(Joint with the Biochemistry department at CMFT)
TPMT (Thiopurine S-Methyltransferase) catalyses the
rate-limiting enzymatic step in the breakdown and excretion of
immunosuppressive and chemotherapeutic drugs including Azathioprine
and 6-Mercaptopurine. Drugs based on these compounds are used
in the treatment of conditions including autoimmune disorders such
as Crohn's disease and rheumatoid arthritis, organ transplant
recipients, and in acute lymphoblastic leukaemia.
1 in 300 Caucasians are deficient in TPMT activity and are thus
prone to life-threatening myelosuppression if treated with standard
thiopurine drug doses. A further 10% of the population have
intermediate TPMT activity and are also prone to thiopurine drug
side effects, requiring lower dosing.
Various clinical guidelines advocate determination of TPMT
status of a patient prior to administration of thiopurine drugs in
order to limit the number of adverse drug reactions.
In the majority of cases, TPMT activity is determined for each
referral by a biochemical assay and only those with intermediate or
deficient TPMT activity will subsequently be referred for TPMT
The majority of the variation in TPMT activity is accounted for
by the presence of one or more non-synonymous SNPs; in those with
intermediate TPMT activity these are present on one allele only,
whilst those with deficient TPMT activity are either homozygotes or
compound heterozygotes for such changes.
Whilst many different TPMT genotypes have been described, 85-95%
of TPMT genetic variations are accounted for by the genotypes
TPMT*3A, *3B, *3C and *2, characterized by SNPs within three exons
of TPMT. The standard test for TPMT genotyping test detects these
common variants only.
If deficient TPMT activity is not described by one of the common
SNPs clinicians may choose, at additional cost, for full TPMT gene
analysis by DNA sequencing. Normally this approach should be
applied after confirmatory TPMT activity testing has been
Patients for which TPMT activity analysis is inappropriate, for
example those that have had a recent blood transfusion, can be
genotyped as a front line test in order to exclude the presence of
the common TPMT variants.
Note that the referral route for TPMT genotyping is
normally via Biochemistry so that the appropriate TPMT activity
assay can be performed, and samples triaged for onward referral to
the MDC for genotyping, where indicated.