The untreated lipoprotein profile of our CESD patient revealed not only a combined hypercholesterolemia and hypertriglyceridemia, but also a severe hypoalphalipoproteinemia, indicating that mutations in LIPA are a rare genetic cause of complex dyslipidemia. Of course, this is in the context of numerous systemic abnormalities, specifically hepatomegaly. We also showed improvement of the plasma lipoprotein profile with low fat diet, with further improvement with statin monotherapy and even further improvement with the addition of ezetimibe in combination with the statin.
Lovastatin has been shown to be safe and effective in treating hypercholesterolemia over the long term in adults [26
]. The ~80 month treatment period for our proband was among the longest time spans for any of our young patients with respect to duration of statin therapy. Over this period, the patient's hepatomegaly improved clinically and the AST and CK have remained stable. The addition of ezetimibe was associated with further improvement of plasma lipoproteins, and was also well tolerated in combination with statin treatment.
Statins have previously been successfully used in adolescents with CESD with some variability in reported efficacy [8
]. This may be explained by genetic heterogeneity in response to lovastatin or by underlying differences in the factors responsible for the hyperlipidemia [3
] Statins block the conversion of 3-hydroxymethylglutaryl-coenzyme A (HMGCoA) to mevalonate, a rate limiting step in cholesterol biosynthesis. This results in an increase in the number and activity of LDL receptors on the hepatocyte membrane, and the rate of LDL catabolism increases. In patients with CESD, the increased activity of the LDL receptors theoretically could lead to increased accumulation of cholesteryl esters in the liver [4
]. However, Ginsberg et al
] showed no change in hepatic cholesteryl ester accumulation after 8 months of lovastatin 40 mg daily in a 9 year old girl with CESD. Furthermore, our patient had reduced hepatomegaly clinically, suggesting that cholesteryl ester accumulation in the liver was unlikely.
Our findings also suggest that ezetimibe may be a useful treatment in patients with CESD. Ezetimibe interferes with the normal function of the NPC1L1
gene product, which regulates sterol absorption in the small intestine [15
]. This is thought to result in depletion of hepatic cholesterol and upregulation of hepatic LDL receptors. The mean plasma LDL-C reduction seen with ezetimibe is ~20%, and this has been remarkably consistent across patient subgroups defined by age, gender, ethnic background and concomitant use of other lipid regulating agents, such as statin drugs [20
]. Inter-individual genetic variation may also play a role in the response to ezetimibe; for instance, a subset of individuals with a particular NPC1L1
haplotype appears to have a larger plasma LDL-C response [28
]. Combination therapy for hypercholesterolemia may allow more patients to achieve target plasma TC and LDL-C goals. We observed that coadministration of ezetimibe with lovastatin resulted in reduction in plasma LDL-C concentration of 16% compared to lovastatin alone. Ezetimibe appeared to be well tolerated by our patient and there were no reported adverse effects. Ezetimibe added to lovastatin did not result in an increase in muscle enzymes. In fact, serum CK (mean ± SD) actually decreased from 185 ± 156 with statin monotherapy to 120 ± 68 during combination treatment with the statin and ezetimibe. AST levels never exceeded the upper limit of normal at any time. The complementary mechanism of action of ezetimibe and statins may offer a new treatment alternative for dyslipidemia management in CESD patients.