Author: Dumitru Moldovan, Department of Allergology-Immunology, University of Medicine and Pharmacy, Tîrgu Mureş
Publication: Revista Societăţii Române de Alergologie şi Imunologie Clinică, vol. nr. p. 12-17, 2005
Although hereditary angioedema (HAE) accounts for only a small fraction of all cases of angioedema, it is the most common genetically linked clinical disorder caused by deficiency of a protein associated with complement activation, low C1-inhibitor (C1-INH) function. There is a currently widespread recognition in the allergy and clinical immunology community as a clinical entity. It is known to cause attacks that may be complicated by incapacitating cutaneous swelling, life-threatening upper airway obstruction, and severe gastrointestinal colic. Recent physiochemical and genetic studies have contributed significantly to our understanding of the structure of the inhibitor protein. Measurement of serum C4 titer is an efficacious screening test, although some authors find that occasionally normal values does not rule out HAE. C1-INH studies should be performed if there is a high index of clinical suspicion.
The importance of making the correct diagnosis cannot be overemphasized. It can avert fatal consequences, such as airway obstruction, and unnecessary abdominal surgery. C1-INH replacement therapy represent an efficacious treatment of acute attacks. The application of preventive measures avoid need for dramatic emergency interventions. Potential new therapies with kallikrein inhibitor, bradykinin receptor antagonist and recombinant C1-INH has been developed and clinical trials are ongoing.
Hereditary angioedema (HAE) is characterized by episodic local subcutaneous edema and mucosal swelling of the upper respiratory and gastrointestinal tracts, caused by a genetic insufficiency of C1 esterase inhibitor (C1-INH). It should be noted that this is a rare disorder and much of the literature is based on case studies or small series.
First medical documents about HAE belongs to Heinrich Quincke (1882) (1) and Sir William Osler (1888). Osler was the first to fully describe its clinical features (2). In 1962, before any of the complement defects were known, Landerman et al (3) suggested that the symptoms might be due to dysregulation of the kinin system. HAE reached its own identity in 1963, when Donaldson and Evans demonstrated a deficiency of C1 esterase inhibitor (C1-INH) in the plasma of patients with this disease (4). The progress made in our knowledge of this rare disease over the last decades is astonishing. There is a currently widespread recognition of C1-INH pathology in the allergy and clinical immunology community as a clinical entity.
The incidence of HAE is estimated by most authors at 1:10,000-1:50,000, and the gene encoding C1-INH mapping is localized in chromosome 11q12-q13.1 (5). Since the disease is very rare, it is not uncommon for patients to remain undiagnosed for many years. Because of serious complications of attacks and the advance in the management of HAE, the condition must be clearly recognized by both primary care physicians and specialists.
Patients can present with any combination of recurring cutaneous angioedema, abdominal pain, or acute airway obstruction lasting from 4 hours to 4 days (6).
The age of HAE onset varies considerably. Most commonly, symptoms begin at school age; half of patients had symptoms within the first decade of life, and another third by the second decade (3). There also seems to be an increased frequency of attacks during puberty or adolescence. No single sex predominates and no reported bias in different ethnic groups were reported. Attacks can be preceded by mood changes, anxiety, exhaustion, which led to the inappropriate term angioneurotic edema.
Angioedema can be precipitated by trauma (approximately half the attacks), emotional stress, coexisting illnesses (i.e., infections) (7), or by certain drugs (i.e., angiotensin converting enzyme inhibitors). Patients have also reported swelling in extremities following typing, prolonged writing, hammering, and other physical activities. Women often have attacks during menses, but attacks are less frequent during pregnancy. Often, the frequency and intensity of attacks lessen after menopause. Use of birth control pills and hormone replacement therapy is associated with an increase in the frequency and severity of attacks (8, 9).
However, many attacks have no clear inciting event. Some patients experience weekly, while others might have longer than one year between attacks. Attacks are not usually daily occurrences.
Attacks usually do not respond to treatment with epinephrine, antihistamines or corticosteroids.
Cutaneous edema is the most common symptom. Angioedema without urticaria is the hallmark of C1-INH deficiency. Edema can affect any part of the skin, but is more common in the extremities. In contrast with edema of other etiology, edema associated with C1-INH doesn't principally manifest in the perioral region. HAE lesions appears swollen, pale, non-pitting and usually without a clear demarcation with healthy parts. Usually is nonpruritic and painless that evolves over several hours (5). Urticaria is not a feature of C1-INH deficiency. However, prodromal erythema has been reported in up to 25% of patients, which may be mistaken for urticaria (10, 11, 12).
More than half of the patients with HAE develop laryngeal edema. The clinical condition may deteriorate within a few hours from mild discomfort to complete airway obstruction. The symptoms of an impending airway obstruction include difficulty swallowing and a change in voice pitch. Symptoms range between mild discomfort to complete airway obstruction progressing over a period of up to 4 hours, requiring emergency intubation or tracheostomy. Prior to the development of effective therapy, the mortality rate was 20-30%. Endoscopic examinations, dental work and surgery involving the head and neck are common precipitants, but laryngeal edema can be spontaneous. Dental work are said to be a cause in up to 50% of all cases (5, 6).
Abdominal pain, nausea and vomiting are the consequences of gastrointestinal wall and mesenteric edema, and are reported in 25-80% all patients with HAE. The abdominal pain associated with HAE is very similar to an acute abdomen e.g. "acute appendicitis", often resulting in unnecessary surgery. The gastrointestinal involvement appears to be segmental and transient with reversion to normal by several days after an attack. Equally, after diagnosis, there is always the concern that true abdominal emergencies will not have surgery performed in good time. Classically, abdominal symptoms develop gradually over several hours, increasing slowly for 12 36h, and recover after 2-5 days. Abdominal ultrasound and computer-assisted tomography demonstrate the presence of free peritoneal fluid and edematous intestinal mucosa. However, patients may experience abdominal attacks with a very sudden and severe onset of pain and no visible edema (5, 6, 14).
Less common presentations are pleural involvement, swelling in the genitals following intercourse. Rarely, patients develop headaches, seizure, or focal neurological defects from intracranial edema. During acute attacks patients can develop hypotension, due to sequestration of fluid in the extravascular space (5, 15).
C1-INH is a serpin, member of proteases family. C1-INH is synthesized mainly by hepatocytes. The regulation of the protein production is not completely understood, but androgens stimulate C1-INH synthesis (5,16).
Within the complement system, C1-INH blocks the activation of C1 and the rest of the classic complement pathway. Without C1-INH, activation of C1, C2, and C4 occur before other inhibitors can halt the cascade. C1-INH also inhibits components of the fibrinolytic, clotting, and kinin pathways. C1-INH inactivates plasmin Hageman factor (factor XII). In the kinin releasing system, C1-INH regulates conversion of prekallikrein to kallikrein (figure 1)(5, 6, 14, 17).
Figure 1 - Presumable pathogenesis of HAE
The factor responsible for the edema formation remain controversial. Some authors have demonstrated activation of the kinin system and increased bradykinin concentration associated with clinical attacks. Bradykinin causes neutrophil chemotaxis, capillary dilation, and smooth muscle relaxation. Others authors implicate C2 kinin, as the active agent in the presence of plasmin. C1-INH is not compulsory for the normal immune function, and fibrinolysis and clotting can function normally without it. Histamine is not involved in the pathogenesis of HAE (5, 6, 17).
Genetics and types of HAE
The inheritance is autosomal dominant with incomplete penetrance. Those inheriting the abnormal gene can have a clinical spectrum ranging from asymptomatic to severely affected. A child has a 50 percent chance of inheriting this disease if one of his or her parents has it. The absence of family history does not rule out the HAE diagnosis, however. As many as one quarter to one third of HAE cases result from patients who had a spontaneous mutation of the C1-INH gene at conception. These patients can pass the defective gene to their offspring (5, 6, 18, 19, 20). The HAEdb, a C1-INH gene mutation database (http://haebiomembrane.hu) was created to facilitate future comprehensive analysis of C1-INH mutations and also provide regular help for molecular diagnostic testing of HAE patients in different centers. (21)
There seems to be little, if any, correlation between symptoms and type of genetic defect with patients from the same family, showing wide differences in phenotype (5, 14).
In HAE type I (up to 85% of all patients), there is marked reduction or the total impairment of C1-INH protein present in the plasma. This is the result of only one gene functioning. Quantitative serum concentrations of C1-INH that are approximately 10-30% of normal.
In HAE type II, in contrast with type I, the circulating C1-INH concentration is normal or high but not fully functional. Type I and II are clinically indistinguishable (5, 6, 14).
HAE type III has been recently described (22). This type of angioedema manifests only in women, symptoms are occur in the presence of normal C1-INH concentrations, only during pregnancy, anticonceptional pills use or estrogen replacement therapy. It was recommended the term of estrogen-associated inherited angioedema.
Acquired angioedema (AAE) affect approximately 10% of patients with C1-INH deficiency. AAE presents in older patients, has no family history and is associated with lymphoproliferative disease, autoimmune, neoplastic, or infectious diseases, antihypertensive drugs associated angioedema, and idiopathic angioedema. In the laboratory C1-INH function, C4, C2 are low, C3 is normal, and C1q is often very low (5, 6, 14, 23, 24, 25, 26).
Although preventable and treatable, the complications of HAE do not respond well to the usual therapies for angioedema as antihistamines, corticosteroids and epinephrine (5, 14, 27, 28). Therefore, establishment of the correct diagnosis is critical.
Diagnosis is established by clinical and laboratory criteria (table 1, figure 2). All such tests should be carried out on a fresh (or freshly frozen) serum sample.
Table 1. Criteria for diagnosis of angioedema caused by C1-INH deficiency (5). Diagnosis can be established in presence of 1 major clinical and 1 laboratory criterion.
||C1-INH antigenic level < 50% of normal at 2 separate determinations with patient in basal condition and after the first year of age
|Self-limiting cutaneous angioedema without urticaria, often recurrent and often lasting > 12 hours
||C1-INH functional levels of < 50% of normal at 2 separate determinations with patient in basal condition and after the first year of age
|Self-remitting abdominal colic without clear etiology often recurrent and often lasting > 6 hours
||Mutation in C1-INH gene altering protein synthesis and/or function
|Recurrent laryngeal edema
|Family history of recurrent angioedema and/or abdominal pain and/or laryngeal edema
Laboratory analysis of blood samples is required to establish the HAE diagnosis, and should be performed in an accredited laboratory. If is a clinical suspicion of C1-INH deficiency screening with serum C4 and C1-INH protein is recommended (figure 2).
Figure 2. Angioedema and associated complement anomalies.
If both are low the diagnosis is type I HAE, in the condition we do not suspect AAE. It is suggested to repeat testing to confirm diagnosis. C1q antigenic protein is low in AAE. If serum C4 and C1-INH antigenic protein are both normal, and the clinical suspicion is strong it is recommended to obtain C1-INH functional assay. A low activity is suggestive for type II HAE. Only < 1% have normal C4 between attacks (5, 6, 14, 27). If both C4 and C1-INH functional assay results are normal types I and II HAE is ruled out, and estrogen-dependent HAE is likely. C1q antigenic protein level is typically reduced in AAE but normal in HAE. Genetic testing is not necessary to confirm the diagnosis of HAE.
C1-INH done before 1 year of age should be confirmed later, because false/positive and false-negative results might occur. C1-INH testing is indicated at any age if there is a clinical suspicion or a positive family history (5, 6, 27, 29).
Ultrasound can be an efficacious tool to follow the short-time evolution of ascites after administration of C1-INH concentrate, and side effects of some long-term therapies (5, 30).
Baseline serology for hemovigilance is recommended before infusion of blood products (for HIV, hepatitis B and C).
GPs should be made aware of any C1 INH-deficient patient registered with their practice. If the patient intends to infuse concentrate at home, the patient's GP should be informed. Appropriate emergency cover for any complications must be provided.
Approaches to the diagnosis, therapy and management of C1-INH deficiency vary between countries, with many countries lacking access to C1-INH replacement products.
It is important to deal with treatable and avoidable triggers of attacks: infected teeth and other foci of infection, eradication of Helicobacter pylori may be beneficial (7), avoidance of estrogen contraceptive pills, in general, progesterone-only pills being preferred (8), angiotensin-converting enzyme (ACE) inhibitors (angiotensin-II receptor antagonists may also induce angioedema in normal patients), although the majority of patients with ACE-inhibitor-induced angioedema tolerate angiotensin-II receptor antagonists (14, 23). It is recommended that patients receiving blood products receive vaccination to hepatitis B.
Long-term preventive treatment
Peripheral angioedema, are not dangerous and usually not require long-term prophylaxis. Prophylaxis with tranexamic acid, androgens or C1-INH concentrate is considered to be necessary if the patient experience more than one severe event per month or is disabled more that 5 days per month (5).
a) Antifibrinolytic agents. Tranexamic acid is preferred to epsilonamicraproic acid, although is not as efficient as the androgen therapy. It is mostly used when prophylaxis is indicated before puberty. A starting dose of 1 1.5 g of tranexamic acid up to two to three times a day should be used depending on disease severity, reducing to 0.5 g once or twice a day as the attacks remit. Diarrhea may be a limiting side effect (5, 6, 28).
b) Attenuated androgens might be more effective than antifibrinolitic agents. Contraindications include pregnancy and lactation, cancer and childhood. The list of side effect is quite long and is dose dependent: virilization, headaches, depression, fatigue, nausea, menstrual irregularities, masculinization of the female fetus, decreased growth rate in children, atherogenesis, liver function derangement, cholestatic jaundice and hepatocellular adenoma (5, 6, 31, 32).
It is important to explain the advantages and disadvantages of the treatment regimen, to discuss fully possible side effects with the patient and to monitor regularly the acceptability of such side effects. The use of prophylactic attenuated androgens in children is hardly ever indicated and, if tranexamic acid is ineffective, then regular infusions of C1 INH concentrate should be considered (33, 34).
Some authors use higher induction dose (as high as 400-400 mg danazol daily for one month) followed by a slow tapering to 50 mg/day 5 days per week (5, 17, 27). Others make an induction with low dose (200 mg danazol daily for one month) and increase or decrease the dose afterward, depending on response obtained (3, 18).
c) Patient possession of C1-INH concentrate. It is recommended to offer to patients C1-INH concentrate on demand for personal use at home or with travel, as 50 75% have a life-threatening attack at some time (5, 27). It is to be either self-administrated or infused by a caregiver. Patients should be allowed to keep a supply o 500-1500 mg U C1-INH concentrate. Self-administration involves a careful education program. Self-possession reduces the time patients spend awaiting infusions (5).
Short term preventive treatment
If mild or more than mild manipulations are planned, an infusion of C1-INH concentrate can be given up to 24 h before the procedure (35). The requirements may vary from 500 to 1500 U. If the C1-INH concentrate is not available administration of antifibrinolytics or attenuated androgens, starting 5 days before the procedure and the following 2 days thereafter, is an alternative: danazol 10 mg/kg/day (maximum 600 mg daily) or tranexamic acid 75 mg/kg/day, split in 2 or 3 times per day (5, 14, 27, 36).
In case of intubation or major procedures best option is C1-INH concentrate 1 hour before surgery (500-1500 U, depending on weight) and a same dose at the time of surgery. It has to be repeated as needed until it is no risk of angioedema (5, 14, 27, 36, 37). If C1-INH concentrate is not available, danazol or tranexamic acid as before is recommended. Less safe alternative options are solvent/detergent-treated fresh frozen plasma or regular fresh frozen plasma (5, 6, 14).
Treatment of acute attacks
If there is available, C1-INH concentrate is first-line therapy in severe events (laryngeal and abdominal attack). Involvement of the upper airway usually begins slowly but cases of progression within 20 min have been reported; voice alteration and dysphagia indicate high risk of total airway obstruction (5, 6, 17). Administering C1-INH concentrate shortens the duration of attacks by about a third and also halves the time to the beginning of the relief of symptoms (5, 36, 37). If the abdominal attack is severe, C1 INH concentrate should be infused. The complete resolution of symptoms is after 24 h (5, 19, 36, 37). If symptoms persist at a high intensity 2 h after infusion, additional C1-INH concentrate should be given and alternative diagnoses should be considered.
If C1-INH concentrate is not available, other therapies may include increasing the danazol dose, tranexamic acid, early use of adrenaline (might be not effective), pain relievers, intravenous fluids or supportive care. Use of frozen plasma can worsen attacks (5, 19).
Pregnancy and delivery
Treatment of HAE during pregnancy has special problems. Ideally, all prophylactic drugs should be stopped during pregnancy and, if possible, before conception. Particularly, attenuated androgens are contraindicated during pregnancy. If prophylaxis is required, tranexamic acid may be used with caution. Severe attacks should be treated with concentrate as in the non-pregnant patient.
The safest approach is to administer a predelivery infusion of 500 1000 U C1-INH concentrate. Regional analgesia is to be preferred to endotracheal intubation in order to avoid laryngeal trauma. The postpartum period is one of higher risk of acute attacks (5, 6, 14, 27, 36).
Attacks are seen during childhood in most patients. Unfortunately, the diagnosis is usually made in the second or third decade of life. Fortunately, attacks in children are usually not as frequent and/or severe as in adults, except the recurrent colicky abdominal pain. Attacks of glottis edema can occur at any age and may be life-threatening. For this reason, particularly where there is a family history, children should be tested at an early age (5, 14, 34). Most references state that the use of antifibrinolytics and androgens are not recommended in childhood because of the serious side effects. Prophylaxis is rarely required, being justified in cases of frequent attacks of laryngeal edema or recurrent attacks of abdominal pain causing distress and disability. In this situation, antifibrinolytics are preferred to androgens. The individual minimal effective dose has to be established and adjusted with growth (5).
Attenuated androgens are associated with increased risk of androgenization, premature puberty, accelerated bone fusion with limited growth, liver disorders, atherogenesis and behavioral problems. In use of danazol in children need caution. It should be use for the shortest period and with the smallest effective dose possible (5, 34).
C1-INH concentrate use in long-term prophylaxis is controversial, but its use is clearly recommended for treatment of acute attacks (5, 6, 14, 27, 34).
For a HAE patient it is very important to keep a patients' infocard which is a written information about their disease, its treatment, and a plan on how to obtain emergency treatment in several languages. Arrange travel insurance that will cover HAE. A doctor's letter will be required in order to take C1-INH through airport controls and medications should be declared at the baggage checks and carried as hand luggage in a cool bag (14). Carry a 24-h emergency advice telephone number (translated if traveling abroad). Assistance of Hereditary Angioedema International, HAE patients' advocate can be of paramount help in many situations.
Patients with HAE can be exposed to risk of hepatitis C as a result of plasma-derived products, but the introduction of new viral inactivating procedures reduces dramatically viral contamination. With these technique no cases of HIV were reported (5, 14, 37). By analogy with the recommendations in hemophiliac patients, consideration should be given to vaccinate patients who are not immune to hepatitis A or B and who currently receive, or may require, blood products (14).
New treatments on the horizon
There are five companies that conduct clinical trials with new drugs. CSL Behring makes Berinert-P, a C1-INH concentrate product, sold throughout the world. Berinert-P has an impressive long-term safety record and, in countries where available, is the drug of choice for acute HAE attacks (5, 37). DX-88 (Dyax Corp., Cambridge, Massachusetts, USA) is a kalikrein inhibitor for acute HAE attack management. It was reported a significant improvement of symptoms, and the drug safety profile was excellent (38). Studies done with Icatibant, a B2 bradykinin receptor antagonist (Jerini AG, Berlin, Germany) indicate that is effective and safe in treating acute HAE attacks. The trial involves a subcutaneous injection - similar to how diabetics inject insulin. Access to this treatment modality would allow patients to treat acute HAE attacks at home (39). Lev Pharma conduct a pivotal trial with a C1-INH product that is manufactured from US source plasma by the Sanquin Blood Supply Foundation ("Sanquin"), a not-for-profit organization based in the Netherlands. The Dutch biotechnology company, Pharming NV has perfected a recombinant C1-INH. The results are reportedly similar to what is observed in patients treated with plasma derived C1-INH concentrate (40).
I gratefully acknowledge the assistance of Prof. Dr. Henriette Farkas and Dr. Lilian Varga, from Semmelweis University, Budapest, Hungary, in critically reviewing the manuscript.
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Last update: 09.01.2009