C1 inhibitor deficiency.

Deficiency of Cl-inhibitor (ClI) leads to the emergence of a characteristic clinical syndrome - hereditary angioedema (HAE). The main clinical manifestation of hereditary angioedema is the recurrent edema, which can threaten the life of the patient when developing in vital localizations.

Pathogenesis of Cl-inhibitor deficiency

The cause of the deficit is the mutation of the Cl-inhibitor-serine protease gene, the inactivating Clr and Cls complement components, as well as the kallikrein-kinin system and the activated factors XI and XII of the coagulation cascade. Although the 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 of edema episodes. The main reason for the increase in vascular permeability in NAO is the excess of bradykinin, which is the result of excessive proteolysis of high-molecular kininogen with kallikrein.

Congenital CI deficiency is an autosomal dominant disease with the same racial and sexual distribution and is the most common of all defects in the complement system. In patients with hereditary angioedema, three main types of defects are distinguished: in 85% of cases, the Cl-inhibitor is reduced or absent due to impaired transcription; in the presence of missense mutation in the active center, the Cl-inhibitor concentration may be normal or even elevated, but the protein is non-functional. NAO of the third type is caused by the presence of autoantibodies to the C1-inhibitor.

Symptoms of Cl-inhibitor deficiency

Signs of the disease in patients with hereditary angioneurotic edema are noted, mainly in the first years of life. In most cases described in the literature, the manifestation of the disease occurred before 18 years of life, although cases of primary detection of the disease at the age of 52 years are known. Clinically, hereditary angioedema is characterized by edema of various parts of the body. The swelling occurs swiftly, reaches a maximum within 1-2 days and spontaneously resolves in 3-4 days. Edema is usually not accompanied by a rash, itching, a violation of the color of the skin, pain symptoms. However, edema of the intestinal wall can be manifested by severe pain in the abdomen. In this regard, patients with this kind of manifestation of hereditary angioedema may be frequent objects of surgical interventions. In some patients, anorexia, vomiting and abdominal cramping are the only clinical manifestations of hereditary angioedema, with no swelling of the subcutaneous tissue. Edema of the larynx often leads to death, especially among young children. Factors provoking edema are not defined, although often patients associate attacks with stress, minor trauma, usually with edema of the extremities. Swelling of the face and respiratory tract can occur after removal of teeth or tonsillectomy.

Diagnosis of Cl-inhibitor deficiency

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

Treatment of Cl-inhibitor deficiency

Various kinds of drugs were offered for the treatment of hereditary angioedema. They can be divided into the following groups:

Androgens. In I960, the first time showed that methyltestosterone has a striking prophylactic effect on the severity and frequency of seizures of the NAO. In 1963, a synthetic analogue of methynyltestosterone Danazol was obtained. The primary pharmacological actions of the drug are inhibition of gonadotropin, inhibition of the synthesis of sex hormones, 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 increase the number of platelets. As it was shown, Danazol increases Cl-I concentration in the majority of patients with hereditary angioedema. Although Danazol is one of the most frequently used drugs in the prophylactic therapy of hereditary angioedema, its mechanism of action remains unknown. Unfortunately, with prolonged prophylactic use, there are side effects typical for drugs like androgen. There is a tendency towards obesity, amenorrhea, decreased libido, increased aminotransferase and cholesterol, muscle spasms, myalgia, fatigue, headaches. Particularly limited use of the drug in children and pregnant women.

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, as well as tranexamic acid, can be used with partial success in preventing episodes of hereditary angioedema, especially when it is not possible to use danazol. 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.

Transfusion of fresh plasma and purified Cl-I. As a rule, when attacking hereditary angioedema, the transfusion of fresh frozen plasma reduces the intensity of the development of edema within minutes. However, fresh-frozen plasma containing C1-I contains all other components of complement, the presence of which in the transfused drug can worsen the patient's condition. Moreover, fresh-frozen plasma is a possible source of such viral infections as HIV, hepatitis B and C. In recent years, Cl-I cryoprecipitate has been successfully used in many countries. From all points of view C1-I is an ideal preparation for patients with a high risk of edema of the upper respiratory tract and for patients in whom the use of Danazol does not lead to an increase in C1-I concentration or is contraindicated.

Summarizing the above, it is necessary to take into account the three-phase approach to the therapy of hereditary angioedema: long-term preventive therapy, preventive therapy with short courses before the planned intervention and therapy of acute attacks of hereditary angioedema. Currently, long-term prophylactic Therapy is carried out by androgens and antifibrinolytic drugs. Prophylactic therapy with short courses, mainly in patients with hereditary angioedema, undergoing dental and surgical procedures, as well as life-threatening edema therapy, is carried out with freshly frozen plasma and, singing is available, C1-I cryoconcentrate.

[1], [2], [3], [4], [5], [6], [7]