scholarly journals Correlation of genotype and phenotype in 32 patients with hereditary hemochromatosis in China

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Liyan Wu ◽  
Wei Zhang ◽  
Yanmeng Li ◽  
Donghu Zhou ◽  
Bei Zhang ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Homeostasis ◽  
Clinical Phenotype ◽  
Hereditary Hemochromatosis ◽  
Clinical Manifestations ◽  
Pairwise Comparison ◽  
Asian Population ◽  
Chinese Patients ◽  
Pathogenic Variants ◽  
Significant Difference

Abstract Background Hereditary hemochromatosis (HH) is widely recognized and clinical manifestations of hemochromatosis-related (HFE-related) HH is well studied in European populations. Less is known about the clinical and laboratory characteristics of non-HFE related HH in Asian population. We aimed to explore the relationship between genotype and clinical phenotype in Chinese patients with non-HFE related hereditary hemochromatosis. Methods Peripheral blood samples and clinical data of patients with primary iron overload were collected from the China Registry of Genetic/Metabolic Liver Diseases. Sanger sequencing was performed in cases with primary iron overload, for 5 known HH related genes (HFE, HJV, HAMP, TFR2 and SLC40A1) and 2 novel iron homeostasis-related genes (DENND3 and SUGP2). The correlation of genotype and clinical phenotype in these patients was analyzed. Results Of the 32 patients with primary iron overload (23 were males and 9 were females), non-HFE variants were detected in 31 (31/32, 97%), including 8 pathogenic variants in HJV, 7 pathogenic variants in SLC40A1, 8 likely pathogenic variants in SUGP2 and 5 likely pathogenic variants in DENND3 cases. Among these 31 cases, 4 cases harbored homozygous variants, 2 cases harbored homozygous + heterozygous variants, 19 cases harbored heterozygous or combined heterozygous variants, and 6 cases harbored no any damaging variants. None of investigated cases carried damaging HAMP and TFR2 variants were found. 8 cases were classified as type 2A HH and 6 cases as type 4 HH, 10 cases as non-classical genotype, and 6 cases had no pathogenic variants from 31 cases. During the statistical analysis, we excluded one case (SLC40A1 IVS3 + 10delGTT + SUGP2 p. R639Q(homo)) with difficulty in grouping due to combined damaging variants. Cases with type 2A HH have an earlier age at diagnosis (p = 0.007). The iron index of cases in type 2A HH and type 4 HH was higher than that in other groups (p = 0.01). Arthropathy was relatively rare in all groups. None of cases with type 2A HH developed cirrhosis. Cirrhosis and diabetes are more prevalent in type 4 HH. The incidence of cirrhosis (p = 0.011), cardiac involvement (p = 0.042), diabetes (p = 0.035) and hypogonadism (p = 0.020) was statistically significant in the four groups. However, due to the limited sample size, the pairwise comparison showed no significant difference. Conclusions This is the first comprehensive analysis about the gene variant spectrum and phenotypic aspects of non-HFE HH in China. The results will be useful to the identification, diagnosis and management of HH in China.

scholarly journals Correlation of Genotype and Phenotype in 32 Patients with Hereditary Hemochromatosis in China

2021 ◽  
Author(s):  
Liyan Wu ◽  
Wei Zhang ◽  
Yanmeng Li ◽  
Donghu Zhou ◽  
Bei Zhang ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Homeostasis ◽  
Clinical Phenotype ◽  
Hereditary Hemochromatosis ◽  
Clinical Manifestations ◽  
Asian Population ◽  
Chinese Patients ◽  
Pathogenic Variants ◽  
The Relationship ◽  
Metabolic Liver Diseases

Abstract Background: Hereditary hemochromatosis (HH) is widely recognized and clinical manifestations of HFE-related HH is well studied in European populations. Less is known about the clinical and laboratory characteristics of non-HFE related HH in Asian population. We aimed to explore the relationship between genotype and clinical phenotype in Chinese patients with non-HFE related hereditary hemochromatosis.Methods: Peripheral blood samples and clinical data of patients with primary iron overload were collected from the China Registry of Genetic/Metabolic Liver Diseases. Sanger sequencing was performed in cases with primary iron overload, for 5 known HH related genes (HFE, HJV, HAMP, TFR2 and SLC40A1) and 2 novel iron homeostasis-related genes (DENND3 and SUGP2). The correlation of genotype and clinical phenotype in these patients was analyzed.Results: Of the 32 patients with primary iron overload (23 were males and 9 were females), non-HFE variants were detected in 31 (31/32, 97%), including 8 pathogenic variants in HJV, 7 pathogenic variants in SLC40A1, 8 likely pathogenic variants in SUGP2 and 5 likely pathogenic variants in DENND3 cases. Among these 31 cases, 4 cases harbored homozygous variants, 2 cases harbored homozygous+ heterozygous variants, 19 cases harbored heterozygous or combined heterozygous variants, and 6 cases harbored no any damaging variants. None of investigated cases carried damaging HAMP and TFR2 variants were found. 8 cases were classified as type 2A HH and 6 cases as type 4 HH, 10 cases as non-classical genotype, and 6 cases had no pathogenic variants from 31 cases. During the statistical analysis, we excluded one case (SLC40A1 IVS3+10delGTT+SUGP2 p. R639Q(homo)) with difficulty in grouping due to combined damaging variants. Cases with type 2A HH have an earlier age at diagnosis. The iron index of cases in type 2A HH and type 4 HH was higher than that in other groups. Arthropathy was relatively rare in all groups. None of cases with type 2A HH developed cirrhosis. Cirrhosis and diabetes are more prevalent in type 4 HH.Conclusions: This is the first comprehensive analysis about the gene variant spectrum and phenotypic aspects of non-HFE HH in China. The results will be useful to the identification, diagnosis and management of HH in China.

DHPLC Scan of Iron Genes in Consecutive Patients with Suspected Iron Overload.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3206-3206
Author(s):  
Domenico Girelli ◽  
Giorgio Biasiotto ◽  
Barbara Foglieni ◽  
Claudia Bozzini ◽  
Anna Polotti ◽  
...  
Keyword(s):  
Iron Overload ◽  
Functional Role ◽  
Iron Homeostasis ◽  
Clinical Phenotype ◽  
Tertiary Care ◽  
Hereditary Hemochromatosis ◽  
Rapid Identification ◽  
Hfe Gene ◽  
Heterozygous Male ◽  
Juvenile Hemochromatosis

Abstract Background: Hereditary Hemochromatosis, once considered a monogenic disorder, is now seen as a polygenic disease, with clinical phenotype also influenced by several environmental factors. Besides the classic HFE gene, other genes involved in modulation of iron homeostasis and clinical phenotype include those coding for hemojuvelin and hepcidin (both responsible for Juvenile Hemochromatosis), ferroportin, and, possibly, H-ferritin. Methods: we used DHPLC to scan mutations in the above mentioned genes in 55 consecutive patients recently referred to our tertiary care unit for iron overload disorders. Many of them had at least biochemical signs of iron overload not explained, or not completely explained, by classic or rare HFE mutations. Main results: the −72 C→T variation in the promoter of hepcidin gene, near the putative TATA box, was found in a H63D heterozygous male with unexplained biochemical signs (serum ferritin 660 μg/L, TS 45%), who, rather, should have been protected by several previous blood donations. We recently found this new hepcidin mutation in a family from another cohort (Biasiotto et al., in press): genotype/phenotype correlation data were also consisting with a functional role of this mutation. Two other hepcidin variations were found in this series, the 108 G→A (new), and the 212 G→A. While the first appeared silent, familial study suggests that the second may be functional in association with C282Y. No new or functional variations were found in hemojuvelin or H-ferritin genes. Several polymorphisms were detected in the ferroportin gene, including two new sequence variations (−116 T→C in the promoter; 691+20C C→T in intron 4), that occurred in two unrelated subjects with wild-type HFE genotype. Their functional role is currently under investigation by extensive family studies and/or quantitative evaluation of hepatic iron by MRI/liver biopsy. Conclusions: DHPLC scan of iron genes appears as a helpful tool for integrating clinical data in selected patients referring for suspected iron overload, as well as for rapid identification of new mutations.

Iron Homeostasis and Disorders in Dogs and Cats: A Review

2011 ◽  
Vol 47 (3) ◽  
pp. 151-160 ◽  
Author(s):  
Jennifer L. McCown ◽  
Andrew J. Specht
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Iron Homeostasis ◽  
Diagnostic Testing ◽  
Clinical Manifestations ◽  
Essential Element ◽  
The Body ◽  
Deficiency Anemia ◽  
Enzyme Systems ◽  
Living Organisms

Iron is an essential element for nearly all living organisms and disruption of iron homeostasis can lead to a number of clinical manifestations. Iron is used in the formation of both hemoglobin and myoglobin, as well as numerous enzyme systems of the body. Disorders of iron in the body include iron deficiency anemia, anemia of inflammatory disease, and iron overload. This article reviews normal iron metabolism, disease syndromes of iron imbalance, diagnostic testing, and treatment of either iron deficiency or excess. Recent advances in diagnosing iron deficiency using reticulocyte indices are reviewed.

A High Through-Put Screen Identifies MCP-1 (CCL2) As a Novel Regulator of Iron Homeostasis and a Modifier of Hereditary Hemochromatosis Disease Severity

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 685-685
Author(s):  
Martina U. Muckenthaler ◽  
Maja Vujic Spasic ◽  
Katarzyna Mleczko-Sanecka ◽  
Mingang Zhu ◽  
Rainer Pepperkok ◽  
...  
Keyword(s):  
Iron Overload ◽  
Mrna Expression ◽  
Disease Severity ◽  
Iron Homeostasis ◽  
Expression Profiles ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Human Cells ◽  
Liver Iron ◽  
Deficient Mice

Abstract Abstract 685 To identify genes that modify the severity of human iron disorders we pre-selected 74 genes from gene expression profiles of cells and tissues with altered iron levels and assessed whether siRNA-mediated knock-down of these genes affects uptake of transferrin, a key cellular process to acquire iron. This screen identifies the monocyte chemoattractant protein-1 (MCP-1), also known as CCL2, as a critical suppressor of transferrin receptor mRNA expression in human cells. We next analyzed CCL2-deficient mice and demonstrate profound alterations of parameters of systemic iron homeostasis. Specifically, CCL2 knock-out mice show decreased serum iron levels and transferrin saturation, strong iron-overload in the spleen and duodenum as well as mild iron accumulation in the liver. Iron imbalance in CCL2−/− mice is unlikely explained by an impairment of the major control system of systemic iron homeostasis, the hepcidin/ferroportin regulatory system: hepcidin mRNA expression is unaltered and splenic ferroportin protein expression is strongly increased in CCL2−/− mice, as would be expected as a consequence of splenic iron overload. We speculate that increased iron absorption from the plasma, possibly mediated by inappropriately high levels of TfR1 in the spleen, duodenum and liver, may be responsible for tissue iron overload. It is of note that CCL2 levels are strongly decreased in Hfe-deficient mice and patients with Hfe-associated Hereditary Hemochromatosis (HH). We therefore asked whether CCL2 levels could modify disease severity of HH. Analysis of 51 HH patients, all homozygous for the C282Y HFE mutation, confirms significantly lower MCP-1 levels in the serum compared to a group of 23 sex- and age-matched normal controls. Importantly, CCL2 levels in HH patients show a significant negative correlation with liver iron overload at the time point of diagnosis. Furthermore, low CCL2 concentrations are significantly associated with the HLA-A3 genotype and the CD8+ T lymphocyte phenotype, both traits previously shown to correlate with iron overload in HH patients. These patient data and the data from CCL2-deficient mice suggest that appropriate CCL2 expression is required to prevent iron overload. Taken together our data demonstrate the power of siRNA screens to identify novel regulators of iron metabolism in human cells that are critically involved in maintaining systemic iron homeostasis in the mouse and that play a role in modifying hepatic iron overload in the frequent iron overload disorder Hereditary Hemochromatosis. Disclosures: No relevant conflicts of interest to declare.

An Essential Role For Transferrin Receptor 2 In Erythropoiesis During Iron Restriction

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 429-429
Author(s):  
Daniel F Wallace ◽  
Cameron J McDonald ◽  
Eriza S Secondes ◽  
Lesa Ostini ◽  
Gautam Rishi ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Iron Deficiency Anemia ◽  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Deficiency Anemia ◽  
Erythroid Cells ◽  
Iron Restriction ◽  
Extramedullary Erythropoiesis

Abstract Iron deficiency and iron overload are common clinical conditions that impact on the health and wellbeing of up to 30% of the world’s population. Understanding mechanisms regulating iron homeostasis will provide improved strategies for treating these disorders. The liver-expressed proteins matriptase-2 (encoded by TMPRSS6), HFE and transferrin receptor 2 (TFR2) play important and opposing roles in systemic iron homeostasis by regulating expression of the iron regulatory hormone hepcidin. Mutations in TMPRSS6 lead to iron refractory iron deficiency anemia, whereas mutations in HFE and TFR2 lead to the iron overload disorder hereditary hemochromatosis. To elucidate the competing roles of these hepcidin regulators, we created mice lacking matriptase-2, Hfe and Tfr2. Tmprss6 -/-/Hfe-/-/Tfr2-/- mice had iron deficiency anemia resulting from hepatic hepcidin over-expression and activation of Smad1/5/8, indicating that matriptase-2 predominates over Hfe and Tfr2 in hepcidin regulation. Surprisingly, this anemia was more severe than in the Tmprss6-/- mice, demonstrated by more extensive alopecia, lower hematocrit and significant extramedullary erythropoiesis in the spleen. There was increased expression of erythroid-specific genes in the spleens of Tmprss6-/-/Hfe-/-/Tfr2-/- mice, consistent with the extramedullary erythropoiesis. Expression of Tfr2 but not Hfe in the spleen was increased in the Tmprss6-/- mice compared to wild type and correlated with the expression of erythroid genes, suggesting that Tfr2 is expressed in erythroid cells. Further analysis of gene expression in the bone marrow suggests that the loss of Tfr2 in the erythroid cells of Tmprss6-/-/Hfe-/-/Tfr2-/- mice causes a delay in the differentiation process leading to a more severe phenotype. In conclusion, our results indicate that Hfe and Tfr2 act upstream of matriptase-2 in hepcidin regulation or in a way that is overridden when matriptase-2 is deleted. These results indicate that inhibition of matriptase-2 would be useful in the treatment of iron overload conditions such as hereditary hemochromatosis. We have also identified a novel role for Tfr2 in erythroid differentiation that is separate from its canonical role as a regulator of iron homeostasis in the liver. This important role of Tfr2 in erythropoiesis only becomes apparent during conditions of iron restriction. Our results provide novel insights into mechanisms regulating and linking iron homeostasis and erythropoiesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Hepatic Iron Overload following Liver Transplantation from a C282Y/H63D Compound Heterozygous Donor

2018 ◽  
Vol 2018 ◽  
pp. 1-4 ◽  
Author(s):  
E. Veitsman ◽  
E. Pras ◽  
O. Pappo ◽  
A. Arish ◽  
R. Eshkenazi ◽  
...  
Keyword(s):  
Iron Overload ◽  
Genetic Disease ◽  
Sclerosing Cholangitis ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Compound Heterozygous ◽  
Primary Role ◽  
Hepatic Iron Overload ◽  
Liver Biopsies ◽  
First Time

Hereditary hemochromatosis (HH) is a genetic disease associated with progressive iron overload, eventually leading in some cases to damage of parenchymal organs, such as the liver, pancreas, and heart. Although the gene had been identified (HFE), HH pathogenesis remains to be fully elucidated. We report here, for the first time, a case of inadvertent transplantation of a liver from a donor with C282Y/H63D compound heterozygosity into a nonhemochromatotic 19-year-old Caucasian male recipient with primary sclerosing cholangitis. Progressive iron overload occurred over 1.5 years, as observed in liver biopsies and iron studies, after ruling out secondary causes of iron overload. This case strengthens the hypothesis that the liver, rather than the small intestine, plays a primary role in the maintenance of iron homeostasis.

scholarly journals Enhanced erythropoiesis in Hfe-KO mice indicates a role for Hfe in the modulation of erythroid iron homeostasis

Blood ◽  
2011 ◽  
Vol 117 (4) ◽  
pp. 1379-1389 ◽  
Author(s):  
Pedro Ramos ◽  
Ella Guy ◽  
Nan Chen ◽  
Catia C. Proenca ◽  
Sara Gardenghi ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Dietary Iron ◽  
Erythroid Cells ◽  
Hepcidin Expression ◽  
Stress Erythropoiesis ◽  
Cellular Iron ◽  
Cellular Iron Uptake

Abstract In hereditary hemochromatosis, mutations in HFE lead to iron overload through abnormally low levels of hepcidin. In addition, HFE potentially modulates cellular iron uptake by interacting with transferrin receptor, a crucial protein during erythropoiesis. However, the role of HFE in this process was never explored. We hypothesize that HFE modulates erythropoiesis by affecting dietary iron absorption and erythroid iron intake. To investigate this, we used Hfe-KO mice in conditions of altered dietary iron and erythropoiesis. We show that Hfe-KO mice can overcome phlebotomy-induced anemia more rapidly than wild-type mice (even when iron loaded). Second, we evaluated mice combining the hemochromatosis and β-thalassemia phenotypes. Our results suggest that lack of Hfe is advantageous in conditions of increased erythropoietic activity because of augmented iron mobilization driven by deficient hepcidin response. Lastly, we demonstrate that Hfe is expressed in erythroid cells and impairs iron uptake, whereas its absence exclusively from the hematopoietic compartment is sufficient to accelerate recovery from phlebotomy. In summary, we demonstrate that Hfe influences erythropoiesis by 2 distinct mechanisms: limiting hepcidin expression under conditions of simultaneous iron overload and stress erythropoiesis, and impairing transferrin-bound iron uptake by erythroid cells. Moreover, our results provide novel suggestions to improve the treatment of hemochromatosis.

Expression of hepcidin in hereditary hemochromatosis: evidence for a regulation in response to the serum transferrin saturation and to non-transferrin-bound iron

Blood ◽  
2003 ◽  
Vol 102 (1) ◽  
pp. 371-376 ◽  
Author(s):  
Sven G. Gehrke ◽  
Hasan Kulaksiz ◽  
Thomas Herrmann ◽  
Hans-Dieter Riedel ◽  
Karin Bents ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Iron Homeostasis ◽  
Iron Status ◽  
Hereditary Hemochromatosis ◽  
Transferrin Saturation ◽  
Serum Transferrin ◽  
Transcript Levels ◽  
Hepcidin Expression

Abstract Experimental data suggest the antimicrobial peptide hepcidin as a central regulator in iron homeostasis. In this study, we characterized the expression of human hepcidin in experimental and clinical iron overload conditions, including hereditary hemochromatosis. Using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we determined expression of hepcidin and the most relevant iron-related genes in liver biopsies from patients with hemochromatosis and iron-stain-negative control subjects. Regulation of hepcidin mRNA expression in response to transferrin-bound iron, non-transferrin-bound iron, and deferoxamine was analyzed in HepG2 cells. Hepcidin expression correlated significantly with serum ferritin levels in controls, whereas no significant up-regulation was observed in patients with hemochromatosis despite iron-overload conditions and high serum ferritin levels. However, patients with hemochromatosis showed an inverse correlation between hepcidin transcript levels and the serum transferrin saturation. Moreover, we found a significant correlation between hepatic transcript levels of hepcidin and transferrin receptor-2 irrespective of the iron status. In vitro data indicated that hepcidin expression is down-regulated in response to non-transferrin-bound iron. In conclusion, the presented data suggest a close relationship between the transferrin saturation and hepatic hepcidin expression in hereditary hemochromatosis. Although the causality is not yet clear, this interaction might result from a down-regulation of hepcidin expression in response to significant levels of non-transferrin-bound iron. (Blood. 2003;102:371-376)

scholarly journals The Hepcidin-Ferroportin System as a Therapeutic Target in Anemias and Iron Overload Disorders

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 538-542 ◽  
Author(s):  
Tomas Ganz ◽  
Elizabeta Nemeth
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Therapeutic Target ◽  
Iron Homeostasis ◽  
Kidney Diseases ◽  
Hereditary Hemochromatosis ◽  
Deficiency Anemia ◽  
Therapeutic Targeting ◽  
Chronic Kidney Diseases

Abstract The review summarizes the current understanding of the role of hepcidin and ferroportin in normal iron homeostasis and its disorders. The various approaches to therapeutic targeting of hepcidin and ferroportin in iron-overload disorders (mainly hereditary hemochromatosis and β-thalassemia) and iron-restrictive anemias (anemias associated with infections, inflammatory disorders, and certain malignancies, anemia of chronic kidney diseases, and iron-refractory iron-deficiency anemia) are also discussed.

scholarly journals Renal Involvement and HBV Infection Are Common in Chinese Patients With Cryoglobulinemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Wei Bai ◽  
Lixia Zhang ◽  
Jiuliang Zhao ◽  
Shangzhu Zhang ◽  
Jiaxin Zhou ◽  
...  
Keyword(s):  
Renal Involvement ◽  
Connective Tissue Diseases ◽  
Clinical Manifestations ◽  
Hbv Infection ◽  
Chinese Patients ◽  
Type I ◽  
College Hospital ◽  
Female Ratio ◽  
Medical College ◽  
Significant Difference

Objectives: This study aimed to describe the main characteristics of Chinese patients with cryoglobulinemia, especially the characteristics of patients with different causes of cryoglobulinemia.Methods: Eighty inpatients diagnosed with cryoglobulinemia from different wards in Peking Union Medical College Hospital were included in this study. Demographic, clinical, biological, and renal pathological data were collected. We analyzed the characteristics of 61 patients with different causes of cryoglobulinemia.Results: Most patients (36/80, 45%) were diagnosed between 40 and 60 years of age. The male: female ratio was 1:1.5. Mixed (II + III) cryoglobulinemia accounted for the majority (43.8%) of cases. Renal involvement (87.5%), cutaneous involvement (57.5%), and fever (27.5%) were the most common clinical manifestations, while other manifestations included serositis and pulmonary and gastrointestinal involvement. The most common renal histopathological pattern was membranoproliferative glomerulonephritis (25/42, 59.5%). The secondary causes of cryoglobulinemia included infectious diseases (26/61, 32.5%), such as hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, and connective tissue diseases (22/61, 27.5%), such as lupus and hematologic tumors (13/61, 16.3%). Patients with hematologic tumors were diagnosed at an older age (P = 0.044) and mostly had type I cryoglobulinemia (P < 0.001). No significant difference in clinical or biological manifestations was found among patients with different causes of cryoglobulinemia.Conclusions: This is the largest cohort of Chinese patients with cryoglobulinemia. We found that renal involvement and HBV infection might be more common in Chinese patients with cryoglobulinemia.

Sign in / Sign up

Export Citation Format

Share Document