All material is copyrighted and the property of mehlmanmedical.
Copyright © 2020 mehlmanmedical.
Privacy Policy and Terms and Conditions
Inheritance is HY
- Although homozygous Z-alleles = disease, the genetics are NOT autosomal recessive; the allelic expression is demonstrated in a codominant fashion.
- If they ask you about the inheritance of α1-antitrypsin deficiency, the answer is codominant inheritance, NOT autosomal recessive.
- AB RBC antigens are also codominant.
USMLE wants you to know what α1-antitrypsin normally does
- α1-antitrypsin is produced in the LIVER. α1-antitrypsin deficiency is notably known to cause emphysema, but the enzyme is NOT produced in the lungs; it is produced in the liver.
- It breaks down elastase. This is really important. In other words, it is not trypsin that builds up (paradoxically); it is elastase that does.
- The misfolded α1-antitrypsin protein never reaches the lungs; it is sequestered in the liver.
Disease presentation
- Causes hepatic cirrhosis generally by middle-age. Patients who drink alcohol have ↑↑ risk of liver disease.
- α1-antitrypsin deficiency causes pan-acinar (or pan-lobular) emphysema – i.e., the entire respiratory zone of the lung, proximal to distal, is affected.
- In contrast, smoking classically causes centri-acinar (or centri-lobular) emphysema, where the more proximal respiratory zone is affected first.
- USMLE will tell you there are bullous changes on CXR, increased anterior-posterior diameter, and/or lucency of lung fields in someone who is relatively young and a non-smoker.
- Frequent question stem is young non-smoker with emphysema who’s father died from alcoholic cirrhosis and who’s brother has similar Sx.
| Smoking increases the risk of emphysema in diseased patients. Yes, that’s obvious, but the USMLE wants you to know this is because smoking also increases elastase activity.
The combination of ↓ elastase breakdown 2° to α1-antitrypsin deficiency + ↑ elastase activity from smoking = faster onset of emphysema. However the emphysema in an α1-antitrypsin deficiency question is always pan-acinar, even if they also mention the patient is a smoker. |
Cellular-level points
- Liver biopsy in a patient with α1-antitrypsin deficiency reveals intracellular PAS-positive aggregates. The USMLE really likes that for some reason, so know it. The aggregates are misfolded glycoprotein.
- The cirrhosis in advanced disease is due to the accumulation of the misfolded protein leading to hepatocyte death, whereas in the lungs, it is the ↑ elastase that causes the emphysema.
- The misfolded α1-AT protein accumulates in the endoplasmic reticulum of hepatocytes. This is the same as with cystic fibrosis, where the misfolded CFTR channel accumulates in the RER of cells and is not delivered to the cell surface.
—
