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...
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?
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
![](https://pbs.twimg.com/media/DnzxFQjXsAAa7R-.png)
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
![](https://pbs.twimg.com/media/Dnz0BxmXoAARff2.png)
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
![](https://pbs.twimg.com/media/Dnz8O04WkAIck1s.png)
This is mechanism 1: excess (high) AST.
But what is it about alcohol-mediated injury that leads to a rise in AST?
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
![](https://pbs.twimg.com/media/Dn0GTs4XsAE93SN.png)
![](https://pbs.twimg.com/media/Dn0KbfRXgAEk_0h.png)
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
![](https://pbs.twimg.com/media/Dn0g71KXsAEI5Q5.png)
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
![](https://pbs.twimg.com/media/Dn0dylOXcAQQseg.png)
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?
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
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…
![](https://pbs.twimg.com/media/Dn2ZbukUYAADdfe.png)
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?
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