Alpha-1 Antitrypsin Deficiency

Clinical characteristics: Alpha-1 antitrypsin deficiency (AATD) can present with hepatic dysfunction in individuals from infancy to adulthood and with chronic obstructive lung disease (emphysema and/or bronchiectasis), characteristically in individuals older than age 30 years. Individuals with AATD are also at increased risk for panniculitis (migratory, inflammatory, tender skin nodules which may ulcerate on legs and lower abdomen) and C-ANCA-positive vasculitis (granulomatosis with polyangiitis). Phenotypic expression varies within and between families. In adults, smoking is the major factor in accelerating the development of COPD; nonsmokers may have a normal life span, but can also develop lung and/or liver disease. Although reported, emphysema in children with AATD is extremely rare. AATD-associated liver disease, which is present in only a small portion of affected children, manifests as neonatal cholestasis. The incidence of liver disease increases with age. Liver disease in adults (manifesting as cirrhosis and fibrosis) may occur in the absence of a history of neonatal or childhood liver disease. The risk for hepatocellular carcinoma (HCC) is increased in individuals with AATD.

Diagnosis/testing: The diagnosis of AATD relies on demonstration of low serum concentration of alpha-1 antitrypsin (AAT) and either identification of biallelic pathogenic variants in SERPINA1 or detection of a functionally deficient AAT protein variant by protease inhibitor (PI) typing. Note: The unconventional nomenclature of SERPINA1 alleles is based on electrophoretic protein variants that were identified long before the gene (SERPINA1) was known. Alleles were named with the prefix PI* (protease inhibitor*) serving as an alias for the gene. Using this nomenclature, the most common (normal) allele is PI*M and the most common pathogenic allele is PI*Z.

Management: Treatment of manifestations: COPD is treated with standard therapy. Augmentation therapy with periodic intravenous infusion of pooled human serum alpha-1 antitrypsin (AAT) is used in individuals who have established emphysema. Lung transplantation may be an appropriate option for individuals with end-stage lung disease. Liver transplantation is the definitive treatment for severe disease (will restore AAT levels). Dapsone or doxycycline therapy is used for panniculitis; if refractory to this, high-dose intravenous AAT augmentation therapy is indicated.

Surveillance: Every six to 12 months: pulmonary function tests including spirometry with bronchodilators and diffusing capacity measurements; liver function tests, platelet count and liver ultrasound, elastography (e.g., FibroScan), magnetic resonance imaging.

Agents/circumstances to avoid: Smoking (both active and passive); occupational exposure to environmental pollutants used in agriculture, mineral dust, gas, and fumes; excessive use of alcohol.

Evaluation of relatives at risk: Evaluation of parents, older and younger sibs, and offspring of an individual with severe AATD in order to identify as early as possible those relatives who would benefit from institution of treatment and preventive measures.

Genetic counseling: AATD is inherited in an autosomal codominant manner. If both parents are heterozygous for one SERPINA1 pathogenic variant (e.g., PI*MZ), each sib of an affected individual has a 25% chance of being affected (PI*ZZ), a 50% chance of being heterozygous (PI*MZ), and a 25% chance of inheriting neither of the pathogenic variants (PI*MM). In the less frequent instance in which one parent is homozygous (PI*ZZ) and one parent is heterozygous (PI*MZ), the risk to each sib of being homozygous (PI*ZZ) is 50%. Unless an individual with AATD has children with an affected individual or a heterozygote, offspring will be obligate heterozygotes for a pathogenic variant. (Risk of lung disease may be increased in heterozygous individuals depending on their environmental exposures such as smoking.) Heterozygote testing for at-risk family members and prenatal and preimplantation genetic testing are possible once the pathogenic SERPINA1 variants have been identified in the family.