Homozygous familial hypercholesterolaemia is a life-threatening autosomal-dominant disorder characterised by plasma LDL cholesterol levels >13 mmol/L, extensive xanthomas, and premature and progressive atherosclerotic cardiovascular disease. The frequency of homozygous familial hypercholesterolaemia has been estimated at 1 in 160,000–300,000.Reference Cuchel, Bruckert and Ginsberg 1 Mutations in the LDLR gene are the main cause for familial hypercholesterolaemia; and mutations in the APOB or PCSK9 genes also result in a similar phenotype.Reference Soutar and Naoumova 2 Most patients with homozygous familial hypercholesterolaemia are compound heterozygotes with different mutations in each allele of the same gene, whereas “simple homozygotes” are those who carry the same mutation on each allele.Reference Cuchel, Bruckert and Ginsberg 1 Untreated individuals with homozygous familial hypercholesterolaemia may experience atherosclerotic cardiovascular disease as early as the first decade of life, thus emphasising the need for comprehensive control of hypercholesterolaemia as early as possible; however, knowledge about the safety and efficacy of lipid-lowering agents in children below 8 years of age is extremely scarce.Reference Cuchel, Bruckert and Ginsberg 1 , Reference Nordestgaard, Chapman and Humphries 3 , 4 In this study, we would like to share our experience of achieving >40% LDL cholesterol reduction in four Chinese homozygous familial hypercholesterolaemia children below 8 years of age with a triple combination of statin, probucol, and ezetimibe for >6 years; the longest follow-up was 13 years from the age of 2 years.
Case presentation
Case 1
A 3-year-old girl presented to us in October, 2001 with multiple xanthomas on the Achilles tendon, wrist, and the buttocks (Fig 1, 1-A, 1-B), as well as with plasma LDL cholesterol concentration of 16.2 mmol/L. Her parents had modest hypercholesterolaemia, and DNA sequencing showed that she was heterozygote for two distinct mutations – c.796 G>C and c.1048 C>T – in the LDLR gene. A clinical diagnosis of homozygous familial hypercholesterolaemia with compound heterozygous LDLR mutations was established. With a written consent signed by her parents, the child started to receive therapy, first, with increasing doses of atorvastatin (Atorv 5–30 mg/day), followed by Atorv+probucol (500–750 mg/day) therapy for 4 years, and her LDL cholesterol levels hovered around 11–12 mmol/L. Ezetimibe (Eze, 5–10 mg/day) was, therefore, included along with Atorv+probucol when she was 7 years old. The triple regimen lowered her LDL cholesterol levels to 6–7 mmol/L within 1 year. She has been on a low-cholesterol diet plus Atorv 40 mg, Eze 10 mg, and probucol 1000 mg/day for 6 years without any adverse responses. The most recent test revealed that her serum LDL cholesterol concentration was 7.1 mmol/L, a 56% reduction compared with pre-treatment levels. At present, no xanthomas are recognised anywhere over her body (Fig 1, 1-C, 1-D).
Figure 1 Comparisons of xanthomas between pre-treatment and after treatment for each case.
Case 2
An 8-year-old boy was referred to us in 2007 with xanthomas on his elbows and knees (Fig 1, 2-A, 2-B) and persistent severe hypercholesterolaemia (LDL cholesterol of 12.6 mmol/L), despite 6 months of diet control and Atorv (10 mg/day) treatment. His pre-treatment LDL cholesterol level was 15 mmol/L, and genetic analysis confirmed that he carries two heterozygous mutations – c.1448 G>A and c.1720C>A – in the LDLR gene inherited from his parents. A diagnosis of homozygous familial hypercholesterolaemia with compound heterozygous LDLR mutation was established. With his parents’ consent, Eze (5 mg/day) was added to his diet and atorvastatin regimen. As a result, his LDL cholesterol level declined to 5.97 mmol/L in 2 months, but there was no clear sign of xanthomas regression after 6 months of Atorv+Eze therapy. Subsequently, probucol was added to the regimen, and since July, 2012 he has remained on Atorv 40 mg, Eze 10 mg, and probucol 1000 mg/day up to the present time. A complete regression of xanthomas was achieved 6 years after the triple therapy began (Fig 1, 2-C, 2-D). His latest LDL cholesterol level obtained in April, 2014 was 5.6 mmol/L, a 55% fall compared with the pre-lipid-lowering treatment.
Case 3
A 3-year-old boy was recognised in April, 2006 to have severe elevation of LDL cholesterol (19.2 mmol/L) and multiple xanthomas on the wrists, popliteal and cubital fossae, buttocks, and the Achilles tendon (Fig 1, 3-A, 3-B). He was found to be a carrier of a homozygous mutation – c.605 T>C – in the LDLR gene, and the diagnosis of homozygous familial hypercholesterolaemia was confirmed. Previous atorvastatin, 10–15 mg, monotherapy for 1 year had failed to improve his lipid profile. We prescribed probucol 500–1000 mg in combination with Atorv 20 mg/day for the patient, and the duo therapy effectively lowered his LDL cholesterol to 10.0 mmol/L within 1.25 years. At the age of 4 years, Eze 5 mg/day was included to the regimen in order to further decrease LDL cholesterol levels; however, the plasma level of LDL cholesterol rebounded and hovered around 13 mmol/L during December, 2010–April, 2013. The hypolipidaemic treatment was subsequently intensified, and he has been maintained on a fixed regimen – Atorv 40 mg+probucol 1000 mg+Eze 10 mg/day – up to the present time. His xanthomas have progressively resolved over the years (Fig 1, 3-C, 3-D). His recent LDL cholesterol level measured in April, 2014 was 11.23 mmol/L, a 43% fall compared with the pre-lipid-lowering treatment.
Case 4
A 3-year-old girl presented to us in January, 2009 with multiple xanthomas on the cubital fossa, buttocks, and the creases of her palms and fingers (Fig 1, 4-A, 4-B). Previously, atorvastatin 10 mg monotherapy for nearly 1 year lowered her plasma levels of LDL cholesterol insignificantly, from 19.8 to 18.4 mmol/L. She was found to have two heterozygous mutations – c.2030 G>A and c.1257 C>A – in the LDLR gene via DNA sequencing. Upon diagnosis, the girl was started on Atorv (20 mg)+probucol (500–750 mg/day) duo therapy, and after 5 months the LDL cholesterol level decreased significantly to 14 mmol/L. To obtain a greater reduction in plasma LDL cholesterol levels , Eze 5 mg/day was administrated as an add-on treatment along with up-titrated doses of Atorv and probucol. This resulted in a further decline in LDL cholesterol values to about 10 mmol/L in January, 2010. Since then, the patient has been maintained on Atorv 40 mg+probucol 1000 mg+Eze 10 mg/day with a cholesterol-restricted diet until now. Her latest LDL cholesterol value measured in June, 2014 was 9.6 mmol/L, a 51% fall compared with the pre-lipid-lowering treatment. The triple medication also resulted in a substantial regression of xanthomas (Fig 1, 4-C, 4-D).
Follow-up
At the last follow-up, the four children had grown into cheerful and active children or teenagers, with normal signs of puberty. All the four children remained free from serious adverse effects and cardiovascular events throughout their treatment of >6 years. Their most recent cardiovascular tests including blood pressure and electrocardiogram were all normal. Their echocardiograms were roughly normal except for the thickening of the aortic valve. Their laboratory tests for alanine and aspartate aminotransferases, bilirubin, creatinine kinase, blood urea nitrogen, creatinine, uric acid, and fasting blood glucose levels remained within normal ranges throughout follow-up. Changes from baseline in lipid parameters with lipid-lowering treatment for each case are shown in Figure 2.
Figure 2 Changes from baseline in lipid parameters with lipid-lowering treatment for each case. LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; TG=triglyceride.
Discussion
Homozygous familial hypercholesterolaemia is associated with extremely high risk for premature cardiovascular events and death;Reference Goldstein, Hobbs and Brown 5 , Reference Rader, Cohen and Hobbs 6 therefore, we need to initiate intensive cholesterol control as early as possible.Reference Umans-Eckenhausen, Defesche, Sijbrands, Scheerder and Kastelein 7 Current guidelines recommend that LDL cholesterol targets in children with homozygous familial hypercholesterolaemia are <3.5 mmol/L and advocate initiation of statin-based regimen, ideally initiated in the 1st year of life or at an initial diagnosis.Reference Cuchel, Bruckert and Ginsberg 1 LDL apheresis and liver transplantation are also proposed as efficient lipid-lowering strategies, but have not found general acceptance. The unavailability of LDL aphaeresis in most medical centres, its high cost, and the need for 2- to 3-hour sessions every 1–2 weeks are limiting factors for its use.Reference Naoumova, Thompson and Soutar 8 , Reference Moriarty 9 With regard to liver transplantation, it involves considerable risk and requires life-long immunosuppression.Reference Moini, Mistry and Schilsky 10 The majority of homozygous familial hypercholesterolaemia patients, therefore, would prefer conventional pharmacotherapy over expensive and invasive therapies. Among homozygous familial hypercholesterolaemia populations, however, long-term efficacy and safety data for pharmacological therapy initiated during childhood do not exist.
To our knowledge, this observational study reports the youngest children with homozygous familial hypercholesterolaemia to receive three LDL cholesterol-lowering agents (Atorv+probucol+Eze) in combination and also the longest cases being followed-up so far. Diagnosis of homozygous familial hypercholesterolaemia were confirmed early via DNA analysis. Guardians of each children chose pharmacologic therapy. With limited choices of LDL-lowering drugs in China, we combined step-wise three classes of lipid-modifying agents with distinct mechanisms of action, right at time of diagnosis. In each case, atorvastatin alone or combined with probucol/ezetimibe exerted limited and non-satisfactory reduction in LDL cholesterol. Combining atorvastatin, probucol, and ezetimibe not only achieved significant reduction of LDL cholesterol but also an impressive regression of xanthomas in all cases. They have been on a low-cholesterol diet plus Atorv 40 mg, Eze 10 mg, and probucol 1000 mg/day up to the present time, with a follow-up duration of 6–13 years. Compared with the pre-treatment levels, three of the patients (compound heterozygotes) achieved >50% reduction in LDL cholesterol (51.5–56.3%), one boy (simple homozygote) had 42.76% decreases in LDL cholesterol levels at the last visit before drafting this manuscript. More importantly, all the children remain free from treatment-related adverse responses and cardiovascular events throughout follow-up.
Despite that LDL cholesterol remains higher than the ideal target, such combination medication have indeed delayed the occurrence of clinical atherosclerotic cardiovascular disease and have given hope to the affected individuals who have no access to more efficacious therapeutic options, especially in undeveloped and developing regions; however, more controlled studies in larger cohorts are absolutely needed to validate the efficacy and safety of such statin–probucol–ezetimibe triple therapy for lipid control in young children with homozygous familial hypercholesterolaemia. In addition, the number of therapeutic strategies has increased following approval of lomitapide and mipomersen for homozygous familial hypercholesterolaemia, and these new agents represent a promising approach for refractory hypercholesterolaemia.
Acknowledgements
None.
Financial Support
This work was supported by National Programme on Key Basic Research Project of China (973 Program) (No. 2012CB517504) and the Fundamental Research Funds of the Central Universities of Central South University (No. 2014zzts086) (to L.M.J).
Conflicts of Interest
None.
Supplementary material
To view supplementary material for this article, please visit http://dx.doi.org/10.1017/S1047951115000591
