Haemochromatosis is a condition emanating from a dysfunction of iron metabolism Beutler et al. 2003, Barton and Adams 2010, Brissot et al. 2010. This characteristically demonstrates the predominance of iron accumulation in parenchymal organs (Beutler et al. 2003, Brissot et al. 2010). The consequence of this excessive deposition leads to accelerated tissue deterioration and functional impairment of the afflicted structures (Barton and Adams 2010, Brissot et al. 2010). Thus, the pathological entity is associated with the clinical onset of liver cirrhosis, Diabetes Mellitus, cardiomyopathies, arthropathies, endocrine pancreatic disease and the classical hyperpigmentation of the skin (C.B. Moyes et al. 2008, john's book). In fact, the multiorgan manifestations of this ailment with its associated toxic amalgamation exhibit insights into the functions of iron in cellular metabolism (Barton and Adams 2010). The complexity of the latter remains largely unresolved which increases the interest and need for further inquisition into the pathogenesis of haemochromatosis.
A Historical Review
In 1847, Rudolf Virchow marked the first reported appearance of "golden brown pigmentation" resident in haemorrhagic sites and areas of congestion(Barton and Adams 2010) The pigments solubility in sulphuric acid was also noted.
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Eighteen years later Armaund Trousseau, a French physician, published his findings in the article "glycosuria diabete sucre"(Olynyk et al. 2008) An lucid description of a diabetic patient with cirrhosis of the liver was portrayed. Trousseau employed terminology such as "pigment cirrhosis" and "bronze diabetes" to convey the pathological entity inflicting the patient. However, the correlation of iron accumulation with cutaneous hyperpigmentation was not yet constructed.
The title 'Heamochromatosis' was designated to the condition. The term was initially coined by a German pathologist, Freidrich Daniel Von Recklinghausen in 1890 who presented the theory of an association of excessive iron deposition and the onset of morbid systemic processing. In 1967, Perl's constitiuted an acid ferrocyanide reaction which aided in the histological examination of tissues and determination of the conditions presence.
In the preceding years Troisier(1871), Hanot and Chauffard(1882) acknowledged the authenticity of Trousseaus account and postulated their own theories of a correlation between iron overload and diabetes.
In 1935, John Seldon , an English gerontologist, described over 311 haemochromatosis cases and proposed it was a heritable entity. Sheldon's landmark publication entitled 'haemochromatosis' contained a vivid monograph of the pathological state suggesting the condition was "an inborn error of metabolism". Hypothesis of diabetes, infections and alcoholism as the causation of the disorder were rejected. The information from many other researchers of the same decade encompassed the role of heritable factors and the phenotypic variability of the condition amongst the sexes.
Simon et al. in 1976 made advancements in the genetic basis of the ailment and documented a strong link between the gene(s) implicated in haemochromatosis and those of the Major Histocompatibility Complex (MHC). A later investigation (Feder et al., 1996) supported Simon's theories for the function of a novel MHC-like gene in the progression to haemochromatosis.
Advancements in the phenotypic characterisation of the condition were accomplished throughout the 1980's. The latter was achieved through conductance of a multiplicity of studies on the association of the morbid state to; arthritis (Bomers and Terpstra 2010) and cardiovascular dysfunctions (Olson et al., 1987; Fitchett et al., 1980).
A breakthrough in research was denoted in 1996 with the discovery of the HFE gene, attributed to hereditary haemochromatosis. Feder and colloegues who constituded a research team at Mercator Genetics, with their revelation of this novel gene confirmed Sheldon's perceptions of the 1930's. The restricted accesability of genetic markers, comparable levels of linkage disequilibrium amongst markers and the limited recombinants exposed upon familial analysis have been advocated to account for the twenty year delay from the localisation of the haemochromatosis gene (Simon et al., 1975) and its molecular identification in 1996.
In 2000, an overview of the genetic basis of haemochromatosis was compiled by Dr. James Dooley and Professor Mark Worwood. A Medline search of world literature was made were review of existing guidelines of haemochromatosis genetics were amalgamated and presented at an open forum in April 1999 at the British society for Haematology. The guidelines attribute bodily iron accumulation to inheritance in the HFE gene on both copies of chromosome 6.
Today most research is enraptured in formulating concepts of why some individuals expressing homozygosity for the C282Y mutation never develop the phenotypic traits of iron overload. The regulation of iron absorption by a gene expressed on a progenitor cell (rather than that of the intestines absorptive cells) is also a fascinating conception captivating the research field.
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Furthermore, uncovering the possible clinical significance of mutant genes that account for a palpabe subset of haematochromatic patients would be largely compelling in the complex puzzle of the condition.
Defects in multiple genes are associated with an iron overload state. Therefore, it is possible to classify this heterogeneous condition according to the gene affected. Heamochromatosis can be differentiated into a primary or secondary disorder. Most incidences of primary haemochromatosis exhibit a hertitable sequence of expression and are entitled Heriditary Haemochromatosis (HH). While the secondary disorder may emanate from an array of conditions that demonstrate a defect of iron administration and ineffective erythropoietic activities. The latter may be congenital such as Î² thalassaemia or acquired including myelodysplasia disorders. Excess iron intake or liver disease also poses the threat of inducing the onset of excess iron deposition and its associated pathological alterations.
The Online Mendelian Inheritance in Man (OMIM) database classification system designates the hereditary haemochromatosis as follows;
Type 1 ("classical heamochromatosis") displays an autosomal recessive inheritance (alice book). It generates from mutations of the HFE gene (chromosome 6p21.3). Prostulated functions of the normal HFE protein are; interaction with transferrin receptor 1 and its modulation of hepcidin secretion from the liver. The major mutations of the HFE gene result from a misenese variant of G to A at nucleotide 845, which causes a cysteine to tyrosine substitution at the amino acid position 282 (C282Y) (Swinkels and Fleming 2011)A second common allelic variant demonstrates a histidine to aspartate substitution at amino acid 63 (H63D). Lesser mutations are S65C, C282S, [5569-A, an intronic polymosphism], VAL53MET, VAL59MET, GLN127HIS, ARG330MET, ILE105THR, GLY93ARG. At least 38 allelic variants of the HFE gene have been identified(Lee and Beutler 2009). However, the clinical significance of many is still uncovered. Determining the possible implications of theses variants remains an area of controversy(Swinkels and Fleming 2011).
Type 2 (juvenile haemochromatosis) is a rare autosomal recessive disorder which demonstrates the early onset of iron overload. It is further designated into two different subtypes reflecting the gene implicated. The defective gene of subtype A is hemojuvelin (HJV), whose locus is mapped on chromosome 1q21( alices book) . Similar to HFE, hemojuvelin alternates hepcidin expression. In rare cases subtype B presents with associated mutations in the hepcidin HAMP gene. Studies describing familial cases describe the homozgosity of the mutation in each of the affected cases( alices book).
Type 3 is an autosomal recessive ailment phenotypically comparable to HFE related haemochromatosis but is caused by mutations of the transferring receptor 2 gene. TFR2 is located on chromosome 7q22 and exhibits considerable homology to TFR, given that it is an isoform of the receptor. How the mutations affect TFR2 functionality remain undistinguished. However, Hepcidin levels are low in subjects expressing type 3, insinuating that TFR2 may regulate the hormones' synthesis. (Alice's book) Other mutations characterised that inactivate TFR2 span across the scope of the gene sequence, of theses Y250X is the dominant mutation under study(biastooto 2008)
Barton, J. C. and Adams, P. C. (2010) 'Clinical guidelines: HFE hemochromatosis-screening, diagnosis and management.', Nat Rev Gastroenterol Hepatol, 7(9), 482-4.
Beutler, E., Hoffbrand, A. V. and Cook, J. D. (2003) 'Iron deficiency and overload.', Hematology Am Soc Hematol Educ Program, 40-61.
Bomers, M. K. and Terpstra, V. (2010) 'Clinical image: arthritis caused by hereditary hemochromatosis.', Arthritis Rheum, 62(12), 3791.
Brissot, P., Bardou-Jacquet, E., Latournerie, M., Ropert-Bouchet, M., Island, M. L., Loréal, O. and Jouanolle, A. M. (2010) '[Hereditary iron overload].', Pathol Biol (Paris), 58(5), 316-23.
Lee, P. L. and Beutler, E. (2009) 'Regulation of hepcidin and iron-overload disease.', Annu Rev Pathol, 4, 489-515.
Olynyk, J. K., Trinder, D., Ramm, G. A., Britton, R. S. and Bacon, B. R. (2008) 'Hereditary hemochromatosis in the post-HFE era.', Hepatology, 48(3), 991-1001.
Swinkels, D. W. and Fleming, R. E. (2011) 'Novel observations in hereditary hemochromatosis: potential implications for clinical strategies.', Haematologica, 96(4), 485-8.