Prevalence, clinical characteristics, and etiologic spectrum of extremely low levels of high-density lipoprotein cholesterol in Thai patients: a single-center study

Extremely low high-density lipoprotein cholesterol (HDL-C) is uncommon and may result from secondary conditions or rare genetic disorders. Data on persistently low HDL-C in Southeast Asians remain limited. We aim to determine the prevalence, clinical characteristics, underlying etiologies, and clinical outcomes of patients with persistent low HDL-C. This retrospective cohort study evaluated adults with persistently low HDL-C (<30 mg/dL) identified via laboratory and electronic medical records between January 2020 and December 2024. Patients were stratified into two phenotypes based on baseline HDL-C severity: markedly low (20–29 mg/dL) or extremely low (<20 mg/dL). Among 217,481 individuals undergoing lipid testing (1,053,662 HDL-C measurements), 164 patients had persistently low HDL-C (mean age, 56.9 years; 68.9% male). The prevalence of persistently low and extremely low HDL-C was 0.08% and 0.008%, respectively. Concomitant hypertriglyceridemia affected ∼75% of patients. Most cases were associated with secondary conditions. Extremely low HDL-C was more frequently associated with liver disease (41.2%) and active malignancy (29.4%), whereas metabolic syndrome predominated among patients with markedly low HDL-C (42.2%). During a median follow-up of 2.57 years, all-cause mortality was higher in the extremely low HDL-C group (29.4% vs. 11.6%; hazard ratio, 4.33; 95% CI, 1.58–11.91; p = 0.004), while atherosclerotic cardiovascular disease rates were similar between groups (35.3% vs. 32.0%). Persistently low HDL-C is an exceedingly rare phenotype driven primarily by secondary systemic conditions. An extremely low HDL-C level appears to be a marker of severe underlying systemic illness and was associated with higher short-term mortality. Persistently low HDL-C is exceptionally rare and is predominantly associated with secondary systemic conditions, particularly hypertriglyceridemia, metabolic syndrome, liver disease, and malignancy.Extremely low HDL-C (<20 mg/dL) identifies a distinct high-risk phenotype, characterized by a greater association with liver disease and malignancy and a substantially higher all-cause mortality than HDL-C 20–29 mg/dL.Extremely low HDL-C should prompt systematic evaluation for underlying systemic illness rather than being viewed as an isolated lipid abnormality, with particular attention to liver disease, malignancy, hypertriglyceridemia, and metabolic disorders. Persistently low HDL-C is exceptionally rare and is predominantly associated with secondary systemic conditions, particularly hypertriglyceridemia, metabolic syndrome, liver disease, and malignancy. Extremely low HDL-C (<20 mg/dL) identifies a distinct high-risk phenotype, characterized by a greater association with liver disease and malignancy and a substantially higher all-cause mortality than HDL-C 20–29 mg/dL. Extremely low HDL-C should prompt systematic evaluation for underlying systemic illness rather than being viewed as an isolated lipid abnormality, with particular attention to liver disease, malignancy, hypertriglyceridemia, and metabolic disorders.