Iron overload in patients with rare hereditary hemolytic anemia: Evidence-based suggestion on whom and how to screen.
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ABSTRACT:
SUBMITTER: van Straaten S
PROVIDER: S-EPMC6220762 | biostudies-literature | 2018 Nov
REPOSITORIES: biostudies-literature
Publications
Iron overload in patients with rare hereditary hemolytic anemia: Evidence-based suggestion on whom and how to screen.
van Straaten Stephanie S Biemond Bart J BJ Kerkhoffs Jean-Louis JL Gitz-Francois Jerney J van Wijk Richard R van Beers Eduard J EJ
American journal of hematology 20180921 11
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Project description:Hemolysis occurring in hematologic diseases is often associated with an iron loading anemia. This iron overload is the result of a massive outflow of hemoglobin into the bloodstream, but the mechanism of hemoglobin handling has not been fully elucidated. Here, in a congenital erythropoietic porphyria mouse model, we evaluate the impact of hemolysis and regenerative anemia on hepcidin synthesis and iron metabolism. Hemolysis was confirmed by a complete drop in haptoglobin, hemopexin and increased plasma lactate dehydrogenase, an increased red blood cell distribution width and osmotic fragility, a reduced half-life of red blood cells, and increased expression of heme oxygenase 1. The erythropoiesis-induced Fam132b was increased, hepcidin mRNA repressed, and transepithelial iron transport in isolated duodenal loops increased. Iron was mostly accumulated in liver and spleen macrophages but transferrin saturation remained within the normal range. The expression levels of hemoglobin-haptoglobin receptor CD163 and hemopexin receptor CD91 were drastically reduced in both liver and spleen, resulting in heme- and hemoglobin-derived iron elimination in urine. In the kidney, the megalin/cubilin endocytic complex, heme oxygenase 1 and the iron exporter ferroportin were induced, which is reminiscent of significant renal handling of hemoglobin-derived iron. Our results highlight ironbound hemoglobin urinary clearance mechanism and strongly suggest that, in addition to the sequestration of iron in macrophages, kidney may play a major role in protecting hepatocytes from iron overload in chronic hemolysis.
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Project description:Combining microfluidics technology with machine learning represents an innovative approach to conduct massive quantitative cell behavior study and implement smart decision-making systems in support of clinical diagnostics. The spleen plays a key-role in rare hereditary hemolytic anemia (RHHA), being the organ responsible for the premature removal of defective red blood cells (RBCs). The goal is to adapt the physiological spleen filtering strategy for in vitro study and monitoring of blood diseases through RBCs shape analysis. Then, a microfluidic device mimicking the slits of the spleen red pulp area and video data analysis are combined for the characterization of RBCs in RHHA. This microfluidic unit is designed to evaluate RBC deformability by maintaining them fixed in planar orientation, allowing the visual inspection of RBC's capacity to restore their original shape after crossing microconstrictions. Then, two cooperative learning approaches are used for the analysis: the majority voting scheme, in which the most voted label for all the cell images is the class assigned to the entire video; and the maximum sum of scores to decide the maximally scored class to assign. The proposed platform shows the capability to discriminate healthy controls and patients with an average efficiency of 91%, but also to distinguish between RHHA subtypes, with an efficiency of 82%.
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Project description:Although the prevalence of hereditary hemolytic anemia (HHA) is relatively low in Korea, it has been gradually increasing in recent decades due to increment in the proportions of hemoglobinopathies from immigrants of South East Asia, raising awareness of the disease among clinicians, and advances in diagnostic technology. As such, the red blood cell (RBC) Disorder Working Party (WP), previously called HHA WP, of the Korean Society of Hematology (KSH) developed the Korean Standard Operating Procedures (SOPs) for the diagnosis of HHA in 2007. These SOPs have been continuously revised and updated following advances in diagnostic technology [e.g., flow cytometric osmotic fragility test (FOFT) and eosin-5-maleimide (EMA) binding test], current methods for membrane protein or enzyme analysis [e.g., liquid chromatography-tandem mass spectrometry (LC-MS/MS), ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), high-performance liquid chromatography (HPLC)], and molecular genetic tests using next-generation sequencing (NGS). However, the diagnosis and treatment of HHA remain challenging as they require considerable experience and understanding of the disease. Therefore, in this new Korean Clinical Practice Guidelines for the Diagnosis of HHA, on behalf of the RBC Disorder WP of KSH, updated guidelines to approach patients suspected of HHA are summarized. NGS is proposed to perform prior to membrane protein or enzyme analysis by LC-MS/MS, UPLC-MS/MS or HPLC techniques due to the availability of gene testing in more laboratories in Korea. We hope that this guideline will be helpful for clinicians in making diagnostic decisions for patients with HHA in Korea.
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Project description:Hereditary hemorrhagic telangiectasias (HHT), also known as Osler-Weber-Rendu syndrome, is an uncommon genetic disorder. It is inherited as an autosomal dominant disorder with varying penetrance and expression. The diagnosis of HHT requires the presence of at least three out of four clinical criteria. These so-called Curaçao criteria include epistaxis, telangiectasias, visceral involvement, and a family history of HHT in a first-degree relative. Visceral involvement can involve the gastrointestinal (GI) tract, resulting in the development of GI telangiectasias. One of the complications is anemia due to the chronic blood loss from these vascular malformations. Here, we present a case of a 26-year-old male who was diagnosed with HHT. He initially had episodes of epistaxis but now presented to us with features of anemia. According to the patient, he didn't have epistaxis for the past many months and on his esophagogastroduodenoscopy (EGD) and colonoscopy, there was evidence of multiple small telangiectasias seen in his stomach, duodenum, and colon. He was managed with blood transfusion and was discharged on oral iron supplementation. This is a rare cause of anemia and should be evaluated if other features of HHT are present.
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Project description:BackgroundHereditary hemolytic anemia (HHA) refers to a heterogeneous group of genetic disorders that share one common feature: destruction of circulating red blood cells (RBCs). The destruction of RBCs may be due to membranopathies, enzymopathies, or hemoglobinopathies. Because these are genetic disorders, incorporation of next-generation sequencing (NGS) has facilitated the diagnostic process of HHA.MethodGenetic data from 29 patients with suspected hereditary anemia in a tertiary hospital were retrospectively reviewed to evaluate the efficacy of NGS on hereditary anemia diagnosis. Targeted NGS was performed with custom probes for 497 genes associated with hematologic disorders. After genomic DNA was extracted from peripheral blood, prepared libraries were hybridized with capture probes and sequenced using NextSeq 550Dx (Illumina, San Diego, CA, USA).ResultAmong the 29 patients, ANK1 variants were detected in five, four of which were pathogenic or likely pathogenic variants. SPTB variants were detected in six patients, five of which were classified as pathogenic or likely pathogenic variants. We detected g6pd pathogenic and spta1 likely pathogenic variants in two patients and one patient, respectively. Whole-gene deletions in both HBA1 and HBA2 were detected in two patients, while only HBA2 deletion was detected in one patient. One likely pathogenic variant in PLKR was detected in one patient, and one likely pathogenic variant in ALAS2 was detected in another.ConclusionHere, NGS played a critical role in definitive diagnosis in 18 out of 29 patients (62.07%) with suspected HHA. Thus, its incorporation into the diagnostic workflow is crucial.
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Project description:This case report outlines a 70-year-old female patient who presented with a concurrent mixed autoimmune hemolytic anemia (AIHA) and a gastric adenocarcinoma. Her treatment course of these two diseases is summarized, which included supportive care, neoadjuvant chemotherapy for her gastric adenocarcinoma, steroids, rituximab, and surgical resection of the tumor. This approach ultimately led to the stabilization of her AIHA and primary cure for her solid malignancy. We briefly review both AIHA and gastric adenocarcinoma as clinical entities, propose working causes of hemolytic anemia including gastric adenocarcinoma, and outline a successful treatment pathway for these two concurrent conditions.
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Project description:Several distinct congenital disorders can lead to tissue-iron overload with anemia. Repeated blood transfusions are one of the major causes of iron overload in several of these disorders, including ?-thalassemia major, which is characterized by a defective ?-globin gene. In this state, hyperabsorption of iron is also observed and can significantly contribute to iron overload. In ?-thalassemia intermedia, which does not require blood transfusion for survival, hyperabsorption of iron is the leading cause of iron overload. The mechanism of increased iron absorption in ?-thalassemia is unclear. We definitively demonstrate, using genetic mouse models, that intestinal hypoxia-inducible factor-2? (HIF2?) and divalent metal transporter-1 (DMT1) are activated early in the pathogenesis of ?-thalassemia and are essential for excess iron accumulation in mouse models of ?-thalassemia. Moreover, thalassemic mice with established iron overload had significant improvement in tissue-iron levels and anemia following disruption of intestinal HIF2?. In addition to repeated blood transfusions and increased iron absorption, chronic hemolysis is the major cause of tissue-iron accumulation in anemic iron-overload disorders caused by hemolytic anemia. Mechanistic studies in a hemolytic anemia mouse model demonstrated that loss of intestinal HIF2?/DMT1 signaling led to decreased tissue-iron accumulation in the liver without worsening the anemia. These data demonstrate that dysregulation of intestinal hypoxia and HIF2? signaling is critical for progressive iron overload in ?-thalassemia and may be a novel therapeutic target in several anemic iron-overload disorders.
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