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.
Keywords: ADH, autosomal dominant hypercholesterolaemia, refers to hypercholesterolaemia owing to a single mutation of an allele of a gene affecting LDLR activity; APOB, apolipoprotein B, is the main protein component of LDL and is the ligand for LDL receptors in the liver; ARH, autosomal recessive hypercholesterolaemia, refers to hypercholesterolaemia owing to a mutation of both alleles of a single gene affecting LDLR activity; Evolucomab; FH, familial hypercholesterolaemia, is an inherited condition causing reduced LDLR activity with consequent hypercholesterolaemia; HeFH, heterozygous familial hypercholesterolaemia, is caused by one mutant allele of genes affecting LDLR activity; HoFH, homozygous familial hypercholesterolaemia is caused by two mutant alleles of genes affecting LDLR activity; Homozygous familial hypercholesterolaemia; LDL, low-density lipoprotein, is a complex of cholesterol attached to a lipoprotein particle which is removed from blood mainly by the liver; LDLC, LDL cholesterol, refers to the cholesterol component of LDL; LDLR, LDL receptors, mediate LDL uptake by the liver; LDLRAP1, a protein called LDLR adaptor protein 1, facilitates LDLR function; Lipoprotein apheresis; Liver transplantation; Lomitapide; Microsomal triglyceride transfer protein is an enzyme involved in the hepatic assembly of triglyceride, cholesterol and APOB into triglyceride-rich particles which are secreted by the liver. These particles are metabolised to LDL; PCSK9; PCSK9, a protein called proprotein convertase subtilisin/kexin type 9, increases the rate of degradation of LDLR.