Hyperferritinaemia;laboratory implications

In this edition, two articles describe cases of hyperferritinaemia. Thurlow et al. ¹ describe two novel mutations in the L-ferritin coding sequence associated with benign hyperferritinaemia showing abnormal ferritin glycosylation. Marshall et al. ² discuss causes of extreme hyperferritinaemia (plasma ferritin concentration >10,000 μg/L).

The body's iron content is controlled through absorption in the duodenum by active processes: free Fe²⁺ via the divalent metal transporter 1 and haem-bound iron via the haem carrier protein 1. Within the enterocyte, some of the iron combines with the protein apoferritin to form ferritin. Ferritin is the main intracellular iron storage protein, present in all cells but mainly in hepatocytes and reticuloendothelial cells. Free iron is exported from enterocytes via ferroportin into the circulation where it binds to transferrin for storage and transport. Transferrin-bound iron then enters target cells via receptor-mediated endocytosis. Hepcidin is an iron regulatory protein (IRP), and inhibits ferroportin. The human haemochromatosis protein (HFE) regulates the binding of transferrin to the transferrin receptor as well as regulating hepcidin. Caeruloplasmin also possesses ferroxidase activity that oxidizes Fe²⁺ into Fe³⁺ ions. ³

Ferritin is a 450 kDa protein that possesses a spherical shell with a central cavity where up to 4500 iron atoms can be oxidized and stored. Ferritin is a multimer protein composed of H (heavy; 21 kDa) and L (light; 19 kDa) subunits in variable proportions depending upon the particular tissue. The ferritin H subunit expresses ferroxidase activity which oxidizes iron from the ferrous (Fe²⁺) to the less toxic ferric (Fe³⁺) form. ^4–7

The H-ferritin gene resides on chromosome 11 and the L-ferritin gene on chromosome 19. Hepatic ferritin synthesis can occur as part of an acute phase response being stimulated by cytokines such as tumour necrosis factor α and interleukin 1α. Ferritin synthesis also involves a relationship between an iron binding protein or IRP and the ferritin mRNA. In the presence of iron overload, the IRP inhibitory system is suppressed, resulting in an increase in ferritin synthesis. ^4–7

In the steady-state, plasma ferritin correlates with total body iron stores. Hyperferritinaemia occurs in iron excess syndromes such as certain forms of haemochromatosis and secondary iron overload conditions such as chronic haemolysis, iron poisoning, porphyria cutanea tarda, multiple blood transfusions and iron loading anaemias, e.g. beta-thalassaemia, congenital sideroblastic or dyserythropoietic anaemias. ^4–7 Hyperferritinaemia is also observed in acute and chronic inflammation, carcinoma, chronic infection and autoimmune disease. Cytolysis from the hepatocytes such as occurs in acute or chronic liver diseases also results in hyperferritinaemia. ^4–7

Hyperferritinaemia can occur in familial combined hyperlipidaemia and in familial hypertriglyceridaemia. ⁸ Plasma ferritin concentration correlates also with diastolic blood pressure and plasma HDL-cholesterol concentration and may be a ‘marker’ of metabolic syndrome. Plasma ferritin may additionally be an independent indicator of poor glycaemic control in type 2 diabetes mellitus. ⁹ It has also been suggested that in liver steatosis, hyperferritinaemia is associated with raised plasma C-peptide concentration and insulin resistance although there is not usually iron overload. ¹⁰ A metabolic disorder associated with hyperferritinaemia and abnormal liver function but no iron overload has been described where patients also had one or more of the following: increased body mass index, dyslipidaemia, abnormal glucose tolerance or hypertension. ¹¹

Benign hyperferritinaemia (BH) is associated with a missense ferritin L-subunit mutation (p.Thr30Ile) without iron overload and usually showing a normal transferrin saturation. ¹ Hereditary hyperferritinaemia cataract syndrome (HHCS) is also a genetic condition that displays hyperferritinaemia without iron overload, usually with normal transferrin saturation and bilateral nuclear cataracts. ¹² Here, mutations of the ferritin L-subunit gene (19q13.1) as part of the iron regulatory element are responsible for the upregulation and hence overexpression of ferritin. Iron overload is not found in BH or HHCS because the raised plasma ferritin concentration is due to increased ferritin L-subunit production which is not involved in the storage of iron. It is important to differentiate such conditions from true iron overload as the BH or HHCS patients may develop iron deficiency anaemia if they undergo venesection. ^13–18

Other causes of hyperferritinaemia that may not present with a raised transferrin saturation include haemochromatosis type 4a, or ferroportin (SLC40A1) disease which displays macrophage iron accumulation (African iron overload mutation) and also acaeruloplasminaemia. This is a genetic disorder of parenchymal iron overload, which manifests neurological abnormalities such as those of the extrapyramidal system and diabetes mellitus and which is sometimes treated with desferrioxamine. ^17–19

In contrast, raised transferrin saturation iron overload hyperferritinaemias include classical adult haemochromatosis type 1 where patients show a mutated HFE gene (usually C282Y or H63D mutations). There are also rarer forms of haemochromatosis also displaying predominately hepatocytic iron overload hyperferritinaemia, namely type 2a (juvenile haemochromatosis mutation of the HJV gene coding for haemojuvelin), type 2b (juvenile haemochromatosis mutation of the HAMP [hepcidin antimicrobial peptide] gene) and type 3 (mutation of TFR2 [transfer receptor protein] gene coding for transferrin receptor 2) as well as type 4b. ^17–21

Extreme hyperferritinaemia of >10,000 μg/L is unusual and found in Still's disease, where plasma ferritin is a marker of disease activity. Extreme hyperferritinaemia can also be due to the macrophage haemophagocytic syndrome which can be genetic or acquired and which is evoked by severe hypercytokinaemia and associated with abnormally raised liver enzymes, hepatosplenomegly, pancytopaenia, persistent fever ≥38°C, hypofibrinogenaemia and hypertriglyceridaemia. The haemophagocytic syndrome is characterized by the infiltration of bone marrow and other tissues with haemophagocytic histiocytes and activation of lymphocytes and macrophages. ^22,23

Sami et al. ²⁴ reported extreme hyperferritinaemia in extrahepatic biliary obstruction and this has also been described in acute severe hepatocellular damage including sepsis and drug toxicity. ²⁵ Drug-induced hypersensitivity syndrome (DIHS) is a severe drug reaction characterized by fever and multiorgan failure, which usually occurs about a month after drug initiation. This is an immune-mediated process associated with activation of T-lymphocytes and macrophages, evoking cytokine release and extreme hyperferritinaemia. ²⁶

Plasma ferritin is glycosylated (usually the L-subunit) as carbohydrate moieties are added to ferritin during its secretion from the tissues: usually ferritin is about 50–80% glycosylated. Glycosylated ferritin assay, performed by specialist laboratories, may be a useful marker for the diagnosis of macrophage haemophagocytic syndrome and also Still's disease, where extreme hyperferritinaemia with reduced glycosylation (<20%) is usual. ^27–28 This assay also has a place in the diagnosis of BH where there is increased ferritin glycosylation (>90%) and also HHCS where reduced glycosylation of about 20–42% occurs. ¹

In conclusion, there are various causes of hyperferritinaemia; not all of these present with a raised transferrin saturation and iron overload (Box 1). One of the commonest causes of hyperferritinaemia is a secondary response to inflammation which may be evidenced by a raised plasma C-reactive protein concentration. Hyperferritinaemia is also associated with insulin resistance, hepatic steatosis and metabolic syndrome.

Box 1

Some causes of hyperferritinaemia

Inflammatory processes such as acute phase response

Liver disease

Acute or chronic infection

Malignant disease

Repeated blood transfusions

Autoimmune disease, e.g. systemic lupus erythematosus and rheumatoid arthritis

Chronic kidney disease

Insulin resistance

Haemolysis and iron overload anaemia

Haemochromatosis

Porphyria cutanea tarda

Still's disease

Macrophage haemophagocytic syndrome

Hereditary hyperferritinaemia cataract syndrome (HHCS)

Benign hyperferritinaemia (BH)

Drug-induced hypersensitivity syndrome

DECLARATIONS

Competing interests: None.

Funding: None.

Ethical approval: Not applicable.

Guarantor: MAC.

Contributorship: MAC is the sole author.