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Alpha-1 Antitrypsin Deficiency: Pathogenesis, Clinical Presentation, Diagnosis, and Treatment

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Abstract

Alpha-1 antitrypsin deficiency is an inherited disease affecting the lung and liver. The typical pulmonary manifestation is chronic obstructive pulmonary disease and emphysema. Severe chronic obstructive pulmonary disease may occur in young adulthood, and terminal respiratory insufficiency causes premature death in many patients. In the liver, alpha-1 antitrypsin deficiency may manifest as benign neonatal hepatitis syndrome; a small percentage of adults develop liver fibrosis, with progression to cirrhosis and hepatocellular carcinoma. The alpha-1 antitrypsin molecule is a serine protease inhibitor that is predominantly produced in the liver. Its most important physiologic functions are the protection of pulmonary tissue from aggressive proteolytic enzymes and regulation of pulmonary immune processes. Diagnosis of alpha-1 antitrypsin deficiency can be established by measurement of the serum alpha-1 antitrypsin concentration or by genetic analysis. Treatment is similar to the usual treatment for patients with chronic obstructive pulmonary disease. A further option is substitution therapy with human alpha-1 antitrypsin. The targets of treatment are the prevention of the accelerated decline of pulmonary function, reduction of lung infections, and improvements in exercise capacity.

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Genetics and Biology

Alpha-1 antitrypsin deficiency is an autosomal recessive disease. The SERPINA1 gene (formerly known as PI), which encodes the alpha-1 antitrypsin protein, is 12.2 kb and located on the long arm of chromosome 14 (14q31-32.3). The gene is highly pleomorphic, and to date more than 100 allelic variants have been identified. The variants can broadly be classified according to their effects on levels of serum alpha-1 antitrypsin protein. The M alleles (M1 to M6) are the most common and are defined as

Prevalence

Caucasians of Europe and North America have the highest allele frequencies for alpha-1 antitrypsin deficiency globally.4 Prevalence estimates for typical deficiency genotypes of the disease are presented in Table 1. In all countries, however, the number of clinically identified patients is far less than the anticipated prevalence based on allele frequencies. It is estimated that 10% to 35% of individuals with homozygous ZZ genotypes do not exhibit clinical symptoms.5 The reasons underlying the

Pathophysiology

In patients with the ZZ variant, alpha-1 antitrypsin proteins have a substitution of lysine for glutamic acid at position 342 of the amino acid sequence. This results in abnormalities in the tertiary structure of the molecule. Protein synthesis in the rough endoplasmic reticulum of hepatocytes is delayed so that approximately 85% of synthesized molecules polymerize into large conglomerates.7 These polymers cannot be processed further and accumulate in the rough endoplasmic reticulum. Only a few

Clinical Manifestations of Alpha-1 Antitrypsin Deficiency

Clinical manifestations are always present in patients with complete absence of serum alpha-1 antitrypsin (null variants). The majority of patients with ZZ or SZ genotypes, and some with the SS genotype, have pulmonary or hepatic symptoms. Heterozygous individuals, with both a normal and a variant allele (eg, MZ or MS) rarely develop clinical symptoms (Table 2). The role of “modifier genes,” which may influence the course of the disease, is still under debate.16

In most patients with symptomatic

Diagnosis of Alpha-1 Antitrypsin Deficiency

Any suspicion of alpha-1 antitrypsin deficiency can be confirmed or rejected by measurement of the serum alpha-1 antitrypsin concentration (Table 3). Because alpha-1 antitrypsin is an acute-phase protein, its synthesis may be up-regulated during all states of inflammation. It is therefore recommended that C-reactive protein levels are determined simultaneously, and that alpha-1 antitrypsin concentration results are rejected if C-reactive protein levels are abnormal.

Because of the variability in

Prophylaxis

The most important prophylactic measure is smoking cessation. Passive smoking and exposure to other toxic air pollutants may accelerate pulmonary disease. All occupations that expose individuals to high concentrations of dust or other airborne particles should be avoided. Regular lung function tests are recommended for early recognition of airway obstruction. Vaccination against pneumococci and annual influenza vaccination may reduce the incidence of airway infections, and hepatitis A and B

Treatment

Treatment of the lung manifestations of alpha-1 antitrypsin deficiency does not differ from standard treatment of COPD.30, 31 Medical treatment consists of chronic application of the long-acting beta-2 agonists, formoterol or salmeterol, combined with the long-acting anticholinergic tiotropium. The benefit of inhaled steroids is widely debated, but the recently published TORCH (TOwards a Revolution in COPD Health) trial did not reveal that inhaled steroids or a combination of salmeterol with

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