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Home , Aceruloplasminemia, Atransferrinemia, HFE H63D gene mutation, Hypotransferrinemia, Iron overload, Juvenile hemochromatosis

Journal of Islamabad Medical & Dental College (JIMDC); 2013:2(1):41-48

Review Article 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 (Fpn, also known as MTP, its involvement in 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 .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 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 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 and weak antimicrobial activity.2 In the same iron levels. year relationship of hepcidin with excessive iron Any abnormality in hepcidin HAMP or in 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 bound excessive plasma the hepcidin expression through BMP- (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 in protease matriptase-2 (TMPRSS6) negatively regulates the HFE gene located on 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 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 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 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 .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 () 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 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 loss of hepcidin binding, while the remaining now. 22 three mutations prevents the internalization of hepcidin Type 3 hemochromatosis ferroportin complex.32 While according to other studies Type 3 hemochromatosis is due to mutations in the Y64N mutation is associated with loss of iron transport. ( TFR2 ) gene.23 Near about 15 Combinations of Genetic Mutations mutations in Tfr2 gene (both homozygote and compound An intermediate iron overload phenotype has been explained heterozygote ) have been described till now. Mutations are in individuals with digenic inheritance of heterozygous R105X, M172K, Y250X, Q317X , R396X, del411H, mutation in HAMP and HFE or heterozygous A444T,R455Q, R481H, L490R,V561X, AVAQ594-597del, mutation in HJV and HFE. This may explains the low Q690P, G792R, ivs17–1G>A.24 The most important rate in classic hereditary hemochromatosis.

42 Journal of Islamabad Medical & Dental College (JIMDC); 2013:2(1):41-48

However, because such digenic inheritance is present in only features, a thoughtful clinician must think about the small proportion of individuals, some other mechanisms possibility of hemochromatosis. may also present to modify the Penetrance.33 Some 4. In comparison to general population, possibility of individuals present with typical clinical manifestations of hereditary hemochromatosis is 5-10 times more in juvenile hemochromatosis in adolescence, but on genetic patients with . Therefore it is generally testing they were found to have no mutation in HJV or recommended that patients with abnormal liver function HAMP. They were diagnosed as compound tests should undergo for iron studies during their heterozygotes for the HFE mutation (p.Cys282Tyr/ evaluation.35 p.His63Asp) and homozygous for the TFR2 mutation After evaluating the clinical sign and symptoms, the next (p.Gln317X).34 step is to carry out iron studies. Majority of asymptomatic Some studies reported the combinations of genetic mutations patients are diagnosed by performing their iron profile. that may enhance the degree of iron load and resultant Increased transferrin saturation (TfS) is thought to be the clinical severity. A male with severe juvenile hereditary most important test. A cut-off value of 45% is most hemochromatosis died at age 21 years due to severe commonly considered, due to its high sensitivity for resulting from excessive iron loading. He detecting type I homozygotes. But due to its lower was homozygous for the common HJV mutation specificity and positive predictive value, patients with p.Gly320Val, compound heterozygous for the HFE mutation transferrin saturation ≥ 45% should be ruled out for; p.His63Asp and p.Ser65Cys and homozygous for the HFE a. Some other cases of genetic iron overload mutation IVS2+4T>C, leading the authors to hypothesize conditions (type2, 3 and 4b hemochromatosis) that the HFE mutation may have exacerbated the clinical b. Chronic (by checking hemoglobin) phenotype in this patient.19 c. Acute /hepatic failure (through Clinical Features and Diagnosis of HFE transaminases + prothrombin index). Hemochromatosis Elevated TfS preferably be confirmed by repeating 1. Type 1 hemochromatosis is more common in men the test especially on fasting sample.31,35 between 40-60 years of age. Women present with signs Importance of ferritin in diagnosis of type I and symptoms approximately 10 years later than men. hemochromatosis is due to its less biological variability as The protectective factors found in women are perhaps compared to TfS, but as it can be elevated in some other menstrual loss and maternal iron loss during conditions like inflammation, it has more false positive rate. pregnancy.35 Plasma CRP can be helpful in order to rule out the 2. Despite the most common form of hemochromatosis, inflammation. In most circumstances, after ruling out the type I C282Y homozygotes have variable range of inflammation, elevated serum ferritin provides valuable clinical symptoms (penetrance). Majority of patients information about tissue Iron overload. Thus serum ferritin were found to have no or very less symptoms like level can be used to quantify the iron overload and to predict weakness, lethargy, abdominal pain and weight loss. advanced fibrosis and . Ferritin level between 300- Very few percentage of patients present with fully 500µg/L indicates mild while levels from 500-1000 µg/L expressed disease having like indicate medium iron overload. Serum Ferritin upto this , (typically of 2nd and 3rd level also predicts absence of cirrhosis, irrespective of metacarpophalyngeal joints), skin darkening, disease duration.While levels > 1000 µg/L shows severe mellitus, impotence, depression, arrthymias, among all iron overload along with elevated aspartate aminotransferase this the prevalence of liver disease is more common.36 (AST) and alanine aminotransferase (ALT) levels predicts In order to rule out the variable penetrance of disease, the presence of cirrhosis in majority of C282Y many candidate genes that may modify the homozygotes.38 hemochromatosis phenotype have been examined, but If a patient presents with relevant signs/symptoms or the exact and proper reason for this variability in positive family history (having first degree relative of humans have not been determined yet.37 hereditary hemochromatosis), then both TfS saturation and 3. Simple C282Y and simple H63D heterozygotes will serum ferritin level should be performed despite of doing never present with sign and symptoms of disease.31 single test. If either of tests detects abnormality then next Majority of compound heterozygote and H63D step is to perform HFE mutation analysis homozygote are very rarely associated with disease At HFE commonly detected mutations are manifestations. In fact in these patients presence of homozygous C282Y (C282Y/C282Y) or heterozygous signs and symptoms will usually be associated with (H63D or S65C).Individuals having mutations of other comorbidities such as or dysmetabolic C282Y/C282Y or C282Y/H63D with severe syndrome. Therefore during the evaluation of patients, signs/symptoms could be screened for mutations in other after ruling out the other common causes of these genes.

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Table 1: Brief description of genetic iron overload diseases

Disease Age of onset Clinical phenotype Gene Chrom Pattern of Common of symptoms osome inheritanc Mutations e HFE related Hemochromatosis Type 1 Middle TfS, SF, Fatigue, HFE 6 AR C282Y age(>40 arthritis, dark skin, liver years) disease

Type 2a Younger age TfS, SF, HJV 1 AR G320V Type 2b (<30 years) Endocriopathies, HAMP 19 AR M31fs, M50fs, without R56X, G71D significant involvement of liver Type 3 Young (30-40 TfS, SF, TFR2 7 AR Y250X years), <30 Cardiomyopathy, liver years (few disease, severity between cases) type 1 & 2 Type 4a 10-80 years TfS , SF, clinical SLC40A1 2 AD A77D, manifestation like type 1 Type 4b >30 years TfS, SF, Clinical C326S, C326Y manifestations like type 1 Aceruloplas Adult TfS, SF, CP 3 AR 607insA, 1285 miemia , ins TACAC neurological symptoms Atransferrin Adult TfS, Pallor TF 3 AR A477P emia TfS (Total ferritin saturation), SF (Serum ferritin), AR (Autosomal recessive), AD (Autosomal dominant), CP ( gene)

MRI can be done in order to assess visceral iron overload Stage 4: Elevated transferrin saturation, increased ferritin Facility of MRI and HFE genetic analysis, decreases the level in association with clinical symptoms importance of liver . It is only recommended in manifesting organ damage leading to worse C282Y homozygotes or compound heterozygotes, having prognosis (cirrhosis with the risk of hepatocellular elevated liver enzymes (ALT, AST) or serum ferritin levels carcinoma, -dependent diabetes mellitus, >1000µg/L. A hepatic iron index of more than 1.9 suggests cardiomyopathy). iron overload. in addition to quantify elevated Clinical features and diagnosis of non-HFE liver iron, gives information about cellular distribution of Hemochromatosis iron (hepatocyte versus macrophage) and about associated In patients after exclusion of type 1 hemochromatosis, abnormalities like , fatty liver and diagnosis of non-HFE iron overload can be made by first ..39 assessing the patients age. If patients age is less than 30 Next step is to stage the phenotypic manifestations of HFE years the possible options can be; a. Type 2 C282Y homozygotes into five grades by Haute Autorité de Santé (HAS) in France.40 This will be helpful for clinicians hemochromatosis b. Type 3 hemochromatosis. If patient’s age is more than 30 years then possible diagnosis can be a. in deciding the right path of treatment and follow up: five Type 3 hemochromatosis b. Type 4b hemochromatosis.31 grades Homozygotes (C282Y) are: In all types of non-HFE hemochromatosis genetic testing is Stage 0: No biochemical or clinical findings advisable only in presence of iron overload.35 Stage 1: Only elevated transferrin saturation (>45%) Type 2 hemochromatosis (Juvenile hemochromatosis) Stage 2: Increased transferrin saturation (>45%) along with  Mostly patients present with hypogonadotrophic high serum ferritin levels (> 300 µg/L in men; > 200 , cardiomyopathies, arthopathy and µg/L in women) diabetes. Prolonged hypogonadism may lead to Stage 3: Both increased transferrin saturation and serum osteopenia and .41 Among all these cardiac ferritin levels along with clinical symptoms affecting disease was thought to be the major clinical the quality of life (asthenia, impotence, arthropathies, manifestation.42 As compared to HFE related etc.). hemochromatosis, hepatocelluar carcinoma is not

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present in juvenile hemochromatosis, perhaps due to the associated tissue iron overload or damage. H63D early death of individuals as a result of cardiac homozygote occasionally can present with mild iron complications.43 overload but in all above cases associated co-morbidities  Patients are diagnosed with high serum ferritin level and should be ruled out. C282Y homozygosity or compound increased transferrin saturation. Serum ferritin heterozygosity along with elevated serum ferritin levels concentration ranges from 1000-7000 µg/L. Transferrin should undergo for therapeutic interventions. If HFE genetic saturation is very high often reaching 100%. testing detects the mutation but liver iron concentration is  MRI is used as a non invasive method of quantifying normal then only follow up is advisable. Thus in order to hepatic iron over load. Superconducting quantum detect hemochromatosis at early stages and to prevent its interference device (SQUID) is also another complications, family screening programme including iron noninvasive method for quantifying liver iron studies and HFE genotypic testing is recommended in first biomagnetometry. But it is available only on a research degree relatives of HFE related hemochromatosis. basis. Screening for non-HFE related hereditary hemochromatosis  Iron overload is more severe in type 2 hemochromatosis is not recommended. If on genetic analysis HFE mutation is as compared to type 1. On liver biopsy hepatic iron not detected but iron overload is present, then screening for 46 index of higher than 1.9 suggests juvenile other gene mutations is advisable. hemochromatosis. Miscellenous Hemochromatosis  Genetic testing may be performed in order to detect Hereditary Aceruloplasminemia HJV mutation and if negative then for HMP mutation.44 It is classic autosomal recessive disease due to mutations in Type 3 Hemochromatosis ceruloplasmin gene on chromosome 3. Five different  Clinical manifestations of disease are similar as of HFE mutations have been studied in ceruloplasmin gene, related hemochromatosis like arthralgia, skin 607insA, 1285 ins TACAC, 2389delG, Trp858ter, 3019- pigmentation, diabetes, failure and cirrhosis. 1G-A. Function of ceruloplasmin is to oxidize ferrous iron into ferric form that will be transported by circulating  Lab results show high transferrin saturation, increase 47 ferritin levels showing hepatocyte iron excess transferrin. Mutations in ceruloplasmin gene causes  The severity of disease lies somewhere between deficiency of ceruloplasmin function, and leads to impaired juvenile and HFE-hemochromatosis cellular iron release due to instability of ferroportin.  Diagnosis can be confirmed by performing specific Resultant altered ferroportin function leads to impaired genetic testing for TfR2 mutation. release of iron into plasma. There will be hypo-sideremia and low transferring saturation. Due to the excessive iron  It is complicated and more time consuming to do the load in basal ganglia (mechanism not explained yet), clinical genetic detection of TfR2 mutations that is why it is manifestations of disease will be more severe than type 4 more preferable to first rule out type 4b hemochromatosis. Patients will present with low plasma hemochromatosis through detection of ferroportin ceruloplasmin, low feroxidase activity, high plasma ferritin mutation. After that testing for TfR2 mutation should be levels, decrease plasma iron and transferring saturation done only in those patients who show negative results along with diabetes, anemia and neurological symptoms.48 for ferroportin mutation., 45 Type 4a & 4b hemochromatosis Divalent metal ion transporter 1(DMT1)-Related iron  Due to hepcidin resistance its clinical manifestations overload imitate the type 1 hemochromatosis. This autosomal recessive disorder is due to homozygous or  There will be elevated ferritin levels in both types 4a compound heterozygous mutation in the SLC11A2 gene and 4b while TfS saturation will be increased in type 4b encoding DMT1. DMT1 protein is not only involved in and will be decreased in type 4a. dietary iron uptake at the apical membrane of duodenal  It is autosomal dominant in nature that’s why history of enterocytes but is also involved in the release of iron hyperferritinemia in first degree relatives may also help from acidified endosomes into the cytosol. Therefore in making the diagnosis mutation in DMT1 leads to visceral iron overload with  Specific genetic testing for ferroportin mutation will slightly elevated plasma ferritin levels.49 confirm the diagnosis.31 Family Screening Programme Hereditary In family screening program, if one partner shows positive It is very rare autosomal recessive disorder and is generally hemochromatosis genotype, but results of other partner are observed in young people due to mutation in TF gene at normal then children of such parents will be obligate chromosome 3. Transferrin deficiency leads to iron overload heterozygote (carrier) and will not require further testing. through different mechanisms, either through direct effect on Simple Heterozygote genotypic individuals (C282Y or erythropoiesis or indirectly through hepcidin regulation. H63D) may found increased markers but without Absent transferrin leads to inability to deliver iron in bone

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Stimulatory factors: 1. Iron overload 2. Inflammation + HFE/TfR2, TfR2, HJV-BMP, Smad

Hepatocyte Hepcidin Inhibitory factors: - production 1.Decrease plasma iron levels 2. Hypoxia 2. Anemia 3. Erythropoiesis Circulating Hepcidin

Iron Iron Macrophage Enterocyte

Fpn Fpn Fpn Fpn

Fig 1: Production of hepcidin and its role in plasma iron regulation through ferroportin (Fpn).

marrow for red cell production. This leads to severe different homozygote or compound heterozygote mutations . This deficiency of iron in will be identified. 52 creates a potent erythroid drive which ultimately leads to Sideroblastic anemia massive absorption of iron from intestine. Person become Genetic form of this disease is characterized by multiple iron overloaded due to increase non transferrin bound iron mutations in different genes like ALAS2, ABCB7, GLRX5 (due to transferring deficiency).50 Transferrin also regulates and SLC25A38 genes. Sideroblastic are associated hepcidin expression either through erythropoiesis dependent with iron overload in perinuclear mitochondria of or independent manner. Deficiency of transferrin leads to erythroblast.53 decreased hepcidin levels. This in turn leads to iron overload.51 Multiple homozygotic or heterozygotic References mutations like e 1429G>C (A477P), 562_571del 1. Ganz T. Hepcidin and iron regulation, 10 years later. Blood. 572_580dup, 1180G>A (E394K) and multiple 2011; 117: 4425-4433. polymorphisms like -84G>G, -2G>G, IVS4 + 110T>T, 2. Park CH, Valore EV, Waring AJ, Ganz T. Hepcidin, a urinary IVS4-60T>T, 739T>T (L247L), IVS8 + 61C>C, and antimicrobial peptide synthesized in the liver. J Biol Chem. 2001;276: 7806–7810 IVS10-23C>C have been identified in transferrin protein. 3. Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot Patient will present with mild clinical manifestation like P, etal. A new mouse liver-specific gene, encoding a protein pallor. On biochemical testing plasma transferrin levels will homologous to human antimicrobial peptide hepcidin, is be approximately half than normal. On genetic testing overexpressed during iron overload. J Biol Chem. 2001; 276:7811–7819.

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