What causes elevated triglyceride (hypertriglyceridemia) levels?

Causes of Elevated Triglycerides

Elevated triglycerides result from a combination of genetic predisposition, lifestyle factors, medications, and underlying medical conditions, with most cases being multifactorial rather than purely genetic. 1

Primary (Genetic) Causes

Genetic disorders account for a minority of hypertriglyceridemia cases but are important to identify:

• Familial hypertriglyceridemia causes triglyceride levels of 200-1000 mg/dL and is not typically associated with coronary heart disease unless metabolic syndrome features are present 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 and increased pancreatitis risk 1
• Apolipoprotein CII and AV deficiencies are rare genetic causes of severe hypertriglyceridemia 1
• Dysbetalipoproteinemia is a rare autosomal recessive disorder with defective apolipoprotein E, requiring a secondary trigger for clinical expression 1

Important caveat: Recent genetic research has shown that many cases previously thought to be monogenic actually have a polygenic basis, with multiple genetic variants contributing cumulatively 2

Secondary Causes

Metabolic and Endocrine Disorders

Metabolic conditions are the most common contributors to elevated triglycerides in clinical practice:

• Obesity and overweight are major contributors to mild-to-moderate hypertriglyceridemia (176-880 mg/dL) 1
• Metabolic syndrome is frequently associated with elevated triglycerides 1, 3
• Poorly controlled diabetes mellitus can cause severely elevated triglycerides and significantly exacerbates hypertriglyceridemia 4, 1
• Hypothyroidism affects lipid metabolism leading to elevated triglycerides 1, 5

Lifestyle Factors

Modifiable lifestyle factors play a paramount role:

• Excessive alcohol intake, particularly when combined with a high saturated-fat diet, can contribute to elevated triglycerides 1, 5
• Physical inactivity contributes to elevated triglycerides 1
• Diet high in refined carbohydrates increases triglyceride production 4, 1
• Excess body weight is an important factor that should be addressed prior to drug therapy 5

Medications

Multiple medication classes can cause or worsen hypertriglyceridemia 4:

• Atypical antipsychotics, particularly clozapine and olanzapine, can raise triglycerides significantly 1, 6
• Beta-blockers, especially atenolol, can increase triglycerides 1
• Thiazide diuretics are commonly prescribed antihypertensives that can increase triglycerides 1, 5
• Estrogens, particularly oral formulations, can affect lipid metabolism and increase triglyceride levels 4, 1, 5
• Bile acid resins can significantly raise triglycerides in predisposed individuals 1
• Protease inhibitors used in HIV treatment can raise triglycerides 1
• Steroids, tamoxifen, sirolimus, and retinoic acid drugs can affect lipid metabolism 1

Critical clinical point: Estrogen therapy, thiazide diuretics, and beta-blockers are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia, and discontinuation of the specific agent may obviate the need for drug therapy 5

Other Medical Conditions

Additional medical conditions that elevate triglycerides include:

• 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
• Non-alcoholic hepatic steatosis (fatty liver) is both a cause and consequence of hypertriglyceridemia 4

Clinical Context and Risk Stratification

Understanding the level of elevation is crucial for determining clinical significance 4, 1:

• Normal: <150 mg/dL
• Borderline high: 150-199 mg/dL
• High: 200-499 mg/dL
• Very high: ≥500 mg/dL (pancreatitis risk threshold)

Triglyceride elevations serve as a biomarker for visceral adiposity, insulin resistance, type 2 diabetes mellitus, and non-alcoholic hepatic steatosis 4

Evaluation Approach

When evaluating hypertriglyceridemia, systematically assess for:

• Secondary causes including diet, alcohol intake, medications, and underlying medical conditions 1, 7
• Other components of metabolic syndrome: abdominal obesity, hypertension, low HDL-C, elevated fasting glucose 4, 7
• Genetic testing in cases of severe hypertriglyceridemia without obvious secondary causes, especially with family history 1
• Diseases contributory to hyperlipidemia such as hypothyroidism or diabetes mellitus should be looked for and adequately treated 5

Common pitfall: Even when a secondary cause is identified, family screening to uncover a genetic lipid disorder is also in order 4