Hereditary angioedema: new findings concerning symptoms, affected organs, and course

Purpose

Hereditary angioedema (HAE) due to C1 inhibitor deficiency is clinically characterized by relapsing skin swellings, abdominal pain attacks, and life-threatening upper airway obstruction. Our aim was to examine a temporal and spatial pattern of the edema episodes by evaluating the long-term course of hereditary angioedema in order to establish a specific swelling pattern.

Subjects and methods

Data were generated from 221 patients with C1 inhibitor deficiency by asking them about symptoms they experienced during their edema episodes. Documentation was accomplished through the use of standardized questionnaires.

Results

A total of 131 110 edema episodes were observed. Clinical symptoms started at a mean age of 11.2 (SD 7.7) years. During the following cumulative 5736 years, only 370 (6.5%) symptom-free years occurred. Skin swellings, including extremity, facial, genital, and trunk swellings, and abdominal attacks occurred in 97.4% of all edema episodes of the disease. The other episodes were laryngeal edema (0.9%); edema of the soft palate (0.6%); tongue swellings (0.3%); headache episodes (0.7%); episodes affecting urinary bladder (0.3%), chest (0.2%), muscles (0.4%), joints (0.1%), kidneys (0.1%), and esophagus (0.05%), and were partly combined with other edema episodes. The per-patient analysis and the per-episode analysis revealed markedly discrepant results. On average, women had a more severe course of the disease than men. Patients with early onset of clinical symptoms were affected more severely than those with late onset.

Conclusion

The described swelling pattern is specific for HAE and allows a tentative diagnosis based on clinical symptoms and the course of the disease.     

Many faces of angioedema: focus on the diagnosis and management of abdominal manifestations of hereditary angioedema

Angioedema of the intestinal tract is an infrequent but well-described cause of abdominal pain that can occur because of inherited, acquired, allergic, or drug-induced causes. Hereditary angioedema (HAE) is a genetic disorder that causes recurrent attacks of severe edema of various body parts, including the intestinal tract. Moderate to severe abdominal pain occurs in 43-93% of such attacks due to intestinal edema. Laryngeal edema is a potentially life-threatening manifestation. Failure to recognize and diagnose HAE or other causes of intestinal angioedema can lead to years of delay in diagnosis, and in the case of HAE, often to unnecessary abdominal surgeries. Recognizing the typical history of recurrent attacks of abdominal pain, oropharyngeal/laryngeal angioedema or cutaneous angioedema, family history of similar symptoms, association of attacks with stress or menses, and exacerbation of attacks after administration of estrogens or angiotensin-converting enzyme inhibitors will increase diagnostic accuracy. Interdisciplinary treatment is often necessary after the diagnosis of HAE, first with acute management in the emergency room or the intensive care unit, followed by either drug prophylaxis against future attacks using a C1-esterase inhibitor concentrate or attenuated androgens and discontinuation of medications known to trigger attacks. Newer drugs approved for treatment of acute attacks may have future roles in the prevention of attacks if further studies support their efficacy. Gastroenterologists in particular should maintain a high index of suspicion for the possibility of HAE or other causes of intestinal angioedema in patients with a history of recurrent abdominal pain.     

Pathogenesis of hereditary angioedema

The hereditary angioedema (HAE) is an autosomal dominant transduced illness. Patients suffer from severe attacks with circumscribed swellings of the skin, or of the gastro-intestinal mucosa, or of whole organs. Laryngeal edema is responsible for airway obstruction and often for sudden death. Very often the abdominal symptoms are leading to false diagnosis and treatment. The diagnosis is proved by estimation of lowered C1-inhibitor (C1-INH) activity. The defect of C1-INH is responsible for the activation of the start phases of the complement system and of the kinin system. The liberation of vasoactive peptides and kinins induces the edematous swellings and severe pain. The acute symptoms of HAE are promptly resolved by intravenous application of C1-inhibitor concentrate.     

Successful resolution of bowel obstruction in a patient with hereditary angioedema

Hereditary angioedema (HAE), a rare genetic disorder caused by a deficiency of the C1 esterase inhibitor, leads to an episodic, self-limiting increase in vascular permeability. Related symptoms commonly include recurrent, intractable abdominal pain, vomiting, and/or diarrhea. DX-88 (ecallantide), a 60-amino acid recombinant protein discovered through phage display technology, is a highly specific, potent inhibitor of human plasma kallikrein that has been used successfully in the treatment of patients experiencing acute HAE attacks. This case study involves a 65-year-old woman who presented with severe abdominal pain, cramping, and nausea. The study describes the use of a video obtained by capsule endoscopy for the direct imaging of bowel occlusion in a patient with HAE that resolved upon treatment with DX-88. After administration of DX-88, 80 mg intravenously, abdominal pain and nausea resolved within 30 min. Capsule endoscopy demonstrated a coincident resolution of the bowel wall edema, with a return to normal within approximately 1.5 h of DX-88 administration. This case study demonstrates that DX-88 can produce dramatic clinical benefits in a patient with an acute abdominal HAE attack, resolving both symptoms and pathologic signs. Furthermore, it illustrates the usefulness of videos obtained from capsule endoscopy in identifying the presence of bowel occlusion and demonstrating its subsequent rapid resolution upon administration of DX-88.     

Hereditary angioedema: a broad review for clinicians.

Hereditary angioedema (HAE) is an autosomal dominant disease that afflicts 1 in 10,000 to 1 in 150,000 persons; HAE has been reported in all races, and no sex predominance has been found. It manifests as recurrent attacks of intense, massive, localized edema without concomitant pruritus, often resulting from one of several known triggers. However, attacks can occur in the absence of any identifiable initiating event. Historically, 2 types of HAE have been described. However, a variant, possibly X-linked, inherited angioedema has recently been described, and tentatively it has been named "type 3" HAE. Signs and symptoms are identical in all types of HAE. Skin and visceral organs may be involved by the typically massive local edema. The most commonly involved viscera are the respiratory and gastrointestinal systems. Involvement of the upper airways can result in severe life-threatening symptoms, including the risk of asphyxiation, unless appropriate interventions are taken. Quantitative and functional analyses of C1 esterase inhibitor and complement components C4 and C1q should be performed when HAE is suspected. Acute exacerbations of the disease should be treated with intravenous purified C1 esterase inhibitor concentrate, where available. Intravenous administration of fresh frozen plasma is also useful in acute HAE; however, it occasionally exacerbates symptoms. Corticosteroids, antihistamines, and epinephrine can be useful adjuncts but typically are not efficacious in aborting acute attacks. Prophylactic management involves long-term use of attenuated androgens or antifibrinolytic agents. Clinicians should keep this disorder in their differential diagnosis of unexplained, episodic cutaneous angioedema or abdominal pain.     

Hereditary angioedema as a cause of transient abdominal pain.

Isolated angioedema, without urticaria or itching, occurs as a result of an inherited or acquired defect in C1 esterase inhibitor activity. Most cases of isolated angioedema are caused by one of two types of hereditary angioedema (HAE). We present a case of the much rarer type II HAE with abdominal pain as the sole presenting symptom. Hereditary angioedema should be suspected in young adults with episodic abdominal pain for which common causes have been excluded. A history of HAE or episodic abdominal pain in family members is not necessary for diagnosis.     

Treatment of 193 episodes of laryngeal edema with C1 inhibitor concentrate in patients with hereditary angioedema

BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant disease (Mendelian Inheritance in Man 106100) caused by an inherited deficiency of C1 inhibitor (C1-INH) function. The clinical symptoms include skin swelling, abdominal pain, and life-threatening episodes of upper airway obstruction. We evaluated the efficacy of C1-INH concentrate for treating sudden airway compromise. METHODS: A series of 95 patients with HAE and a functional deficiency of C1-INH belonging to 59 families underwent screening for laryngeal edema. Double-blind treatment of randomized patients was not justifiable because of the life-threatening nature of this condition. Efficacy was evaluated by determining the interval from injection of C1-INH concentrate to the beginning of resolution of symptoms. The mean duration of episodes of laryngeal edema was compared in treated and untreated patients. Clinical information was obtained from emergency department physicians, the hospitals involved, reports of the general practitioners, and patients and their relatives. RESULTS: Forty-two patients had 517 episodes of laryngeal edema. Eighteen patients received 500- or 1000-U injections of C1-INH concentrate in 193 episodes. The C1-INH concentrate was effective in all laryngeal edemas. The interval from injection to interruption in progress of symptoms ranged from 10 minutes to 4 hours (mean +/- SD, 42.2 +/- 19.9 minutes). The mean +/- SD duration of laryngeal edema was 15.3 +/- 9.3 hours in patients who received C1-INH concentrate and 100.8 +/- 26.2 hours in those who did not. CONCLUSIONS: Injected C1-INH concentrate is highly and rapidly effective in the treatment of laryngeal edema of HAE. Relief and resolution of symptoms begins 30 to 60 minutes after injection, and duration of the upper airway obstruction is substantially reduced.     

Hereditary angioedema: classification, pathogenesis, and diagnosis

Hereditary angioedema (HAE) is a rare autosomal dominant genetic disorder associated with a deficiency in C1 inhibitor. More than 200 mutations in this gene, located on chromosome 11, have been identified. Although HAE is often inherited, 20-25% of cases are from new spontaneous mutations and they have no family history of swelling. Decreased C1 inhibitor activity leads to inappropriate activation of multiple pathways, including the complement and contact systems and the fibrinolysis and coagulation systems. Reduced C1 inhibitor activity results in increased activation of plasma kallikrein-kinin system proteases and increased bradykinin levels. Bradykinin is felt to be the main mediator of symptoms in HAE. Patients with HAE have recurrent episodes of swelling of the extremities, abdomen, face, and upper airway. Angioedema involving the gastrointestinal tract can lead to intestinal wall edema, which results in abdominal pain, nausea, vomiting, and diarrhea. Laryngeal swelling is life-threatening and may lead to asphyxia. Common triggers of an attack include trauma, stress, infection, menstruation, oral contraceptives, hormone replacement therapy, and angiotensin-converting enzyme inhibitors. Laboratory testing including C4, C1 inhibitor level, and function is needed to confirm or rule out the diagnosis of HAE. The treatment of HAE has improved significantly in recent years with the availability of several safe and effective therapies. Several consensus guidelines have been created to further assist in the management of HAE patients. This review will provide an update on the classification, pathophysiology, clinical presentation, and diagnosis of HAE.     

A case of polyarteritis nodosa with lesions of the superior mesenteric artery illustrating the diagnostic usefulness of three-dimensional computed tomographic angiography

A 40-year-old Japanese man who developed upper abdominal pain, weight loss, and hypertension was diagnosed as suffering with polyarteritis nodosa (PAN) with lesions of the superior mesenteric artery (SMA). Three-dimensional computed tomographic angiography (3D-CTA) and conventional angiography revealed smooth segmental luminal narrowing of the branches of the SMA. In addition, an enhanced abdominal CT scan demonstrated diffuse thickening of the wall of the affected SMA. Treatment with high-dose corticosteroids resulted in immediate improvement of the abdominal manifestations and normalized the serum C-reactive protein levels. Furthermore, the subsequent enhanced CT and 3D-CTA revealed improvement of the wall thickening and luminal narrowing of the SMA and its branches during the treatment period. In addition to possessing the diagnostic usefulness of conventional angiography, 3D-CTA is also less invasive and facilitates the prompt and accurate diagnosis of PAN. Furthermore, thickening of the wall of medium-sized arteries evidenced by enhanced CT scan may also support a diagnosis of PAN.     

A case of hereditary angioedema involving recurrent abdominal attacks

A 44-year-old Japanese woman was diagnosed with type 1 hereditary angioedema (HAE) at the age of 30. In March 2007, she began suffering from severe abdominal pain due to intestinal edema. After treatment with C1-INH concentrate, her symptoms disappeared. However, during the subsequent three years, the frequency of the attacks increased continuously, and C1-INH concentrate was necessary for treatment of every attack. The increase in the number of attacks might have been due to the frequent injection of C1-INH concentrate or the deterioration of her disease course. In a genetic investigation, the patient was found to have a novel mutation in the C1-INH gene.     

Hereditary Angioedema Due to C1-Inhibitor Deficiency in Romania: First National Study,Diagnostic and Treatment Challenges

Background: Hereditary angioedema (HAE) is a rare genetic potentially life-threatening disease characterized by episodic non-pruritic subcutaneous and submucosal edema attacks in different parts of the body. Objective: To assess the status of Romanian HAE patients after the recent introduction of a new therapy through a nationwide program. Methods: This cross-sectional observational study included patients from the Romanian HAE Registry. Results: The study included 84 patients with HAE type I (91.7%) and type II (8.3%). The mean delay in diagnosis was 2.4 years in children and 16.7 years in adults (p=0.019). Stress and tiredness were the most frequent trigger factors. The majority of the HAE episodes involved subcutaneous (89.3%), abdominal (77.4%), genital (51.2%), facial (41.7%), and laryngeal (39.3%) symptoms during the preceding 12 months. One or several misdiagnoses were reported in 83.33% patients and 44.1 % of the patients were subjected to or proposed unnecessary surgery during abdominal episodes. Plasma-derived C1-INH (pdC1-INH) and recombinant C1-INH (rhC1-INH) were respectively used in 10 (11.9%) and 13 (15.5%) of the HAE patients for life-threatening attacks over the past 12 months. Fortythree (51.19%) patients practiced home treatment with subcutaneous injection of the bradykinin B2-receptor antagonist for acute HAE attacks. Conclusion: The significantly lower delay observed in children suggests an improvement in the awareness of C1-INH-HAE among physicians in recent years. The management of HAE in Romania has been somewhat enhanced as the majority of HAE patients have recently gained access to pdC1-INH, rhC1-INH, and bradykinin B2-receptor antagonist.     

Jujitsu kick to the abdomen: a case of blunt abdominal trauma resulting in hematochezia and transient ischemic colitis

Blunt abdominal trauma is a common presentation to the emergency department. Ischemic colitis is a rare complication of this and its possible sequelae are important for an emergency physician to recognize. A 21-year-old man presented to the emergency department with abdominal pain and hourly episodes of bright red blood per rectum shortly after being kicked in the stomach at his jujitsu class. He had no significant medical history, and results of his systems review were otherwise unremarkable. On examination, he appeared well, with normal vital signs. He had mild lower abdominal tenderness, but there were no peritoneal signs present. There was blood on the digital rectal examination. His hemoglobin, platelet, and international normalized ratio levels were normal and his abdominal radiograph was unremarkable. The gastroenterology service was contacted because of the hematochezia and a flexible sigmoidoscopy was performed. The sigmoidoscopy showed erythema, ulceration, and edema of a segment in the left colon, consistent with ischemic colitis. This was later confirmed on biopsy. A computed tomography (CT) scan of the abdomen was conducted, which revealed left colonic inflammation consistent with colonic ischemia. There was no mesenteric vascular thrombosis or mesenteric hematoma found on CT. His hematochezia and abdominal pain subsided spontaneously, and he was discharged home. This case illustrates transient ischemic colitis as a potential presentation of blunt abdominal trauma, and emergency physicians should consider this uncommon diagnosis in the differential diagnosis of patients presenting after abdominal trauma.     

Ecallantide for treatment of acute hereditary angioedema attacks: analysis of efficacy by patient characteristics

Hereditary angioedema (HAE) is characterized by episodic attacks of edema. HAE is caused by low levels of the protein C1 esterase inhibitor, which inhibits plasma kallikrein, the enzyme responsible for converting high-molecular-weight kininogen to bradykinin. Unregulated production of bradykinin leads to the characteristic clinical symptoms of swelling and pain. Ecallantide is a novel plasma kallikrein inhibitor effective for treatment of acute HAE attacks. This study was designed to analyze the efficacy of ecallantide for treating HAE attacks by attack location, attack severity, patient gender, and body mass index (BMI). An analysis of integrated data from two double-blind, placebo-controlled trials of ecallantide for treatment of acute HAE attacks was undertaken. For the purpose of analysis, symptoms were classified by anatomic location and, for each location, by the patient-assessed severity of the attack. Efficacy versus placebo was examined using two validated patient-reported outcomes: treatment outcome score and mean symptom complex severity score. One hundred forty-three attacks were analyzed (73 ecallantide and 70 placebo). Ecallantide was equally effective in both male and female subjects. Ecallantide had decreased efficacy for patients with BMI > 30 kg/m(2). Ecallantide showed efficacy for treatment of severe and moderate attacks, and was effective for abdominal, internal head and neck, external head and neck, and cutaneous locations. In summary, ecallantide is effective for treatment of acute HAE attacks of different symptom locations and severity; outcomes were similar for men and women. However, the standard dose was less effective for obese patients.     

Hereditary angioedema with a de novo mutation of exon 8 in the C1 inhibitor gene showing recurrent edema of the hands around the peripheral joints: importance for the differential diagnosis of joint swelling

We describe a patient with hereditary angioedema (HAE), showing recurrent edema around the peripheral joints. Her symptoms began at the age of 18 with hand swelling distal to the wrist joints. Until she was referred to our hospital 3 years after her initial symptoms, she was still undiagnosed, although she was suspected of having rheumatoid arthritis. Laboratory examination showed reduced levels of CH50 and C4 with normal C3 levels. The C1 inhibitor (C1-INH) was decreased to 5 mg/ml, with remarkably reduced activity. Although these findings were compatible with a diagnosis of HAE, there were no episodes of skin edema in her family. To establish the diagnosis, we carried out DNA analysis of the C1-INH gene, which revealed a newly identified de novo mutation of G to A at nucleotide 16869 in exon 8. As described in this patient, localized edema around the peripheral joints may be the only manifestation of HAE. HAE should therefore be taken into consideration for the differential diagnosis of joint swelling.     

Acute pancreatitis associated with hereditary angioedema

Hereditary angioedema (HAE) is an infrequent, recurrent, and potentially lethal disorder caused by a deficiency of C(1) inhibitor or its activity. Abdominal pain secondary to bowel edema is common in these patients. However, a thorough literature search yielded only six previously reported cases of pancreatitis associated with this entity.     

肠系膜急性闭合性损伤的CT影像学特征及临床分析

目的通过对腹部闭合性外伤肠及肠系膜损伤的术前CT检查影像学表现与临床手术进行对比,探讨CT检查在腹部外伤肠及肠系膜损伤影像学表现及诊断优势,从而提高CT影像在肠及肠系膜损伤中的诊断符合率。 方法选取2008至2020年40例中山市东升医院收治疑似腹部闭合性损伤患者,均实施CT检查,将患者的CT检查结果与确诊结果进行对比,总结CT影像检查的诊断符合率,不同肠系膜损伤患者的CT影像学特征。 结果CT诊断符合率、漏诊率分别为97.5%、2.5%,与确诊结果比较,差异无统计学意义(P>0.05);CT检查的影像学特征有腹腔游离气体、腹腔以及肠间隙积血与积液、肠壁增厚水肿及肠壁血肿及肠系膜水肿。 结论CT检查在肠系膜急性闭合性损伤患者诊断中效果理想,其影像学特征显著,可鉴别不同类型肠系膜损伤,且诊断符合率高。     

Hereditary angio-oedema: new clinical observations and autoimmune screening, complement and kallikrein-kinin analyses

Objectives. To study clinical and laboratory manifestations of hereditary angio-oedema (HAE).
Subjects. Thirty-three affected members of a kindred of 63.
Results. Oedematous attacks in the skin, mucous membranes and gastrointestinal tract with fluid displacement were elicited by mental and physical stress, minor traumas, dental and surgical procedures, eruption of teeth, tonsillitis, pregnancies, and use of oestrogen-containing pills including menopausal substitution. Every adult woman with symptomatic HAE ( n =11) showed symptoms of urinary tract infections in conjunction with the attacks ( P = 0.010), and also experienced more spontaneous abortions or premature labours ( P =0.037) than healthy relatives. Patients with HAE of both sexes more frequently reported heartburn or peptic ulcers ( P =0.002). Rheumatic complaints were reported by 53% of HAE patients and 12% of their unaffected relatives ( P =0.013), but biochemical screening for 18 autoantibodies and quantitation of immunoglobulins did not reveal statistically significant differences between the two groups. C3, prekallikrein, total kininogen, high molecular weight kininogen (HK), alpha-2-macroglobulin and factor XII were not significantly different in HAE patients. In contrast, levels of C1-INH and C4 were depressed and cleaved HK increased in patients compared to unaffected relatives.
Conclusions. HAE manifests in a variety of ways, and may influence risk of spontaneous abortions and premature labour.     

Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency

OBJECTIVES: Recurrent abdominal attacks belong to the cardinal and most distressing symptoms of hereditary angioedema (HAE) due to C1 inhibitor deficiency. They are characterized by crampy pain, but may include vomiting, diarrhea, and other features. Detailed clinical data about the symptoms and course of abdominal attacks have not been reported. METHODS: We retrospectively observed a total of 33,671 abdominal attacks in 153 patients with HAE including a prospectively examined subgroup of 23 patients. Symptoms, course, frequency of attacks, and complications were analyzed. RESULTS: The relation of mild, moderate, and severe attacks was 1:1.4:5.6 in the prospective part of the study. Extra-abdominal symptoms preceded the abdominal symptoms. The mean maximal pain score was 8.4 (range 1-10). Vomiting occurred in 73% (24,696) and diarrhea in 41% (13,682) of the attacks. Circulatory collapse accompanied 4.4% (1,468) of the attacks, with loss of consciousness (LOC) occurring in 2.2% (739). Nine patients could clearly distinguish two types of abdominal attacks: vomiting and diarrhea. Rare complications included tetany, hemorrhagic stools, and intussusception of the colon. In 28% (43) of the patients, recurrent abdominal attacks had started before the characteristic swelling of the skin had ever occurred. A model is proposed to classify the severity of the attacks and to describe the clinical course. CONCLUSIONS: Abdominal attacks in HAE constitute a more disabling and complex syndrome than previously assumed. Our results add to the understanding of symptoms and course of HAE and may aid in the early recognition of an impending attack and improve clinical management.     

Gastrointestinal involvement in a case of hereditary angioedema: could the early weaning have had a role?

Hereditary angioedema (HAE) is a noninflammatory disorder due to reduced C1-inhibitor level and/or function and characterized by recurrent, circumscribed, and self-limiting episodes of cutaneous and mucous membrane swellings involving different organs. A heterogeneous group of mutations in the C1-inhibitor gene have been found. HAE might present with diverse clinical pictures, even within families with the same mutation, but the cause of this variability is not known yet. We describe the case of type II HAE in a young adult presenting with recurrent abdominal pain for many years, occasionally associated with ascites. We suppose that an early weaning might have influenced his phenotype, making his gastrointestinal tract a "vulnerable organ," in which hereditary angioedema could express itself.     

特发性肠系膜静脉硬化性结肠炎14例的临床、影像学和内镜特征分析

目的:探讨特发性肠系膜静脉硬化性结肠炎(IMP)患者的临床、影像学和内镜特征。方法:纳入2010年1月至2020年12月温州医科大学附属衢州医院(衢州市人民医院)收治的14例IMP患者。所有患者均行腹部X线、增强计算机断层扫描(CT)和内镜检查;3例行气钡灌肠造影检查,11例行内镜活体组织检查(以下简称活检)。14例I...