Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency

Definition

Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency is uncommon and complete deficiency is rare. Patients who have genetic variations in the dihydropyrimidine dehydrogenase gene (DPYD) that results in excess fluoropyrimidine accumulation experience significantly greater toxicity and are at risk of death.

Pathophysiology

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

There are many genetic polymorphisms of the DPYD gene with DPYD*2A being the most common variant associated with DPD deficiency. 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.^r

Incidence/prevalence

There is a wide range of DPD activity between patients with an estimated 3 - 8% of the population having a DPD deficiency of up to 50% less enzyme activity. Complete DPD deficiency is 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 reduce DPD activity. Increased levels of the fluorouracil active metabolite is associated with an increased risk of severe or even fatal toxicity.^r

As a result patients will have typical fluoropyrimidine toxicity but this tends to appear much earlier and be more severe and prolonged. Patients who develop severe toxicity in the first few days of therapy should be considered likely to have DPD deficiency. 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

There are two main tests for DPD deficiency – genotyping of DPYD or measuring the DPD phenotype (uracil and dihydrouracil blood levels).^r

Genotyping of DPYD and DPD phenotype testing are available in Australia, however, they are currently not reimbursed and the cost and turnaround times may be limiting factors in testing upfront. The genotyping test is available through Douglas Hanley Moir Pathology (Sonic Pathology network) and is approximately $200 with a 1 - 2 week turnaround time. Preuracil and dihydrouracil levels are available through NSW Government Pathology. The current cost is $275 and turnaround time is unclear but expected to be a couple of weeks.

Currently no regulatory body - US Food and Drug Administration (FDA), European Medicines Agency (EMA) or Therapeutics Goods Administration (TGA) – or international guidelines – including European Society of Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) - require or recommend genetic testing prior to the administration of fluoropyrimidines.

Whilst the product information for both capecitabine and fluorouracil warn about the potentially fatal reactions attributed to DPD deficiency, it does not stipulate that genetic testing must be performed.

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 widely available; specimens may need to be sent interstate
• Testing is not reimbursed by Medicare so patient payment could be up to $475
• Turnaround time for testing may preclude timely initiation of therapy
• Treatment options for those that are found to have DPD deficiency are unclear

Managing DPD deficiency once identified may include a dose reduction of the fluoropyrimidine or changing to an alternative treatment. Genotype guided dose modification has been described in the literature with dose reduction ranging from 50 to 75% depending on the heterozygous DPYD variant identified. For complete DPD deficient patients (ie homozygous DPYD variants) alternative treatment is recommended.^r

It is unclear to what extent genotype modified dosing impacts treatment outcomes; it does reduce adverse effects, but severe adverse effects are not abolished.

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