Diagnosis Of Hereditary Angioedema Research Articles

Hereditary angioedema with normal C1 esterase inhibitor: Current paradigms and clinical dilemmas.

Background: A diagnosis of hereditary angioedema (HAE) with normal C1 esterase inhibitor (HAE-nl-C1-INH) can be challenging and pharmacologic management is not well defined. Objective: The objective was to discuss practical considerations in the clinical management of HAE-nl-C1-INH by using illustrative clinical vignettes to highlight and/or address select challenges. Methods: This was a narrative review. Results: Symptoms of HAE-nl-C1-INH overlap with HAE types I and II; the heterogeneity of presentation and symptom burden are diagnostic challenges. A patient history, with particular attention to whether urticaria or other symptoms of mast cell mediator release are present, is important because such symptoms would strongly suggest a mast cell-mediated pathway. A family history of angioedema is informative but a lack thereof does not rule out diagnosis. Expected laboratory findings would be normal for C4, C1-INH level and function, and Complement 1q; a genetic mutational analysis may be helpful, but current assays do not include all known mutations; most cases are categorized as unknown. To align with guideline-directed treatment approaches, the following stepwise approach is suggested for suspected HAE-nl-C1-INH: (1) thoroughly investigate the possibility of response to histaminergic and/or mast cell-targeting treatments; (2) if patients with normal C4, C1-INH level and/or function fail adequate trials with histamine/mast cell-directed therapy or have a mutation that suggests bradykinin pathway involvement, follow HAE type I and II treatment guidelines. Response to medications approved for HAE types I/II provides compelling support for a high clinical suspicion of HAE-nl-C1-INH. De-labeling an HAE-nl-C1-INH diagnosis may be appropriate if the initial diagnosis was made without adequate evaluation or if new information and/or testing indicates that the patient does not actually have HAE. Conclusion: Key unmet needs in HAE-nl-C1-INH include lack of confirmatory biomarker(s) for diagnosis and lack of prospective controlled clinical studies of pharmacologic products in this patient population.

Exploring disease-specific metabolite signatures in hereditary angioedema patients.

Hereditary 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). Blood 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. A 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. Our 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.

Management of Hereditary Angioedema in Pediatric, Pregnant, and Breast-Feeding Patients: An Expert Opinion – A Secondary Publication

Hereditary angioedema (HAE) is a rare inherited condition marked by recurrent skin and submucosal edema. HAE is caused by a C1 inhibitor deficiency or decreased C1 inhibitor function. The initial attack may occur during childhood or pregnancy, with symptoms ranging from classic angioedema to nonspecific stomach cramps. In this review, we discuss strategies for children and pregnant women to manage HAE attacks effectively and safely in light of the recent increase in HAE diagnosis. To begin, an aggressive work-up is necessary to confirm HAE-1/2 and to determine the most effective countermeasures. Secondly, in the event of an acute attack, plasma-derived C1-inhibitor is the first line of defense for children and pregnant women. Icatibant is also appropriate for use, except in pregnant women. Fresh frozen plasma (FFP) may be suggested as an alternative. Thirdly, proactive measures to prevent HAE attacks should be considered whenever a procedure is performed that may result in an exacerbation. Finally, FFP, attenuated androgen, and antifibrinolytic agents are recommended for long-term prophylaxis in South Korea where the C1 inhibitor is scarce. However, when making a decision, it is necessary to consider both the efficacy and the risk of adverse effects. For proper management, written action plans and first-aid kits are required. The action plans should be customized to the patient’s unique circumstances.

Association between Hereditary Angioedema and Venous Thromboembolism in a Large Population-Based Case-Control Study

Introduction: Hereditary Angioedema (HAE) is a rare congenital disorder primarily caused by mutations in the SERPING1 gene that results in C1 inhibitor (C1INH) deficiency or dysfunction. C1INH is a multifunctional serine protease inhibitor that functions as a major endogenous negative regulator of the kallikrein-kinin, contact pathway of coagulation and complement systems. HAE typically presents with episodes of unpredictable subcutaneous and submucosal swelling. However, HAE patients also have evidence of systemic activation of coagulation including elevated plasma prothrombin fragments, thrombin antithrombin complexes and D-dimers. Further, patients with HAE have recently been reported to have an increased risk of venous thromboembolism (VTE). Methods: To evaluate the risk of VTE in patients with HAE we conducted a large population-based case-control study leveraging data from the United Kingdom Clinical Practice Research Datalink (CPRD). The CPRD Aurum dataset used here maintains anonymized electronic medical records of over 40 million individuals from over 1600 primary care practices in the United Kingdom. SNOMED CT medical codes were used to identify a cohort of 2,198 patients diagnosed with HAE between 1992 and 2022 in the CPRD Aurum dataset with a matched (age, gender, family practice, and index date for HAE) cohort of 4,376 controls selected. VTE events including deep vein thrombosis (DVT) and pulmonary embolism in the HAE case and control cohorts were identified using SNOMED CT medical codes. The Cox proportional hazards model was used to determine hazard ratios (HR) for VTE events in HAE cases versus controls adjusting for covariates age, sex, body mass index, blood pressure, smoking status and a number of co-morbidities specifically; neoplasm, type 2 diabetes, ischemic heart disease, chronic obstructive pulmonary disease, chronic kidney disease, autoimmune disorders and depression. Results: A greater proportion of the HAE cases were female (62%) with a mean age at HAE diagnosis of 37 years. The median follow-up period for both cases and controls was 17 years (interquartile range (IQR):8-28 years). The overall incidence of VTE in HAE cases was 1.1/1000 patient years versus 0.6/1000 patient years in the control cohort. In unadjusted analyses HAE was associated with a significantly increased risk of VTE (HR 1.70, 95% CI 1.37-2.22, P<0.0001). Importantly, in adjusted analyses HAE remained significantly associated with an increased risk of VTE (HR 1.44, 95% CI 1.12-1.83, P=0.004, Figure 1). Of note, this association is similar in magnitude to that previously reported for heterozygous carriers of FV Leiden, the prothrombin gene mutation and high confidence loss of function mutations in Protein C and Protein S in comparable population-based case-control studies. In adjusted sub-analyses HAE was associated with a significantly increased risk of DVT (HR: 1.42, 95% CI 1.09-1.87, P=0.01) with a trend towards an increased risk of PE (HR 1.37, 95% CI 0.84-2.27, P=0.2). Conclusions: The results of this population-based case-control study, roughly an order of magnitude larger in size than prior reports, demonstrate that HAE is associated with a significantly increased risk of VTE similar to that reported for common hereditary thrombophilias. These findings reinforce the important role of endogenous C1INH as a negative regulator of prothrombotic processes involved in VTE in the setting of HAE.

Case of newly diagnosed primary immunodeficiency at age 65

Low awareness of doctors of various specialties about such an initial defect in immunity as hereditary angioedema leads to poor detection of this disease, as a result of which patients often receive ineffective drugs for a long time and are at risk of developing life-threatening complications.
 A clinical case was presented of a patient whose diagnosis of hereditary angioedema was first established at the age of 65 despite a long history of edema. There were no urticarial rashes. For edema for 3 years, the patient took Loratadine, systemic glucocorticosteroids were repeatedly administered. In addition, for many years she was worried about abdominal syndrome with an episode rate of up to several times a week, for the purpose of stopping which she used Tempalgin. There is a burdened family history of angioedema. This hospitalization was due to the development of edema of the lower lip and left cheek, the appearance of which is associated with a bite of the inner side of the cheek in sleep, there was no effect from the use of systemic glucocorticosteroids and antihistamines. The examination revealed a decrease in both the amount and functional activity of the C1-inhibitor, thus, hereditary angioedema of type I was diagnosed. Genetic examination revealed a previously undescribed variant of mutations in the SERPING1 gene.
 The pathogenesis of edema in hereditary angioedema is due to the accumulation of bradykinin, therefore, the use of glucocorticosteroids and antihistamines is ineffective. Currently, there are modern highly effective and safe means, both for stopping and for the prevention of such edema.
 It is important to inform specialists of various profiles about this disease and the principles of its therapy.

Clinical efficiency of the cleaved high-molecular-weight kininogen detection in the diagnosis of hereditary angioedema

Hereditary angioedema (HAE) is an orphan genetically determined disorder with recurrent episodes of swelling in various localization. HAE is divided into two groups: HAE with C1-inhibitor deficiency and without C1-inhibitor deficiency. The main diagnostic tests are: meas urements of levels and function of C1-inhibitor, and levels of C4. These tests are not useful in all cases, for example, in HAE without C1-inhibitor deficiency. The detection of cleaved high-molecular-weight kininogen (cHK), which, even in remission, is expected to be elevated both in patients with HAE due to C1-inhibitor deficiency and in HAE with normal C1-inhibitor is a promising biomarker. The aim of this study was to determine the clinical efficiency of the cHK detection in the diagnosis of HAE. According to the results of the measurements of cHK, the patients were divided into two groups. Group №1 (100% of cHK): 27 patients, of which 19 in the study regions had variants associated with HAE, 8 didn’t have. Group №2 (not 100% of cHK): 13 patients, of which one patient had a variant associated with HAE, 12 didn’t have. The obtained data demonstrate acceptable results of using the measurement of cleaved high- molecular-weight kininogen in laboratory practice in the diagnosis of HAE.

How Does Pregnancy and Type of Delivery Affect the Clinical Course of Hereditary Angioedema?

Introduction: Knowledge on the clinical course of hereditary angioedema (HAE) during pregnancy, delivery, and breastfeeding is very limited. In this study, we aimed to evaluate the course of HAE during these periods. Methods: The HAE attacks C1-INH prophylaxis before and during pregnancy and during breastfeeding, and the delivery types were retrospectively determined. The severity of attacks was assessed by a 10-point Visual Analogue Scale (VAS). Results: We evaluated 88 pregnancies in 48 HAE patients among whom 20 were primiparous. Among those who had a HAE diagnosis during pregnancy (n = 34), the median attack numbers before pregnancy, during pregnancy, breastfeeding, and after breastfeeding were 17, 39, 24, and 14 (before pregnancy vs. pregnancy, p < 0.001; during pregnancy vs. breastfeeding, p = 0.001). The mean VASs (SD) were 6.59 (1.82), 8.33 (1.58), 7.32 (1.66), and 6.95 (1.90) (before pregnancy vs. pregnancy, p < 0.001; during pregnancy vs. breastfeeding, p = 0.016), respectively. Among those who received a HAE diagnosis after pregnancy (n = 54), the number (59.3%) and the severity (60%) of HAE attacks were high in pregnancy. 47 of the deliveries were normal vaginal delivery (NVD). Regional anesthesia was applied in 8 NVDs. 20 of caesarean deliveries were performed under general anesthesia, and 21 were under spinal anesthesia. Lowest numbers of attacks were found in patients who did not receive anesthesia during NVD (p = 0.001). Conclusion: The course of HAE can be worse during pregnancy and breastfeeding. NVD is related to fewer HAE attacks and prophylaxis with C1-INH during NVD is not necessary to prevent a HAE attack.

Diagnosis and treatment procedures and health management for patients with hereditary angioedema

As a recognized rare and highly fatal disease, hereditary angioedema (HAE) is difficult to diagnose and characterized by recurrent edema involving the head, limbs, genitals and larynx, etc. Diagnosis of HAE is not difficult. However, low incidence and lack of clinical characteristics lead to difficulty of doctors on timely diagnosis and correct intervention for HAE patients. Therefore, it is crucial to improve the awareness of this disease and prevent its recurrence. for HAE patients. In view of absent cognition of doctors and the general public on HAE, patients often suffer from sudden death or become disabled due to laryngeal edema which cannot be treated in time. Thus, based on the Internet mobile terminal platform, the team set up an all-day rapid emergency response system which is provided for HAE patients by setting up "one-click help". The aim is to offer optimization on overall management of HAE and designed the intelligent follow-up management to provide timely assistance and specialized suggestion for patients with acute attacks.

Quantification of C1 esterase inhibitor in human serum by enzyme-linked immunosorbent assay: Correlation with turbidimetric immunoassay

C1 inhibitor of serine proteases (C1-INH) performs a regulatory function in the complement system and vascular permeability. Deficiency of C1-INH leads to various forms of angioedema, including hereditary angioedema (HAE). The cause of HAE is a genetically determined violation of the synthesis of C1-INH. A decrease in the level of C1-INH to 50% relative to the norm leads to an increase in the production of bradykinin, which is the basis for the diagnosis of HAE. The development of affordable ELISA for the quantitative determination of C1-INH is a popular direction for clinicians. During the development of a new kit for quantitative determination of C1-INH, two mouse monoclonal antibodies (mAb) with different epitope specificities were obtained. On their basis, a sandwich-type ELISA was developed. The specificity of the obtained mAb's was confirmed using the medical device “Berinert”. To prepare calibrators, C1-INH was affinity purified from human blood plasma using a sorbent with immobilized mAbs. The identity of the C1-INH protein was confirmed by PAGE electrophoresis, immunoblotting, and mass spectrometry on MALDI-TOF/TOF UltrafleXtreme mass spectrometer. To assess the quality indicators of developed reagents kit, studies were carried out in accordance with GOST R 51352-2013 and TU 21.20.23-041-01967164-2022. Values of quality indicators: accuracy — 93.53%; measurement linearity interval — 22.00-176.07 ng/mL. Using the developed ELISA test system, we examined 28 blood sera from healthy donors and 7 blood sera from patients with confirmed HAE. In the same samples, the content of C1-INH was determined by turbidimetric method, using the "Diagnostic reagents for in vitro immunochemical studies of specific blood proteins. Model: C1-esterase inhibitor (C1 EsteraseInhibitor)" (Aptec, Belgium). The correlation coefficient was 0.94 (p &lt; 0.05). It was found that the diagnostic sensitivity and specificity of the developed ELISA is 100%. As a result of the study, an original ELISA test system for the quantitative determination of C1-INH was developed "Reagent kit for enzyme-linked immunosorbent assay of human C1-inhibitor (C1-inh PS)".

Clinical practice of hereditary angioedema in Belgium: opportunities for optimized care

ABSTRACT Introduction Hereditary angioedema (HAE) is a rare disorder characterized by unpredictable painful and potentially life-threatening swelling episodes. The international WAO/EAACI guideline on the diagnosis and management of HAE was recently updated and provides up-to-date guidance for the management of. In this paper, we assessed to what extent the Belgian clinical practice was aligned with the revised guideline, and whether there were opportunities to optimise Belgian clinical practice in HAE. Methods We compared the updated international guideline for HAE with information we acquired on Belgian clinical practice, a Belgian patient registry and expert opinion analysis. The Belgian patient registry was developed with the involvement of eight Belgian reference centers for HAE patients. Eight Belgian experts, physicians in the participating centers, included patients in the patient registry and participated in the expert opinion analysis. Results The main action points to further optimise the Belgian clinical practice of HAE are Work towards total disease control and normalize patients’ life by considering the use of new and innovative long-term prophylactic treatment options; (2) inform C1-INH-HAE patients about new long-term prophylactic therapies; (3) assure the availability of on-demand therapy for all C1-INH-HAE patients; (4) implement a more universally used assessment including multiple aspects of the disease (e.g. quality of life assessment) in daily clinical practice; and (5) continue and expand an existing patient registry to assure continued data availability on C1-INH-HAE in Belgium. Conclusions In light of the updated WAO/EAACI guideline, five action points were identified and several other suggestions were made to optimise the Belgian clinical practice in C1-INH-HAE.

АНАЛИЗ ЭФФЕКТИВНОСТИ И БЕЗОПАСНОСТИ ПРИМЕНЕНИЯ ПАТОГЕНЕТИЧЕСКОЙ ТЕРАПИИ С ЦЕЛЬЮ КУПИРОВАНИЯ АТАК У ДЕТЕЙ С НАСЛЕДСТВЕННЫМ АНГИОНЕВРОТИЧЕСКИМ ОТЕКОМ

Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency (HAE-C1-INH) is a rare (orphan) autosomal-dominant disease related to primary immunodeficiencies with a defect in the complement system and is characterized by recurrent, unpredictable edema attacks involving various organs and tissues. The recurrent episodes of edema are not amenable to the usual therapy methods and often are life-threatening conditions, especially in pediatric patients. The most pressing issue for the attending physician is the choice of the drug from the available range, taking into consideration its mechanism of action, route of administration and other parameters. This Article summarizes the properties of drugs currently available for the HAE attacks relief in pediatric patients in Russia, including the results of clinical trials, and the Authors’ own experience in the use of Icatibant and a human C1-esterase inhibitor as drugs of choice for the edema relief in the pediatric patient cohort. The purpose of this retrospective study was to evaluate the equivalence and safety of Icatibant and a C1-inhibitor concentrate for the edema management. Materials and methods used: the study included 34 HAE-C1-INH patients who had experienced 302 attack episodes in total. The inclusion criteria were a registered episode of angioedema in a patient aged 0 up to 18 y/o, confirmed HAE diagnosis and one of the two studying drugs intake within 24 hours after the onset of the first edema symptoms. Patients were administered with Icatibant, subcutaneously, or with C1-esterase inhibitor, intravenously. The efficacy was evaluated by comparing the presence of relief and/or relief of symptoms during the mentioned therapy. All of the adverse reactions during the therapy were also recorded in order to assess the drugs’ safety. Results: a total of 302 attack episodes were analyzed in 34 patients in the period from 2016 to 2021. Icatibant was used in 225 (74.5%) cases in 34 patients, and human C1-esterase inhibitor was used in 77 (25.5%) cases in 27 patients. It was allowed to use both drugs in the same patient in different angioedema episodes. The age of the children included in the analysis at the time of the first episode ranged from 1 to 14 y/o (Me 4.5 y/o). The edema was peripheral in most of the studied cases. The drugs were found to be equivalent in terms of duration until the edema symptoms’ relief (Me duration was 30 min. in both drugs, p=0.005), but not in terms of duration until the symptoms cut-off, - with greater values for Icatibant compared to the C1-inhibitor human esterase (p=0.394). Conclusion: a relatively similar efficacy and safety of both drugs as well as the possibility for their use in all age groups were recorded. It is therefore necessary to take into consideration the availability of the satisfactory venous access when choosing a drug for stopping the edema; the patient’s age (in order to ensure the fastest possible administration of the drug counting from the onset of edema); the remoteness of a patient’s location during the attack from the nearest available and satisfying medical facility; the patient’s and/or his/her parent(s)/caretaker(s) preferences. The study demonstrated that both Icatibant and the C1-inhibitor concentrate have high safety profile.

Validation of a suspicion index to identify patients at risk for hereditary angioedema.

Hereditary angioedema (HAE) is a genetic condition characterized by dysregulation of the contact (kallikrein-bradykinin) pathway, leading to recurrent episodes of angioedema. This project sought to determine whether a suspicion index screening tool using electronic health record (EHR) data can identify patients with an increased likelihood of a diagnosis of HAE. A suspicion index screening tool for HAE was created and validated by using known patients with HAE from the medical literature as well as positive and negative controls from HAE-focused centers. Through the use of key features of medical and family history, a series of logistic regression models for 5 known genetic causes of HAE were created. Top variables populated the digital suspicion scoring system and were run against deidentified EHR data. Patients at 2 diverse sites were categorized as being at increased, possible, or no increased risk of HAE. Prediction scoring using the strongest 13 variables on the "real-world" EHR-positive control data identified all but 1 patient with C1 inhibitor deficiency and patient with non-C1 inhibitor deficiency without false-positive results. The 2 missed patients had no documented family history of HAE in their EHR. When the prediction scoring variables were expanded to 25, the screening algorithm approached 100% sensitivity and specificity. The 25-variable algorithm run on general population EHR data identified 26 patients at the medical centers as being at increased risk for HAE. These results suggest that development, validation, and implementation of suspicion index screening tools can be useful to aid providers in identifying patients with rare genetic conditions.

Flow cytometry-based immunoassays for determining functional levels of plasma protease C1 inhibitor for the diagnosis of hereditary angioedema (HAE)

HAE types I and II are caused by a deficiency of functional C1 inhibitor (fC1-INH), leading to overproduction of bradykinin. Specific and sensitive methods to quantitate fC1-INH are required for accurate and timely diagnosis of HAE. Two commercially available assays either measure residual C1-esterase (C1s) activity or a complex ELISA measuring activated C1s. More physiologically relevant alternative methods measuring functional binding of Factor XIIa or kallikrein have been reported but they are not commercially available.

Epidemiology, Management, and Treatment Access of Hereditary Angioedema in the Asia Pacific Region: Outcomes From an International Survey

Hereditary angioedema (HAE) is a rare genetic disease with significant morbidity and mortality for which early diagnosis and effective therapy are critical. Many Asia Pacific (AP) countries still lack access to diagnostic tests and evidence-based therapies. Epidemiologic data from the AP is needed to formulate regional guidelines to improve standards of care for HAE. To investigate the estimated minimal prevalence, needs, and potential interventions for the diagnosis and management of HAE in the AP. A structured questionnaire was distributed to representative experts from member societies of the Asia Pacific Association of Allergy, Asthma and Clinical Immunology. Patient profiles and the presence of diagnostic facilities or tests, regional and national HAE guidelines, and patient support groups were reported and compared. Completed questionnaires were received from 14 representatives of 12 member countries and territories, representing 46% of the world population. Overall minimal prevalence of HAE in the AP region was 0.02/100,000 population, with significant heterogeneity across different centers. Only one-half and one-third had registered on-demand and prophylactic medications, respectively. Few had patient support groups (58%) or regional guidelines (33%), and their existence was associated with the availability of HAE-specific medications. Availability of C1-inhibitor level testing was associated with a lower age at HAE diagnosis (P= .017). Hereditary angioedema in the AP differs from that in Western countries. Hereditary angioedema-specific medications were registered in only a minority of countries and territories, but those with patient support groups or regional guidelines were more likely to have better access. Asia Pacific-specific consensus and guidelines are lacking and urgently needed.

Hereditary angioedema: 24 years of experience in a Portuguese Reference Center.

Hereditary angioedema (HAE) poses a high burden of disease, being its epidemiological and clinical data heterogeneous among countries, with no recent published studies concerning Portuguese patients. Therefore, we aimed to raise awareness of HAE and to contribute to clinical knowledge. An observational, descriptive, retrospective, and cross-sectional study was performed, that included a cohort of 126 patients followed in a single Portuguese Center. We observed a high prevalence of HAE-C1-INH type II (45.2% of patients). Most HAE patients (67.4%) presented the initial manifestations of the disease before adulthood, at a mean age of 12.6 ± 8.4 years. However, we found a long delay in HAE diagnosis, especially in those without family history (mean 20.7 ± 17.3 years). Stress was the most common trigger, followed by trauma and infection. Symptoms involving different systems were increasingly reported with increased disease duration. Cutaneous symptoms (95.0%) were more frequent, followed by gastrointestinal (80.7%), and respiratory symptoms (50.4%). HAE symptoms led to abdominal surgery in 22 (17.5%) patients and induced laryngeal edema requiring intubation/tracheostomy in 8 (6.3%) patients. Most patients were under long-term prophylaxis, mainly with attenuated androgens (62.7% of patients).The correct distinction between HAE and other common causes of angioedema is critical, allowing reduction of diagnostic delay, improvement of adequate management, and ultimately improving outcomes and quality of life of HAE patients.

Hereditary angioedema is associated with an increased risk of venous thromboembolism

Hereditary angioedema is associated with an increased risk of venous thromboembolism

Determining biomarkers for evaluation and diagnosis of hereditary angioedema

RationaleKallikrein‐bradykinin‐forming cascade is known to cause hereditary angioedema (HAE) acute angioedema (AE) attacks. Further research of HAE attacks is needed to explain disease heterogeneity, predict treatment response and identify biomarkers for monitoring HAE attacks. Differential expression of the microvascular endothelial cell‐surface receptors for example, g‐C1qR, cytokeratin‐1, and plasminogen‐activator‐urokinase‐receptor (PLAUR) were hypothesized as biomarkers of AE attacks.MethodTo understand HAE attacks, the differentially expressed genes (DEGs) in RNAseq and mi‐RNAseq data of total RNA extracted from skin biopsies of lesional versus non‐lesional skin collected during and between attacks in Type‐1 HAE patients (n = 11; F:M = 8:3) were compared. To understand the HAE variants, DEGs in skin biopsies from HAE with normal C1 inhibitor (n = 5, F:M = 5:0), and non‐HAE (n = 7; F:M = 3:4) patients were compared. Gene‐set enrichment analyses and regulator effects analysis of these DEGs identified biological pathways in HAE attacks and their regulators.ResultsPLAUR gene, encoding urokinase‐type plasminogen activator (u‐PAR), was constitutively over‐expressed in HAE‐Type‐1 versus non‐HAE controls suggestive of overactive u‐PAR‐mediated signaling via binding to Factor‐XII. Baseline PLAUR expression was associated with severe AE (p = 0.05). The 18 significant DEGs investigated between baseline and AE attack samples in Type1‐HAE were enriched in beta1/beta3‐integrin cell surface interactions and IL‐6‐mediated signaling. Regulator effects analysis suggests a role for IL‐1b in HAE flares. AKT2, the mRNA regulated by the differentially‐expressed miR‐184A, was also associated with HAE attacks.ConclusionAngiopoetin‐activated β1‐integrin signaling pathways causing endothelial destabilization, and avid binding of factor XII to u‐PAR are possible novel mechanisms for progression of the endothelial kinin‐bradykinin‐forming cascade in HAE attacks.

Consider Hereditary Angioedema in the Differential Diagnosis for Unexplained Recurring Abdominal Pain.

Health care providers are likely to encounter patients with recurrent unexplained abdominal pain. Because hereditary angioedema (HAE) is a rare disease, it may not be part of the differential diagnosis, especially for patients who do not have concurrent skin swelling in addition to abdominal symptoms. Abdominal pain is very common in patients with HAE, occurring in up to 93% of patients, with recurrent abdominal pain reported in up to 80% of patients. In 49% of HAE attacks with abdominal symptoms, isolated abdominal pain was the only symptom. Other abdominal symptoms that commonly present in patients with HAE include distension, cramping, nausea, vomiting, and diarrhea. The average time from onset of symptoms to diagnosis is 6 to 23 years. Under-recognition of HAE in patients presenting with predominant gastrointestinal symptoms is a key factor contributing to the delay in diagnosis, increasing the likelihood of unnecessary or exploratory surgeries or procedures and the potential risk of related complications. HAE should be considered in the differential diagnosis for patients with unexplained abdominal pain, nausea, vomiting, and/or diarrhea who have complete resolution of symptoms between episodes. As highly effective targeted therapies for HAE exist, recognition and diagnosis of HAE in patients presenting with isolated abdominal pain may significantly improve morbidity and mortality for these individuals.

Delayed diagnosis of hereditary angioedema in the setting of Prader-Willi syndrome

Hereditary angioedema (HAE) is a rare and potentially life-threatening disorder, with a prevalence of approximately 1:60,000.1,2 It is first suspected on the basis of certain clinical factors such as recurrent angioedema and severe and remitting abdominal pain. The diagnosis of HAE has notoriously been delayed owing to initial misdiagnoses. A study by Schöffl et al determined the median age of symptom onset was 6.5 years, with a median age of correct diagnosis of 21 years, showing a 15-year delay in diagnosis.

Prospective Study on the Efficacy and Impact of Cascade Screening and Evaluation of Hereditary Angioedema (CaSE-HAE)

Recommendations regarding family screening for hereditary angioedema (HAE) remain variable and mostly based on expert opinion. Studies evaluating its implementation and efficacy are lacking. A novel HAE screening program was established to evaluate the efficacy and impact of cascade family screening (CFS) for at-risk relatives. Potential HAE relatives were screened through the CFS approach. Prospective data on clinical, psychological, and HAE-related outcomes were collected at baseline and 1-year follow-up. Longitudinal outcomes were analyzed and compared between index patients and those given a diagnosis through CFS. Of 179 relatives, 53% were contactable, 67% of whom consented to screening. Twenty-nine patients (46%) were newly given the diagnosis of HAE; half were symptomatic at baseline (52%). There was a stronger trend toward higher diagnostic yield among first-degree families, although this did not meet statistical significance (57.6% vs 33.3%; P= .077). Among symptomatic patients, there was a higher proportion with complete annual HAE remission (15% vs 46%; P= .021) and a reduction in annual HAE-related hospital admissions (1 vs 0; P= .016) and length of stay (3 vs 2 days; P= .001) after 1 year. Among all patients, there were reduced Hospital Anxiety and Depression Scale-anxiety (14.35 ± 6.32 vs 6.47 ± 4.14; P=.001) and improved Angioedema Quality of Life scores (55% vs 35%; P < .001). By extrapolation, CFS led to a reduction of at least HK $1,200 (US $153) in HAE-related costs per patient per year. Screening using a greater than suggested C4 cutoff of 22.9 mg/dL yielded superior sensitivity (100%) and specificity (77%). Cascade family screening is an effective approach to family screening in HAE, improving clinical and psychological outcomes, and reducing disease-related costs.