The liver is a metabolic powerhouse, performing functions from detoxification to nutrient processing. When liver cells (hepatocytes) are damaged, they release specific enzymes into the bloodstream that act as sensitive markers of injury. Two commonly measured markers are Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT). While typical liver injury involves a much higher ALT level, a reverse pattern—where AST levels exceed ALT—signals severe, chronic disease progression, most notably cirrhosis.
Understanding the Liver Enzymes
Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) are enzymes responsible for transferring amino groups between amino acids and keto-acids, a process called transamination. This metabolic activity is necessary for protein production, breakdown, and energy generation within the cell. Although both enzymes are abundant within hepatocytes, their distinct locations dictate their release pattern following injury.
ALT is concentrated in the cytoplasm (the fluid inside the cell membrane). This makes it a specific marker for liver injury, as it is heavily concentrated there compared to other organs. Conversely, AST is distributed in two compartments: approximately 20% is found in the cytoplasm, while about 80% is sequestered within the cell’s mitochondria. This difference in subcellular localization explains why the two enzyme levels behave differently depending on the type and severity of liver damage.
Typical Enzyme Patterns in Acute Injury
In sudden, acute liver injury, such as from viral hepatitis or an acetaminophen overdose, ALT levels are typically much higher than AST levels. This occurs because initial damage often involves inflammation and increased permeability of the hepatocyte cell membrane. Mild damage causes the contents of the cytoplasm to leak out into the bloodstream first.
Since ALT is almost entirely cytoplasmic, it is the most abundantly released enzyme in this scenario, leading to an ALT-dominant elevation. This pattern (ALT > AST) is associated with less severe, more reversible forms of liver distress, such as non-alcoholic fatty liver disease (NAFLD). In these situations, the mitochondria are generally left intact, protecting the large pool of mitochondrial AST from immediate release.
Why AST Levels Exceed ALT in Cirrhosis
The shift where AST levels become higher than ALT levels (AST > ALT) is a hallmark indicator of advanced, chronic liver disease and cirrhosis. This reversal occurs due to two mechanisms linked to the severity and duration of the damage.
Mitochondrial Release
First, the prolonged, severe injury characterizing cirrhosis causes the complete destruction of hepatocytes. This disrupts the cell membrane and internal structures, including the mitochondria. The deep, destructive nature of the injury releases the large mitochondrial reservoir of AST, which was protected during acute phases. Since the mitochondrial form accounts for the majority of the liver’s total AST activity, its release causes a disproportionate surge in circulating AST.
Impaired ALT Synthesis
Secondly, the progressive scarring and loss of functional liver cells defining cirrhosis impair the liver’s capacity to synthesize new proteins, including ALT. This reduced synthesis leads to a relative decrease in the available ALT pool, compounding the ratio skew toward AST dominance. In alcohol-associated liver disease, this effect is amplified by alcohol-induced depletion of Vitamin B6 (pyridoxal phosphate). Because Vitamin B6 is a necessary cofactor for ALT activity, its deficiency specifically impairs the function of the remaining ALT, making the AST/ALT ratio even higher.
Interpreting the AST/ALT Ratio in Diagnosis
The comparison of these two enzymes is often referred to as the De Ritis ratio, and its value provides information about the stage and likely cause of liver disease. An AST/ALT ratio greater than 1 (AST/ALT > 1) strongly suggests chronic liver damage, advanced fibrosis, or established cirrhosis. This value signifies that the injury has progressed beyond simple membrane damage to involve the deep cellular infrastructure.
When the ratio exceeds 2, and especially when it is greater than 3, it suggests alcohol-associated liver disease. However, the ratio is only one piece of the diagnostic puzzle. It must be considered alongside other blood markers that reflect the liver’s synthetic function, such as low albumin levels and elevated international normalized ratio (INR). Interpreting this ratio helps clinicians differentiate injury patterns and assess the prognosis and severity of the liver’s deterioration.