Discussion
There are four types of HH based on the genetic defects leading to the
disorder. Type 1 hemochromatosis results from mutations in
the HFE gene; type 2 from mutations in either
the HJV or HAMP gene; type 3 from mutations in
the TFR2 gene; and type 4 from mutations in
the SLC40A1 gene. Type 1 is the commonest form of HH, and results
mostly from two mutations in the HFE gene: C282Y mutation and
H63D mutation.4 C282Y mutation occurs when there is
guanine to adenine change at nucleotide 845 in the HFE gene,
whereas H63D mutation occurs due to cytosine to guanine change at
nucleotide 187 in the HFE gene.5 The
normal HFE gene product functions, primarily in hepatocytes, to
increase hepcidin transcription and reduce serum iron levels. When
the HFE gene is mutated, the abnormal protein does not function
properly, resulting in increased absorption of iron.
The most common HH genotype is homozygosity for the C282Y variant
(C282Y/C282Y), and is mainly responsible for clinical hemochromatosis in
Caucasians.6,7 In non-Caucasians, the C282Y homozygous
mutation is less prevalent.7 Clinical manifestations
and a spectrum of risk for iron overload have been observed most
commonly among C282Y homozygotes followed by C282Y/H63D, C282Y/wt,
H63D/H63D, and H63D/wt genotypes in the descending
order.6 H63D/wt or H63D/H63D genotypes are not found
to be associated with iron loading or manifest only mild to moderate
iron overload unless they are associated with C282Y as a compound
heterozygote: C282Y/H63D.2
H63D mutation, in isolation, does not cause significant iron overload
despite being associated with increased serum transferrin saturation,
and requires additional modifying factors to express overt iron
overload.8 Several authors have studied how H63D
mutations affect iron load in β-thalassemia carriers. In their study,
Wilson et al9 found that Egyptian β-thalassemia
patients and carriers, who had homozygous H63D mutation, had
significantly higher serum ferritin levels than those who did not. In
another study, Melis et al10 found that β-thalassemia
carriers, who were homozygous for H63D mutations, had higher ferritin
levels than those who were heterozygous for this HFE allele, or
those who did not have it. They found the mean ferritin levels to be
389±75 mcg/L (mean±SD) in homozygotes for the H63D mutation. However,
Yang et al11 found differing conclusions in a review
of similar studies that investigated the effect of H63D mutations on
iron load in β-thalassemia major or carrier conditions. Some studies
from Italy, Portugal, India, and Egypt suggested that the interacting
effect of β-thalassemia with homozygous or even heterozygous H63D
mutations might lead to iron overload; other reports from Italy, India,
Thailand, Brazil, and Spain indicated that the iron status was not
related to H63D mutation.
BTM, which results from heterozygosity for β-thalassemia, is clinically
asymptomatic, and is defined by characteristic hematological features:
microcytosis, hypochromia, and increased HbA2 level. The
hemoglobin pattern of β-thalassemia heterozygotes is characterized by
92% to 95% HbA, >3.8% HbA2, and a
variable amount of HbF (0.5% to 4%). BTM is identified by determining
MCV, MCHC, and HBA2.12 Mentzer index
is one of several discrimination indices that can be calculated from RBC
indices during routine complete blood count. It is regarded as an
inexpensive measure to differentiate BTM from IDA, especially in
settings where iron profile and HPLC are unavailable. It is less time
consuming, and does not necessitate additional laboratory work. Mentzer
index greater than 13 is compatible with IDA, and a value less than 13
is suggestive of BTM.13 In our case, the Mentzer index
was 22.39, which would indicate IDA, but HPLC findings suggested the
diagnosis of BTM.
Individuals with BTM tend to increase iron absorption because of mild
anemia and slightly increased erythropoiesis, and the level of ferritin
increases moderately with age. Only a minority of them develop iron
overload, depending on the presence of other acquired or genetic
factors. Some cases develop iron overload due to additional genetic
determinants, whereas others do so due to long-term iron
supplementation.10,14 Owing to mild anemia and
microcytosis, BTM is often mistaken as IDA, and supplementary iron is
prescribed. Our patient, too, was repeatedly prescribed iron supplement
with the suspicion of IDA because of which he might have developed iron
overload; H63D homozygous mutation might have played an augmenting role.
Knox Macaulay et al15 have reported a similar
occurrence as ours in a 68-yr-old woman who received iron intermittently
for 15 years due to the misdiagnosis of BTM as IDA. On presentation, she
had a fully saturated iron binding capacity and clinical evidence of
iron overload. Therefore, serum iron studies must be done in an
individual with microcytic anemia to distinguish thalassemia from IDA
(low ferritin suggests iron deficiency), and to look for iron overload
in individuals with thalassemia.3
BTM is usually associated with mild anemia.12 Our
patient’s hemoglobin on presentation was 6.4 gm/dL. One reason for such
low hemoglobin could be the physiological effect of iron overload on
heme synthesis. It has been suggested that increased iron concentration
at the site of hemoglobin synthesis in patients with iron overload forms
an iron-pyridoxal complex, and prevents pyridoxal-5-phosphate from
serving as a coenzyme in heme synthesis.16
Chronic alcohol consumption, in moderate to excessive amounts, is
associated with elevated levels of serum ferritin and transferrin
saturation, and can result in increased hepatic iron
stores.17 Ethanol induces the downregulation of the
transcription factor that regulates hepcidin expression. This effect
results in the upregulation of the intestinal iron transporters, thereby
increasing intestinal iron absorption.17 Iron overload
occurs not only in patients with HH but also in individuals with
alcoholic liver disease, nonalcoholic fatty liver disease, and hepatitis
C infection. Chronic liver disease decreases the synthetic function of
the liver, including the production of hepcidin. Lower levels of
hepcidin increase the iron load.17
Hemochromatosis requires a high degree of suspicion for clinical
identification as most of the patients present with symptoms like
extreme fatigue, arthralgia, and loss of libido, which are usually
attributed to other diseases. Skin pigmentation, diabetes mellitus, and
liver cirrhosis, which are thought to be the usual manifestations of
hemochromatosis, occur infrequently.18 Our patient
reported easy fatigability, and had diabetes mellitus and liver
cirrhosis. He did not report arthralgia or loss of libido.
Hemochromatosis might have eluded suspicion for a long time in our
patient because fatigue is more likely to be attributed to anemia than
to hemochromatosis, and liver cirrhosis to chronic alcohol consumption.
Additionally, patients with iron overload are more prone to infections
due to organisms whose virulence is increased in the presence of excess
iron, such as Listeria monocytogenes , Yersinia
enterocolitica , Escherichia coli, and Vibrio
vulnificus .4 In our patient, we could only suspect
that these infections might have caused the past episodes of recurrent
fever and diarrhea.
Patients with iron overload are treated with phlebotomy. Those who
cannot tolerate phlebotomy due to concomitant anemia can be treated with
iron chelation if the iron load is significant.4 Iron
chelation therapy is not recommended in individuals with isolated
ferritin elevations below 1000 ng/mL because the adverse effects are
likely to outweigh the benefits.19 As our patient had
severe anemia with iron overload (ferritin 1215.9 ng/mL), we avoided
phlebotomy, and offered iron chelation with deferoxamine instead.
Kowdley et al4 recommend
performing HFE mutation analysis and iron studies of all
first-degree relatives of patients with HFE -related HH to detect
disease early and prevent complications. Detection of C282Y homozygosity
or compound heterozygosity in the relative, in the presence of increased
serum ferritin levels, requires the initiation of therapeutic phlebotomy
and yearly follow-up with iron-studies. C282Y heterozygotes, H63D
heterozygotes, and H63D homozygotes can be reassured that they are not
at risk for developing progressive or symptomatic iron overload. Our
patient had a son, who was counseled for HFE mutation analysis
and iron studies. HFE mutation analysis could not be performed
due to financial limitation, but the iron profile was normal.
Long-term survival in patients with hemochromatosis is dependent on the
degree and the duration of iron overload.20 The most
important prognostic factor at the time of diagnosis is the presence of
liver fibrosis or cirrhosis. Patients treated before the occurrence of
liver cirrhosis have a normal life expectancy, whereas untreated
patients die, most frequently from heart failure, cirrhosis,
or HCC.19 We encountered our patient at a late stage
of illness when hemochromatosis was already complicated with liver
cirrhosis and HCC. Though liver transplantation is indicated in patients
with HH who develop HCC,4 it was not possible in our
patient due to the adherence of the tumor with the anterior abdominal
wall. He might have died as a consequence of HCC.