Professor University of British Columbia Vancouver, British Columbia, Canada
Case background: A four-year-old male of Lebanese origin was referred after being noted to have multiple tuberous skin xanthomas. Family history was notable for his mother having untreated low-density lipoprotein cholesterol (LDL-C) of 9.74 mM and father 6.65 mM. The patients’ LDL-C on no treatment was 26.0 mM. At initial presentation a fat-restricted diet plus rosuvastatin 20 mg and ezetimibe 10 mg daily had been started, but LDL-C had only dropped to 22.4 mM. There were no other stigmata of hyperlipidemia. Past medical history was otherwise unremarkable.
Genetic testing revealed the patient is homozygous for LDL Receptor (LDLR) p.Cys681; c2043C>A, a common Lebanese variant resulting in truncated LDLR protein with less than 2% residual activity (“LDL receptor null”), on both LDLR alleles. The parents were not aware of being related. Carotid ultrasound revealed bilateral calcified plaques. Additional laboratory tests including lipoprotein(a) were unremarkable.
Management Challenges: In addition to statin and ezetimibe treatment, the patient was considered too small to initiate LDL apheresis or plasma exchange (PLEX). Liver transplant was considered, but due to lack of experience with the procedure in children at our center and opposition by the parents it was not pursued. The family returned to Lebanon and the patient remained on statin and ezetimibe treatment alone. At age 13 the patient and his family returned to Canada, at which time the rosuvastatin dose was increased to 40 mg daily, and along with ezetimibe 10 mg daily resulted in average LDL-C level of 18.4 mM. As expected, a trial of the PCSK9 inhibitor evolocumab resulted in no reduction in LDL-C due to absence of LDLR activity. LDL apheresis was not available at our site. PLEX via bilateral antecubital vein access was initiated at 2 weekly intervals along with rosuvastatin and ezetimibe, was well tolerated, and following which average LDL-C level achieved just prior to the next PLEX treatment was 11.6 mM. Addition of PLEX resulted in resolution of all skin xanthomas. Lomitapide was added at age 16 and titrated gradually to 25 mg daily, which was generally well tolerated. Average LDL-C achieved pre-PLEX while taking lomitapide 25 mg daily was 3.62 mM. PLEX frequency was reduced to every 4 weeks. Alanine aminotransferase (ALT) level rose from normal to an average 87 U/L or 1.75-fold above normal limits while on lomitapide 25 mg daily (normal < 50 U/L, patient range 56-128 U/L). Liver ultrasound revealed new-onset mild fatty liver following addition of lomitapide, with no fibrosis by fibroscan. Evinacumab 15 mg/kg delivered IV after PLEX every 4 weeks was added to all other treatments at age 19. Time averaged LDL-C just prior to PLEX in the year following addition of evinacumab was 1.97 mM, a 45% further reduction in LDL compared to all other treatments, despite a reduction in lomitapide dose to 20 mg daily. At age 16 the patient complained of mild chest tightness on exertion; coronary catheterization revealed a 40% stenosis of the left main coronary; ASA 81 mg daily was initiated. He has subsequently remained free of vascular symptoms. Coronary CT angiogram 6 months prior to addition of evinacumab revealed 1-24% noncalcified stenosis of the right, 25-49% calcified stenosis of the left main, and 25-49% noncalcified stenosis of D1 coronary arteries. Repeat coronary CT angiogram 3.5 years after initiation of evinacumab revealed no significant plaque progression from the previous exam.
DISCUSSION HoFH is a rare and severe genetic disorder occurring in 1 in 350,000 individuals worldwide that leads to profoundly elevated LDL-C levels and a high risk of mortality due to atherosclerotic cardiovascular disease (ASCVD) before age 20 if untreated. True HoFH as in this case involves identical variants on both LDLR alleles (biallelic identical variants), with our patient having a common Lebanese LDLR variant resulting in < 2% residual LDLR activity (“LDLR null"). For such patients multiple modes of treatment are required to attempt to achieve recommended LDL-C targets for primary or secondary prevention of ASCVD (Figure 1 indicates average and lowest LDL-C level achieved with the indicated treatments). While statins have the majority of their effect by stimulating upregulation of LDL receptors in the liver, they can still lower LDL-C in the absence of LDLR activity by limiting the availability of cholesterol for production of very low-density lipoproteins (VLDL) by the liver. Ezetimibe similarly has the majority of its effect by stimulating LDLR expression in the liver, but has some effect on lowering LDL-C by reducing return of cholesterol from the intestine to the liver that can be used for VLDL production. While LDL apheresis is the preferred form of extracorporeal removal of plasma LDL-C, PLEX can be used in the absence of availability of this therapy and can achieve LDL-C lowering similar to LDL apheresis. PLEX reduces LDL-C acutely by removal of plasma in exchange for albumin replacement, and is generally well tolerated. Recent years have seen the introduction of novel treatments that can lower LDL-C in HoFH patients by mechanisms that do not require upregulation of the LDL receptor. Lomitapide inhibits microsomal triglyceride transfer protein, which reduces lipidation of apolipoprotein B in the liver and intestine, thereby inhibiting VLDL and chylomicron production. Potential side effects include hepatic steatosis and steatorrhea, particularly if dietary fat is not markedly restricted. Liver ultrasound showed onset of mild hepatic steatosis following addition of lomitapide, but no evidence of liver fibrosis to date. Evinacumab is a monoclonal antibody inhibitor of angiopoietin-like protein 3 (ANGPTL3), reduction of which allows lipoprotein lipase and endothelial lipase to increase hydrolysis and hepatic clearance of VLDL and VLDL remnants, thereby reducing conversion to LDL. Evinacumab can lower LDL-C in HoFH a further 43% on top of existing treatments in patients with null-null LDLR variants and 49% in patients with non-null LDLR variants, irrespective of the initial LDL-C level. The availability of lomitapide and evinacumab along with his other treatments has therefore allowed our patient with the most severe form of HoFH to achieve LDL-C levels that were previously unattainable, and hopefully halt the progression of his atherosclerosis.
