Cause Of Iron Overload Research Articles

Iron overload patients with unknown etiology from national survey in Japan.

Transfusion is believed to be the main cause of iron overload in Japan. A nationwide survey on post-transfusional iron overload subsequently led to the establishment of guidelines for iron chelation therapy in this country. To date, however, detailed clinical information on the entire iron overload population in Japan has not been fully investigated. In the present study, we obtained and studied detailed clinical information on the iron overload patient population in Japan. Of 1109 iron overload cases, 93.1% were considered to have occurred post-transfusion. There were, however, 76 cases of iron overload of unknown origin, which suggest that many clinicians in Japan may encounter some difficulty in correctly diagnosing and treating iron overload. Further clinical data were obtained for 32 cases of iron overload of unknown origin; median of serum ferritin was 1860.5ng/mL. As occurs in post-transfusional iron overload, liver dysfunction was found to be as high as 95.7% when serum ferritin levels exceeded 1000ng/mL in these patients. Gene mutation analysis of the iron metabolism-related genes in 27 cases of iron overload with unknown etiology revealed mutations in the gene coding hemojuvelin, transferrin receptor 2, and ferroportin; this indicates that although rare, hereditary hemochromatosis does occur in Japan.

Serum ferritin and risk for new-onset heart failure and cardiovascular events in the community.

Heart failure (HF) is a common manifestation of patients with primary and secondary causes of iron overload, whereas in patients with established HF iron deficiency impairs outcome. Whether iron stores, either depleted or in overload, amplify the risk for new-onset HF among healthy individuals is unknown. The present study aimed to assess whether markers of iron status or the iron-regulatory hormone hepcidin are associated with new-onset HF or cardiovascular (CV) events in the general population. In 6386 subjects from the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) trial, a prospective, community-based, cohort study, markers of iron status and the iron-regulatory hormone hepcidin were measured. Mean age was 53.1 ± 12.0 years, and 50.7% of the cohort was female. During a median follow-up of 8.3 (interquartile range 7.8-8.9) years, 199 subjects (3.1%) were newly diagnosed with HF, 456 (7.1%) experienced a CV event, and 356 (5.6%) died from all causes. A higher annual HF incidence per ferritin quartile was observed in women (P < 0.001), but not in men (P for interaction 0.032). Multivariable analyses demonstrated ferritin levels to remain independently predictive for new-onset HF in women only (P = 0.024). This association persisted within strata defined by markers of the metabolic syndrome, markers of inflammation, or other markers of iron homeostasis, including hepcidin. No association between ferritin or hepcidin and incident CV events or all-cause mortality was observed in either sex. Increased serum ferritin levels independently amplify the risk for new-onset HF in women in the community.

Study of abnormal iron metabolism parameters and iron overload in patients with myelodysplastic syndromes

目的研究骨髓增生异常综合征(MDS)患者铁代谢参数和临床特征。方法对2015年6月至2016年3月间初诊未经祛铁治疗的94例MDS患者的铁代谢参数和临床特征进行回顾性调查。结果94例初治MDS患者中，71例(75.53%)贫血，56例(59.57%)存在输血依赖，52例(55.32%)存在铁过载。IPSS低危／中危-1较中危-2/高危铁过载多见(P<0.01)。铁过载组和非铁过载组比较，血清铁(SI)升高[36.5(8.5~64.7)µmol/L对25.2(3.7~45.3)µmol/L，P<0.01]，转铁蛋白饱和度(TSAT)降低[43.5%(12.2%~77.2%)对53.4%(14.8%~97.5%)，P<0.01]，不稳定细胞铁(LCI)及细胞内活性氧簇(ROS)差异无统计学意义。靶器官(心、肝、胰岛等)功能临床资料比较中，铁过载组ALT及B型钠尿肽前体分别为25(3~158)U/L及190(6~4 281)ng/L，均明显高于非铁过载组的16(5~80)U/L及84(12~2 275)ng/L(P=0.03及P=0.05)。难治性贫血伴环状铁粒幼红细胞(RARS)患者与非RARS患者铁代谢参数差异均无统计学意义(P>0.05)，输血依赖程度和输血量显著影响SI、TSAT及SF(P值均<0.01)，但LCI及ROS组间差异无统计学意义。无输血依赖、非铁过载的38例患者中，骨髓红系病态造血、幼红细胞比例增高组LCI水平显著增高。结论初治MDS患者贫血及输血依赖现象较为常见，输血频率和输血量显著影响铁代谢参数。而无输血依赖的非铁过载患者骨髓红系病态造血、幼红细胞比例增高影响LCI水平，LCI可以作为衡量铁过载和铁分布重要的早期指标。

Znaczenie terapii chelatującej u pacjentów z przeładowaniem żelaza w wyniku częstych transfuzji krwi

The most common cause of iron overload (IO) are red blood cells transfusions, in less extend also increase of iron absorption from the gut due to ineffective erythropoiesis. IO leads to liver fibrosis/cirrhosis, cardiac dysfunction, diabetes and other endocrinopathies, changes in immunity worsening of survival in patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT). To prevent and delay complications associated with iron deposition in organs, iron chelation therapy with deferoxamine, deferiprone, deferasirox in monotherapy or in combination is recommended. Chelation therapy should be considered in transfussion-dependent patients diagnosed with inherited anemias (sickle cell anemia, thalassemias), low risk myelodysplastic syndromes, primary idiopatic myelofibrosis, with ferritin concentration higher than 1000 ng/mL or with iron depositions (confirmed in liver biopsy or nuclear magnetic resonance). Patients who have undergone allo-HSCT with persistent IO may also be candidates for treatment with iron chelators. We have more consistent data and evidences that chelating therapy improves the function of damaged organs, improves hematological response, and prolongs the survival of patients.

Gastric siderosis: An under-recognized and rare clinical entity

The increased deposition of iron in gastric mucosa is known as gastric siderosis. It is believed that the only regulated step of the iron metabolism cycle occurs during absorption in the small intestine. Once this system becomes overwhelmed due to either local or widespread iron levels, then iron can be absorbed very quickly by a passive concentration-dependent mechanism. This excess iron is initially stored in the liver but later can be found in the pancreas, heart and joints. Excess iron is not expected to deposit in the gastric mucosa. This gastric deposition has been found in association with hemochromatosis, oral iron medications, alcohol abuse, blood transfusions, hepatic cirrhosis and spontaneous portacaval shunt with esophageal varices. The precise mechanism of this iron deposition in gastric epithelial and stromal cells is still not well understood; thus, identification of iron in gastric mucosa raises many questions. On histology, the pattern of deposition is variable, and recognition of the pattern is often useful to choose the appropriate workup for the patient and to diagnose and possibly treat the cause of iron overload. In this article, we have described a well-referenced review of this rare clinical entity with different histological patterns, diagnostic tests and the clinical significance of the different patterns of iron deposition.

Metabolic response to subacute and subchronic iron overload in a rat model.

One of the common causes of iron overload is excessive iron intake in cases of iron-poor anemia, where iron saccharate complex (ISC) is routinely used to optimize erythropoiesis. However, non-standardized ISC administration could entail the risk of iron overload. To induce iron overload, Wistar rats were intraperitoneally injected with subacute (0.2 mg kg⁻¹) and subchronic (0.1 mg kg⁻¹) overdoses of ISC for 2 and 4 weeks, respectively. Iron status was displayed by an increase in transferrin saturation (up to 332%) and serum and liver iron burden (up to 19.3 μmol L⁻¹ and 13.2 μmol g⁻¹ wet tissue, respectively) together with a drop in total and unsaturated iron binding capacities "TIBC, UIBC" as surrogate markers of transferrin activity. Iron-induced leukocytosis (up to 140%), along with the decline in serum transferrin markers (up to 43%), respectively, mark positive and negative acute phase reactions. Chemical stress was demonstrated by a significant rise (p > 0.05) in indices of the hemogram (erythrocytes, hemoglobin, hematocrit, leukocytes) and stress metabolites [corticosterone (CORT) and lactate]. Yet, potential causes of the unexpected decline in serum activities of ALT, AST and LDH (p > 0.05) might include decreased hepatocellular enzyme production and/or inhibition or reduction of the enzyme activities. The current findings highlight the toxic role of elevated serum and liver iron in initiating erythropoiesis and acute phase reactions, modifying iron status and animal organ function, changing energy metabolism and bringing about accelerated glycolysis and impaired lactate clearance supposedly by decreasing anaerobic threshold and causing premature entering to the anaerobic system.

Erythron to the Liver: Send Iron

For successful expansion of erythropoiesis, the activity of the hormone erythropoietin (EPO) must be coordinated with the supply of iron to erythroid precursors. Increased iron supply for erythropoiesis is ensured by the suppression of hepcidin, the iron-regulatory hormone produced by the liver. Low hepcidin levels allow greater absorption of dietary iron and greater mobilization of iron from the stores in the spleen and the liver. The mechanisms coordinating erythropoietic activity with iron delivery are not well understood. We recently identified erythroferrone as a new mediator of hepcidin suppression during stress erythropoiesis1. Erythroferrone (ERFE) is a member of the C1q/TNF-related protein (CTRP) family of metabolic mediators. ERFE is produced in response to EPO by erythroblasts of the bone marrow and spleen of mice. The induction of ERFE by EPO was dependent on Jak2/Stat5 signaling. Ex vivo treatment of human erythroblasts with EPO also resulted in a dramatic induction of ERFE expression. The essential role of ERFE in acute hepcidin suppression by erythropoiesis was demonstrated in ERFE-deficient mice. In contrast to wild-type mice which suppressed hepcidin ~10-fold within hours after hemorrhage or erythropoietin injection, no hepcidin suppression was observed in ERFE knockout mice within 24 h. As a consequence, ERFE-deficient mice exhibited delayed recovery of hemoglobin after hemorrhage or severe inflammation. Treatment of mice or hepatocytes with recombinant ERFE protein confirmed the hepcidin-suppressive activity of the protein. It remains to be seen whether administration of ERFE protein would be useful for the treatment of anemia of inflammation mediated by elevated hepcidin. In iron-loading anemias including β-thalassemia, hepcidin is chronically suppressed by the exuberant but ineffective erythropoietic activity. This is the cause of iron overload in untransfused thalassemia patients and may contribute to iron loading even in transfused patients. We found that ERFE expression is greatly increased in the bone marrow and spleen of mice with β-thalassemia intermedia (th3 model). Transgenic ablation of ERFE in th3 mice normalized hepcidin and partially corrected their iron overload. Although human studies of the role of ERFE in health and disease are clearly needed, ERFE is a promising candidate for the pathological suppressor of hepcidin in anemias with ineffective erythropoiesis.

The Safety, Tolerability and Efficacy of Deferasirox in Older Patients with Transfusional Dependent Anemia

BackgroundThe majority of myelodysplastic syndrome (MDS), primary myelofibrosis (MPN) and aplastic anemia (AA) patients during the course of the disease develops a symptomatic anemia requiring transfusions of packed red blood cells (PRBC), each of them containing approximately 200 mg of elementary iron. Because of the fact that human beings are unable to actively eliminate iron from the body, secondary emosiderosis yet becomes evident when body iron content is above 7-14 grams, an amount easily reached after receiving as few as 15-30 PRCB units.From a pathophysiologic point of view, long-term transfusion therapy is certainly the most important cause of iron overload (IOL) in these patients; nevertheless, others mechanism account for this phenomenon, and in particular the role of the ineffective erythropoiesis.Deferasirox (DSX) is the principal option currently available for iron chelation therapy in the management of IOL due to transfusion dependent anemia. DSX is also a potent NF-kB inhibitor, and this effect may explain in part the phenomenon of hematological improvements reported in different clinical trials and in case reports.Materials and MethodsWe analyzed 21 patients,16 male and 5 female, with transfusion dependent anemia and with a transfusional history of almost 10 packed PRBC, treated with DSX from 1 February 2013 to 1 February 2014. Median age was 80 years (65-88). 20 patients (95%) have almost a comorbidity, 7 of them (30%) have more than 3 comorbidities. Heart disease was the most common comorbidity. At baseline median creatinine clearance was 76 ml/min; in 12 patients was < 60ml/min but >40 ml/min, according to NCCN Guidelines. All patients (16 MDS, 3 MPN, 1 AA, 1 hemolytic anemia) were evaluated for IOL by serum ferritin (SF), while only 7 with RM T2*.Median SF at baseline was 1750 μg/L and median PRBC was 32.The starting dose of DSX was 10 mg/kg/day; the dosage should be adjusted up to 20–30 mg/kg/daily according to the transfusional regimen, SF and IOL, if tolerated.ObjectivesTo observe safety, tolerability, and efficacy of iron chelation therapy with DSX in older patients with transfusion dependent anemia.ResultsThe SF decreased of 50% and 66% after 3 and 6 months respectively. The SF was normalized (SF<500 μg/L) in 5 patients (24%) after six months. The IOL occurred also in patients with a short transfusional history, inferior to 10 packed red blood cells, and SF <1000 μg/L. That was more evident in MDS patients especially in RARS. The median dose tolerated of DSX was 20 mg/kg/daily.The drug related adverse events (AE) was evaluated by the Common Terminology Criteria for Adverse Events (CTCAE versione 4.02). The severe adverse events (SAE) occurred in 10%.The most Common AE were diarrhea, nausea, upper abdominal pain, serum creatinine increase and rash. Hematologic response according to IWG criteria 2006 with DSX were observed in 17% of patients and was more frequent in MPN than MDS, independently from IOL.ConclusionDSX has shown high efficacy in a variety of iron overloaded patients with different anemias. Appropriate patient selection and regular clinical multidisciplinary evaluation of comorbidity and concomitant therapy remains a critical components of successful ther­apy, combined with carefull monitoring for both adverse effects and clinical efficacy, in order to derive the most benefit from a carefully imple­mented chelation strategy.In our cohort improvement of erythropoiesis was marginal. This might be due to the very small patient group analyzed. DisclosuresNo relevant conflicts of interest to declare.

New Insights on Iron Study in Myelodysplasia

Objective: Hepcidin plays a pivotal role in iron homeostasis. It is predominantly produced by hepatocytes and inhibits iron release from macrophages and iron uptake by intestinal epithelial cells. Competitive ELISA is the current method of choice for the quantification of serum hepcidin because of its lower detection limit, low costs, and high throughput. This study aims to discuss the role of hepcidin in the pathogenesis of iron overload in recently diagnosed myelodysplasia (MDS) cases. Materials and Methods: The study included 21 recently diagnosed MDS patients and 13 healthy controls. Ferritin, hepcidin, and soluble transferrin receptor (sTFR) were measured in all subjects. Results: There were 7 cases of hypocellular MDS, 8 cases of refractory cytopenia with multilineage dysplasia, and 6 cases of refractory anemia with excess blasts. No difference was observed among the 3 MDS subtypes in terms of hepcidin, sTFR, and ferritin levels (p>0.05). Mean hepcidin levels in the MDS and control groups were 55.8±21.5 ng/mL and 19.9±2.6 ng/mL, respectively. Mean sTFR was 45.7±8.8 nmol/L in MDS patients and 31.1±5.6 nmol/L in the controls. Mean ferritin levels were significantly higher in MDS patients than in controls (539.14±83.5 ng/mL vs. 104.6±42.9 ng/mL, p<0.005). There was a statistically significant correlation between hepcidin and sTFR (r=0.45, p=0.039). No difference in hepcidin levels between males and females was observed, although it was lower in males in comparison to females (47.9±27.6 vs. 66.7±35.7, p>0.05). Conclusion: Hepcidin may not be the main cause of iron overload in MDS. Further studies are required to test failure of production or peripheral unresponsiveness to hepcidin in MDS cases.

Hereditary hypotransferrinemia can lead to elevated transferrin saturation and, when associated to HFE or HAMP mutations, to iron overload.

As our understanding of iron metabolism improves through the more accurate description of iron metabolism actors, new causes of iron overload are identified. We, here, report 16 cases of hereditary hypotransferrinemia related to 4 previously undescribed TF (transferrin) mutations (p.Val221Gly, p.Arg609Trp, p.Glu370Lys, p.Tyr533X and p.Cys421Arg). We show that, besides increasing serum transferrin saturation without iron overload, hypotransferrinemia, when associated to mutations in HFE or HAMP or to acquired factors, can lead to clinically relevant iron burden. These cases emphasize the usefulness of serum transferrin determination in the diagnostic evaluation of iron overload and the importance for clinicians to be aware of this syndrome.

Cardiac Involvement in Hemochromatosis

Cardiac hemochromatosis or primary iron-overload cardiomyopathy is an important and potentially preventable cause of heart failure. This is initially characterized by diastolic dysfunction and arrhythmias and in later stages by dilated cardiomyopathy. Diagnosis of iron overload is established by elevated transferrin saturation (>55%) and elevated serum ferritin (>300 ng/mL). Genetic testing for mutations in the HFE (high iron) gene and other proteins, such as hemojuvelin, transferrin receptor, and ferroportin, should be performed if secondary causes of iron overload are ruled out. Patients should undergo comprehensive 2D and Doppler echocardiography to evaluate their systolic and diastolic function. Newer modalities like strain imaging and speckle-tracking echocardiography hold promise for earlier detection of cardiac involvement. Cardiac magnetic resonance imaging with measurement of T2* relaxation times can help quantify myocardial iron overload. In addition to its value in diagnosis of cardiac iron overload, response to iron reduction therapy can be assessed by serial imaging. Therapeutic phlebotomy and iron chelation are the cornerstones of therapy. The average survival is less than a year in untreated patients with severe cardiac impairment. However, if treated early and aggressively, the survival rate approaches that of the regular heart failure population.

Correlation ofhemochromatosisgene mutations and cardiovascular disease in hemodialysis patients

BACKGROUND AND OBJECTIVESCardiovascular disease (CVD) is a major cause of death in hemodialysis (HD) patients. Hemochromatosis (HFE) gene mutations are reported to be associated with CVD. The present study aims to investigate the association of HFE gene polymorphism with CVD in HD patients.DESIGN AND SETTINGSCross-sectional case-control.METHODSC282Y/H63D mutations of HFE gene were evaluated in 560 HD patients and 480 healthy controls from 4 HD centers in North China. The results obtained from this evaluation process were correlated with biochemical parameters including iron status (serum iron, ferritin, and transferrin concentration), cardiovascular disease, and inflammation marker CRP, IL-6, TNF-α.RESULTSNo C282Y mutations were detected in HD patients or healthy controls in this study. The genotype of H63D heterozygous mutation was similar in HD patients with CVD, HD patients without CVD, and controls. H63D homozygous mutation was 7.4% (19/257), 3.1% (9/303), and 1.0% (5/480) for the 3 groups, respectively. Compound heterozygosity was not found in this study. The relative risk for CVD in HD patients with H63D homozygous mutation was 2.59 (95% CI: 1.15–5.84). H63D homozygous mutation had significantly higher serum ferritin concentrations compared with wild-type individuals. Moreover, HD patients had significantly higher levels of inflammatory biomarkers such as CRP, IL-6, and TNF-α. The multivariate logistic regression analysis revealed that H63D mutation instead of ferritin level was an independent risk factor of CVD for HD patients.CONCLUSIONSOur study demonstrates for the first time that there was an association between H63D homozygous mutations and CVD in HD patients. Elevated serum CRP, IL-6, and TNF-α levels were also related to CVD in HD patients.

The Red Cell: How Erythropoiesis Modulates Hepcidin Expression

Abstract SCI-24Erythroid precursors in the bone marrow require transferrin-bound iron for hemoglobin synthesis. Therefore, it is not surprising that the regulation of erythropoiesis and iron metabolism is interlinked. Iron demand for erythropoiesis is communicated to the iron-regulatory machinery through incompletely understood mechanisms. At the core of systemic iron homeostasis is the peptide hormone hepcidin, restricting cellular iron export to plasma by inducing the endocytosis and proteolysis of ferroportin. Hepcidin, a liver-synthesized peptide hormone, is released in response to increased iron load, and there is early evidence that circulating hepcidin concentrations affect the distribution of iron between the macrophage storage compartment (favored by higher hepcidin concentrations) and parenchymal cells, including cardiac myocytes and hepatocytes (favored by low hepcidin). Furthermore, ferroportin has recently been identified on erythroid precursors. Its purpose in this cell type and its function in the interface between erythropoiesis and iron metabolism are unclear. Additionally, in response to bleeding or the administration of erythropoietin, expansion of erythroid precursors suppresses hepcidin, most likely through one or more mediators released by the bone marrow and acting on hepatocytes. Iron-loading anemias with ineffective erythropoiesis, in particular β-thalassemia, demonstrate the effects of pathological “erythroid regulators” of hepcidin. Although erythrocyte transfusions are the main cause of iron loading in patients who receive them (β-thalassemia major), lethal iron overload is seen also in patients who are rarely or never transfused (β-thalassemia intermedia). Here, iron hyperabsorption is the cause of iron overload and, as in hereditary hemochromatosis, is caused by low hepcidin. Decreased hepcidin expression in β-thalassemia, with concurrent ineffective erythropoiesis and iron overload, indicates that the “erythroid regulator” may play an even more substantial role in iron metabolism than the “stores regulator.” Two members of the bone morphogenetic protein (BMP) family, growth differentiation factor (GDF) 15 and Twisted Gastrulation (TWSG1), have been implicated as candidate bone marrow-derived hepcidin suppressors in β-thalassemia. Neither factor is responsible for the physiologic hepcidin suppression in response to hemorrhage-induced stress erythropoiesis, and the physiologic suppressor is not known. We focus here on the current state of knowledge regarding the regulation of iron metabolism and attempt to elucidate the interface between iron regulation and erythropoiesis using evidence in part derived from animal models of β-thalassemia. A more complete understanding of the coregulation of erythropoiesis and iron metabolism may lay the foundation for improving diagnosis, increasing treatment options, and ultimately impacting the well-being of patients afflicted with different anemias and/or iron overload related-disorders. Disclosures:No relevant conflicts of interest to declare.

Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis

AbstractThe deficiency of hepcidin, the hormone that controls iron absorption and its tissue distribution, is the cause of iron overload in nearly all forms of hereditary hemochromatosis and in untransfused iron-loading anemias. In a recent study, we reported the development of minihepcidins, small drug-like hepcidin agonists. Here we explore the feasibility of using minihepcidins for the prevention and treatment of iron overload in hepcidin-deficient mice. An optimized minihepcidin (PR65) was developed that had superior potency and duration of action compared with natural hepcidin or other minihepcidins, and favorable cost of synthesis. PR65 was administered by subcutaneous injection daily for 2 weeks to iron-depleted or iron-loaded hepcidin knockout mice. PR65 administration to iron-depleted mice prevented liver iron loading, decreased heart iron levels, and caused the expected iron retention in the spleen and duodenum. At high doses, PR65 treatment also caused anemia because of profound iron restriction. PR65 administration to hepcidin knockout mice with pre-existing iron overload had a more moderate effect and caused partial redistribution of iron from the liver to the spleen. Our study demonstrates that minihepcidins could be beneficial in iron overload disorders either used alone for prevention or possibly as adjunctive therapy with phlebotomy or chelation.

PWE-280 Ferroportin disease—an important cause of iron overload

IntroductionFerroportin disease is a recently characterised cause of iron overload. Unlike hereditary haemochromatosis it involves genetic mutations of SLC40A1 gene, and has autosomal dominant transmission. We describe here 3 siblings...

HFE Gene Mutations in Cryptogenic Cirrhosis Patients

Dear Editor, In Western countries, HFE-linked hereditary hemochromatosis (HH) is considered to be the most common cause of iron overload. The HFE gene, first identified in 1996, is located on the short arm of chromosome 6. The majority of patients with phenotypic HH are homozygous for the C282Y mutation, a major mutation of the HFE gene, whereas compound heterozygosity (C282Y/H63D) is found in patients with a milder iron loading phenotype [1]. Because hepatic iron overload promotes liver fibrogenesis in HH, it is crucial to know whether the presence of any HFE gene mutations might accelerate liver damage. In a study by Jowkar et al. [2] published in the November issue of Hepatitis Monthly, the C282Y mutation was not detected in cryptogenic cirrhosis patients as well as healthy individuals; however, 22% of the patients and 28% of the healthy individuals were found to be heterozygous for the H63D mutation. Therefore, they concluded that HH is not the major cause of cryptogenic cirrhosis in the Iranian population. Although this study adds to the general knowledge on the molecular genetics of HH in the different regions of Iran, the findings of this study should be debated. We, as well as other researchers, have studied the frequency of HFE gene mutation among Iranian patients with chronic hepatitis and healthy individuals [3][4][5]. In the aforementioned studies, it was found that the allele frequency of the C282Y mutation was between 0% and 0.1%, whereas the allele frequency of the H63D mutation varied between 8.6 and 12.5% in healthy individuals. It is also noteworthy to mention that cryptogenic cirrhosis is a diagnosis of exclusion. Therefore, it is assumed that several of the patients in these studies are in fact alcoholic hepatitis or nonalcoholic steatohepatitis (NASH) patients. The patients' reluctance to admit to alcohol consumption along with the absence of advanced molecular techniques result in a higher number of false positive cases of cryptogenic cirrhosis in Iran. It is also not quite plausible to conclude that "HH is not a major cause of cryptogenic cirrhosis in the Iranian population" as Jowkar et al. have indicated in their study [2]. Perhaps, the authors meant to say that the development of cirrhosis in these patients cannot be attributed to HFE mutations. In the absence of any positive laboratory index of iron overload, there would be no evidence to correlate merely HFE mutations with hepatic cirrhosis even if these patients harbored HFE mutations. Taken together, our understanding of the role of HFE mutations in liver fibrogenesis in the context of viral hepatitis, alcoholic hepatitis, or other unknown accelerating factors is very premature, and further research and broader translational studies are required to unravel the underlying mechanisms.

HFE Gene Mutations in Cryptogenic Cirrhosis Patients

Dear Editor, In Western countries, HFE-linked hereditary hemochromatosis (HH) is considered to be the most common cause of iron overload. The HFE gene, first identified in 1996, is located on the short arm of chromosome 6. The majority of patients with phenotypic are homozygous for the C282Y mutation, a major mutation of the HFE gene, whereas compound heterozygosity (C282Y/H63D) is found in patients with a milder iron loading phenotype [1]. Because hepatic iron overload promotes liver fibrogenesis in HH, it is crucial to know whether the presence of any HFE gene mutations might accelerate liver damage. In a study by Jowkar et al. [2] published in the November issue of Hepatitis Monthly, the C282Y mutation was not detected in cryptogenic cirrhosis patients as well as healthy individuals; however, 22% of the patients and 28% of the healthy individuals were found to be heterozygous for the H63D mutation. Therefore, they concluded that is not the major cause of cryptogenic cirrhosis in the Iranian population. Although this study adds to the general knowledge on the molecular genetics of in the different regions of Iran, the findings of this study should be debated. We, as well as other researchers, have studied the frequency of HFE gene mutation among Iranian patients with chronic hepatitis and healthy individuals [3][4][5]. In the aforementioned studies, it was found that the allele frequency of the C282Y mutation was between 0% and 0.1%, whereas the allele frequency of the H63D mutation varied between 8.6 and 12.5% in healthy individuals. It is also noteworthy to mention that cryptogenic cirrhosis is a diagnosis of exclusion. Therefore, it is assumed that several of the patients in these studies are in fact alcoholic hepatitis or nonalcoholic steatohepatitis (NASH) patients. The patients' reluctance to admit to alcohol consumption along with the absence of advanced molecular techniques result in a higher number of false positive cases of cryptogenic cirrhosis in Iran. It is also not quite plausible to conclude that HH is not a major cause of cryptogenic cirrhosis in the Iranian population as Jowkar et al. have indicated in their study [2]. Perhaps, the authors meant to say that the development of cirrhosis in these patients cannot be attributed to HFE mutations. In the absence of any positive laboratory index of iron overload, there would be no evidence to correlate merely HFE mutations with hepatic cirrhosis even if these patients harbored HFE mutations. Taken together, our understanding of the role of HFE mutations in liver fibrogenesis in the context of viral hepatitis, alcoholic hepatitis, or other unknown accelerating factors is very premature, and further research and broader translational studies are required to unravel the underlying mechanisms.

Hepatic iron overload following liver transplantation of a C282y homozygous allograft: a case report and literature review

Hereditary haemochromatosis is a common genetic disease associated with progressive iron overload and parenchymal organ damage including liver, pancreas and heart. We report a case of inadvertent transplantation of a liver from a haemochromatosis donor to a 56-year-old Asian female. Progressive iron overload occurred over a 2 year follow up as assessed by liver biopsy and iron studies in the absence of a secondary cause of iron overload, supporting a primary role of liver rather than small intestine in the regulation of iron homeostasis in hereditary haemochromatosis.

Transferrin Saturation and Mortality

To the Editor: Ellervik and colleagues (1) recently reported a positive association between transferrin saturation (TS) and mortality. Several questions arise from this observation: Is the association due to all causes of iron overload or to hereditary hemochromatosis only? Does the study underestimate the true association? And, is mortality due to variation in iron, transferrin, or both? We have relevant data from population-based studies of twins and families of European descent living in Australia (2, 3). TS values (calculated from serum transferrin and iron) and HFE (hemochromatosis) genotypes for C282Y (rs1800562, genotyped) and H63D (rs1799945, imputed) are available for 8096 adults (3151 men and 4945 women; mean age, 47 years). Replicate TS measurements are available for 460 participants (178 men and 282 women) from studies in 1993–1996 and 2001–2005. Their mean age at the time of the second study was 50 years (range, 39–72 years). The Discussion in the Ellervik et al. report implies that the association of TS with mortality is driven by the C282Y variant (which is associated with …

The global burden of iron overload

There have been major developments in the field of iron metabolism in the past decade following the identification of the HFE gene and the mutation responsible for the C282Y substitution in the HFE protein. While HFE-associated hemochromatosis occurs predominantly in people of northern European extraction, other less-common mutations can lead to the same clinical syndrome and these may occur in other populations in the Asian-Pacific region. The most common of these is the mutation that leads to changes in the ferroportin molecule, the protein responsible for the transport of iron across the basolateral membrane of the enterocyte and from macrophages. Recent research has unraveled the molecular processes of iron transport and regulation of how these are disturbed in hemochromatosis and other iron-loading disorders. At the same time, at least one new oral iron chelating agent has been developed that shows promise in the therapy of hemochromatosis as well as thalassemia and other secondary causes of iron overload. It is pertinent therefore to examine the developments in the global field of iron overload that have provided insights into the pathogenesis, disease penetrance, comorbid factors, and management.