Why do transaminases (ALT, AST) improve while the international normalized ratio (INR) increases?

Why Transaminases Improve While INR Increases

When liver enzymes (ALT/AST) improve but INR rises, this typically indicates worsening hepatic synthetic function despite reduced hepatocellular inflammation—a pattern suggesting progression from acute hepatocellular injury to chronic liver dysfunction with impaired production of coagulation factors.

Understanding the Dissociation Between Transaminases and INR

Different Markers Reflect Different Liver Functions

• Transaminases (ALT/AST) reflect hepatocellular injury and inflammation, not synthetic capacity—they leak from damaged hepatocytes into serum 1, 2
• INR measures hepatic synthetic function by assessing production of vitamin K-dependent clotting factors (II, VII, X) and factor V, which are produced exclusively by the liver 3, 4
• Albumin and INR are the actual markers of liver synthetic function, while transaminases indicate active cellular damage 3

Clinical Scenarios Where This Pattern Occurs

Progressive Chronic Liver Disease

• In cirrhosis and advanced fibrosis, transaminases may normalize as inflammation subsides, but INR continues to rise as synthetic capacity deteriorates 5, 6
• An INR of 1.6-1.7 marks the starting point where coagulation dysfunction accelerates with rapid mortality increase in both cirrhosis and advanced fibrosis patients 5
• In chronic hepatitis C with advanced fibrosis (stage III/IV), elevated INR is independently associated with disease severity even when transaminases are not markedly elevated 6

Acute-on-Chronic Liver Failure

• Patients may show improving transaminases as acute hepatocellular necrosis resolves, while rising INR reflects cumulative loss of functional hepatic mass 5
• Each 0.1 increase in INR independently increases 90-day mortality risk (HR 1.06 in cirrhosis, HR 1.09 in advanced fibrosis) 5

Post-Acute Injury Recovery

• Following acute hepatitis or drug-induced liver injury, transaminases fall as inflammation resolves, but INR may remain elevated or worsen if sufficient hepatocyte loss has occurred to impair synthetic capacity 1, 2

Critical Clinical Implications

Prognostic Significance

• Rising INR despite improving transaminases is an ominous sign indicating inadequate hepatic reserve 5
• An INR of 2.1 corresponds to 15% 28-day mortality in both cirrhosis and advanced fibrosis patients, regardless of transaminase levels 5
• INR elevation reflects the liver's inability to synthesize adequate coagulation factors, which requires substantial functional hepatic mass 3, 4

Monitoring Requirements

• Patients with advanced liver disease require measurement of AST, ALT, alkaline phosphatase, GGT, conjugated bilirubin, albumin, platelets, and INR at least every 6 months to detect progression 3
• Progressive thrombocytopenia alongside rising INR may indicate portal hypertension development 3

Important Caveats About INR Interpretation in Liver Disease

INR Was Not Designed for Liver Disease Assessment

• The INR was specifically designed and validated only for monitoring vitamin K antagonist (warfarin) therapy, not as a predictor of bleeding risk in liver disease 3, 4
• In liver disease, the MELD score uses INR to assign disease severity, yet INR does not predict bleeding risk spontaneously or in connection with procedures in these patients 3
• Standard INR may not be appropriate for liver disease and could require modified calculation using liver-disease-specific ISI values 4

Factors Affecting INR Beyond Synthetic Function

• In passive hepatic congestion (as in Fontan-associated liver disease), elevated INR may reflect congestion rather than true synthetic dysfunction 3
• Prolonged INR can result from vitamin K deficiency, consumption coagulopathy, or medications—not solely from hepatic synthetic failure 4, 7

Practical Management Approach

When You See This Pattern:

1. Recognize this as potential disease progression requiring urgent hepatology consultation 3
2. Assess for signs of decompensated cirrhosis: ascites, encephalopathy, variceal bleeding 3
3. Measure albumin and platelet count to complete the synthetic function assessment 3
4. Do not assume elevated INR predicts bleeding risk—randomized trials show no reduction in bleeding when prophylactic plasma is given to correct INR in liver disease patients 3
5. Consider liver transplant evaluation if INR continues rising, as this indicates inadequate hepatic reserve 5

Common Pitfall to Avoid

• Do not be falsely reassured by improving transaminases—the rising INR is the more concerning finding that demands immediate attention and specialist involvement 5, 6