Deficiency of alpha1-antitrypsin

Deficiency of alpha 1-antitrypsin is a congenital deficiency of predominantly pulmonary antiproteinase alpha-1 antitrypsin, leading to increased protease destruction of tissue and emphysema in adults. Accumulation in the liver of pathological alpha-1 antitrypsin can cause liver disease in both children and adults. Serum antitrypsin level less than 11 mmol / l (80 mg / dl) confirms the diagnosis. Treatment of a deficiency of alpha1-antitrypsin involves smoking cessation, bronchodilators, early treatment of infection and, in some cases, substitution therapy with alpha1-antitrypsin. Severe liver disease may require transplantation.

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

Epidemiology of deficiency of alpha1-antitrypsin

More than 95% of people with severe deficiency of alpha1-antitrypsin and emphysema are homozygous for the Z (PI * ZZ) allele and have alpha-antitrypsin levels of approximately 30-40 mg / dL (5-6 μmol / L). The prevalence in the general population is 1 for 1500-5000. The most affected are the Caucasians of Northern Europe; allele Z is rare in natives of Asia and representatives of the Negroid race. Although emphysema often occurs in patients with PI * ZZ, many non-smoking homozygotes do not develop emphysema; those who develop emphysema usually have a family history of COPD. Smokers PI * ZZ have a lower life expectancy than non-smokers PI * ZZ, and for both, life expectancy is less than for non-smokers and smokers PI * MM. Non-smoking PI * MM heterozygotes may have an increased risk of developing a faster decline in FEV in the course of time than normal individuals.

Other rare phenotypes include PI * SZ and 2 types with unexpressed alleles, PI * Z-null and Pl * null-null. The null phenotype leads to undetectable serum levels of alpha1-antitrypsin. Normal serological levels of low-function alpha1-antitrypsin can be detected with rare mutations.

[6], [7], [8], [9], [10]

What causes a deficiency of alpha1-antitrypsin?

Alpha-1 antitrypsin is an inhibitor of neutrophil elastase (antiprotease), the main function of which is to protect the lungs from protease-mediated tissue destruction. Most of the alpha1 antitrypsin is synthesized by the liver cells and monocytes and passes passively through the bloodstream into the lungs; some part is secondarily produced by alveolar macrophages and epitheliocytes. The structure of the protein (and, hence, the functionality) and the amount of circulating alpha1-antitrypsin is determined by the codominant expression of parental alleles; more than 90 different alleles were identified and described by the phenotype of a protease inhibitor (PI *).

The inheritance of some variants of alleles causes changes in the structure of the alpha1-antitrypsin molecule, which lead to its polymerization and retention in hepatocytes. Hepatic accumulation of aberrant molecules of alpha 1 -antitrypsin causes cholestatic jaundice of newborns in 10-20% of patients; in others, the pathological protein is likely to be destroyed, although the exact defense mechanism is not completely clear. Approximately 20% of cases of liver damage in newborns lead to the development of cirrhosis in childhood. Approximately 10% of patients who had no liver disease as a child develop cirrhosis of the liver in adulthood. Involving the liver increases the risk of liver cancer.

In a mild deficiency of alpha1-antitrypsin increases the activity of neutrophil elastase, it contributes to the destruction of pulmonary tissue leading to emphysema (especially in smokers, since cigarette smoke also increases protease activity). Deficiency of alpha1-antitrypsin is believed to be responsible for 1-2% of all COPD cases.

Other disorders possibly associated with alpha1 antitrypsin variants include panniculitis, life-threatening bleeding (due to a mutation that redirects the inhibitory effect of alpha 1 -antitrypsin from neutrophil elastase to coagulation factor), aneurysms, ulcerative colitis and glomerulonephritis.

Deficiency Symptoms of Alpha-Antitrypsin

Infants with liver damage have cholestatic jaundice and hepatomegaly during the first week of life; jaundice is usually resolved until two or four months of age. Cirrhosis of the liver can develop in childhood or in adulthood.

Deficiency of alpha1-antitrypsin usually causes early emphysema; symptoms of deficiency of alpha 1-antitrypsin are the same as in COPD. Involvement in the lung process occurs earlier in smokers than in non-smokers, but in both cases it rarely develops until the age of 25 years. The severity of the damage to the lungs varies greatly; The pulmonary function is well preserved in some PI * ZZ smokers and can be seriously impaired in some non-smoking PI * ZZ. People PI * ZZ, identified in population studies (that is, without symptoms or pulmonary diseases), have a better pulmonary function, regardless of whether they smoke or not, in comparison with the identified patients (which were detected due to the presence of pulmonary diseases). People from the group not identified, with severe deficiency of antitrypsin, who have never smoked, have a normal life expectancy and only slight deterioration of pulmonary function. Obstruction of the respiratory tract is more common in men and people with bronchial asthma, repeated infections of the respiratory tract, occupational exposure to dust and a family history of pulmonary diseases. The most common cause of death in the deficit of alpha1-antitrypsin is emphysema, followed by cirrhosis, often with liver cancer.

Panniculitis - an inflammatory disease of the subcutaneous soft tissue - manifests as indurated, tender, discolored spots or nodules, usually on the lower part of the abdominal wall, buttocks and thighs.

[11], [12], [13]

Diagnosis of alpha1 antitrypsin deficiency

Deficiency of alpha1-antitrypsin is suspected in smokers who develop emphysema up to 45 years; in non-smokers without occupational hazards, who develop emphysema at any age; in patients with emphysema mainly in the lower lobes (according to chest radiography); in patients with a family history of emphysema or unexplained cirrhosis; in patients with panniculitis; in newborns with jaundice or increased liver enzymes and in any patient with unexplained liver disease. The diagnosis is confirmed by the serum level of alpha1-antitrypsin (<80 mg / dL or <11 μmol / L).

[14], [15], [16], [17], [18]

Treatment of deficiency of alpha1-antitrypsin

Treatment of the pulmonary form of the disease is performed by purified human alpha 1 antitrypsin (60 mg / kg intravenously for more than 45-60 minutes, administered once a week, or 250 mg / kg for more than 4-6 hours, administered once a month) which can maintain serum alpha 1 antitrypsin levels above the target protective level of 80 mg / dl (35% of the norm). Since emphysema leads to permanent structural changes, therapy can not improve the damaged lung structure or function, but is performed to stop progression. Treatment of deficiency of alpha1-antitrypsin is extremely expensive and is therefore intended for non-smoking patients with minor or moderate pathological changes in pulmonary function and a serum level of alpha1-antitrypsin <80 mg / dL (<11 μmol / L). Treatment of a deficiency of α1-antitrypsin is not prescribed for patients with severe disease or with a normal or heterozygous phenotype.

Cessation of smoking, the use of bronchodilators and the early treatment of respiratory infections are especially important for alpha 1-antitrypsin-deficient patients with emphysema. Experimental preparations such as phenylbutyric acid, which can completely change the metabolism of pathological antitrypsin proteins in hepatocytes, thus stimulating the release of proteins, are at the research stage. For people with severe deficiency under the age of 60 years, it is necessary to consider a variant of lung transplantation. The reduction in lung volume for the treatment of emphysema with antitrypsin deficiency is controversial. Gene therapy is at the research stage.

Treatment of liver disease is effective. Replacement enzyme therapy is ineffective, since the deficit of alpha1-antitrypsin is caused by pathological metabolism, rather than by enzyme deficiency. Patients with hepatic insufficiency can undergo liver transplantation.

Treatment of panniculitis is not developed enough. Glucocorticoids, antimalarials and tetracyclines are used.

What prognosis is deficiency of alpha1-antitrypsin?

Deficiency of alpha1-antitrypsin has a different prognosis. It is mainly associated with the degree of lung damage.