† Elevated HDL in familial hyper-alpha-lipoproteinemia: Atheroprotective or atherogenic?

Background/Synopsis

Familial hyper-alpha-lipoproteinemia (HALP) is a heterogenous genetic lipid disorder that is found in only 8% of the population and manifests as elevated high-density lipoprotein (HDL) levels above the 90th percentile. HALP is due to mutations in various genes including cholesteryl ester transfer protein (CETP), hepatic lipase, or apolipoprotein C-III (APOC3).

Objective/Purpose

While epidemiological studies have noted an inverse relationship between high HDL and the development of coronary artery disease, recent data have shown a lack of causal atheroprotective effects. Thus, the purpose of this case is to highlight a patient with significantly elevated HDL and peripheral vascular disease.

Methods

Patient is a 64-year-old female with past medical history of peripheral vascular disease of the right lower extremity status post angioplasty with subsequent development of left lower extremity pseudoaneurysm status post resection and thrombectomy, hypertension, type 2 diabetes, alcohol and tobacco use, and CKD Stage 4 who presented to the advanced lipid clinic for management of elevated lipoproteins. Patient's labs were significant for a total cholesterol (TC) of 375 mg/dL, HDL of > 200 mg/dL, triglycerides (TG) of 66 mg/dL, and a low-density lipoprotein (LDL) of 175 mg/dL. Apolipoprotein A-I was elevated at 231 mg/dL.

Results

Patient was uptitrated to a high intensity statin with improvement in her lipid panel with a TC of 191 mg/dL, HDL of 120 mg/dL, TG of 57 mg/dL, and LDL of 60 mg/dL, achieving target LDL < 70 mg/dL. Abdominal ultrasound was obtained to rule out secondary causes of elevated HDL and was unremarkable. Tobacco and alcohol cessation were advised.

Conclusions

CETP exchanges cholesteryl esters from HDL in exchange for TG, making HDL smaller and more TG-rich. Studies have shown that in vitro addition of CETP and hepatic lipase, which hydrolyzes phospholipids and TG, into CETP-deficient patients led to the development of very small HDL particles that were able to remove cholesterol from lipid laden macrophages. Conversely, larger HDL molecules seen in CETP-deficient patients did not have such anti-atherogenic properties. This case highlights the importance of recognizing HALP in the setting of elevated HDL, but also of excluding secondary causes of elevated HDL, such as primary biliary cirrhosis and high dose niacin. Genetic testing and evaluation of coronary artery disease via cardiac catheterization should also be considered.

Previously Published: Circulation, American Heart Association Scientific Sessions 2024