- Alpha-1 antitrypsin (A1AT) is a glycoprotein which is largely produced in the liver.
- It is is a serine protease inhibitor. Its main function is to balance the action of neutrophil-protease enzymes in the lungs, eg neutrophil elastase produced by neutrophils in the presence of inflammation, infection or smoking.
- If there is a deficiency of A1AT then elastase can break down elastin unchecked; in the lungs this can lead to the destruction of alveolar walls and emphysematous change.
- A1AT deficiency is an inherited condition.
- In those with A1AT deficiency, the protein is still produced but the genetic defect means that the A1AT molecule configuration is changed. As a result, it cannot pass out of the liver into the bloodstream and so cannot pass to the lungs and the rest of the body.
- Some people with A1AT deficiency develop liver disease. This results from the congestion of A1AT in the liver cells, leading to cell destruction.
- The usual serum level of A1AT is between 20 and 60 μmol/L (see local laboratory's reference range) but, if the level falls below 11μmol/L then lung damage is more likely.
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- There is a mutation in the SERPINA1 gene (previously known as the Pi gene) on chromosome 14.
- Over 100 different allelic variants of the alpha-1 antitrypsin (A1AT) gene have been described.
- M alleles are the normal variants of the gene. Other common variants are S and Z.
- As a result of these different allelic variants, over 20 different variants of the A1AT molecule have been identified, all inherited as co-dominant alleles.
- Humans have two copies of the A1AT gene and can be homozygous or heterozygous.
- Someone who is homozygous MM, will produce normal amounts of A1AT.
- Common genotypes for people with A1AT deficiency are SS, ZZ, MS, MZ, SZ.
- However, not everyone with A1AT deficiency develops clinically significant disease. The different genotypes will lead to different serum levels of A1AT. It is the serum level of A1AT that will determine the likelihood of developing clinically significant disease.
- Most patients with clinical disease are homozygous SS or ZZ. They have the lowest serum levels of A1AT.
- A heterozygote MS or MZ will be a carrier of the disease. They produce lower than normal levels of A1AT (around 35% of normal) but do not develop clinically significant disease.
- Alpha-1 antitrypsin (A1AT) deficiency is one of the most common inherited disorders among white people.
- North-western Europeans are most likely to carry a mutant A1AT gene.
- In the UK it is estimated that 1 person in 3,000-5,000 has A1AT deficiency.
- It is a condition that is markedly under-diagnosed which probably relates to the fact that even some people with very low levels of the protein may not exhibit problems.
- Furthermore, manifestation of the disease is a mixture of genetic predisposition and environmental factors. For example, a person who is heterozygous may simply have a predisposition to chronic obstructive pulmonary disease (COPD) if they smoke.
- Between 1-3% of people diagnosed with COPD are thought to have A1AT deficiency.
The organs most commonly involved are the lungs and the liver.
- Lung disease does not usually present until people are in their 30s and 40s.
- Smokers tend to develop symptoms around 10 years earlier than non-smokers.
- The symptoms are those usual for COPD. Compared with non-alpha-1 antitrypsin (non-A1AT) deficiency COPD the following features are seen:
- Lung cancer has also been reported but it is difficult to ascertain causal association due to other environmental factors.
- Not everyone with A1AT deficiency will develop liver disease.
- Those with the ZZ genotype are more likely to develop liver disease.
- Neonates with A1AT deficiency may present with neonatal jaundice and hepatitis; older children may develop hepatitis, cirrhosis and liver failure due to A1AT deficiency.
- A Swedish study followed up 184 children with A1AT deficiency until they were 18:
- Of 127 children with the ZZ genotype, 22 developed clinical signs of liver disease in infancy. Of these 22, two died in early life of cirrhosis.
- Of the 121 children tested at check-ups when they were 16 and 18 years old, none with the ZZ or SZ genotypes had clinical signs of liver disease.
- LFT abnormalities were found in 17% of ZZ and 8% of SZ adolescents at the age of 16 and in 12% of ZZ and 15% of SZ subjects at the age of 18.
- Many adults with A1AT deficiency will show some signs of abnormalities in LFTs but, in some, the build-up of A1AT in the liver can lead to hepatitis, fibrosis, cirrhosis and liver failure. With cirrhosis there is a risk of hepatocellular carcinoma.
- Serum levels of alpha-1 antitrypsin (A1AT) can be measured.
- Phenotyping can be carried out on those with low serum levels.
- CXR and lung function testing (even in the absence of symptoms). Consider high-resolution CT scanning of the chest.
- LFTs and possibly liver biopsy.
Family members of an index case should also be investigated.
Alpha-1 antitrypsin (A1AT) deficiency without symptoms
- Where the diagnosis is made in the absence of symptoms there should be advice about not smoking and referral to a chest clinic for the assessment of possible occult disease.
- Many advise restraint with regard to alcohol consumption. However, one study suggests that neither alcohol nor viral hepatitis predisposes to advanced liver disease; however, two factors that do are obesity and being male.
- COPD is managed as per non-A1AT deficiency COPD cases - ie cessation of smoking, bronchodilators, pulmonary rehabilitation and energetic treatment of infection. See separate Chronic Obstructive Pulmonary Disease article for further details.
- Lung volume reduction surgery may be helpful in selected patients.
- Lung transplantation may also be considered in appropriate cases.
- Pneumococcal and yearly influenza vaccinations are recommended.
- Liver function should be monitored and liver disease treated as for liver disease and cirrhosis of other causes. See separate Cirrhosis article and Liver Failure article for further details.
- Hepatocellular carcinoma screening is also needed (more common in males than in females).
- Liver failure may require transplantation.
Recombinant A1AT therapy
- As the underlying problem is deficiency of circulating A1AT, a logical form of treatment is to replace it.
- Plasma is pooled from many blood donors to produce an intravenous infusion that is rich in the missing protein.
- Replacement of A1AT effectively elevates circulating levels but the cost-effectiveness and clinical effect are still not ascertained.
- Some countries reserve augmentation therapy for those patients with forced expiratory volume in one second (FEV1) values at 35-50% who have stopped smoking and are otherwise on optimal therapy but the FEV1 continues to decline rapidly.
- In the UK, National Institute for Health and Clinical Excellence (NICE) guidance does not recommend the use of augmentation therapy in A1AT deficiency at present.
Those people who are diagnosed with alpha-1 antitrypsin (A1AT) deficiency after screening (so before they develop any symptoms), have a better prognosis than those who are diagnosed after symptoms have already developed.
The following features are associated with a worse prognosis:
- A more severe degree of airflow obstruction:
- With FEV1 >50%, the five-year mortality rate is 4%.
- With FEV1 35-49%, the five-year mortality rate is 12%.
- With FEV1 <35%, the five-year mortality rate is 50%.
- A significant bronchodilator response (>12% and >200 mL).
- Smoking - people who smoke are more seriously affected and have a greater risk of dying from the disease.
- Being male.
Further reading & references
- Fairman P et al, Alpha1-Antitrypsin Deficiency, Medscape, Mar 2011
- Kaplan A, Cosentino L; Alpha1-antitrypsin deficiency: forgotten etiology. Can Fam Physician. 2010 Jan;56(1):19-24.
- Alpha-1-Antitrypsin Deficiency, Online Mendelian Inheritance in Man (OMIM)
- DeMeo DL, Silverman EK; Alpha1-antitrypsin deficiency. 2: genetic aspects of alpha(1)-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk. Thorax. 2004 Mar;59(3):259-64.
- Holme J, Stockley RA; Radiologic and clinical features of COPD patients with discordant pulmonary physiology: lessons from alpha1-antitrypsin deficiency. Chest. 2007 Sep;132(3):909-15. Epub 2007 Jun 15.
- Yang P, Bamlet WR, Sun Z, et al; Alpha1-antitrypsin and neutrophil elastase imbalance and lung cancer risk. Chest. 2005 Jul;128(1):445-52.
- Hussain M, Mieli-Vergani G, Mowat AP; Alpha 1-antitrypsin deficiency and liver disease: clinical presentation, diagnosis and treatment. J Inherit Metab Dis. 1991;14(4):497-511.
- Sveger T; Liver disease in alpha1-antitrypsin deficiency detected by screening of 200,000 infants. N Engl J Med. 1976 Jun 10;294(24):1316-21.
- Sveger T; alpha 1-antitrypsin deficiency in early childhood. Pediatrics. 1978 Jul;62(1):22-5.
- Sveger T; The natural history of liver disease in alpha 1-antitrypsin deficient children. Acta Paediatr Scand. 1988 Nov;77(6):847-51.
- Sveger T, Eriksson S; The liver in adolescents with alpha 1-antitrypsin deficiency. Hepatology. 1995 Aug;22(2):514-7.
- Norman MR, Mowat AP, Hutchison DC; Molecular basis, clinical consequences and diagnosis of alpha-1 antitrypsin deficiency. Ann Clin Biochem. 1997 May;34 ( Pt 3):230-46.
- Bowlus CL, Willner I, Zern MA, et al; Factors associated with advanced liver disease in adults with alpha1-antitrypsin deficiency. Clin Gastroenterol Hepatol. 2005 Apr;3(4):390-6.
- Gotzsche PC, Johansen HK; Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with Cochrane Database Syst Rev. 2010 Jul 7;(7):CD007851.
- Chronic obstructive pulmonary disease, NICE Clinical Guideline (June 2010)
- Stecenko AA, Brigham KL; Gene therapy progress and prospects: alpha-1 antitrypsin. Gene Ther. 2003 Jan;10(2):95-9.
- Davies JC, Alton EW; Airway gene therapy. Adv Genet. 2005;54:291-314.
- Kolb M, Martin G, Medina M, et al; Gene therapy for pulmonary diseases. Chest. 2006 Sep;130(3):879-84.
- McNab GL, Dafforn TR, Wood A, et al; A novel model and molecular therapy for Z alpha-1 antitrypsin deficiency. Mamm Genome. 2011 Nov 11.
- Yusa K, Rashid ST, Strick-Marchand H, et al; Targeted gene correction of alpha1-antitrypsin deficiency in induced pluripotent Nature. 2011 Oct 12;478(7369):391-4. doi: 10.1038/nature10424.
|Original Author: Dr Gurvinder Rull||Current Version: Dr Michelle Wright||Peer Reviewer: Prof Cathy Jackson|
|Last Checked: 19/04/2012||Document ID: 1789 Version: 23||© EMIS|
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