Pseudohypertriglyceridemia in a Teenager: Evaluation, Management, Implications, and Literature Review

Pediatric hypertriglyceridemia (fasting triglycerides ≥ 130 mg/dL) was identified by routine screening in a healthy 14-year-old male. He was subsequently referred to our pediatric lipid clinic for evaluation.  A fasting lipid profile confirmed hypertriglyceridemia: total cholesterol (TC): 136 mg/dL, triglyceride (TG): 357 mg/dL, low-density lipoprotein cholesterol (LDL-C): 18 mg/dL, high-density lipoprotein cholesterol (HDL-C): 47 mg/dL, and non-HDL-C: 89 mg/dL.

The patient is an active ninth grader who participates in track and cross country, follows a prudent diet, and does well academically. He denies tobacco, alcohol, and illicit drug use. His medical history is unremarkable and he does not take medications. He was born at full term, without complications.

Family history: The patient has a 12-year-old sister, whose lipid profile is not known. His mother (age 45 years) is being treated for hypothyroidism, and is otherwise healthy. His maternal grandparents (ages 72 and 75 years) are healthy, as is his maternal great-grandmother at age 90 years. His father (age 48 years) has a normal lipid profile. The patient’s paternal grandparents are in their mid-80s and healthy. No significant family history of early atherosclerotic cardiovascular disease (ASCVD), hyperlipidemia, or diabetes was reported.

Physical examination: His body mass index (BMI) was 16.2 Kg/m2 (6th percentile for age and gender). The patient was alert, oriented, and appeared well-nourished. The physical exam was unremarkable.

Pertinent chemistry results: Thyroid stimulating hormone: 1.58 mcU/mL; free thyroxine: 1.3 ng/dL; fasting blood glucose: 96 mg/dL; hemoglobin A1c: 5.4 percent; creatinine: 0.9 mg/dL; aspartate aminotransferase: 7 IUnits/L; alanine aminotransferase: 30 units/L.

Impressions and recommendations: The elevated fasting triglyceride level, the absence of secondary causes, and the lack of a significant family history of hyperlipidemia suggested the diagnosis of sporadic hypertriglyceridemia.¹

Sporadic hypertriglyceridemia is a primary dyslipidemia that is distinguished from familial hypertriglyceridemia by the lack of a family history of isolated hypertriglyceridemia in 50 percent or more of first- and second-degree maternal or paternal family relatives.¹ The triglyceride concentration is generally modestly elevated (250–400 mg/dL), although it can be very high (≥ 500 mg/dL) if associated with secondary causes of hypertriglyceridemia (e.g., unhealthy body weight, hyperglycemia, hydrochlorothiazide, steroids, beta-blocker use, and/or excess alcohol consumption).²

An over-the-counter (OTC) marine omega-3 fatty acid supplement containing 300 mg of eicosapentaenoic acid (EPA)/ docosahexaenoic acid (DHA) per one gram (1 gram capsule, twice daily), along with dietary reduction of refined carbohydrates was recommended. A repeat fasting lipid profile assessment after three months of following these recommendations indicated no significant change in the fasting triglycerides level; TC: 134 mg/ dL, TG: 353 mg/dL, LDL-C: 17 mg/dL, apolipoprotein B (apoB): 75 mg/dL, HDL-C: 46 mg/dL. The OTC marine omega-3 fatty acid supplement was discontinued and replaced with the prescription omega-3- fatty acid ethyl ester (465 mg EPA and 375 mg DHA per 1 gram capsule), at one gram capsule taken twice daily. This change to the prescription omega-3 fatty acid ethyl ester was instituted to eliminate the potential variability in EPA/DHA content in OTC omega-3 fatty acid supplements. The prescription omega-3 fatty acid ethyl ester has a standard composition of EPA and DHA content. Dietary and adherence recommendations were reinforced.

Follow-up:  A clinical chemistry assessment after six weeks of taking the prescription omega-3-fatty acid ethyl ester indicated no reduction in the fasting triglyceride level; TC: 153 mg/dL, TG: 385 mg/dL, LDL-C: 30 mg/dL, HDL-C: 45 mg/dL. This suggested “pseudohypertriglyceridemia.”³ A subsequent glycerol-blanked triglyceride assessment confirmed pseudohypertriglyceridemia: glycerol- blanked TG: 68 mg/dL, glycerol: 3763 mmol/L. With confirmation of glycerolemia and normal triglycerides, a letter documenting pseudohypertriglyceridemia was provided to the family to accompany subsequent lipid profile analyses.

Pseudohypertriglyceridemia: The American Academy of Pediatrics (AAP) defines fasting triglyceride levels into three categories: acceptable (<90  mg/ dL), borderline-high  (90–129 mg/dL) and high (≥130 mg/dL).4 It is recommended that elevated triglycerides initially be treated with lifestyle changes, including dietary modification (i.e. reduced intake of refined carbohydrate), weight reduction, decreased consumption of alcohol, and control of underlying disorders such as diabetes mellitus and hypothyroidism. Pharmacologic therapies including omega-3 fatty acids, niacin, and fibrates can be considered for fasting triglyceride levels greater than 500 mg/dL.^3,4 Should an elevated fasting triglyceride remain unchanged following lifestyle modification with or without pharmacological therapy, pseudohypertriglyceridemia should be considered.³

An elevated plasma concentration of glycerol can cause pseudohyper- triglyceridemia. Glycerolemia can be secondary to stress, glycerol-containing intravenous medications, parental nutrition and metabolic disorders such as glycerol kinase deficiency (GKD). This is an X-linked recessive disorder occurring in isolation or in complex form involving adrenal malfunction.5 The frequency of asymptomatic isolated GKD is unclear, although rare, with only 25 cases reported.³

Almost all clinical laboratories analyze triglyceride concentrations using enzymatic methods that involve three basic steps. The first step uses lipases for the hydrolysis of triglycerides to glycerol and fatty acids. The second step utilizes glycerol kinase to phosphorylate glycerol. The final step is the formation of a colored phosphorylated glycerol that can be measured spectrophotometrically to provide an estimate of the triglyceride concentration. Since these enzymatic assays measure triglycerides as the quantity of glycerol in a specimen, the elevated plasma glycerol concentration in hyperglycerolemia causes an overestimation of the true triglyceride concentration. Glycerol-blanking triglyceride assays “blank” or subtract the free plasma glycerol from the specimen and assay only the glycerol produced from the enzymatic hydrolysis of the triglycerides.³

Summary: The evaluation of hypertriglyceridemia should always include a detailed medical and family history. A 12-hour fast is recommended to optimally assess triglyceride levels. Should lifestyle changes (dietary improvement, physical activity, weight reduction), control of secondary metabolic or pharmacologic causes, and/or triglyceride-lowering therapy fail to reduce the triglyceride level, the presence of pseudohypertriglyceridemia stemming from hyperglycerolemia should be included in the differential diagnosis. A glycerol-blanked triglyceride assay should be performed to confirm this diagnosis.

Disclosure statement: Dr. Maciejko has no disclosures to report. Dr. Anne has no disclosures to report. Manisha Ravi has no disclosures to report.

References are listed on page 47 of the PDF.