Homozygous familial hypercholesterolemia evaluation and survival single center study in Saudi Arabia: The HESSA registry

Abstract

Background and aims background: Homozygous Familial Hypercholesterolemia (HoFH) is a rare, life-threatening genetic disorder causing extremely high low density lipoprotein cholesterol (LDL-C) levels, leading to early cardiovascular disease (CVD) and premature death. In Saudi Arabia, where consanguinity is common, HoFH prevalence is higher with unique genetic pathogenic familial hypercholesterolemia (FH) causing variants and treatment challenges. This study aims to analyze the clinical, genetic, treatment, and cardiovascular outcomes data of Saudi pediatric and adult HoFH patients treated at King Faisal Specialist Hospital & Research Centre (KFSHRC) over 23 years.

Methods: A retrospective review of all patients (LDL-C >8 mmol/L) at KFSHRC (2000-2023) using European Atherosclerosis Society 2023 criteria to confirm HoFH. Data from those confirmed included demographics, lipid profiles, pathogenic FH-causing variants, treatments, mortality, and cardiovascular outcomes.

Results: Among 514 severe hypercholesterolemia cases, 127 had HoFH. Diagnosis occurred at an average age of 14.3 ± 9.7 years. The mortality was 16 %, and 12 % were lost to follow-up. Cardiovascular interventions were performed in 31 % (coronary interventions in 28 % and aortic valve replacement in 17 %). The most common pathogenic FH-causing variants (57 %) was the founder null mutation c.2027del p.(Gly676Alafs∗33). Statins and ezetimibe were the primary treatments (73 %), but many required LDL-apheresis (36 %) or liver transplantation (LTx) (21 %). The peri-operative mortality for LTx was 7 %, but there was no long-term mortality on average follow-up of 6.2 ± 3.6 years, with only one patient requiring percutaneous coronary intervention. Adults were more likely to receive statins/ezetimibe (94 %/91 % vs. 50 %/53 % in pediatrics, p < 0.01) and LDL-apheresis (64 % vs. 8 %, p < 0.001), while liver transplantation was more common in children (38 % vs. 7 %, p < 0.001).

Conclusions: This study highlights the burden of null LDL-R pathogenic FH-causing variants and the frequent need for invasive treatments in Saudi HoFH patients. Liver transplantation is a viable option with low peri-operative mortality and favorable long-term disease-free survival. Early diagnosis, regional genetic screening, and access to advanced therapies are essential in achieving better outcomes.