Question

A 60-year-old male presents to your clinic for a skin cancer screening. He has no history of skin cancer or skin cancer treatments, but does admit to a heavy sun exposure history. You identify the pictured scalp lesions during your exam (Figure 1). Given the extent of scalp involvement, you prescribe a topical field therapy. A few days after beginning treatment, he develops rapidly progressive erythema, edema, erosions, and ulceration at the application sites, accompanied by fever, nausea, vomiting, and diarrhea.

Which of the following enzymes is the patient most likely deficient in?

1. Thymidylate synthase
2. Thiopurine methyltransferase
3. Dihydropyrimidine dehydrogenase
4. Inosine monophosphate dehydrogenase

Correct Answer

Correct Answer: C) Dihydropyrimidine dehydrogenase

Explanation

C) This patient presented with actinic keratoses (Figure 1) that were treated with topical 5-fluorouracil (5-FU). A deficiency in dihydropyrimidine dehydrogenase (DPD) can lead to impaired metabolism of 5-fluorouracil (5-FU). DPD is the rate-limiting enzyme responsible for the catabolism of over 80% of administered 5-FU. In patients with partial or complete DPD deficiency, even topical exposure can result in excessive local toxicity due to drug accumulation. ^1-3

Reactions typically occur within the first several days of initiating topical therapy and can manifest as severe erosive dermatitis, ulceration, pain that is markedly more intense than the expected inflammatory response seen with standard 5-FU treatment, as well as systemic symptoms. Recognition of this entity is important, as continued exposure can lead to severe cutaneous injury, and systemic 5-FU administration in patients with undiagnosed DPD deficiency may result in life-threatening toxicity. Management involves immediate cessation of 5-FU, supportive wound care, and avoidance of future fluoropyrimidine exposure. Genetic testing for DPD mutations may be considered.⁴

A) Thymidylate synthase is the intracellular target of 5-fluorouracil, which inhibits DNA synthesis by preventing the conversion of deoxyuridylate to thymidylate. While inhibition of this enzyme mediates the therapeutic effect of 5-FU, deficiency or alteration of thymidylate synthase does not explain excessive toxicity due to impaired drug metabolism.⁵ B) Thiopurine methyltransferase (TPMT) is involved in the metabolism of thiopurine medications, including azathioprine, 6-mercaptopurine, and 6-thioguanine. Deficiency in TPMT can lead to life-threatening myelosuppression with the administration of these agents, but it has no role in fluoropyrimidine metabolism.⁶ D) Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme in de novo guanine nucleotide synthesis and is inhibited by medications such as mycophenolate mofetil. Deficiency or inhibition of this enzyme does not affect 5-FU metabolism and is unrelated to fluoropyrimidine toxicity.⁷

References

References 1. Amstutz U, Henricks LM, Offer SM, Barbarino J, Schellens JH, Swen JJ, Klein TE, McLeod HL, Caudle KE, Diasio RB, Schwab M. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 update. Clinical Pharmacology & Therapeutics. 2018 Feb;103(2):210-6. 2. Ezzeldin H, Diasio R. Dihydropyrimidine dehydrogenase deficiency, a pharmacogenetic syndrome associated with potentially life-threatening toxicity following 5-fluorouracil administration. Clinical colorectal cancer. 2004 Sep 1;4(3):181-9. 3. Henricks LM, Lunenburg CA, de Man FM, Meulendijks D, Frederix GW, Kienhuis E, Creemers GJ, Baars A, Dezentjé VO, Rosing H, Beijnen JH. DPYD genotype-guided dose individualization of fluoropyrimidine therapy: A prospective safety and cost-analysis on DPYD variants DPYD* 2A, c. 2846A> T, c. 1679T> G and c. 1236G> A. Annals of Oncology. 2018 Oct 1;29:viii150. 4. Meulendijks D, Henricks LM, Sonke GS, Deenen MJ, Froehlich TK, Amstutz U, Largiadèr CR, Jennings BA, Marinaki AM, Sanderson JD, Kleibl Z. Clinical relevance of DPYD variants c. 1679T> G, c. 1236G> A/HapB3, and c. 1601G> A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. The Lancet Oncology. 2015 Dec 1;16(16):1639-50. 5. Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nature reviews cancer. 2003 May 1;3(5):330-8. 6. Relling MV, Schwab M, Whirl‐Carrillo M, Suarez‐Kurtz G, Pui CH, Stein CM, Moyer AM, Evans WE, Klein TE, Antillon‐Klussmann FG, Caudle KE. Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT 15 genotypes: 2018 update. Clinical Pharmacology & Therapeutics. 2019 May;105(5):1095-105. 7. Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology. 2000 May 1;47(2-3):85-118.