Thread by @AvrahamCooperMD

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Why does alpha-1 antitrypsin deficiency (A1AT) cause liver disease (e.g. cirrhosis or hepatocellular carcinoma)?

I always assumed the mechanism was the same as for lung injury and emphysema, but it's not.

#tweetorial #medtwitter

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Let's review the pathophys of A1AT:

- Alpha-1 antitrypsin (AAT) is a protease inhibitor, made in the liver, targeting neutrophil elastase

- Mutated alleles lead to decreased production of AAT (MM = normal genotype, ZZ = most common variant in A1AT)

pubmed.ncbi.nlm.nih.gov/29070580/

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A1AT is most well known as an inherited cause of emphysema.

This occurs b/c of a "toxic loss of function" where elastase would normally be inhibited by AAT.

Loss of AAT production leads to uninhibited elastase activity and alveolar destruction.

pubmed.ncbi.nlm.nih.gov/32268028/

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What about the mechanism of liver disease in A1AT?

One clue is that only some AAT mutations lead to liver disease: Z (genotype ZZ) + M-malton (and, rarely, S).

Z is the most common mutation in A1AT and has the strongest association w/ liver disease.

pubmed.ncbi.nlm.nih.gov/14985567/

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Next, let's learn the effects of the Z mutation to see why it can cause liver disease.

With Z, lysine substitutes for glutamic acid at a hinge point in AAT.

This causes protein misfolding/polymerization in the hepatocyte endoplasmic reticulum (ER).

pubmed.ncbi.nlm.nih.gov/1608473/

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Polymerized AAT clumps together in hepatocytes, leading to histologically visible, PAS-positive inclusions.

⚡️This accumulation is called a "toxic gain of function", as opposed to the toxic loss of function that leads to emphysema.

pubmed.ncbi.nlm.nih.gov/28752441/

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A follow-up question: how do these clumps of AATs actually lead to hepatic injury?

The exact causes are not known but the leading theory involves mitochondrial damage...

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Mouse A1AT models and human patient studies have shown that clumps of AAT in the ER injure hepatic mitochondria, in a process called proteotoxic stress.

The injured mitochondria release reactive oxygen species, contributing to hepatocyte damage.

pubmed.ncbi.nlm.nih.gov/14684378/

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A "null" genotype, where no circulating AAT is produced at all, get severe emphysema (b/c they make no AAT). But liver disease has never been observed.

This reinforces that the key event for liver disease development is hepatocyte AAT accumulation.

pubmed.ncbi.nlm.nih.gov/2254451/

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The mechanism of liver disease in A1AT has therapeutic implications as well.

For patients with severe deficiencies of AAT and emphysema, pooled donor plasma w/ AAT is often used therapeutically to replace the enzyme they don't produce.

pubmed.ncbi.nlm.nih.gov/22536580/

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💥 But because liver disease results from intra-hepatocyte inclusions of AAT, not protease deficiency, enzyme replacement has no role.

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Let's end w/ an interesting association:

A1AT liver disease and obesity appear to be linked.

For one, obesity is a primary risk factor for progression of A1AT liver disease to cirrhosis.

pubmed.ncbi.nlm.nih.gov/15822045/

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And, amazingly, heterozygosity for A1AT alleles is associated w/ progression of fatty liver disease to NASH cirrhosis.

In one study, 20% of patients w/ NASH cirrhosis had one Z mutation (much higher than would be expected in the general population).

pubmed.ncbi.nlm.nih.gov/31597010/

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Why would heterozygosity for the Z AAT allele worsen NASH?

Z heterozygotes do make some abnormal AAT. It may be that inflammatory injury from NASH interferes w/ removal of abnormal AAT (autophagy), exacerbating the underlying fatty liver disease.

pubmed.ncbi.nlm.nih.gov/31597010/

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💡A1AT liver dx is due to AAT misfolding and clumping in hepatocytes, injuring mitochondria
💡= "toxic gain of function"
💡Differs from "toxic loss of function" in A1AT emphysema
💡Link b/w A1AT and obesity (obesity ⬆️ A1AT liver dx, Z allele ⬆️ risk for NASH cirrhosis)