【論文摘要】Familial Hypercholesterolaemia A Therapeutic Challenge Akira Yamamoto Memorial Lecture

10.6907/SCJ.201909/SP_1(2).0195

Edward Denis Janus

海峽循環醫學雜誌

1卷2S期（2019 / 09 / 01）

234 - 234

英文

Familial Hypercholesterolaemia (FH) usually due to one of numerous LDL receptor gene mutations causing failure to remove circulating LDL occurs in 1 in 250 people worldwide. FH heterozygotes have elevated LDL cholesterols (LDL-C) from birth and untreated develop premature coronary heart disease (CHD) commonly fatal before age 60. Premature corneal arcus and tendon xanthomas occur in some not all untreated patients. FH Homozygotes have extremely high total (TC) and LDL-C, tendon and cutaneous xanthomas, very early onset CHD and aortic stenosis and untreated commonly die before age 20. Bile acid sequestrants, nicotinic acid, fibrates and probucol reduced LDL-C by 10-20% in heterozygotes but RCTs could not demonstrate clinical benefit. Homozygotes improved when LDL apheresis, which Akira Yamamoto pioneered in Japan in 1979, was added to medications. In 1978 he first used compactin (a HMG-CoA reductase inhibitor and prototype statin) donated by Dr Endo to treat a homozygous patient reducing TC from 900mg/dL to 720mg/dL and a severely affected heterozygote reducing TC from 400 to 250 mg/dL. Statin therapy then escalated rapidly with proven 30% or more LDL-C reductions and clearly demonstrated clinical benefits in numerous RCTs. Dramatic improvement in outcomes for FH heterozygotes in Netherlands triggered case finding and cascade testing. Case finding at vaccination of one year olds and subsequent cascade testing has also been shown to be effective. Worldwide case finding remains a major challenge A few FH patients have mutations of apoB in LDL so it doesn’t bind to LDL receptors. The protein PCSK- 9 prevents LDL receptors recycling. Gain of function mutations cause severe FH but loss of function mutations cause very low LDL-C without adverse effects and with evidence for reductions in CHD. PCSK- 9 inhibitors have been rapidly developed, trialed and put into clinical use. They lower LDL-C by 50-60% alone or when added to statins and ezetimibe. They allow FH heterozygotes to reach LDL-C of 70mg/dL or better. In FH Homozygotes they reduce LDL-C by around 30% except in individuals totally lacking LDL receptors. The newer drugs Mipomersin and Lomitapide are added in treating homozygotes whose life expectancy has improved greatly. Another genetically inherited CVD risk factor is lipoprotein (a) and coexistence of increased Lipoprotein (a) with FH further increases CHD risk. Nicotinic acid and in some cases PCSK-9 inhibitors reduce this but clinical benefit is unproven and awaits RCTs of anti-sense oligonucleotide treatments which in recent studies reduced Lipoprotein (a) by over 80%.