alpha 1 antitrypsin def liver damage

[mayn]

---

Members do not see this ad.

I've got a question about alpha 1 anti trypsin deficiency (PiZZ variant) and associated liver damage.. I know the enzyme is made there, and you can find it disease states in granules using PAS + diastase stains, and its made improperly and accumulates.

My question is, if its made improperly.. why isn't it just ubiquinated and degraded? (like what happens with the CFTR protein in CF)

 

[Phloston]

All biological systems exist as equilibria, so it's more than likely that there's a percentage that's ubiquinated as well as that which isn't.

And as far as I'm aware, diastase isn't a stain. Going off my head here from a UWorld practice question I had done some time ago, the periodic acid oxidizes C=C in glycopeptides (and fungal polysaccharides) to aldehydes, which react with fuschin-sulfurous acid to form a magenta color. Diastase is then added in order to dissolve the glycogen, meaning that it yields a negative reaction with PAS staining. The only reason T. whippelii appears magenta is because the glycopeptide is diastase-resistant.

Also, regarding CFTR, I'm not so sure that that's notably ubiquinated as you've stated. Almost any practice question I've come across has suggested that it's found sequestered as misfolded protein within the RER.

With respect to ubiquination, I do recall from UWorld that autosomal recessive Parkinson's disease with age of onset < 50 yrs can occur due to mutations in Parkin (and two other genes that I can't remember the names of right now), which result in a defective ubiquination complex.

 

[mayn]

Well the reason I even thought of this was I was just reviewing some biochem, and the kaplan guy mentioned ubiquitination, and specifically the CFTR protein as an example.

I guess most questions regarding CFTR and misfolding try to test the knowledge if the student knows the systematic process of protein synthesis, and if misfolded, where would it get stuck.

http://www.ncbi.nlm.nih.gov/pubmed/7553863 Here is a pubmed article about it, proof that I am not hallucinating lol. Plus.. if it wasn't significantly degraded.. wouldn't that also lead to eventual pancreatic damage thru the same mechanism? (as opposed to clogging up the pancreatic ducts)

Also.. Thanks for bringing up the diastase. I always kept it in the back of my head to read more about it, but never did.

 

[mayn]

K for anyone interested:

Glycogen is PAS +ve, diastase sensitive; which means the staining with PAS would vanish if the tissue is pretreated with diastase which would break down glycogen
Mucin/glycoprotein/glycolipids are PAS +ve, diastase resistant ; which means the staining with PAS would persists even though the tissue is pretreated with diastase as diastase would not alter mucin.

So the diastase can be used to differentiate glycogen from glycoproteins/glycolipids/mucin.

Any who, still don't get the non degraded alpha 1 antitrypsin.

 

[Phloston]

As we've discussed before, if you have a large amount of misfolded protein, that will likely exceed the amount which can be ubiquinated (which is an ATP-dependent process btw).

How this might show up on the USMLE (as I've seen in practice questions):

1) They'll show you a LM with eosinophilic (= proteinaceous) granules, and then give you a classive vignette where you know the Dx easily. They'll then ask you what the granules are. It's not hard, but remember that they're misfolded A1AT, not elastase.

Here's an image: http://library.med.utah.edu/WebPath/LIVEHTML/LIVER052.html

2) They'll give you a vignette of a guy with bowel issues (and maybe lymphadenopathy, etc.) and show you a heavily magenta-colored slide. Then they'll ask what the magenta color is actually staining. It's glycoprotein. The fungal cell wall tidbit is good to know, but T. whippelii is HY, and it's glycoprotein.