How do I interpret an elevated DILI (Drug-Induced Liver Injury) R Value lab result?

Interpreting the DILI R Value

The DILI R value is calculated as (ALT/ULN) ÷ (ALP/ULN) and classifies liver injury patterns: R ≥5 indicates hepatocellular injury, R <2 indicates cholestatic injury, and R between 2-5 indicates mixed injury. 1

How to Calculate the R Value

• Formula: R = (ALT ÷ upper limit of normal for ALT) ÷ (alkaline phosphatase ÷ upper limit of normal for ALP) 1
• Use laboratory values obtained at the peak of the suspected drug-induced liver injury 1
• The upper limit of normal (ULN) varies among laboratories and may differ by sex and age groups 1

Interpreting the R Value Result

R ≥ 5: Hepatocellular Pattern

• Indicates acute hepatocellular injury with predominant elevation of transaminases (ALT/AST) 1
• This pattern suggests direct hepatocyte damage from the drug 1

R < 2: Cholestatic Pattern

• Indicates cholestatic liver injury with predominant elevation of alkaline phosphatase 1
• This pattern suggests bile duct injury or impaired bile flow 1

R Between 2-5: Mixed Pattern

• Indicates mixed hepatocellular-cholestatic injury with both transaminase and alkaline phosphatase elevations 1
• This pattern shows features of both hepatocyte and bile duct injury 1

Special Considerations for Patients with Pre-existing Liver Disease

• For patients with underlying liver disease and baseline abnormal liver tests, calculate the R value using the patient's mean baseline values instead of the laboratory's ULN 1
• Compare the R value at the peak of suspected DILI to the patient's baseline R value 1
• The utility of the R value in patients with cholestatic liver disease (such as primary biliary cholangitis or primary sclerosing cholangitis) has not been systematically validated and needs to be established 1
• If using the R value in patients with PBC or PSC, compare the suspected event's R value to the baseline R value of the underlying disease, though the significance of a shift from baseline has not been assessed 1

Alternative Biomarkers for R Value Calculation

• AST can reliably replace ALT when calculating the R value, with 76% overall agreement and 96% agreement in hepatocellular cases 2
• GGT can substitute for ALP only when the R value scores as hepatocellular (R ≥5), with 94% agreement in hepatocellular cases but weak agreement (59%) overall 2
• The biochemical signature of the causative drug influences the validity of using AST or GGT in the R value calculation 2

Clinical Implications Based on Pattern

Hepatocellular Pattern (R ≥5)

• Repeat testing within 2-5 days to monitor trajectory 3, 4
• Higher risk of severe outcomes including hepatic failure 1
• Consider stopping the suspected drug immediately if ALT >3× ULN with symptoms or >5× ULN without symptoms 1

Cholestatic Pattern (R <2)

• Repeat testing within 7-10 days to monitor trajectory 3, 4
• May be indistinguishable from progression of underlying cholestatic liver disease both clinically and histologically 1
• GGT increases occur earlier and persist longer than ALP elevations in cholestatic disorders 3

Mixed Pattern (R 2-5)

• Follow-up timing should be individualized based on severity of elevation and clinical context 3
• This pattern has the lowest agreement (41%) when comparing different calculation methods 2

Important Caveats and Pitfalls

• Patients with chronic liver disease who develop DILI have increased morbidity and mortality compared to those with healthy livers, even though they don't appear to have increased susceptibility to DILI 1
• Acute DILI in patients with cholestatic liver diseases, especially those with advanced disease, should be considered associated with worse outcomes until proven otherwise 1
• In patients with advanced cirrhosis, the AST/ALT ratio is typically >1.0 (instead of the normal 0.8), which may affect interpretation 1
• Cholestatic DILI may be biochemically and histologically indistinguishable from disease progression in patients with underlying cholestatic liver disease 1
• The R value alone does not establish causality—it only defines the pattern of liver injury 1