The importance of identifying pseudohypertriglyceridaemia

Dear Editor,

Hypertriglyceridaemia features prominently in the recent statement on standardising lipid testing and reporting in the United Kingdom; however, the importance of excluding pseudohypertriglyceridaemia is not mentioned. ¹ Awareness and detection of this analytical interference is important to avoid unnecessary interventions and may identify clinically significant inherited disorders of glycerol metabolism.

Pseudohypertriglyceridaemia is caused by increased serum glycerol which exerts positive interference in routine triglyceride (TG) assays, the first step of which is the enzymatic hydrolysis of TG by lipase releasing free glycerol. ² The cause of increased glycerol may be exogenous, such as ingestion of slushie drinks, certain alcoholic beverages or soap,^3–5 or may be due to one of two inherited disorders of glycerol metabolism. Patients with fructose-1,6-bisphosphatase deficiency exhibit transient hyperglycerolaemia during periods of metabolic stress. ⁶ Glycerol kinase deficiency (GKD) in contrast causes persistently elevated glycerol and therefore has particular potential for diagnostic confusion. ⁷

Patients with GKD are often asymptomatic, ⁷ but if serum triglycerides are measured, the apparent hypertriglyceridaemia may result in referral to specialist lipid services leading to multiple appointments and exposure to unnecessary medications.^2,7

How can pseudohypertriglyceridaemia be detected? This may be suspected by the clinician when results are unexpected or refractory to treatment.^2,7 The laboratory also has an important role to play: a discrepantly low lipaemia index (LI) or lack of sample turbidity in the presence of increased TG gives an early opportunity to identify glycerol interference. ⁵

Expected LI cut-offs have been calculated for a range of serum TG concentrations using Roche methods, which other Roche users may wish to validate and use for themselves. ⁵ LI results below these cut-offs should lead to further investigations into the veracity of a raised TG result and, in our experience, these cut-offs are useful for identification of pseudohypertriglyceridaemia (Figure 1). A similar approach should be possible for non-Roche methods; however, this may be more difficult if qualitative or semi-quantitative LI is used. The ratio log[TG]/log[LI] has also been proposed to be useful for the same purpose for Roche assays. ⁸

Figure 1.

Serum triglycerides between 20 and 25 mmol/L compared to lipaemia index (LI) collected over a 1-year period with duplicate patients removed. The dashed line indicates the LI suggested as cut-offs to suspect pseudohypertriglyceridaemia by Farooq et al. ⁵ The triangles represent cases of pseudohypertriglyceridaemia due to slushie ingestion and suspected glycerol kinase deficiency.

Further investigations once pseudohypertriglyceridaemia is suspected may include urine organic acids (to detect glyceroluria), lipoprotein electrophoresis (by which severe genuine and pseudohypertriglyceridaemia should be readily distinguishable), correcting triglyceride for the presence of glycerol, ⁹ and ultimately genetic testing if GKD is suspected. GKD is X-linked and genotype does not predict phenotype; therefore the condition is important to diagnose for family studies as well as to avoid unnecessary interventions in the index case.^2,7

Hypertriglyceridaemia is important to diagnose and treat to avoid serious clinical consequences, but it is also important that patients with pseudohypertriglyceridaemia are identified to ensure unnecessary interventions are avoided and the underlying cause identified.