Journal of Islamabad Medical & Dental College (JIMDC); 2013:2(1):41-48 Review Article Iron Overload Diseases of Genetic Origin: Pathophysiology and Diagnosis Wajiha Mahjabeen Assistant Professor, Department of Pathology, Islamabad Medical & Dental College, Islamabad (Bahria University, Islamabad) Importance of iron in human body cannot be ignored due to occurs through ferroportin (Fpn, also known as MTP, its involvement in hemoglobin synthesis, oxidation reduction IREG1, SLC40A1). It is an iron export protein located at reactions and cellular proliferation. There are multiple iron duodenal epithelial cells, reticuloendothelial macrophages, overload diseases, either of genetic origin or due to hepatocytes and placenta. Fpn acts as a receptor for secondary causes. This review paper summarizes the hepcidin.9 mechanisms involved in iron hemostasis, role of hepcidin in Plasma iron levels maintains through hepcidin up or down its regulation and current advances in pathophysiology and regulation (Fig 1). Plasma iron over load increases the diagnosis of iron overload diseases related to genetic origin. hepcidin levels. Hepcidin in turns binds with Fpn and causes its degradation through multiple steps. Thus the transport of Hepcidin and its Regulation iron from cells to plasma decreases and plasma iron levels The discovery of hepcidin, a 25 amino acid peptide and its return toward normal.10 Decrease plasma iron levels result in role in iron regulation has helped a lot in understanding the reduced hepcidin concentration. Low levels of hepcidin pathogenesis of iron overload and deficiency disorders.1 In through restoration of normal Fpn, leads to correction of 2001 hepcidin was named due to increased expression of its plasma iron levels. In this way hepcidin regulates the plasma mRNA in liver and weak antimicrobial activity.2 In the same iron levels. year relationship of hepcidin with excessive iron Any abnormality in hepcidin gene HAMP or in genes concentration was identified. 3 Humans have single copy of affecting its synthesis (HEF, HJV, TfR2) or ferroportin hepcidin gene HAMP and there are multiple stimulatory and function can cause ineffective or inadequate levels of inhibitory factors that regulate the production of hepcidin hepcidin. This will results in plasma iron overload, iron through its mRNA expression.4 (Fig 1) depleted eneterocytes and macrophages. Reason of iron Bone morphogenic proteins (BMPs), members of overloaded hepatocyte is probably increased tendency of transforming growth factor β superfamily significantly effect liver to take up more non transferrin bound excessive plasma the hepcidin expression through BMP- hemojuvelin (BMP- iron.1 HJV) complex. HJV in membrane bound form acts as a Two types of genetic iron overload disease have been cofactor and accelerates the ability of BMP to increase identified (Table 1). hepcidin concentration through phosphorylation of Smad HFE Dependent Hemochromatosis (Type 1 (son of mothers against Decapentaplegic) protein.5 Soluble hemochromatosis) form of hemojuvelin (HJVs) and transmembrane serine Adult onset Hemochromatosis characterized by mutation in protease matriptase-2 (TMPRSS6) negatively regulates the HFE gene located on chromosome 6 is most frequently HJV levels.6 Neogenin regulates the cleavage of HJV after identified genetic recessive disorder. Being a recessive gene, making complex with matriptase.7 mutations both from father and mother are required for Human hemochromatosis (HFE) protein enhances the development of disease. The most common and the first hepcidin expression after binding with transferrin (Tf) and detected mutation was C282Y, identified as G>A missense transferrin receptor 2 (TfR2). After sensing the increased mutation. Cysteine was replaced by tyrosine at amino acid plasma iron levels through Tf saturation, HFE dissociates position 282.11 About80-85% of patients with typical from TfR1 and through Tf/TfR2/HFE complex enhances herditary hemochromatosis are homozygotes hepcidin expression.8 All of the above mentioned factors (C282Y/C282Y). 12 It is most common among white people. work independently. Asians are much less affected, probably due to the ethnic Regulation of Plasma Iron through Hepcidin admixture.13 Small percentage of people show compound Plasma iron levels depend upon two factors. First is the heterozygous mutation in HFE, one allele has C282Y dietary iron absorption through duodenal mucosa and mutation and the other allele has either H63D or S65C second is the rate of recycling of heme iron released from mutation. H63D mutation can be defined as substitution of senescent erythrocytes through macrophages. Transport of aspartate for histidine at aminoacid position 63. 14 While in iron from cells (duodenum or macrophages) to plasma S65C mutation cysteine is substituted for serine at amino 41 Journal of Islamabad Medical & Dental College (JIMDC); 2013:2(1):41-48 acid position 65.15 Besides this, other uncommon mutations mutation among all of them is nonsense mutation (Y250X) like E168Q, p.Val59Met (V59 M), p.Arg66Cys (R66C), at chromosome 7 that truncates TfR2 at amino acid p.Gly93Arg (G93R ),p.Ile105Thr (I105T), p.Arg224Gly 250.Disease is present in male or female within 30-40 years (R224G) and p.Val295Ala (V295A) have been identified in of age. It has equal frequencies in both white and non white heterozygous form on one allele and C282Y mutation on people.25 But the age of onset and severity of disease may second parallel allele. Among these, E168Q was exclusively vary in some cases. In some patients disease can be present along with H63D mutation.16 Among Asian manifested before age of 30 years. 26 ancestries a novel mutation (IVS5+1 G→A) has also been Type 4 hemochromatosis described. 17 Type 4 hemochromatosis is due to the mutation in Non HFE related hemochromatosis ferroportin gene at chromosome 2.27 Disease can be further All types of non HFE related hemochromatosis are classified into two types. autosomal recessive except type 4 that is autosomal Type 4a hemochromatosis dominant in nature. Mutations in ferroportin leads to loss of its function or loss Type 2 hemochromatosis (Juvenile hemochromatosis) of its cell surface localization that leads to absent iron export It is due to mutations in genes encoding hemojuvelin (HJV) activity. Mutation will be heterozygotic in nature. Protein and hepcidin (HAMP) proteins. Prevalence of disease is contained one mutant and one normal allele. Through equal among males and females. 18 normal allele, although intestinal iron transport will occur Hemojuvelin but it will not be possible to transport macrophage iron. Hemochromatosis due to HJV mutation has a high Thus impaired iron recycling from macrophages leads to prevalence and accounts for more than 90% of cases of Kupffer cell iron loading and decrease transferrin saturation. juvenile hemochromatosis. Disease has been reported in Plasma ferritin concentration will be increased. Patients (10- individuals of Europe, Asia and Africa. About more than 30 80 years of age) are seen with rare clinical symptoms and various HJV mutations have been discovered, either in decrease morbidity in the absence of genetic or acquired homozygous or compound heterozygous forms.19 More cofactors.28 Mutations associated with loss of iron export common mutation found is G320V at chromosome 1q, activity are mostly present in cytoplasmic region or defined as substitution of valine in place of glycine at transmembrane segments (Membrane cytoplasm interface). aminoacid position 320. It is detected in 50% of families There are variations regarding iron transport ability or cell having history of juvenile hemochromatosis. It usually surface localization of certain mutations. N144H, N144T, presents with severe iron overload.20 Disease present at A77D, V162del and S338R are the mutations associated younger age, more commonly in teens or twenties. However with loss of iron export ability.29 A polymorphism in the findings of HJV mutations in adult at about age 50 years ferroportin Q248H is found predominantly with iron highlights the wide spectrum of disease ranging from classic overload in African males.30 Other mutation involved with juvenile hemochromatosis at one extreme to late onset adult type 4a hemochromatosis include Y64N, V72F, G80V, form at the other extreme. The identified homozygous D157G, D181V, N185D, G267D, G490D etc. mutations are 745G>C (p.Asp249His), 934C>T Type 4b hemochromatosis (p.Gln312X).21 Some other mutations like R54X, C80R, It is of rare type in which heterozygous mutation in C119F, F170S, W191C,G250V,D249H,N269fs,R288W, ferroportin leads to loss in hepcidin binding capacity. Loss R326X, R385X etc have been identified in hemojuvelin of hepcidin induced internalization and degradation of hemochromatosis. ferroportin leads to unchecked transfer of iron from intestine Hepcidin and macrophages. The resultant plasma iron overload leads This is a type of Hemochromatosis due to mutation in to increased transferrin saturation that results in hepatocyte HAMP gene located at chromosome 19. It occurs at lower iron accumulation. Patients present mostly after 30 years of frequency and accounts for fewer than 10% of cases. About age.31 Some researchers found that N144D, N144T, Y64N nine different HAMP mutations, M31fs, M50fs, R56X, and especially C326S, C326Y are mutations associated with R59G, C70R, G71D, C78T, T84T, C153T (in both coding type 4b hemochromatosis. Among them C326S/Y mutation and non coding regions of gene) have been identified till is linked with