The Causes of High Triglycerides

Stay Informed Download the Genetic Testing for FCS flyer and CORE Clinical Trials Fact Sheet
Stay Informed Download the Genetic Testing for FCS flyer and CORE Clinical Trials Fact Sheet

Overview

HTG arises from combinations of three factors, which vary across individuals:1

  • Increased TG production
  • Altered processing and catabolism of (TRLs)
  • Reduced clearance of TRLs or TRL remnants

These three factors can have:4

  • Genetic causes (commonly referred to as “Primary HTG”), often a complex polygenetic susceptibility.
  • Nongenetic causes (commonly referred to as “Secondary HTG”), including diet, lifestyle, medical conditions, and drugs.

Often, HTG is a complex mix of polygenetic and secondary causes. In some cases, genetic factors may explain high TG levels that are refractory to lifestyle changes and guideline-directed therapy.4,12

Nongenetic Causes of HTG2,4,9

Lifestyle and medical factors

Lifestyle and medical factors

  • Uncontrolled hypothyroidism
  • Pregnancy (especially third trimester)
  • Poorly controlled diabetes
  • Obesity
  • Alcohol intake
  • Insulin resistance
  • Metabolic syndrome
  • Renal disease (nephrotic syndrome, glomerulonephritis)
  • Acute hepatitis
  • Diet (high saturated fat or high glycemic index)
  • Sedentary lifestyle
  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • HIV
  • Cushing syndrome
  • Lipodystrophy
  • Glycogen storage disease
  • Multiple myeloma
Drugs

Drugs

  • Nonselective β blockers
  • Corticosteroids
  • Oral estrogens
  • Thiazide diuretics
  • Tamoxifen, raloxifene
  • Androgens
  • Bile acid sequestrants
  • Cyclosporine
  • Second-generation antipsychotics (eg, clozapine and olanzapine)
  • Sirolimus, tacrolimus
  • L-asparaginase
  • Retinoic acid drugs (isotretinoin)
  • Bexarotene
  • Cyclophosphamide
  • HIV Protease inhibitors
  • Interferon

Hypertriglyceridemia can occur as part of the metabolic syndrome and complicate the management of obesity, diabetes, and insulin resistance.2,4,13

Genetic Causes of HTG

Patients with severe or extreme HTG are more likely to have genetic factors.4,14

Genetic Causes of High Triglycerides
Genetic Causes of High Triglycerides

Genetic Causes of Moderately Elevated TG and Severe HTG4

Genetic Causes of Extreme HTG4

Distinguishing FCS from MCS

Without genetic testing, it can be challenging to distinguish monogenic chylomicronemia (also known as familial chylomicronemia syndrome; FCS) from multifactorial (polygenic) chylomicronemia syndrome (MCS). 12,14
The following table shows characteristics of these syndromes.12,1

Multifactorial chylomicronemia
syndrome (MCS) 		Familial chylomicronemia
syndrome (FCS)
TG Levels Transiently or variable > 880 mg/dl (10mmol/L) Persistently >880 mg/dL (10mmol/L)
Prevalence ~ 1 in 600 ~ 1 in 500,000 to 1 in 1,000,000
Genes Heterozygous mutations in high-effect genes; small-effect variants in ~40 genes Homozygous mutations in LPL or genes involved in LPL processing (APOC2, APOA5, GPD1, GPIHBP1, LMF1)
Contribution of secondary factors Major Minimal
Inheritance Familial trend but no clear pattern Autosomal recessive
Age of onset Adulthood Childhood or adolescence
Shared clinical features (usually more common in FCS than MCS) Abdominal pain
Nausea
Vomiting
Eruptive xanthomas
Lipemia retinalis
Pancreatitis 		Abdominal pain
Nausea
Vomiting
Eruptive xanthomas
Lipemia retinalis
Pancreatitis
Other clinical features - Failure to thrive, and Hepatosplenomegaly
Response to pharmacotherapy Variable response to w-3 fatty acids and niacin Minimal effect of vibrates, w-3 fatty acids, niacin, statins

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