Oral fluoropyrimidine-induced severe hyperlipidemia

Abstract

Background: Severe hyperlipidemia secondary to capecitabine, an oral fluoropyrimidine, is a very rare condition. There are no reported cases of hyperlipidemia associated with Uracil/tegafur (UFT). Objective: Report UFT-induced severe hyperlipidemia. Method: A 71-year-old male patient with metastatic colorectal cancer receiving capecitabine treatment was hospitalized at the end of the eighth cycle with the complaint of fatigue. Capecitabine treatment was discontinued in the patient in whom severe hyperlipidemia was detected together with disease progression. Gemphibrozile 1200 mg/day was initiated; patient’s triglyceride level and serum cholesterol decreased from 1768 to 149 mg/dL and from 497 to 99 mg/dL, respectively, five weeks later. The patient started to receive UFT chemotherapy and after the second cycle, he presented to our hospital again with the complaints of fatigue, headache, and yellow vision. The investigations revealed a serum triglyceride level of 4115 mg/dL and a cholesterol level of 734 mg/dL. Results: UFT chemotherapy was discontinued and lipopheresis was administered for three consecutive days, and gemphibrozile was initiated again at a dose of 1200 mg/day. The clinical presentation might be due to oral fluoropyrimidine. Three weeks later, serum cholesterol and triglyceride levels decreased to 106 and 403 mg/dL, respectively. Conclusion: This case is a unique case of hyperlipidemia secondary to UFT. Monitoring of lipid levels, when using Fluoropyrimidine, as well as hemograms, liver and renal functions would be appropriate.

Capecitabine-induced hypertriglyceridemia: a rare but clinically relevant treatment-related adverse event

“…We are in agreement with the recommendations of several groups for the regular monitoring of lipid profiles in patients treated with capecitabine, particularly in those with risk factors for cardiovascular disease, including dyslipidemia, diabetes, hypertension, obesity, and coronary heart disease (8,11,12,18,(20)(21)(22)(23). Others groups have mandated checking of a lipid panel before initiation of capecitabine or other 5-fluorouracil prodrugs (12).…”

“…There are increasing cases of grade ≥3 CIHT being reported elsewhere around the world ( Table 1) in patients treated for MBC and mCRC with (6,8,9,(11)(12)(13)(14)(15) and without preexisting obesity, hyperlipidemia, or diabetes (6,7,10,14,16,17). In many cases, CIHT is accompanied by mixed disturbances of the metabolic profile including: increased very-lowdensity lipoprotein (VLDL), increased total cholesterol (TC), increased or decreased low-density lipoprotein (LDL), increased or decreased high-density lipoprotein (HDL), increased blood glucose or glycated hemoglobin (HbA1c), or increased lipemic index, when compared to baseline (6)(7)(8)(9)(11)(12)(13)(14)17). The dose-dependency of CIHT remains unclear as it has been shown to develop across a range of capecitabine doses, as monotherapy or as part of combination regimens, and as early as after 2 cycles or as delayed as 12 cycles of therapy ( Table 1).…”

“…Several reports have postulated that HT is induced by capecitabine itself or its generated metabolites prior to formation of 5-fluorouracil by thymidine phosphorylase (8,18,19,22,23). Enzymatic interference by capecitabine of lipid metabolism pathways involving lipoprotein lipase (LPL), hepatic triglyceride lipase, and apoproteins has also been described as a potential mechanism of HT, suggesting that CIHT may be more prevalent in individuals with susceptible genetic polymorphisms resulting in differential drug metabolism or hereditary defects in lipid metabolism such as inherited LPL deficiency (6)(7)(8)11,18,22,23). Impaired activity of LPL results in accumulation of chylomicrons and VLDL, whereas statins activate LPL and increase clearance of such triglyceride-rich lipoproteins, providing a basis for the often rapid and significant responses of CIHT to statin therapy (6,22).…”

Increase in triglyceride blood level in patients treated with capecitabine

“…The activity of the LPL is damaged, which would cause an accumulation of chylomicrons and very-low-density lipoprotein in the cells. Tegafur was also described as being capable of causing significant hypertriglyceridemia [4]. It is noteworthy that tamoxifen causes hypertriglyceridemia in the following way: in a retrospective study of 16 patients treated with tamoxifen who developed hypertriglyceridemia, all the patients were found to have lower levels of LPL and hepatic triglyceride lipase in their blood [18].…”

Severe hypertriglyceridaemia during treatment with capecitabine

“…Many cases of severe hypertriglyceridaemia were described with capecitabine, but to the best of our knowledge only one study has dealt with the influence of 5-FU on serum and it did not report any changes in triglyceride level in human ( Stathopoulos et al , 1995 ). Recently, a case of recurrent grade-4 hypertriglyceridaemia in a patient treated with capecitabine and tegafur/uracil was reported ( Yildiz et al , 2010 ). This observation of hypertriglyceridaemia with another prodrug of 5-FU suggest that capecitabine and tegafur might share a mechanism responsible for hypertriglyceridaemia.…”