Hereditary Haemochromatosis: An Overview of Genetic Etiology and Clinical Considerations

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Abstract. The syndrome involves abnormally high absorption of iron in the duodenum and is associated with hepcidin deficiency. It was shown chromosome-6 harboured the allelic variations associated with haemochromatosis; The specific gene implicated in the syndrome was discovered, termed HFE by the World Health Organization in 1997. There are currently recognized distinct clinical entities constituting five syndromes within this spectrum, which are as follows: “classic haemochromatosis” (HFE) autosomal recessive, maps to chromosome 6p21.3; juvenile haemochromatosis (HFE2) autosomal recessive (HFE2A) maps to chromosome 1q21 and (HFE2B) maps to chromosome 19q13; haemochromatosis type 3 (HFE3) autosomal recessive, maps to chromosome 7q22 and haemochromatosis type 4 (HFE4) autosomal dominant, maps to chromosome 2q32. It was noted, in the absence of organomeagaly due to haemochromatosis, therapeutic phlebotomy ensures normal life expectance, while in advanced haemochromatosis, life expectancy is shortened, even with therapeutic phlebotomy. Introduction. Haemochromatosis, a syndrome of latent onset and especially prevalent among Irish populations (Ryan et al., 1998; Murphy et al., 1998; Byrnes et al., 2001), is said to have an incidence rate within European descent Caucasians as a whole of between 1:200 and 1:500. The syndrome involves abnormally high absorption of iron in the duodenum and is associated with hepcidin deficiency (Ahmad et al., 2002; Bridle et al., 2003; Limdi and Crampton, 2004). Treatment is by phlebotomy weekly. Trousseau, in 1865, first described the now classic triad of diabetes mellitus, hyperpigmentation, and portal cirrhosis (Limdi and Crampton, 2004). Von Recklinghaussen, in 1889, coined the term haemochromatosis, and Sheldon, in 1935, described the heritable nature of the syndrome, now of great import in diagnosing the susceptibility of patients in an effort to mitigate the morbidity wrought by the syndrome (Limdi and Crampton, 2004). Genetic Etiology and Classification. Simon et al (1976; 1987) showed chromosome-6 harboured the allelic variations associated with haemochromatosis; Feder et al. (1996) discovered the specific gene implicated in the syndrome, termed HFE by the World Health Organization (WHO) in 1997. Feder et al. (1996) also identified the two most common allelic variations, missense type, resulting in susceptibility and possible clinical phenotypic manifestation of haemochromatosis, the C282Y allelic variation, cysteine to tyrosine, and the H63D, histidine to aspartate, with the former being most prevalent (84%) among those presenting with clinical phenotypic manifestations of haemochromatosis. Mura et al. (1999) provided evidence for an allelic variation, S65C, serine to cysteine, associated with a less severe form of haemochromatosis. While the undernoted allelic variations are associated with autosomal recessive inheritance, Pietrangelo et al. (1999) has suggested the existence of an autosomal dominant inheritance pattern associated with their discovery of another gene, SLC11A3; moreover, other patterns of inheritance are suspected but currently lack clinical practicality for diagnosing haemochromatosis (Limdi and Crampton, 2004). The possibility exists for a patient to have haemochromatosis in the heterozygote state as a compound (C282Y/ H63D) allelic variation (Limdi and Crampton, 2004). Although usually termed “carriers” of the syndrome, in very rare expressions of the syndrome there may be a heterozygous individual having only one allelic variation in a singe gene (Limdi and Crampton, 2004). Townsend and Drakesmith (2002) postulated, based on clinical observations of the mechanisms of haemochromatosis, HFE acts to either inhibit uptake of release of iron, in the crypt cells and reticuloendothelial system. Disruption of this mechanism, then, would result in haemochromatosis (McKusick, 2005). The four groups of syndromes within the spectrum of haemochromatosis, organized by the following general characteristics of severity, clinical, and biochemical findings, include the following: group I, transferrin saturation, serum ferritin; group II, overall greater severity and earlier onset than group I; group III, affects “total body iron stores” without other remarkable biochemical findings; and group IV, involves remarkable findings only with regards to serum biochemical studies (transferrin saturation, serum ferritin) (McKusick, 2005). There are currently recognized distinct clinical entities constituting five syndromes within this spectrum, which are as follows: “classic haemochromatosis” (HFE) autosomal recessive, maps to chromosome 6p21.3; juvenile haemochromatosis (HFE2) autosomal recessive (HFE2A) maps to chromosome 1q21 and (HFE2B) maps to chromosome 19q13; haemochromatosis type 3 (HFE3) autosomal recessive, maps to chromosome 7q22 and haemochromatosis type 4 (HFE4) autosomal dominant, maps to chromosome 2q32 (McKusick, 2005). Diagnosis. While hepatic iron count is the best test for haemochromatosis (Rowe et al., 1977), transferrin saturation scores (Appendix A, Fig. 1) are comparable and can be used as a screening or as the preliminary test in suspected patients, but Rowe et al. (1977) and Edwards et al. (1977) did not recommend serum ferritin as the initial measure, though some cite its role along with transferrin in making a differential diagnosis. Transferrin above 62% is indicative of the homozygous state, with a specifity of 92% (Dadone et al., 1982). Transferrin, however, can only predict homozygous individuals and not heterozygous individuals (Borecki et al., 1990). Leggett et al (1990) purposed including transferrin saturation scores in normal health screenings, and Worwood et al. (1991) said such a routine screening should be conducted in the general populous but use ferritin concentrations as a measure. In family screening, where one member is already identified as being homozygous for haemochromatosis, or in patients who have already had transferrin saturation, serum ferritin, genetic testing is advised, most often involving C282Y and H63D (Limdi and Crampton, 2004). Moreover, it should be considered that the finding of a homozygous or compound heterozygous individual alone does not qualify or quantify a clinical manifestation of disease and should be proceeded by biochemical studies to determine the clinical status of the individual (Limdi and Crampton, 2004; McKusick, 2005). According to Limdi and Crampton (2004) the American Association for the Study of Liver Diseases (AASLD) recommends hepatic biopsy in patients suspected of haemochromatosis, only when they are symptomatic, >40 years, or have serum ferritin >1000 µ/L. Treatment. Barton et al. (1998) set the serum ferritin parameters at 300 µ/L (men) and 200 µ/L (women) for therapeutic phlebotomy. In such patents, McKusick (2005) indicated therapeutic phlebotomy should be performed weekly, removing 450-500 m/L of blood, until serum ferritin is brought to 10-20 µ/L and maintain at <50 µ/L; many symptoms associated with haemochromatosis can be “substantially alleviated.” Limdi and Crampton (2004) recommended checking transferrin saturation and serum ferritin every 3 months, with phlebotomy every 3-4 months for life. Furthermore, Worwood et al. (1991) suggested rather than therapeutic phlebotomy, homozygotes ought to donate blood regularly, so society benefits as well. Niederau et al. (1985) noted, in the absence of organomagaely due to haemochromatosis, therapeutic phlebotomy ensures normal life expectance, while in advanced haemochromatosis, life expectancy is shortened, even with therapeutic phlebotomy. Simons and Mahler (1987) found that therapeutic phlebotomy also restores fertility in patients with hypogonadotrophic hypogonadism due to haemochromatosis. Complications. Chromium deficiency has been suggested to be associated with haemochromatosis, which, with chromium’s relationship with insulin, would account for the diabetes mellitus often seen in haemochromatosis patients (Sargent et al., 1979). Hussain et al. (2000) showed a relationship between mutations in the p53 tumour suppressor gene and iron overload in patients with haemochromatosis, which could explain the increased incidence of hepatocellular carcinoma in such patients, responsible for 33.3% of mortalities associated with haemochromatosis (McKusick, 2005). Other considerable complications of haemochromatosis include cardiac failure and arrhythmias (Appendix A., Fig. 2.). Conclusion. Given good clinical treatment for the syndrome exists and best results achieved early in the syndrome’s progression, it is imperative to detect such individuals early, preferably before the onset of clinically recognisable manifestations of disease occur (McKusick, 2005). 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