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Alpha-1-Antitrypsin Deficiency

This PatientPlus article is written for healthcare professionals so the language may be more technical than the condition leaflets. You may find the abbreviations list helpful.

Introduction

Alpha-1-antitrypsin (A1AT) is a serine protease inhibitor. Its main function is to inhibit the action of proteases, e.g. elastase produced by neutrophils in the presence of inflammation. If there is a deficiency of A1AT then elastase can break down elastin unchecked; in the lungs this leads to emphysematous change.

It is an under-recognised disease which should be considered in any young patient presenting with chronic obstructive pulmonary disease (COPD) or any patient with severe, aggressive COPD

Genetics

  • This is an autosomal dominant disorder of the SERPINA1 gene on the chromosome site 14q32.1.1
  • It can also be co-dominant and, more rarely, recessive too.2
  • Over 100 different alleles have been described, of which the Z is the most common.2
  • Humans have two copies of the Alpha-1-antitrypsin (A1AT) gene and can be homozygous or heterozygous.
  • A heterozygote has a low level of the enzyme and so is at risk; however, a homozygote has a very low level and is at marked risk.
  • Protein electrophoresis may reveal heterozygosity (although strictly speaking it is an electrofocus method) as the following table depicts:

    Banding of A1AT levels
    Genotypes
    Approximate serum levels of A1AT
    PiMM*100%
    PiMS80%
    PiSS or PiMZ60%
    PiSZ40%
    PiZZ10% (Severe A1AT deficiency)

    *Pi = protease inhibitor

    It is important to note that someone who has a ZZ genotype still has some A1AT present - albeit a low level.

Pathophysiology

  • Alpha-1-antitrypsin (A1AT) is a glycoprotein which is largely produced in the liver.
  • Its most important function is not as an antitrypsin but to protect the lungs from damage from neutrophil elastase that tends to be produced as a result of infection or smoking.
  • In A1AT deficiency the protein is produced but stays in the liver, failing to reach the blood, lungs and the rest of the body.
  • Most variants of this disease produce lung disease and many also induce liver disease. Liver disease results from the congestion of A1AT in the liver cells, leading to cell destruction.3
  • The usual level of A1AT is between 20 and 53 μmol/L (see local laboratories for range) but, if the level falls below 11, then lung damage is likely.

Epidemiology

  • The incidence of the gene is estimated at between 20-50 cases per 100,000 population. In the UK it is estimated that 1 in 3,000 has the deficiency.
  • North-western Europeans are most likely to carry a mutant A1AT gene.3
  • It is a condition that is markedly under-diagnosed which probably relates to the fact that even those with very low levels of the protein may not exhibit problems.
  • Recent research reveals that clinicians are improving in time to making the diagnosis. However, the delay is still significant especially in older patients and women.4
  • Furthermore, manifestation of the disease is a mixture of genetic predisposition and environmental factors.5 For example, a person who is heterozygous may simply have a predisposition to COPD if they smoke.

Presentation

Consider the diagnosis in a young patient who presents with COPD (whether or not they are smoking).

Organs most commonly involved:

  1. Lungs
  2. Liver (in most variants including the Z form)

Lung disease

  • Presents as COPD with emphysema and bronchiectasis. Compared with non-alpha-1-antitrypsin (non-A1AT) COPD the following features are seen:
    • COPD presents early (e.g. age 20-30) - especially in nonsmokers
    • In those with ZZ phenotype there is emphysema in 65% of nonsmokers and 90% of smokers6
  • Emphysema affects predominantly the lower lobes7
  • Lung cancer has also been reported - but it is difficult to ascertain causal association due to other environmental factors8

Liver disease

Other manifestations

  • Vascular disease - e.g. Wegener's granulomatosis, and intracranial and abdominal aortic aneurysms9,10
  • Panniculitis11
  • Abdominal involvement (other than liver) - coeliac disease, colorectal carcinoma and pancreatitis
  • Genitourinary tract involvement - e.g. glomerulonephritis, and bladder cancer

Liver disease

Liver disease does not affect all variants of the disease. The following studies reveal some interesting insights into liver involvement in A1AT deficiency.

Swedish infants with A1AT deficiency

  • In Sweden, 200,000 infants were screened between 1972 and 1974 and 120 were found to have A1AT deficiency.12 Of these children, 14 had prolonged obstructive jaundice, and 9 severe clinical and laboratory evidence of liver disease. A number of children had abnormal LFTs at 3 months with that number falling at 6 months.
  • By 2 years of age, 3 of the children that had had neonatal jaundice had cirrhosis and 2 of them also had persistent cough.13
  • Of the other affected children, 8 others had wheezing with infection. By the time they reached 12 years old, 2 children had died of cirrhosis and 1, who had died of aplastic anaemia, was found to have had cirrhosis.14 Abnormal LFTs that had occurred in 20% of the group had declined to 2% by age 12.
  • Follow-up at ages 16 and 18 years revealed between 8-18% with abnormal LFTs, dependent upon phenotype, but none had overt liver disease.15

King's College Child Health Unit and A1AT deficiency16

  • A study from King's College Hospital in London examined heterozygotes with a ZZ phenotype.
  • They reported more severe involvement of the liver in A1AT deficiency.
  • 11% of those presenting with conjugated hyperbilirubinaemia had hepatitis and 2% had a bleeding state due to vitamin K malabsorption.
  • Cirrhosis occurred in 50%, and 25% died in the first decade of life.
  • A further 2% presented with cirrhosis in later childhood. Adult males were more at risk of hepatocellular carcinoma with or without cirrhosis.

Investigations

  • Plasma electrophoresis may show deficiency in the alpha-1 albumin range
  • Levels of alpha-1-antitrypsin (A1AT) can be measured
  • Exact genotype can be assessed
  • Even in the absence of symptoms, lung function should be assessed along with liver function and possibly biopsy

Management

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.17
  • Some advise restraint with regard to alcohol consumption. However, the evidence suggests that neither alcohol nor viral hepatitis predispose to advanced liver disease but two factors that do are obesity and being male.18

Lung disease

  • COPD is managed as non-A1AT deficiency cases - i.e. cessation of smoking, bronchodilators and energetic treatment of infection.
  • Lung volume reduction surgery is not usually helpful.

Liver disease

  • This too is treated as other types of liver disease and cirrhosis.
  • Hepatocellular carcinoma screening is also needed (more common in males than in females).
  • Liver failure may require transplantation.

Recombinant A1AT therapy - 'augmentation 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.3
  • Some countries reserve augmentation therapy for those patients with forced expiratory volume in one second (FEV1) values at 35% to 50% who have stopped smoking and are otherwise on optimal therapy but the FEV1 continues to decline rapidly.3 In the UK, National Institute for Health and Clinical Excellence (NICE) guidance does not recommend the use of augmentation therapy in A1AT deficiency.19
  • Further research is determining the effects of inhaled A1AT. This results in better bioavailability of A1AT to the lungs.20

Gene therapy

  • In the long-term, gene therapy may be a more promising line.21,22 However, current gene therapy for A1AT deficiency is disappointing. The situation is made more difficult as it is unclear whether gene therapy in patients with emphysema will improve outcomes.23

Genetic counselling

  • As it is a familial disease, genetic counselling and testing of relatives is in order. Some interesting research reveals that genetic testing of children in confidence may be more amenable to patients with A1AT genotypic abnormalities. This allows parents or guardians to help their children to avoid the environmental precipitants necessary to develop A1AT deficiency-associated lung disease.24

Prognosis

The cause of death from lung disease is 50 to 70% and liver disease is 10 to 15%. Data from the USA confirmed that severe A1AT deficiency is associated with high mortality (18% in 1,129 patients). Lung disease accounted for 70% of the deaths and cirrhosis for 10%.25

Document references

  1. Alpha-1-antitrypsin deficiency; Online Mendelian Inheritance in Man (OMIM).
  2. Silverman EK, Sandhaus RA; Clinical practice. Alpha1-antitrypsin deficiency. N Engl J Med. 2009 Jun 25;360(26):2749-57.
  3. Kaplan A, Cosentino L; Alpha1-antitrypsin deficiency: forgotten etiology. Can Fam Physician. 2010 Jan;56(1):19-24. [abstract]
  4. Stoller JK, Sandhaus RA, Turino G, et al; Delay in diagnosis of alpha1-antitrypsin deficiency: a continuing problem. Chest. 2005 Oct;128(4):1989-94. [abstract]
  5. 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. [abstract]
  6. Tobin MJ, Cook PJ, Hutchison DC; Alpha 1 antitrypsin deficiency: the clinical and physiological features of pulmonary emphysema in subjects homozygous for Pi type Z. A survey by the British Thoracic Association. Br J Dis Chest. 1983 Jan;77(1):14-27. [abstract]
  7. 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. [abstract]
  8. 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. [abstract]
  9. Takii Y, Inoue H, Karashima E, et al; Systemic vasculitis associated with alphal-antitrypsin deficiency. Intern Med. 2003 Jul;42(7):619-23. [abstract]
  10. Patterson CC, Ross P Jr, Pope-Harman AL, et al; Alpha-1 anti-trypsin deficiency and Henoch-Schonlein purpura associated with anti-neutrophil cytoplasmic and anti-endothelial cell antibodies of immunoglobulin-A isotype. J Cutan Pathol. 2005 Apr;32(4):300-6. [abstract]
  11. Ortiz PG, Skov BG, Benfeldt E; Alpha1-antitrypsin deficiency-associated panniculitis: case report and review of treatment options. J Eur Acad Dermatol Venereol. 2005 Jul;19(4):487-90. [abstract]
  12. 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. [abstract]
  13. Sveger T; alpha 1-antitrypsin deficiency in early childhood. Pediatrics. 1978 Jul;62(1):22-5. [abstract]
  14. Sveger T; The natural history of liver disease in alpha 1-antitrypsin deficient children. Acta Paediatr Scand. 1988 Nov;77(6):847-51. [abstract]
  15. Sveger T, Eriksson S; The liver in adolescents with alpha 1-antitrypsin deficiency. Hepatology. 1995 Aug;22(2):514-7. [abstract]
  16. 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. [abstract]
  17. 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. [abstract]
  18. 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. [abstract]
  19. Chronic obstructive pulmonary disease, NICE Clinical Guideline (June 2010); Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update). This guideline partially updates and replaces NICE clinical guideline 12
  20. Brand P, Beckmann H, Maas Enriquez M, et al; Peripheral deposition of alpha1-protease inhibitor using commercial inhalation devices. Eur Respir J. 2003 Aug;22(2):263-7. [abstract]
  21. Stecenko AA, Brigham KL; Gene therapy progress and prospects: alpha-1 antitrypsin. Gene Ther. 2003 Jan;10(2):95-9. [abstract]
  22. Davies JC, Alton EW; Airway gene therapy. Adv Genet. 2005;54:291-314. [abstract]
  23. Kolb M, Martin G, Medina M, et al; Gene therapy for pulmonary diseases. Chest. 2006 Sep;130(3):879-84. [abstract]
  24. Strange C, Moseley MA, Jones Y, et al; Genetic testing of minors for alpha1-antitrypsin deficiency. Arch Pediatr Adolesc Med. 2006 May;160(5):531-4. [abstract]
  25. Stoller JK, Tomashefski J Jr, Crystal RG, et al; Mortality in individuals with severe deficiency of alpha1-antitrypsin: findings from the National Heart, Lung, and Blood Institute Registry. Chest. 2005 Apr;127(4):1196-204. [abstract]

Internet and further reading

  • Alpha-1 UK, Support Group for people with Alpha-1 Antitrypsin Deficiency

Acknowledgements

EMIS is grateful to Dr Gurvinder Rull for writing this article. The final copy has passed scrutiny by the independent Mentor GP reviewing team. ©EMIS 2010.
Document ID: 1789
Document Version: 22
Document Reference: bgp1760
Last Updated: 24 May 2010
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