Thread by @tony_breu

1/
Why is the AST/ALT ratio >2 in alcoholic liver disease?

If ALT is “specific” for the liver, one might expect that any liver process would lead to a low AST/ALT ratio.

Let’s review some potential mechanistic explanations...

2/
The high AST/ALT ratio seen in alcoholic liver disease could result from a disproportionately high AST, a disproportionately low ALT, or a combination of both.

What's your current explanation for the elevated AST/ALT ratio in alcoholic liver disease?

3/
The answer is (probably) BOTH. Before getting into the mechanisms, some background will be useful.

The AST/ALT ratio was first described by Fernando De Ritis in 1957. He observed that a LOW (i.e., <1) ratio was associated with acute viral hepatitis.

ncbi.nlm.nih.gov/pubmed/13447217

4/
In 1979, Cohen and Kaplan examined the AST/ALT ratio and noted that it is >2 in those with alcoholic liver disease.

They also confirmed De Ritis observation of a low ratio in acute viral hepatitis.

ncbi.nlm.nih.gov/pubmed/520102

5/
A final piece of history helps explain one of the reasons the AST/ALT ratio is >2 in alcoholic liver disease.

In 1967, Harinasuta reported that the absolute value of AST is high in alcoholic liver disease, without a matching elevation of ALT.

ncbi.nlm.nih.gov/pubmed/5338701

6/
This is mechanism 1: excess (high) AST.

But what is it about alcohol-mediated injury that leads to a rise in AST?

7/
Three key points:

*there are two AST isoenzymes in the liver: cytoplasmic (cAST) and mitochondrial (mAST)
*80% of AST activity in human liver is mAST (Pic 1)
*alcohol leads to increases mAST, via mitochondrial injury (Pic 2)

ncbi.nlm.nih.gov/pubmed/213206
ncbi.nlm.nih.gov/pubmed/6148299

8/
Mechanism 1 (updated): excess (high) mAST
Mechanism 2: suppressed ALT

B6 is a required cofactor for AST and ALT activity. Decreased B6 levels are associated with decreased serum activity, though the suppressive effect seems more pronounced with ALT.

ncbi.nlm.nih.gov/pubmed/7429115

9/
Low B6 levels are seen in patients with alcoholic hepatitis. If you give back B6, the liver ALT rises. The AST does as well, but not nearly as much.

ncbi.nlm.nih.gov/pubmed/6698365

10/
The clearance of AST and ALT is also relevant to their ratio.

*half-life for AST = 18 hours
*half-life for ALT = 36 hours

Given this, what would you predict happens to the AST/ALT ratio after an acute liver injury?

11/
As AST has a shorter half-life, the AST/ALT ratio may decrease over the course of a hospitalization. One study found:

Day 1: AST/ALT ratio = 2.7
Day 4-6: 2.2
Day 7-10: 1.7

ncbi.nlm.nih.gov/pubmed/15208167

12/
On the other hand, because AST is cleared within the liver by sinusoidal cells, as cirrhosis develops, clearance may decrease.

Result: the AST/ALT ratio increases as cirrhosis develops; this change may be seen over years.

link.springer.com/article/10.100…

13/
Before summarizing, let's ask re-ask a question from above:

What's your current explanation for the elevated AST/ALT ratio in alcoholic liver disease?

14/
In summary, explanations for the AST/ALT ratio >2 in alcoholic liver disease include:

⭐️mitochondrial damage leading to mAST release
⭐️low B6, leading to suppressed ALT

And, if cirrhosis is present:

⭐️decreased clearance of AST