Hereditary C1-inhibitor esterase deficiency: a rather well defined entity

Authors: Dumitru Moldovan (1), Enikő Mihály (2), Florin-Dan Popescu (3), Géza - Attila Szöllösi (4), Minodora Dobreanu (5)

1. University of Medicine and Pharmacy Tîrgu Mureș, Mures County Hospital, Internal Medicine Clinic, Allergology and Clinical Immunology Department
2. Romanian Hereditary Angioedema Network
3. University of Medicine and Pharmacy "Carol Davila" Bucharest, Allergy and Clinical Immunology Department, Hospital "Nicolae Malaxa", Bucharest, Romania
4. Klinik für Innere Medizin, Ilmenau, Germany
5. University of Medicine and Pharmacy Tîrgu Mureş, Mureş Emergency County Hospital, Central Medical Laboratory

Publication: Romanian Review of Laboratory Medicine, Vol. 15, Nr. 2, Jun 2009, p. 41-48. Used with permision.

 

Abstract
Hereditary angioedema (HAE) is a rare disease, associated with quantitative or qualitative genetic deficiency of C1-esterase inhibitor (C1-INH) caused by different point mutations within an abnormal C1-INH gene on chromosome 11. During attacks, endothelial cells in postcapillary venules contract which allow fluid and plasma proteins to leak between them. Bradykinin, liberated from HM kininogen by the unopposed enzymes kallikrein and factor XII is important, as C1-INH is the major inhibitor of these proteases.
Symptoms include recurrent skin sweelings, abdominal and laryngeal attacks. Recurrent abdominal pain attacks have been reported to occur in majority of cases. Laryngeal edema is responsible for death in 20-30% of untreated cases. The disease has often been misinterpreted by clinicians. Symptoms of recurrent swellings and crampy abdominal pain lasting for days, with serum samples showing reduced C1-INH function or antigen, often below 20%, accompanied by low C4 values are hallmarks of HAE. A suggestive family history is obtained in most cases. Conversely, a finding of C1-INH values compatible with HAE in only one single person, should raise suspicion of dealing with in vitro artefacts or acquired angioedema. In some cases, a full equipped complement laboratory is needed for a right diagnosis, but genetic tests are not compulsory.
The aim of this review is to increase the awareness of HAE among colleagues, in order to refer these patients to a specialized center.

Keywords: hereditary angioedema, C1-inhibitor esterase concentration and function essay


Introduction

Hereditary angioedema (HAE) is a rare genetic disease, clinically characterized by recurrent, self-limiting episodes of marked edema involving the skin, gastrointestinal tract, and other organs and might be fatal due to edema of the larynx. The prevalence of HAE is estimated between 1/50,000 and 1/100,000 (1; 2; 3; 4). Since the disease is very rare, the patients remain undiagnosed for many years. Because of serious complications of attacks and the advances in the management, HAE must be clearly recognized.
First medical documents about HAE belong to Heinrich Quincke (1882) and Sir William Osler (1888)(1). In 1962, before any of the complement defects were known, Landerman et al. suggested that symptoms might be due to dysregulation of the kinin system . HAE reached its own identity in 1963, when Donaldson and Evans demonstrated the C1-INH deficiency in HAE patients’ plasma (1; 4; 5; 6). The progress made in our knowledge of this rare disease over the last decades is impressive and now, HAE is a well defined clinical entity.
Symptoms usually appear early in life and are normally accompanied by a family history. The disease is inherited in an autosomal dominant manner. The spontaneous mutation rate is about 25% and 150 different C1-INH gene mutations have been described. Only heterozygous individuals are described and the mutants can transmit to their offspring the deficient gene (1; 3; 4; 7).


Pathogenesis of HAE

C1-INH is the main regulator of the early activation steps of the classical complement pathway. Hepatocytes are the main source of C1-INH. It also regulates the contact phase coagulation and the fibrinolytic cascade. It inhibits factor XII by 90% and kallikrein and plasmin by 42%. In the case of a C1-INH deficit, any endothelial trauma will overactivate the contact phase of coagulation and the classical complement pathway and will lead to the release of large quantities of bradykinin and kinin-like substances (1; 2; 3; 4; 5). The end result is increased vascular permeability and massive local uncontrolled edema. While there was some debate as to the exact component that contributes to the angioedema, it is now well accepted that bradykinin is the main mediator of the increased vascular permeability (figure 1) (4; 6; 7).

Figure 1. Bradykinin, the main mediator in HAE

It is important to stress that histamine is not involved in HAE pathogenesis. Similarities to allergic conditions and inappropriate framing as part of the urticaria-angioedema syndrome frequently lead patients with HAE to be considered allergic and treated with antihistamines and corticosteroids, ineffective in this disorder (1; 4).


Clinical Manifestations

HAE is characterized by recurrent episodes of nonpruritic, nonpitting, subcutaneous or submucosal edema typically involving the extremities, genitalia, trunk, face, tongue, bowel or larynx (Figures 2 and 3). Symptoms typically begin in childhood (50% on the first decade of life), worsen around puberty, and persist throughout life. Severity is not predictable (1; 2; 8).

Figure 2. An example of asymmetric swelling of the hands.

 

Figure 3. Facial edema in a patient with type 1 C1-inhibitor deficiency

Untreated patients may have attacks every 7 to 14 days on average, with the frequency ranging from virtually never to every 3 days. There is considerable variation in the severity of hereditary angioedema, even within a kindred. Results of observational studies suggest that minor trauma and stress are frequent precipitants of episodes of swelling, but many attacks occur without an apparent trigger. Pregnancy has a variable effect on disease severity, but attacks are rare at the time of delivery (1; 3; 8).
Many attacks are preceded by a prodrome (usually a tingling sensation), and approximately a third are accompanied by erythema marginatum (figure 4), a nonpruritic, serpiginous rash. It is important to mention the HAE patients have no urticaria (1; 3; 4; 8).

Figure 4. Serpiginous rush (erythema marginatum) in HAE

The swelling classically worsens gradually over the first 24 hours, then slowly subsides over the subsequent 48 to 72 hours. The arms, legs, hands, feet, and abdomen are the most common sites of swelling. Attacks may start in one location and then spread to another before resolving (1; 8).
Abdominal attacks characterized by crampy pain, but may include vomiting, diarrhea, nausea and meteorism. Among patients with HAE, recurrent abdominal pain attacks have been reported to occur in >90% of cases (8; 9). These attacks can mimic surgical emergencies and, before a diagnosis of HAE is established, patients frequently undergo unnecessary appendicectomy or exploratory laparotomy (14%-34%)(1; 8; 9). Ascites and edema of the intestinal wall can be detected by abdominal ultrasound (10) or CT scan (figure 5). A shift of fluids into the interstitium or peritoneal cavity during abdominal attacks can cause clinically significant hypotension. A history of these surgeries increases the suspicion of HAE (9).

Figure 5. Abdominal CT scan showing an impressive bowel edema (arrows) during a severe abdominal attack

Oropharyngeal swelling is less frequent, but over half of patients have had at least one episode of laryngeal angioedema during their lifetime (1; 2; 4). Laryngeal edema poses the greatest risk for patients with hereditary angioedema. Asphyxiation caused over 30% of deaths among patients with this disease in the past. Even today, patients occasionally die from asphyxiation, particularly in the absence of a proper diagnosis (11).
Patients remain uncertain when the next attack may appear and whether an episode will affect the skin, the gastrointestinal tract, the larynx or any other site (5; 6).
Rare clinical symptoms are collapse, dysuria, hemorrhagic diarrhea, acute pancreatitis, tetany, intussusception, pleural effusions, headaches, aphasia, hemiplegia and seizures, possibly due to localized brain tissue edema (1; 9).


Diagnosis

The HAE diagnosis is suggested by a history of recurrent peripheral angioedema, abdominal and laryngeal attacks. It has to be noted that there is no urticaria. In 30% of cases HAE attacks can be preceded by an erythema marginatum or serpiginous rash, than can be misinterpreted as urticaria (1; 2; 3; 4; 7; 9). Family history is present in 80% of cases (figure 6), the rest of 20% representing the novel mutation. C4 is low in almost all cases, even between attacks (1; 2; 3; 7).
The frequency of attacks increases during puberty. The age at onset of first HAE symptoms is below 20 years of age in 85 % of cases and the frequency of attacks seems to decrease in the elderly (1; 3). The attacks are variable from 1 per week to 1 per year and the duration of an attack is between 2 and 8 days (1; 3; 4; 7).
HAE symptoms may be induced by triggering events, as minor trauma, surgery (even dental anesthesia)‏, stress, oral contraceptives, pregnancy, menstruation, infections, autoimmune disorders, ACE inhibitors (1; 3;4; 8). Fatal laryngeal attacks have been reported following tooth extraction. In several cases no triggers can be found, and attacks are unpredictable. In many patients extensive dental work may be carried out without complication and conversely minor work may sometimes precipitate an attack (1; 3; 7; 8).

Figure 6. Pedigree of a family with HAE type I

If clinical it is a suspicion of C1-INH deficiency, it is recommended screening with serum C4 and C1-INH proteins (table 1). If serum C4 and C1-INH antigenic proteins are both low and acquired angioedema (AAE) not suspected, then the diagnosis is compatible with type 1 HAE (85% of cases) (1; 3; 4). If case of suspicion of AAE is possible (later onset of symptoms, age over 40, no family history, associated with lymphoproliferative disease or, less commonly, autoimmunity), then serum C1q antigenic protein testing is required (1; 3; 4; 12). If low, the diagnosis is highly compatible with AAE. If C4 is normal or low and C1-INH antigenic protein normal but clinical suspicion is strong, it is recommended to obtain a C1-INH functional assay. If low C1-INH functional activity with normal or elevated C1-INH antigenic protein type 2 HAE diagnosis is likely (1; 2; 3; 4). If C4 antigenic protein and C1-INH functional assays are both normal, this rules out types 1 and 2 HAE, but it does not rule out the recently described type 3 HAE or estrogen dependent angioedema, with normal C1-INH protein and function occurring mainly in women (13). The same is true for ACEI-related angioedema. Genetic testing is not necessary to confirm the diagnosis of HAE types 1 and 2. However, genetic testing may be necessary to investigate type 3 (4; 13).
C1-INH functional assays vary and it is strongly recommended standardization of the functional assays and establishing specialized laboratories capable of accurately measuring C1-INH function (7).
In summary, HAE is classified in three phenotypes:
type 1 (approximately 85% of cases), characterized by impairment or absence of C1-INH protein
type 2, with normal C1-INH levels, but impaired or absent activity, and
type 3, with normal C1-INH activity, but clinical symptoms present.
The clinical features of these types of HAE are indistinguishable. The differential diagnosis of nonallergic angioedema is shown in table 1 and figure 7.

 

Table 1. At-a-glance comparison of C1-INH function and complement protein concentration in HAE, AAE and ACE inhibitor-induced angioedema.

 

Figure 7. Algorhytm of HAE diagnosis

Management
It is important to stress that treatment with corticosteroids, antihistamines and adrenaline are not effective in HAE attacks or prevention (1; 16). Current treatment of patients with HAE includes long-term prophylaxis and treatment of acute attacks.
The preventive treatment consists on attenuated androgens (danazol and stanozolol) with a good response on the majority of patients, e.g., reduces the number and severity of the attacks. However, a number of side effects were reported, but only on high doses (virilization in females, weight gain, and even carcinoma of the liver). Use in children, teenagers, and women in child-bearing age is problematic (14; 15). Long-term administration of tranexamic acid is less effective, but shows fewer side effects (16).
Acute attacks can be efficiently treated with C1-INH concentrate derived from human plasma, and has to be injected intravenously (1; 3; 4; 7;16). Bradykinin receptor 2 antagonist Icatibant proved to be a good alternative (4; 16). In countries were these drugs are not available fresh frozen plasma remains the single choice. The recombinant human C1-INH and plasma kallikrein inhibitor are currently being investigated as potential therapies for attacks of HAE (16).


Romanian Network for Hereditary Angioedema

Our first efforts to implement the modern management of the HAE patients in this country have begun by attending the 4th Workshop for C1-inhibitor deficiency held in Budapest, in 2005 (17). With the sustained support of friends we made there we started to build-up a national network, being awared that in a rare disease a network is the most appropiate solution (18). Until we buit-up our own complement lab we were supported mainly by the Hungarian Centre for Hereditary Angioedema from Semmelweis University in Budapest, Hungary. Also Pharming Technologies Ltd from The Netherland have supported some of the infrastructure of our complement laboratory.
Since 2005 we held lessons for general practitioners, specialists in internal medicine, allergology and clinical immunology, pediatricians, dermatologists. Five workshops were held at the annual conferences of those national societies (19). In 2006 we founded the ”Romanian Hereditary Angioedema Network” aimed to provide assistance to HAE patients and colleagues. Our efforts are visible on www.haenet.ro (figure 8)(18; 19; 20).

Figure 8. www.haenet.ro, the site for information regarding HAE in Romania, in both Romanian and English

Presently we have registered 53 patients belonging to 19 families. Thirty six of them were enrolled in two consecutive clinical trials concerning the effect of two drugs on the acute attacks. An open-label study, still ongoing, is presently the sole therapeutic alternative for some of these patients, real orphans of our medical system. Fortunately, in these 4 years, from our database (patients who came at least once to our centre) nobody died.


Desiderata

Romania is far behind many nations regarding the management of HAE. Our purposes for the near future are to build-up a national registry of HAE patients, registration and availability of drugs for acute attack treatment, finding new cases, continuing medical education of various specialists, making a team work with the society for primary immunodeficiency and national alliance for rare diseases as well as with those of internal medicine, pediatrics, dermatologist etc., empowering the quality of complement labs, especially of functional C1-INH, to help the registration and put to work a patient association to represent better their interests.
In this context, we want to think we are a specialized centre with a sufficient case load to acquire the clinical expertise, we have personnel trained in this disease, and an associated laboratory, able both to measure the complement proteins and to provide interpretative comment on the results, preferably on site in view of the potential for sample degradation. We hope this article will be helpful in finding new cases, since it is still a lot of work to be done in descovering the remaining undiagnosed 150-250 patients expected to be in Romania, according to the prevalence rate of this rare disease. It is likely, that most of these patients presently have a wrong diagnostic label. This misinterpretation is due to the to the rarity of the disorder and the scarcity of specialist centres and insufficient clinical experience in managing the condition.


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Last update: 08.31.2009