Overall Bottom Line
- Alpha-1 antitrypsin (AAT) deficiency is an inherited disease primarily affecting the lungs and liver, which is most often due to a defect in the release of AAT from hepatocytes into the circulation.
- Diagnosis involves measurement of serum levels of AAT along with determination of the phenotype or genotype.
- Apart from liver transplantation, specific liver-related treatment is not available but enzyme replacement therapy is available for those with lung disease.
Section 1: Background
Definition of disease
- AAT deficiency is a rare autosomal codominant disorder due to mutation in the SERPINA1 gene.
- The most common manifestation is emphysema, which becomes evident by the third to fourth decade. Liver disease is a less common manifestation of the deficiency and may affect children and adults.
Disease classification
- At least 100 alleles of SERPINA1 have been identified. On the basis of plasma levels and function of AAT, alleles are classified into four basic groups.
- Normal – normal allele (M type), phenotype (MM). It is associated with normal levels (>20 mol/L) and function of AAT.
- Deficient – deficient alleles (Z type) and (S type), phenotype (ZZ) and (SS) respectively. The Z allele is carried by approximately 2–3% of the White population in the USA. The homozygous ZZ phenotype is associated with a high risk of both emphysema and liver disease. The S type, which is mainly found in the Mediterranean area, is not associated with liver disease.
- Dysfunctional – dysfunctional alleles produce a normal quantity of AAT protein but the protein does not function properly. Liver disease is less common in this group.
- Null – null alleles are associated with no detectable AAT protein in the plasma. Lung disease is the most severe in this group, but they do not develop liver disease.
- Normal – normal allele (M type), phenotype (MM). It is associated with normal levels (>20 mol/L) and function of AAT.
Prevalence
- In the USA approximately 100 000 individuals (1 in 2000 to 8000 population) are severely affected (phenotype ZZ, SZ). The overall prevalence of AAT deficiency may be as high as 1 in 300, but disease penetrance is less than 100%.
- AAT deficiency is equally common in men and women.
- White people are more commonly affected than other races.
Economic impact
- Due to the limited number of affected individuals the overall economic impact of AAT deficiency is not significant though the costs for individual treatment can be high.
- Most of the costs are due to repeated hospitalizations for those with emphysema.
- AAT protein replacement therapy is an expensive intervention ($30 000–$40 000 per patient annually).
- AAT deficiency and WD combined account for less than 5% of liver transplants each year.
- According to the UNOS each liver transplant costs $314 600 on average with annual follow-up care costs averaging $21 900.
Etiology
- AAT deficiency is an inherited autosomal codominant disease caused by mutation in the SERPINA1 gene (locus 14q32.1). Homozygosity for the Z allele is the most common disease phenotype.
- Environmental (e.g. smoking) and genetic cofactors affect disease penetrance.
Pathology/pathogenesis
- AAT is a serine proteinase (elastase) inhibitor and acute phase protein produced by hepatocytes.
- In patients homozygous for the Z type allele, the AAT polypeptide chain undergoes abnormal conformational changes resulting in polymerization and accumulation of AAT within the hepatocyte endoplasmic reticulum. This disrupts the normal cellular protein synthesis leading to oxidative stress and progressive liver injury.
- About 10% of newborn ZZ homozygotes develop liver disease that often leads to fatal childhood cirrhosis. However, overall only 12–15% of individuals with this phenotype develop liver disease, implying that other cofactors modulate protein accumulation and oxidative stress due to AAT polymerization.
- A lag in degradation of polymerized AAT may be specific for the development of liver disease in ZZ homozygotes.
- AAT deficiency causes unopposed activation of neutrophilic elastases in the lung, leading to progressive emphysema.
- Smoking and environmental or occupational toxin exposure is known to exacerbate lung damage due to AAT deficiency.
Predictive/risk factors
- SERPINA1 gene mutations – but disease penetrance is less than 100%.
- More common in people of northern European, North American and Iberian descent.
- Smoking and environmental and occupational toxin exposure increase progression of lung disease in AAT deficiency patients.
- Hepatic inflammation/oxidative stress worsen liver disease due to AAT deficiency.
Section 2: Prevention
- Avoid tobacco smoke and environmental/occupational toxin exposure.
- Avoid alcohol use.
Screening
- It is immensely important to screen patients for AAT deficiency since avoidance of risk factors can prevent progression of disease. It is not cost-effective to screen the general population. The AASLD and EASL have no practice guidelines for AAT deficiency. According to American and European Lung Societies, AAT screening is recommended in the following circumstances:
- Early-onset pulmonary emphysema (regardless of smoking history).
- Dyspnea and cough occurring in multiple family members in the same or different generations.
- Family members of known AAT deficiency patients.
- Liver disease of unknown cause.
- All subjects with chronic obstructive pulmonary disease.
- Adults with bronchiectasis without evident etiology.
- Patients with asthma whose spirometry fails to return to normal with therapy.
- Unexplained panniculitis and anti–proteinase-3 vasculitis.
- Early-onset pulmonary emphysema (regardless of smoking history).
Primary prevention
- Genetic counseling for couples may be helpful though no recommendations exist.
- For newborns with known ZZ phenotype, avoidance of oxidative stress limits liver damage.
- Onset of symptoms can be prevented by avoidance of smoking and environmental and occupational toxins.
Secondary prevention
- Recurrent symptoms can be minimized by avoidance of smoking and environmental and occupational toxins.
Section 3: Diagnosis (Algorithm 17.1)
Clinical Pearls
- AAT deficiency should be suspected in any person who presents with unexplained liver or respiratory symptoms.
- The gold standard for diagnosis is AAT phenotype determination (e.g. MM, ZZ) by serum protein isoelectric focusing.
- Measurement of serum AAT activity is not diagnostic.
- SERPINA1 genetic analysis is rarely necessary.
Differential diagnosis
| Differential diagnosis | Features |
|---|---|
| Bronchiectasis | History of chronic respiratory symptoms, such as a cough and viscous sputum production, along with CT findings such as bronchial wall thickening and luminal dilatation. AAT phenotype is normal |
| Chronic bronchitis | Cough with sputum production for at least 3 months a year in two consecutive years. AAT phenotype is normal |
| Viral hepatitis | History of travel, needle sharing, tattoo. Positive viral serological markers along with a normal AAT phenotype |
| AIH | More common in younger women. Positive serum ANA or ASMA and a normal AAT phenotype |
Related posts:
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25: Pregnancy-Related Liver Disease
38: Liver Transplantation: A Pediatric Perspective
36: Approach to Jaundice in Infancy
53: Recurrent Disease Post-Liver Transplantation: Autoimmune Diseases, Hepatitis B and NASH
34: Diagnosis and Management of Acute Liver Failure: A Pediatric Perspective
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