which iron deficiency is likely in most contexts. In the presence of inflammation, chronic kidney disease or heart failure, higher thresholds apply: for example, heart failure guidelines define iron deficiency as a ferritin below 100, or between 100 and 299 with a transferrin saturation below 20 percent. Laboratory reference ranges for ferritin sometimes have lower limits well below these clinical thresholds, which is one reason deficiency can be missed.

Iron deficiency without anaemia

Iron deficiency develops in stages: first stores fall, then iron supply to tissues becomes limited, and only then does haemoglobin fall. The middle stage, iron deficiency without anaemia, is common, particularly in women of reproductive age, and can cause fatigue, reduced exercise tolerance, poor concentration, restless legs and hair shedding. In a randomised trial in women with unexplained fatigue, low ferritin and normal haemoglobin, intravenous iron reduced fatigue compared with placebo. Checking ferritin, rather than haemoglobin alone, is therefore important in fatigued patients.

Common patterns

Always ask why

Iron deficiency is a finding, not a diagnosis. Its cause must be identified.

• Blood loss: heavy menstrual bleeding is the most common cause in premenopausal women. In men and postmenopausal women, gastrointestinal blood loss, including from cancer, must be considered, and gastroenterology guidelines recommend investigation.
• Malabsorption: coeliac disease, Helicobacter pylori infection, atrophic gastritis, long term acid suppression, inflammatory bowel disease and bariatric surgery.
• Increased needs: pregnancy, growth, regular blood donation and endurance sport.
• Low intake: vegetarian or vegan diets without attention to iron, restrictive diets and food insecurity.

Coeliac disease serology is recommended in people with unexplained iron deficiency.

Iron overload

Hereditary haemochromatosis, most commonly due to homozygosity for the C282Y variant of the HFE gene in people of northern European ancestry, causes excessive iron absorption over years. A raised transferrin saturation is often the earliest sign, followed by rising ferritin. Untreated, it can damage the liver, pancreas, heart and joints. Early diagnosis allows treatment by regular venesection. Other causes of iron overload include repeated transfusions and some blood disorders. Iron supplements should not be taken by people with overload.

Treatment principles

• Oral iron is first line for most people. Taking it on alternate days, or once daily rather than several times a day, may improve absorption and reduce side effects, reflecting the effect of hepcidin.
• Vitamin C taken with iron may modestly enhance absorption; tea, coffee, calcium and antacids reduce it.
• Gastrointestinal side effects such as constipation and nausea are common and often limit adherence; adjusting the dose or formulation can help.
• Intravenous iron is used when oral iron is ineffective, not tolerated, or when rapid repletion is needed, as in late pregnancy, heart failure, chronic kidney disease or inflammatory bowel disease.
• Recheck haemoglobin and ferritin to confirm response, and continue until stores are replenished.
• Treat the cause, such as heavy menstrual bleeding, in partnership with the patient’s doctor.

An illustrative case

A 34 year old woman with fatigue, breathlessness on exercise and hair shedding has a normal haemoglobin and a ferritin of 14 micrograms per litre, reported as at the lower end of her laboratory’s range. Her periods are heavy and she has recently become vegetarian. Her CRP is normal. Iron deficiency without anaemia is diagnosed. Her doctor assesses the heavy menstrual bleeding and starts oral iron on alternate days, taken with orange juice and away from tea. Her diet is reviewed to include more iron rich plant foods. Coeliac serology is negative. At 3 months her ferritin has risen, her energy has improved and her periods are being managed. 2 causes, blood loss and reduced intake, were addressed together.

Reading iron as a story

No single iron marker tells the whole story. Ferritin, transferrin saturation, the blood count and an inflammatory marker, read together and interpreted alongside the history, give a far more accurate picture than any one of them. And every abnormal result, low or high, deserves the question: why?