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    R Factor for Liver Injury

    Differentiates cholestatic from hepatocellular liver injury.
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    INSTRUCTIONS

    Use the first lab values (ALT and ALP) indicating acute liver injury to calculate the R factor.

    When to Use
    Pearls/Pitfalls
    Why Use

    Patients with suspected drug induced liver injury (DILI) with abnormal liver chemistries.

    • The pattern of acute liver injury (and therefore the R Factor) can vary throughout the clinical course of the illness.
    • Identifying the pattern of liver injury can guide diagnostic approach to DILI, including appropriate further diagnostic testing necessary to rule out other causes of liver injury.
    • Calculating the R Factor is the first step in calculating the Roussel Uclaf Causality Assessment Method (RUCAM) when determining if liver injury is related to a specific drug.
    • Because the pattern of liver injury can evolve over time, the time point at which liver chemistries are used to calculate the R Factor can alter the final result. It is recommended that the initial liver chemistries suggesting liver injury be used, but ultimately left to the clinician to decide what set of liver chemistries to use when making an assessment.
    • The use of upper limit of normal (ULN) in the equation creates some room for variability. The ULN varies among different laboratories. This calculator uses 40 as the ULN of ALT and 120 as the ULN of ALP.
    • While not validated, the R Factor is widely used and has been incorporated into guideline recommendations for assessing liver injury.
    • Allows clinicians to collectively identify and describe the pattern of liver injury in an objective manner.
    • Allows clinicians suspecting a diagnosis of DILI to formulate an organized diagnostic strategy to rule out other causes of acute liver injury and to narrow the list of possible culprit drugs based on the pattern of liver injury.
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    Result:

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    Next Steps
    Evidence
    Creator Insights

    Advice

    R Factor >5 suggests hepatocellular pattern of liver injury.

    • Acute viral hepatitis, ischemic liver injury, Budd-Chiari syndrome, autoimmune hepatitis, and Wilson’s disease (in younger patients) should be ruled out as causes.
    • Commonly used drugs that can cause this pattern of liver injury include: isoniazid, macrolides, nitrofurantoin, minocycline, anti-epileptics, NSAIDs, green tea extract, and inhaled anesthetics.

    R Factor

    • Pancreatic malignancy, cholangiocarcinoma, primary malignancy of the gallbladder, choledocholithiasis, sepsis, TPN, heart failure, PSC, and PBC should be ruled out as causes.
    • Commonly used drugs that can cause this pattern of liver injury include: amoxicillin/clavulanate, trimethoprim/sulfamethoxazole, azathioprine, and anabolic steroids.

    R Factor between 2 and 5 suggests a mixed pattern of liver injury.

    Management

    Recommendations for workup based on R Factor, adapted from Chalasani 2014.

    Critical Actions

    Though the R Factor does not incorporate coagulopathy (INR) and mental status, these two factors should always be immediately assessed in all cases of acute liver injury to rule out acute liver failure.

    Formula

    R Factor = ( patient’s ALT / upper limit of normal ALT ) / ( patient’s ALP / upper limit of normal ALP )

    Note: calculator uses 40 U/L as upper limit of normal ALT and 120 U/L as upper limit of normal ALP. Normal values may vary by lab.

    Facts & Figures

    Interpretation:

    R Factor

    Injury type

    Recommended 1st line tests*

    >5

    Hepatocellular

    Acute viral hepatitis serologies, HCV RNA and autoimmune hepatitis serologies, imaging studies (e.g. abdominal ultrasound)

    2–5

    Mixed

    Acute viral hepatitis serologies, HCV RNA and autoimmune hepatitis serologies, imaging studies (e.g. abdominal ultrasound)

    <2

    Cholestatic

    Imaging studies (e.g. abdominal ultrasound)

    *From Chalasani 2014.

    Evidence Appraisal

    The R Factor (also known as the R ratio or R value) was introduced after an international consensus meeting in 1989 aimed at preparing definitions and criteria related to drug related liver injury. At the request of the Council for International Organizations of Medical Sciences (CIOMS), a pilot program led by pharmaceutical company Roussel Uclaf was initiated to help classify different patterns of acute liver injury, introducing the R Factor.

    The R Factor itself has not been validated, but remains commonly used in clinical practice to objectively define different patterns of liver injury. The American College of Gastroenterology (ACG) has incorporated the R Factor in its guidelines for diagnosis and management of idiosyncratic drug-induced liver injury.

     

    Dr. Christian Bénichou

    About the Creator

    Christian Bénichou, MD, (d. 1999) was a rheumatologist and advocate for drug safety. He served as the head of drug safety at Roussel Uclaf in France, expert reviewer for the World Health Organization's Uppsala Monitoring Centre, and on all drug safety working groups for the Council for International Organizations of Medical Sciences (CIOMS). Dr. Bénichou’s research interests were primarily monitoring of drug safety.

    To view Dr. Christian Bénichou's publications, visit PubMed

    Content Contributors
    • Zaid Tafesh, MD
    About the Creator
    Dr. Christian Bénichou
    Content Contributors
    • Zaid Tafesh, MD