Alpha 1-antitrypsin deficiency

Alpha 1-antitrypsin deficiency (A1AD or Alpha-1) is a genetic disorder caused by reduced levels of alpha 1-antitrypsin in the blood. It can lead to emphysema and, in some cases, to liver disease.

Signs and symptoms

Symptoms of alpha-1 antitrypsin deficiency include shortness of breath, recurring respiratory infections, or obstructive asthma that does not respond to treatment. Individuals with alpha-1 may develop emphysema during their thirties or forties, without a history of significant smoking (although smoking greatly increases the risk for emphysema). A1AD also causes impaired liver function in some patients and may lead to cirrhosis and liver failure (15%). It is the leading cause of liver transplantation in newborns.

Pathophysiology

Please see alpha 1-antitrypsin for a discussion of the various genotypes and phenotypes associated with A1AD.

Alpha 1-antitrypsin (AAT) is produced in the liver, and one of its functions is to protect the lungs from the neutrophil elastase enzyme. Normal blood levels of alpha-1 antitrypsin are 1.5-3.5 gm/l. In individuals with PiSS, PiMZ and PiSZ phenotypes, blood levels of AAT are reduced to between 40 and 60 % of normal levels. This is sufficient to protect the lungs from the effects of elastase in people who do not smoke. However, in individuals with the PiZZ phenotype, AAT levels are less than 15 % of normal, and patients are likely to develop emphysema at a young age; 50 % of these patients will develop liver cirrhosis, because the A1AT is not secreted properly and instead accumulates in the liver. A liver biopsy in such cases will reveal PAS-positive, diastase-negative granules.

Cigarette smoke is especially harmful to individuals with A1AD. In addition to increasing the inflammatory reaction in the airways, cigarette smoke directly inactivates alpha 1-antitrypsin by oxidizing essential methionine residues to sulfoxide forms, decreasing the enzyme activity by a rate of 2000.

Treatment

In the United States, Canada, and several European countries, lung-affected A1AD patients may receive intravenous infusions of alpha-1 antitrypsin, derived from donated human plasma. This augmentation therapy is thought to arrest the course of the disease and halt any further damage to the lungs. Long-term studies of the effectiveness of AAT replacement therapy are not available. It is currently recommended that patients begin augmentation therapy only after the onset of emphysema symptoms.

Augmentation therapy is not appropriate for liver-affected patients; treatment of A1AD-related liver damage focuses on alleviating the symptoms of the disease. In severe cases, liver transplantation may be necessary.

As α₁-antitrypsin is an acute phase reactant, its transcription is markedly increased during inflammation elsewhere in response to increased interleukin-1 and 6 and TNFα production. Any treatment that blunts this response, specifically paracetamol (acetaminophen), can delay the accumulation of A1AD polymers in the liver and (hence) cirrhosis. A1AD patients are therefore encouraged to use paracetamol when slightly to moderately ill, even if they would otherwise not have used antipyretics.

Treatments currently being studied include recombinant and inhaled forms of AAT. Other experimental therapies are aimed at the prevention of polymer formation in the liver.

Epidemiology

People of northern European, Iberian and Saudi Arabian ancestry are at the highest risk for A1AD. Four percent carry the PiZ allele; between 1 in 625 and 1 in 2000 are homozygous.

Associated diseases

α₁-antitrypsin deficiency has been associated with a number of diseases:

History

A1AD was discovered in 1963 when Dr Carl-Bertil Laurell (1919–2001), at the university of Lund, Sweden, discovered the absence of the α₁ band in 5 gels in a large series (1500) offered to his laboratory of 6 months. Sten Eriksson, a medical resident, discovered that three of these patients had developed emphysema at a young age.

The link with liver disease was made six years later, when Sharp et al described A1AD in the context of liver disease.

External links

Liver Families - support group for pediatric liver disease
Alpha2alpha - support group for people with Alpha-1

References

Laurell CB, Eriksson S. The electrophoretic alpha 1-globulin pattern of serum in alpha 1-antitrypsin deficiency. Scand J Clin Lab Invest 1963;15:132-40.
Sharp HL, Bridges RA, Krivit W, Freier EF. Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognized inherited disorder. J Lab Clin Med. 1969;73:934-9. PMID 4182334.
Stoller JK, Aboussouan LS. α1-antitrypsin deficiency. Lancet 2005;365:2225-36. PMID 15978931.

Gastroenterology | Genetic disorders | Pulmonology | Hepatology

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