Hereditary angioedema is a genetic disease in which there is a deficiency of the inhibitor of the C1 component of the complement. Symptoms are recurrent swelling of the skin, mucous membranes and abdominal organs, which may be accompanied by suffocation (with laryngeal edema), vomiting and abdominal pain (with abdominal lesions). Diagnosis is made on the basis of examination, study of hereditary history, determination of C1-inhibitor, components C4 and C2 in blood plasma, molecular genetic studies. Treatment is carried out by compensating for the absolute or functional deficiency of the C1 inhibitor, the use of bradykinin and kallikrein blockers, and the use of freshly frozen donor plasma.
Hereditary angioedema (NAO) is a variant of primary immunodeficiency caused by a violation of the inhibition of the complement system, more precisely, its main fraction C1. This condition was first described in 1888 by W. Osier, who identified recurrent edema in a young woman, and also found that at least five generations of her family had a similar disease. It is noteworthy that the angioedema itself was discovered by I. Quincke just 6 years before the discovery of the hereditary form of this pathology – in 1882. Hereditary angioedema has an autosomal dominant nature of transmission and affects both men and women with the same frequency. According to some reports, the disease is more severe in women and occurs earlier, but no reliable studies have been conducted on this issue. The incidence of hereditary angioedema, apparently, varies significantly among different ethnic groups, which gives very heterogeneous figures of this indicator – from 1:10,000 to 1:200,000.
The immediate cause of the development of hereditary angioedema is primary immunodeficiency, consisting in a deficiency or functional inferiority of an esterase inhibitor of one of the complement components – C1. As a result, the inhibition of activation of other components of this system – C4 and C2 – is also disrupted, which leads to an even greater disruption of this immune mechanism. Geneticists were able to identify the gene responsible for 98% of the forms of hereditary angioedema – it is C1NH, located on the 11th chromosome and encoding the above-mentioned C1 esterase inhibitor. Various mutations can lead to forms of the disease that differ in their course, which have fairly similar clinical manifestations, but differ in a number of diagnostic tests.
With some types of mutation of the C1NH gene, the synthesis of the C1 inhibitor protein is completely stopped, as a result of which it is absent in the blood plasma, and the complement system is stopped by ineffective sideways. In other cases, hereditary angioedema occurs against the background of the normal content of the inhibitor in the blood, while the genetic defect C1NH leads to a violation of the structure of the active center of this enzyme. As a result, the C1 inhibitor becomes functionally defective, which causes the development of pathology. There are also rare forms of hereditary angioedema, in which there are no changes in the amount or activity of the C1 esterase inhibitor, and mutations in the C1NH gene – the etiology and pathogenesis of such diseases are currently unknown.
Stopping the inhibition of the activity of complement components (C1, C2, C4) leads to the launch of an immune reaction similar in its course to allergic, especially urticaria. The complement components are able to expand the blood vessels of the deep layers of the dermis, increase the permeability of their walls, which provokes the diffusion of blood plasma components into the intercellular space of skin tissues and mucous membranes and leads to their edema. In addition, vasoactive polypeptides – bradykinin and kallikrein – play an important role in the pathogenesis of hereditary angioedema, which further increase the degree of edema, and can also cause spasm of smooth muscle muscles of the gastrointestinal tract. These processes cause all the variety of symptoms of hereditary angioedema: swelling of the skin (in the extremities, face, neck) and mucous membranes (oral cavity, larynx, pharynx), abdominal pain and dyspeptic disorders provoked by a combination of edema and spasms.
In total, three main types of hereditary angioedema have been identified to date. Their differences in terms of the clinical course of pathology are very insignificant, special diagnostic techniques are used to determine the form of the disease. It is extremely important for an immunologist to find out the type of hereditary angioedema, since the tactics of treatment of this pathology largely depends on this:
- Hereditary angioedema type 1 (NAO-1) is the most common form of the disease, it is registered in 80-85% of patients with this pathology. The cause of this type of NAO is the absence of the C1NH gene or a nonsense mutation in it, as a result of which the C1 inhibitor is not formed in the body.
- Hereditary angioedema type 2 (NAO-2) is a rarer form of pathology, detected only in 15% of patients. It is also caused by a genetic defect in C1NH, however, the expression of the C1 inhibitor protein does not stop, and the enzyme itself has an altered structure of its active center. This leads to his inferiority, and he becomes unable to properly perform his functions.
- Hereditary angioedema type 3 is a relatively recently discovered form of the disease with virtually unexplored etiology and pathogenesis. It was reliably found out that with this type of edema there are no mutations of the C1NH gene, the normal amount of the esterase inhibitor of the complement component C1 and its functional activity are preserved. There is no more data on this form (or their combination) of hereditary angioedema.
As a rule, at birth and in childhood (except in rare cases) hereditary angioedema does not manifest itself in any way. Quite often, the first signs of the disease occur in adolescence, as they are provoked by stress and hormonal changes occurring in the body at this time. However, hereditary angioedema often appears later – at the age of 20-30 years or even in the elderly. Most often, the development of the first attack is preceded by some provoking phenomenon: powerful emotional stress, serious illness, surgery, taking certain medications. In the future, the “threshold of sensitivity” in relation to provoking factors decreases, seizures occur more often – hereditary angioedema becomes recurrent.
The main manifestation of the disease in most patients is swelling of the skin and subcutaneous tissue on the hands, feet, sometimes the face and neck. In more severe cases, edematous phenomena occur on the mucous membranes of the oral cavity, larynx and pharynx – suffocation (asphyxia) may develop, which is the most common cause of death from hereditary angioedema. In other cases, symptoms from the gastrointestinal tract come to the fore: nausea, vomiting, abdominal pain and pain, sometimes a similar clinical picture acquires the features of an “acute abdomen”. In some cases, hereditary angioedema is characterized by a combination of swelling of the skin, mucous membranes and lesions of the gastrointestinal tract.
To identify hereditary angioedema, data from a physical examination of the patient, studying his hereditary history, determining the amount of C1 inhibitor in the blood, as well as complement components C1, C2, C4, and molecular genetic studies are used. Examination during the acute phase of the disease reveals swelling of the skin or mucous membranes, patients may complain of abdominal pain, vomiting, diarrhea. In the presence of hereditary angioedema of type 1, the C1 esterase inhibitor is completely absent in the blood, the concentrations of the indicator components of the complement are significantly reduced. With type 2 of the disease, a small amount of C1 inhibitor can be detected in the blood plasma, in rare cases its level corresponds to the norm, but the compound has reduced functional activity. In all three variants of hereditary angioedema, the level of C1, C2 and C4 does not exceed 30-40% of the norm, so this indicator is key in the diagnosis of this condition.
The study of the patient’s hereditary history often reveals the presence of such a disease in at least several generations of his ancestors and other relatives. However, the absence of signs of familial pathology is not an unambiguous criterion that makes it possible to exclude hereditary angioedema – in about a quarter of patients, this condition is caused by spontaneous mutations and is detected for the first time in the family. Molecular genetic diagnostics is carried out by automatic sequencing of the C1NH gene in order to detect mutations. Differential diagnosis should be made with angioedema of allergic origin and acquired forms of C1 inhibitor deficiency.
Therapy of hereditary angioedema is divided into two types – treatment for the relief of an acute attack of the disease and preventive medication to prevent their development. In the case of acute Quincke edema caused by NAO, traditional antianaphylactic measures (adrenaline, steroids) are ineffective, it is necessary to use a native or recombinant C1 inhibitor, bradykinin and kallikrein antagonists, in their absence, transfusion of freshly frozen plasma is indicated. It is necessary to start such treatment as early as possible, ideally – at the very first attacks of hereditary angioedema.
Long-term prevention of the disease is carried out in cases when seizures occur too often (more often than once a month), if there were cases of laryngeal edema or suffocation in the anamnesis, or hospitalization in the intensive care unit. Prevention includes the use of androgens, exogenous (recombinant or native) forms of C1 esterase inhibitor, antifibrinolytic drugs. With a benign course of hereditary angioedema – rare attacks and their relatively rapid disappearance – such treatment may not be prescribed. However, on the eve of surgical or dental interventions, physical and mental stress, it is recommended to take the above remedies for a short time to reduce the risk of an attack.
Prognosis and prevention
In most cases, the prognosis of hereditary angioedema is relatively favorable in terms of survival – with reasonable treatment and prevention, seizures occur extremely rarely and do not threaten the patient’s life. At the same time, there is always a risk of laryngeal edema, which can lead to asphyxia and death. Such patients should not only avoid significant physical and emotional stress, but it is also desirable to have a card or medallion with an indication of the diagnosis. A huge number of deaths from hereditary angioedema were caused by incorrect actions of doctors who do not know the diagnosis and therefore use traditional drugs for allergic Quincke edema, which are ineffective in NAO.