What are the causes of hypertriglyceridemia?

Causes of Elevated Triglycerides

Primary (Genetic) Causes

Genetic disorders account for severe hypertriglyceridemia and require specific identification for targeted management. 1, 2

Monogenic Disorders

• Lipoprotein lipase (LPL) deficiency causes familial chylomicronemia syndrome with severely elevated triglycerides (often >1000 mg/dL) and high pancreatitis risk 1, 2
• Apolipoprotein CII deficiency is a rare autosomal recessive disorder that impairs LPL activation, leading to severe hypertriglyceridemia 1, 2
• Apolipoprotein AV deficiency disrupts triglyceride metabolism through impaired lipoprotein lipase function 1, 2
• GPIHBP1 deficiency (glycosylphosphatidylinositol-anchored HDL-binding protein 1) prevents proper LPL anchoring to capillary endothelium 1, 2
• LMF1 deficiency affects lipase maturation factor 1, impairing LPL and hepatic lipase function 1

Polygenic and Complex Genetic Disorders

• Familial combined hyperlipidemia (FCHL) is common (1-2% in white populations) with increased apolipoprotein B production, presenting with variable combinations of elevated cholesterol, triglycerides, and/or apoB levels 1, 2
• Familial hypertriglyceridemia typically presents with triglycerides 200-1000 mg/dL and is not associated with coronary heart disease unless metabolic syndrome features coexist 2
• Dysbetalipoproteinemia is an autosomal recessive disorder (usually apoE2/E2 phenotype) causing accumulation of chylomicron and VLDL remnants, with both triglycerides and cholesterol elevated to similar levels 1, 2
• Multifactorial chylomicronemia (MCM) results from rare heterozygous variants in FCS genes combined with common polygenic variants, occurring in approximately 1 in 600 individuals—50-100 times more common than monogenic FCS 3, 4

Secondary (Acquired) Causes

Secondary causes are the most common etiology in clinical practice and must be systematically evaluated before attributing hypertriglyceridemia to primary disorders. 1, 5, 6

Metabolic and Endocrine Disorders

• Poorly controlled diabetes mellitus (insulinopenic diabetes) is often the primary driver of severe hypertriglyceridemia, as hyperglycemia increases hepatic VLDL production and impairs lipoprotein lipase activity 1, 7, 2
• Hypothyroidism reduces LPL activity and hepatic clearance of triglyceride-rich lipoproteins 1, 2
• Obesity and visceral adiposity increase hepatic VLDL production and reduce fatty acid oxidation, contributing to mild-to-moderate hypertriglyceridemia (176-880 mg/dL) 1, 2
• Metabolic syndrome combines insulin resistance, central obesity, hypertension, low HDL-C, and elevated triglycerides 1, 2
• Pregnancy, especially third trimester, causes physiological triglyceride elevation that can become symptomatic in susceptible patients 1, 2

Lifestyle Factors

• Excessive alcohol consumption (even 1 ounce daily increases triglycerides 5-10%) impairs chylomicron hydrolysis and increases VLDL production, with effects synergistically exaggerated when combined with high saturated fat intake 1, 7, 2
• Physical inactivity and sedentary lifestyle strongly associate with elevated triglycerides 1, 2
• Diet high in refined carbohydrates and added sugars directly increases hepatic triglyceride synthesis 1, 7
• High saturated fat diet worsens hypertriglyceridemia, particularly when combined with alcohol 1, 2

Medications

• Atypical antipsychotics (clozapine and olanzapine carry highest risk, followed by quetiapine and risperidone) can cause severe hypertriglyceridemia >500 mg/dL with pancreatitis risk 1, 8
• Protease inhibitors (particularly ritonavir and lopinavir) significantly elevate triglycerides in HIV patients 1, 8
• Oral estrogens (contraceptives and postmenopausal hormone therapy) increase triglycerides more than transdermal preparations 1, 2, 8
• Beta-blockers (especially atenolol) raise triglycerides, though carvedilol is preferred in diabetic patients 1, 8
• Thiazide diuretics commonly increase triglycerides 1, 2, 8
• Bile acid resins can significantly worsen hypertriglyceridemia and should not be used when triglycerides >200 mg/dL 1, 7, 8
• Corticosteroids affect lipid metabolism and raise triglycerides 1, 2, 8
• Immunosuppressants (cyclosporine, sirolimus, tacrolimus) elevate triglyceride levels 1, 8
• Tamoxifen and raloxifene can raise triglycerides, particularly in women who experienced hypertriglyceridemia with estrogen therapy 1, 2, 8
• Retinoic acid drugs (isotretinoin, acitretin) affect lipid metabolism 1, 2
• Interferon can elevate triglycerides 1
• L-asparaginase used in chemotherapy raises triglycerides 1

Other Medical Conditions

• Chronic kidney disease and nephrotic syndrome impair triglyceride clearance and increase hepatic VLDL production 1, 2
• Chronic liver disease disrupts normal lipid metabolism 1, 2
• Autoimmune disorders (systemic lupus erythematosus with antibodies to LPL) can cause autoimmune chylomicronemia 1, 2
• Chronic idiopathic urticaria associates with lipid abnormalities 1, 2

Clinical Approach to Identifying Causes

Before initiating pharmacologic therapy, systematically evaluate for secondary causes as addressing these can markedly lower triglycerides without medication. 7, 5, 6

Essential Evaluation Steps

• Assess alcohol intake thoroughly, as complete abstinence is mandatory for severe hypertriglyceridemia (≥500 mg/dL) 7, 2
• Review all medications for triglyceride-raising agents and discontinue or substitute when possible 1, 7, 8
• Check hemoglobin A1c and fasting glucose to identify uncontrolled diabetes, which can reduce triglycerides 20-50% when optimized 7
• Measure TSH to rule out hypothyroidism, which must be treated before expecting full response to lipid therapy 7
• Assess renal function (creatinine, eGFR) and liver function (AST, ALT) as chronic kidney and liver disease contribute to hypertriglyceridemia 7
• Screen for metabolic syndrome components: abdominal obesity (waist-to-hip ratio), hypertension, low HDL-C, elevated fasting glucose 1, 6

Genetic Testing Considerations

• Consider genetic testing in severe hypertriglyceridemia (≥1000 mg/dL) without obvious secondary causes, especially with family history or early onset 2, 6, 9
• Calculate apolipoprotein B levels when FCHL is suspected, as upper 10th percentile apoB with hypertriglyceridemia (≥133 mg/dL) and hyperapoB (≥120 mg/dL) suggest FCHL 1
• Check apoE genotype when dysbetalipoproteinemia is suspected (triglycerides and cholesterol elevated to similar levels, VLDL-C to plasma TG ratio ≥0.3) 1, 9
• Next-generation sequencing panels may identify rare variants in LPL, APOC2, APOA5, LMF1, and GPIHBP1 genes for suspected familial chylomicronemia syndrome 9, 4

Common Pitfalls to Avoid

• Do not overlook medication-induced hypertriglyceridemia as a reversible secondary cause before starting lipid-lowering drugs 8
• Do not attribute hypertriglyceridemia to genetic causes without first excluding diabetes, hypothyroidism, alcohol, and medications 5, 6
• Do not use bile acid resins when triglycerides >200 mg/dL as they worsen hypertriglyceridemia 7, 8
• Do not ignore weight gain and adiposity as key drivers of FCHL expression, where elevated waist-to-hip ratio greatly increases apoB production 1