Causes of Hypertriglyceridemia
Clinicians must systematically investigate and treat secondary causes of hypertriglyceridemia before considering primary genetic disorders, as secondary factors are far more common and often reversible. 1
Secondary Causes (Most Common)
Secondary causes either directly cause or significantly exacerbate triglyceride elevations and must be addressed first 1:
Lifestyle and Dietary Factors
- Obesity and overweight status - among the most prevalent contributors 1, 2
- Physical inactivity - directly elevates triglycerides 1, 2
- Excessive alcohol intake - a major modifiable cause 1, 3
- High-fat diet and diet rich in simple carbohydrates - particularly refined carbohydrates 1, 2
Metabolic and Endocrine Diseases
- Uncontrolled diabetes mellitus - poor glycemic control significantly influences plasma lipid levels and exacerbates hypertriglyceridemia 1, 3
- Metabolic syndrome - a constellation including central obesity, insulin resistance, and hypertension 1, 2
- Hypothyroidism - disrupts lipid metabolism 1, 4
- Cushing's syndrome - less common endocrine cause 5
- Acromegaly - rare endocrine disorder 5
Renal and Hepatic Disorders
- Nephrotic syndrome - causes significant triglyceride elevation 1, 5
- Chronic kidney disease - impairs triglyceride clearance 1
- Hepatic disorders and nonalcoholic hepatic steatosis (fatty liver) - both cause and consequence of hypertriglyceridemia 1
Medications (Critical to Review)
The following drugs cause moderate to severe hypertriglyceridemia 1:
- Thiazide diuretics 1, 5
- Beta blockers 1, 5
- Estrogen (oral administration) - increases triglycerides, whereas progestins ameliorate this effect 1, 5
- Isotretinoin - significant effect 1, 5
- Corticosteroids/glucocorticoids 1, 5
- Bile acid-binding resins 1
- Antiretroviral protease inhibitors - important in HIV patients 1
- Immunosuppressants (including L-asparaginase) 1, 5
- Atypical antipsychotics - increasingly recognized cause 1, 5
Other Secondary Causes
Primary (Genetic) Causes
Primary hypertriglyceridemia should be suspected when secondary causes are excluded or when family history suggests genetic lipid disorders 1:
Common Primary Disorders
- Familial combined hyperlipidemia - most common genetic cause 6
- Familial hypertriglyceridemia - polygenic disorder 1, 4
- Familial dysbetalipoproteinemia (remnant hyperlipidemia) - related to apolipoprotein E variants 1, 6
Severe Primary Disorders (Rare but Critical)
- Multifactorial chylomicronemia syndrome - the most common condition causing triglycerides high enough to provoke clinical features (lipemia retinalis, eruptive xanthomas, abdominal pain, pancreatitis), occurring 40-60 fold more frequently than monogenic causes 1
- Autosomal recessive familial chylomicronemia syndrome - rare monogenic disorder 1
- Familial partial lipodystrophy - rare genetic condition 1
Critical Clinical Context
Most cases result from a combination of multiple genetic variations with small effects plus environmental factors, rather than single-gene disorders. 3 Genetic predisposition increases the likelihood and severity of elevated triglycerides when secondary factors are present 1. Even when a secondary cause is identified, family screening to uncover genetic lipid disorders remains important, particularly in those with family history of premature cardiovascular disease 1.
Common Pitfall to Avoid
Do not assume isolated genetic causes without thoroughly evaluating and addressing modifiable secondary factors first, as these are far more prevalent and treatable 3, 5. The interaction between genetic susceptibility and secondary causes often produces the most severe hypertriglyceridemia 5.