Alpha 1-antitrypsin deficiency overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mazia Fatima, MBBS [2]
Overview
Alpha 1-antitrypsin deficiency (A1AD or Alpha-1) is a genetic disorder caused by defective production of alpha 1-antitrypsin, deficient activity in the blood and lungs, and deposition of excessive amounts of abnormal A1AT protein in liver cells.[1] There are several forms and degrees of deficiency. Severe A1A deficiency causes emphysema and/or COPD in adult life in nearly all people with the condition, various liver diseases in a minority of children and adults, and occasionally more unusual problems.[2] It is treated by avoidance of damaging inhalants, by intravenous infusions of the A1AT protein, by transplantation of liver or lungs, and by a variety of other measures, but it usually produces some degree of disability and shortens life.
Historical Perspective
Alpha 1-antitrypsin deficiency (A1AD) was discovered in 1963 by Carl-Bertil Laurell (1919–2001) and Eriksson at the University of Lund, Sweden. In 1969, Sharp et al was the first to discover the association between liver disease and development of A1AD.
Classification
There is no established system for the classification of alpha 1-antitrypsin deficiency.
Pathophysiology
Alpha 1-antitrypsin (A1AT) is synthesized and secreted mainly by hepatocytes. However, other sources of the enzyme include macrophages and bronchial epithelial cells.Alpha1-antitrypsin enzyme is a member of the serine protease inhibitor (serpin) family of proteins. Alpha 1-antitrypsin (A1AT) protects the lungs from proteases like the neutrophil elastase enzyme.Genetic mutation in the SERPINA1 gene results in decreased levels of alveolar alpha1 antitrypsin. Proteases accumulate in the alveoli causing a destruction of alveolar walls and resultant emphysema. Excess alpha1-antitrypsin in hepatocytes results in chronic liver disease.SERPINA1 gene mutation alters the configuration of the alpha1-antitrypsin molecule and prevents its release from hepatocytes. By far, the most common severe deficient variant is the Z allele, which is produced by substitution of a lysine for glutamate at position 342 of the molecule. This accounts for 95% of the clinically recognized cases of severe alpha-1 AT deficiency.On cut section of the lung, emphysematous process is evidenced by dilated air spaces and loss of lung parenchyma. Superimposed infections can result in scarring. Panacinar emphysema is commonly associated with AATD with loss of all portions of the acinus from the respiratory bronchiole to the alveoli.In alpha1-antitrypsin deficiency (AATD), the emphysematous areas are uniformly distributed throughout the lobule found more commonly in the basilar portions of the lung.
Differentiating Alpha 1-antitrypsin deficiency from Other Diseases
Alpha 1-antitrypsin deficiency has to be differentiated from other conditions with similar presentation like autoimmune hepatitis, bronchiectasis, bronchitis, chronic obstructive pulmonary disease (COPD),cystic fibrosis,emphysema,primary ciliary dyskinesia (Kartagener Syndrome),viral hepatitis.
Epidemiology and Demographics
Alpha 1-antitrypsin deficiency (A1AD) is more common in people of Northern European, Iberian, and Saudi Arabian descent. Most researchers believe it is markedly underrecognized.The incidence of AATD is estimated to be 20 cases per 100,000 individuals worldwide.The prevalence of AATD is estimated to be 70,000-100,000 cases annually. Alpha1-antitrypsin deficiency (AATD) is one of most common lethal genetic diseases among adult white population. AATD has estimated 117 million carriers and 3.4 million affected individuals.AATD is more prevalent among the white population.Alpha 1-antitrypsin deficiency (A1AD) is more common in people of Northern European, Iberian, and Saudi Arabian descent. Most researchers believe it is markedly under-recognized.Men and women are affected equally by AATD.
Risk Factors
First degree relatives of patients with known AAT deficiency are at an increased risk for the condition. Smoking is risk factor for development of serious lung disease in patients with AAT deficiency. Risk for lung disease also increases with exposure to dust, fumes, or other toxic substances.
Screening
According to the Spanish Society of Pneumology and Thoracic Surgery (SEPAR), All COPD patients should be screened for AATD at least once in their lifetime.All patients with unexplained liver disease with or without respiratory symptoms should be evaluated for AATD.
Natural History, Complications, and Prognosis
If left untreated, not all patients with deficient gene develop symptomatic emphysema or cirrhosis.In symptomatic patients, the median time between observation of symptoms and diagnosis is approximately 8 years.The symptoms of alpha1-antitrypsin deficiency (AATD) in the first two decades of life are mainly of associated liver disease progressing to pulmonary manifestations appear later in life.Emphysema, is seen in nonsmokers in the fifth decade of life and during the fourth decade of life in smokers.Less common associations are panniculitis and cytoplasmic antineutrophil cytoplasmic antibody‒positive vasculitis.The most common cause of death is emphysema. chronic liver disease is the second most common cause of death.Common complications of AATD include pneumothorax,pneumonia, acute exacerbation of airflow obstruction,respiratory failure.Prognosis depends on how patients are identified. Patients identified as a result of screening often have excellent prognosis.Those identified because of their symptoms have poor prognosis.
Diagnosis
Diagnostic Criteria
History and Symptoms
Physical Examination
Physical examination of patients with AATD is usually remarkable for signs characteristic of increased respiratory work,airflow obstruction and hyperinflation that varies according to the severity of emphysema.Patients with mild emphysema usually have no abnormal findings on physical examination.Patient may appear normal.Those with severe emphysema develop tachypnea and pursed-lip breathing. Other findings on physical examination include pulsus paradoxus,scalene muscle retraction,intercostal muscle retraction,wheezing,hepatomegaly,hyperinflation results in barrel chest,increased percussion note,decreased breath sound intensity,distant heart sounds.