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 HbAlevel. 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 monocytogenesYersinia enterocoliticaEscherichia 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.