title: Multiple organ failure due to 5-fluorouracil chemotherapy in a patient with a rare dihydropyrimidine dehydrogenase gene variant.
abstract: BACKGROUND
  Dihydropyrimidine dehydrogenase (DPD) is the initial and rate-limiting enzyme in the metabolism of the chemotherapeutic drug 5-fluorouracil (5-FU). Application of 5-FU is restricted by a narrow therapeutic index because of severe toxicity of WHO grades III-IV. The exon 14-skipping mutation (c.1905+1G>A) accounts for approximately a quarter of all severely toxic cases. However, numerous other polymorphisms have been identified within the DPYD gene in affected patients, and the pathophysiological significance of most of them is unclear.
  
  
  METHODS
  We report a patient with advanced caecum cancer who twice received 950 mg 5-FU and 45 mg folinic acid as adjuvant by bolus injection. 2 days after onset of chemotherapy, the patient developed a multiple organ dysfunction exhibiting a cardiogenic shock with severe left ventricular insufficiency, marked reduction of renal function, and beginning hepatic encephalopathy with somnolence, myoclonus, and a seizure. In order to investigate a possible defect within the DPYD gene direct sequencing of all 23 exons was carried out.
  
  
  RESULTS
  Genotyping revealed a rare c.1601G>A polymorphism which causes a change in the protein sequence (S534N). Data regarding the clinical relevance are ambiguous. The polymorphism has been detected together with an intronic mutation and both polymorphisms have consistently been reported with reduced enzyme activity.
  
  
  CONCLUSIONS
  The present case provides further evidence of an etiologic role of the c.1601G>A mutation for DPD deficiency and the occurrence of severe 5-FU-related toxicity and underlines the value of comprehensive pharmakogenetic diagnostics with respect to the dihydropyrimidine dehydrogenase.
authors.affiliation: Institut für Pharmakologie, Klinikum der Universität zu Köln, Germany. andreas.lazar@medizin.uni-koeln.de
authors.forename: A
authors.initials: A
authors.lastname: Lazar
authors.forename: U A
authors.initials: UA
authors.lastname: Mau-Holzmann
authors.forename: H
authors.initials: H
authors.lastname: Kolb
authors.forename: H E
authors.initials: HE
authors.lastname: Reichenmiller
authors.forename: O
authors.initials: O
authors.lastname: Riess
authors.forename: E
authors.initials: E
authors.lastname: Schömig
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D002430:Cecal Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D054067:Dihydropyrimidine Dehydrogenase Deficiency; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000032:analysis / Q000235:genetics; D005472:Fluorouracil / Q000009:adverse effects* / Q000627:therapeutic use*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008659:Metabolic Diseases / Q000150:complications / Q000175:diagnosis* / Q000201:enzymology* / Q000235:genetics; D009102:Multiple Organ Failure / Q000139:chemically induced*; D035583:Rare Diseases / Q000150:complications / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil