The Iron Overload Syndromes
The Iron Overload Syndromes
HFE-related haemochromatosis (HH) is the most common inherited disorder of iron metabolism. It is inherited in an autosomal recessive pattern, with variable penetrance. It usually manifests in the fourth or fifth decade and the phenotypic features are more common and more pronounced in males. A homozygous mutation in the hereditary haemochromatosis gene, HFE is responsible for HH. HFE, a nonclassical major histocompatibility class I–like molecule, binds to β2-microglobulin and this association enables it to be moved to the cell surface where it binds to TfR1. The normal function of HFE has been difficult to elucidate and the mechanisms by which HFE affects hepcidin transcription are only now beginning to emerge ( Table 3 ).
Under normal physiological conditions TBI binds with high affinity to TfR1 expressed on the cell membrane. HFE protein competes with Tf for binding TfR1 to modulate cellular iron uptake. The presence of HFE in duodenal crypt cells and the interaction between HFE andTfR1 led to the 'crypt –programming model' to explain the systemic iron homeostasis. Crypt enterocytes take up iron from plasma Tf at their basolateral surfaces and migrate to the villus region where they differentiate into absorptive cells.Hfe mice were found to have significant impairment in the duodenal uptake of circulating TBI. This led to the hypothesis that crypt cell HFE may act as an iron sensor and, in the presence of an abnormal HFE protein, iron uptake into the enterocyte does not occur resulting in iron-deficient crypt cells. When these cells then migrate to the villus region, there is an inappropriate up-regulation of iron transport proteins and increased dietary iron absorption to correct the erroneously perceived deficit.
The discovery of the hormone hepcidin, a negative regulator of iron absorption, has shifted the focus to the liver as the main regulatory site for dietary iron absorption.Hfe mice have decreased hepatic hepcidin mRNA expression and increased hepatic iron deposition similar to a human haemochromatosis phenotype. Moreover, when Hfe mice were crossed with transgenic mice that over express hepcidin, there was prevention of the iron overload phenotype, implicating an overriding role of hepcidin in iron homeostasis. Furthermore, ablation of HFE expression in mouse enterocytes does not disrupt normal physiological iron metabolism. These observations argue for a more important role for HFE in the liver rather than the intestinal crypt cells.
The three molecules, HFE, HJV, TfR2, all of which are expressed in the liver likely play a major role in hepcidin regulation. According to the 'hepcidin hypothesis', in iron overload states that there is an appropriate increase in hepcidin expression, resulting in reduced cellular expression of FPN and decreased iron efflux from duodenal enterocytes, macrophages involved in the recycling of iron from senescent erythrocytes and from hepatocytes, the site of most storage iron. Conversely, in iron depleted states, hepcidin expression is reduced and FPN expression is high, resulting in increased iron absorption and transport. Hepcidin also likely affects the expression and activity of other iron-transport molecules, such as DMT1 by altering the labile iron pool (LIP) in enterocytes and thereby indirectly affecting the gene transcription of the iron transport proteins.
A number of HFE mutations have been identified. The most common clinically relevant mutations, however, are the C282Y and H63D. The C282Y mutation is a missense mutation on the short arm of chromosome 6 that causes the amino acid tyrosine to replace cysteine at position 282 in the HFE protein. The H63D mutation is characterised by a histidine to aspartic acid substitution at amino acid 63. Approximately 85–90% of patients with the typical phenotype of HH are C282Y homozygotes whereas 3–5% are C282Y/H63D compound heterozygotes. The prevalence of C282Y homozygosity is 1 in 250 persons in the general population and about 1 in 200 persons of northern European ancestry. However, iron overload features do not manifest in many C282Y homozygotes, suggesting incomplete penetrance and the possibility that there may be other genes that act as modifiers of the HH phenotype. The H63D mutation is more common compared to C282Y with a carrier frequency of 10–20% of population of European descent. The clinical significance of the H63D mutation remains unclear in the absence of C282Y; only 0.5–2% of subjects with compound heterozygosity for C282/H63D develop iron overload. H63D homozygosity is unlikely to cause clinical disease in the absence of other factors, such as viral hepatitis and alcohol.
Data from a large population-based 12-year follow-up study involving over 31 000 persons of Northern European ancestry revealed that 28% of C282Y homozygous males but only 1% of female C282Y homozygotes developed iron-overload related disease. In comparison, among the compound heterozygotes only one in 82 men and no women had iron overload-related disease. The two main factors associated with increased phenotypic expression of the homozygous C282Y mutation are male gender and increased alcohol consumption. Other factors that have been suggested are excessive dietary heme consumption, protective effect of tea drinking and noncitrus fruit. It has also been proposed that calcium channel blockers by prolonging DMT1 activity and PPI by its effect of gastric acid suppression may decrease nonheme iron absorption.
HFE-Related Haemochromatosis (Type 1 or Classical Haemochromatosis) (Table 3)
HFE-related haemochromatosis (HH) is the most common inherited disorder of iron metabolism. It is inherited in an autosomal recessive pattern, with variable penetrance. It usually manifests in the fourth or fifth decade and the phenotypic features are more common and more pronounced in males. A homozygous mutation in the hereditary haemochromatosis gene, HFE is responsible for HH. HFE, a nonclassical major histocompatibility class I–like molecule, binds to β2-microglobulin and this association enables it to be moved to the cell surface where it binds to TfR1. The normal function of HFE has been difficult to elucidate and the mechanisms by which HFE affects hepcidin transcription are only now beginning to emerge ( Table 3 ).
Under normal physiological conditions TBI binds with high affinity to TfR1 expressed on the cell membrane. HFE protein competes with Tf for binding TfR1 to modulate cellular iron uptake. The presence of HFE in duodenal crypt cells and the interaction between HFE andTfR1 led to the 'crypt –programming model' to explain the systemic iron homeostasis. Crypt enterocytes take up iron from plasma Tf at their basolateral surfaces and migrate to the villus region where they differentiate into absorptive cells.Hfe mice were found to have significant impairment in the duodenal uptake of circulating TBI. This led to the hypothesis that crypt cell HFE may act as an iron sensor and, in the presence of an abnormal HFE protein, iron uptake into the enterocyte does not occur resulting in iron-deficient crypt cells. When these cells then migrate to the villus region, there is an inappropriate up-regulation of iron transport proteins and increased dietary iron absorption to correct the erroneously perceived deficit.
The discovery of the hormone hepcidin, a negative regulator of iron absorption, has shifted the focus to the liver as the main regulatory site for dietary iron absorption.Hfe mice have decreased hepatic hepcidin mRNA expression and increased hepatic iron deposition similar to a human haemochromatosis phenotype. Moreover, when Hfe mice were crossed with transgenic mice that over express hepcidin, there was prevention of the iron overload phenotype, implicating an overriding role of hepcidin in iron homeostasis. Furthermore, ablation of HFE expression in mouse enterocytes does not disrupt normal physiological iron metabolism. These observations argue for a more important role for HFE in the liver rather than the intestinal crypt cells.
The three molecules, HFE, HJV, TfR2, all of which are expressed in the liver likely play a major role in hepcidin regulation. According to the 'hepcidin hypothesis', in iron overload states that there is an appropriate increase in hepcidin expression, resulting in reduced cellular expression of FPN and decreased iron efflux from duodenal enterocytes, macrophages involved in the recycling of iron from senescent erythrocytes and from hepatocytes, the site of most storage iron. Conversely, in iron depleted states, hepcidin expression is reduced and FPN expression is high, resulting in increased iron absorption and transport. Hepcidin also likely affects the expression and activity of other iron-transport molecules, such as DMT1 by altering the labile iron pool (LIP) in enterocytes and thereby indirectly affecting the gene transcription of the iron transport proteins.
A number of HFE mutations have been identified. The most common clinically relevant mutations, however, are the C282Y and H63D. The C282Y mutation is a missense mutation on the short arm of chromosome 6 that causes the amino acid tyrosine to replace cysteine at position 282 in the HFE protein. The H63D mutation is characterised by a histidine to aspartic acid substitution at amino acid 63. Approximately 85–90% of patients with the typical phenotype of HH are C282Y homozygotes whereas 3–5% are C282Y/H63D compound heterozygotes. The prevalence of C282Y homozygosity is 1 in 250 persons in the general population and about 1 in 200 persons of northern European ancestry. However, iron overload features do not manifest in many C282Y homozygotes, suggesting incomplete penetrance and the possibility that there may be other genes that act as modifiers of the HH phenotype. The H63D mutation is more common compared to C282Y with a carrier frequency of 10–20% of population of European descent. The clinical significance of the H63D mutation remains unclear in the absence of C282Y; only 0.5–2% of subjects with compound heterozygosity for C282/H63D develop iron overload. H63D homozygosity is unlikely to cause clinical disease in the absence of other factors, such as viral hepatitis and alcohol.
Data from a large population-based 12-year follow-up study involving over 31 000 persons of Northern European ancestry revealed that 28% of C282Y homozygous males but only 1% of female C282Y homozygotes developed iron-overload related disease. In comparison, among the compound heterozygotes only one in 82 men and no women had iron overload-related disease. The two main factors associated with increased phenotypic expression of the homozygous C282Y mutation are male gender and increased alcohol consumption. Other factors that have been suggested are excessive dietary heme consumption, protective effect of tea drinking and noncitrus fruit. It has also been proposed that calcium channel blockers by prolonging DMT1 activity and PPI by its effect of gastric acid suppression may decrease nonheme iron absorption.
Source...