MEDICINE

REVIEW ARTICLE

The Treatment of Secondary Hemochromatosis

Norbert Gattermann

SUMMARY
Background: Because secondary hemochromatosis is
I ron overload can cause major damage to the organs
of the body. Homozygous patients with Mediterra-
nean anemia (thalassemia major) who do not undergo
due to hereditary or acquired anemia, phlebotomy is not
intensive iron-chelation therapy die in their twenties of
a suitable means of removing excess iron in this situation.
heart failure caused by iron deposition in the myocardium.
Rather, the treatment is based on the targeted elimination
In September 2006, the oral iron chelator deferasirox
of iron by means of iron chelators.
was approved for use in Europe. For patients who pre-
Methods: Selective review of the literature. viously had to content themselves, for years or decades,
Results: Disorders causing secondary hemochromatosis with cumbersome parenteral deferoxamine treatment,
(e.g., thalassemia) are characterized by ineffective the new medication is an important therapeutic advance.
erythropoiesis leading to increased duodenal uptake of Thalassemia being rare in Germany, the problem of
iron. Most patients are also chronically transfusion- secondary hemochromatosis here mainly affects elderly
dependent and receive 200–250 mg of iron with each patients with myelodysplastic syndromes (MDS). These
transfused unit of packed red blood cells. As the excess diseases have a total incidence of about 4 per 100 000
iron cannot be actively excreted, iron overload ensues, persons per year. The indication for iron chelation in
which can cause organ damage. Most patients with this MDS should be determined only after careful considera-
condition in Germany are elderly persons with tion. This article, prepared on the basis of a selective
myelodysplastic syndromes (MDS). The standard treatment literature review (PubMed and abstracts presented at the
to date, parenterally administered deferoxamine, is often annual meetings of the American Society of Hematology),
hampered by poor compliance. In September 2006, a new describes how secondary hemochromatosis comes
oral iron chelator, deferasirox, was approved for use in about, and how it can be treated with chelators.
Germany. According to current findings, this medication is
In both thalassemia and MDS, secondary hemochro-
safe, except for a low risk of renal or hepatic failure.
matosis is caused by more than just transfusion treat-
Conclusions: Iron chelation is a treatment option not only ment. Increased intestinal resorption of iron causes iron
for thalassemia patients, but also for those with lower-risk to accumulate even before the patient receives the first
MDS who can be expected to need several years of unit of transfused erythrocytes. (For more on pathophy-
transfusion therapy. siology, see the supplement that accompanies this
Dtsch Arztebl Int 2009; 106(30): 499–504 article, and the diagram (eFigure) found in the supple-
DOI: 10.3238/arztebl.2009.0499 ment.)
Key words: hemochromatosis, anemia, chelators, Thus, the concept of secondary hemochromatosis is a
treatment, myelodysplastic syndrome broad one, encompassing all cases of iron overload that
are not due to a primary, hereditary disorder of iron
metabolism (Box 1). Such cases are usually caused, in-
stead, by an inherited or acquired type of "iron-loading
anemia"—in other words, by anemia accompanied by
resorptive iron overloading.

Iron overloading due to blood transfusions

The most important cause of secondary hemochromatosis
is chronic transfusion therapy. Every unit of
erythrocytes that is transfused contains about 200 to
250 mg of iron as a component of the red heme pigment
(Box 2). When the erythrocytes are broken down by the
macrophage system, iron is freed from heme and stored
in the body. As the normal daily loss of iron in sweat and
in shed cutaneous and mucosal epithelial cells is only
about 1 mg, a single unit of erythrocytes corresponds to
about 200 daily rations of iron. Because excess iron can-
not be eliminated from the body, it necessarily follows
Klinik für Hämatologie, Onkologie und klinische Immunologie, Heinrich-Heine- that chronic transfusion therapy brings the body's iron
Universität Düsseldorf: Prof. Dr. med. Gattermann balance very far out of equilibrium.

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BOX 1 can no longer be disposed of by the cell's antioxidative

mechanisms, and the formation of radicals ensues.
> Primary (hereditary) hemochromatosis is due to an inherited defect of iron
metabolism. Diseases causing secondary hemochromatosis
The spectrum of iron-loading anemias encompasses
> Secondary hemochromatosis is almost always due to a hereditary or acquired
both hereditary and acquired disorders of erythro-
disorder of erythropoiesis and/or the treatment of such a disorder with blood
poiesis. The congenital diseases in this category include
transfusions.
the various types of thalassemia as well as sickle-cell
anemia, pyruvate kinase deficiency, the various types of
congenital dyserythropoietic anemia (CDA), hereditary
spherocytosis, and X-linked sideroblastic anemia
Clinical consequences (XLSA) (Box 3). Iron overloading is especially severe in
The clinical and pathological findings of iron overload homozygous ß-thalassemia.
in secondary hemochromatosis are similar to those seen Among the acquired causes, idiopathic sideroblastic
in hereditary hemochromatosis. Hepatomegaly and anemia is found in the WHO classification among the
splenomegaly may be present, the latter due to increased myelodysplastic syndromes and is designated there as
sequestration of erythrocytes in the spleen. Hepatic RARS (refractory anemia with ring sideroblasts). Idio-
function is usually still normal, or only mildly impaired, pathic myelofibrosis (osteomyelofibrosis) is another
at the time of diagnosis. Patients with thalassemia often potential cause of secondary hemochromatosis, as is
develop finely nodular hepatic cirrhosis three or four treatment-resistant aplastic anemia. In the last-named
decades into the course of their illness. Further conse- condition, there is no secondary increase of intestinal
quences of iron overload include decreased glucose iron uptake; chronic transfusion therapy is the sole cause
tolerance or overt diabetes mellitus, as well as cardiac of iron overload.
arrhythmias and heart failure (1). Patients with MDS
may have such a short life expectancy because of their Myelodysplastic syndromes (MDS)
bone marrow disease that certain consequences of iron The indication for iron chelation in MDS should be
overload, such as hepatic cirrhosis, do not have time to determined only after careful consideration (2). Patients
become severe. with "advanced MDS," i.e., those with a high percentage
of blasts in the bone marrow or blood, generally do not
The pathophysiology of iron toxicity live long enough to develop severe complications of
The dictum "Only the dose keeps any substance from iron overload. Thus, the use of iron chelators generally
being a poison" (Paracelsus) is true of iron as well. Its cannot help these patients.
toxicity in high doses comes from its ability to react with In low-risk MDS, on the other hand, the situation is
molecular oxygen, transferring electrons to it to create different. Here, ineffective erythropoiesis dominates the
intermediate oxygen species, which, in turn, in the pres- clinical picture. Patients with refractory anemia (RA),
ence of iron, cause yet other highly reactive radicals to refractory anemia with ring sideroblasts (RARS), or the
come into being. These can then attack lipids, proteins, 5q syndrome are often treated with erythrocyte transfu-
and DNA, inducing cellular damage that ultimately sions for years. According to Schafer et al. (3), regular
becomes clinically manifest as organ dysfunction. transfusion therapy in adult patients can lead to glucose
Iron is not dangerous if it is held in the storage mole- intolerance, focal portal hepatic fibrosis, and heart
cule ferritin or bound to the transport protein transferrin. damage after less than four years of treatment. Iron
Once the storage and transport capacities of these mole- chelation should be begun when the serum ferritin level
cules are exceeded, however, non-transferrin-bound exceeds 1000 ng/mL (2). Interestingly, the successful
iron (NTBI) begins to appear in the blood plasma. The reduction of an iron overload can also improve bone
redox-reactive part of NTBI, known as labile plasma marrow function, not just in MDS, but also in myelo-
iron (LPI), is rapidly taken up into cells by endocytosis. fibrosis (4, 5).
When the intracellular pool of LPI becomes too large, it A benefit for iron chelation in MDS was long assumed,
in analogy to its known benefit in thalassemia major.
Study results are now available that document both the
BOX 2 diminished life expectancy of MDS patients due to iron
overloading (6) and improved survival after chelation
Calculation of iron balance in transfusion therapy therapy, particularly in low-risk MDS ([7] and Rose C et
(example) al.: Positive impact of iron chelation therapy on survival
in regularly transfused MDS patients. A prospective
> Donated blood contains about 0.5 mg iron per mL erythrocyte concentrate. analysis by the GFM. Blood 2007; 110 [11]: 80a.)
> A 400 mL unit of donated erythrocytes contains about 200 mg of iron.
> Transfusion of 100 units therefore involves loading with 20 g of iron. The diagnosis of iron overload
The laboratory test with the most favorable cost-benefit
> Total body iron is normally 3 to 4 g. ratio is measurement of the serum ferritin level; this can,
however, be elevated not just because of iron overload,

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but also in the setting of inflammation. A suspected BOX 3

diagnosis of secondary hemochromatosis should, there-
fore, be confirmed with imaging studies. This is particu- The most common causes of
larly true because even a liver biopsy is not reliable as a secondary hemochromatosis
gold standard for the diagnosis, as hepatic iron accumu-
lation is markedly inhomogeneous. Furthermore, the
biopsy procedure can be complicated by hemorrhage. A. Hereditary diseases
After extensive development, magnetic resonance > Thalassemia
imaging (MRI) with so-called T2* weighting can now
> Sickle-cell anemia
reliably and non-invasively quantify iron in the liver and
heart. There is no linear correlation between hepatic and > Pyruvate kinase deficiency
cardiac iron overload; severe iron overload of the myo- > Congenital dyserythropoietic anemia (CDA)
cardium arises only after the iron storage capacity of the > Diamond-Blackfan anemia
liver has been exceeded (8, 9). The diagnosis of iron
> Hereditary spherocytosis
overload with MRI requires special expertise and is, un-
fortunately, not yet reimbursable in Germany. > X-linked sideroblastic anemia (ALAS2 deficiency)

Treatment with chelators B. Acquired diseases

The most effective method of removing iron from the
> Acquired idiopathic sideroblastic anemia (AISA)
body is phlebotomy. Patients with secondary hemo-
chromatosis, however, suffer from an inherited or ac- > Other myelodysplastic syndromes (MDS)
quired anemia, and therefore generally cannot be treated > Myelofibrosis
in this way. Chelators offer a different means of achieving > Intractable aplastic anemia
a negative iron balance and tolerable iron concentrations
in body tissues, and they can also neutralize deleterious
NTBI (non-transferrin-bound iron). It is important to C. Excessive oral or parenteral iron loading (very rare)
bear in mind that only a small percentage of the iron in
the body is accessible to the chelator molecules because
the majority of iron ions are tightly liganded to suitable
storage or transport molecules; it follows that the chelator
should be present continuously, or as nearly so as possible. early. Allergic reactions to deferoxamine (independent
The intermittent administration of high doses is not effi- of the dose) are rare, but can range in severity all the way
cient. to anaphylaxis (12).
Three iron chelators are now available for clinical Poor compliance is a major problem besetting treat-
use: deferoxamine, deferiprone, and deferasirox. The ment with DFO, mainly because of the inconvenient
properties and side effects of these substances are sum- long-lasting parenteral infusions and their local side
marized in the Table. effects. This, in turn, can affect the patient's prognosis
adversely. Brittenham et al. (13) showed that thalassemia
Deferoxamine (desferrioxamine, DFO) patients who do not undergo a 12-hour Desferal infusion
Deferoxamine has been the standard therapy for about at least 250 times a year have a markedly shorter survival
three decades. The medication must be given parenterally than those who steadily maintained their iron chelation
and has a very short plasma half-life (20 minutes). It is therapy (12% of the former patients survived to the age
usually administered subcutaneously. In thalassemia, of 30, compared with 95% of the latter).
and probably in other types of iron-loading anemia as
well, a neutral iron balance can be achieved despite con- Deferiprone (DFP, L1)
tinuing transfusion therapy by the administration of Deferiprone is resorbed in the gastrointestinal tract. In
deferoxamine in a dose of 40 mg per kg of body weight order to achieve a negative iron balance, it must be
(30 to 50 mg/kg), as an infusion lasting 8 to 10 hours, given in a total dose of 75 mg/kg/day; because of the
five nights per week. Several research groups have shown short half-life of the drug (about 1.5 hours), this amount
that subcutaneous bolus injections given twice daily (as must be given in three divided doses. In a randomized
slowly as possible, over several minutes) can produce a comparison of DFP and DFO involving 144 patients
similar degree of iron excretion in the urine as a 10-hour with thalassemia major who had a serum ferritin level
infusion (10, 11). In cases of extreme iron overload, between 1500 and 3000 ng/mL, no significant difference
deferoxamine can also be given in higher doses of 50 to between the two groups was found after one year of
60 mg/kg/day by continuous intravenous infusion treatment with respect to the decline of the ferritin level,
through a port system. the iron content of the liver as determined by biopsy, or
Most patients develop local irritation at the sites of the iron loading of the liver and heart as determined by
infusion or injection, with redness, induration, and mild MRI (14). Multiple studies now indicate that deferiprone
pain. Further side effects are listed in the Table. The prevents or reduces cardiac iron overload better than
adverse effects are generally reversible if diagnosed deferoxamine (15–17).

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TABLE

Properties of iron chelators that have been approved for medical use (25)

Deferoxamine (DFO) Deferiprone (DFP) Deferasirox (DFX)

Chelator molecule: 1:1 3:1 2:1
iron atom
Usual dose 25–40(–50) mg/kg 75–90 mg/kg (10–)20–30 mg/kg
Administration Subcutaneous, intravenous Oral, b.i.d.–t.i.d. Oral, once daily
(8–12 hrs.), 5 days per week
Plasma half-life 20–30 minutes 3–4 hours 12–16 hours
Elimination Renal and biliary Renal (biliary) Biliary excretion
Side effects Local inflammatory reactions, Gastrointestinal manifestations, Gastrointestinal manifestations,
visual and auditory disturbances, agranulocytosis/neutropenia, skin exanthem, rise in serum
disturbance of bone growth, arthralgia, elevated liver enzymes creatinine level, visual and auditory
allergic reactions, pulmonary, disturbances (rare)
renal, and neurological
manifestations (rare, usually
only at high doses)
Approval Approved in thalassemia and Approved in thalassemia major if Approved for all patients with
other types of anemia requiring the use of DFO is contraindicated thalassemia major over age 6 years,
transfusion (SCA, DBA, or inappropriate also for younger thalassemia major
PK deficiency, MDS, etc.) patients and patients with other
types of anemia if deferoxamine
therapy is contraindicated or
inappropriate

SCA, sickle-cell anemia; DBA, Diamond-Blackfan anemia; PK, pyruvate kinase; MDS, myelodysplastic syndrome

The most important side effect is agranulocytosis, or 30 mg/kg/day resulted in an equivalent reduction of
with granulocyte counts below 500 per microliter; this hepatic iron, and of ferritin values, to that produced by
complication is, however, quite rare (0.5%, or 0.2 cases DFO (21). Deferasirox increased the elimination of iron
per 100 patient-years). Mild neutropenia is more com- in dose-dependent fashion, not only in patients with
mon (8.5%, or 2.8 cases per 100 patient-years) (16). Fre- ß-thalassemia (n = 85), but also to a comparable extent
quent (weekly) checking of the complete blood count is in 184 patients with secondary hemochromatosis due to
mandatory, so that the treatment can be stopped in time various types of anemia, including MDS (n = 47),
in case the granulocyte count drops. Deferiprone has Diamond-Blackfan anemia (n = 30), and other types
been approved in Europe, but not in the USA. (n = 22) (22). In a further trial in the USA, the serum
ferritin level of MDS patients treated by iron chelation
The combination of deferoxamine (DFO) and deferiprone (DFP) with deferasirox for one year declined by about
In the last few years, studies have addressed the question 800 µg/L. Moreover, the labile plasma iron (LPI) nor-
of the possible benefit of a combination of DFO and malized in all patients (List A et al.: ICL670 [Exjade®]
DFP (18). Such a benefit does seem to exist. Patients reduces serum ferritin [SF] and labile plasma iron [LPI]
stand to benefit from combination therapy particularly in patients with myelodysplastic syndromes. Blood
when cardiac iron overload has not adequately responded 2007; 110 [11]: 440a) (Figure).
to DFO treatment alone (19). The common side effects of DFX are abdominal
symptoms (usually diarrhea), skin exanthems, and ele-
Deferasirox (DFX, ICL670) vation of the serum creatinine level. Diarrhea can usually
Deferasirox is an iron chelator that can be given orally. be brought under control by reducing the DFX dose and
It was licensed in the USA in late 2004, and in Europe in giving appropriate symptomatic treatment. In case of a
2006. It is licensed for use not only in thalassemia, but skin exanthem, treatment with DFX can be temporarily
also to treat chronic, transfusion-induced iron overload interrupted and then begun again in a slowly rising dose,
in patients with other types of anemia, when deferoxa- possibly accompanied by short-term protection with
mine therapy is contraindicated or inappropriate (20). corticosteroids. In clinical trials, a rise in the serum
DFX needs only to be swallowed in liquid form once a creatinine level was found in 36% of patients; in 33%, it
day; the tablets are dissolved in water or juice before exceeded the upper limit of normal in two consecutive
they are consumed. visits (23). These creatinine elevations, however, did not
In a randomized, Phase III trial involving 591 thalas- progress in 2.5 years of further follow-up. In the American
semia patients who were treated with either DFO or MDS study, the serum creatinine level rose in 25% of
DFX for one year, it was found that DFX in a dose of 20 the cases in which it had initially been normal, to a

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maximum value of 2.2 mg/dL. When the initial value FIGURE Iron excretion as a
was elevated, it rose by more than one-third in 8% of function of the type
cases (List et al., 2007). Since deferasirox was approved, of disease and the
dose of the iron
acute renal failure (defined as elevation of the serum
chelator deferasirox.
creatinine level over 3 mg/dL) has been observed in a There is an evident
few patients. There have been cases with a fatal outcome, dose-response
but the cause of death was multifactorial in all cases; effect. The efficacy
according to the manufacturer's assessment, death was of deferasirox does
mainly due to complications of the underlying disease, not vary to any
rather than the treatment (Novartis Safety Database, significant degree
2007). In some cases of reversible renal failure, DFX among the various
diseases requiring
could not be ruled out as a contributory cause. It is, there-
chronic transfusion
fore, recommended that patients with renal risk factors therapy (23).
should have their serum creatinine levels checked weekly
in the first month of treatment, and monthly thereafter. A
rise of more than one-third in the serum creatinine level
should be followed by a reduction of the dose by (initi-
ally) 10 mg/kg/day.
Pancytopenia has been observed as well, but only in
patients whose bone marrow disease provided a possible
explanation for it. Agranulocytosis was apparently not
induced by DFX.
As with any new medication, physicians sometimes
become aware of rare, but severe side effects only after
the medication has been in use for years or decades. Conflict of interest statement
Professor Gattermann has received lecture honoraria, reimbursement of travel
After 37 000 patients had been treated with deferasirox expenses, and study support from Novartis Pharma GmbH.
around the world up to October 2007, the information
for physicians was supplemented in July 2008 with the Manuscript received on 17 September 2007; revised version accepted on
2 December 2008.
mention of rare cases of liver dysfunction and liver
failure (occasionally fatal), rare cases of renal tubulopathy, Translated from the original German by Ethan Taub, M.D.
and rare cases of esophagitis, ulceration, and hemorrhage
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can usually be prevented with a deferasirox dose of 20 to increased iron resorption in the small intestine.
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www.aerzteblatt-international.de/article09m499

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REVIEW ARTICLE

The Treatment of Secondary Hemochromatosis

Norbert Gattermann

Increased iron resorption due to ineffective erythropoiesis

The iron loading anemias are characterized by ineffective erythropoiesis, i.e., a high percentage of the erythropoietic
precursor cells in the bone marrow do not survive. In patients with thalassemia who are homozygotic for the disease,
ineffective erythropoiesis is mainly due to the precipitation of excessive (alpha or beta) globin chains, leading to
oxidative stress. In the myelodysplastic syndromes, on the other hand, the cause of increased apoptosis remains un-
clear. Ineffective erythropoiesis leads to compensatory erythroid hyperplasia, as well as to chronically increased
iron uptake in the duodenum. The mechanism of this increase in iron uptake was sought for years without success.
Recent studies have shown that hepcidin and growth differentiation factor 15 (GDF15) play important roles in this
process.
Hepcidin, the central regulator of iron metabolism, is synthesized in the liver. This peptide normally inhibits iron
uptake in the duodenum as well as iron release from macrophages. GDF15 belongs to the family of the transforming
growth factor ß cytokines; it is secreted by erythroblasts and suppresses the hepatic production of hepcidin. In
thalassemia, the serum GDF15 level
is extremely high, and suppression
eFIGURE of hepatic hepcidin production is
considered to be the cause of the in-
creased intestinal iron uptake (1).
Initial studies suggest that the same
is true in MDS (2). Thus, the in-
creased intestinal iron resorption
accompanying increased, ineffective
erythropoiesis is probably due to the
lack of suppression by hepcidin
(eFigure).

REFERENCES
1. Tanno T, Bhanu NV, Oneal PA, Goh SH, Sta-
ker P, Lee YT et al.: High levels of GDF15 in
thalassemia suppress expression of the iron
regulatory protein hepcidin. Nat Med 2007;
13: 1096–101.
2. Winder A, Lefkowitz R, Ghoti H, Leiba M,
Ganz T, Nemeth E et al.: Urinary hepcidin
excretion in patients with myelodysplastic
syndrome and myelofibrosis. Br J Haematol
2008; 142: 669–71.

The normal circuit of iron metabolism, including intake and physiological losses.
Also: the influence of ineffective erythropoiesis on duodenal iron resorption

⏐ Dtsch Arztebl Int 2009; 106(30)⏐

Deutsches Ärzteblatt International⏐ ⏐ Gattermann: supplement I