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Metabolic Liver Diseases: Hemochromatosis 405
24. Metabolic Liver Diseases:
Hemochromatosis
Claus Niederau
Definition and classification of iron overload
diseases
Hereditary hemochromatosis is classified into 4 subtypes (Table 1). Type 1 is the
well known form of iron overload due to an autosomal-recessive genetic metabolic
malfunction; the homozygous C282Y mutation of the HFE gene on chromosome 6
accounts for more than 90% of clinical phenotypes in populations of Caucasian
origin (Feder 1996). The mutation leads to an inadequately high intestinal iron
absorption that after decades may cause iron overload and damage to various organs
(Figure 1). Types 2a and 2b of genetic hemochromatosis are juvenile forms of iron
overload that lead to a severe outcome prior to age 30, with cardiomyopathy and
hypogonadism. The corresponding mutations are located in the hemojuveline and
hepcidin genes, respectively (Roetto 1999). Type 3 has mainly been described in
Italian families and refers to a mutation in the transferrin receptor 2 gene (Girelli
2002). Clinical consequences of type 3 hemochromatosis are similar to type 1.
Types 2 and 3 are autosomal-recessive traits. The mutations of the autosomal-dominant type 4 hemochromatosis are located in the gene coding for the basolateral
iron transporter ferroportin 1 (Njajou 2001). In contrast to the other types, iron is
accumulated in type 4 mainly in macrophages; ferritin values are markedly elevated
although transferrin saturation is only slightly higher.
Secondary hemochromatosis is usually caused by multiple blood transfusions in
hemolytic anemias such as thalassemia, sickle cell anemia and myelodysplasia
syndrome. Iron first accumulates in RES macrophages and is later transferred to
parenchymal cells. With frequent blood transfusions, iron may accumulate faster
than with genetic hemochromatosis; iron overload often leads to severe
cardiomyopathy and liver cirrhosis, limiting effective prognosis. Therapy consists of
iron chelators because phlebotomies cannot be done due to the underlying anemia.
This review will focus on type 1 HFE hemochromatosis, the most prevalent genetic
form in Germany. Most consequences of iron overload are similar, whatever the
406 Hepatology 2012
cause. Thus, the pathophysiology of tissue and organ damage by iron excess is
discussed in detail only for HFE hemochromatosis.
Figure 1. Scheme of natural history of type 1 genetic hemochromatosis.
Table 1. Classification of hemochromatosis.
I) Genetic hemochromatosis
Types Gene defect on Affected gene Inheritance High
prevalence
Type 2a Chromosome 1 Hemojuveline Autosomal-recessive
Juvenile form
Type 2b Chromosome 19 Hepcidin Autosomal-recessive
Juvenile form
Type 3 Chromosome 7 Transferrin
receptor 2
Autosomal-recessive
Italy
Type 4 Chromosome 2 Ferroportin 1 Autosomal-dominant
Italy
Neonatal Unknown Unknown Unknown Very rare
Others Unknown Unknown Unknown Of non-Caucasian origin
II) Secondary hemochromatosis
a) Chronic anemias (thalassemia, sickle cell disease, MDS, other rare hemolytic
anemias)
b) Multiple blood transfusions in general
c) Long-term oral intake of high amounts of iron (diet-related or IV)
III) Non-classified, ill-defined iron overload syndromes
a) iron overload in Bantu Africans
b) iron overload in aceruloplasminemia
Type 1 HFE hemochromatosis
History
The association between liver cirrhosis, pigment deposits in the liver, and diabetes
mellitus was recognized over a century ago (Trosseau 1865, Troisier 1871, Hanot
Metabolic Liver Diseases: Hemochromatosis 407
and Schachmann 1886). The term hemochromatosis was first introduced in the 19
th
century (Recklinghausen 1889), but was not generally accepted until used as the
title of a classic monograph (Sheldon 1935). The controversy over whether
hemochromatosis was merely a form of alcoholic liver cirrhosis (MacDonald 1960)
or a genetic error of iron metabolism (Sheldon 1935, Crosby 1966) lasted almost a
century until the association between special HLA haplotypes and hemochromatosis
which recognized the genetic nature of the disease was described (Simon 1975). The
mode of inheritance was identified as an autosomal recessive disorder (Simon
1977). Finally, the major mutation on the HFE gene associated with clinical
manifestations was identified (Feder 1996).
Epidemiology
Type 1 hemochromatosis is probably the most prevalent genetic metabolic error in
Caucasian populations (Adams 2005). The prevalence of C282Y homozygotes is
approximately 0.5% in central Europe and in the Caucasian population of North
America; the prevalence of C282Y and H63D heterozygotes approaches 40% in
similar populations (Adams 2005). Phenotypic expression also depends on several
non-genetic factors such the amount of dietary iron and blood loss (Figure 2). For
example, females develop clinical consequences of iron overload 5-8 times less
frequently and 10-20 years later than males due to menses. It is now widely
accepted that not all C282Y homozygous men will develop the full clinical
manifestation of hemochromatosis. It is unknown, however, whether 5% or 50%
will show clinical disease during their lifetime and what factors determine that
phenotype.
As mentioned previously, the homozygous C282Y mutation accounts for more
than 90% of the clinical phenotype in Caucasian populations (Feder 1996, Adams
2005) (Table 2). A point mutation at H63D is also frequently identified in the HFE
gene as well as other less frequent mutations. None of these gene alterations or
polymorphisms, found in up to 40% of Caucasians, correlates with the phenotype. A
subject with a C282Y variation on one allele and a H63D variation on the other is
called a "compound heterozygote" (Table 2). Only a small percentage of such
compound heterozygotes are at risk for clinical consequences of iron overload.
C282Y and H63D heterozygotes are at no risk of iron overload (Table 2). In non-Caucasian populations other genes may be involved in causing iron overload.
Etiology and pathogenesis
Intestinal iron absorption and iron losses are finely balanced under physiological
conditions. Approximately 10% of the total daily intake (10-20 mg) is absorbed by
the small intestine (1-2 mg). However, subjects with the homozygous C282Y
mutation may absorb up to 20% of iron intake; i.e., up to 2-4 mg/day. Thus,
homozygotes have an excessive iron intake of approximately 1 mg/day. It may
therefore take several decades until iron stores approach 10 g above which organ
damage is considered to be induced. Many patients at the clinical end stage of
hemochromatosis, including liver cirrhosis and diabetes mellitus, have total body
iron stores of 20-30 g. Their intestinal iron absorption is downregulated when iron
stores increase, as it is in patients with genetic hemochromatosis. This
downregulation, however, occurs on an increased level when compared to subjects
without the HFE gene mutation. Correspondingly, intestinal iron absorption is
408 Hepatology 2012
massively increased in patients with hemochromatosis when iron stores have been
depleted by phlebotomy. Phlebotomies should be continued after iron depletion in
order to prevent reaccumulation. These regulatory processes however do not explain
how HFE gene mutations cause the increase in intestinal iron absorption since the
HFE gene product is neither an iron transporter nor an iron reductase or oxidase.
Only recently have carriers and regulators of cellular iron uptake and release been
identified (Pietrangelo 2002, Fleming 2002, Townsend 2002, Fletcher 2002).
It has also become increasingly evident that some of them interact with the HFE
gene product in the regulation of intestinal iron absorption (Pietrangelo 2002,
Fleming 2002, Townsend 2002, Fletcher 2002). Recent studies have shown that the
Nramp2 protein is the luminal iron carrier. Shortly thereafter, the luminal iron
reductase was identified as the Dcytb protein (duodenal cytochrome B) (Pietrangelo
2002, Fleming 2002, Townsend 2002, Fletcher 2002). At the same time, the
basolateral iron transporter ferroportin 1 (also named Ireg1 or MTP1) was identified
(Donovan 2000, Abboud 2000) as well as the basolateral iron oxidase hephestin
(Vulpe 1999). Mutations in some of these proteins are responsible for the rarer types
2-4 of genetic hemochromatosis, although none of these genes is altered in type 1
hemochromatosis. Recently, two other proteins have been shown to act as important
iron regulating proteins, transferrin receptor 2 and hepcidin (Pietrangelo 2002;
Fletcher 2002; Fleming 2005). Mutations in the transferrin receptor 2 gene may lead
to the rare type 3 hemochromatosis, and mutations in the ferroportin 1 gene to type
4 hemochromatosis. More recent studies also indicate that hepcidin may be the most
important regulator of iron metabolism, involved in iron deficiency and overload.
Hepcidin has been shown to down regulate the basolateral iron carrier ferroportin. It
has also been demonstrated that hepcidin itself is up regulated by HFE. Thus, an
HFE mutation may reduce the upregulation of hepcidin that then does not down
regulate ferroportin; the corresponding increase in ferroportin expression finally
causes the increase in intestinal iron uptake (DeDomenico 2007). There may be
further interactions between HFE, transferrin receptor 2, Nramp2, Dcytb,
ferroportin, hephestin and hepcidin, all of which are currently being studied.
Figure 2. Non-genetic factors that may influence iron absorption.
Metabolic Liver Diseases: Hemochromatosis 409
Table 2. Genotype/phenotype correlation in hemochromatosis.
Mutations/
polymorphisms
Prevalence in
Caucasian populations
Risk of advanced
clinical phenotype
C282Y/C282Y 85-95% low if ferritin is <1000 ng/ml
H63D/C282Y 3-8% very low
C282Y/wild type - none
H63D/wild type - none
Others 1% unknown
Diagnosis
Laboratory tests. Any increase in serum iron should start with the exclusion of
hemochromatosis so as not to overlook early disease. Normal serum iron, however,
does not exclude hemochromatosis and increased serum iron often occurs in the
absence of hemochromatosis. Serum iron values are highly variable and should not
be used either for diagnosis or for screening of hemochromatosis. The determination
of transferrin saturation is a better indicator of iron overload than serum iron. The
increase in transferrin saturation usually precedes the ferritin increase (Figure 1).
Transferrin saturation is more sensitive and specific for detection of
hemochromatosis when compared to serum ferritin. For screening, a threshold of
50% for transferrin saturation may be optimal under fasting conditions. Ferritin on
the other hand is a good indicator of largely increased iron stores and reliably
indicates iron deficiency. It has less value for early detection of hemochromatosis.
In hemochromatosis a slightly increased serum ferritin (300-500 ng/ml) is usually
accompanied by transferrin saturations exceeding 80-90%. Unfortunately, serum
ferritin is also increased, often in the presence of infections and malignancies, and
thus has a low specificity for indicating hemochromatosis (Niederau 1998). Ferritin
increases not due to genetic hemochromatosis are usually associated with normal or
only slightly elevated transferrin saturation. Therefore, transferrin saturation should
be measured in order to correctly interpret ferritin increases.
Liver biopsy and determination of liver iron concentration. Although
simultaneous increases of both serum ferritin and transferrin saturation strongly
indicate a risk for hemochromatosis, diagnosis needs to be confirmed by genetic
testing or by liver biopsy with a determination of iron content in the liver. Hepatic
iron concentration also increases with time in subjects with an HFE gene mutation.
It is recommended to divide the liver iron concentrations by the patient’s age in
order to obtain the “hepatic iron index” (Summers 1990). The semi-quantitative
estimation of liver iron stores by the Berlin blue colour is less sensitive and specific
than the chemical quantification of liver iron concentration. In case of a
homozygous C282Y gene test, liver biopsy is not required for the diagnosis of
genetic hemochromatosis (Table 2).
There may, however, be other reasons to perform a liver biopsy in iron overload:
(1) subjects with biochemical or clinical evidence of iron overload in the absence of
the homozygous C282Y mutation should have a liver biopsy to substantiate iron
overload; (2) in C282Y homozygotes the risk for liver fibrosis and cirrhosis
increases at ferritin values >1000 ng/ml (Loreal 1992); in those patients liver biopsy
410 Hepatology 2012
is recommended because the presence of liver cirrhosis markedly increases later
HCC risk and thus warrants HCC screening.
Deferoxamine testing and ferrokinetic measurements. Determinations of
urinary excretion of iron after administration of deferoxamine allows some
estimation of total body iron stores. The deferoxamine test, however, often only
shows pathological results when serum ferritin and transferrin saturation are
markedly increased and does not allow diagnosis of early disease. Ferrokinetic
measurements today are only done for scientific research or in difficult diagnostic
situations.
Computed tomography (CT), magnetic resonance tomography (MRT) and
biomagnetometry. CT density measurements of the liver allow a semi-quantitative
estimation of iron concentration in the liver. This method however is associated
with radiation and therefore not allowed in many countries where alternative
methods are available. MRT, on the other hand, allows a reliable measurement of
liver iron content, provided that special software is used and the equipment is
calibrated for such measurement. In clinical practice most MRT do not fulfil these
criteria. Biomagnetometry allows the most accurate non-invasive measurement of
liver iron concentration. However, this equipment is expensive and only allows
measurement of iron concentration. Consequently, biomagnetometry is done only at
a few centres worldwide and is primarily used for scientific studies and not in daily
clinical practice. With the availability of reliable and inexpensive genetic testing,
CT, MRT, and biomagnetometry do not need to be done for most patients.
Figure 3. Diagnosis and treatment algorithm for type 1 hemochromatosis.
Genetic tests. As outlined previously, in Caucasian populations the homozygous
C282Y mutation accounts for more than 90% of patients with the clinical phenotype
of type 1 hemochromatosis (Adams 2005, Erhardt 1999). Approximately 5% of
patients with the clinical phenotype are C282Y/H63D compound heterozygotes; the
prevalence of C282Y or H63D heterozygosity in patients with the clinical
Metabolic Liver Diseases: Hemochromatosis 411
phenotype of hemochromatosis is considerably lower than in the general population.
Thus, a subject who is heterozygous for C282Y or H63D per se has no risk of iron
overload. In subjects homozygous for C282Y, both serum ferritin and transferrin
saturation are frequently increased; however, only male subjects have an increased
risk for liver disease when compared to subjects without HFE gene alterations in a
recent large screening study. It is unknown how many C282Y homozygotes will
later develop clinical signs and symptoms due to iron overload. It is increasingly
evident that only a minority of C282Y homozygotes progress to end stage iron
overload with liver cirrhosis and diabetes mellitus. In subjects who are not C282Y
homozygotes but have laboratory, histological or clinical evidence of iron overload,
further genes may be analysed for mutations such as hemojuveline, transferrin
receptor 2, ferroportin 1 and hepcidin.
Early diagnosis and screening
The prevalence of C282Y homozygotes is 0.5 % in Caucasian populations (Adams
2005, Erhardt 1999). Clinical manifestations however are variable and depend on
non-genetic factors such as dietary iron intake and blood loss. Until 1980 most
patients with hemochromatosis were detected with late irreversible complications
such as liver cirrhosis and diabetes mellitus. With a better understanding of the
disease, the broad use of ferritin and transferrin saturation measurements and the
availability of a reliable genetic test, diagnostic efforts have concentrated on the
detection of early disease before liver cirrhosis and diabetes mellitus. Several
studies have shown that iron removal by phlebotomy is associated with normal life
expectancy in patients diagnosed early (Niederau 1985, Niederau 1996, Fargion
1992) (Figure 3). Several other studies have focused on screening procedures in
order to diagnose more subjects with early disease (Edwards 1988). These studies
include populations with special risks, family members, as well as the general
population (Table 3) (see Niederau 2002). It has been shown that an increasing
number of patients are now diagnosed early and that this trend increases survival
(Figure 4).
A large number of studies have shown that screening is useful for detection of
asymptomatic C282Y homozygotes by using transferrin saturation and serum
ferritin as well a genetic test for the C282Y mutation (Edwards 1988, Phatak 1998,
Niederau 1998). A broad screening of the general population however is as yet not
recommended by WHO and CDC mainly because its is unknown how many of the
asymptomatic C282Y homozygotes will later develop clinical disease (see US
Preventive Services Task Force 2007). The largest screening study analyzed HFE
gene mutations in almost 100,000 subjects in North America. In Caucasians, C282Y
homozygosity was found in 0.44%, a value similar to many previous studies in other
populations with a similar background. Asian or Black people in contrast almost
never have an HFE gene mutation (Adams 2005). Among the Caucasian C282Y
homozygotes only males had a significant increase in liver disease when compared
to subjects without an HFE gene variation (Adams 2005). Only further prospective
follow-up studies will determine how many asymptomatic C282Y homozygotes will
develop clinical consequences of iron overload.
