Cut-off value of C1-inhibitor function for the diagnosis of hereditary angioedema due to C1-inhibitor deficiency

Honda, Daisuke; Ohsawa, Isao; Mano, Satoshi; Rinno, Hisaki; Tomino, Yasuhiko; Suzuki, Yusuke

doi:10.5582/irdr.2020.03099

Cited by 4 publications

(3 citation statements)

References 14 publications

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“…C1-INH produced in patients with HAE is 50% lower than that produced in healthy individuals because of an autosomal dominant inheritance caused by mutations in SERPING1. However, most patients with HAE exhibit C1-INH function of < 25% because of chronic consumption of C1-INH in the kallikrein–kinin, contact, complement, coagulation, and fibrinolysis cascades during homeostasis [ 10 ]. Therefore, replacement therapy with C1-INH concentrates is recommended as one of the first-line therapies for acute attacks, and for short- and long-term prophylaxes in the World Allergy Organization/European Academy of Allergy and Clinical Immunology (WAO/EAACI) guideline owing to the fact that C1-INH can help to comprehensively suppress several activations occurring throughout the abovementioned cascades, thereby inhibiting bradykinin production [ 11 ].…”

Section: Discussionmentioning

confidence: 99%

Hereditary angioedema with an acute attack resolved after bone marrow transplantation for acute myeloid leukemia: a case report

Honda

Ohsawa

Aizawa

et al. 2023

Allergy Asthma Clin Immunol

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Background Hereditary angioedema (HAE), which is caused by C1-inhibitor (C1-INH) deficiency or dysfunction, is a rare and potentially life-threatening disease. In patients with HAE, excess production of bradykinin causes acute unpredictable recurrent attacks of angioedema in localized regions, including the larynx and intestines. Given the fact that HAE is an autosomal dominant disease, C1-INH produced in patients with HAE is 50% of that produced in healthy individuals. However, most patients with HAE present plasma C1-INH function of < 25% owing to the chronic consumption of C1-INH by kallikrein–kinin, contact, complement, coagulation, and fibrinolysis cascades. Recently, several therapeutic options have been developed for acute attacks and prophylaxis in the treatment of HAE; however, currently, there is no curative therapy for HAE. Case presentation Here we report the case of a 48-year-old male patient who presented with a long-standing history of HAE and underwent bone marrow transplantation (BMT) for acute myeloid leukemia (AML) at the age of 39 years and has been in complete remission of AML and HAE thereafter. Notably, after BMT, his C1-INH function gradually increased as follows: < 25%, 29%, 37%, and 45.6%. Since his 20 s, he intermittently presented with an acute attack of HAE once every 3 months from the initial attack. Further, after undergoing BMT, the number of acute attacks decreased to twice within 4 years until the age of 45 years, and subsequently, the patient has been free of acute attacks. C1-INH is mainly synthesized by hepatocytes, but it is known to be partially produced and secreted from peripheral blood monocytes, macrophages, endothelial cells, and fibroblasts. We speculate that the C1-INH function may be increased by extrahepatic production of C1-INH, possibly synthesized by differentiated cells derived from hematopoietic and mesenchymal stem cells after BMT. Conclusions This case report supports efforts to focus on extrahepatic production of C1-INH in the next strategy of new treatment development for HAE.

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Section: Discussionmentioning

confidence: 99%

Hereditary angioedema with an acute attack resolved after bone marrow transplantation for acute myeloid leukemia: a case report

Honda

Ohsawa

Aizawa

et al. 2023

Allergy Asthma Clin Immunol

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“…HAE is an autosomal dominant disease and patients are heterozygous for the defected SERPING1 allele. However, C1 inhibitor’s functional level is sometimes below 50%, sometimes reaching very low or undetectable levels ( Cicardi et al, 1987 ; Honda et al, 2021 ), which can be interpreted as reduced production from both alleles in these specific cases ( Kramer et al, 1993 ). Haslund et al (2019) showed that the dominant-negative effect of mutant SERPING1 alleles can inhibit the secretion of wild-type C1 inhibitor from hepatocyte-like cells by forming intracellular C1 inhibitor protein aggregates.…”

Section: Discussionmentioning

confidence: 99%

Myeloid lineage cells evince distinct steady-state level of certain gene groups in dependence on hereditary angioedema severity

et al. 2023

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Hereditary angioedema (HAE) is a rare genetic disorder with variable expressivity even in carriers of the same underlying genetic defect, suggesting other genetic and epigenetic factors participate in modifying HAE severity. Recent knowledge indicates the role of immune cells in several aspects of HAE pathogenesis, which makes monocytes and macrophages candidates to mediate these effects. Here we combined a search for HAE phenotype modifying gene variants with the characterization of selected genes’ mRNA levels in monocyte and macrophages in a symptom-free period. While no such gene variant was found to be associated with a more severe or milder disease, patients revealed a higher number of dysregulated genes and their expression profile was significantly altered, which was typically manifested by changes in individual gene expression or by strengthened or weakened relations in mutually co-expressed gene groups, depending on HAE severity. SERPING1 showed decreased expression in HAE-C1INH patients, but this effect was significant only in patients carrying mutations supposedly activating nonsense-mediated decay. Pro-inflammatory CXC chemokine superfamily members CXCL8, 10 and 11 were downregulated, while other genes such as FCGR1A, or long non-coding RNA NEAT1 were upregulated in patients. Co-expression within some gene groups (such as an NF-kappaB function related group) was strengthened in patients with a severe and/or mild course compared to controls. All these findings show that transcript levels in myeloid cells achieve different activation or depression levels in HAE-C1INH patients than in healthy controls and/or based on disease severity and could participate in determining the HAE phenotype.

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“…Until now, based on recommendations, C4 level, C1-INH level, and activity are used to diagnose HAE 1/2 ( 4 ). Test results that point to HAE 1/2 should be repeated in a certified laboratory because time, temperature, and sample handling significantly impact C1-INH level and activity, leading to potentially incorrect values, inaccurate diagnoses, and thus inappropriate treatment ( 4 , 6 – 8 ). Moreover, no specific biochemical method exists for the exact diagnosis of HAE-nC1-INH.…”

Section: Introductionmentioning

confidence: 99%

Exploring disease-specific metabolite signatures in hereditary angioedema patients

Kanepa,

Fan,

Rots

et al. 2024

Front. Immunol.

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IntroductionHereditary angioedema (HAE) is a rare, life-threatening autosomal dominant genetic disorder caused by a deficient and/or dysfunctional C1 esterase inhibitor (C1-INH) (type 1 and type 2) leading to recurrent episodes of edema. This study aims to explore HAE patients’ metabolomic profiles and identify novel potential diagnostic biomarkers for HAE. The study also examined distinguishing HAE from idiopathic angioedema (AE).MethodsBlood plasma samples from 10 HAE (types 1/2) patients, 15 patients with idiopathic AE, and 20 healthy controls were collected in Latvia and analyzed using LC-MS based targeted metabolomics workflow. T-test and fold change calculation were used to identify metabolites with significant differences between diseases and control groups. ROC analysis was performed to evaluate metabolite based classification model.ResultsA total of 33 metabolites were detected and quantified. The results showed that isovalerylcarnitine, cystine, and hydroxyproline were the most significantly altered metabolites between the disease and control groups. Aspartic acid was identified as a significant metabolite that could differentiate between HAE and idiopathic AE. The mathematical combination of metabolites (hydroxyproline * cystine)/(creatinine * isovalerylcarnitine) was identified as the diagnosis signature for HAE. Furthermore, glycine/asparagine ratio could differentiate between HAE and idiopathic AE.ConclusionOur study identified isovalerylcarnitine, cystine, and hydroxyproline as potential biomarkers for HAE diagnosis. Identifying new biomarkers may offer enhanced prospects for accurate, timely, and economical diagnosis of HAE, as well as tailored treatment selection for optimal patient care.

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Cut-off value of C1-inhibitor function for the diagnosis of hereditary angioedema due to C1-inhibitor deficiency

Cited by 4 publications

References 14 publications

Hereditary angioedema with an acute attack resolved after bone marrow transplantation for acute myeloid leukemia: a case report

Hereditary angioedema with an acute attack resolved after bone marrow transplantation for acute myeloid leukemia: a case report

Myeloid lineage cells evince distinct steady-state level of certain gene groups in dependence on hereditary angioedema severity

Exploring disease-specific metabolite signatures in hereditary angioedema patients

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