Variants of Unknown Significance in Hyperlipidemia: A Diagnostic Quandary

A 39-year-old woman was referred to a secondary care lipidology service after she was found to have severe mixed dyslipidemia at a workplace health check. The total cholesterol concentration was 7.8, nonfasting triglyceride 3.0, high-density lipoprotein cholesterol 1.8, low-density lipoprotein (LDL) cholesterol 5.2 [estimated using the Friedewald equation (1)] and non-high-density lipoprotein cholesterol 6.6 mmol/L. She was an ex-smoker and consumed approximately 5 units of alcohol per week (1 unit is equal to 8 g or 10 mL of pure alcohol). Her medical history was remarkable only for treated hypothyroidism; there was no personal history of atherosclerotic cardiovascular disease. Her mother had hypercholesterolemia, but there were no other relevant findings in the family. On examination, her body mass index was 24.0 kg/m2; there was no corneal arcus and no tendon xanthomata or cutaneous manifestations of dyslipidemia. She described intermittent chest pain, although the history was not typical of angina. Further biochemical investigations revealed hemoglobin A1c 35 mmol/mol, TSH 1.10 mIU/L, total bilirubin 4 µmol/L, alkaline phosphatase 57 U/L, aspartate transferase 13 U/L, gamma-glutamyl transferase 19 U/L, alanine aminotransferase 10 U/L, albumin 47 g/L, urea 4.1 mmol/L, and creatinine 56 µmol/L, all within reference ranges. Lipoprotein(a) was 290 nmol/L, deemed to be in the high risk range for cardiovascular disease (2). Ten-year cardiovascular risk was estimated at 1.4% using the QRISK3 calculator (3). This represented a relative risk of 2.0 compared to a healthy woman of her age and ethnicity. Computed tomography coronary angiography revealed a small focus of calcification in the left anterior descending coronary artery but no occlusive coronary artery disease. The Agatson computed tomography coronary artery calcium score was 14.5 (90th percentile for age and sex).