Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency

Definition

Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency is uncommon and complete deficiency is rare. Patients who carry genetic variations in the dihydropyrimidine dehydrogenase (DPYD) gene experience significantly greater toxicity due to fluoropyrimidine accumulation, and are at risk of death.^r

Pathophysiology

DPD is an enzyme encoded by the DPYD gene, DPD is responsible for the breakdown of fluoropyrimidines (i.e. fluorouracil [5-FU] and the oral fluorouracil prodrug capecitabine) and inactivates approximately 80 - 90% of fluorouracil in the body.^r DPD enzyme deficiency results in fluorouracil drug accumulation and may cause life-threatening toxicities such as diarrhoea, mucositis, myelosuppression and neurotoxicity.^r

There are many functional and non-functional polymorphisms of the DPYD gene, DPYD*2A (c.1905+1G>A) being the most well known variant associated with DPD deficiency.^r Three other variants identified as resulting in reduced function or a non-functional DPD enzyme are c.2846A>T, c.1679T>G, and c.1236G>A.^rr Patients who are carriers of DPYD variant genes produce differing degrees of DPD metabolic activity depending on the variant.^r

Incidence/prevalence

DPD deficiency can account for up to 60% of severe fluoropyrimidine toxicity.^r There is a wide range of DPD activity between patients with an estimated 5% of the population having a DPD deficiency of up to 50% less enzyme activity. Complete DPD deficiency is very rare, estimated to be only 0.1% of the population.^r

Symptoms and signs

Patients with partial or complete DPD deficiency who are treated with a standard dose of fluoropyrimidine will have increased levels of the active metabolites of fluorouracil due to the reduced DPD activity. Increased levels of the fluorouracil active metabolites are associated with an increased risk of severe or even fatal toxicity.^r

DPD deficient patients will develop typical fluoropyrimidine toxicity but this typically appears much earlier and is more severe and prolonged. DPD deficiency should be considered in patients who develop severe toxicity within the first few days of therapy. An antidote is available for fluoropyrimidine overdose or overexposure and is highly effective if given within 96 hours. Read more about Fluoropyrimidine overdose or overexposure. 

Investigations and diagnosis

DPD deficiency can be investigated by DPYD genotyping and measuring the DPD phenotype (dihydrouracil/uracil ratio blood levels).^rr Both tests are available in Australia, however, they are currently not reimbursed and the cost and turnaround times may be limiting factors in testing upfront.

DPYD genotype test is available commercially through:

• Douglas Hanly Moir Pathology (Sonic Pathology network) and costs $160 with 5 business days turnaround time.
• Australian Clinical Labs and costs $90 with 7-10 business days turnaround time.
• Selected hospital pathology genomics laboratories have capacity to do genotyping, also at cost to patients.

Dihydrouracil/uracil ratios are available through NSW Health Pathology. The current cost is $250 with a maximum turnaround time of 2 weeks from receipt of sample.

In 2020, the Pharmacovigilance Risk Assessment Committee (PRAC) in association with the European Medicines Agency (EMA) released a statement endorsing pre-treatment DPD testing for patients undertaking treatment with fluoropyrimidines.^r Updated guidelines from the  European Society for Medical Oncology (ESMO) also reflect this recommendation.^r Currently the US Food and Drug Administration (FDA) and National Comprehensive Cancer Network (NCCN) do not recommend routine genetic testing prior to the administration of fluoropyrimidines.

While the product information for both capecitabine and fluorouracil warn about the potentially fatal reactions attributed to DPD deficiency, they do not recommend routine testing for DPD deficiency.

Managing DPD deficiency once identified may include a dose reduction of the fluoropyrimidine or changing to an alternative treatment. Genotype guided dose modifications has been described in the literature with dose reduction ranging from 50 to 75% depending on the DPYD variant identified.^r For complete DPD deficient patients (i.e. homozygous DPYD *2A carriers or compound heterozygote DPYD*2A/c.1679T>G carriers) alternative treatment is recommended.^r Current genotype-guided dose reduction guidelines are available from the Clinical Pharmacogenetics Implementation Consortium (CPIC) 2017 Update.^r It is important to note that the currently identified DPYD variants only account for approximately 8% of DPD deficient patients, and as such should not be the sole factor determining dose adjustment in patients who are suspected to be DPD deficient.

There are a number of barriers to carrying out routine testing on all patients prior to receiving fluoropyrimidine treatment including:

• Which test to perform: genotyping vs phenotyping vs mixed testing
• Testing is not yet widely available; specimens may need to be sent interstate
• Neither genotyping nor phenotype testing is currently reimbursed by Medicare so patient payment could be substantial
• Turnaround time for testing may preclude timely initiation of therapy
• Treatment options for those that are found to have DPD deficiency are unclear unless a functional DPYD variant is identified.

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