Diagnosis and Treatment of Hereditary Hemochromatosis
Diagnosis and Treatment of Hereditary Hemochromatosis
Two large population studies have evaluated the penetrance rate of the HH biochemical phenotype in C282Y homozygotes. In the HEIRS study, approximately 77% of men and 47% of women had elevated SF and TS values on initial evaluation. However, the HEIRS data did not have long term follow up in patients (only a mean of 112 days) to evaluate for long-term variability in these biochemical tests and possibility of a chance to predict outcomes.
The HealthIron study was a population-based study wherein subjects underwent HFE genotyping from baseline samples, repeat samples were tested for biochemical progression and subjects were examined for iron overload symptoms and complications after 12 years. Approximately 78% of men and 52% of women with the C282Y homozygous genotype had elevated SF and TS at baseline. Approximately 37% of males and 3% of females in the study had SF >1000 µg/l at baseline. As noted elsewhere, a SF >1000 µg/l at diagnosis has been shown to be associated with an increased risk of cirrhosis and mortality. The predicted probability of advancing to SF >1000 µg/l after 12 years among individuals with baseline SF between 300–1000 µg/l was 13–35% in males and 16–22% in females. The investigators found that one third of the cohort with SF 300–1000µg/l and markedly elevated TS progressed to SF >1000 µg/l, the majority by 55 years of age; based on these data, it appears reasonable to recommend therapeutic phlebotomy to such individuals. Thus, although iron indices at a particular point of time are a 'snap-shot' in the clinical course of disease; they may predict the chance of progression to cirrhosis.
Data from the HealthIron study also showed that C282Y/H63D compound heterozygotes have higher baseline SF levels and TS levels when compared to wild-type genotypes; however these levels do not change much with time in men and postmenopausal women. In premenopausal women, these levels do increase, possibly due to lack of menstrual iron losses with the onset of menopause.
In summary, based on the HealthIron Study in a population-based sample, not all patients with a genotypic susceptibility for HH, develop elevated iron indices (biochemical phenotype). Similarly, not all patients with genetic propensity and biochemical phenotype develop iron overload symptoms (clinical phenotype) and only one third of patients with iron overload finally develop end organ damage causing iron overload-related disease.
Patients with other HFE genotypes such as H63D homozygous may develop significantly elevated iron indices, both TS and SF, compared to wild-type genotype. However, they do not develop clinically significant iron overload except when associated with concomitant risk factors such as alcohol and steatosis.
The incomplete clinical and biochemical penetrance of the HFE mutation could be related to multiple genetic and environmental factors. Environmental factors such as alcohol, viral hepatitis and liver steatosis act as cofactors for liver injury and are implicated in accelerated hepatic fibrosis. Presence of beta thalassemia trait has long been debated as a risk factor for iron overload, with different studies showing contradictory results. A recent study in 142 beta thalassemia carriers by Lopez-Escribano et al. did not show any significant difference in iron stores in those with and without HFE mutations. The lack of significant increase in iron overload can be explained by the fact that the geographical distribution of beta thalassemia corresponds with that of H63D and most studies involved mutation of this allele only. An Italian study showed that presence of beta thalassemia trait in C282Y homozygous patients is associated with worsened clinical expression of the phenotype; this was not seen with single C282Y or H63D mutations.
The genetic factors that may affect penetrance include sex, multiple single-nucleotide polymorphisms (SNPs) in different iron-related genes involved in iron metabolism that may regulate the expression of the disease in C282Y homozygous individuals. These SNPs have been shown to be associated with increased iron indices such as SF and TS. There are also genetic modifiers located in genomic regions unrelated to iron metabolism, which have been shown to be associated with phenotypic expression in HH patients. However the most important variables enhancing penetrance are male sex and alcohol use.
Biochemical Penetrance
Two large population studies have evaluated the penetrance rate of the HH biochemical phenotype in C282Y homozygotes. In the HEIRS study, approximately 77% of men and 47% of women had elevated SF and TS values on initial evaluation. However, the HEIRS data did not have long term follow up in patients (only a mean of 112 days) to evaluate for long-term variability in these biochemical tests and possibility of a chance to predict outcomes.
The HealthIron study was a population-based study wherein subjects underwent HFE genotyping from baseline samples, repeat samples were tested for biochemical progression and subjects were examined for iron overload symptoms and complications after 12 years. Approximately 78% of men and 52% of women with the C282Y homozygous genotype had elevated SF and TS at baseline. Approximately 37% of males and 3% of females in the study had SF >1000 µg/l at baseline. As noted elsewhere, a SF >1000 µg/l at diagnosis has been shown to be associated with an increased risk of cirrhosis and mortality. The predicted probability of advancing to SF >1000 µg/l after 12 years among individuals with baseline SF between 300–1000 µg/l was 13–35% in males and 16–22% in females. The investigators found that one third of the cohort with SF 300–1000µg/l and markedly elevated TS progressed to SF >1000 µg/l, the majority by 55 years of age; based on these data, it appears reasonable to recommend therapeutic phlebotomy to such individuals. Thus, although iron indices at a particular point of time are a 'snap-shot' in the clinical course of disease; they may predict the chance of progression to cirrhosis.
Data from the HealthIron study also showed that C282Y/H63D compound heterozygotes have higher baseline SF levels and TS levels when compared to wild-type genotypes; however these levels do not change much with time in men and postmenopausal women. In premenopausal women, these levels do increase, possibly due to lack of menstrual iron losses with the onset of menopause.
In summary, based on the HealthIron Study in a population-based sample, not all patients with a genotypic susceptibility for HH, develop elevated iron indices (biochemical phenotype). Similarly, not all patients with genetic propensity and biochemical phenotype develop iron overload symptoms (clinical phenotype) and only one third of patients with iron overload finally develop end organ damage causing iron overload-related disease.
Patients with other HFE genotypes such as H63D homozygous may develop significantly elevated iron indices, both TS and SF, compared to wild-type genotype. However, they do not develop clinically significant iron overload except when associated with concomitant risk factors such as alcohol and steatosis.
The incomplete clinical and biochemical penetrance of the HFE mutation could be related to multiple genetic and environmental factors. Environmental factors such as alcohol, viral hepatitis and liver steatosis act as cofactors for liver injury and are implicated in accelerated hepatic fibrosis. Presence of beta thalassemia trait has long been debated as a risk factor for iron overload, with different studies showing contradictory results. A recent study in 142 beta thalassemia carriers by Lopez-Escribano et al. did not show any significant difference in iron stores in those with and without HFE mutations. The lack of significant increase in iron overload can be explained by the fact that the geographical distribution of beta thalassemia corresponds with that of H63D and most studies involved mutation of this allele only. An Italian study showed that presence of beta thalassemia trait in C282Y homozygous patients is associated with worsened clinical expression of the phenotype; this was not seen with single C282Y or H63D mutations.
The genetic factors that may affect penetrance include sex, multiple single-nucleotide polymorphisms (SNPs) in different iron-related genes involved in iron metabolism that may regulate the expression of the disease in C282Y homozygous individuals. These SNPs have been shown to be associated with increased iron indices such as SF and TS. There are also genetic modifiers located in genomic regions unrelated to iron metabolism, which have been shown to be associated with phenotypic expression in HH patients. However the most important variables enhancing penetrance are male sex and alcohol use.
