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Alpha 1-antitrypsin deficiency
Alpha 1-antitrypsin deficiency (A1AD) is a genetic disorder caused by
reduced levels of alpha 1-antitrypsin in blood. It leads to pulmonary
(lung) emphysema and, in severe cases, to liver disease.
Epidemiology
Northwest Europeans are at the highest risk for A1AD, with 4% carrying
the PiZ allele and - therefore - a risk of homozygosity in about 1:625
to 1:2000.
Associated diseases
α1-antitrypsin deficiency has been associated with a number of
diseases:
- Asthma
- Wegener's granulomatosis
- Pancreatitis
- Gallstones
- Bronchiectasia (possibly)
- Prolapse
- Cancer
- Hepatocellular carcinoma (liver)
- Bladder carcinoma
- Gallbladder carcinoma
- Lymphoma
- Lung cancer
Signs and symptoms
These are generally undistinguishable from the "normal" emphysema and
cirrhosis.
Pathophysiology
Please refer to the alpha 1-antitrypsin for the various protease
inhibitor (Pi) genotypes and phenotypes.
Normally, alpha 1-antitrypsin is produced in the liver and exists in
levels of 1.5-3.5 gram/litre. When the levels are reduced (40-60%, in
the PiSS, PiMZ and PiSZ phenotypes), most people will only suffer
symptoms if they smoke, as the levels are still sufficient to
counteract "normal" elastase activity in inflammation. Only in the
PiZZ phenotype, when the levels are less than 15%, emphysema develops
at a young age, and 50% will develop liver cirrhosis due to the
accumulated protein, which is not secreted properly. On liver biopsy,
they show as PAS-positive, diastase-negative granules.
Apart from increasing the inflammatory reaction in the airways,
cigarette smoke also directly inactivates alpha 1-antitrypsin by
oxidizing essential methionine residues to sulfoxide forms, decreasing
the enzyme activity by a rate of 2000.
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Treatment
There is no specific treatment for A1AD; present management is
identical for the "normal" treatment of emphysema and cirrhosis.
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, can delay the
accumulation of A1AD polymers in the liver and (hence) cirrhosis. A1AT
patients are therefore encouraged to use paracetamol when slightly to
moderately ill, even if they would otherwise not have used
antipyretics.
Experimental therapies are aimed at the prevention of polymer
formation in the liver.
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