27471 RW Iron Balance

7/27/2019 27471 RW Iron Balance

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review

Journal of Appplied Hematology 20124

Iron is an indispensable element for sustaining life

in almost all living organisms. The human body

tightly regulates iron homeostasis. Certain disor-

ders, such as thalassemia or anemia, can shift the bal-

ance of iron, leading to either iron overload or iron

deciency. Iron imbalance can further lead to damage

promoting oxidative stress, inammation, and infec-

tion. Therefore, iron hemostasis is essential, i.e., either

too much iron or too little iron is harmful.

Thalassemia is a group of inherited disorders result-

ing from mutations of hemoglobin genes, affecting themakeup of hemoglobin in red blood cells. The genesresponsible for hemoglobin synthesis are located on

chromosomes 16 and 11, encoding-like globins and

-like globins, respectively (1). The genetic disorder

is characterized by the absolute or partial synthesis of

one or more -or -globin chains (2). The 3 types of

-thalassemia are called major, intermedia, and minor.

Iron Balance in -thalassemia: Maintaining

an Antioxidant / Oxidant Ratio

Heena V. Patel1, Mohamad Qari2, Shaker A. Mousa1 *

1The Pharmaceutical Research Institute atAlbany College of Pharmacy and Health Sciences,Rensselear, NY, USA, 2King Abdel Aziz University,Faculty of Medicine, Hematology Department,

Jeddah, KSA*Corresponding authorShaker A. Mousa, PhD, MBA, FACC, FACBProfessor of Pharmacology, Vice ProvostExecutive Vice President and ChairmanPharmaceutical Research Institute at Albany Collegeof Pharmacy and Health Sciences1 Discovery Drive (Room 238)Rensselaer, NY 12144, USA

518-694-7397 (phone), 518-694-7567 (fax)[email protected]

-Thalassemia is a genetic disorder affecting approximately 1.5% of men and

women worldwide. Many affected individuals die by the age of 30 years as a

result of cardiac complications caused by iron overload. Iron overload can lead

to increased oxidative stress and iron deposition in vital organs such as the

heart, liver, and endocrine glands. In contrast, excessive removal of iron can lead

to infection and other complications. Hence, iron hemostasis is essential for

the balance of the redox system. An extensive literature search was conducted

using PubMed for studies on iron chelation therapy and antioxidant use in -

thalassemia. The search parameters included the period from 1997 to the pres-ent along with specific key words. The key words searched included antioxi-

dants, iron chelation, and complications in beta thalassemia. Iron overload

in patients with -thalassemia should be managed by a combination therapy that

includes iron chelation and antioxidants, to better manage thalassemia compli-

cations and optimize the benefit/risk ratio of iron chelation therapy. Adjunct

therapy with antioxidants such as zinc, vitamin D, CoQ10, and vitamin E should

be considered. -Thalassemia patients are at risk of increased oxidative stress.

Antioxidants in conjunction with chelation therapy would play a key role in re-

storing the antioxidant / oxidant balance while maintaining iron hemostasis.

KEYWORDS: iron balance, reactive oxygen species, oxidants, free radicals,

antioxidants, iron chelation, Vitamin D, minerals, complications in beta thalas-

semia, thalassemia major

-Thalassemia major, also known as thalassemia ma-

jor or Cooleys anemia, is caused by a defect in 2 genes

(TT) that leads to a severe decrease in -globin syn-

thesis. -Thalassemia intermedia is caused by a defect in

2 genes that leads to a mild to moderate decrease in

-globin synthesis. -Thalassemia minor, or thalassemia

trait, occurs when the defect is present in only 1 gene

(/T).

-Thalassemia carriers comprise 1.5% of the world-

wide population, with an estimated 60,000 infants with

a serious defect being born every year (1). In the UnitedStates, approximately 1,000 individuals have -thalas-semia major, the most severe form of thalassemia (3).

It is most commonly found in people of Mediterranean

descent, such as Italians and Greeks, but also affects

people from other parts of world such as Africa, the

Middle East, the Indian subcontinent, and Southeast

Asia (4).


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review Iron Balance In -thalassemIa

Journal of Applied Hematology 20125

Blood transfusions are often required to treat pa-

tients with thalassemia. Transfusion-dependent patients

receive 2 to 4 units per month (714 mL kg-1 month-1)

of packed red blood cells (5). Patients with -thalas-

semia major require transfusions throughout life toachieve the target hemoglobin level in the range from 9

to 10 g/dL, and to promote normal growth (6-7). Iron

overload can develop in transfusion-dependent patients

as a result of non-removal of physiological excess iron.

This super-physiological iron concentration can causecomplications due to iron deposition in organs such as

the heart, liver, and endocrine glands.

In this review, we examine the importance of iron

balance and how its maintenance is associated with

avoiding deleterious effects to the body. We also discuss

therapy options for treating iron overload, with a focus

on combination therapy with iron chelators and antioxi-

dants (Figure 1).

DIAGNOSTIC ASSESSMENT OF IRON ANDOXIDATIVE DAMAGE

In transfusional iron overload, almost all the excess

iron is sequestered intracellularly as ferritin iron, a sol-uble and rapidly mobilizable fraction dispersed within

the cytoplasm, and hemosiderin iron, an insoluble ag-

gregate within lysosomes that serves as a long-term

reserve. Because intracellular ferritin iron is evidently

in equilibrium with the low-molecular-weight cytosolic

iron pool, measurements of ferritin iron potentially

provide a clinically useful indicator of changes in cyto-

solic iron (8).Serum ferritin is the most commonly used param-

eter for monitoring iron overload. It correlates with

cardiac impairment and survival, but can be elevated

by many confounding factors, including acute-phase

reactions, such as infections, inammation, or malig-

nancy, or by hepatic damage. It has a poor correla-tion with hepatic iron. Nevertheless, the close relation

between serum ferritin and survival and the relative

ease of serum ferritin measurement makes it the most

practical parameter for sequential monitoring of iron

levels (9). Liver biopsy was previously considered to be

the gold standard for liver iron assessment; however, it

is an invasive procedure associated with complication

risks and is subject to sampling error (10). While the

measurements of liver and cardiac iron by magnetic

resonance imaging (MRI) are important developments

in facilitating the tailoring of iron chelation therapy, it

is important to note that discrepancies exist between

liver and cardiac iron load, likely due to differences inthe kinetics of iron loading and clearance between the

liver and the heart. The most widely adopted method

is based on the measurement of tissue proton trans-

verse relaxation rates (R2), showing excellent correla-

tion with liver iron concentration measured by biopsy

and T2* to quantify the heart iron content (9).

Oxidative damage was measured in thalassemia pa-tients in several studies; micronucleus assay showed a

higher frequency of micronuclei formation indicating

a higher frequency of chromosomal breaks in per-

sons with thalassemia compared with healthy controls

(11). Flow cytometric methods were used to measurethe generation of reactive oxygen species (ROS), the

reduced glutathione content, and the peroxidation of

membrane lipids as an indication of membrane dam-

age (12). Another study showed that the mean con-

centrations of conjugated diene lipid hydroperoxides,

lipoperoxides evaluated as malondialdehyde/thiobarbi-

turic acid (MDA/TBA) adducts, and protein carbonyls

increased about 2-fold with respect to control, and bothpositively correlated with ferritin level. Evidence is pre-

sented of a net drop in the concentration of ascorbate

(-44%), vitamin E (-42%), vitamin A (-44%), -caro-

tene (-29%), and lycopene (-67%). As a result, the total

serum antioxidant potential, measured as the Troloxequivalent antioxidant capacity, appeared signicantly

decreased by 14% (13).

IRON REGULATIONIron regulation in the body is tightly controlled.

Iron is recycled and conserved from old red blood cells

by the reticulo-endothelial system, and is then reused.

The monocyte/macrophage system is responsible forthe adequate iron supply for erythropoiesis and main-

tenance of iron homeostasis (14). Approximately 10%

of iron is absorbed from the duodenum, through di-

etary supply, and the remainder of the supply comes

from recycled erythrocytes. Macrophages degrade red

blood cells at the end of their life cycle, releasing ironback into the plasma (15). Iron absorption requires the

use of transporters such as divalent metal transporter

1 (DMT1) for absorption. Dietary non-heme must be

reduced from the ferric form (Fe3+) to the ferrous

form (Fe2+) for transportation from the gastrointes-

tinal tract. Regulation of iron loss is minimal, unlike

iron absorption. Iron excretion occurs through blood

loss, perspiration, and the shedding of epithelial cells.

Collectively, approximately 1 to 2 mg of iron is lost per

day.


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IRON TOXICITY IN TRANSFUSION-

DEPENDENT -THALASSEMIA PATIENTSPatients with -thalassemia can become iron over-

loaded owing to the excess iron available from blood

transfusions, hemolysis, and dietary uptake. Iron cancatalyze the Fenton/Haber-Weiss reaction to generate

highly reactive hydroxyl radicals that can oxidize lipids,

DNA, and protein (Figure 2). Iron overload leads to

transferrin saturation, increasing the circulating free

iron concentration, termed non-transferrin-bound iron(NTBI). Repeated blood transfusions can lead to accu-

mulation of NTBI (16-17). In patients with -thalas-

semia, increased iron burden in tissues can potentially

damage vital organs such as the heart, liver, and endo-

crine glands (16).

potentially reducing ROS production and radical-me-

diated damage. The 3 main iron chelators available in

the US market include deferoxamine (DFO) (Desferal;

Novartis), deferasirox (DFX) (Exjade; Novartis), and

deferiprone (DFP) (Ferriprox; Apotex). Evidenceshows that iron chelation therapy is highly effective in

decreasing iron burden in patients.

Chelation Monotherapy: DFO forms feroxamine

complexes by binding to a single atom of iron, to

eliminate chelated iron primarily through renal excre-tion (18). A study showed that DFO, when given as a

continuous intravenous infusion, can improve ventricu-

lar dysfunction and reverse serious cardiac arrhythmias

(19). A major limitation of DFO is the route of admin-

istration. DFO is given daily either subcutaneously or as

an intravenous infusion. In contrast to DFO, DFX and

DFP are oral iron chelators, administered once daily

and 3 times a day, respectively.DFX is an iron-chelating agent that selectively binds

to plasma iron, facilitating hepatobiliary excretion (20).

DFX is an alternative option to DFO in patients un-

able to tolerate DFO or who have poor compliance

with DFO therapy. Cappellini et al. conducted a studycomparing DFX with DFO. Non-inferiority was estab-

lished in patients receiving a dose of 20 or 30 mg/kg of

DFX compared with 35 mg/kg of DFO. The study

found that administration of 20 or 30 mg kg-1 day-1 of

DFX signicantly reduced liver iron concentrations in

patients after 1 year (p < 0.001). DFX administered at

30 mg kg-1 day-1 also resulted in reduced serum ferritin

values; however, the differences were not statisticallysignicant (5). Patient satisfaction is higher with DFX

than with DFO (21). Nisbet-Brown et al. found that

a higher dose of DFX (40 mg kg-1 day-1) caused pa-

tients to experience unwanted side effects such as skin

rashes (22). DFX therapy was found to provide more

improved quality of life and have better treatment ad-herence (23).

DFP is the newest of the 3 chelators, receiving Food

and Drug Administration (FDA) approval in October

2011. DFP is an agent that binds to ferric ion, creating

complexes that are predominately excreted in the urine

(18). In the rst randomized clinical trial comparing

DFP and DFO, a similar reduction of mean serum fer-

ritin was found for the 2 chelators (222 783 ng/ml for

DFP and 232 619 ng/ml for DFO; p = 0.8) (24). The

study found no statistical difference in the reduction of

liver and heart iron content between the DFP and DFO

groups (24). Sequential administration of DFO and

DFP has an additive effect, improving myocardial func-tion (25-27). The additive effects of DFO and DFP

were also found to reduce liver iron concentration (26)

Figure 2: Iron toxicity and ROS generation.

Figure1: Iron hemostasis in minimizing oxidative damage through balancing theantioxidant / oxidant ratio.

Oxidants (ROS)

O2H2O2OH

CoQ10/ Vitamin E, CVitamin DZinc

Ironoverload

Iron chelators

An1oxidants/Vitamins/Minerals

OrgandamageInfec1on

Fe (II)(ferrous)

Fe (III)(ferric)

Fenton/Haber-Weiss reaction

OH-radical

ROS(reactive oxygen species)

Oxidative damageLipidsProteinsDNA

Ironoverload(bloodtransfusions+

gastrointes4nalironabsorp4on)

MANAGEMENT OF IRON TOXICITY

Chelation TherapyAlong with blood transfusions, the current manage-

ment of thalassemia also includes regular administra-

tions of iron chelators. Physiological iron excretion is

minimal; therefore, transfusion-dependent patients

require regular chelation therapy starting as early as 5

years of age. Chelation therapy aims to remove excess

iron, decreasing the amount of liable iron available and


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and increase urinary iron excretion (25). Combination

or sequential therapy with DFP and DFO, compared

with monotherapy, improved ejection fraction in trans-

fusion-dependent patients with -thalassemia (28). The

additive effects of DFO and DFP are a result of theiron shuttle hypothesis, in which simultaneous adminis-

tration of DFO and DFP results in transfer of chelated

iron from DFP to DFO (29). As a result, the combi-

nation therapy increases the iron clearance better than

monotherapy with DFP or DFO.

Combination Therapy: Iron Chelators plusAntioxidants.

Under certain circumstances, monotherapy with

iron chelators such as DFP (referred to as L1 in one

study) can promote generation of hydroxyl radicals (30-

31). Simultaneous administration of chelators and an-

tioxidants along with mineral supplementation can bean effective combination therapy option for thalassemia

patients. Antioxidant therapy can potentially inhibit 2

major processes that provoke ROS-mediated damage

during iron chelation therapy due to the formation of

free radicals by the ferrous ion-chelator complexes andthe peroxidation of lipid membranes (31). Patients with

-thalassemia are also known to have signicantly lower

antioxidants levels (17,32), and therefore co-administra-

tion can be a benecial approach. The administration of

antioxidants with iron chelators can potentially improve

the antioxidant/oxidant balance.

Deciency in vitamins such as folic acid (7) and vi-

tamin D (6,33) has been reported in -thalassemia pa-tients. Wood et al. found 25-OH vitamin D levels to

be below the lower limit of 50 nmol/L in 13 out of 24

-thalassemia patients (mean age of 14.7 7.6 years)

(6). The study also found that 25-OH vitamin D levels

decreased with age and negatively correlated with liver

iron (p < 0.04). This is the rst study to suggest a rela-tion between cardiac iron uptake and vitamin 25-OH

vitamin D level, and a positive correlation between 25-

OH vitamin D levels and left ventricular ejection frac-

tion (p = 0.002) (6).

Vitamins play an essential role in biochemical reac-

tions; for example, folic acid is a coenzyme involved

in the production of purines and pyrimidines (34).

Mojtahedzadeh et al. examined the possible benets of

folic acid supplementation in -thalassemia patients and

found 29% of the patients to have a severely low serum

folic acid level, 0.8 0.6 ng/mL. The study concluded

that supplementation of daily, oral 1,000 mg folic acid

is recommended in thalassemia major patients (34), tocorrect the deciency and as a prophylaxis. Vitamin E

can potentially protect against free radical generation by

reducing ROS generation and ultimately preventing or-

gan damage (35). Patients with thalassemia intermedia

were given 400 IU of vitamin E orally for 3 months

in one study, and a signicant reduction in thiobarbitu-

ric acid-reactive substances was observed (p = 0.016),potentially providing defense against lipid peroxidation

(35).

-Thalassemia patients are reported to have low

serum zinc levels, which can result from hemolysis,

renal clearance, and poor nutrition (36). A decreasedzinc concentration is associated with poor growth.

Zinc supplementation may be benecial as adjuvant

therapy along with iron chelation therapy to promote

growth. Arcasoy et al. found that supplementation of

22.5 to 90 mg of elemental zinc resulted in an increase

in height growth velocity in -thalassemia patients (p

< 0.01) (37). Fikry et al. found a positive association

between serum zinc level and height/age (36). In con-trast, Mehdizadeh et al. concluded that zinc deciency

is rare in -thalassemia patients and supplementation

is not needed (38). However, it has been shown that

the use of certain iron chelators can increase the risk

of the development of zinc deciency (39), and there-fore adjunct therapy with zinc supplementation can be

considered. DFX and DFP signicantly increases renal

zinc clearance (39); therefore, supplementing patients

with zinc can be benecial when zinc serum levels are

suboptimal.

Coenzyme Q10 (CoQ10 or ubiquinone) levels are

also markedly decreased in thalassemia major patients.

CoQ10, when present in excessive amounts in plasma,provides antioxidant protection in the body and func-

tions as an effective scavenger of free radicals (32). In

one study, administration of 100 mg CoQ10 daily, oral-

ly, for 6 months resulted in decreased oxidative stress

in -thalassemia patients as a result of the signicantly

lower MDA levels (p < 0.05) (32).

COMPLICATIONS IN THALASSEMIAA range of complications, including endocrinopa-

thies, hypersplenism, infertility, and hepatobiliary, mus-

culoskeletal, and cardiopulmonary disorders, can arise

in patients with -thalassemia. These complications are

linked to overstimulation of the bone marrow, dysfunc-

tional erythropoiesis, increase in iron burden, imbalance

of the antioxidant / oxidant ratio, and chelation of es-

sential elements (7,40). Treatment by red cell transfu-

sion can minimize some complications by promoting

normal growth and development, and suppressing

ineffective erythropoiesis. However, iron overload is amajor concern in these patients. Frequent and lifelong

red cell transfusions in conjunction with gastrointestinal


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iron absorption can drastically increase the iron concen-

trations in the body over time. Higher concentrations

of iron can damage organs such as the heart, liver, and

endocrine glands as a result of iron deposition, affect-

ing normal function and leading to organ failure.

EndocrinopathiesEndocrinopathies such as poor growth, delayed pu-

berty, impaired glucose tolerance, and osteoporosis are

some complications that can occur in thalassemia pa-tients. Hypogonadism is the most common complica-

tion, which occurs because of gonadotrophins decien-

cy, mainly due to a high iron burden (40-42). Endocrine

complications arise possibly owing to factors that inu-

ence the anterior pituitary gland and to zinc deciency.

The anterior pituitary gland is known to be sensitive to

free radical oxidative stress, which affects the normal

functions of the pituitary and hypothalamic glands, re-sulting in growth hormone deciency (43). The number

of endocrinopathies has been related to the duration of

transfusion (40).

Hypogonadism can lead to growth failure and in-

fertility. Early and appropriate management is crucialin -thalassemia patients. Hormone therapy is an ef-

fective option in the management of hypogonadism, to

stimulate normal growth and puberty. In a study that

included 35 patients, 60% had not reached puberty and

had low sex hormone levels by age 13 to 16 years (44).

Providing hormone therapy to young -thalassemia

patients with a low iron burden can induce increases

in height, and stimulate puberty Chatterjee et al. foundthat giving young-thalassemia patients (as early as age

14 years) low-dose sex steroid priming with either tes-

tosterone (2550 mg/month intramuscularly in males)

or ethinyl estradiol (100 ng kg-1 day-1 orally in females)

can promote puberty. Eighty percent of patients with

failed puberty experienced an increase in height growthspurt and improvement in sexual maturation (45).

Initiating aggressive and appropriate chelation therapy

is important along with hormone therapy to minimize

iron deposition in the endocrine glands. Zinc deciency

plays a role in the development of hypogonadism in pa-

tients with -thalassemia (40,45). Along with hormone

therapy, zinc supplementation is recommended in pa-

tients who have growth impairment and low serum zinc

levels (40).

HypersplenismThe spleen plays a vital role in maintaining im-

mune function and recycling mature erythrocytes.Hypersplenism is a complication observed in patients

who have either -thalassemia or thalassemia inter-

media. Hypersplenism is associated with leukopenia,

thrombocytopenia, and increased requirement for

transfusions. Splenomegaly, or an enlarged spleen, de-

velops in these patients, often requiring a splenectomy.

Splenectomy is often conducted to reduce the needfor red cell transfusion. However, total removal of the

spleen can lead to platelet-active activation (46), promo-

tion of thrombin generation, and an increase in the rate

of hemolysis (47). Partial ablation with a radiofrequency

technique is another option that has been effective inpatients with thalassemia intermedia (48). The partial

removal of the spleen can potentially preserve splenic

function to avoid complications associated with sple-

nectomy.

InfertilityIn women with -thalassemia, infertility is a com-

mon issue due to iron deposition in endocrine organs asa result of blood transfusions. However, with advances

in the management of thalassemia, chances of conceiv-

ing have increased and pregnancy has become more

prevalent. Pregnancy, however, is not recommended in

women who have cardiac dysfunction or who have notbeen on long-term red cell transfusion therapy (49). For

women who are at high risk of iron overload and who

intend to conceive, an echocardiogram is recommend-

ed before conception and during pregnancy to evaluate

cardiac function (50).

Management of pregnant women with thalassemia

major includes blood transfusions and maintaining a

hemoglobin level of at least 10 g/dL (49). Accordingto the American Congress of Obstetricians and

Gynecologists guidelines, iron chelation therapy with

DFO is not recommended during pregnancy because

its safety has not been well established (49,51). For pa-

tients who are at high risk of increased iron deposition

in the heart and liver, chelation therapy should be usedwith caution with DFO closer to the second trimester

(51). After pregnancy, patients can resume iron chela-

tion therapy.

Hepatobiliary disordersThe liver is a primary site for iron accumulation

in transfusion-dependent patients. Within 2 years of

transfusion initiation, hepatocellular injury can occur

when the liver iron concentrations exceed normal levels,

leading to tissue damage, collagen formation, and por-

tal brosis (52). In the presence of infections such as

hepatitis C virus infection, the risk of the development

of liver brogenesis is further increased. Liver iron con-centrations greater than 7 mg Fe/g dw are linked to in-

creased morbidity and mortality (52). Therefore, reduc-


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ing iron burden can improve survival in -thalassemia

patients. One way to detect and evaluate liver brosis is

through the use of transient elastography.

Aggressive and consistent therapy with iron chela-

tors can decrease iron burden in the liver and reduceliver brosis. In a study with -thalassemia patients re-

ceiving DFX, patients experienced regression of liver

brosis, as measured by a reduction in their Ishak scale

and improvement in necroinammation determined by

the Ishak necroinammatory grading system (52). Bythe end of the study, when compared to baseline, 68%

of the patients (n = 149) experienced an improvement

in their Ishak stage of -2, -1, or 0, and a statistically

signicant improvement was found in the Ishak necro-

inammatory scores in all patients (p


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a tool for the measurement of oxidative damage, and a

therapy for these patients that includes iron chelation

along with antioxidants is warranted to help manage

the complications of iron overload. A nal observa-

tion can be made from the evidence provided in this re-view: The future management of-thalassemia patients

can include antioxidants to counteract oxidative stress.

Therapy for -thalassemia patients should be designed

to include antioxidant supplementation in addition to

iron chelation and transfusion. Patients should be as-

sessed to determine the presence of an antioxidant/

oxidant imbalance, and the therapy should be tailored

to specic antioxidant imbalances. Very few trials have

looked at combination therapies with iron chelators andantioxidants for -thalassemia patients. Therefore, in

this review, we suggest that larger and longer-duration

randomized clinical trials are needed to determine the

signicant effects of combination therapies.

Table 1: Comparative analysis between different iron chelators used in transfusion iron overload.

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

Brand name Desferal Ferriprox Exjade

Chelator-iron

complexHexadentate, 1:1 complex Bidentate, 3:1 complex Tridentate, 2:1 complex

Dose 2550 mg kg-1 day-1 75100 mg kg-1 day-1 2040 mg kg-1 day-1

Combination andtitration doses

(mg kg-1 day-1)

Combination therapy with DFO and DFP (26,27,58):

40-50 for (at least) 2 days/wk DFO and 75 DFP daily

Titration therapy (59):


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27471 RW Iron Balance