Alpha-1 antitrypsin deficiency workshop week 5

Question 1

What is alpha-1 antitrypsin deficiency?

Answer 1

Multi-system disease resulting from aberrant secretion and function of a single serum protein.

Question 2

How can abnormal secrection of serum protein cause disease? (3 ways)

Answer 2

Abnormal secretion of serum protein causes disease by:

i. blocked secretion leading to building up of abnormal proteins in the cell
ii. absence of protein function
iii. body’s reaction to accumulated abnormal proteins

Question 3

What is alpha-1 antitrypsin? Where is it synthesized? Where is it released?

Answer 3

It is a protease inhibitor that is synthesized in the liver and is secreted into blood. It inhibits proteases such as elastase, collagenase, trypsin, and chymotrypsin. Alpha-1 antitrypsin protects tissues from being digested by proteases, especially proteases released from neutrophils with inflammation/infection.

Alpha-1 antitrypsin is 90% of the alpha-1 fraction.

Question 4

Over 90 different alpha1-antitrypsin variants have been identified based on their migration in electrophoresis. The variants are named from M to Z with ‘M’ being the ‘normal’ or wild type. What 4 mutations are variants with functional deficiencies?

Answer 4

Variants with functional deficiencies:

1. Z-mutation: Results in polymerization and accumulation of the enzyme inside hepatocytes resulting in impaired secretion out of the liver.
2. S-mutation: Results in excessive intracellular degradation and therefore low secretion out of liver.
3. Pi-mutation: The enzyme is converted to ‘thrombin inhibitor’ and although it is secreted out of liver, its alpha1-antitrypsin function is lost and bleeding disorders occur
4. Q-mutation: The alpha1-antitrypsin gene is truncated so no protein synthesized at all in the liver.

Question 5

WHat role does alpha-1 antitrypsin deficiency play in liver disease? What type of mutation will liver disease be seen in?

Answer 5

Liver Disease (Cirrhosis): Neonatal or chronic (hepatomegaly, edema, ascites, jaundice, increased liver enzymes and bilirubin in serum).
Only with ZZ form; SS patients and even null patients do not get liver disease.

Question 6

What role does alpha-1 antitrypsin deficiency play in lung disease? How do macrophages, cigarette smoke and neutrophils participate in alpha-1 antitrypsin deficiency/function and its role in lung disease?

Answer 6

Lung Disease (EMPHYSEMA):

• Pneumothorax, asthma-like symptoms, wheezing, hyperexpansion of chest, shortness of breath, chronic cough.
• Lack of presence and function of alpha1-antitrypsin enzyme in the lung
• Loss of elasticity of the lungs due to unchecked activity of elastase enzyme
• Lung macrophages release lots of proteases resulting in chronic imbalance of protease to inhibitor
• Excess proteases attack and destroy lung tissues
• Smoking stimulates neutrophils to release oxidants that can inactivate alpha1-antitrypsin function