alpha-1-antitrypsin Deficiency

Sample

1. The patient needs to fast for several hours before giving the sample.
2. This test is done in the serum or plasma.
   1. Separate serum immediately and store properly.
3. Take 3 to 5 ml of blood in the disposable syringe. Keep the syringe for 15 to 30 minutes, and then centrifuge for 2 to 4 minutes. In this way, you can get a clear serum.
4. Serum or plasma is stable for ≥ 7 days at 4 °C.
   • At -70 °C is stable for 3 months.

Purpose of the test (Indications) of alpha-1-antitrypsin Deficiency

1. This helps in the diagnosis of juvenile and adult cirrhosis of the liver.
2. For neonatal respiratory distress syndrome.
3. For emphysema (there is a deficiency or absence of this enzyme).
4. This is useful for the diagnosis of familial chronic obstructive lung disease.
5. This enzyme may be deficient in protein-losing disorder.
6. This is also an acute-phase protein raised in inflammation, infections, and malignancy.

Precautions for alpha-1-antitrypsin Deficiency

1. This is raised during pregnancy.
2. Oral contraceptives increase the level of AAT.
3. Any inflammatory process will raise the AAT level because it is raised in the inflammation.

Pathophysiology of alpha-1-antitrypsin Deficiency

1. This is present in the alpha globulin fraction and mainly consists of the glycoprotein.
   1. AAT deficiency is autosomal recessive, present on chromosome 14.
   2. This is a serine protease inhibitor; the main substrate is neutrophil elastase, which, when unchecked, is associated with familial pulmonary emphysema and liver diseases.
   3. The heterozygous state occurs in 10% to 15% of the general population, who have a serum level of AAT ∼60% of the normal.
      1. Homozygous patients are seen in 1:2000 persons with a serum level ∼of 10% of the normal.
   4. AAT is a relatively small size and can diffuse into the tissues and is important in preventing loss of elastic recoil.
   5. The deficiency of AAT or excess of elastase in uninhibited elastase in the bronchial tree leads to emphysema.

2. This is the most potent protein (AAT), which inhibits proteolytic enzymes produced by neutrophils during inflammation and the phagocytic process.

3. This is also called an α-1 proteinase inhibitor.
   1. AAT is the highest concentration proteinase inhibitor in the plasma on a molar basis.
   2. This is the most important inhibitor of the leucocyte elastase, which is produced in the process of inflammation for phagocytosis.
   3. This enzyme reacts with elastin in the tracheobronchial system and the vascular endothelium.
4. This is synthesized in the liver by hepatocytes.
   1. Catabolism is also taken by the liver parenchymal cells. This takes two routes:
      1. AAT -protease complex is removed by the serpin-enzyme complex receptor.
      2. The asialoglycoprotein receptors remove desialylated AAT.
5. It breaks enzymes like Trypsin, Chymotrypsin, Elastase, Thrombin, and Plasmin.

6. Its level rises non-specifically in acute inflammations, severe infections, and necrosis.
   

   AAT function and inhibition

α1-Antitrypsin Deficiency may be:

1. 1. Genetic.
   2. Acquired.
2. There are 75 known variants of the AAT, and some of these are associated with a low concentration. of AAT.
3. Pi MM’s most common phenotype and the most common deficiency of phenotype are Pi ZZ and Pi SZ.
4. Its deficiency gives rise to lung and liver diseases.
5. This enzyme protects the lungs from the elastase enzyme action.

6. Acquired deficiency may be seen in protein deficiency like malnutrition, liver diseases, Nephrotic syndrome, and neonatal respiratory distress syndrome.
7. People with a1a deficiency develop emphysema in the 3rd or 4th decades of life.
8. Congenital deficiency of ATT results in premature emphysema.
   1. An inherited AAT deficiency is associated with symptoms in early life than the acquired AAT deficiency.
   2. Inherited AAT deficiency is associated with liver and biliary diseases.
   3. Homozygous people have severe pulmonary and liver disease very early in life.
   4. 5 to 14% of the adult population is in the heterozygous state and is considered at greater risk for developing emphysema.
9. Chronic bronchitis is prominent with a1a deficiency who smoke.
   1. Cigarettes smoking and other volatile irritants stimulate the release of enzymes from the white blood cells in the lung.
   2. Without the presence of ATT, these enzymes destroy the lung parenchyma.
   3. There will be severe emphysema usually seen in the 3rd or 4th decades.

10. This is a positive acute-phase protein.
11. This enzyme deficiency is an inherited disorder that gives rise to liver and lung diseases.
    1. There are 75 known genetic variants of AAT associated with deficiency.
    2. The most common phenotype is Pi MM, and the deficiency of AAT is Pi ZZ and SZ.
12. The congenital decrease may cause the early onset of:
    1. Emphysema.
    2. Infantile hepatitis ultimately leads to cirrhosis.
    3. Neonatal cholestasis or hepatitis is present most commonly at 3 to 8 weeks of age.
    4. Extrahepatic and intrahepatic bile ducts may be small because of decreased bile flow.
    5. Hepatocellular carcinoma.
13. This is inherited as an autosomal codominant.
14.  There is a mutation in the gene SERPINA1.
15. There are two common diseases, emphysema, and liver cirrhosis.
    1. This is also seen in liver diseases like:
       1. Neonatal cholestasis or hepatitis are common at the age of 3 to 8 weeks and regress after a few weeks.
          1. Differentiation from the biliary atresia is significant.
          2. Because there is very high mortality if surgery is done in the patients with Pi ZZ infants.
       2. Cirrhosis.
       3. Hepatocellular carcinoma.

Signs and symptoms of  Alpha 1-Antitrypsin Deficiency:

1. There is tiredness.
2. Patients have shortness of breath and wheezing.
   1. Pulmonary emphysema is seen in heterozygotes and homozygotes.
   2. Secondary bronchitis and bronchiectasis may be seen in these patients.

1. The patient will have repeated episodes of lung infection.
2. There may be a vision problem.
3. There is weight loss.
4. The patient may have tachycardia on standing.
5. 10 % of infants develop liver disease, which leads to the yellowness of the skin and eyes being white.
   1. Liver disease occurs in 10% to 20% of the children with AAT deficiency.
   2. There may be neonatal hepatitis in 15% of the Pi ZZ phenotype.
   3. These patients have prolonged obstructive jaundice during infancy.
   4. These patients will develop cirrhosis.
   5. Some of these patients may be asymptomatic.
   6. Clinical and biochemical abnormalities become normal in ∼25% of these infants by 3 to 10 years.
   7. 25% survive the first decade with confirmed cirrhosis.
6. 15 % of adults have liver damage and develop cirrhosis.

Diagnosis of alpha-1- antitrypsin deficiency:

1. This disease can be diagnosed:
   1. Estimation of a1-antitrypsin in the blood.
   2. Genetic analysis (Genotype or phenotype of the blood).
   3. A sample of DNA from the mouth cell to detect α1-antitrypsin.
   4. Routine serum protein electrophoresis is a good screening test for AAT deficiency.
      • 90% of the AAT is in the α1-globulin portion.

Normal alpha-1-antitrypsin Deficiency

Newborn	145 to 270 mg/dL
Adult	78 to 200 mg/dL
>60 years	115 to 200 mg/dL

Source 2

• Normal = 85 to 213 mg/dL (0.85 to 2.13 g/L).

Source 4

• 100 to 200 mg/dL (18.4 to 36.8 µmol/L) by nephelometry.

Critical value for deficiency = around 35 mg/dL

• The patient with serum AAT <70 mg/dL (<12.9 µmol/L) may have a homozygous deficiency and are at risk of developing early lung disease.

The raised AAT level is seen in:

1. Inflammatory disorders.
2. Cancers, especially cervical carcinoma and lymphomas.
3. Hormonal effects.
4. Systemic lupus erythematosus.
5. Brain infarction.
6. Hashimoto’s thyroiditis.
7. Pregnancy.
8. Oral contraceptive tablets.

The decreased AAT level is seen in:

1. Typically <50 mg/dL.
2. Kidney diseases like Nephrotic syndrome.
3. Prematurity.
4. Malnutrition.
5. Liver diseases like acute hepatitis.
6. In lung as respiratory distress syndrome and Emphysema.
7. Protein-losing gastro- enteropathies.
8. Pancreatitis.
9. Congenital defects.
10. AAT levels are  secondarily low in patients like:
    1. Neonatal respiratory distress syndrome.
    2. Severe pancreatitis.
    3. Protein-losing disorders.

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