Towards explaining "unexplained hyperferritinemia"

Abstract

© F e r r a t a S t o r t i F o u n d a t i o nIron (NTBI), the toxic moiety of iron, responsible for liver damage and eventually damage to the heart, pancreas and pituitary gland. Very high levels of ferritin may be found in hemochromatosis type 4 or ferroportin disease which does not result from impaired hepcidin but rather from heterozygous mutations of the hepcidin receptor ferroportin. 5 The disease is autosomal dominant and has a variable clinical phenotype. The true ferroportin disease (hemochromatosis type 4a in Table 1) is due to mutant proteins that are not correctly targeted to the cell surface and is characterized by macrophage iron accumulation, low/normal transferrin saturation and iron-restricted erythropoiesis.6 A second form (hemochromatosis type 4b), due to mutant ferroportins that reach the cell surface but are resistant to hepcidin-induced internalization, 7 is characterized by hepatocyte iron accumulation and high transferrin saturation, as in hemochromatosis. The distinction is clinically relevant, because the true ferroportin disease seems not to be associated with clinical complications. These observations strengthen the relevance of assessing serum ferritin always in the context of transferrin saturation ( Figure 1).Ferritin is increased in iron overload secondary to chronic blood transfusions irrespective of the reason and also in the so called iron loading anemias, which include beta-thalassemia syndromes 8 and congenital sideroblastic or dyserythropoietic anemias, 9 characterized by high levels of ineffective erythropoiesis and low hepcidin production. All these conditions are usually well known from the patient's history and may be diagnosed by specific tests. Several methods such as magnetic resonance imaging (MRI) 10 or SQUID 11 have become available to non-invasively assess hepatic iron concentration: however, serial ferritin determinations remain a useful guide to assess iron overload and to monitor iron chelation therapy in these patients. 12Moderate increase of serum ferritin with normal/high transferrin saturation and mild/moderate liver iron accumulation may be common in chronic liver disorders, such as alcoholic liver disease and chronic viral hepatitis. These conditions require attention because iron may amplify the toxic effect of alcohol and viruses, accelerating the evolution towards fibrosis and cirrhosis. In porphyria cutanea tarda hyperferritinemia is a sign of iron overload (in some cases due to HFE mutations) 13 and, like alcohol and chronic hepatitis, is a trigger of porphyria attacks.In the metabolic syndrome (variable combination of hypertension, diabetes, hypertrigliceridemia, obesity, steatohepatitis or fatty liver) moderate elevation of ferritin is common, but usually ferritin levels are disproportionately high in comparison with iron stores, 14 whereas transferrin saturation is not increased.In recent years, new forms of inherited hyperferritinemia not associated with iron overload have been identified, adding new elements for differential diagnosis. A rare d...

A novel deletion in the iron-response element of the L-ferritin gene, causing hyperferritinaemia cataract syndrome

“…6 In the absence of a history of cataracts, two other rare genetic causes of hyperferritinaemia to consider are aceruloplasminaemia and ferroportin disease. 4 There are also missense mutations in the coding region of FTL (p.Thr30Ile, p. Gln26Ile and p.Ala27Val) known to cause hyperferritinaemia associated with hyperglycosylation of ferritin, without iron overload or cataracts. 7,8 HHCS normally follows an autosomal dominant pattern of inheritance.…”

“…3,4 Additional history did not suggest of any of these conditions. The patient had not received any prior transfusions or parenteral iron therapy.…”

“…4 We also considered spurious hyperferritinaemia caused by heterophile antibody interference. The ferritin measurement was repeated after treating the sample in a heterophilic blocking tube (Scantibodies Laboratory Inc.), and no such interference was detected.…”

Serum ferritin and transferrin saturation levels in β0 and β+ thalassemia patients

“…Most times, serum ferritin levels are related to the quantity of iron stored in the body; however, countless other genetic and acquired conditions, with and without iron overload, can influence these results (Camaschella and Poggiali, 2009). An increase in ferritin concentrations with no excess iron body can be observed in acute or chronic inflammatory processes, autoimmune diseases, neoplasias, chronic renal insufficiency, hepatopathies, and metabolic syndrome.…”

Serum hepcidin: a novel diagnostic tool in disorders of iron metabolism

“…In addition, hepcidin assays could be useful in the differential diagnosis of primary forms of iron overload and of genetic and acquired disorders associated with hyperferritinemia (Table 1), 22 in the detection of iron deficiency in patients with inflammation, a condition in which traditional parameters of iron status such as serum ferritin and transferrin saturation are not reliable, and for the prediction of response to treatment with erythropoiesis stimulating agents (ESA). In patients undergoing treatment with ESA, in fact, the increase in red cell production and hemoglobin level is preceded by an expansion of erythropoiesis that, in turn, stimulates iron absorption/mobilization through the suppression of hepcidin production.…”