Статті в журналах: "Non HFE Hemochromatosi"

1

Hernández, Gonzalo, Xenia Ferrer-Cortès, Veronica Venturi, Melina Musri, Martin Floor Pilquil, Pau Marc Muñoz Torres, Ines Hernandez Rodríguez, et al. "New Mutations in HFE2 and TFR2 Genes Causing Non HFE-Related Hereditary Hemochromatosis." Genes 12, no. 12 (December 13, 2021): 1980. http://dx.doi.org/10.3390/genes12121980.

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Hereditary hemochromatosis (HH) is an iron metabolism disease clinically characterized by excessive iron deposition in parenchymal organs such as liver, heart, pancreas, and joints. It is caused by mutations in at least five different genes. HFE hemochromatosis is the most common type of hemochromatosis, while non-HFE related hemochromatosis are rare cases. Here, we describe six new patients of non-HFE related HH from five different families. Two families (Family 1 and 2) have novel nonsense mutations in the HFE2 gene have novel nonsense mutations (p.Arg63Ter and Asp36ThrfsTer96). Three families have mutations in the TFR2 gene, one case has one previously unreported mutation (Family A—p.Asp680Tyr) and two cases have known pathogenic mutations (Family B and D—p.Trp781Ter and p.Gln672Ter respectively). Clinical, biochemical, and genetic data are discussed in all these cases. These rare cases of non-HFE related hereditary hemochromatosis highlight the importance of an earlier molecular diagnosis in a specialized center to prevent serious clinical complications.

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2

Anderson, Gregory J., and Lawrie W. Powell. "HFE and Non-HFE Hemochromatosis." International Journal of Hematology 76, no. 3 (October 2002): 203–7. http://dx.doi.org/10.1007/bf02982788.

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3

Pietrangelo, Antonello. "Non-HFE Hemochromatosis." Seminars in Liver Disease 25, no. 04 (2005): 450–60. http://dx.doi.org/10.1055/s-2005-923316.

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4

Lima Santos, Paulo Caleb Júnior d., Carla Luana Dinardo, Rodolfo Delfini Cançado, Isolmar Tadeu Schettert, José Eduardo Krieger, and Alexandre Costa Pereira. "Non-HFE hemochromatosis." Revista Brasileira de Hematologia e Hemoterapia 34, no. 4 (2012): 311–16. http://dx.doi.org/10.5581/1516-8484.20120079.

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5

Pietrangelo, Antonello. "Non-HFE hemochromatosis." Hepatology 39, no. 1 (January 2004): 21–29. http://dx.doi.org/10.1002/hep.20007.

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6

Viprakasit, Vip, Alison T. Merryweather-Clarke, Yingyong Chinthammitr, Lisa Schimanski, Hal Drakesmith, Somdet Srichairatanakool, Chanin Limwongse, Alain Townsend, and Kathryn J. H. Robson. "Molecular Diagnosis of the First Ferroportin Mutation (C326Y) in the Far East Causing a Dominant Form of Inherited Iron Overload." Blood 104, no. 11 (November 16, 2004): 3204. http://dx.doi.org/10.1182/blood.v104.11.3204.3204.

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Abstract Genetic hemochromatosis (HH) is a common inherited disorder in populations of European origin in which different types of genetic hemochromatosis (type 1–4) have been characterized. Most hemochromatosis-type 1 patients are homozygotes or compound heterozygotes for two HFE mutations C282Y and H63D. Studies of several non-HFE iron overload families led to identification of mutations in hemojuvelin and hepcidin (juvenile form-HFE2A and B), transferrin receptor 2 (HFE3) and ferroportin (HFE4) as a cause of different forms of hemochromatosis. In the Far East, inherited hemochromatosis has rarely been reported and may have been misdiagnosed due to the high prevalence of secondary iron loading from hemoglobin disorders. This report describes, for the first time, non-HFE iron overload in patients from Southeast Asia. The affected Thai family presented with a distinctive clinical phenotype including macrocytosis and elevated transferrin saturation (>95%), increased non-transferrin bound iron (NTBI) as well as raised serum ferritin and marked hepatic hemochromatosis. Our patients tolerated therapeutic phlebotomy well. DNAs from peripheral blood leukocytes were firstly analyzed for three common HFE mutations (C282Y, H63D and IVS5+1 G→A). Subsequently, we screened all coding sequences, promoters and exon/intron boundaries of the HFE, HAMP, TfR2, HJV and SLC40A1 genes using denaturing high performance liquid chromatography (DHPLC). The entire coding region and splice sites of these genes were amplified and directly sequenced. We identified a novel mutation (C326Y) in ferroportin (SLC40A1, IREG-1, MTP-1), a membrane iron transport protein due to a G→A substitution at nucleotide 1281 in exon 7. This mutation was confirmed by restriction fragment length polymorphism (RFLP) analysis using Sfa NI. Six hundred Thai and two hundred Vietnamese chromosomes were analyzed for the C326Y mutation by RFLP analysis and it was not detected in any of the healthy controls studied. This result suggested that the G→A substitution is not a common polymorphism and is likely to be the causative mutation for the phenotype in this family. Previous reported mutations of ferroportin, including A77D and V162del, which lead to type IV hemochromatosis, were characterized by increased serum ferritin despite normal transferrin saturation, in contrast to our patients’ phenotype. These autosomal dominant mutants are postulated to lead to disease due to loss of iron exporting function. Preliminary in vivo assay using transient transfection of wild-type and ferroportin mutants in HeLa or 293T cells revealed, as expected, a loss of function and diminished surface membrane localisation in A77D and V162del mutants. Surprisingly, the C326Y mutant was indistinguishable from wt ferroportin in both iron status of the cell and protein localization suggesting different pathophysiology leading to iron overload in our patients.

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7

Bardou-Jacquet, Edouard, and Pierre Brissot. "Diagnostic Evaluation of Hereditary Hemochromatosis (HFE and Non-HFE)." Hematology/Oncology Clinics of North America 28, no. 4 (August 2014): 625–35. http://dx.doi.org/10.1016/j.hoc.2014.04.006.

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8

Turshudzhyan, Alla, David C. Wu, and George Y. Wu. "Primary Non-HFE Hemochromatosis: A Review." Journal of Clinical and Translational Hepatology 000, no. 000 (February 2, 2023): 000. http://dx.doi.org/10.14218/jcth.2022.00373.

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9

Rabideau, Marina M., Hannah J. White, Michael Anderson, and Anne Deucher. "Clinical Testing of Five Hereditary Hemochromatosis-Related Genes: Preliminary Evidence for the Benefit of Next Generation Sequencing." Blood 124, no. 21 (December 6, 2014): 1355. http://dx.doi.org/10.1182/blood.v124.21.1355.1355.

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Abstract Introduction Hereditary hemochromatosis (HH) is a genetic form of iron overload. In cases of excessive iron deposition, serious clinical manifestations may occur, such as liver damage, cardiomyopathy, diabetes, and arthritis. First described in 1996, the HFE gene leads to autosomal recessive HH with reduced penetrance. In other words, two mutations in the HFE gene need to be present in a patient in order to develop symptoms of HFE-related HH, but not all patients with two mutations are affected. In the last 15 years, 4 additional genes were discovered that cause HH: HAMP (hepcidin), HFE2 (hemojuvelin), SLC40A1 (ferroportin), and TFR2 (transferrin receptor 2). HAMP, HFE2 and TFR2 mutations are inherited in a recessive pattern, whereas SLC40A1 mutations are inherited in a dominant pattern. HAMP and HFE2 mutations cause a severe, early-onset form of HH. There is some evidence that sequence changes in HAMP, HFE2 and TFR2 may interact with homozygous HFE mutations, causing a more severe phenotype. Current HH testing guidelines only exist for the most common HFE mutations (C282Y and H63D), with no specific recommendations regarding full gene sequencing for any of the HH genes. Recent research suggests that sequential sequencing may be beneficial in patients who test negative for the most common HFE mutations, exhibit a more severe or early-onset phenotype compared to what is normally seen in HFE-related HH, and/or are of non-Caucasian ethnicity. Next Generation Sequencing (NGS) is a new high-throughput sequencing technology that allows testing of multiple genes concurrently and can detect rare and novel HH-causing mutations that are not typically assayed using targeted methods. However, sequencing can also identify sequence changes known as variants of uncertain significance (VUS) - changes that have not yet been characterized as disease-causing or benign. This abstract summarizes the results of clinical NGS for the five HH-related genes, and shows preliminary evidence as to its’ increased diagnostic yield for HH diagnosis. Methods Patients were referred for clinical full gene sequencing of HFE, HAMP, HFE2, SLC40A1, and/or TFR2 using Next Generation Sequencing (Illumina MiSeq). Results from patients with a clinical indication of iron overload or HH who were tested from 9/2013 - 7/2014 were reviewed. The diagnostic yield of sequencing for all five HH genes was determined. Patients who only had sequencing for a subset of the five genes were analyzed separately. Patients who had testing for a familial mutation were excluded from the review. Results In total, 56 patients underwent HH-related NGS. Thirty-five (62.5%) were males and 21 (37.5%) were females. Ages ranged from 3-77yrs (avg. 40.9yrs). Fifty-one percent were Caucasian, 9% Hispanic, 4% African American, 16% Asian, and 20% not specified. Forty-one patients were tested for all five genes. HH-causing mutations were found in 9 patients: 5 (12.2%) were c.187C>G (p.H63D) HFE homozygous, 1 (2.4%) was c.845G>A (p.C282Y) HFE homozygous, and 3 (7.3%) had mutations in non-HFE genes: SLC40A1 c.430A>T (p.N144Y) heterozygous, SLC40A1 c.533G>A (p.R178Q) heterozygous, and HFE2 c.959G>T (p.R178Q) homozygous. Nine patients (22%) were heterozygous carriers of an HFE mutation. One or more VUSes were found in 5 patients (12.2%). In 18 patients (43.9%), no pathogenic mutations or VUSes were found. There were 15 additional patients who only had sequencing of 1-3 of the available genes. Results for those patients consisted of 1 H63D HFE homozygote, 3 HFE heterozygotes (2 H63D and 1 C282Y) and 1 VUS. Conclusions The new sequencing technology of NGS makes it possible to test multiple genes at the same time. In this sample, sequencing of HFE, HAMP, HFE2, SLC40A1, and TFR2 genes resulted in an additional diagnostic yield compared to HFE C282Y and H63D testing alone. In patients who have a genetic explanation for their HH, management can be personalized based on genotype-phenotype correlation (e.g. N144Y SLC40A1 mutations may lead to reduced phlebotomy tolerance) and at-risk family members can be screened. In addition, all patients in this sample with non-HFE positive results were reportedly Caucasian, highlighting the benefit of sequencing regardless of ethnic background. This preliminary study is an important step toward gaining a better understanding of the genetics of HH. Ultimately, NGS data may make it possible to update current clinical guidelines for HH. Disclosures Rabideau: Invitae: Employment, Equity Ownership.

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10

Sandhu, Kam, Kaledas Flintoff, Mark D. Chatfield, Jeannette L. Dixon, Louise E. Ramm, Grant A. Ramm, Lawrie W. Powell, V. Nathan Subramaniam, and Daniel F. Wallace. "Phenotypic analysis of hemochromatosis subtypes reveals variations in severity of iron overload and clinical disease." Blood 132, no. 1 (July 5, 2018): 101–10. http://dx.doi.org/10.1182/blood-2018-02-830562.

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Key PointsThis comprehensive comparison of the genetic subtypes of hemochromatosis reveals more severe iron overload and disease in non-HFE forms. Arthropathy is more common in HFE-related hemochromatosis, suggesting that joint disease may not be associated with iron.

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11

Bardou-Jacquet, Edouard, Zeineb Ben Ali, Marie-Pascale Beaumont-Epinette, Olivier Loreal, Anne-Marie Jouanolle, and Pierre Brissot. "Non-HFE hemochromatosis: Pathophysiological and diagnostic aspects." Clinics and Research in Hepatology and Gastroenterology 38, no. 2 (April 2014): 143–54. http://dx.doi.org/10.1016/j.clinre.2013.11.003.

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12

Zoller, Heinz, and Benjamin Henninger. "Pathogenesis, Diagnosis and Treatment of Hemochromatosis." Digestive Diseases 34, no. 4 (2016): 364–73. http://dx.doi.org/10.1159/000444549.

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Hemochromatosis is a common cause of chronic liver disease and HFE genotyping allows decisive and non-invasive diagnosis. Molecular and clinical genetic studies have led to the identification of genes other than HFE in patients with inherited diseases associated with increased hepatic iron storage that can cause hemochromatosis, which adds complexity to a diagnostic approach to patients with suspected hemochromatosis. Despite major advances in genetics, hepatic iron quantification by non-invasive methods therefore remains the key to the diagnosis of hemochromatosis. Although associated with homozygosity for the C282Y polymorphism in the HFE gene in >80% of patients, hemochromatosis is a complex genetic disease with strong environmental disease modifiers. Testing for mutations in the non-HFE hemochromatosis genes transferrin receptor 2, hemojuvelin, HAMP and SLC40A1 is complex, costly and time-consuming. Demonstration of hepatic iron overload by liver biopsy or MRI is therefore required before such complex tests are carried out. The pathogenesis of chronic liver disease in hemochromatosis is mainly attributed to the redox potential of tissue iron, and only the more recent studies have focused on the toxic properties of circulating iron. Considering the fact that an increased saturation of transferrin and high iron in plasma are the hallmark of all hemochromatosis forms, an alternative view would be that toxic iron in the circulation is involved in the pathogenesis of hemochromatosis. Recent studies have shown an increased concentration of redox-active iron in plasma in patients with increased transferrin saturation. This finding supports the hypothesis that tissue iron may be the ‘smoking gun' of iron-induced organ damage. Taken together, caring for patients with suspected or established hemochromatosis still remains a challenge, where understanding the genetics, biochemistry and cell biology of hemochromatosis will aid better diagnosis and treatment of affected individuals.

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Barton, James C., and J. Clayborn Barton. "Dupuytren's Contracture in Alabama HFE Hemochromatosis Probands." Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders 5 (January 2012): CMAMD.S9935. http://dx.doi.org/10.4137/cmamd.s9935.

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Background Dupuytren's contracture (DC) and HFE hemochromatosis occur in some of the same at-risk populations and present with similar comorbid conditions. Methods We estimated DC prevalence in two cohorts of white Alabama hemochromatosis probands (294 C282Y homozygotes, 67 C282Y/H63D compound heterozygotes) in a retrospective study. We performed logistic regressions on DC using the following independent variables: age, body mass index, heavy ethanol consumption, serum ferritin, elevated serum AST/ALT, non-alcoholic fatty liver disease, viral hepatitis, cirrhosis, and diabetes. Results One man and two women with C282Y homozygosity had DC (prevalence 1.02%; 95% CI 0.35%–2.96%). A man with C282Y/H63D had DC (prevalence 1.49%; 95% CI 0.26%–7.98%). DC occurred as an autosomal dominant trait in his kinship. In regression analyses, no single variable predicted DC. We observed no new DC cases after the diagnosis of hemochromatosis (mean follow-up 12.9 ± 7.5 years (1 SD), and 9.0 ±5.1 years, respectively). Conclusions Our prevalence estimates of DC in white Alabama hemochromatosis probands are similar to those found in the white US population cohorts. DC risk was unrelated to the variables we studied.

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Nelson, James E., and Kris V. Kowdley. "Non-HFE hemochromatosis: Genetics, pathogenesis, and clinical management." Current Gastroenterology Reports 7, no. 1 (January 2005): 71–80. http://dx.doi.org/10.1007/s11894-005-0069-y.

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Chaudhry, Hunza, Aalam Sohal, Arpine Petrosyan, Gieric Laput, Marina Roytman, and Devang Prajapati. "Iron Man: Non-HFE Hemochromatosis Without Significant Fibrosis." ACG Case Reports Journal 10, no. 1 (January 2023): e00982. http://dx.doi.org/10.14309/crj.0000000000000982.

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Finberg, Karin E., Rebecca Whittlesey, Mark D. Fleming, and Nancy C. Andrews. "Tmprss6 Is a Genetic Modifier of the Hfe-Hemochromatosis Phenotype in Mice." Blood 114, no. 22 (November 20, 2009): 625. http://dx.doi.org/10.1182/blood.v114.22.625.625.

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Abstract Abstract 625 HFE-associated hereditary hemochromatosis is an autosomal recessive disorder characterized by inappropriately elevated absorption of dietary iron by the gastrointestinal mucosa, resulting in excessive storage of iron in multiple organs. A significant proportion of individuals who are homozygous for HFE mutations fail to develop clinical symptoms, suggesting that environmental and/or genetic factors may influence the penetrance of this disorder. In vitro and animal studies have revealed that HFE promotes the expression of hepcidin, a circulating hormone produced by the liver that acts to inhibit iron absorption by the duodenum. In contrast, TMPRSS6, a transmembrane serine protease produced by the liver, acts to inhibit hepcidin expression; both humans and mice harboring TMPRSS6 mutations display impaired intestinal iron absorption, resulting in a phenotype of iron-refractory iron deficiency anemia (IRIDA). Here we asked if heterozygous or homozygous loss of Tmprss6 function could modify the iron overload phenotype of Hfe null (Hfe-/-) mice, a mouse model of human HFE-hemochromatosis. To test this, we bred Hfe-/- mice to Tmprss6-/- mice; the latter harbor a targeted disruption of the Tmprss6 serine protease domain and exhibit an IRIDA phenotype. We generated Hfe-/-Tmprss6+/+, Hfe-/-Tmprss6+/-, and Hfe-/-Tmprss6-/- female mice (6-10 mice per genotype), in which parameters of systemic iron homeostasis were compared at eight weeks of age by Student's t test. Consistent with previous study of Hfe-/- mice, Hfe-/- mice harboring two wild type Tmprss6 alleles (Hfe-/-Tmprss6+/+ mice) showed serum iron concentration, transferrin saturation, and hepatic non-heme iron content that were significantly elevated compared to wild type mice of similar genetic background. Heterozygosity for Tmprss6 mutation, however, markedly reduced the severity of the hemochromatosis phenotype of Hfe-/- mice. Compared to Hfe-/- mice with two wild type Tmprss6 alleles, Hfe-/- mice that were heterozygous for Tmprss6 mutation (Hfe-/-Tmprss6+/- mice) showed significant reductions in serum iron concentration (p<0.01), transferrin saturation (p<0.005), and non-heme iron content of liver (p<10-4). Furthermore, homozygosity for Tmprss6 mutation completely ameliorated the iron overload phenotype of Hfe-/- mice and in fact led to systemic iron deficiency. Compared to both Hfe-/-Tmprss6+/+ and Hfe-/-Tmprss6+/- mice, Hfe-/-Tmprss6-/- mice showed markedly reduced serum iron concentration (p<10-7), transferrin saturation (p<10-10), and non-heme iron content of liver (p<10-4). Hfe-/-Tmprss6-/- mice also displayed iron deficiency anemia and appeared phenotypically similar to previously characterized Tmprss6-/- mice harboring two wild type copies of Hfe. In summary, these results demonstrate that Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice. These findings suggest that natural genetic variation in the human ortholog TMPRSS6 might modify the clinical penetrance of HFE-hemochromatosis and raise the possibility that pharmacological inhibition of TMPRSS6 activity might prove an effective therapy in this disorder. Disclosures: No relevant conflicts of interest to declare.

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Wallace, Daniel F., Palle Pedersen, Jeannette L. Dixon, Peter Stephenson, Jeffrey W. Searle, Lawrie W. Powell, and V. Nathan Subramaniam. "Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis." Blood 100, no. 2 (July 15, 2002): 692–94. http://dx.doi.org/10.1182/blood.v100.2.692.

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Abstract Hemochromatosis is a common disorder characterized by excess iron absorption and accumulation of iron in tissues. Usually hemochromatosis is inherited in an autosomal recessive pattern and is caused by mutations in the HFE gene. Less common non-HFE–related forms of hemochromatosis have been reported and are caused by mutations in the transferrin receptor 2 gene and in a gene localized to chromosome 1q. Autosomal dominant forms of hemochromatosis have also been described. Recently, 2 mutations in theferroportin1 gene, which encodes the iron transport protein ferroportin1, have been implicated in families with autosomal dominant hemochromatosis from the Netherlands and Italy. We report the finding of a novel mutation (V162del) in ferroportin1 in an Australian family with autosomal dominant hemochromatosis. We propose that this mutation disrupts the function of the ferroportin1 protein, leading to impaired iron homeostasis and iron overload.

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Panigrahi, I., F. Ahmad, R. Kapoor, PK Sharma, G. Makharia, and R. Saxena. "Evidence for non-HFE linked hemochromatosis in Asian Indians." Indian Journal of Medical Sciences 60, no. 12 (2006): 491. http://dx.doi.org/10.4103/0019-5359.28978.

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Washington, Kay. "Hepatic Iron Deposition: New Observations in non-HFE Hemochromatosis." Advances in Anatomic Pathology 13, no. 6 (November 2006): 341–42. http://dx.doi.org/10.1097/01.pap.0000213060.51639.23.

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Castiella, Agustin, Eva Zapata, Pedro Otazua, Leire Zubiaurre, and Javier Fernandez. "Non-HFE-related hemochromatosis: The role of genetic factors." Hepatology 51, no. 4 (February 19, 2010): 1473–74. http://dx.doi.org/10.1002/hep.23603.

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Fracanzani, Anna Ludovica, Alberto Piperno, Luca Valenti, Mirella Fraquelli, Sabina Coletti, Alessandra Maraschi, Dario Consonni, Enzo Coviello, Dario Conte, and Silvia Fargion. "Hemochromatosis in Italy in the Last 30 Years. Role of Genetic and Acquired Factors." Blood 114, no. 22 (November 20, 2009): 2003. http://dx.doi.org/10.1182/blood.v114.22.2003.2003.

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Abstract Abstract 2003 Poster Board I-1025 Background & Aims Clinical presentation of hereditary hemochromatosis markedly changed in the recent years. The aim of the study was to analyze a large series of consecutive Italian patients with hemochromatosis diagnosed between 1976 and 2007 to define whether the genetic background and the presence of acquired risk factors influenced the severity of iron overload and the natural history of the disease across the years. Methods: A cohort of 452 Italian patients with iron overload, of whom 338 HFE-related (C282Y homozygotes or compound C82Y/H63D heterozygotes, and 114 non-HFE-related, prospectively followed for a median of 112 months. Results: Alcohol intake, smoking habits and iron removed to depletion were similar in patients with and without HFE-related iron overload. HBV (4% and 10% p=0.03) and HCV (9% and 17% p=0.02) infections were more frequent in patients with non-HFE-related iron overload. Seventy-three percent and 61% of the patients with HFE and non-HFE-related disease had no acquired risk factor. Cirrhosis was significantly more frequent in non-HFE patients, independently of the presence of acquired risk factors (p=0.02). Gender, alcohol intake, prevalence of smokers, HCV infection, glucose, lipids, iron-related parameters and prevalence of C282Y/H63D significantly differed across the years. At enrolment cirrhosis was present in 145 cases, being significantly more frequent in the first decade (80%, 47% and 13%, p=0.001). Survival did not differ across the decades in cirrhotic patients, HCC occurring similarly in HFE and non-HFE patients. Conclusion: Patients with HFE and non-HFE related iron overload have comparable iron overload and similar clinical history. Patients, unless cirrhotics at enrolment, diagnosed during the last 10 years have less severe disease and lower prevalence of acquired risk factors, independently of genetic background. Disclosures: No relevant conflicts of interest to declare.

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Saruc, Murat, Ender Altiok, Gultekin Barut, Ozlem Saygili, Umit Ince, Olcay Cizmeli, Metin Cakmakci, and Nurdan Tozun. "P0096 IT IS NOT ALWAYS NON-HFE HEMOCHROMATOSIS IN TURKEY." European Journal of Internal Medicine 20 (May 2009): S37. http://dx.doi.org/10.1016/s0953-6205(09)60116-3.

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Farrell, Colin P., Charles J. Parker, and John D. Phillips. "Exome sequencing for molecular characterization of non-HFE hereditary hemochromatosis." Blood Cells, Molecules, and Diseases 55, no. 2 (August 2015): 101–3. http://dx.doi.org/10.1016/j.bcmd.2015.04.002.

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Stöllberger, Claudia, and Josef Finsterer. "Non-compaction and polyneuropathy in a patient homozygous for the H63D HFE gene mutation." Open Medicine 6, no. 3 (June 1, 2011): 309–11. http://dx.doi.org/10.2478/s11536-011-0015-3.

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AbstractLeft ventricular hypertrabeculation/non-compaction (LVHT) is a cardiac abnormality that is increasingly reported with an association to several genetic disorders. We report an association of LVHT with genetically confirmed hemochromatosis and polyneuropathy in a 54-year old Caucasian female.

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Pagliosa, Cristiane Manfé, Francilene Gracieli Kunradi Vieira, Bruno Vieira Dias, Vivian Karla Brognoli Franco, Hanna Pillmann Ramos, and Edson Luiz da Silva. "Ilex paraguariensis (A. St.-Hil.) leaf infusion decreases iron absorption in patients with hereditary hemochromatosis: a randomized controlled crossover study." Food & Function 12, no. 16 (2021): 7321–28. http://dx.doi.org/10.1039/d1fo00482d.

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The acute intake of Ilex paraguariensis leaf infusion significantly inhibited the absorption of non-heme iron in hereditary hemochromatosis patients with the HFE genotype and should be considered as a potential adjuvant for iron overload control.

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Legros, Ludivine, Edouard Bardou-Jacquet, Marianne Latournerie, Anne Guillygomarc'h, Bruno Turlin, Caroline Le Lan, Yoann Désille, et al. "Non-invasive assessment of liver fibrosis in C282Y homozygous HFE hemochromatosis." Liver International 35, no. 6 (February 4, 2015): 1731–38. http://dx.doi.org/10.1111/liv.12762.

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Sandnes, Miriam, Marta Vorland, Rune J. Ulvik, and Håkon Reikvam. "HFE Genotype, Ferritin Levels and Transferrin Saturation in Patients with Suspected Hereditary Hemochromatosis." Genes 12, no. 8 (July 28, 2021): 1162. http://dx.doi.org/10.3390/genes12081162.

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HFE hemochromatosis is characterized by increased iron absorption and iron overload due to variants of the iron-regulating HFE gene. Overt disease is mainly associated with homozygosity for the C282Y variant, although the H63D variant in compound heterozygosity with C282Y (C282Y/H63D) contributes to disease manifestation. In this observational study, we describe the association between biochemical findings, age, gender and HFE genotype in patients referred from general practice to a tertiary care referral center for diagnostic workup based on suspected hemochromatosis due to persistent hyperferritinemia and HFE variants. C282Y and H63D homozygosity were, respectively, the most and least prevalent genotypes and we found a considerable variation in transferrin saturation and ferritin levels independent of HFE genotype, which may indeed represent a diagnostic challenge in general practice. While our results confirm C282Y homozygosity as the major cause of iron accumulation, non-C282Y homozygotes also displayed mild to moderate hyperferritinemia with median ferritin levels at 500–700 µg/L, well above the reference cut-off. Such findings have traditionally been ignored in the clinic, and initiation of iron depletion has largely been restricted to C282Y homozygotes. Nevertheless, superfluous iron can aggravate pathogenesis in combination with other diseases and risk factors, such as inflammation, cancer and hepatopathy, and this possibility should not be neglected by clinicians.

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Wallace, Daniel F., and V. Nathan Subramaniam. "The global prevalence of HFE and non-HFE hemochromatosis estimated from analysis of next-generation sequencing data." Genetics in Medicine 18, no. 6 (December 3, 2015): 618–26. http://dx.doi.org/10.1038/gim.2015.140.

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29

Brissot, Pierre, and Frédéric de Bels. "Current Approaches to the Management of Hemochromatosis." Hematology 2006, no. 1 (January 1, 2006): 36–41. http://dx.doi.org/10.1182/asheducation.v2006.1.36.0010036.

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Анотація:

The term hemochromatosis encompasses at least four types of genetic iron overload conditions, most of them recently distinguished from one another as a result of the identification of a series of genes related to iron metabolism. At least three of these entities (HFE hemochromatosis, juvenile hemochromatosis and transferrin receptor 2 hemochromatosis) involve systemic hepcidin deficiency as a key pathogenetic factor. Major advances in the management of hemochromatosis influence the diagnostic approach to the disease, with the development of an overall non invasive strategy, mainly based on clinical, biological (iron parameters and genetic testing), and imaging (especially magnetic resonance imaging) data. Therapeutic management remains, on the curative side, dominated by phlebotomy (venesection), practical aspects of which have been recently revisited by the Guidelines Department of the French “Haute Autorité de Santé.” However, innovative treatment approaches, based on the improved pathophysiological understanding of these diseases and the progress in iron chelation therapy, are emerging. Preventive therapy, focused on family screening, remains a key part of the management of hemochromatosis.

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30

McLaren, Gordon D., and Victor R. Gordeuk. "Hereditary hemochromatosis: insights from the Hemochromatosis and Iron Overload Screening (HEIRS) Study." Hematology 2009, no. 1 (January 1, 2009): 195–206. http://dx.doi.org/10.1182/asheducation-2009.1.195.

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Abstract Hemochromatosis comprises a group of inherited disorders resulting from mutations of genes involved in regulating iron metabolism. The multicenter, multi-ethnic Hemochromatosis and Iron Overload Screening (HEIRS) Study screened ~100,000 participants in the US and Canada, testing for HFE mutations, serum ferritin and transferrin saturation. As in other studies, HFE C282Y homozygosity was common in Caucasians but rare in other ethnic groups, and there was a marked heterogeneity of disease expression in C282Y homozygotes. Nevertheless, this genotype was often associated with elevations of serum ferritin and transferrin saturation and with iron stores of more than four grams in men but not in women. If liver biopsy was performed, in some cases because of evidence of hepatic dysfunction, fibrosis or cirrhosis was often found. Combined elevations of serum ferritin and transferrin saturation were observed in non-C282Y homozygotes of all ethnic groups, most prominently Asians, but not often with iron stores of more than four grams. Future studies to discover modifier genes that affect phenotypic expression in C282Y hemochromatosis should help identify patients who are at greatest risk of developing iron overload and who may benefit from continued monitoring of iron status to detect progressive iron loading.

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31

Skrlec, Ivana, Robert Steiner, Jasenka Wagner, and Mirela Florijancic. "Hereditary hemochromatosis gene mutations in patients with myocardial infarction." Molecular and experimental biology in medicine 2, no. 1 (April 4, 2019): 24–28. http://dx.doi.org/10.33602/mebm.2.1.4.

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Hereditary hemochromatosis (HH) is a disorder of iron accumulation in tissues, which is related to coronary heart diseases. Free radicals and reactive oxygen species, created because of iron deposition, promote oxidation of LDL cholesterol and could lead to the development of atherosclerosis. Studies have shown that HFE gene mutation carriers might be at higher risk of developing cardiovascular diseases compared with non-carriers. This study aimed to determine the frequency of HFE gene mutations in patients with myocardial infarction compared to a healthy group in eastern Slavonia. A retrospective case-control study was carried out on a population of 400 participants. In the first group there were 200 patients (114 males and 86 females) with myocardial infarction. The second group consisted of 200 controls (103 males and 97 females) without a history of cardiovascular diseases. All patients were genotyped for the three most common mutations of the HH in the HFE gene: C282Y, H63D, and S65C, by real-time PCR. The difference in the frequency of carriers of these mutations between the patients and the controls was not significant (C282Y: 4.5 vs. 8.1%; H63D: 19 vs. 24.5%; S65C: 3.5 versus 4%), and neither was the frequency and distribution of possible HFE gene genotypes and compound heterozygotes. There were no statistically significant associations of cardiovascular risk factors and HFE gene mutations in patients with myocardial infarction. In this study, no association was found between the HFE gene mutation for HH and myocardial infarction in the population of eastern Slavonia.

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32

Jacolot, Sandrine, Gerald Le Gac, Virginie Scotet, Isabelle Quere, Catherine Mura, and Claude Ferec. "HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype." Blood 103, no. 7 (April 1, 2004): 2835–40. http://dx.doi.org/10.1182/blood-2003-10-3366.

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Abstract Hereditary hemochromatosis is a genetically heterogeneous disease of iron metabolism. The most common form of the disorder is an adult-onset form that has mainly been associated with the HFE pC282Y/pC282Y genotype. The phenotypic expression of this genotype is very heterogeneous and could be modulated by both environmental factors and modifier genes. The non-HFE hereditary hemochromatosis forms include a juvenile onset form associated with mutations in HAMP. From a cohort of 392 C282Y homozygous patients, we found 5 carriers of an additional HAMP mutation at the heterozygous state (pR59G, pG71D, or pR56X). We found that iron indices of these 5 patients were among the most elevated of the cohort. Moreover, we specified that the HAMP mutations were not detected in 300 control subjects. These results revealed that mutations in HAMP might increase the phenotypic expression of the pC282Y/pC282Y genotype. From a cohort of 31 patients with at least one chromosome lacking an HFE mutation, we further identified 4 males carrying a heterozygous HAMP mutation (pR59G or pG71D). Based on a digenic model of inheritance, these data suggest that the association of heterozygous mutations in the HFE and HAMP genes could lead, at least in some cases, to an adult-onset form of primary iron overload. (Blood. 2004;103:2835-2840)

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33

Lee, Pauline L., James C. Barton, David J. Brandhagen, Sandrine Niyongere, Sean Bohannon, Charles A. Rivers, Ronald A. Acton, and Ernest Beutler. "Hemojuvelin Mutations in Whites, Blacks and Asians with Primary Iron Overload and in Control Subjects." Blood 104, no. 11 (November 16, 2004): 3198. http://dx.doi.org/10.1182/blood.v104.11.3198.3198.

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Abstract Mutations in the hemojuvelin gene (HJV) are a cause of juvenile hemochromatosis (JH), but do they influence the phenotype of patients with adult-onset hemochromatosis with or without mutations of the HFE gene? We sequenced the coding region of the HJV gene of 133 subjects with primary iron overload (75 whites: 50 HFE, 25 non-HFE associated; 51 blacks: 1 HFE-associated; 7 Asians). A 63 year old white woman with non-HFE iron overload was found to be a compound heterozygote for HJV mutations: one previously identified (G320V); the other novel (C321W). The patient was diagnosed at age 30 (SI 223 μg/100 mL, TIBC 293 μg/100 mL, TS 76%, hepatic iron 31,154 μg/g, hepatic iron index 19.2). She had 2 healthy children, developed amenorrhea at age 23, had a history of hypothyroidism and developed Type 2 diabetes at age 59. She was iron depleted after 66 phlebotomies. Among 74 other white subjects with iron overload we found 3 polymorphisms: IVS2-6 C>G (3 subjects); nt 165 T>A (G55G), and IVS4-50 C>T (1 subject, each). Among 51 black iron overloaded and 132 black control subjects, the most notable polymorphism was a DNA triplet insert predicting an insertion of glycine. This was found in 2 subjects, one with and one without iron storage disease. Among the iron overloaded black subjects, we also found IVS2-6 C>G (1 subject), nt -140 G>C (3 subjects), nt 792 G>C (S264S) (1 subject), nt 828 C>A (I275I) (1 subject), and nt 929 C>G (A310G) (2 subjects). These polymorphisms, excluding S264S and I275I, were found in control subjects as well. No coding region mutations or polymorphisms were found in the 7 Asian iron overloaded subjects. We also determined the gene frequency of the HJV I222N and G320V mutations in adult control subjects from central Alabama, where a JH index case had been found with these mutations. Allele frequencies of I222N and G320V were 0.002 (n=240) and 0 (n=241) respectively in control whites. A white control female heterozygous for the I222N was also heterozygous for HFE C282Y but had normal iron measures. No I222N and G320V mutations were found in 124 and 118 black subjects respectively. We conclude that: 1) iron overloaded patients without HFE mutations, with or without a JH phenotype should be screened for HJV; 2) HJV mutations do not account for most cases of increased penetrance of HFE-associated hemochromatosis; 3) double heterozygosity for HFE C282Y and HJV I222N does not necessarily cause iron overload.

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34

Chaudhry, Hunza, Aalam Sohal, Arpine Petrosyan, and Devang Prajapati. "S3052 Iron Man: A Case of Non-HFE Hemochromatosis Without Significant Fibrosis." American Journal of Gastroenterology 117, no. 10S (October 2022): e1970-e1971. http://dx.doi.org/10.14309/01.ajg.0000868848.14319.ea.

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35

Hamdi‐Rozé, Houda, Marie‐Pascale Beaumont‐Epinette, Zeineb Ben Ali, Caroline Le Lan, Véronique Loustaud‐Ratti, Xavier Causse, Olivier Loreal, et al. "Rare HFE variants are the most frequent cause of hemochromatosis in non‐c282y homozygous patients with hemochromatosis." American Journal of Hematology 91, no. 12 (August 22, 2016): 1202–5. http://dx.doi.org/10.1002/ajh.24535.

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36

Brissot, Pierre, and Frédéric de Bels. "Current Approaches to the Management of Hemochromatosis." Hematology 2006, no. 1 (January 1, 2006): 36–41. http://dx.doi.org/10.1182/asheducation-2006.1.36.

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Анотація:

Abstract The term hemochromatosis encompasses at least four types of genetic iron overload conditions, most of them recently distinguished from one another as a result of the identification of a series of genes related to iron metabolism. At least three of these entities (HFE hemochromatosis, juvenile hemochromatosis and transferrin receptor 2 hemochromatosis) involve systemic hepcidin deficiency as a key pathogenetic factor. Major advances in the management of hemochromatosis influence the diagnostic approach to the disease, with the development of an overall non invasive strategy, mainly based on clinical, biological (iron parameters and genetic testing), and imaging (especially magnetic resonance imaging) data. Therapeutic management remains, on the curative side, dominated by phlebotomy (venesection), practical aspects of which have been recently revisited by the Guidelines Department of the French “Haute Autorité de Santé.” However, innovative treatment approaches, based on the improved pathophysiological understanding of these diseases and the progress in iron chelation therapy, are emerging. Preventive therapy, focused on family screening, remains a key part of the management of hemochromatosis.

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37

Badar, Sadaf, Fabiana Busti, Giampiero Zamperin, Alberto Ferrarini, Paolo Bozzini, Daniele Manna, Natascia Campostrini, Giovanna De Matteis, Massimo Delledonne, and Domenico Girelli. "Targeted Next Generation Sequencing of the Five Hemochromatosis Genes in Italian Patients with Iron Overload and Non-Diagnostic First Level Genetic Test: A Pilot Study." Blood 124, no. 21 (December 6, 2014): 4030. http://dx.doi.org/10.1182/blood.v124.21.4030.4030.

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Abstract Background and Aim: Molecular diagnosis of HFE-related hereditary hemochromatosis (HH) is typically made by searching for the C282Y and H63D mutations (first level genetic test). However, in the Mediterranean area up to one third of patients with HH phenotype do not have the “diagnostic” genotypes (C282Y homozygosity, or C282Y/H63D compound heterozygosity). This pilot study was designed to develop a “second level” next generation sequencing (NGS)-based test for rapid and simultaneous analysis of the five HH genes (HFE, HFE2, HAMP, TFR2 and SLC40A1). Methodology: we studied 61 patients with relevant biochemical signs of iron overload (IO) and non-diagnostic first level genetic test suggesting a possible “non-HFE” HH. The five HH genes were captured by Halo-Plex™ technology, and then sequenced using aNGS platform (Illumina HiSeq 1000). Sequenced reads were aligned against human reference HG19 and analyzed by GoldenHelix™ software to annotate all the variants possibly involved in the disease. Results: In IO patients a large number of new non-synonymous variants (according to bioinformatics tools based on publicly available databases including the 1000-genomes project) were found. Many of them were relatively frequent and detected also in controls, thus being considered likely “non-pathogenic”, unless clearly enriched in patients. On the other hand, some rare variants (i.e. limited to a single or very few individuals), particularly in SCL40A1, TFR2, and HFE, were found exclusively in patients, and could be considered “potentially pathogenic”. Conclusions: The combination of the Halo-Plex™ approach with NGS platform and GoldenHelix™ algorithm appears a suitable approach for a better molecular characterization of patients with unexplained HH phenotype, and could represent a good option for second level genetic testing in referral centers. However, establishing the clinical relevance of NGS-detected “novel” genetic variants in a prevalently autosomal recessive disorder like HH remains a difficult task, requiring further functional studies and national/international collaborative efforts. Disclosures No relevant conflicts of interest to declare.

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38

Mura, Catherine, Odile Raguenes, and Claude Férec. "HFE Mutations Analysis in 711 Hemochromatosis Probands: Evidence for S65C Implication in Mild Form of Hemochromatosis." Blood 93, no. 8 (April 15, 1999): 2502–5. http://dx.doi.org/10.1182/blood.v93.8.2502.

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Abstract Hereditary hemochromatosis (HH) is a common autosomal recessive genetic disorder of iron metabolism. The HFE candidate gene encoding an HLA class I-like protein involved in HH was identified in 1996. Two missense mutations have been described: C282Y, accounting for 80% to 90% of HH chromosomes, and H63D, which is associated with a milder form of the disease representing 40% to 70% of non-C282Y HH chromosomes. We report here on the analysis of C282Y, H63D, and the 193A→T substitution leading to the S65C missense substitution in a large series of probands and controls. The results confirm that the C282Y substitution was the main mutation involved in hemochromatosis, accounting for 85% of carrier chromosomes, whereas the H63D substitution represented 39% of the HH chromosomes that did not carry the C282Y mutation. In addition, our screening showed that the S65C substitution was significantly enriched in probands with at least one chromosome without an assigned mutation. This substitution accounted for 7.8% of HH chromosomes that were neither C282Y nor H63D. This enrichment of S65C among HH chromosomes suggests that the S65C substitution is associated with the mild form of hemochromatosis.

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39

Mura, Catherine, Odile Raguenes, and Claude Férec. "HFE Mutations Analysis in 711 Hemochromatosis Probands: Evidence for S65C Implication in Mild Form of Hemochromatosis." Blood 93, no. 8 (April 15, 1999): 2502–5. http://dx.doi.org/10.1182/blood.v93.8.2502.408k27_2502_2505.

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Анотація:

Hereditary hemochromatosis (HH) is a common autosomal recessive genetic disorder of iron metabolism. The HFE candidate gene encoding an HLA class I-like protein involved in HH was identified in 1996. Two missense mutations have been described: C282Y, accounting for 80% to 90% of HH chromosomes, and H63D, which is associated with a milder form of the disease representing 40% to 70% of non-C282Y HH chromosomes. We report here on the analysis of C282Y, H63D, and the 193A→T substitution leading to the S65C missense substitution in a large series of probands and controls. The results confirm that the C282Y substitution was the main mutation involved in hemochromatosis, accounting for 85% of carrier chromosomes, whereas the H63D substitution represented 39% of the HH chromosomes that did not carry the C282Y mutation. In addition, our screening showed that the S65C substitution was significantly enriched in probands with at least one chromosome without an assigned mutation. This substitution accounted for 7.8% of HH chromosomes that were neither C282Y nor H63D. This enrichment of S65C among HH chromosomes suggests that the S65C substitution is associated with the mild form of hemochromatosis.

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40

Carlson, Hanqian, An-Sheng Zhang, William H. Fleming, and Caroline A. Enns. "The hereditary hemochromatosis protein, HFE, lowers intracellular iron levels independently of transferrin receptor 1 in TRVb cells." Blood 105, no. 6 (March 15, 2005): 2564–70. http://dx.doi.org/10.1182/blood-2004-03-1204.

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AbstractHereditary hemochromatosis (HH) is an autosomal recessive disease that leads to parenchymal iron accumulation. The most common form of HH is caused by a single amino acid substitution in the HH protein, HFE, but the mechanism by which HFE regulates iron homeostasis is not known. In the absence of transferrin (Tf), HFE interacts with transferrin receptor 1 (TfR1) and the 2 proteins co-internalize, and in vitro studies have shown that HFE and Tf compete for TfR1 binding. Using a cell line lacking endogenous transferrin receptors (TRVb cells) transfected with different forms of HFE and TfR1, we demonstrate that even at low concentrations Tf competes effectively with HFE for binding to TfR1 on living cells. Transfection of TRVb cells or the derivative line TRVb1 (which stably expresses human TfR1) with HFE resulted in lower ferritin levels and decreased Fe2+ uptake. These data indicate that HFE can regulate intracellular iron storage independently of its interaction with TfR1. Earlier studies found that in HeLa cells, HFE expression lowers Tf-mediated iron uptake; here we show that HFE lowers non–Tf-bound iron in TRVb cells and add to a growing body of evidence that HFE may play different roles in different cell types.

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41

Ramos, Pedro, Ella Guy, Laura Breda, Sara Gardenghi, Robert W. Grady, Maria De Sousa, and Stefano Rivella. "Absence of the Hemochromatosis Gene HFE Confers Protection Under Conditions of Stress Erythropoiesis." Blood 112, no. 11 (November 16, 2008): 3848. http://dx.doi.org/10.1182/blood.v112.11.3848.3848.

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Abstract A single mutation in the HFE gene (C282Y), a non-classical member of the MHC-I family, may lead to hereditary hemochromatosis (HH). Although the hallmark of HH is iron overload, several lines of evidence point to a distinct hematopoietic function for HFE: HH reticuloendothelial cells are iron deficient; reconstitution of Hfe-KO mice with bone marrow (BM) from wild-type (wt) animals leads to organ iron redistribution; erythropoietic abnormalities have been reported in HH patients, including altered red cell parameters, which have been associated with iron overload. In particular, however, the HFE promoter contains several GATA.1 responsive elements suggesting that it might be expressed in erythroid cells. Our goal was to characterize erythropoiesis in a mouse model of HH, discriminating between intrinsic roles for Hfe and iron overload in these process. Various parameters in Hfe-KO mice were compared to those in wt controls. Atomic absorption was used to measure organ iron content. Erythropoietic analysis was performed by complete blood cell counts and flow cytometry at 2, 5 and 12 months of life (N≥6 mice per group). Erythropoiesis was stressed by administration of phenylhydrazine, phlebotomy (N≥8 mice per group) or elimination of macrophages using clodronate liposomes (N≥4 mice per group). Hematological parameters were followed over time. Finally, lentiviral vectors were used to overexpress Hfe in the BM or liver of Hfe-KO animals (N≥3 mice per group), erythropoietic values being analyzed as described above. Our results indicate increased erythropoiesis at steady state in Hfe-KO animals, characterized by altered red blood cell (RBC) parameters. Analysis of erythroid populations in BM and spleen revealed an increase in the proportion of immature erythroid cells in these compartments of Hfe-KO mice, especially the spleen (9.4% ± 1.8% vs 5.1% ± 1.2% in wt mice, p≤0.05). Compared to normal mice, Hfe-KO mice recovered faster from anemia or hemolytic anemia induced, respectively, by phlebotomy and administration of phenylhydrazine. By day 8 their hemoglobin and hematocrit levels returned to steady state, while normalization required 10 days in wt mice. Preliminary results showed similar behavior in wt mice transplanted with Hfe-KO BM, compared to mice transplanted with wt BM. Since macrophages play an important role in erythropoiesis, we analyzed the erythropoietic behavior of wt and Hfe-KO mice after elimination of macrophages. Anemia induced by macrophage depletion was milder in Hfe-KO mice compared to wt mice (14.0 ± 0.4 g/dL vs 11.5 ± 0.1 g/dL), and characterized by a reduction in the hemoglobin content of RBC (MCH), with little change in the RBC count compared to steady state. In contrast anemia in wt mice was characterized by a reduction in both RBC the count and the MCH. To further investigate the correlation between Hfe, erythropoiesis and the potential role of iron overload in the erythropoietic alterations observed, we generated several lentiviral vectors to express Hfe in specific compartments, including the BM and liver. High levels of Hfe expression in BM led to a lethal anemia. On the other hand, low/normal level of expression led to reversion of the alterations in erythropoiesis at steady state, with no alteration in iron content or distribution compared to Hfe-KO control animals. Lentiviral Hfe gene transfer into the liver of Hfe-KO mice led to reduction of iron in the liver and some redistribution of this metal to the spleen. These mice showed the same erythropoietic alterations as Hfe-KO controls.

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42

Yamashita, Cory, and Paul C. Adams. "Natural history of the non-expressing C282Y homozygote for the hemochromatosis gene (HFE)." Gastroenterology 124, no. 4 (April 2003): A713. http://dx.doi.org/10.1016/s0016-5085(03)83599-0.

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43

Guerra-Shinohara, Elvira Maria, Paulo Caleb Santos, Rodolfo Cancado, Alexandre Pereira, Isolmar Schettert, Renata Soares, Rosario D. C. Hirata, et al. "Global Sequencing for the Molecular Background of Hereditary Hemochomatosis In Brazilian Patients." Blood 116, no. 21 (November 19, 2010): 5146. http://dx.doi.org/10.1182/blood.v116.21.5146.5146.

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Abstract Abstract 5146 INTRODUTION: Most hereditary hemochromatosis (HH) patients are homozygous for the p.C282Y mutation in the HFE gene. But rare HFE variants have been shown to be associated with HH. In addition, four main types of non-HFE HH are caused by mutations in the hemojuvelin (HJV), hepcidin (HAMP), transferrin receptor 2 (TFR2) and ferroportin (SLC40A1) genes. The main aim of this study was to screen for HFE, HJV, HAMP, TFR2 and SLC40A1 mutations and to investigate their relationship with HH. MATERIAL E METHODS: Fifty-one Brazilian patients with primary iron overload (transferrin saturation > 50% in females and 60% in males) were eligible. Subsequent bidirectional sequencing for each exon of HFE, HJV, HAMP, TFR2 and SLC40A1 genes was performed. The effect of HFE p.V256I novel mutations on protein structure was analyzed by in silico molecular dynamic and free energy calculations. RESULTS: Thirty-seven (72.5%) out of the 51 patients presented at least one HFE mutation. The most frequent genotype associated with HH was the homozygous p.C282Y mutation (n = 11, 21.6%). In addition, the p.S65C mutation was found in heterozygosis with p.H63D in two patients and the homozygous genotype for the p.H63D was found in two patients. One novel mutation (p.V256I) was indentified in heterozygosis with the p.H63D mutation. In silico modeling analysis of protein behavior suggested that the p.V256I mutation does not reduce the binding affinity between HFE and β2-microglobulin (β2M) in the same way the p.C282Y mutation does compared with the native HFE protein. Sequencing HJV revealed one patient presenting Juvenile hemochromatosis (JH) (homozygous genotype for the HJV p.G320V mutation); two patients carrying heterozygous genotype for the p.E302K mutation; and one patient with heterozygosis p.A310G polymorphism. Sequencing HAMP revealed one patient carrying p.P48G novel mutation in the heterozygous form. Three and five non-pathogenic polymorphisms were observed in the TFR2 and SLC40A1 genes, respectively. Sequencing SLC40A1 also identified one patient with homozygous genotype for the p.R561G described mutation; and one patient with homozygous genotype for the p.G204S novel mutation. CONCLUSION: The HFE p.C282Y in homozygosis or in heterozygosis with p.H63D was the most frequent mutation associated with HH in our sample population. The novel HFE p.V256I mutation could not be implicated in the molecular basis of the HH phenotype. Two described mutations, HJV p.E302K and SLC40A1 p.R561G, could have functional consequences according to previously studies contributing to HH phenotype. Two novel mutations, HAMP p.R48G and SLC40A1 p.G204S, may be implicated with iron overload in these patients, but further studies are need to explain their impact on proteins. Disclosures: No relevant conflicts of interest to declare.

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44

Evangelista, Andreia Silva, Maria Cristina Nakhle, Thiago Ferreira de Araújo, Clarice Pires Abrantes-Lemos, Marta Mitiko Deguti, Flair José Carrilho, and Eduardo Luiz Rachid Cançado. "HFE Genotyping in Patients with Elevated Serum Iron Indices and Liver Diseases." BioMed Research International 2015 (2015): 1–8. http://dx.doi.org/10.1155/2015/164671.

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Iron abnormalities in chronic liver disease may be the result of genetic diseases or secondary factors. The present study aimed to identify subjects with HFE-HH in order to describe the frequency of clinical manifestations, identify risk factors for iron elevation, and compare the iron profile of HFE-HH to other genotypes in liver disease patients. A total of 108 individuals with hepatic disease, transferrin saturation (TS) > 45%, and serum ferritin (SF) > 350 ng/mL were tested for HFE mutations. Two groups were characterized: C282Y/C282Y or C282Y/H63D genotypes (n=16) were the HFE hereditary hemochromatosis (HFE-HH) group; and C282Y and H63D single heterozygotes, the H63D/H63D genotype, and wild-type were considered group 2 (n=92). Nonalcoholic liver disease, alcoholism, and chronic hepatitis C were detected more frequently in group 2, whereas arthropathy, hepatocarcinoma, diabetes, and osteoporosis rates were significantly higher in the HFE-HH group. TS > 82%, SF > 2685 ng/mL, and serum iron > 178 μg/dL were the cutoffs for diagnosis of HFE-HH in patients with liver disease. Thus, in non-Caucasian populations with chronic liver disease, HFE-HH diagnosis is more predictable in those with iron levels higher than those proposed in current guidelines for the general population.

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45

Latour, Chloe, Celine Besson-Fournier, Nelly Rouquie, Léon Kautz, Patricia Aguilar-Martinez, Marie-Paule Roth, and Helene Coppin. "Inactivating Hfe Totally Abolishes Hepcidin Production and Further Aggravates Iron Overload In Bmp6-Deficient Mice." Blood 122, no. 21 (November 15, 2013): 178. http://dx.doi.org/10.1182/blood.v122.21.178.178.

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Abstract Hepcidin, a circulating hormone produced primarily by the liver, plays a central role in the regulation of systemic iron homeostasis necessary to ensure sufficient availability of iron for hemoglobin synthesis and other metabolic processes while avoiding the oxidative damage to cells that can result from excess free iron. Hepcidin triggers internalization and degradation of ferroportin, the only known iron export channel from cells into the plasma, which leads to the decrease of dietary iron absorption from duodenal enterocytes and to the sequestration of iron recycled from senescent blood cells within macrophages. Iron overload induces the expression of bone morphogenetic protein 6 (BMP6), a member of the TGF-beta superfamily of ligands, which activates a signaling cascade leading to SMAD1/5/8 phosphorylation, translocation of the phosphorylated SMADs bound to SMAD4 to the nucleus, and upregulation of hepcidin gene transcription. Inactivation of Bmp6 in mice leads to considerably reduced hepcidin production, compared with wild-type mice, and severe hepatic iron overload. However, there are major differences in hepcidin expression and extrahepatic tissue iron loading between Bmp6-deficient males and females, due to the suppressive effect of testosterone on hepcidin in males. In contrast to males, Bmp6-/- females still produce some hepcidin and do not massively accumulate iron in their pancreas, their heart or their kidneys. The goal of this study was to investigate the role of Hfe in the residual hepcidin production observed in the absence of Bmp6 in females. Mutations in the HFE gene are causing the most common form of hereditary hemochromatosis, a disorder characterized by a chronic inappropriate increase in dietary iron uptake, progressive iron overload and tissue injury. Human patients and mouse models of HFE-related hemochromatosis show inappropriately low expression of hepcidin. However, the mechanism by which HFE influences hepcidin expression is still unclear. In Hfe-/- mice and in patients with HFE-associated hemochromatosis, the induction of BMP6 mRNA by iron is intact, but hepcidin production is impaired. In the mouse, Hfe and Bmp6 genes are separated by less than 8 cM on chromosome 13, and the probability of obtaining recombinants between the 2 loci is low. However, HFE is a non-classical MHC class 1-like molecule which associates with β2-microglobulin and β2m-/- mice develop spontaneously hepatic iron overload with a distribution similar to that seen in the liver of Hfe-/- mice. We therefore generated β2m/Bmp6 double knockout mice in which the function of both Hfe and Bmp6 is impaired. Briefly, Bmp6-/- mice on a CD1 background were mated to β2m-/- mice on a C57BL/6 background and double heterozygote F1 mice were intercrossed. We assessed Smad1/5/8 phosphorylation, hepcidin expression, and the sites of iron accumulation in wild-type, simple knockout (β2m-/- or Bmp6-/-) and double knockout (β2m-/- and Bmp6-/-) mice of the F2 progeny. Interestingly, the lack of functional Hfe in Bmp6-/- females led to a much more severe phenotype than the single impairment of Bmp6, with massive iron loading in extrahepatic tissues, most notably the exocrine pancreas, the heart, and the proximal and distal convoluted tubules of the kidney. Phosphorylation of Smad1/5/8 in double knockout (β2m-/- and Bmp6-/-) mice was virtually abolished and hepcidin mRNA in double knockout females was much more strongly downregulated than in single Bmp6-/- females. In contrast to Bmp6-/- females, no protein was detectable by ELISA in double knockout mice. Our findings show that Bmp6 and Hfe regulate hepcidin production by two independent pathways that converge on Smad1/5/8 phosphorylation. The role of transferrin receptor 2 (TFR2), another hemochromatosis-associated molecule, remains a key question. The total suppression of hepcidin in mice in which both Hfe and Bmp6 have been impaired suggests that TFR2 does not regulate hepcidin through an additional pathway. Moreover, the observation that Hfe-/-/Tfr2-/- mice have a more severe phenotype than simple Hfe-/- or Tfr2-/- mice favors the interference of Tfr2 with the Bmp6 pathway. Comparison of the phenotype of mice with inactivation of both Bmp6 and Tfr2 to that of Bmp6-/- mice is likely to definitively solve this still open question. Disclosures: No relevant conflicts of interest to declare.

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46

Barton, James C., J. Clayborn Barton, Neha Patel, and Gordon D. McLaren. "Abdominal pain and cirrhosis at diagnosis of hemochromatosis: Analysis of 219 referred probands with HFE p.C282Y homozygosity and a literature review." PLOS ONE 16, no. 12 (December 21, 2021): e0261690. http://dx.doi.org/10.1371/journal.pone.0261690.

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Background In hemochromatosis, causes of abdominal pain and its associations with cirrhosis are poorly understood. Methods We retrospectively compared characteristics of referred hemochromatosis probands with HFE p.C282Y homozygosity with/without biopsy-proven cirrhosis: sex, age, diabetes, heavy alcohol consumption, abdominal pain/tenderness, hepatomegaly, splenomegaly, non-alcoholic fatty liver disease, chronic viral hepatitis, ascites, transferrin saturation (TS), serum ferritin (SF), and iron removed by phlebotomy (QFe). We performed logistic regression on cirrhosis using characteristics identified in univariate comparisons. We performed computerized and manual searches to identify hemochromatosis case series and compiled prevalence data on cirrhosis and abdominal pain and causes of abdominal pain. Results Of 219 probands, 57.1% were men. Mean age was 48±13 y. In 22 probands with cirrhosis, proportions of men, mean age, prevalences of heavy alcohol consumption, abdominal pain, abdominal tenderness, hepatomegaly, splenomegaly, and chronic viral hepatitis, and median TS, SF, and QFe were significantly greater than in probands without cirrhosis. Regression analysis revealed three associations with cirrhosis: abdominal pain (p = 0.0292; odds ratio 9.8 (95% CI: 1.2, 76.9)); chronic viral hepatitis (p = 0.0153; 11.5 (95% CI: 1.6, 83.3)); and QFe (p = 0.0009; 1.2 (95% CI: 1.1, 1.3)). Of eight probands with abdominal pain, five had cirrhosis and four had diabetes. One proband each with abdominal pain had heavy alcohol consumption, chronic viral hepatitis B, hepatic sarcoidosis, hepatocellular carcinoma, and chronic cholecystitis, cholelithiasis, and sigmoid diverticulitis. Abdominal pain was alleviated after phlebotomy alone in four probands. In 12 previous reports (1935–2011), there was a negative correlation of cirrhosis prevalence and publication year (p = 0.0033). In 11 previous reports (1935–1996), a positive association of abdominal pain prevalence and publication year was not significant (p = 0.0802). Conclusions Abdominal pain, chronic viral hepatitis, and QFe are significantly associated with cirrhosis in referred hemochromatosis probands with HFE p.C282Y homozygosity. Iron-related and non-iron-related factors contribute to the occurrence of abdominal pain.

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Krivosheev, A. B., V. N. Maksimov, K. Yu Boyko, E. E. Levykina, E. S. Mikhaylova, N. A. Varaksin, M. A. Kondratova, I. A. Krivosheeva, and A. I. Autenshlyus. "Molecular genetic markers and metabolic disorders in non-alcoholic fatty liver disease." Russian Medical Inquiry 6, no. 5 (2022): 206–12. http://dx.doi.org/10.32364/2587-6821-2022-6-5-206-212.

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Aim: to assess the probability of unfavorable outcomes of non-alcoholic fatty liver disease (NAFLD) based on clinical, biochemical, and molecular genetic parameters. Patients and Methods: 440 individuals were examined. Among them, 115 patients (84 men and 31 women) aged 23–69 (mean 49.3±1.1 years) were diagnosed with NAFLD and 325 healthy volunteers (172 men and 153 women) aged 25–67 (mean age 47.9±0.6 years) were controls. Molecular genetic testing for TCF7L2 (ТС, СС, and ТТ genotypes) was performed in all participants. The rates of Glu342Lys (PIZ) and Glu264Val (PIS) mutations of α1-antitrypsin gene (SERPINA1) and 282Y and 63D alleles of hemochromatosis (HFE) gene were evaluated. Standard liver function tests (ASAT, ALAT, bilirubin), lipid metabolism (total cholesterol, triglycerides, HDL, LDL), excretory porphyrin metabolism (porphyrin precursors [δ-aminolaevulinic acid and porphobilinogen] and fractions [uroporphyrin and coproporphyrin]), and cytokine profile (interleukins 1β, 6, 8, 10, and 1Ra, tumor necrosis factor/TNF α) were assessed. Results: the rates of TCF7L2 genotype, 282Y and 63D HFE gene alleles were similar in NAFLD patients and healthy controls. Meanwhile, Glu342Lys (PIZ) and Glu264Val (PIS) SERPINA1 gene polymorphisms were significantly more common in NAFLD patients vs. general population. The odds ratio (OR) has demonstrated that Glu342Lys (PIZ) genotype occurrence is 3.9 times greater in the NAFLD group than in healthy controls (NZ + ZZ vs. NN: OR=3.90, 95% CI 1.5–10.5, p=0.007), while Glu264Vol (PIS) genotype occurrence is 6.6 times greater in the NAFLD group than in healthy controls (NS vs. NN: OR=6.6, 95 CI 2.4–18.3, p<0.001). Abnormalities of porphyrin metabolism and cytokine profile were detected in most participants (71.3% and 82.6%, respectively). Unfavorable NAFLD outcomes were reported in 30 patients (26.1%). Conclusions: molecular genetic testing and specific blood biochemistry allows for predicting NAFLD outcome. Describing metabolic disorders allows for assessing the risk of unfavorable outcome. KEYWORDS: non-alcoholic fatty liver disease, molecular genetic testing, TCF7L2 gene, α1-antitrypsin gene (SERPINA1), hemochromatosis gene (HFE), lipid metabolism, porphyrin metabolism, cytokine profile, unfavorable outcome. FOR CITATION: Krivosheev A.B., Maksimov V.N., Boyko K.Yu. et al. Molecular genetic markers and metabolic disorders in non-alcoholic fatty liver disease. Russian Medical Inquiry. 2022;6(5):206–212 (in Russ.). DOI: 10.32364/2587-6821-2022-6-5-206-212.

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Jermyn, Rita, Eiei Soe, David D’Alessandro, Julia Shin, William Jakobleff, Daniel Schwartz, Milan Kinkhabwala, and Paul J. Gaglio. "Cardiac Failure after Liver Transplantation Requiring a Biventricular Assist Device." Case Reports in Transplantation 2014 (2014): 1–4. http://dx.doi.org/10.1155/2014/946961.

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Increased hepatic iron load in extrahepatic organs of cirrhotic patients with and without hereditary hemochromatosis portends a poorer long term prognosis after liver transplant. Hepatic as well as nonhepatic iron overload is associated with increased infectious and postoperative complications, including cardiac dysfunction. In this case report, we describe a cirrhotic patient with alpha 1 antitrypsin deficiency and nonhereditary hemochromatosis (non-HFE) that developed cardiogenic shock requiring mechanical circulatory support for twenty days after liver transplant. Upon further investigation, she was found to have significant iron deposition in both the liver and heart biopsies. Her heart regained complete and sustained recovery following ten days of mechanical biventricular support. This case highlights the importance of preoperatively recognizing extrahepatic iron deposition in patients referred for liver transplantation irrespective of etiology of liver disease as this may prevent postoperative complications.

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49

KUPPAHALLY, S., S. HUNT, H. VALANTINE, and G. BERRY. "Recurrence of Iron Deposition in the Cardiac Allograft in a Patient With Non-HFE Hemochromatosis." Journal of Heart and Lung Transplantation 25, no. 1 (January 2006): 144–47. http://dx.doi.org/10.1016/j.healun.2005.08.002.

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50

Jacobs, Esther M. G., Jan C. M. Hendriks, Herman G. Kreeftenberg, Richard A. de Vries, Joannes J. M. Marx, Cees Th B. M. van Deursen, Anton F. H. Stalenhoef, Andre L. M. Verbeek, and Dorine W. Swinkels. "Determinants for Iron Overload-Related Disease in Siblings of Probands with Clinically Detected HFE Hereditary Hemochromatosis: The Hemochromatosis Family Study." Blood 112, no. 11 (November 16, 2008): 1857. http://dx.doi.org/10.1182/blood.v112.11.1857.1857.

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Abstract The clinical expression of HFE-associated hereditary hemochromatosis (HH) gen is highly variable and may be influenced by nongenetic factors and coinherited genetic modifiers, complicating early screening options to prevent iron-overload related disease. The aim of this study was to verify the existence of HH-related disease in C282Y homozygous siblings of C282Y homozygous probands with clinically detected HFE-related HH and to identify factors predictive for the iron-related disease within these siblings. To this end, C282Y homozygous (n=110, males n=53) and non-homozygous siblings (n=318, males n=145) of 224 probands were compared for levels of serum iron parameters, and self-reported environmental and lifestyle factors and previously diagnosed HH-related diseases. Compared to non-homozygous C282Y siblings, C282Y homozygous siblings more often mentioned to have been diagnosed with arthropathy (Odds Ratio [OR] 2.76, 95% Confidential Interval [CI] 1.71–4.46) and liver disease (OR 2.90, 95%CI 1.27– 6.62). Using multivariate logistic regression modelling, genotype (OR 2.29, 95%CI 1.04– 5.02), age (OR 1.07, 95% CI 1.04–1.09) and gender (OR 1.71, 95%CI 1.04–2.80) were found predictive for the development of iron-associated organ disease. With genotype in the model, there was neither an additive predictive value of the serum iron parameters, nor of body mass index (BMI) or alcohol intake. However, when the predictive value of the iron parameters was analyzed in siblings above 55 yrs, the input of the serum ferritin levels was also significant, with a less prominent influence of gender. In conclusion, our results show that the prevalence of hemochromatosis-attributed morbid conditions is increased in the C282Y homozygous siblings compared to their non-homozygous counterparts. Results furthermore suggest that age and gender, but not BMI and alcohol intake, add to the identification of C282Y homozygous siblings most at risk to develop hemochromatosis-associated disease. These findings will be instrumental in the definition of a high-risk group for iron overload-related disease among siblings of clinically detected C282Y homozygous probands and may contribute to the cost-effectiveness of family screening.

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