Disease Site

Alpha-1 antitrypsin deficiency is a genetic disorder which predisposes the patient to chronic liver disease and early-onset emphysema.6 The alpha 1-antitrypsin enzyme is a serine protease inhibitor that is synthesised primarily in the liver.4 Its major action is in the lung, where it protects tissue against proteolytic damage from neutrophil elastase.6

Incidence

Alpha-1 antitrypsin deficiency is thought to affect approximately 1:2000 – 5000 people.6 1-2% of patients with chronic obstructive pulmonary disease (COPD) have inherited severe alpha-1 antitrypsin deficiency.2 Alpha-1 antitrypsin deficiency is probably under-diagnosed due to lack of awareness about the disease. This may have significant adverse effects as affected patients may not be receiving appropriate therapy.1, 6

Predisposing Factors

Alpha-1 antitrypsin deficiency is a disorder of autosomal co-dominant inheritance.6 Three major genetic variants of the alpha-1 antitrypsin gene have been typed by electrophoretic mobility as medium (M), and the deficiency variants slow (S) and very slow (Z).5

The most common phenotype, PiMM, is found in 90% of individuals.3 Patients with this phenotype are considered to produce normal amounts of alpha-1 antitrypsin and do not show signs of clinical disease. Heterozygotes PiMS and PiMZ, while common, also do not usually exhibit symptoms.5

PiZZ homozygotes produce approximately 15% of the normal levels of antitrypsin, while PiSS homozygotes have levels around 60% of normal.4 PiZZ homozygotes almost always develop disease in childhood or early adulthood.4

Rare null variants (Pi-null) may also occur, with no detectable serum alpha-1 antitrypsin. These patients are severely affected.6

Macroscopic Features

The liver may be enlarged early in the disease, but later with the development of progressive fibrosis it will have the same appearance as any other cause of cirrhosis.5

The lungs will show features of emphysema when affected.5 Emphysema in patients with alpha-1 antitrypsin deficiency is usually panacinar.3 Prominent basilar hyperlucency may be a particular feature.1

Microscopic Features

The hepatocytes in alpha-1 antitrypsin deficiency have a distinctive appearance: they are characterised by round to oval acidophilic cytoplasmic globular inclusions, which are indistinctly demarcated from surrounding cytoplasm.3 These characteristic globules are almost always evident in severe deficiency, but may be seen in diminished size and number in even moderate alpha-1 antitrypsin deficiency.3

Infrequently, steatohepatitis and Mallory bodies are present.3

Microscopic examination of emphysematous lungs may demonstrate abnormal fenestrations in alveolar walls, destruction of septal walls, and large abnormal airspaces, blebs or bullae.3

Natural History

PiZZ homozygotes are at very high risk of developing liver or lung disease.4 Around 10-20% will present with hepatitis in infancy or childhood, and a large proportion of the rest will present with emphysema or liver disease in adulthood.3 Attacks of hepatitis in early adulthood may resolve completely, or  they may progressively lead to cirrhosis.3

Patients with alpha-1 antitrypsin deficiency also have a 2-3% chance of developing hepatocellular carcinoma.Other clinical manifestations of alpha-1 antitrypsin deficiency include skin diseases, such as panniculitis and vasculitis (particularly anticytoplasmic antibody-positive vasculitis).6

Some other associations, including glomerulonephritis, certain types of cancer, pancreatitis, coeliac disease, intracranial and intra-abdominal aneurysms, have also been suggested but are less well established.6

Clinical History

Persons beginning to develop emphysema may complain of a gradual onset of shortness of breath, wheezing or coughing. They often present at a younger age than other emphysema patients. The possibility of alpha-1 antitrypsin deficiency should be seriously considered in patients presenting with emphysema with no or only minimal history of cigarette smoking.5,6

Patients presenting with liver disease in the form of cholestatic hepatitis (regardless of age) may present with jaundice or abdominal pain, with dark urine and pale stools. Later on, patients who develop liver cirrhosis may present with signs of portal hypertension and liver failure.5

Overall, clinicians should be aware of the possibility of alpha-1 antitrypsin deficiency in patients with the following characteristics:1

  • Emphysema of early onset (<45 years);
  • Emphysema developing in the absence of recognised risk factors, eg. cigarette smoking;
  • Emphysema with prominent basilar hyperlucency;
  • Unexplained liver disease;
  • Necrotising panniculitis;
  • c-ANCA positive vasculitis;
  • A family history of emphysema, liver disease, bronchiectasis, or panniculitis;
  • Some patients with unexplained bronchiectasis.

Clinical Examination

Patients may display clinical signs of emphysema and/or liver cirrhosis.4

General Investigation

Specific Investigations

  • Serum alpha-1 antitrypsin levels should be measured in patients with characteristics described above.1, 2
  • Definitive diagnosis of alpha-1 antitrypsin deficiency requires genotyping. This can be done by isoelectric focusing of serum, which reflects the genotype at the Pi locus for the common and some rare Pi alleles. Molecular genotyping is also possible for the common M, S and Z alleles.2
  • Liver biopsy may show a distinctive microscopic appearance as described above.4
  • Prenatal diagnosis may be possible through chorionic villus sampling.4

Prognosis

The most significant factor determining the rate of lung function deterioration in patients with emphysema is cigarette smoking.3 This is because smoking decreases basal anti-elastase activity in the lung, and increases elastase enzyme availability. Combined with a deficiency in alpha-1 antitrypsin enzyme activity, smoking hastens progression of lung damage.3

The overall yearly mortality rate in patients with alpha-1 antitrypsin deficiency is 1.7-3.5%. The commonest causes of death are respiratory failure and cirrhosis.6 Poor prognostic factors include older age, lower education, lower predicted FEV1, and lack of augmentation therapy.6

References

  1. American Thoracic Society/European Respiratory Society statement: Standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818-900. [Full text]
  2. Braunwald E, Fauci AS, Kasper DL, et al. Harrison’s Principles of Internal Medicine (15th edition). New York: McGraw-Hill Publishing; 2001. [Book]
  3. Cotran RS, Kumar V, Collins T, Robbins SL. Robbins Pathologic Basis of Disease (6th edition). Philadelphia: WB Saunders Company; 1999. [Book]
  4. Longmore M, Wilkinson I, Torok E. Oxford Handbook of Clinical Medicine (5th edition). Oxford: Oxford University Press; 2001. [Book]
  5. Kumar P, Clark M (eds). Clinical Medicine (5th edition). Edinburgh: WB Saunders Company; 2002. [Book]
  6. Stoller JK, Aboussouan LS. Alpha1-antitrypsin deficiency. Lancet. 2005;365(9478):2225-36. [Abstract]