Book on hepatitis from page 412 to 425

Book on hepatitis from page 412 to 425

412  Hepatology 2012
Figure 4. Survival of 251 patients with genetic hemochromatosis (with and without
cirrhosis) in comparison with matched general population. Modified from Niederau 1996.
Table 3. Methods for early diagnosis of hemochromatosis.
It is also unknown at which ferritin values phlebotomy treatment should be
initiated in asymptomatic C282Y homozygotes (Table 4). The values recommended
by the AASLD (American Association for the Study of Liver Diseases) are based
more on the judgment of experts than on solid data. The only solid data shows that
the risk for liver fibrosis and cirrhosis increases above the threshold of 1000 ng/ml
Metabolic Liver Diseases: Hemochromatosis  413
for serum ferritin (Loreal 1996). The value of screening family members is obvious
when a first-degree relative has clinical hemochromatosis. Such family screening is
easy to do with the genetic test. Heterozygous family members are not at risk for
hemochromatosis unless they have other risk factors.
The clinical phenotype of hemochromatosis is seen in 1-2% of patients with
newly diagnosed diabetes mellitus and in 3-15% of patients with liver cirrhosis
(Niederau 1999). These latter patients should be screened for iron overload although
such screening obviously does not aim at a very early diagnosis. Nevertheless,
cirrhotic and diabetic patients with hemochromatosis can benefit significantly from
phlebotomy therapy. Little is known about the prevalence of hemochromatosis in
patients with arthropathy or cardiomyopathy of unclear etiology. Several smaller
studies indicate that arthropathy may be a rather early clinical sign of iron overload,
whereas cardiomyopathy usually occurs in severe iron overload.
Figure 5. Cumulative survival in 251 patients with genetic hemochromatosis according
to the time of diagnosis. Modified from Niederau 1996.
414  Hepatology 2012
Table 4. Iron overload therapy.
1. Phlebotomy
a) In symptomatic genetic hemochromatosis
•  Aims: complete iron depletion in 12-24 months;
•  Treatment: 1-2 phlebotomies of 500 ml each week until serum ferritin is in the range
of 20-50 ng/ml;
long-term therapy with 4-8 phlebotomies per year to keep ferritin between 20-50
ng/ml and thus prevent reaccumulation of iron
b) In asymptomatic C828Y homozygotes therapy should be initiated above these
ferritin values:
•  Subjects <18 years   >200 ng/ml
•  Men      >300 ng/ml
•  Women (not pregnant)  >200 ng/ml
•  Women (pregnant)    >500 ng/ml
2. Therapy with iron chelators in secondary hemochromatosis and anemia
•  Aims: removal of iron overload by increase of iron excretion in feces and urine
•  In case of further blood transfusions at high frequency at stabilisation of iron
balance and reduction of further iron accumulation
•  Treatment: until recently, 25-50 mg deferoxamine/kg as SC infusion for 10-12 h
daily; today, deferoxamine is largely replaced by the oral chelator deferasirox - 20
mg/kg deferasirox once daily to prevent iron accumulation up to 800 ml erythrocytes
concentrates/month
•  Long-term treatment necessary
•  Normalisation of ferritin and liver iron concentration is often not possible
3. Diet
•  Recommended: avoidance of food with very high iron content (e.g., liver) and iron-supplemented food;
•  A further strict iron-depleted diet is very difficult to adhere to and not recommended
•  A single phlebotomy of 500 ml blood is as effective for iron removal as a very rigid
iron-restricted diet for a full year
Figure 6. Signs and symptoms in 185 patients with genetic
hemochromatosis prior to and after iron removal. Modified
from Niederau 1996.
Metabolic Liver Diseases: Hemochromatosis  415
Complications of iron overload
Liver cirrhosis, diabetes mellitus, and increased skin pigmentation are the classical
trio of  genetic hemochromatosis. Cardiomyopathy, cardiac arrhythmias, and
impotence are also typical complications of advanced iron overload. Arthropathy in
contrast may be an early sign of hemochromatosis, which may help with diagnosis
in the precirrhotic stage (Niederau 1996).
Liver disease. The liver is the organ that is affected by genetic iron overload most
early and heavily. At early stages excess iron stores are mainly found in periportal
parenchymal cells as ferritin and hemosiderin. When iron excess further increases,
there is development of perilobular fibrosis and iron stores are also found in bile
ducts and Kupffer cells. Septal fibrosis eventually progresses towards complete
cirrhosis. The stage of fibrosis is closely associated with the degree of excess of
iron. In many affected symptomatic patients with type 1 hemochromatosis there are
some signs of liver disease at the time of diagnosis (Niederau 1985, Niederau 1996).
Many nonspecific symptoms such as abdominal discomfort and fatigue may also be
due to liver involvement. In asymptomatic patients diagnosed by a screening
procedure, signs of liver disease are infrequent. Complications due to cirrhosis such
as ascites, jaundice and portal hypertension are seen only rarely and only in cases of
advanced severe iron overload (Niederau 1985, Niederau 1996). The risk for liver
cirrhosis increases at ferritin values >1000 ng/ml (Loreal 1996). Similar to insulin-dependent diabetes, liver cirrhosis cannot be reversed by removal of iron (Niederau
1996). However, less advanced stages like hepatic fibrosis and abnormalities in liver
enzymes and function respond well to iron removal (Niederau 1996) (Figure 5).
Survival is significantly reduced in the presence of liver cirrhosis whereas patients
diagnosed in the precirrhotic stage have a normal life expectancy when treated by
phlebotomy (Niederau 1996) (Figure 3).
Association of hemochromatosis with other liver diseases. Some studies indicate
that C282Y heterozygosity may aggravate the progression of concomitant liver
diseases such as porphyria cutanea tarda, chronic hepatitis C, alcoholic hepatitis and
non-alcoholic steatohepatitis (NASH). In these latter patients one might find slightly
elevated liver iron concentrations and serum ferritin levels when they are C282Y
heterozygotes (for review see Erhardt 2003). Most studies however have shown that
these associations are of only minor importance in the clinical course of the disease.
Phlebotomy as yet has only been proven meaningful in porphyria cutanea tarda
because it can ameliorate the cutaneous manifestations.
Liver carcinoma. Liver carcinoma develops in approximately 30% of patients
with hemochromatosis and cirrhosis independent of iron depletion (Niederau 1996).
The interval between complete iron depletion and reported diagnosis of liver cancer
is approximately 9 years in large cohorts in German patients (Niederau 1985
Niederau 1996). The risk of liver cancer is increased in patients with
hemochromatosis 100-200-fold when compared to the general population (Figure
6). Among liver cancers there are hepatocellular carcinomas (HCC) as well as
cholangiocellular carcinomas. Most liver cancers develop in patients with cirrhosis.
Thus, cancer screening by ultrasound and APF (twice a year) is only recommended
for cirrhotic patients. Patients who develop liver cancer usually have the largest
amount of mobilisable iron among various subgroups (Niederau 1996, Niederau
1999).
416  Hepatology 2012
Figure 7. Relative mortality risk of 251 patients with genetic
hemochromatosis in comparison to the general population.
Modified from Niederau 1996.
Diabetes mellitus.  In studies the prevalence of diabetes in hereditary
hemochromatosis ranges from 20-50% (Niederau 1996, Adams 1991). The
prevalence and stage of diabetes is related to the degree of iron deposition in the
pancreas. Patients with diabetes have a twofold higher mobilisable iron content than
non-diabetics (Yaouanq 1995). Investigations into the prevalence of unrecognized
genetic hemochromatosis in diabetic patients show some variation in Europe vs.
elsewhere; i.e., screening revealed a prevalence of 5-8 per 1000 unrecognized cases
in Europe (Singh 1992) and 9.6 per 1000 in Australia (Phelps 1989). Diabetes
mellitus and impaired glucose tolerance are frequent features in several chronic liver
diseases (Creutzfeldt 1970, Blei 1982). This author’s study (Niederau 1984) showed
hyperinsulinemia and hence insulin resistance without impaired glucose tolerance in
noncirrhotic hemochromatosis. The increase in circulating insulin concentrations is
likely to be due to a decrease in diminished hepatic extraction of insulin. With the
progression of iron overload and destruction of beta cells, insulin secretion becomes
impaired (Dymock 1972, Bierens de Haan 1973). In end-stage hemochromatosis,
insulin deficiency is associated with severe reduction in the mass of beta cells
(Rahier 1987). Insulin resistance observed in early iron overload may be partially
reversible after phlebotomy therapy (Niederau 1985, Niederau 1996) whereas
insulin-dependent diabetes is irreversible (Niederau 1996). Survival is significantly
reduced in patients with diabetes mellitus at diagnosis compared to patients without
diabetes (Niederau 1996). Survival of non-diabetic patients is virtually identical to
that of a matched normal population.
Heart disease.  Cardiomyopathy  and cardiac arrhythmias  are specific
complications of hemochromatosis caused by iron deposition in the heart (Buja and
Roberts 1971, Short 1981). Clinical or electrocardiographic signs of heart disease
can be found in 20-35% of patients with HFE hemochromatosis (Niederau 1985).
Arrhythmias usually respond well to iron removal (Short 1981, Niederau 1996). In
type 1 hemochromatosis cardiomyopathy  is rare and usually associated with
advanced iron overload and an older patient population. However, particularly in
young patients who present with cardiac disease due to hemochromatosis,
cardiomyopathy is a frequent cause of death (Finch 1966, Short 1981). Only
Metabolic Liver Diseases: Hemochromatosis  417
recently has it become clear that young patients with severe cardiomyopathy may be
affected by juvenile type 2 hemochromatosis; these patients may show severe iron
overload, hypogonadism, cardiomyopathy, liver cirrhosis, and amennorrhea by ages
15-24. The type 2-associated cardiomyopathy is often irreversible despite initiation
of phlebotomy or chelation therapy and may require an immediate transplant of the
heart and potentially of the liver as well (von Herbay 1996, Jensen 1993).
Arthropathy.  Joint changes in genetic hemochromatosis may occur in two
different ways (Schuhmacher 1964, Dymock 1970, Niederau 1985, Niederau 1996).
The most prevalent changes are seen in the metacarpophalangeal joints II and III, in
the form of cystic and sclerotic changes, cartilage damage and a narrowing of the
intraarticular space. Sometimes other joints of the hands and the feet are affected.
Large joints, i.e., of the knees and hips, may be affected in the form of
chondrocalcinosis. The pathogenesis of joint changes in hemochromatosis remains
unclear. Arthropathy is one of the few complications not associated with the degree
of iron overload. It has been speculated that iron may inhibit pyrophosphatase and
may thereby lead to a crystallisation of calcium pyrophosphates. Alternatively, iron
may have direct toxic effects on the joints. Arthropathy may be an early sign of
hemochromatosis and may help to make the diagnosis at a precirrhotic stage
(Niederau 1996). Hemochromatosis should therefore been considered in all patients
with an arthropathy of unknown etiology.
Endocrine abnormalities. In contrast to the early onset of arthropathic changes,
endocrine abnormalities are a late consequence of iron overload. Sexual impotence
and loss of libido may occur in up to 40% of male patients (Niederau 1985). The
endocrine abnormalities in hemochromatosis are mainly, if not exclusively, due to
pituitary failure. This is in contrast to alcoholic cirrhosis where testicular failure is
predominant (Kley 1985a, Kley 1985b). In contrast to alcoholic cirrhosis, where
estrogen levels are usually increased, estrogen levels were found decreased in
hemochromatosis (Kley 1985a). Most endocrine changes are late and irreversible
complications of genetic hemochromatosis and do not respond well to phlebotomy
treatment (Niederau 1996). Iron overload only infrequently affects other endocrine
organs such as the thyroid and adrenal glands. Severe hypogonadism with
amennorrhea in young women and impotence in young men is today thought to be
due to type 2 hemochromatosis.
Skin. Increased skin pigmentation is mainly seen in areas exposed to sunlight. A
large part of the darkening of pigmentation is thought to be due to an increase in
melanin and not due to iron excess itself. The increase in skin pigmentation is
reversible on iron removal (i.e., phlebotomy).
Other potential complications. Iron overload has been speculated to aggravate
atherosclerosis; however, the evidence for that is rather weak (for review see
Niederau 2000). There have also been reports that extrahepatic malignancies may be
increased in HFE hemochromatosis (Amman 1980, Fracanzani 2001) while other
studies have not found extrahepatic associations (Bain 1984, Niederau 1996,
Elmberg 2003). It is not clear whether HFE gene mutations are involved in the
pathogenesis of porphyria cutanea tarda since the prevalence of both risk factors
vary greatly in different parts of the world; associations between HFE gene
mutations and porphyria have often been described in southern Europe but not in
northern Europe (Toll 2006).
418  Hepatology 2012
Therapy
Phlebotomy treatment. Phlebotomy treatment is the standard of care to remove iron
in genetic hemochromatosis. One phlebotomy session removes approximately 250
mg iron from the body. Since patients with the classical clinical phenotype may
have an excess of 10-30 g iron, it may take 12-24 months to remove the iron
overload when phlebotomies of 500 ml blood are done weekly (Table 4).
Phlebotomy treatment is generally well tolerated and hemoglobin usually does not
drop below 12 g/dl. Several studies have shown that liver iron is completely
removed at such low ferritin values; thus the effect of therapy can be checked by
ferritin measurements and a control liver biopsy is not necessary. After complete
removal of excess iron the intervals of phlebotomies may be increased to once every
2-3 months; serum ferritin should be kept in the lower normal range, between 20-50
ng/ml. Phlebotomy should not be interrupted for longer intervals; there is a risk of
reaccumulation of iron due to the genetic autosomal recessive metabolic
malfunction.
Iron removal by chelators. Deferoxamine therapy for genetic hemochromatosis is
not recommended because phlebotomy is more effective with less side effects and
lower cost. Recently, a Phase II study has started, looking for safety and
effectiveness of the new oral iron chelator deferasirox in genetic hemochromatosis.
As yet, deferasirox is only approved for secondary hemochromatosis.
Diet.  An iron-low diet is not recommended for patients with genetic
hemochromatosis. One phlebotomy of 500 ml blood removes approximately 250 mg
iron. A difficult to follow rigid iron-restricted diet for a complete year would have
the effect of a single phlebotomy. It is thus recommended that patients simply do
not eat excessive amounts of food with very high iron content (such as liver) and
that they do not eat food to which iron has been added (Table 4).
Liver transplantation. Advanced liver cirrhosis and carcinoma may be indications
for a liver transplant in hemochromatosis (Kowdley 1995, Brandhagen 2000). The
prognosis of patients who have a liver transplant for hemochromatosis is markedly
worse than that for patients with other liver diseases; a considerable number of
patients with hemochromatosis die after transplant from infectious complications or
heart failure (Brandhagen 2000). Liver transplantation does not heal the original
genetic defect.
Prognosis
Untreated hemochromatosis often has a bad prognosis in the presence of liver
cirrhosis and diabetes mellitus. The prognosis is markedly worse in patients with
cirrhosis than in those without cirrhosis at diagnosis (Figure 3); the same is true for
diabetes mellitus. It is generally accepted that phlebotomy therapy improves the
prognosis. Patients diagnosed and treated in the early non-cirrhotic stage have a
normal life expectancy (Figure 3) (Niederau 1985, Niederau 1996). Thus, early
diagnosis markedly improves the prognosis (Figure 4). Iron removal by phlebotomy
also improves the outcome in patients with liver cirrhosis. The prognosis of liver
cirrhosis due to hemochromatosis is markedly better than those with other types of
cirrhosis (Powell 1971). Hepatomegaly and elevation of aminotransferases often
regress after iron removal (Niederau 1985, Niederau 1996) (Figure 5). Insulin-dependent diabetes mellitus and hypogondism are irreversible complications despite
complete iron removal (Niederau 1996) (Figure 5). Earlier changes in glucose and
Metabolic Liver Diseases: Hemochromatosis  419
insulin metabolism, however, may be ameliorated after iron removal. For unknown
reasons arthropathy does not respond well to phlebotomy treatment although it may
be an early sign of iron overload (Figure 5). The AASLD consensus guidelines
recommend to start phlebotomy treatment at ferritin values >300 ng/ml in men and
>200 ng/ml in women. The risk for liver fibrosis and cirrhosis is increased only at
ferritin levels >1000 ng/ml. Further studies need to determine whether
asymptomatic C282Y homozygotes with ferritin values between 300 and 1000
ng/ml need to be treated or whether one might wait and monitor ferritin at that
stage.
Juvenile hereditary hemochromatosis
Two genes have been shown to be associated with juvenile hemochromatosis: 90%
of cases are associated with mutations in hemojuveline (HJV) (locus name HFE2A,
which encodes HJV), while 10% of cases are associated with HAMP (locus name
HFE2B, which encodes hepcidin). Despite the nomenclature of HFE2A and
HFE2B, juvenile hemochromatosis is not associated with HFE mutations. In order
to avoid confusion most physicians use the terms type 2A (hemojuvelin mutations)
and type 2B (HAMP mutations). Mutations in hemojuvelin are associated with low
levels of hepcidin in urine suggesting that hemojuvelin regulates hepcidin. Hepcidin
is the key regulator of intestinal iron absorption and iron release from macrophages.
Hepcidin facilitates ferroportin internalisation and degradation. Hepcidin mutations
may thereby lead to an increase in ferroportin and thus iron uptake from the
intestine. Juvenile hemochromatosis is very rare. A clustering of HJV mutations is
seen in Italy and Greece although few families account for this phenomenon.
Mutations in HJV represent the majority of worldwide cases of juvenile
hemochromatosis.
Only a small number of patients have been identified with HAMP-related juvenile
hemochromatosis. Juvenile hemochromatosis is characterized by an onset of severe
iron overload in the first to third decades of life.  Clinical features include
hypogonadism, cardiomyopathy, and liver cirrhosis (Diamond 1989, Vaiopoulos
2003). The main cause of death is cardiomyopathy (De Gobbi 2002, Filali 2004). In
contrast to HFE type 1 hemochromatosis, both sexes are equally affected. Mortality
can be reduced in juvenile hemochromatosis when it is diagnosed early and treated
properly. Phlebotomy is the standard therapy in juvenile hemochromatosis as well
and is treated similarly to HFE hemochromatosis (Tavill 2001). In patients with
juvenile hemochromatosis and anemia or severe cardiac failure, administration of
chelators such as deferoxamine have been tried to reduce mortality; some case
reports suggest that this might improve left ventricular ejection fraction (Kelly
1998).
Transferrin receptor 2 (TFR2)-related type 3
hemochromatosis
TFR2-related hemochromatosis is defined as type 3 and is also known as HFE3;
however, the term HFE3 should not be used because the HFE gene is not affected in
type 3 hemochromatosis. TFR2-related hemochromatosis is inherited in an
autosomal recessive manner. TFR2 is a type II 801-amino acid transmembrane
glycoprotein expressed in hepatocytes and at lower levels in Kupffer cells (Zhang
2004). A finely regulated interaction between TFR2, TFR1 and HFE is now thought
420  Hepatology 2012
to affect the hepcidin pathway, and, consequently, iron homeostasis (Fleming 2005).
Patients with homozygous TFR2 mutations have increased intestinal iron absorption
that leads to iron overload. Hepcidin concentrations in urine are low in TFR2
hemochromatosis (Nemeth 2005). TFR2-related hemochromatosis is very rare with
only about 20 patients reported worldwide (Mattman 2002). Age of onset in TFR2-related type 3 hemochromatosis is earlier than in HFE-associated type 1 (Piperno
2004, Girelli 2002, Hattori 2003). Progression is, however, slower than in juvenile
type 2 (De Gobbi 2002, Roetto 2001, Girelli 2002). The phenotype is similar to type
1. Many patients present with fatigue, arthralgia, abdominal pain, decreased libido,
or with biochemical signs of iron overload (Roetto 2001, Girelli 2002, Hattori
2003). Complications of type 3 hemochromatosis include cirrhosis, hypogonadism,
and arthropathy. Cardiomyopathy and diabetes mellitus appear to be rather rare.
Hepatocellular carcinoma has not been observed in the small number of cases
diagnosed. Most individuals with type 3 hemochromatosis have an Italian or
Japanese genetic background. Some of the Japanese males have had liver cirrhosis
at diagnosis (Hattori 2003). Similar to type 1 hemochromatosis, the penetration of
type 3 hemochromatosis is also considerably less than 100% (Roetto 2001).
Standard therapy is iron removal by weekly phlebotomy similar to the management
of type 1 disease. Individuals with increased ferritin should be treated similar to
those with HFE hemochromatosis.
Type 4 hemochromatosis – Ferroportin Disease
Ferroportin-associated iron overload (also called Ferroportin Disease) was first
recognised by Pietrangelo (1999) who described an Italian family with an autosomal
dominant non-HFE hemochromatosis. Many family members had iron overload
resulting in liver fibrosis, diabetes, impotence, and cardiac arrhythmias. In addition
to autosomal dominant inheritance, features distinguishing this from HFE
hemochromatosis included early iron accumulation in reticuloendothelial cells and a
marked increase in ferritin earlier than what is seen in transferrin saturation
(Pietrangelo 1999, Rivard 2003, Montosi 2001, Wallace 2004, Fleming 2001).
Several patients showed a reduced tolerance to phlebotomy and became anemic
despite elevated ferritin (Pietrangelo 1999, Jouanolle 2003).
In 2001 this form of non-HFE hemochromatosis was linked to mutations of
ferroportin (Montosi 2001) that had just been identified as the basolateral iron
transporter (Abboud 2000, Donovan 2000). Since that time, numerous mutations in
the gene have been implicated in patients from diverse ethnic origins with
previously unexplained hemochromatosis. Iron overload disease due to ferroportin
mutations has been defined as type 4 hemochromatosis or Ferroportin Disease (for
review see Pietrangelo 2004). The iron export is tightly regulated because both iron
deficiency and iron excess are harmful. The main regulator of this mechanism is the
peptide hepcidin which binds to ferroportin, induces its internalization and
degradation, thereby reducing iron efflux (Nemeth 2004). Increase in iron
absorption may be caused either by hepcidin deficiency or its ineffective interaction
with ferroportin. All recent studies have shown that hepcidin deficiency appears to
be the common characteristic of most types of genetic hemochromatosis (mutations
in HFE, transferrin receptor 2, hemojuvelin, or hepcidin itself). The remaining cases
of genetic iron overload are due to heterozygous mutations in the hepcidin target,
ferroportin. Because of the mild clinical penetrance of the genetic defect there were
Metabolic Liver Diseases: Hemochromatosis  421
doubts about the rationale for iron removal therapy. However, a recent study shows
that there may be clinically relevant iron overload with organ damage and liver
cancer in patients carrying the A77D mutation of ferroportin (Corradini 2007).
Treatment schemes are similar to those described for other types of genetic
hemochromatosis.
Secondary hemochromatosis
Pathophysiology
Most forms of secondary hemochromatosis are due to hemolytic anemia associated
with polytransfusions such as thalassemia, sickle cell disease, and MDS. Most of
these patients need blood transfusions on a regular basis for survival. However, in
the long run, multiple blood transfusions often lead to iron overload if patients are
not treated with iron chelators. In general, iron overload due to blood transfusions is
similar to genetic hemochromatosis; however, secondary iron overload develops
much faster than the genetic forms (McLaren 1983), sometimes as soon as after 10-12 blood transfusions (Porter 2001). Subsequently secondary iron overload can
result in more rapid organ damage when compared with genetic hemochromatosis.
Secondary iron overload can obviously not be treated by phlebotomy because a
marked anemia is the clinical marker of the disease. Secondary iron overload often
limits the prognosis of patients with thalassemia; life expectancy deteriorates with
increasing iron concentrations in the liver (Telfer 2000). Therapy with iron chelator
may reduce the transfusional iron burden if the frequency of transfusion is not too
high. The development of HFE versus secondary hemochromatosis not only differs
in terms of the speed of iron accumulation but also in the type of organ damage; in
secondary hemochromatosis cardiomyopathy is often the complication that limits
the prognosis (Liu 1994). It is interesting that heart disease is also very frequent in
juvenile genetic hemochromatosis where there is also rapid iron accumulation. In
general, serum ferritin values closely reflect liver iron concentration and may be
used as an indication for timing of therapy as well as to check the effects of iron
chelation.
Until recently deferoxamine was the only iron chelator available in most
countries; in some countries the drug deferiprone is approved for patients who do
not tolerate deferoxamine (Hoffbrandt 2003). The clinical use of deferiprone was
limited due to side effects such as agranulocytosis and neutropenia (Refaie 1995).
Long-term data prove that deferoxamine can reduce iron overload and its organ
complications (Olivieri 1994, Cohen 1981). Deferoxamine, however, needs to be
given daily subcutaneously or by IV infusion for several hours. Thus, patients with
thalassemia often consider the deferoxamine treatment worse than thalassemia itself
(Goldbeck 2000). There are minor compliance problems that often limit the
beneficial effects of this iron chelator (Cohen 1989).
Without iron chelation, children with thalassemia often develop a severe
cardiomyopathy prior to age 15 (Cohen 1987). After that age, liver cirrhosis is also
a significant complication in secondary iron overload due to thalassemia (Zurlo
1992). Iron chelation should start early to prevent complications of iron overload.
By the ages of 3-5, liver iron concentration may reach values associated with a
significant risk for liver fibrosis in severe thalassemia (Angelucci 1995). Children
younger than 5 should therefore be cautiously treated with chelators if they have
422  Hepatology 2012
received transfusions for more than a year (Olivieri 1997). Deferoxamine can
reduce the incidence and ameliorate the course of iron-associated cardiomyopathy
(Olivieri 1994, Brittenham 1994, Miskin 2003).
Deferasirox is an oral iron chelator with high selectivity for iron III (Nick 2003).
Deferasirox binds iron in a 2:1 proportion with a high affinity and increases the
biliary iron excretion (Nick 2003). This chelator is able to reduce iron overload in
hepatocytes and cardiomyocytes (Nick 2003, Hershko 2001). Due to its half-life of
11-18 hours it needs to be taken only once daily (Nisbet-Brown 2003). Deferasirox
exerted a similar iron chelation when compared with deferoxamine in patients with
thalassemia; the effect of 40 mg/kg deferoxamine was similar to that of 20 mg/kg
deferasirox (Piga 2006). Both in adults and children 20-30 mg/kg/day deferasirox
significantly reduced liver iron concentration and serum ferritin (Cappellini 2006).
Magnetic resonance imaging showed that 10-30 mg/day deferasirox may also
reduce iron concentration in the heart within one year of maintenance therapy.
Deferasirox may cause minor increases in serum creatinine as well as
gastrointestinal discomfort and skin exanthema which are usually self-limiting.
Considering the compliance problems with deferoxamine, deferasirox has a better
cost-effectiveness ratio (Vichinsky 2005). Deferasirox is defined as standard
therapy both in the guidelines of the National Comprehensive Cancer Network
(NCCN) (USA) and in the international guidelines on MDS (Greenberg 2006,
Gattermann 2005).
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