What causes elevated triglycerides?

Causes of Elevated Triglycerides

Elevated triglycerides result from a combination of genetic disorders, metabolic conditions, lifestyle factors, and medications, with obesity, diabetes, and excessive carbohydrate/alcohol intake being the most common modifiable causes. 1

Primary (Genetic) Causes

The following inherited disorders directly affect triglyceride metabolism:

• Familial hypertriglyceridemia produces triglyceride levels of 200-1000 mg/dL and typically does not increase coronary heart disease risk unless metabolic syndrome features coexist 1
• Familial combined hyperlipidemia (FCHL) affects 1-2% of white populations and involves increased production of apolipoprotein B lipoproteins 1
• Lipoprotein lipase deficiency is a rare genetic disorder causing severely elevated triglycerides with markedly increased pancreatitis risk 1
• Apolipoprotein CII deficiency and apolipoprotein AV deficiency are rare genetic causes of severe hypertriglyceridemia 1
• Dysbetalipoproteinemia is a rare autosomal recessive disorder with defective apolipoprotein E that requires a secondary trigger for clinical expression 1

Secondary Causes

Metabolic and Endocrine Disorders

These conditions alter lipid metabolism and are among the most common causes:

• Obesity and overweight are major contributors to mild-to-moderate hypertriglyceridemia (176-880 mg/dL), affecting 25% of the U.S. population 1, 2
• Metabolic syndrome is frequently associated with elevated triglycerides and represents a cluster of cardiovascular risk factors 1
• Poorly controlled diabetes mellitus can cause severely elevated triglycerides through impaired lipoprotein lipase activity 1
• Hypothyroidism affects lipid metabolism leading to elevated triglycerides 1

Lifestyle Factors

Modifiable behaviors that significantly impact triglyceride levels:

• Excessive alcohol intake, particularly when combined with a high saturated-fat diet, substantially raises triglycerides 1
• Physical inactivity contributes to elevated triglycerides and should be addressed before pharmacologic intervention 1, 3
• Diet high in refined carbohydrates increases triglyceride production, while reducing carbohydrate intake (especially refined carbohydrates) can lower levels 1, 2

Medications

Multiple drug classes can elevate triglycerides as a side effect:

• Atypical antipsychotics, particularly clozapine and olanzapine 1
• Beta-blockers, especially atenolol 1
• Bile acid resins can significantly raise triglycerides in predisposed individuals 1
• Estrogens, particularly oral formulations, affect lipid metabolism and are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia 1, 4
• Protease inhibitors used in HIV treatment 1
• Thiazide diuretics are commonly prescribed antihypertensives that can increase triglycerides and should be managed prior to drug therapy for hypertriglyceridemia 1, 3, 4
• Steroids, tamoxifen, sirolimus, and retinoic acid drugs can all affect lipid metabolism 1

Other Medical Conditions

Additional clinical scenarios associated with elevated triglycerides:

• Pregnancy, especially in the third trimester, can lead to elevated triglycerides 1
• Chronic kidney disease affects lipid metabolism 1
• Autoimmune disorders, such as systemic lupus erythematosus, can be associated with lipid abnormalities 1

Clinical Pitfalls and Evaluation Priorities

When evaluating hypertriglyceridemia, always assess for secondary causes before considering genetic disorders:

• Screen for dietary factors (refined carbohydrates, alcohol), medication effects, and underlying conditions (diabetes, hypothyroidism, kidney disease) 1
• Evaluate for other metabolic syndrome components: abdominal obesity, hypertension, low HDL-C, and elevated fasting glucose 1
• Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus, should be looked for and adequately treated before initiating specific drug therapy 3, 4
• Consider genetic testing only in cases of severe hypertriglyceridemia (≥1,000 mg/dL) without obvious secondary causes, especially with family history 1

A critical caveat: Estrogen therapy and thiazide diuretics are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia—discontinuation of these agents may obviate the need for specific drug therapy 3, 4