Alpha-1-antitrypsin deficiency is a hereditary disease resulting from a lack of a protein enzyme that prevents the destructive effect of proteases on lung tissue. In newborns, cholestasis syndrome manifests itself, later cirrhosis of the liver develops with characteristic symptoms. In adults, bronchial obstruction syndrome, pulmonary emphysema are detected, less often – symptoms of liver failure. The diagnosis is confirmed by determining the level of alpha-1-antitrypsin in the blood, by genetic methods. Hepatoprotectors, bronchodilators, corticosteroids are prescribed, replacement therapy is carried out. In severe cases, transplantation of damaged organs is performed.
E88.0 Disorders of plasma protein metabolism, not classified
Alpha-1-antitrypsin deficiency develops as a result of a gene mutation and may occur with predominant liver damage in children or lung damage in adults. Cholestatic jaundice occurs in 20% of all newborns with a lack of alpha-1-antitrypsin, and subsequently cirrhosis of the liver is detected in some of them. Antiprotease deficiency causes COPD in approximately 2% of all sufferers of this disease. However, in many patients with chronic obstructive pulmonary disease, the necessary genetic studies have not been carried out. The prevalence of pathology is insufficiently studied. According to available statistics, protease inhibitor deficiency is more common in people of the Caucasian race. The incidence among European residents is 1 per 1500-5000 people.
The gene mutation causing antiprotease deficiency is inherited by autosomal recessive or codominant type. A gene located on chromosome 14 is responsible for the production and release of alpha-1-antitrypsin. This gene is polymorphic. There are more than 500 different forms of it – alleles. There are the following main variants of damaged alleles responsible for various mechanisms of pathology:
- Scarce. With such a mutation, enough alpha-1-antitrypsin is synthesized. Its ability to penetrate the cytoplasmic membrane decreases. The secretion of the enzyme into the bloodstream is disrupted, it enters there in a minimal amount. As a result, antiprotease accumulates in liver cells, damaging them.
- Zero. Deficiency occurs due to the synthesis of defective and unstable antiprotease. The enzyme breaks down quickly before it is released into the bloodstream. It does not have a damaging effect on liver cells. With this pathology, pulmonary emphysema develops early. Null alleles are the rarest mutation of the gene encoding the production of a protease inhibitor.
- Dysfunctional. In this case, a normal amount of protease inhibitor is produced and enters the bloodstream. The properties of the enzyme itself are violated. Antiprotease activity is reduced or completely lost. With some mutations, the enzyme acquires other qualities, for example, similarity to antithrombin and the ability to cause fatal bleeding.
Smoking has a great influence on the development of pulmonary pathology against the background of a lack of alpha-1-antitrypsin. Tobacco smoke increases the activity of proteases and enhances the destruction of alveolar tissue. The deficiency of the protein protecting the lung tissue in smokers leads to emphysema and COPD much earlier than in non-smokers with the same genetic defect.
The main function of the antiprotease enzyme is to inhibit the destructive action of neutrophil elastase and some other proteases released during stressful situations. Its deficiency leads to a decrease or absence of such protection of the pulmonary parenchyma. There is a gradual destruction of the interalveolar septa, emphysema and emphysematous variant of COPD occur. In the presence of deficient alleles in the human genotype, the enzyme accumulates in large quantities at the site of its synthesis – hepatocytes. Excess antiprotease damages liver cells and causes liver cirrhosis and hepatocellular cancer.
The manifestations of the disease differ somewhat in adulthood and childhood. The clinical picture directly depends on the nature of the genetic defect. However, both liver damage and impaired respiratory system functions can occur in any age group. In clinical pulmonology and hepatology, alpha-1-antitrypsin deficiency is divided into the following variants:
- With a predominant hepatobiliary lesion. It occurs more often in children. Signs of the disease appear in the first 4 months of life.
- With a predominant lesion of the lungs. Pathology is more often detected in adults. This genetic disease is also detected in some children suffering from bronchial asthma.
- With a combined defeat. Occurs with severe enzymatic insufficiency. Characteristic clinical symptoms are observed in early childhood.
A significant deficiency of an inhibitor of the activity of proteolytic enzymes is manifested by cholestatic syndrome already in the newborn period. The skin, sclera of the baby acquire a jaundice color. In some cases, the child has vomiting, hemorrhagic rashes. Cholestasis usually resolves by 3-4 months of age, sometimes there is a progression of the process with the formation of liver failure.
Signs of damage to the hepatobiliary system may occur later in childhood, adolescence or adulthood. The patient has pain in the right hypochondrium, accompanied by nausea, sometimes vomiting, flatulence, decreased appetite. Worries about unmotivated weakness, increased fatigue. The skin and visible mucous membranes turn yellow, skin itching joins. Complications characteristic of cirrhosis of the liver are gradually developing. Violations of the function of the respiratory system occur in isolation, or are accompanied by liver failure.
The main manifestation of respiratory damage is shortness of breath. At first, it occurs when running, climbing stairs above the 3rd floor, sports loads. Over time, the difficulty of breathing gradually progresses and worries the patient with little activity and at rest. Other symptoms of enzymatic insufficiency include an unproductive cough, attacks of suffocation with difficulty whistling exhalation. Enzyme deficiency is characterized by early (up to 40-45 years of age) development of emphysema or COPD, including in non-smokers and non-harmful production patients. Sometimes the disease debuts with the occurrence of spontaneous pneumothorax.
Sometimes enzymatic insufficiency of alpha-1-antitrypsin leads to the development of necrotizing panniculitis. The patient is concerned about the appearance of subcutaneous nodular formations. The skin above them acquires a purplish-bluish color. Nodes are usually located on the upper and lower extremities, but can form on any part of the human body. They are painful, have a tendency to merge, are suppressed and open, leaving sinking scars.
With a predominant lesion of the respiratory system, the alpha-1-antitrypsin deficiency is complicated by the formation of a pulmonary heart. The timing of the occurrence of this complication largely depends on the genotype of the patient. With a significant deficiency of the enzyme, pulmonary heart failure develops in childhood, adolescence or in young adults. A less pronounced deficiency in non-smokers who are not regularly exposed to aeropollutants does not affect life expectancy. Damage to the hepatobiliary system develops in some patients with deficient alleles. Cirrhotic liver changes occur in approximately 20% of children and 10% of adults with a history of cholestatic jaundice. Often, a genetic defect causes hepatocellular cancer and lung carcinoma.
Patients with alpha-1-antitrypsin deficiency should be examined by a pulmonologist and a hepatologist. An important stage of diagnostic measures is the collection of anamnesis. If COPD or emphysema is detected in persons younger than 45 years, bronchiectasis of unclear etiology, the presence of therapy-resistant bronchial asthma, idiopathic cirrhosis of the liver, necrotizing panniculitis, a consultation with a geneticist is indicated. Diseases of the hepatobiliary system and (or) respiratory tract in the patient’s relatives are an indirect sign of a lack of antiprotease. The final confirmation of the diagnosis is carried out using:
- Laboratory tests. The quantitative content of serum alpha-1-antitrypsin is determined. When using the immunoturbodimetry method, normal values are in the range of 0.9 – 2 g / l, when measured using nephelometry – 2-4 g / liter.
- Genetic research. The molecular structure of alpha-1-antitrypsin is determined by phenotyping. Isoforms of the enzyme are revealed, confirming its insufficiency in the human body. DNA testing helps to determine the type of gene mutation in the patient and his relatives and to identify the degree of risk of hereditary transmission of the disease.
- Instrumental diagnostics. On an X-ray of a patient with a pulmonary or combined form of a deficiency condition, an increase in the airiness of the pulmonary parenchyma is determined mainly in the basal parts. Ultrasound, CT or MRI of the abdominal cavity can reveal hepatosplenomegaly, signs of hepatic fibrosis.
- Liver biopsies. When examining a liver biopsy using electron microscopy, alpha-1-antitrypsin granules in hepatocytes of the periportal zone are determined. With age and as the pathological process progresses, the size and number of granules increase.
The only etiotropic method of treating antiprotease deficiency with severe damage to the respiratory tract is substitution therapy. Intravenous administration of purified human alpha-1-antitrypsin is performed. Such treatment is not indicated for patients with damage to the hepatobiliary zone, as this does not prevent the development of cirrhosis. Research is underway on the stimulation of antiprotease production by liver cells, gene therapy. Patients with respiratory pathology are prescribed pathogenetic therapy with bronchodilators and corticosteroids, patients with hepatic manifestations – hepatoprotectors. In severe hepatic insufficiency, liver transplantation is possible, in pulmonary-cardiac insufficiency, heart–lung organocomplex transplantation is possible.
Prognosis and prevention
The prognosis of alpha-1-antitrypsin deficiency largely depends on the genetic characteristics of the patient and therapeutic measures. In the absence of treatment, the prognosis for any variant of the course of the disease is unfavorable. Hepatic or respiratory-heart failure early lead to profound disability. Secondary prevention is of great importance for patients with pulmonary forms of the disease. They need to give up smoking, work in harmful conditions is contraindicated. You should be vaccinated against influenza and pneumococcal infection. Patients with hepatobiliary manifestations need vaccination against viral hepatitis. It is mandatory to abstain from alcohol and follow a liver-sparing diet.