Alpha-1-Antitrypsin Deficiency

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 lack of A1AT then elastase can break down elastin unchecked, in the lungs this leads to emphysematous change.

• 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.
• Over 100 different alleles have been described of which the Z is the commonest.
• Humans have two copies of the A1AT gene and can be homozygous or heterozygotes.
• A heterozygote has a low level of the enzyme and so is at risk but 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) e.g.
  

  Banding of A1AT levels Genotypes Approximate serum levels of A1AT PiMM* 100% PiMS 80% PiSS or PiMZ 60% PiSZ 40% PiZZ 10% (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.

• A1AT is a glycoprotein which is largely produced in the liver.
• Its most important function is not as an anti-trypsin but to protect the lungs from damage from neutrophil elastase that tends to be produced as a result of infection or smoking.
• In A1AT 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.
• The usual level of A1AT is between 20 and 53 μmol/L (see local labs for range) but if the level falls below 11 then lung damage is likely.

• The incidence of the gene is estimated at between 20 - 50 cases per 100,000 population.
• North-western Europeans are most likely to carry a mutant A1AT gene.
• 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.²
• Furthermore, manifestation of the disease is a mixture of genetic predisposition and environmental factors.³ For example, a person who is heterozygous may simply have a predisposition to COPD if they smokes.

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

• Presents as COPD with emphysema and bronchiectasis. Compared to non-A1AT COPD the following features are seen:
  • COPD presents early (e.g. age 20-30) - especially in non-smoker
  • In those with ZZ phenotype there is emphysema in 65% of non-smokers and 90% of smokers⁴
• Emphysema effects predominantly the lower lobes⁵
• Lung cancer has also been reported - but it is difficult to ascertain causal association due to other environmental factors⁶

• Presents as chronic hepatitis and cirrhosis
• With cirrhosis there is a risk of development of hepatocellular carcinoma

• Vascular disease - e.g. Wegener's granulomatosis, intracranial and abdominal aortic aneurysms^7,8
• Panniculitis⁹
• Abdominal involvement (other than liver) - coeliac disease, colo-rectal carcinoma and pancreatitis
• Genitourinary tract involvement - e.g. glomerulonephritis, bladder cancer

• Plasma electrophoresis may show deficiency in the alpha 1 albumin range
• Levels of 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

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.¹⁵
• 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.¹⁶

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 (commoner in males than 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.
• Further research is determining the effects of inhaled A1AT. This results in better bioavailability of A1AT to the lungs.¹⁷

Gene therapy

• In the long term gene therapy may be a more promising line.^18,19 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.²⁰

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.²¹

The cause of death is lung disease in 50 to 70% and liver disease in 10 to 15%. Data from the United States 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%.²²