Homozygous familial hypercholesterolaemia: update on management

Homozygous familial hypercholesterolaemia (HoFH) is an inherited disease causing an approximately fourfold increase in blood low-density lipoprotein cholesterol (LDLC) from birth compared with the age-matched normal population owing to reduced low-density lipoprotein receptor (LDLR) activity. Such elevated cholesterol is associated with accelerated atheromatous disease, particularly of the aortic root and coronary arteries. However, HoFH is clinically heterogeneous, reflecting residual low-density lipoprotein receptor (LDLR) activity. The main objective in treating children may be stated to be the avoidance of irreversible cardiac damage requiring heart transplantation by sufficient lowering of blood cholesterol. Lipoprotein apheresis or plasmapheresis are safe means of lowering cholesterol but may be insufficient on their own. Statin drugs, PCSK9 inhibitors ezetimibe and bile acid sequestrants are relatively ineffective if LDLR activity is lacking, but should be used if effective. Two new drugs, lomitapide and mipomersen, have been licensed specifically for HoFH by some regulatory authorities. They work by reducing LDL production rate. They have been associated with fatty liver in adults. Evidence of safety in children is lacking. An alternative is liver transplantation, which replaces the missing LDLR and normalises cholesterol. Clinicians are faced with a dilemma in choosing between these options or deferring such treatment associated with potential harm. Individual case descriptions are an important means of informing clinical judgement. Management of the two cases described in this issue is discussed in the light of modern developments in transplantation and pharmacotherapy.