What are the causes and implications of elevated Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), and Alkaline Phosphatase (ALK PHOS) levels?

From the Guidelines

Elevated liver enzymes AST, ALT, and ALP indicate potential liver damage or dysfunction, and the most recent and highest quality study 1 suggests that hepatocellular injury is the most common cause, with ALT being more liver-specific.

Causes of Elevated Liver Enzymes

The causes of elevated liver enzymes can be categorized into hepatocellular and cholestatic causes. Hepatocellular causes include:

• Viral hepatitis
• Alcohol use
• Fatty liver disease
• Certain medications (like acetaminophen, statins, antibiotics)
• Autoimmune hepatitis Cholestatic causes include:
• Biliary obstruction
• Gallstones
• Primary biliary cholangitis
• Certain medications

Implications of Elevated Liver Enzymes

The implications of elevated liver enzymes depend on the underlying cause and the severity of the elevation. Mild elevations (less than 2-3 times normal) may be monitored, while significant elevations warrant further investigation with additional blood tests, imaging studies, or possibly liver biopsy.

Initial Interventions

Initial interventions for elevated liver enzymes include:

• Lifestyle modifications like reducing alcohol intake and weight management
• Medication adjustments
• Specific treatment depending on the underlying cause

Pattern of Elevation

The pattern of elevation helps determine the type of liver problem - hepatocellular (predominantly AST/ALT elevation) versus cholestatic (predominantly ALP elevation). According to the study 2, hepatocellular predominant abnormal liver function tests are reflected as an increase in aminotransferases, ALT, and AST.

Severity of Abnormal Aminotransferase

The severity of abnormal aminotransferase can be classified as mild, moderate, or severe, with moderate and severe elevations warranting further investigation 2.

Causality Assessment

Causality assessment for suspected drug-induced liver injury (DILI) is usually challenging, especially in patients with pre-existing liver disease such as nonalcoholic steatohepatitis (NASH) 3. A comprehensive discussion of the various methods of causality assessment is beyond the scope of this answer, but it is essential to consider other causes such as viral hepatitis, autoimmune hepatitis, and gallstone disease.

Liver Biopsy

A liver biopsy may be helpful in ruling out idiopathic autoimmune hepatitis (AIH), especially in patients with concomitant hypergammaglobulinemia or other clinical features suggesting AIH 3. However, a liver biopsy is usually not required for causality assessment, but when performed, it can provide important and useful information on the pattern of injury and its severity.

From the Research

Causes of Elevated AST, ALT, and ALK PHOS Levels

• Elevated serum levels of transaminases (AST and ALT) usually indicate hepatocellular damage 4
• ALT elevations can also be of extrahepatic origin, such as muscle damage 4
• Alkaline phosphatase (ALK PHOS) elevation can be due to cholestasis, and its hepatic origin can be confirmed by evaluating GGT levels 5
• Hepatocellular injury is defined as disproportionate elevation of AST and ALT levels compared with alkaline phosphatase levels 6
• Cholestatic injury is defined as disproportionate elevation of alkaline phosphatase level as compared with AST and ALT levels 6

Implications of Elevated AST, ALT, and ALK PHOS Levels

• Elevated AST and ALT levels can indicate liver damage, and the degree of elevation can guide the evaluation 6
• Elevated ALK PHOS levels can indicate cholestasis, and further testing is needed to determine the origin and cause of the elevation 5
• The evaluation of hepatocellular injury includes testing for viral hepatitis, nonalcoholic fatty liver disease, alcoholic liver disease, and other conditions 6
• The evaluation of cholestatic injury includes testing for primary biliary cholangitis, primary sclerosing cholangitis, and other conditions 6
• A liver biopsy may be considered when serologic testing and imaging fail to elucidate a diagnosis, or when multiple diagnoses are possible 6

Differentiation between Alcoholic and Non-Alcoholic Liver Disease

• The AST/ALT ratio, GGT, and ALP levels can be used to differentiate between alcoholic liver disease (ALD) and non-alcoholic liver disease (non-ALD) 7
• ALD patients tend to have a higher AST/ALT ratio, GGT, and ALP levels compared to non-ALD patients 7
• The De Ritis ratio (>2) can be used to indicate alcohol-induced hepatic mitochondrial injury and pyridoxine deficiency in ALD patients 7

Future of Liver Injury Biomarkers

• Current liver tests, including ALT and AST, have limitations in terms of prognostic utility in acute liver injury and liver failure 8
• New biomarkers of liver injury are being developed, and may complement or replace ALT and AST in the future 8
• The US Food and Drug Administration and the European Medicines Agency have expressed support for the use of some of these new biomarkers in drug trials 8