We experienced an acute exacerbation of hypertriglyceridemia after tamoxifen administration in patient who had already suffered from hypertriglyceridemia due to chronic kidney disease (CKD), diabetes, nonalcoholic fatty liver disease (NAFLD).
unbalanced diet with carbohydrates and no exercise habit. Some authors have reported that severe hypertriglyceridemia by tamoxifen therapy usually occurs in those patients who have a previous diagnosis of familial hypertriglyceridemia or familial combined hyperlipidemia, and that in normolipidemic patients there is only moderate elevation of triglycerides [13]. Although she had no family history of dyslipidemia or cardiovascular disease within the interview survey, we could not completely rule out hereditary disorders, such as familial combined hyperlipidemia, because we could not perform further investigation due to the patient’s special family situation. The possible presence of hereditary dyslipidemia remains a factor in the marked exacerbation of hypertriglyceridemia with tamoxifen treatment. In this case, the onset of hypertriglyceridemia-induced acute pancreatitis due to tamoxifen therapy was not confirmed, but previous reports have revealed that tamoxifen increases serum triglyceride level and triggers hypertriglyceridemia-induced acute pancreatitis, whereas its incidence is rare [11]. Marked hypertriglyceridemia is an uncommon but well-established etiology of acute pancreatitis, with a reported incidence of 2–4% [14,15,16]. Data from European population studies reported that incidence of acute pancreatitis was 10–19% in subjects with severe hypertriglyceridemia, e.g. TG level is ≥1000 mg/dL [16]. Several studies have revealed that hypertriglyceridemia-induced acute pancreatitis is more likely to follow more severe clinical course, e.g. pancreatic necrosis, infected pancreatic necrosis, organ failure, prolonged hospitalization and death, compared to acute pancreatitis by other causes [17,18,19]. Therefore, it is particularly important to identify the cause in disturbance of lipid metabolism and treat hypertriglyceridemia in order to avoid the crisis of life.
Tamoxifen is one of SERMs with tissue-specific effects on estrogen signaling used predominantly for treatment and chemoprevention of breast cancers. SERMs have estrogen-like effects (agonistic action) on some tissues, but antiestrogen effects (antagonistic action) on other tissues [20]. In general, it is known that tamoxifen mainly affects lipid metabolism by its estrogenic actions, resulting in decreased LDL-C level and increased TG concentration [8,9,10]. Previous reports showed that estrogen impaired TG-rich lipoproteins metabolism and clearance due to suppression of post-heparin lipolytic activity [21,22,23]. Post-heparin lipolytic activity has been shown to consist of two activities: hepatic TG lipase (HTGL) and extrahepatic lipoprotein lipase (LPL). HTGL is the enzyme responsible for the hydrolysis of TG in different lipoproteins, contributing to the remodeling of VLDL remnants, as well as IDL, LDL and HDL. Furthermore, HTGL also acts as a ligand in accelerating the hepatic uptake of remnants and IDL particles [24]. On the other hands, LPL catalyzes the hydrolysis of TG in chylomicron and VLDL, producing chylomicron remnant and IDL, respectively. Furthermore, LPL can also act as a ligand for lipoprotein receptors to facilitate lipoprotein uptake [25]. Some groups reported that tamoxifen lowered activities of both LPL and HTGL, resulting in hypertriglyceridemia [26, 27]. The results of lipoprotein fraction test by using HPLC and PAGE methods on admission in our case also implied decreased activities of both LPL and HTGL (Fig. 1a and b). On the other hand, tamoxifen might have reduced the activity of LPL more than that of HTGL in our case, because the fractions of small dense LDL were detected clearly in the lipoprotein fraction test by PAGE method (Fig. 1b). Surprisingly, the metabolisms of endogenous lipoproteins were changed drastically 7 days after cessation of tamoxifen (Fig. 4a). Its change may imply that withdrawal of tamoxifen promptly alleviated the decrease in LPL activity. From these results, we confirmed that tamoxifen certainly changes lipoprotein metabolism through the effect on activity of LPL and HTGL.
In our case, the metabolism of TG-rich lipoproteins had already stagnated before tamoxifen administration although it is one of the causes that she could not have received the treatment with statin and/or fibrate because of renal side effect. Serum TG concentration gradually exacerbated some months after the start of adjuvant therapy for breast cancer using tamoxifen. In general, tamoxifen may need rather prolonged therapy to increase triglyceride level [13, 28], since short-term studies [29,30,31] failed to detect the changes in serum triglyceride levels. In the previous report [13], there are few cases of severe hypertriglyceridemia (TG > 1000 mg/dl) after dosing tamoxifen. The majority of these patients had past history of hypertriglyceridemia. In addition, when family history was provided, strong family history of dyslipidemia was evident. Additionally, tamoxifen is likely to increase TG level in patients with predisposition factors that may influence susceptibility to hypertriglyceridemia including increased TG concentration before prescription, such as diabetes, obesity, chronic kidney disease (CKD), nonalcoholic fatty liver disease (NAFLD), alcohol abuse, the concomitant use of certain medications and endogenous dyslipidemia (familial hypertriglyceridemia, familial combined hyperlipidemia) [32,33,34]. In our case, it did not take a long time to worsen TG concentration remarkably. It may be due to overlapping of above-mentioned various risk factors, e.g. uncontrolled TG, diabetes, CKD, NAFLD and hereditary dyslipidemia.
Lastly, we prescribed pemafibrate which is a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα) and has superior benefit-risk balance compared to conventional fibrates [35]. Pemafibrate resulted in further improvement in lipid metabolism as mentioned above in case presentation section.
In conclusion, we experienced a case with severe hypertriglyceridemia after administration of tamoxifen. Hypertriglyceridemia-induced acute pancreatitis might have brought out more severe clinical course. It is very important to evaluate the balance between benefit and risk before dosing tamoxifen and survey lipid profiles constantly during treatment to avoid life-threatening complication when prescription of tamoxifen is planned.
