C1 inhibitor deficiency.

Deficiency of Cl-inhibitor (С1И) leads to the development of a characteristic clinical syndrome - hereditary angioedema (HAE). The main clinical manifestation of hereditary angioedema is recurrent edema, which can threaten the patient's life if it develops in vital localizations.

Pathogenesis of Cl-inhibitor deficiency

The deficiency is caused by a mutation in the gene for Cl-inhibitor, a serine protease that inactivates the complement components C1r and Cls, as well as the kallikrein-kinin system and activated factors XI and XII of the coagulation cascade. Although C1-inhibitor is not a significant plasmin inhibitor, it is consumed by plasmin, and in its absence, plasmin activation is one of the most important triggers for edema episodes. The main cause of increased vascular permeability in HAE is excess bradykinin, which is a consequence of excessive proteolysis of high-molecular kininogen by kallikrein.

Congenital C1I deficiency is an autosomal dominant disorder with equal racial and sexual distribution and is the most common of all complement defects. Three main types of defects are distinguished in patients with hereditary angioedema: in 85% of cases, there is a decrease or absence of Cl-inhibitor due to impaired transcription; in the presence of a missense mutation in the active center, the concentration of Cl-inhibitor may be normal or even increased, but the protein is nonfunctional. HAE type III is caused by the presence of autoantibodies to Cl-inhibitor.

Symptoms of Cl-inhibitor deficiency

Signs of the disease in patients with hereditary angioedema are observed mainly in the first years of life. In most cases described in the literature, the manifestation of the disease occurred before the age of 18, although there are cases of primary detection of the disease at the age of 52. Clinically, hereditary angioedema is characterized by edema of various parts of the body. Edema occurs rapidly, reaches a maximum within 1-2 days and spontaneously resolves after 3-4 days. Edema is usually not accompanied by rash, itching, discoloration of the skin, pain symptoms. However, edema of the intestinal wall can manifest itself as severe abdominal pain. In this regard, patients with this kind of manifestations of hereditary angioedema are frequent subjects of surgical interventions. In some patients, loss of appetite, vomiting, and abdominal cramps are the only clinical manifestations of hereditary angioedema, with no subcutaneous edema. Edema of the larynx is often fatal, especially in young children. The factors that provoke edema are not defined, although patients often associate attacks with stress, minor trauma, usually with edema of the extremities. Edema of the face and respiratory tract may occur after tooth extraction or tonsillectomy.

Diagnosis of Cl-inhibitor deficiency

The normal Cl-I level is 0.15-0.33 g/L for adults and 0.11-0.22 g/L for children. The functional activity of Cl-I in children of the first year of life is 47-85% of that in adults. A decrease in the concentration of C1I or a significant decrease in the functional activity of C1I is diagnostic. During an acute attack of hereditary angioedema, there is a significant decrease in hemolytic titers of C4 and C2, and, unlike patients with systemic lupus erythematosus and other immune complex diseases, the level of C3 remains normal. Due to the autosomal dominant type of inheritance, patients with hereditary angioedema often have a positive family history.

Treatment of Cl-inhibitor deficiency

Various types of drugs have been proposed for the treatment of hereditary angioedema. They can be divided into the following groups:

Androgens. In 1960, methyltestosterone was first shown to have a striking prophylactic effect on the severity and frequency of HAE attacks. In 1963, a synthetic analogue of methinyltestosterone, Danazol, was obtained. The primary pharmacological actions of the drug are gonadotropin inhibition, suppression of sex hormone synthesis, and competitive binding to progesterone and androgen receptors. Danazol is used in the treatment of endometriosis, gynecomastia, increased blood loss associated with menstruation, hemophilia A and B to reduce bleeding, and in idiopathic thrombocytopenia, where the drug can help increase the platelet count. Danazol has been shown to increase Cl-I concentrations in most patients with hereditary angioedema. Although Danazol is one of the most commonly used agents in the prophylactic therapy of hereditary angioedema, its mechanism of action remains unknown. Unfortunately, with prolonged prophylactic use, the presence of side effects typical of androgen-type drugs is noted. There is a tendency to obesity, amenorrhea, decreased libido, increased aminotransferases and cholesterol, muscle spasms, myalgia, increased fatigue, headaches. The use of the drug in children and pregnant women is especially limited.

Antifibrinolytic drugs. The first successful use of antifibrinolytic drugs in hereditary angioedema was described by Swedish doctors. Alpha-aminocaproic acid, which is a plasmin inhibitor, and tranexamic acid can be used with partial success to prevent attacks of hereditary angioedema, especially when danazol cannot be used. In acute attacks of hereditary angioedema, therapy with these drugs is ineffective. Alpha-aminocaproic acid has the following side effects: nausea, headaches, diarrhea, myositis, a tendency to develop thrombosis.

Transfusions of fresh plasma and purified Cl-I. As a rule, when attacking hereditary angioedema, transfusion of fresh frozen plasma reduces the intensity of edema within minutes. However, fresh frozen plasma containing Cl-I also contains all other complement components, the presence of which in the transfused preparation can worsen the patient's condition. Moreover, fresh frozen plasma is a possible source of viral infections such as HIV, hepatitis B and C. In recent years, Cl-I cryoprecipitate has been successfully used in many countries. From all points of view, Cl-I is an ideal drug for patients with a high risk of developing upper respiratory tract edema and for patients in whom the use of Danazol does not lead to an increase in Cl-I concentrations or is contraindicated.

In summary, it is necessary to take into account the three-phase approach to the treatment of hereditary angioedema: long-term prophylactic therapy, short-course prophylactic therapy before planned intervention, and therapy for acute attacks of hereditary angioedema. Currently, long-term prophylactic therapy is carried out with androgens and antifibrinolytic drugs. Short-course prophylactic therapy, mainly in patients with hereditary angioedema undergoing dental and surgical procedures, as well as therapy for life-threatening edema, is carried out with fresh frozen plasma and, if available, C1-I cryoconcentrate.

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