In this edition, two articles describe cases of hyperferritinaemia. Thurlow et al. describe two novel mutations in the L-ferritin coding sequence associated with benign hyperferritinaemia showing abnormal ferritin glycosylation. Marshall et al. discuss causes of extreme hyperferritinaemia (plasma ferritin concentration .10,000 mg/L). The body’s iron content is controlled through absorption in the duodenum by active processes: free Fe2þ 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 Fe2þ into Fe3þ ions. 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 (Fe2þ) to the less toxic ferric (Fe3þ) form. 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 a and interleukin 1a. 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. 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. betathalassaemia, congenital sideroblastic or dyserythropoietic anaemias. 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. Hyperferritinaemia can occur in familial combined hyperlipidaemia and in familial hypertriglyceridaemia. 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. 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. 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. Benign hyperferritinaemia (BH) is associated with a missense ferritin L-subunit mutation (p.Thr30Ile) without iron overload and usually showing a normal transferrin saturation. 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. 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. Other causes of hyperferritinaemia that may not present witha raised transferrin saturation includehaemochromatosis 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
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Jan 1, 2023
Simran Syal + 4
Open Access
