Ferritin

Ferritin is composed of 24 subunits (heavy and light chain isoforms) assembled into a spherical shell that can accommodate up to 4,500 iron atoms as ferrihydrite. Iron is released when cells require it, under the control of the regulatory protein IRP (iron regulatory protein) and the systemic iron hormone hepcidin.

Hepcidin — produced by the liver — is the master regulator of systemic iron homeostasis. It degrades ferroportin (the iron export protein on enterocytes, macrophages, and hepatocytes), reducing iron absorption and release. Elevated hepcidin (driven by inflammation via IL-6) causes iron sequestration — a key mechanism in the anaemia of chronic disease.

Serum ferritin reflects primarily the iron stored in the reticuloendothelial system (macrophages of liver, spleen, and bone marrow). Because it is also an acute-phase protein produced by hepatocytes and macrophages in response to inflammation, its interpretation requires accounting for concurrent inflammatory state.

Serum ferritin reference ranges: men: 30-300 ng/mL (μg/L); women: 13-150 ng/mL. These are assay-specific and laboratory-dependent. Functional iron deficiency (impaired erythropoiesis despite normal haemoglobin) may occur at ferritin values below 30-50 ng/mL in the presence of symptoms.

Iron deficiency is defined clinically by depleted stores (ferritin <12-15 ng/mL) with or without anaemia. Iron deficiency without anaemia can cause fatigue, poor cold tolerance, impaired exercise capacity, restless legs, and reduced cognitive performance — symptoms often overlooked when haemoglobin is normal.

Elevated ferritin thresholds: values >300 ng/mL in men warrant investigation; values >1,000 ng/mL significantly raise the probability of haemochromatosis, liver disease (where ferritin leaks from damaged hepatocytes), haematological malignancy, macrophage activation syndrome, or significant alcohol use. Transferrin saturation should always accompany elevated ferritin evaluation.

Because ferritin is an acute-phase reactant, inflammatory states (infection, autoimmune disease, metabolic syndrome, NAFLD, excess alcohol) raise serum ferritin disproportionate to true iron stores. A ferritin of 150-400 ng/mL in a man with obesity, elevated CRP, and elevated ALT more likely reflects metabolic inflammation than true iron overload.

In clinical practice, transferrin saturation (serum iron ÷ total iron binding capacity × 100) is used alongside ferritin to distinguish iron overload from inflammatory ferritin elevation. Transferrin saturation >45% (men) with elevated ferritin points toward hereditary haemochromatosis (HFE gene mutation testing is indicated). Normal transferrin saturation with elevated ferritin more often reflects inflammation or metabolic liver disease.

Hyperferritinaemia-cataract syndrome is a rare genetic disorder where mutations in the ferritin light-chain IRE cause ferritin overproduction without iron overload — demonstrating that ferritin and iron stores can be dissociated.

Iron deficiency (low ferritin) is the most common nutritional deficiency globally and is significantly under-recognised in men who are typically not screened routinely. Causes in men include dietary insufficiency (particularly in plant-based diets without adequate non-haem iron), gastrointestinal blood loss (peptic ulcer, colorectal pathology), malabsorption (coeliac disease, post-bariatric surgery), and chronic haematuria.

Hereditary haemochromatosis (most commonly HFE C282Y homozygosity) causes progressive iron overload affecting liver (cirrhosis), pancreas (diabetes), heart (cardiomyopathy), joints (chondrocalcinosis), and endocrine glands — including the pituitary (hypogonadism) and testes. Early identification via ferritin + transferrin saturation screening in at-risk individuals (Northern European ancestry, family history) is critical, as therapeutic venesection (phlebotomy) is curative when started before organ damage.

In the context of men's hormonal health: haemochromatosis-related pituitary iron deposition directly suppresses gonadotropin (LH, FSH) release, causing hypogonadotrophic hypogonadism with very low testosterone. This should always be considered in men with unexplained secondary hypogonadism, particularly with elevated ferritin and liver enzyme abnormalities.

Monitoring ferritin during testosterone replacement therapy is advisable, as TRT stimulates erythropoiesis and can increase red cell turnover — altering iron dynamics and occasionally causing iron redistribution effects.