Sirolimus-Induced Severe Hypertriglyceridemia in a Lung Transplant Recipient

Sirolimus is a macrolide isolated from the actinomycete Streptomyces hygroscopicus. It binds to immunophilins, and thus, its mechanism of action is similar to tacrolimus but it does not cause nephrotoxicity or neurotoxicity associated with calcineurin inhibitors. Sirolimus, however, is associated with hypertriglyceridemia and hypercholesterolemia. Our patient was on sirolimus as a calcineurin inhibitor sparing agent due to renal dysfunction. He developed severe hypertriglyceridemia after being on sirolimus for 9 months. Plasmapheresis was initiated and proved to be an effective treatment modality. In this case report, we discuss the proposed mechanism of sirolimus-induced hypertriglyceridemia, the monitoring of a patient on sirolimus, and the benefits of plasmapheresis in such cases. Case Presentation A 59-year-old man with diabetes underwent right lung transplantation for pulmonary fibrosis in 2005. Tacrolimus was replaced with sirolimus because of worsening renal function. The patient had been on sirolimus for 9 months at a dose of 1 mg/day, when he was hospitalized with nonspecific complaints of dizziness, light headedness, chest discomfort, and decreased appetite for 2 weeks. The patient's blood sample was noted to be markedly lipemic. Triglycerides level was 9340 mg/dL (normal range 60–149 mg/dL), total cholesterol was 1362 mg/dL (normal range 160–199 mg/dL), high-density lipoprotein was 78 mg/dL (normal range 40–70 mg/dL), and low-density lipoprotein could not be calculated because of high triglyceride level. Other abnormal values included: sodium 123 mg/dL, glucose 167 mg/dL, HbA1C 8%, creatinine 2.8 mg/dL, and blood urea nitrogen 28 mg/dL. Amylase and lipase levels were normal. Because the patient had cardiac and central nervous system symptoms, plasmapheresis was performed (Fig. 1). After completion of the first session, triglyceride levels fell from 9340 to 2069 mg/dL. A repeat procedure was performed, and triglycerides level decreased further to 594 mg/dL. All symptoms resolved. The patient was placed back on tacrolimus, but his kidney function again deteriorated within a few days. He was discharged on statins, niacin, and a reduced sirolimus dose and tight glucose control. His subsequent triglycerides levels have been consistently less than 380 mg/dL for the last 6 months.FIGURE 1.: Milky-looking plasma after plasmapheresis.DISCUSSION Sirolimus as a single agent does not cause the renal insufficiency that is seen with calcineurin inhibitors. Sirolimus-induced hypertriglyceridemia occurs in up to 45% of patients (1). The increase in triglyceride levels is typically in the range of 50% to 100% (1, 2). Hypertriglyceridemia with sirolimus use is usually dose dependent (2), but our patient's sirolimus level was therapeutic at 11 μg/L. Diabetes does cause hypertriglyceridemia because insulin resistance leads to both overproduction and decreased clearance of triglycerides. However, our patient's degree of hypertriglyceridemia could not be solely explained on the basis of moderately increased blood glucose levels. The dyslipidemia of renal insufficiency is due to urinary lipoprotein loss (3), but our patient had no evidence of proteinuria. He had no history of significant alcohol intake, and his thyroid- stimulating hormone was within normal limits, ruling out alcoholism and hypothyroidism as possible causes of hyperlipidemia. His low sodium was believed to be "pseudohyponatremia," which can be seen in association with hyperlipidemia. As no other cause for hypertriglyceridemia could be found, a sirolimus-induced adverse reaction was the only plausible explanation. The probable mechanism for sirolimus-induced hypertriglyceridemia is believed to be due to enhancement of hormone-sensitive lipase activity and inhibition of lipoprotein lipase activity. These insulin antagonist effects suggest that sirolimus causes hypertriglyceridemia by an insulin-dependent signaling pathway (4). It has also been suggested that sirolimus leads to decreased free fatty acid (FFA) oxidation leading to increased FFA availability (2, 5) and more FFAs for triglyceride synthesis. Case reports suggest that plasmapheresis is safe and effective in patients with hypertriglyceridemia, but the existing evidence is insufficient to definitively establish its efficacy (6). Plasmapheresis lowers triglycerides levels and reduces hyperviscosity of blood (7). It has shown to be most effective when initiated early (8). Plasmapheresis achieves a reported 65% to 85% decrease in triglyceride levels after the first plasma exchange session (9, 10). In our patient, the approximate decrease after each of the two sessions was 78% and 71%, respectively. In summary, this case illustrates severe sirolimus-induced hypertriglyceridemia with an atypical clinical presentation requiring emergent treatment. It also emphasizes the importance of triglyceride monitoring in patients on sirolimus. Our report also supports a role for plasmapheresis as treatment of severe sirolimus-induced hypertriglyceridemia. Sebastian Fernandez-Bussy Olufemi Akindipe Maher Baz Division of Pulmonary and Critical Care Medicine University of Florida Health Sciences Center Gainesville, Florida Priyanka Gosain College of Medical Sciences University of Delhi Delhi, India Amy Rosenberg Division of Pharmacology University of Florida Health Sciences Center Gainesville, Florida Marc Zumberg Division of Hematology and Oncology University of Florida Health Sciences Center Gainesville, Florida