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Successful pharmacological management of a child with compound heterozygous familial hypercholesterolemia and review of the recent literature.
Sreedharan, AV, Pek, SLT, Tan, TH, Tavintharan, S, Yap, F
Journal of clinical lipidology. 2020;(5):639-645
Abstract
Severe familial hypercholesterolemia (SFH) is characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) and severe early-onset cardiovascular disease if left untreated. We report on the decade-long therapeutic journey of a 15-year-old boy with SFH due to a severe compound heterozygous genotype. He presented at the age of 5 years with widespread xanthomas and LDL-C of 17.4 mmol/L. He was diagnosed with SFH, initially treated with colestyramine that was subsequently combined with simvastatin. At the age of 12 years, he was diagnosed to have supravalvular aortic stenosis and ezetimibe/atorvastatin was introduced in place of colestyramine/simvastatin. At the age of 14 years, he received triple therapy with evolocumab, initially at the recommended dose of 420 mg monthly and then reduced to 140 mg biweekly. Currently at the age of 15 years, he is on atorvastatin 40 mg ON, ezetimibe 10 mg OM, and evolocumab 140 mg biweekly, achieving LDL-C levels of 2.4 mmol/L. Genetic testing identified compound heterozygous mutations in the LDL receptor genes [c.(940 + 1_941-1) (1845 + 1_1846-1)dup] and exon 12, nucleotide c.1747 C > T, amino acid p.(His583Tyr). Medical management without lipoprotein apheresis can achieve target LDL-C in children with SFH. Our patient, who developed supravalvular aortic stenosis at the age of 12 years, needed early aggressive treatment when SFH guidelines and newer drugs for young children were unavailable. Our patient demonstrated that 140 mg biweekly of evolocumab has the same cholesterol-lowering effect as the recommended 420 mg monthly dose.
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Improvement in arterial stiffness after short-term treatment with PCSK9 inhibitors.
Cicero, AFG, Toth, PP, Fogacci, F, Virdis, A, Borghi, C
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2019;(5):527-529
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3.
Managing homozygous familial hypercholesterolaemia from cradle to grave.
Thompson, GR
Atherosclerosis. Supplements. 2015;:16-20
Abstract
OBJECTIVE To describe the phenotypic and genotypic features and management of clinically homozygous familial hypercholesterolaemia (FH). METHODS An analysis of current knowledge based on personal experience and published evidence. RESULTS Atherosclerotic involvement of the aortic root is common in homozygous FH and can cause death before age 5. Receptor negative patients are at greatest risk, irrespective of whether they have identical mutations (homozygous) or dissimilar mutations (compound heterozygous). CONCLUSIONS Lipoprotein apheresis combined with high dose statin and ezetimibe slows but does not arrest progression of atherosclerosis. Adjunctive use of novel compounds such as lomitapide and evolocumab should facilitate achieving the latter objective by enhancing the reduction in LDL cholesterol.
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4.
Clinical experience of lomitapide therapy in patients with homozygous familial hypercholesterolaemia.
Cuchel, M, Blom, DJ, Averna, MR
Atherosclerosis. Supplements. 2014;(2):33-45
Abstract
The microsomal triglyceride transfer protein (MTP) inhibitor lomitapide is a licenced adjunct to a low-fat diet and other lipid-lowering medication, with or without low-density lipoprotein apheresis, for the treatment of adults with homozygous familial hypercholesterolaemia (HoFH). In a recently published phase 3 study, patients with HoFH received lomitapide in addition to maximally tolerated lipid-lowering therapy. Treatment with lomitapide resulted in a mean approximate 50% reduction in LDL-C levels after 26 weeks compared with baseline levels (p < 0.0001). This decrease in LDL-C was maintained at Weeks 56 and 78 (44% [p < 0.0001] and 38% [p = 0.0001], respectively). This paper offers clinical perspectives based on selected case histories of patients participating in the phase 3 lomitapide study. These cases provide illustrative examples of the efficacy of lomitapide, with or without apheresis, and show that the effective management of adverse effects can enable patients to remain on effective treatment.
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5.
Current therapy for patients with sitosterolemia--effect of ezetimibe on plant sterol metabolism.
Tsubakio-Yamamoto, K, Nishida, M, Nakagawa-Toyama, Y, Masuda, D, Ohama, T, Yamashita, S
Journal of atherosclerosis and thrombosis. 2010;(9):891-900
Abstract
Sitosterolemia is a rare, autosomal recessive inherited sterol storage disease associated with high tissue and serum plant sterol concentrations, caused by mutations in the adenosine triphosphate-bind-ing cassette (ABC) transporter ABCG5 or ABCG8 genes. Markedly increased serum concentration of plant sterols. such as sitosterol and campesterol, cause premature atherosclerosis and massive xanthomas. Hitherto known treatments for sitosterolemia, including a low-sterol diet, bile-salt binding resins, ileal bypass surgery and low density lipoprotein (LDL) apheresis have not yielded sufficient reduction of serum plant sterol levels and many patients show a sustained elevation of plant sterol levels, subsequently developing premature atherosclerotic cardiovascular diseases. Ezetimibe, an inhibitor of intestinal cholesterol absorption through its binding to Niemann-Pick C1-like 1 (NPC1L1), has been widely used for decreasing serum LDL-cholesterol levels in patients with hypercholesterolemia. Ezetimibe also reduces the gastrointestinal absorption of plant sterols, thereby also lowering the serum concentrations of plant sterols. This pharmacological property of ezetimibe shows its potential as a novel effective therapy for sitosterolemia. In the current review, we discuss the current therapy for patients with sitosterolemia and present two Japanese adolescent patients with this disease, one of whom underwent percutaneous coronary intervention for accelerated coronary atherosclerosis. Ezetimibe administration in addition to conventional drug therapy successfully reduced serum sitosterol levels by 51.3% and 48.9%, respectively, in the two patients, demonstrating ezetimibe as a novel and potent treatment agent for sitosterolemia that could work additively with conventional drug therapy.
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6.
Statin-associated myopathy with normal creatine kinase levels.
Phillips, PS, Haas, RH, Bannykh, S, Hathaway, S, Gray, NL, Kimura, BJ, Vladutiu, GD, England, JD, ,
Annals of internal medicine. 2002;(7):581-5
Abstract
BACKGROUND Muscle symptoms in patients who are treated with statins and have normal creatine kinase levels are not well understood. OBJECTIVE To report biopsy-confirmed myopathy and normal creatine kinase levels associated with statin use. DESIGN Case reports from preliminary analysis of an ongoing clinical trial. SETTING Clinical research center in a community hospital. PATIENTS Four patients with muscle symptoms that developed during statin therapy and reversed during placebo use. MEASUREMENTS 1) Patients' ability to identify blinded statin therapy and 2) standard measures of functional capacity and muscle strength. RESULTS All four patients repeatedly distinguished blinded statin therapy from placebo. Strength testing confirmed weakness during statin therapy that reversed during placebo use. Muscle biopsies showed evidence of mitochondrial dysfunction, including abnormally increased lipid stores, fibers that did not stain for cytochrome oxidase activity, and ragged red fibers. These findings reversed in the three patients who had repeated biopsy when they were not receiving statins. Creatine kinase levels were normal in all four patients despite the presence of significant myopathy. CONCLUSION Some patients who develop muscle symptoms while receiving statin therapy have demonstrable weakness and histopathologic findings of myopathy despite normal serum creatine kinase levels.
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7.
Patient profile: secondary prevention.
Hobbs, FD
International journal of clinical practice. Supplement. 2002;(130):13-4