Alpha 1 Antitrypsin

Alpha-1-antitrypsin deficiency (A1ATD):

What is A1AT?

A1AT is a serine protease inhibitor secreted primarily in liver parenchymal cells and to a lesser extent in macrophages.

It protects tissues from enzymes of inflammatory cells by inactivating especially neutrophil elastase (and also a variety of other proteases like collagenase, trypsin and chymotrypsin)

It has a reference range in blood of 1.5 – 3.5 gram/liter but the concentration can rise many fold upon acute inflammation.

In its absence, neutrophil elastase is free to break down elastin, which contributes to the elasticity of the lungs, resulting in respiratory complications such as emphysema, in adults and cirrhosis in adults or children. However the exact mechanism of liver injury is less precise compared to lung injury.

Discuss the phenotypes of A1ATD?

The gene coding for A1AT is located on chromosome 14 and there are more than 90 genetic variants producing different types of A1AT.

Serum AAT when allowed to migrate in a pH gradient gel (IEF or isoelectric focus gel)  travels at different speed according to the protein molecule property- the fastest are termed A and slowest Z.

As every person has two copies of the A1AT gene, a heterozygote with two different copies of the gene may have two different bands showing on electrofocusing. The blood test results (i.e. IEF results) are notated as in PiMM, where Pi stands for protease inhibitor and “MM” is the banding pattern of that patient.

It has a reference range in blood of 1.5 – 3.5 gram/liter but the concentration can rise many fold upon acute inflammation.

The serum levels of some of the common genotypes are:

  • PiMM: 100% (normal)
  • PiMS: 80% of normal serum level of A1AT
  • PiSS: 60% of normal serum level of A1AT
  • PiMZ: 60% of normal serum level of A1AT
  • PiSZ: 40% of normal serum level of A1AT
  • PiZZ: 10-15% (severe alpha 1-antitrypsin deficiency)

M is the most common allele, accounting for 95% of those found in Caucasian people whereas S and Z are the most common mutant alleles.

How common is the condition?

It is the most common metabolic disease affecting the liver and the commonest cause of paediatric liver transplantation.

Prevalence is highest in northern European white population (incidence of homozygous deficiency is 1in 1500). Roughly one in ten in Northern Europe carry a deficiency gene. In USA the incidence is 1 in 1800-2000.

What does liver histology shows?

Periodic acid-Schiff (PAS) positive, diastase resistance globules are seen in periportal hepatocytes. These can be shown to be A1AT using specific antiserum. Fibrosis and cirrhosis can be present in some cases.

How many of the patient with abnormal allele will actually develop the liver disease according to the phenotype?

More than 90 phenotypic variants of alpha1-antitrypsin deficiency have been identified, but one phenotype, PiZZ, is responsible for nearly all cases of AAT deficiency emphysema and liver disease. PiZZ phenotype serum levels range from 3.4-7 µmol/L, about 10-20% of the reference range levels. Other phenotypes associated with alpha1-antitrypsin emphysema and liver disease include PiSZ and PiZ/Null. PiNull/Null is not associated with liver disease but is associated with alpha1-antitrypsin deficiency emphysema.

PiZZ phenotype is associated with development of liver disease in about 15-30% and affects both children and adults.

Prognosis of patients with liver disease presenting in infancy secondary to AAT deficiency (PiZZ) is variable- not all patients progress to end stage liver disease.

Approx 10-15% of the adult patients will develop cirrhosis, usually over 50yrs of age and 75% will have respiratory problems

Heterozygotes (PiSZ or PiMZ) may develop liver disease but the risk is small.

Discuss the clinical features of the condition?

Children and infant normally present with neonatal jaundice, unexplained hepatomegaly, elevated transaminase, failure to thrive.

Adults can present with abnormal LFT, Chronic hepatitis, cirrhosis and its complications or HCC.

Discuss the diagnosis of A1AT deficiency?

  1. Low serum AAT level
  2. Serum A1 phenotype determination (Pi typing)
  3. Liver biopsy: to confirm, exclude other causes and determine prognosis

Discuss the mechanism of damage to liver and lungs in A1AT deficiency?

The most common pathologic form, which causes both lung and liver disease is the PiZZ variant which produces A1ATZ protein.

A1AT is produced in hepatocytes in rough endoplasmic reticulum and the secreted in the circulation via Golgi apparatus. Structural misfolding and polymerization of A1ATZ cause this protein to be retained in the ER but how that subsequently produces liver injury is not clear. However the lung injury is relatively straight forward by uninhibited damage by alveolar elastin fibres by neutrophil elastase present in the alveolar fluid.

Discuss the treatment of the condition?

  1. In absence of liver damage- patients are encouraged to avoid smoking (including passive smoking) and alcohol, maintain adequate nutritional intake and take oral fat soluble vitamins if needed.
  2. Managing the complications of liver and lung disease once developed.
  3. Patients with hepatic decompensation should be considered for liver transplant- donor liver synthesizes normal protein- so condition does not recur in the graft.
  4. Experimental treatment for both pulmonary and hepatic disease are infusion/inhalation of purified AAT and gene therapy
  5. Offering genetic counselling and phenotype identification of the relatives to determine those with high risk.

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