NIV 2014

Introduction: Cholesteryl-Ester Storage Disease (CESD) is a rare recessive disease caused by mutations in the LIPA gene, encoding lysosomal acid lipase (LAL). LAL deficiency typically results in intra-cellular accumulation of cholesteryl-esters and triglycerides in hepatic, adrenal and intestinal cells. By virtue of this pathological substrate, CESD is characterized by hepatomegaly, splenomegaly and mixed hyperlipidemia. To date, ~140 CESD patients have been reported while the prevalence of the disease has been estimated to be ~1:40,000, which would translate in ~400 patients in the Netherlands. The discrepancy in reported and estimated number of patients is likely to be caused by phenotypical variation of the disease and unawareness among medical professionals. We here report two family cases with an unusual presentation of CESD. Case 1. A 23 year old female was diagnosed with a clinical phenotype of primary hypercholesterolemia (TC 13.1; LDL-C 10.6; HDL-C 1.75; TG 1.69mmol/L). Family screening revealed 2 affected siblings, while parental lipid levels were normal (brother LDL-C 7.7; monozygotic twin LDL-C 10.0; father LDL-C 3.2; mother LDL-C 4.2 mmol/L). No mutation was identified in one of the well annotated genes for either autosomal dominant or recessive hypercholesterolemi (LDLR, APOB, PCSK9 or LDLRAP). Homozygosity for the E8SJ mutation in LIPA was identified upon exome sequencing (Stitziel et al. ATVB 2013), leading to the diagnosis of CESD which was biochemically confirmed by a residual LAL activity of 8% in the proband. ALT levels were mildly increased upto 56 U/L. Magnetic Resonance Spectroscopy showed hepatic cholesteryl-ester accumulation without hepato-splenomegaly. Case 2. A 34 year old male with a medical history of hypercholesterolemia (TC 9.0mmol/L, TC/HDL ratio 16.3) from childhood onwards, was referred because of upper abdominal pain, diarrhea and anal blood loss. Signs of portal hypertension were identified during endoscopy. The combination of bone marrow cytology (‘sea blue histiocytes’ and vacuolated macrophages), liver histology (microvesicular steatosis, bridging fibrosis and lipid laden macrophages), increased LDL-C, and decreased HDL-C levels led to the diagnosis of CESD. Mutation analysis revealed compound heterozygosity for mutations in exon 8 (E8SJM) and exon 10 (T1107G) in LIPA. Family screening also led to this diagnosis in two of probands’ siblings. Conclusion. In patients with hypercholesterolemia of unknown origin, LIPA mutations should be considered. Since the phenotypic characteristics of CESD seem to be largely underreported and the natural course of this disease is (partly) unknown, systematic patient follow-up including both lipids and liver parameters (i.e. transaminases and MRS) is recommended.