Homozygous familial hypercholesterolemia (HoFH) is a rare, life-threatening, inherited condition characterized by extremely elevated levels of low-density lipoprotein cholesterol (LDL-C). Patients are at high risk of atherosclerotic cardiovascular disease, adverse cardiovascular events, and associated early mortality. Liver transplant is sometimes used with curative intent. The objective of the current case series was to evaluate the follow-up of a range of patients who have undergone liver transplant for the treatment of HoFH.
Patients with clinical and/or genetic diagnoses of HoFH were treated according to local practices in four units in Europe and the Middle East. All patients underwent liver transplantation. Baseline and long-term follow-up data were collected, including LDL-C levels, DNA mutations, lipid-lowering medications, and complications due to surgery and immunosuppressive therapy.
Nine patients were included with up to 22 years\' follow-up (mean ± SD 11.7 ± 11.7 years; range 0.5-28 years). Three of the patients died as a result of complications of transplant surgery (mortality rate 33%). Among the surviving six patients, four required continued lipid-lowering therapy (LLT) to maintain LDL-C levels and two patients show signs of increasing LDL-C levels that require management. One case (11%) required two consecutive transplants to achieve a viable graft and is awaiting a third transplant because of graft failure.
Liver transplant did not enable attainment of recommended LDL-C targets in most patients with HoFH, and the majority of patients still required post-transplant LLT. Liver transplant was not curative in most of the patients with HoFH followed. Guidelines suggest that transplant is a treatment of last resort if contemporary treatments are not available or possible.

Familial hypercholesterolemia (FH) is a genetic autosomal dominant disorder caused by an impaired receptor-mediated low-density lipoprotein (LDL) removal from the circulation, mainly due to disruptive autosomal co-dominant mutations in the LDL receptor (LDLr) gene, but also less frequently in the apolipoprotein B100 (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. A rare form of autosomal recessive FH has been also described due to LDLr adaptor protein 1 (LDLRAP1) gene mutations. FH is characterized by very high levels of plasma LDL cholesterol associated with the high incidence of premature atherosclerotic cardiovascular disease (CVD). Despite heterozygous FH (HeFH) patients are still poorly recognized and treated, there is today a large availability of drugs (i.e., statins, ezetimibe and PCSK9 inhibitors) allowing theoretically the normalization of plasma LDL cholesterol levels in this population. Homozygous FH patients (HoFH) have a more severe form of FH, characterized by low responsiveness to the conventional lipid-lowering treatment and often associated with unfavorable prognosis in the young age. Inspired by promising outcomes obtained by orthotopic liver transplantation (OLT), scientists are investigating the possibility of correcting the defective LDLr in these patients by using gene therapy approaches to achieve a novel therapeutic solution with high efficiency. In this article, we tried to review the in vitro, ex vivo, and in vivo attempts conducted to correct FH-causing LDLr gene mutations by using different methods of gene delivery, gene editing, and stem cell manipulation. We also discussed some clinical trials performed in this context.