What qualifies as transaminitis (elevation of liver enzymes, specifically alanine transaminase (ALT) and aspartate transaminase (AST))?

What Qualifies as Transaminitis

Transaminitis refers to elevation of liver aminotransferases (ALT and AST), with clinical significance beginning at ≥3× the upper limit of normal (ULN), though the term itself is imprecise and should be reserved for inflammatory hepatocellular processes. 1

Definition and Terminology

The term "transaminitis" is used inconsistently in medical literature and should specifically describe inflammatory hepatocellular processes characterized by elevated ALT and AST 2. However, this terminology has important limitations:

• Mild asymptomatic increases (>1× to <3× ULN) without elevated bilirubin are often non-specific and may relate to nonalcoholic fatty liver disease, dietary changes, or vigorous exercise rather than true hepatocellular injury 1
• The consensus among DILI experts is that elevations >1× to <3× ULN in the absence of elevated bilirubin do not represent clinically significant liver injury and are more accurately termed "elevations in serum aminotransferases" 1

Sex-Specific Normal Reference Ranges

Understanding what constitutes elevation requires knowing the correct reference ranges, which differ significantly by sex:

• Normal ALT for men: 29-33 IU/L (0.48-0.55 μkat/L) 1, 3
• Normal ALT for women: 19-25 IU/L (0.32-0.42 μkat/L) 1, 3
• These values are substantially lower than many commercial laboratory cutoffs, making sex-specific interpretation essential 3

Severity Classification System

The American College of Radiology provides a standardized classification based on multiples of the upper reference limit: 1, 3

• Mild elevation: <5× ULN (e.g., <145-165 IU/L for men, <95-125 IU/L for women)
• Moderate elevation: 5-10× ULN
• Severe elevation: >10× ULN

This classification system is critical because moderate and severe elevations warrant different clinical approaches than mild elevations, with significant clinical overlap between moderate and severe categories 1.

Clinical Significance Thresholds

The evidence establishes specific thresholds for clinical action:

• ALT ≥3× ULN represents the threshold for clinically significant hepatocellular injury requiring systematic evaluation rather than observation 1, 4
• ALT ≥5× ULN is rare in conditions like NAFLD/NASH and should prompt urgent investigation for viral hepatitis, autoimmune hepatitis, medication-induced injury, or acute biliary obstruction 3, 4
• ALT >10× ULN constitutes severe elevation requiring immediate evaluation for acute hepatitis, toxic injury, or ischemic insult 1

Enzyme Specificity Considerations

ALT is the most specific marker for hepatocellular injury because it is primarily concentrated in liver tissue with minimal presence in cardiac muscle, skeletal muscle, or red blood cells 1, 3, 5. In contrast:

• AST is significantly less liver-specific, being present in cardiac muscle, skeletal muscle, kidneys, brain, and red blood cells 1, 3, 6
• AST elevation without ALT elevation should prompt evaluation for non-hepatic sources including cardiac injury, muscle disorders (check creatine kinase), or hemolysis 3, 4

Pattern Recognition for Diagnosis

The AST:ALT ratio provides diagnostic clues about underlying etiology:

• AST:ALT ratio <1 suggests nonalcoholic fatty liver disease, viral hepatitis, or medication-induced injury 3, 4
• AST:ALT ratio ≥2 is highly suggestive of alcoholic liver disease, with ratios >3 being particularly specific 3
• AST:ALT ratio >1 in nonalcoholic disease strongly suggests cirrhosis and warrants evaluation for complications 3

Common Pitfalls to Avoid

• Do not use commercial laboratory "normal" ranges without considering sex-specific reference values, as this leads to underdiagnosis in women and overdiagnosis in men 3
• Do not attribute ALT ≥5× ULN to NAFLD alone without excluding viral hepatitis, autoimmune hepatitis, and medication-induced injury 3, 4
• Do not overlook non-hepatic causes of isolated AST elevation, particularly in patients with cardiac disease or recent vigorous exercise 3, 4
• Do not use the term "transaminitis" for mild elevations (<3× ULN) without evidence of true hepatocellular inflammation, as this may be physiologic variation or adaptation 1

When Elevation Becomes Clinically Actionable

The threshold for clinical action is ALT ≥3× ULN confirmed on repeat testing, which warrants:

• Complete liver panel including alkaline phosphatase, GGT, bilirubin, albumin, and PT/INR 3, 4
• Viral hepatitis serologies (HBsAg, anti-HBc IgM, anti-HCV) 3, 4
• Comprehensive medication review against LiverTox® database 3, 4
• Assessment of metabolic risk factors and alcohol consumption 3
• Abdominal ultrasound if elevation persists after initial workup 3

For ALT ≥5× ULN or any elevation with bilirubin >2× ULN, urgent hepatology referral within 2-3 days is warranted due to risk of acute liver failure 3, 4.