Alpha 1-antitrypsin deficiency

Alpha 1-antitrypsin deficiency (α1-antitrypsin deficiency, A1AD or Alpha-1) is a genetic disorder caused by defective production of alpha 1-antitrypsin (A1AT), leading to decreased A1AT activity in the blood and lungs, and deposition of excessive 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, as well as 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 the liver or lungs, and by a variety of other measures, but it usually produces some degree of disability and reduced life expectancy.

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Signs and symptoms

Symptoms of alpha-1 antitrypsin deficiency include shortness of breath, wheezing, rhonchi, and rales. The patient's symptoms may resemble recurrent respiratory infections or asthma that does not respond to treatment. Individuals with A1AD may develop emphysema during their thirties or forties even without a history of significant smoking, though 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 (A1AT) is produced in the liver, and one of its functions is to protect the lungs from the neutrophil elastase enzyme, which can disrupt connective tissue. 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 A1AT 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, A1AT 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 factor 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 A1AT 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 A1AT 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 A1AT. 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:

• COPD
• Asthma
• Wegener's granulomatosis
• Pancreatitis
• Gallstones
• Bronchiectasis (possibly)
• Prolapse[1]
• Primary sclerosing cholangitis
• Autoimmune hepatitis
• Emphysema
• Cancer
  • Hepatocellular carcinoma (liver)
  • Bladder carcinoma
  • Gallbladder cancer
  • Lymphoma
  • Lung cancer

History

A1AD was discovered in 1963 by Carl-Bertil Laurell (1919–2001), at the University of Lund, Sweden.^[3] Laurell, along with a medical resident, Sten Eriksson, made the discovery after noting the absence of the α₁ band on protein electrophoresis in five of 1500 samples; three of the five patient samples were found to have 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.^[4]

See also

• COPD
• Emphysema
• Cirrhosis

References

1. ^ Stoller J, Aboussouan L. "Alpha1-antitrypsin deficiency.". Lancet 365 (9478): 2225-36. PMID 15978931.
2. ^ Needham M, Stockley RA (2004). "α1-antitrypsin deficiency 3: Clinical manifestations and natural history.". Thorax 59: 441-5. PMID 15115878.
3. ^ Laurell CB, Eriksson S (1963). "The electrophoretic alpha 1-globulin pattern of serum in alpha 1-antitrypsin deficiency". Scand J Clin Lab Invest 15: 132–140.
4. ^ Sharp H, Bridges R, Krivit W, Freier E (1969). "Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognized inherited disorder.". J Lab Clin Med 73 (6): 934-9. PMID 4182334.