R factor: liver injury pattern from ALT and ALP (Bénichou 1990)

The R factor compares how far ALT is raised with how far ALP is raised, each measured against its own laboratory upper limit of normal (ULN). An R factor of 5 or more is called hepatocellular, 2 or less is cholestatic, and anything between is mixed. Magent's calculator takes ALT, ALP and both upper limits, returns R to one decimal and names the pattern.

Not a medical device. Not a diagnosis or dosing recommendation.

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Liver calculators
Bénichou C · 1990
The R factor formula
Worked examples
Frequently asked questions

What is the R factor?

When liver enzymes rise, the balance between them hints at where the injury sits. ALT comes mainly from liver cells. ALP rises more when bile flow is blocked. Expressing each as a multiple of its upper limit puts them on the same footing, and the ratio of the two multiples is R.

The R ratio was set out in a 1990 international consensus meeting organised through CIOMS and reported by Christian Bénichou. It describes the pattern of an enzyme rise. It doesn't say what caused it.

The R factor formula

R = (ALT / ALT upper limit of normal) / (ALP / ALP upper limit of normal)

R 5 or more        hepatocellular
R between 2 and 5  mixed
R 2 or less        cholestatic

Exact expression the calculator uses:

R = (ALT / ALT_ULN) / (ALP / ALP_ULN)

Inputs

Input	Meaning	Unit	Range
`alt_u_l`	Alanine aminotransferase	U/L	1 to 10000
`alt_uln_u_l`	Laboratory ALT upper limit of normal	U/L	5 to 200
`alp_u_l`	Alkaline phosphatase	U/L	1 to 10000
`alp_uln_u_l`	Laboratory ALP upper limit of normal	U/L	20 to 500

Both upper limits are required. The calculator doesn't assume a default, because laboratories set their own.

How the calculation works

Scale ALT. Divide ALT by its upper limit.
Scale ALP. Divide ALP by its upper limit.
Divide. The ALT multiple over the ALP multiple is R, rounded to 1 decimal.
Name the pattern. The rounded R is compared with 5 and 2. Exactly 5.0 is hepatocellular and exactly 2.0 is cholestatic.

Units

ALT, ALP and their upper limits all go in as U/L. Because each enzyme is divided by its own limit in the same unit, R has no unit.

Worked examples

These use Magent's own expected values for the calculator. In each, the ALT upper limit is 40 U/L, ALP is 100 U/L and the ALP upper limit is 100 U/L, so the ALP multiple is 1.

Example 1: ALT 400 U/L

ALT multiple 400 / 40 = 10.
R 10.0. Hepatocellular.

Example 2: ALT 200 U/L

ALT multiple 200 / 40 = 5.
R 5.0. Exactly 5, so hepatocellular.

Example 3: ALT 120 U/L

ALT multiple 120 / 40 = 3.
R 3.0. Between 2 and 5, so mixed.

Example 4: ALT 80 U/L

ALT multiple 80 / 40 = 2.
R 2.0. Exactly 2, so cholestatic.

Example 5: ALT 40 U/L

ALT multiple 40 / 40 = 1.
R 1.0. Cholestatic.

History of the R factor

Bénichou C reported the outcome of an international consensus meeting in the Journal of Hepatology in 1990, in "Criteria of drug-induced liver disorders. Report of an international consensus meeting". The report defined liver injury patterns using ALT and ALP as multiples of their upper limits, which became the R ratio. Later causality methods such as RUCAM build on the same pattern but are separate tools.

When it's used

R is worked out when ALT and ALP are both raised and a clinician wants to describe the pattern of the rise, often as one step in thinking about drug-related liver injury.

Where it's used

Hepatology and gastroenterology clinics, hospital wards, pharmacovigilance and drug safety work.

Who uses it

Hepatologists, physicians, pharmacists and drug safety teams. The calculator does the two divisions, the ratio and the pattern.

Limits of the calculation

R names an enzyme pattern. It doesn't establish that a drug, or anything else, caused the injury.
It doesn't produce a causality score.
The pattern can change over time, so R depends on when the blood was drawn.
It relies on the laboratory's own upper limits; a wrong limit gives a wrong R.
This page doesn't say what a result means for a particular person.

Clinical decisions belong to a qualified clinician who knows the patient.

Child-Pugh and ALBI grade liver function in chronic liver disease, not the pattern of an enzyme rise.
FIB-4 estimates fibrosis from age, AST, ALT and platelets.
Maddrey scores alcohol-related hepatitis.

Glossary

ALT: alanine aminotransferase, an enzyme found mostly in liver cells.
ALP: alkaline phosphatase, an enzyme that rises with blocked bile flow, among other causes.
ULN: upper limit of normal, set by each laboratory.
Hepatocellular: a pattern pointing at liver cells.
Cholestatic: a pattern pointing at bile flow.

Common mistakes

Using raw enzyme values. Each enzyme has to be divided by its own upper limit first.
Borrowing another lab's upper limit. Use the limits printed with the result.
Reading R as cause. R describes the pattern, not the culprit.
Calling 5.0 or 2.0 mixed. Exactly 5.0 is hepatocellular and exactly 2.0 is cholestatic.

Source

Bénichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol. 1990;11(2):272-276. DOI: 10.1016/0168-8278(90)90124-A. PMID: 2254635

Frequently asked questions

What R factor is hepatocellular?

5 or more.

What R factor is cholestatic?

2 or less. Values between 2 and 5 are mixed.

Is the R factor the same as a RUCAM score?

No. R is the enzyme pattern. RUCAM is a separate causality method that uses the pattern as one input, and the calculator doesn't compute it.

Why do I need the upper limits of normal?

R compares multiples of each enzyme's upper limit. Without the lab's limits, the multiples can't be worked out.

How is R rounded?

To 1 decimal, and the pattern is named from the rounded value.