Angioedema is a pathological condition accompanied by the accumulation of fluid in the skin tissues and subcutaneous fat due to an increase in the permeability of the walls of the vessels of the microcirculatory bed. It is manifested by swelling of the skin of various localization (face, neck, limbs), often combined with urticaria and skin itching. Diagnosis is made by physical examination, laboratory blood tests, studying the hereditary and allergological history of the patient. Therapeutic tactics depend on the causes that caused the development of the syndrome, may include the appointment of antihistamines, androgens, fibrinolysis inhibitors and diuretics.
Angioedema was first described in 1882 by the German scientist Heinrich Quincke. The researcher considered it an independent disease – angioedema. Currently, it has been established that about half of the cases of pathology occur as a result of allergic processes of the reagin type, while the rest are independent acquired or hereditary conditions. The concept of “isolated angioedema” includes a number of diseases, which are based on violations of fluid circulation between the circulatory system and tissues. Angioedema can be diagnosed at any age, women are detected about 1.5-2 times more often than men. Genetically determined variants of the pathological condition are transmitted by an autosomal dominant type.
Causes of angioedema
There are a huge number of external and internal factors contributing to the development of angioedema. The immediate cause of the pathology is changes in the complement system and a violation of some other physiological processes (blood coagulation, fibrinolytic and kinin reactions). In the vast majority of cases, the anomaly is caused by a deficiency or insufficient activity of the C1-inhibitor – blood protease, which slows down and stops a number of biochemical reactions in blood and tissues. This phenomenon occurs under the influence of the following factors:
- Genetic features. A significant part of the episodes of congenital angioedema is caused by a mutation of the SEPRING1 gene located on the 11th chromosome. It encodes the protein sequence of the C1 inhibitor, therefore, when this gene is changed, there is a protease deficiency or loss of its function.
- Lymphoproliferative pathologies. Some conditions with accelerated proliferation of lymphocytes or their progenitor cells (for example, lymphomas) may be accompanied by angioedema. The reason for this lies in the increase in the rate of destruction of the C1 inhibitor.
- Autoimmune reactions. Under certain conditions, antibodies to C1-esterase are formed, binding this enzyme and contributing to its destruction. The process can occur both in isolation and with systemic allergic reactions or other disorders.
A rare variant of the pathology is angioedema, which develops at an optimal level of C1-inhibitor – mainly the so-called estrogen-dependent edema is attributed to it. It is assumed that they are caused by genetic factors and are transmitted by a mechanism linked to the X chromosome, the course of the disease is aggravated when taking estrogen preparations. There is also a type of disease provoked by the use of angiotensin-converting enzyme inhibitors, which are part of numerous antihypertensive agents.
The deficiency of the C1 inhibitor that occurs for one reason or another leads to the activation of the complement system, increases the concentration of kallikrein and bradykinin. The latter stimulate the formation of vasoactive peptide compounds that affect vascular walls and smooth muscles. As a result, the precapillary arterioles first expand, then the plasma elements of the cell exit from the bloodstream into the intercellular space. Thus, a local angioedema is formed, manifested by a characteristic clinical picture. In addition, reactions of the bradykinin link can cause spasm of smooth muscle cells of the digestive and respiratory systems, disrupting their motility.
Taking into account the peculiarities of the clinical course in clinical allergology, all cases of angioedema are divided into two large groups – isolated and combined. The former are manifested only by swelling of subcutaneous fat and skin, the latter may be accompanied by urticaria, respiratory spasm and other symptoms. The separation is rather conditional, poorly reflects the causes of the disease. According to the etiological sign, hereditary and acquired forms of angioedema are distinguished. Congenital varieties account for approximately 2-5% of the total number of cases of the disease, include the following types:
- Type 1. Is caused by the almost complete absence of a C1 inhibitor, which occurs when the SEPRING1 gene is mutated. It is characterized by a rather severe course – generalization and severity of edema, their appearance not only on the skin, but also on the mucous membranes of the respiratory tract or digestive tract. It is registered in 85% of cases of hereditary angioedema.
- Type 2. Develops with a relative lack of an inhibitor due to its slow formation or reduced activity due to an incorrect enzyme structure. The clinic is less severe, edema affects mainly the tissues of the extremities, sometimes the face. This variant of the disease is diagnosed in 12-14% of patients with hereditary forms of angioedema.
- Type 3. Occurs extremely rarely, usually – against the background of the absence of a deficiency of C1-esterase. As a rule, it is represented by estrogen-dependent edema – exacerbations of pathology during pregnancy, taking combined oral contraceptives, substitution therapy during menopause.
All variants of hereditary angioedema are isolated, not accompanied by urticaria or other disorders. The acquired varieties have a different classification, which includes only two main types of the disease:
- Type 1. It is detected against the background of lymphoproliferative conditions – lymphomas, with some infectious lesions. The reason is an increase in the consumption of C1-inhibitor and its subsequent deficiency.
- Type 2. Occurs due to the synthesis of autoantibodies to the inhibitor, which dramatically reduces its concentration in the blood. This phenomenon occurs in some autoimmune and allergic conditions, immunodeficiency and other pathologies.
Symptoms of angioedema
The main symptom of pathology is the appearance of painless swelling of the skin of various sizes. Patients note a feeling of bursting and tension, there are no other subjective complaints. Unlike inflammatory edema, the affected area is characterized by a paler color than the surrounding skin areas and the absence of a local increase in tissue temperature. Most often, edematous manifestations are found on the upper and lower extremities, face (lips, cheeks, eyelids, auricles), neck, in the genital area. Skin itching is uncharacteristic, but can be determined by combining angioedema with urticaria.
In some patients, edema is detected in the area of the mucous membranes, sometimes the pathological process also affects the submucosal plate. The most frequently affected organs of the oral cavity (tongue, soft palate), respiratory tract, gastrointestinal tract. With the development of angioedema of the respiratory system organs, there is a feeling of lack of air, hoarseness or complete loss of voice, barking cough. Involvement of the gastrointestinal tract is manifested by a pronounced abdominal syndrome – pain, nausea, vomiting. There is a tension of the abdominal wall muscles, creating a false picture of peritonitis or acute intestinal obstruction.
Extremely rare symptoms of the disease are signs of pleural effusion (cough, chest pain, difficulty breathing). Other rare variants of pathology include local edema of the brain (depression of consciousness, hemiparesis is recorded), angioedema of the bladder (accompanied by acute urinary retention), muscle and joint damage. Isolated forms of the disease develop slowly for 12-48 hours. After that, in the absence of complications, a slow resolution of swelling occurs within 5-8 days. Some combined variants of angioedema (especially allergic genesis) can progress much faster – within a few minutes or hours.
The probability of complications in angioedema depends on the localization of the pathological process. Most often (about half of all complicated cases) patients have difficulty breathing due to narrowing of the larynx or bronchial lumen. In the absence of medical care, a violation can cause a fatal outcome. Abdominal forms of pathology are relatively dangerous, which can cause disorders of peristalsis with the development of obstruction and peritonitis. Often, edema of the gastrointestinal tract becomes the cause of unnecessary surgical intervention due to erroneous diagnosis. Brain damage can lead to coma and a number of neurological consequences (impaired coordination, speech, perception). Acute urinary retention with edematous phenomena in the bladder is the cause of fluid reflux, hydronephrosis and renal failure.
In most cases, the diagnosis of angioedema is made by an immunologist. Specialists of other fields – dermatologists, pediatricians, gastroenterologists, therapists – face this pathology less often. The definition of the disease is often difficult due to its diverse etiology and a very wide range of clinical manifestations. The main attention is paid to anamnestic information and the results of specific laboratory tests. Diagnosis of angioedema includes the following techniques:
- Survey and inspection. During external examination, the prevalence and localization of the edematous area are clarified, and the absence of soreness is confirmed. By the method of questioning, they find out what preceded the development of pathological manifestations (stress, the use of any products, taking medications), whether there were similar reactions in relatives.
- Laboratory tests. A specific method of diagnosing angioedema is to determine the level of a C1-inhibitor of blood plasma – its absence or a decrease in the amount indicates the presence of the disease. It is possible to determine the titer of antibodies to the C1 inhibitor – this technique allows you to find out whether the disease has an acquired autoimmune character.
- Additional research. When the respiratory system is affected, bronchoscopy and chest X-ray are performed. Usually, swelling of the laryngeal tissues, bronchospasm is detected, occasionally pleural effusion is detected. Ultrasound of the abdominal cavity organs makes it possible to differentiate abdominal forms of angioedema from peritonitis and other pathologies of the gastrointestinal tract.
In addition to the above methods, a huge number of various factors are taken into account when diagnosing this condition. For example, the age of the patient: hereditary varieties are more often found in people younger than 20 years, acquired forms – in people older than 40 years with a burdened history. Take into account the presence or absence of concomitant symptoms – urticaria, respiratory disorders. Differential diagnosis is carried out with edema of a different genesis – as a result of renal pathology, venomous insect bite, local allergic and inflammatory reactions.
Treatment of angioedema
Therapeutic measures for angioedema are divided into two groups – methods for relieving an acute attack and techniques for preventing its subsequent development. In both cases, similar medicinal substances are used – depending on the purpose of their appointment, only the intake scheme and dosage change. The following drugs are most often used for the treatment of angioedema in modern immunology:
- Androgens. Some analogues of male sex hormones (danazol, methyltestosterone) they are able to enhance the synthesis of C1-esterase in liver cells. They reduce the severity of the symptoms of pathology and reduce the likelihood of an attack of the disease in the future.
- Fibrinolysis inhibitors. Drugs that interfere with fibrinolytic processes also slow down the reactions of the kallikrein pathway. This reduces the rate of plasma diffusion in the tissue, reduces the likelihood of angioedema. The use of drugs of this group (e-aminocaproic or tranexamic acid) is carried out under the control of the state of the blood coagulation system.
- Freshly frozen plasma. Transfusion of donor plasma containing a C1-inhibitor is an effective method of relieving acute edema, especially of a hereditary nature.
In the presence of autoantibodies against complement components, their removal from the bloodstream using plasmapheresis is indicated. This is a temporary measure that can significantly weaken the severity of edematous manifestations. If the patient’s life is threatened (for example, due to airway obstruction), the introduction of adrenaline is recommended, and if it is ineffective, a conico- or tracheotomy is recommended. If the cause of angioedema was the presence of another disease (allergic, autoimmune or other nature), a treatment regimen is being developed according to the indications. There are also promising inhibitor drugs used in some countries for the treatment of this condition.
Prognosis and prevention
The prognosis of angioedema is considered uncertain until its etiology is clarified in a particular patient. With the hereditary nature of the pathology, there is always a risk of developing lethal laryngeal edema, so it is advisable for patients to have a card with an indication of the diagnosis. With proper preventive treatment, seizures occur rarely, do not pose a threat to the patient’s life. The prognosis of acquired forms depends on the nature of the underlying disease. Preventive measures include timely treatment of allergic and autoimmune conditions.