The Case of Negative Low Density Lipoprotein Cholesterol

Accurate estimation of low-density lipoprotein cholesterol (LDL-C) is critical for lipid assessment and cardiovascular risk stratification, yet conventional calculation methods may fail in specific clinical contexts in pediatric population. The Friedewald equation, long considered standard, is unreliable in moderately elevated TG (TG ≥400 mg/dL) and in low total cholesterol (TC) scenarios. Alternative equations, including Martin-Hopkins and Sampson-NIH, have been developed to improve accuracy, but pediatric validation remains limited. We present two pediatric cases highlighting these challenges. Case 1 involved a 5-year-old male with perinatally acquired HIV/AIDS, low TC, and moderately elevated triglyceride (TG) <300 mg/dL. Friedewald-calculated LDL-C was negative, while direct beta-quantification revealed LDL-C of 36 mg/dL and Martin-Hopkins equation underestimated LDL-C by 70%. Case 2 involved a female with type 2 diabetes and high-risk B-cell acute lymphoblastic leukemia, with extreme hypertriglyceridemia >1000 mg/dL and elevated TC. In this case, both Friedewald and Martin-Hopkins calculations failed, whereas Sampson-NIH 2025 provided a calculable LDL-C of 26 mg/dL. These cases demonstrate that TG-to-TC ratios, rather than TG alone, predict calculation failure, and that alternative equations, particularly Sampson-NIH 2025, offer improved reliability. These findings are especially relevant for patients receiving cholesterol-lowering therapies, in whom low LDL-C and elevated TG may lead to significant underestimation of residual atherogenic risk. Further studies using comparative beta-quantification are needed to identify the most accurate LDL-C estimation methods across diverse pediatric populations and low-cholesterol states.