What are the etiologies of hypertriglyceridemia and its management?

How Triglycerides Become Elevated: Etiologies and Mechanisms

Primary (Genetic) Causes of Hypertriglyceridemia

Genetic disorders represent a fundamental mechanism by which triglycerides become elevated, either through defective clearance or excessive production of triglyceride-rich lipoproteins. 1

Defects in Triglyceride Clearance

• Lipoprotein lipase (LPL) deficiency causes familial chylomicronemia syndrome by preventing hydrolysis of chylomicrons and VLDL, typically producing triglyceride levels exceeding 1,000 mg/dL with dramatic pancreatitis risk 1
• Apolipoprotein CII deficiency is an autosomal-recessive disorder that impairs LPL activation, blocking the enzyme responsible for clearing triglyceride-rich particles from circulation 1
• Apolipoprotein AV deficiency disrupts triglyceride metabolism by reducing LPL activity at the capillary endothelium 1
• GPIHBP1 deficiency prevents proper anchoring of LPL to blood vessel walls, leaving triglyceride-rich particles circulating without enzymatic breakdown 1
• LMF1 deficiency interferes with maturation of both LPL and hepatic lipase, contributing to impaired triglyceride clearance 1

Defects in Triglyceride Production and Remnant Clearance

• Familial combined hyperlipidemia (FCHL) affects 1-2% of white populations and is characterized by increased hepatic production of apolipoprotein B-containing lipoproteins (VLDL), leading to variable elevations in cholesterol, triglycerides, or both 1
• Dysbetalipoproteinemia (usually apoE2/E2 genotype) causes accumulation of chylomicron and VLDL remnants because defective apolipoprotein E cannot bind properly to hepatic receptors for clearance 1
• Familial hypertriglyceridemia produces triglyceride levels of 200-1,000 mg/dL through polygenic mechanisms affecting VLDL production and clearance 1

Secondary (Acquired) Causes: Metabolic and Endocrine Mechanisms

Secondary causes are far more common than genetic disorders and often represent the "second hit" that precipitates severe hypertriglyceridemia in genetically predisposed individuals. 2

Diabetes Mellitus and Insulin Resistance

• Uncontrolled insulin-deficient diabetes markedly raises triglycerides through two mechanisms: increased hepatic VLDL production (because insulin normally suppresses hepatic triglyceride synthesis) and reduced LPL activity (because insulin normally activates LPL) 1
• Poor glycemic control is often the primary driver of severe hypertriglyceridemia, and optimizing glucose control can reduce triglycerides by 20-50% independent of lipid medications 3
• Metabolic syndrome—a cluster of insulin resistance, central obesity, hypertension, low HDL-C, and elevated triglycerides—significantly raises triglyceride levels through multiple interconnected mechanisms 1, 4

Thyroid Dysfunction

• Hypothyroidism lowers LPL activity and reduces hepatic clearance of triglyceride-rich lipoproteins, causing triglycerides to accumulate in circulation 1

Obesity and Physical Inactivity

• Obesity and visceral adiposity generate mild-to-moderate triglyceride elevations (approximately 176-880 mg/dL) through increased hepatic VLDL output and reduced fatty-acid oxidation in muscle 1
• Excess body weight is associated with reduced oxidation of muscle fatty acids, leading to increased delivery of free fatty acids to the liver for VLDL synthesis 2
• Physical inactivity is strongly associated with higher triglyceride concentrations through reduced muscle fatty acid oxidation and decreased LPL activity 1

Pregnancy

• Pregnancy (third trimester) physiologically raises triglycerides to provide energy substrate for the fetus, but may precipitate symptomatic hypertriglyceridemia in susceptible individuals 1

Dietary and Lifestyle Mechanisms

Dietary factors directly influence hepatic triglyceride synthesis and can dramatically elevate levels, especially when combined with genetic predisposition. 2

Alcohol

• Excessive alcohol intake (as little as 1 ounce daily) raises triglycerides by 5-10% through multiple mechanisms: impaired chylomicron hydrolysis, increased hepatic triglyceride-rich VLDL production, and reduced LPL activity 1
• The effects of alcohol are synergistically exaggerated when coupled with meals high in saturated fat, as alcohol impairs the normal clearance of dietary fat from the bloodstream 2
• Excess alcohol consumption can precipitate marked triglyceride elevation often ≥250 mg/dL and trigger hypertriglyceridemic pancreatitis, particularly in individuals with pre-existing hypertriglyceridemia 2

Dietary Carbohydrates and Sugars

• Diets high in refined carbohydrates and added sugars directly increase hepatic triglyceride synthesis because excess carbohydrate is converted to triglyceride in the liver through de novo lipogenesis 1
• Simple sugars increase triglycerides more than complex carbohydrates, with higher versus lower dietary sugar intake increasing triglycerides by approximately 10 mg/dL independent of body weight effects 3
• For every 1% of energy from saturated fatty acids replaced by carbohydrates (not refined sugars, but fiber-rich complex carbohydrates), triglycerides increase by approximately 1.9 mg/dL 2

Dietary Fat Quality

• High saturated-fat diets exacerbate hypertriglyceridemia, especially when alcohol is also consumed, by providing substrate for chylomicron formation and impairing clearance 1
• When 1% of energy from carbohydrates is replaced by polyunsaturated fatty acids (PUFAs), triglycerides are lowered by 2.3 mg/dL, demonstrating that fat quality matters more than quantity in many cases 2

Medication-Induced Mechanisms

Many commonly prescribed medications elevate triglycerides through various mechanisms affecting production, clearance, or both. 1

Psychiatric Medications

• Atypical antipsychotics (especially clozapine and olanzapine) can produce severe triglyceride elevations (>500 mg/dL) with risk of pancreatitis through mechanisms involving weight gain, insulin resistance, and direct effects on hepatic lipid metabolism 1

Cardiovascular Medications

• Beta-blockers (particularly atenolol) elevate triglycerides by reducing LPL activity and increasing hepatic VLDL production 1
• Thiazide diuretics commonly increase triglyceride levels through insulin resistance and altered hepatic metabolism 1

Hormonal Medications

• Oral estrogen therapies (contraceptives, post-menopausal hormone therapy) raise triglycerides more than transdermal preparations by increasing hepatic VLDL production through first-pass hepatic metabolism 1
• Tamoxifen and raloxifene can raise triglycerides through estrogenic effects on hepatic lipid metabolism 1

Immunosuppressants and Other Agents

• Protease inhibitors (ritonavir, lopinavir) markedly increase triglycerides in patients with HIV through direct effects on lipid metabolism 1
• Corticosteroids affect lipid metabolism by increasing hepatic VLDL production and promoting insulin resistance 1
• Immunosuppressants (cyclosporine, sirolimus, tacrolimus) raise triglycerides through multiple mechanisms including insulin resistance 1
• Retinoic-acid derivatives (isotretinoin, acitretin) affect lipid metabolism through direct hepatic effects 1
• Bile-acid resins should be avoided when triglycerides exceed 200 mg/dL because they can significantly worsen hypertriglyceridemia by upregulating hepatic VLDL production 1

Renal and Hepatic Mechanisms

• Chronic kidney disease and nephrotic syndrome impair triglyceride clearance through reduced LPL activity and stimulate hepatic VLDL production, creating a dual mechanism for elevation 1
• Chronic liver disease disrupts normal lipid metabolism through impaired synthesis of apolipoproteins and enzymes required for triglyceride clearance 1

Autoimmune Mechanisms

• Autoimmune disorders such as systemic lupus erythematosus with anti-LPL antibodies can cause autoimmune chylomicronemia by directly inhibiting the enzyme responsible for triglyceride clearance 1

Pathophysiologic Mechanism of Severe Hypertriglyceridemia

Understanding the saturable nature of triglyceride clearance explains why levels can escalate dramatically once a threshold is exceeded. 2

• Triglycerides are transported in both chylomicrons (which transport dietary fat) and VLDL (which transports endogenous triglycerides formed by the liver), and both are hydrolyzed by lipoprotein lipase 2
• Clearance of triglycerides from plasma is saturable when plasma triglyceride levels exceed approximately 500-700 mg/dL, and further input of chylomicrons and VLDL into plasma cannot readily be removed 2
• This leads to marked hypertriglyceridemia and chylomicronemia, even after an overnight fast, because the clearance mechanism becomes overwhelmed 2
• Multifactorial chylomicronemia syndrome is the most common condition elevating triglycerides high enough to provoke lipemia retinalis, eruptive xanthomas, abdominal pain, and hyperlipidemic pancreatitis, and is 40-60 fold more prevalent than monogenic conditions 2