towards explaining unexplained hyperferritinemia

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haematologica | 2009; 94(3) | 307 |

EDITORIALS & PERSPECTIVES

Ferritin has a central role in iron homeostasis since itbinds and sequesters intracellular iron. It is a sphericshell with a central cavity where up to 4,500 atoms

of iron are oxidized and stored. Ferritin is a multimercomposed of 24 H (heavy) and L (light) subunits in vari-able proportions in different tissues. The two subunitsare highly conserved during evolution, but only the Hsubunit has ferroxidase activity.1 Ferritin is also releasedin the circulation prevalently as L-ferritin or G-(glycosy-lated)-subunit through a largely unknown process. Sinceover recent years serum ferritin measurement hasbecome a routine laboratory test, elevated serum ferritinis a common finding in clinical practice. High serum fer-ritin is found in a large spectrum of conditions both

genetic and acquired, associated or not with iron over-load. For this reason a precise diagnosis of hyperferritine-mia requires a strategy that includes family and personalmedical history, biochemical and eventually genetic orother tests, especially those related to tissue iron meas-urement.

It is well known that both acute and chronic inflamma-tion, as occurring in infections, autoimmune disorders,chronic renal failure and also cancer all conditions com-mon in hospitalized patients are associated with highferritin levels. Another common process is cytolysis, anevent that releases ferritin from the hepatocytes inpatients with acute or chronic liver diseases. Very highlevels of serum ferritin are found in Stills disease, where

hyperferritinemia is a marker of disease activity. It is bio-logically of interest that in this condition the glycosylat-

ed ferritin levels are lower (< 20%) than in normal sub-jects, whereas the glycosylated form represents 50-80%of the total ferritin.2 A simple determination of CRP is ofhelp in excluding inflammation when the problem is notclinically evident. In addition, in inflammatory condi-tions high ferritin is not associated with increased satura-tion of transferrin that is usually normal or evendecreased, according to the high hepcidin productionwhich may lead to anemia of chronic disorders (ACD).3

Elevated serum ferritin in association with high trans-ferrin saturation (Table 1 and Figure 1) is usually a sign ofiron overload. Increased body iron stores are found in thedifferent forms of hereditary hemochromatosis (Table 1),where serum ferritin levels broadly parallel the entity of

iron stores. Type 1 hemochromatosis is the most com-mon form, prevalently expressed in middle age males. Inmost cases it is due to a homozygous C282Y mutation ofthe HFE gene and in a minority of patients to compoundheterozygosity for both C282Y and H63D mutations orhomozygosity for the latter mutation. Type 2 hemochro-matosis, the juvenile form, are very rare due to mutationsof hemojuvelin or of hepcidin and type 3 hemochro-matosis which is characterized by mutations of TFR2. Allthese autosomal recessive disorders have inappropriatelylow hepcidin levels4 with consequent excessive ironrelease to the plasma from enterocytes and macrophages.For this reason transferrin saturation is high (>45%, butusually >60% up to 100% in the juvenile forms); its

increase antedates the increase of serum ferritin and isassociated with high levels of Non Transferrin Bound

Towards explaining unexplained hyperferritinemia

Clara Camaschella and Erika Poggiali

Vita-Salute San Raffaele University and IRCCS San Raffaele, Milan, Italy

E-mail: [email protected]. doi: 10.3324/haematol.2008.005405

Table 1. Genetic and acquired disorders associated with hyperferritinemia (not associated with anemia).

Genetic Disorders Inheritance Gene Transferrin saturation Hepcidin levels Iron overload

Type 1 AR HFE High Inappropriate Hepatocyteshemochromatosis (low)

Type 2a AR HJV High Low Hepatocyteshemochromatosis

Type 2b AR HAMP High Undetectable Hepatocyteshemochromatosis

Type 3 AR TFR2 High Low Hepatocyteshemochromatosis

Type 4a AD SLC40A1 Low/normal High Macrophageshemochromatosis

Type 4b AD SLC40A1 High High Hepatocyteshemochromatosis

HHCS AD L-FT IRE Normal - No

Benign hyperferritinemia AD L-FT Normal - No

Acquired DisordersInflammation Low High Macrophages

Chronic liver diseases Variable Variable Hepatocytes, mixedMetabolic syndrome Low/normal Normal/high Mixed/macrophages

TF: transferrin;AR: autosomal recessive;AD: autosomal dominant; HJV: hemojuvelin; HAMP:hepcidin;TFR2: transferrin receptor 2; SLC40A1:ferroportin; HHCS:hereditary

hyperferritinemia/cataract syndrom;L-FT IRE: iron responsive element of L-ferritin; L-FT: L-ferritin.


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Editorials and Perspectives

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Iron (NTBI), the toxic moiety of iron, responsible for liverdamage and eventually damage to the heart, pancreasand pituitary gland.

Very high levels of ferritin may be found in hemochro-matosis type 4 or ferroportin disease which does not resultfrom impaired hepcidin but rather from heterozygousmutations of the hepcidin receptorferroportin.5 The disease

is autosomal dominant and has a variable clinical pheno-type. The true ferroportin disease (hemochromatosistype 4a in Table 1) is due to mutant proteins that are notcorrectly targeted to the cell surface and is characterizedby macrophage iron accumulation, low/normal transfer-rin saturation and iron-restricted erythropoiesis.6 A sec-ond form (hemochromatosis type 4b), due to mutant fer-roportins that reach the cell surface but are resistant tohepcidin-induced internalization,7 is characterized byhepatocyte iron accumulation and high transferrin satu-ration, as in hemochromatosis. The distinction is clinical-ly relevant, because the true ferroportin disease seemsnot to be associated with clinical complications. Theseobservations strengthen the relevance of assessing serum

ferritin always in the context of transferrin saturation(Figure 1).

Ferritin is increased in iron overload secondary tochronic blood transfusions irrespective of the reason andalso in the so called iron loading anemias, which includebeta-thalassemia syndromes8 and congenital sideroblas-tic or dyserythropoietic anemias,9 characterized by highlevels of ineffective erythropoiesis and low hepcidin pro-duction. All these conditions are usually well knownfrom the patients history and may be diagnosed by spe-cific tests. Several methods such as magnetic resonanceimaging (MRI)10 or SQUID11 have become available tonon-invasively assess hepatic iron concentration: howev-

er, serial ferritin determinations remain a useful guide toassess iron overload and to monitor iron chelation thera-py in these patients.12

Moderate increase of serum ferritin with normal/hightransferrin saturation and mild/moderate liver iron accu-mulation may be common in chronic liver disorders,such as alcoholic liver disease and chronic viral hepatitis.

These conditions require attention because iron mayamplify the toxic effect of alcohol and viruses, accelerat-ing the evolution towards fibrosis and cirrhosis. In por-phyria cutanea tarda hyperferritinemia is a sign of ironoverload (in some cases due to HFE mutations)13 and, likealcohol and chronic hepatitis, is a trigger of porphyriaattacks.

In the metabolic syndrome (variable combination ofhypertension, diabetes, hypertrigliceridemia, obesity,steatohepatitis or fatty liver) moderate elevation of fer-ritin is common, but usually ferritin levels are dispropor-tionately high in comparison with iron stores,14 whereastransferrin saturation is not increased.

In recent years, new forms of inherited hyperfer-

ritinemia not associated with iron overload have beenidentified, adding new elements for differential diagno-sis. A rare dominant trait is hereditary hyperferritine-mia/cataract syndrome (HHCS), due to mutation in theIRE element of the 5 untranslated region of L-ferritinmRNA.15-17 The mutation results in lack of repression ofL-ferritin translation that becomes independent of ironavailability and of iron regulatory protein regulation andoccurs also in iron deficiency. Thus in HHCS, the highserum ferritin levels reflect an increased synthesis of theL-ferritin, but not of total body iron, since the L subunitdoes not participate in iron oxidation and storage. Thecondition is benign, the only clinical manifestation being

Figure 1. Diagnostic diagram of hyperferritinemianot associated with anemia or l iver disorders.

TFS: transferrin saturation; CRP: C reactive protein; HH: hereditary hemochromatosis; HHCS: hereditary hyperferritinemia/cataract syndrome;TFR2: transferrin receptor 2;

L-FT IRE: iron responsive element of L-ferritin; L-FT: L-ferritin.

Hyperferritinemia

Transferrin saturation

Low/normal High

Adult Juvenile

Hereditary hemochromatosis

Type 1(HFE)

(+235200)

Type 3(TFR2)

(#604250)

Type 4b(SLC40A1)(#606069)

Type 2a(HJV)

(#602390)

Type 2b(HAMP)

(#602390)

Inflammatory conditions(elevated c-reactive protein)

Metabolic syndrome

Hemochromatosis type 4a orferroportin disease(SLC40A1) (#606069)

HHCS(L-FT IRE) (#600886)Benign hyperferritinemia(L-FT)


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early-onset bilateral cataract. Except for eye surgery, notreatment is required: the few patients who have beentreated with phlebotomy developed anemia withoutchanges in serum ferritin levels.15

In this issue of the journal, Kannengiesser et al.18 reporta novel genetic dominant hyperferritinemia, thatappears to have a benign course in the absence of iron

overload (indicated as benign hyperferritinemia in Table 1and Figure 1). These authors have collected a large num-ber of samples from both familial (n=25) and isolated(n=66) subjects with unexplainedhyperferritinemia. Theydefined as unexplaineda condition of high serum ferritin(>200 ng/mL in women and >300 ng/mL in males) withtransferrin saturation

towards explaining unexplained hyperferritinemia

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