Learning that we are neither freaks nor hypochondriacs is a great relief for us. A new era has begun in my life. I am simply overwhelmed by the opportunity to move around almost without any restrictions and there is no need to apologize. Our current safety had to be fought dearly.”

(Excerpts from patient diaries)

Information on HAE for medical professionals

> Definition
> Pathomechanism
> Etiology
> Clinical manifestations
> Differential diagnosis
> Diagnosis
> Management and prophylaxis
> Recommended reading

Definition
Hereditary angioneurotic edema (HAE) is a rare inborn disorder, characterized by paroxysms of subcutaneous or submucosal edema formation. Types I and II of HAE result from the deficiency or reduced function of the C1-esterase inhibitor (C1-INH) protein. The clinical symptoms of type III (previously known as 'estrogen-dependent') HAE are identical to those seen in types I and II – with the exception that C1-INH deficiency cannot be demonstrated. Missense mutations of the gene encoding coagulation factor XII (Hageman's factor) can be detected in a proportion of cases. However, there are patients in whom no genetic abnormalities of etiological importance could be identified to date.

Pathomechanism
C1-INH – a serum protease inhibitor of the serpine type – regulates four, closely interrelated cascade systems, specifically the blood coagulation, quinine, fibrinolytic and complement systems. If tissue injury or activation of the Hageman factor occurs for whatever reason, the latter releases kallikrein from prekallikrein, and bradykinin from high molecular weight quininogen. Bradykinin is a vasoactive mediator that increases capillary permeability. This leads to the exravasation of plasma from the vascular compartment into the extracellular space, resulting in edema formation.

Etiology
The C1-INH gene is located in the 1,2-q13 subregion of the human chromosome 11. HAE resulting from the mutation of the C1-INH gene is inherited as an autosomal dominant trait and is manifested by either of two phenotypes. Type I is characterized by low antigenicity of C1-INH and low functional activity of the protein. In Type II, however, serum level is normal or abnormally high, while the protein is a non-functioning mutant with reduced activity. In 80 per cent of cases, HAE can be ascertained in first-degree relatives, whereas the remaining 20 per cent are attributed to de novo mutations. In HAE-FXII, the mutation of the gene encoding coagulation factor XII enhances the activity of the latter and thereby leads to the accumulation of bradykinin.

Prevalence
According to data from the international literature, the prevalence of HAE is between 1:50,000 to 1:10,000.

Clinical features
In types I and II of HAE, clinical manifestations first occur usually as late as at the age of 6 to 8 years only. Edematous episodes involve the subcutis, or submucosa of the airways or the gut.

1. Subcutaneous edema most commonly develops on the extremities, face, neck, torso, in the gluteal region, and on the external genitals. Edematous lesions are non-tender, not erythematous and non-pruritic. Urticaria is absent.

2. Submucosal edema:
a. in the upper airways, untreated edema can cause airway obstruction and thereby lead to suffocation;
b. in the gastrointestinal tract, edema of the intestinal wall can mimic the symptomatology of an acute abdominal catastrophe. Typical manifestations include nausea, vomiting, spastic abdominal pain, and watery diarrhea following attacks.

Infrequently, edema can develop in other organs, including the chest (heralded e.g. by squeezing/pressing chest pain without visible edema externally) or the esophagus (with dysphagia, subjective retrosternal sensation of difficult swallowing). Involvement of the central nervous system may cause transitory headache, aphasia, hemiplegia, and convulsions. Erythema marginatum, a characteristic prodromal sign in 30 per cent of patients, evolves during the 12 to 48 hours preceding the attack.

Differential diagnosis

1. Angioedema resulting from mast cell activation
The clinical picture is similar or identical to that of HAE, and this may lead to misdiagnosis. Edema of this type results from histamine-mediated processes, primarilyand the latter are commonly accompanied by urticaria. It responds to antihistamines, corticosteroids, and epinephrine.

2. Bradykinin-mediated angioedema

a. Acquired C1-INH deficiency
In acquired angioedema resulting from the deficiency of C1-INH (acquired angioneurotic edema – AAE), edematous episodes first occur usually during adulthood; the family history is negative. This type may accompany various diseases, such as autoimmune disorders, malignancy, lymphoproliferative disorders, and infections. In acquired C1-INH deficiency, C4 and C1-INH concentration and activity are both reduced, as well as serum C1q level is typically decreased. The latter is a useful clue for differentiating AAE from the hereditary form, where C1q level is normal. In type I AAE, C1-INH deficiency evolves through the enhanced consumption of C1-INH. In type II AAE, the formation of autoantibodies against C1-INH can be detected in the patient's blood. In addition to these oligo- or monocolonal autoantibodies, Type II AAE is characterized by reduced C4 and C1-INH activity. As a rule, no underlying diseases can be identified in this type of autoimmune C1-INH deficiency.

b. Angioedema caused by inhibitors of the renin-angiotensin-aldosterone system (RAAS)
Most commonly, angioedema formation is a potential adverse reaction to angiotensin converting enzyme (ACE) inhibitors. ACE is responsible – among others – for the cleavage of bradykinin and its inhibition results in the accumulation of bradykinin and thereby edema-formation. Early signs can ensue immediately after the start of dosage with ACEI or after a latency of several years. Angioedema wanes and then, resolves after the discontinuation of ACEI. Angioedema may be triggered also by angiotensin I receptor blockers; however, this occurs less frequently.

c. Idiopathic angioedema

4. Acute abdominal disorders

Diagnosis
Diagnosis can be established by the following:
1. Characteristic clinical manifestations
2. Laboratory tests [link -- laboratory diagnosis] – along with a positive family history. Molecular genetics studies lend additional support in uncertain cases and in prenatal diagnostics.

HAE Type I: C1-INH concentration, C1-INH activity, and C4 concentration are reduced, whereas C1q and C3 levels are normal.
HAE Type II: C1-INH concentration is normal or elevated, C1-INH activity and C4 level are reduced, C1q and C3 levels are normal.

Management
Management comprises prophylaxis on one hand, and emergency therapy of edematous attacks on the other. The initial step of prophylaxis is to eliminate the triggering factors mentioned earlier. Frequent recurrence of the attacks in severe form warrants long-term pharmacotherapy with antifibrinolytics (e.g. tranexamic acid 20 to 40 mg/kg/day), or attenuated androgens (danazol 50 to 200 mg/day), or C1-INH concentrate (500 to 1500 IU once or twice weekly). Adverse effects can be avoided by titration to the lowest effective dose. Tranexamic acid is the agent of choice for children and female patients. Before diagnostic (gastroscopy, bronchoscopy) or surgical procedures (including endotracheal intubation) contemplated in the head and neck region, short-term prophylaxis is recommended with escalated (400- to 600-mg) doses of danazol over 5 to 6 days or with C1-INH administered one hour before the intervention. Edematous attacks always require emergency therapy, if the edematous swelling involves the mucosa of the upper airways or the face, as well as if severe abdominal or subcutaneous edema has evolved. Treatment may be necessary also in milder episodes, if these interfere with the activities of daily living. It is important to emphasize that conventional remedies for edema – such as epinephrin, (H2- or H1-) antihistamines, and corticosteroids – are ineffective in HAE. Several medicinal products are available for emergency use including C1-INH concentrates, a kallikrein inhibitor, and a bradykinin receptor 2 antagonist. Berinert P® (CSL Behring GmbH, www.cslbehring.com) is authorized for marketing in Hungary and in many other countries, whereas Cetor® (Sanquin, www.sanquin.nl) is avaliable in the Netherlands. In the USA, Cinryze® (ViroPharma Inc; www.viropharma.com) has been approved – at present for prophylaxis only. All of these three medicinal products are manufactured from human blood through pasteurization; Cetor® and Cinryze® are subjected to further purification by nanofiltration. In Europe, a new rhC1-INH preparation, conestat-alfa (Ruconest®, Pharming Group NV, www.pharming.com and SOBI AB, www.sobi.com) has been launched. The actions of this agent – derived from the breast milk of transgenic rabbits by a more recent recombinant technology – are similar to those of C1-INH obtained from human blood. All C1-INH preparations are intended for intravenous administration; see their dosages in the SmPCs of the individual mendicinal products.

Berinert P Patient Information pdf
Cetor Patient Information pdf
Cinryze Patient Information pdf
Ruconest Patient Information pdf

In Europe, additional options for the treatment of HAE include administering icatibant (Firazyr®, Shire, www.shire.com). The active substance of this drug is a synthetic decapeptide, the structure of which is similar to that of bradykinin and therefore, it can bind to the bradykinin B2 receptor with high affinity. Firazyr® is available in pre-filled syringes for subcutaneous injection, for adult HAE patients (see the SmPC). Ecallantide (Kalbitor®, www.kalbitor.com), developed by Dyax Co is available for the time being in the USA only. This recombinant protein consisting of 60 amino acids acts as a kallikrein inhibitor and thereby prevents the accumulation of bradykinin. It is administered by subcutaneous injection (see the SmPC). Fresh frozen plasma may be administered if none of these state-of-the-art medications is avaliable.

weblapok:

Behring
Viropharma
Pharming
SOBI
Shire
Dyax

dokumentumok:

Berinert P Patient Information pdf
Cetor Patient Information pdf
Cinryze Patient Information pdf
Ruconest Patient Information pdf
Firazyr Patient Information pdf
Kalbitor Patient Information pdf

Complex management
In view of the characteristics of rare disorders (such as lack of familiarity and/or experience with the condition, special diagnostics and therapy), patient care is best delivered by specialist centers capable of undertaking further assignments (including patient education, scientific research and development) in addition to rendering state-of-the-art medical services. The first important step of complex management is education of the patient – or the parents, in case of pediatric patients – on the nature of the disease. This is aided by the multilingual info-card containing a brief description of the disease along with the outline of therapeutic interventions and contact information of the physician or hospital in charge of the patient's management. HAE patients should be supplied with medicinal products for emergency use – this they should keep ready at home. Additionally, it is expedient to provide the patient with a diary for recording the number, localization, duration, triggering factors of attacks, as well as the treatments received to relieve these. Complex management should include regular health checks, performed at the HAE Center. Doctors should encourage their patients and relatives to seek contact with Hungarian and international self-help organizations.

Prognosis
The severity of individual symptoms shows high inter-individual variation and can be extremely variable in different members of the same family. In view of its nature, HAE is yet incurable, but adequate prophylaxis and patient education can reduce the frequency of symptomatic episodes susbstantially, and this translates into a meaningful improvement of the patient's quality of life.

Recommended reading

1. A Agostoni, E Aygoren-Pursun, KE Binkley et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004; 114(3 Suppl):S51-131.

2. T Bowen, M Cicardi, H Farkas et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol 2010; 6(1):24.

3. K Bork. Diagnosis and treatment of hereditary angioedema with normal C1 inhibitor. Allergy Asthma Clin Immunol 2010; 6(1):15.

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