Dihydropyrimidine dehydrogenase deficiency

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Dihydropyrimidine dehydrogenase deficiency
Other names: DPD deficiency
Dihydropyrimidine dehydrogenase deficiency has an autosomal recessive pattern of inheritance.

Dihydropyrimidine dehydrogenase deficiency is an autosomal recessive[1] metabolic disorder in which there is absent or significantly decreased activity of dihydropyrimidine dehydrogenase, an enzyme involved in the metabolism of uracil and thymine.

Individuals with this condition may develop life-threatening toxicity following exposure to 5-fluorouracil (5-FU), a chemotherapy drug that is used in the treatment of cancer.[2][3] Beside 5-FU, widely prescribed oral fluoropyrimidine capecitabine (Xeloda) could put DPD-deficient patients at risk of experiencing severe or lethal toxicities as well.[4][5]

Signs and symptoms

The presentation of DPD deficiency is as follows:[6]


DPD deficiency is inherited in an autosomal recessive manner.[1] This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.[citation needed]


Central epithelial defect

A small number of genetic variants have been repeatedly associated with DPD deficiency, such as IVS14+1G>A mutation in intron 14 coupled with exon 14 deletion (a.k.a. DPYD*2A), 496A>G in exon 6; 2846A>T in exon 22 and T1679G (a.k.a. DPYD*13) in exon 13. However, testing patients for these allelic variants usually show high specificity (i.e., bearing the mutation means that severe toxicity will occur indeed) but very low sensitivity (i.e., not bearing the mutation does not mean that there is no risk for severe toxicities). Alternatively, phenotyping DPD using ex-vivo enzymatic assay or surrogate testing (i.e., monitoring physiological dihydrouracil to uracil ratio in plasma) has been presented as a possible upfront strategy to detect DPD deficiency. 5-FU test dose (i.e., preliminary administration of a small dose of 5-FU with pharmacokinetics evaluation) has been proposed as another possible alternative strategy to secure the use of fluoropyrimidine drugs.

Although DPYD pre-treatment screening has been proven to improve drug safety for DPYD*2A carriers by the Food and Drug Administration, the current (version 2016) European Society for Medical Oncology (ESMO) guidelines do not “routinely recommend” upfront genotyping of DPYD*2A before the administration of 5‐FU in metastatic CRC (mCRC) patients.[7]


in terms of treatment we find that in cases with partial DPD deficiency, treatment with fluoropyrimidines can be initiated with caution, frequent monitoring, and dose adjustments[8]


  1. 1.0 1.1 Diasio RB, Beavers TL, Carpenter JT (Jan 1988). "Familial deficiency of dihydropyrimidine dehydrogenase: biochemical basis for familial pyrimidinemia and severe 5-fluorouracil-induced toxicity". J Clin Invest. 81 (1): 47–51. doi:10.1172/JCI113308. PMC 442471. PMID 3335642.
  2. Van Kuilenburg AB (Mar 2006). "Screening for dihydropyrimidine dehydrogenase deficiency: to do or not to do, that's the question". Cancer Investigation. 24 (2): 215–217. doi:10.1080/07357900500524702. PMID 16537192. S2CID 5746790.
  3. Lee A, Ezzeldin H, Fourie J, Diasio R (Aug 2004). "Dihydropyrimidine dehydrogenase deficiency: impact of pharmacogenetics on 5-fluorouracil therapy". Clinical Advances in Hematology & Oncology. 2 (8): 527–532. ISSN 1543-0790. PMID 16163233.
  4. Mercier C, Ciccolini J (Nov 2006). "Profiling dihydropyrimidine dehydrogenase deficiency in patients with cancer undergoing 5-fluorouracil/capecitabine therapy". Clinical Colorectal Cancer. 6 (4): 288–296. doi:10.3816/CCC.2006.n.047. ISSN 1533-0028. PMID 17241513.
  5. Mercier C, Ciccolini J (Dec 2007). "Severe or lethal toxicities upon capecitabine intake: is DPYD genetic polymorphism the ideal culprit?". Trends in Pharmacological Sciences. 28 (12): 597–598. doi:10.1016/j.tips.2007.09.009. PMID 18001850.
  6. "Dihydropyrimidine dehydrogenase deficiency: MedlinePlus Genetics". medlineplus.gov. Archived from the original on 5 August 2023. Retrieved 17 September 2023.
  7. Yau, Tung On (October 2019). "Precision treatment in colorectal cancer: Now and the future". JGH Open. 3 (5): 361–369. doi:10.1002/jgh3.12153. ISSN 2397-9070. PMC 6788378. PMID 31633039.
  8. "Role of dihydropyrimidine dehydrogenase deficiency in systemic fluoropyrimidine-related toxicity". medsafe.govt.nz. Archived from the original on 1 April 2023. Retrieved 17 September 2023.

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