How should I begin the workup of an isolated triglyceride level of 350 mg/dL?

Workup of Isolated Triglyceride Level of 350 mg/dL

Begin by obtaining a fasting lipid panel to confirm the triglyceride level and accurately calculate LDL-C, then systematically evaluate for secondary causes including diabetes, thyroid disease, renal disease, alcohol use, and medications. 1

Initial Laboratory Confirmation

• Order a fasting lipid panel (12-hour fast) because the Friedewald equation for calculating LDL-C becomes unreliable when triglycerides are ≥200 mg/dL, and your patient's level of 350 mg/dL falls well above this threshold. 1

• The fasting panel will provide accurate measurements of total cholesterol, HDL-C, LDL-C (either calculated or direct), and confirm the triglyceride elevation. 1

• If the initial measurement was non-fasting, a repeat fasting sample is mandatory when triglycerides are ≥400 mg/dL; at 350 mg/dL, fasting confirmation improves accuracy of LDL-C calculation and baseline assessment. 1

Risk Stratification

This triglyceride level of 350 mg/dL is classified as "high" (200–499 mg/dL range) according to American Heart Association criteria. 1

• High triglycerides (200–499 mg/dL) are associated with increased cardiovascular disease risk through their association with atherogenic remnant particles and apolipoprotein CIII. 1

• Triglycerides at this level do not pose an immediate pancreatitis risk, which typically occurs when levels exceed 500–1,000 mg/dL. 1, 2

• Calculate the patient's 10-year atherosclerotic cardiovascular disease (ASCVD) risk using the pooled cohort equations to guide intensity of lipid-lowering therapy. 1, 2

Systematic Evaluation for Secondary Causes

Evaluate for the following secondary causes before attributing hypertriglyceridemia to primary genetic disorders:

Metabolic and Endocrine Causes

• Diabetes mellitus and prediabetes: Order fasting plasma glucose and hemoglobin A1c. Insulin resistance and hyperglycemia directly elevate triglyceride synthesis and impair clearance. 1, 2

• Hypothyroidism: Measure thyroid-stimulating hormone (TSH). Thyroid hormone deficiency reduces lipoprotein lipase activity and triglyceride clearance. 1

• Metabolic syndrome: Assess for central obesity (waist circumference), elevated blood pressure, low HDL-C, and impaired fasting glucose—this cluster commonly presents with triglycerides in the 200–400 mg/dL range. 1

Renal Disease

• Chronic kidney disease and nephrotic syndrome: Order serum creatinine, estimated glomerular filtration rate (eGFR), and urinalysis with urine protein-to-creatinine ratio. Nephrotic syndrome causes marked hypertriglyceridemia through increased hepatic VLDL synthesis. 1

Lifestyle and Behavioral Factors

• Alcohol intake: Quantify alcohol consumption in grams per day. Even moderate alcohol use (2–3 drinks daily) can elevate triglycerides by 50–100 mg/dL, and excessive intake is a common reversible cause. 1, 2

• Obesity and physical inactivity: Document body mass index (BMI) and physical activity level. Weight reduction of 5–10% can lower triglycerides by 20%, and moderate-to-high intensity aerobic activity provides additional 10–20% reduction. 1, 2

• Dietary patterns: Assess intake of simple sugars, refined carbohydrates, and saturated fats. High carbohydrate intake (especially fructose and added sugars) directly stimulates hepatic triglyceride synthesis. 1, 2

Medication Review

Review the medication list for drugs known to elevate triglycerides:

• Estrogen-containing oral contraceptives and hormone replacement therapy: Oral estrogen increases hepatic VLDL production; consider switching to transdermal preparations or alternative contraception. 1

• Thiazide diuretics and beta-blockers: These antihypertensives can raise triglycerides by 10–30%. 1

• Corticosteroids: Both systemic and high-dose inhaled steroids elevate triglycerides through insulin resistance. 1

• Retinoic acid derivatives (isotretinoin, acitretin): These cause dose-dependent hypertriglyceridemia in 25–50% of patients. 1

• Antiretroviral therapy: Protease inhibitors and some nucleoside reverse transcriptase inhibitors cause dyslipidemia. 1

• Immunosuppressants: Cyclosporine, tacrolimus, and sirolimus elevate triglycerides. 1

• Atypical antipsychotics: Clozapine, olanzapine, and quetiapine are associated with metabolic syndrome and hypertriglyceridemia. 1

Additional Testing to Consider

• Apolipoprotein B (ApoB): Measurement is reasonable when triglycerides are ≥200 mg/dL because calculated LDL-C underestimates atherogenic particle burden in hypertriglyceridemic states. ApoB ≥130 mg/dL is a risk-enhancing factor. 1, 3

• Non-HDL cholesterol: Calculate as total cholesterol minus HDL-C. This captures all atherogenic particles (LDL, VLDL, IDL, remnants) and serves as a secondary treatment target when triglycerides are elevated. 1

• Lipoprotein(a): Measure once for lifetime risk stratification if there is a family history of premature ASCVD or if ASCVD risk remains uncertain after standard assessment. Lp(a) ≥50 mg/dL is a risk-enhancing factor. 1, 3

Common Pitfalls to Avoid

• Do not use the Friedewald formula to calculate LDL-C when triglycerides are ≥400 mg/dL; at 350 mg/dL the formula is less accurate but still usable. Consider direct LDL-C measurement or modified calculation methods if precision is needed. 1, 3

• Do not assume normal fasting triglycerides exclude postprandial hypertriglyceridemia: Some patients with fasting triglycerides <150 mg/dL demonstrate exaggerated postprandial responses (>260 mg/dL after fat load), which independently predict cardiovascular risk. 4, 5

• Do not overlook familial combined hyperlipidemia: If multiple first-degree relatives have premature ASCVD or mixed dyslipidemia, consider genetic lipid disorders even when secondary causes are present. 1

• Do not delay lifestyle intervention while awaiting laboratory results: Initiate dietary counseling (reduce simple sugars and refined carbohydrates, increase omega-3 fatty acids) and recommend aerobic exercise immediately, as these interventions can lower triglycerides by 30–50% within weeks. 1, 2

Treatment Considerations Based on Workup Results

• If secondary causes are identified: Address the underlying condition first (optimize diabetes control, treat hypothyroidism, discontinue or substitute offending medications, reduce alcohol intake). 1, 2

• If ASCVD risk is borderline (5–7.4%) or intermediate (7.5–19.9%): Initiate moderate-to-high intensity statin therapy, which lowers triglycerides by 20–40% in addition to reducing LDL-C and cardiovascular events. 1, 2

• If triglycerides remain elevated despite statin therapy and lifestyle modification in high-risk patients: Consider adding high-dose icosapent ethyl (purified EPA 4 grams daily), which reduces cardiovascular mortality (NNT = 111 over 5 years). 2

• If triglycerides rise to ≥500 mg/dL: Add fibrate therapy (fenofibrate preferred over gemfibrozil due to lower risk of statin interaction) or high-dose omega-3 fatty acids to prevent acute pancreatitis, though this indication lacks randomized trial evidence. 1, 2