What is familial hypertriglyceridemia?

Familial Hypertriglyceridemia

Familial hypertriglyceridemia (FHTG) is a common polygenic disorder affecting 5-10% of the population, characterized by moderately elevated triglycerides (200-1000 mg/dL) due to VLDL overproduction and reduced VLDL catabolism that saturates lipoprotein lipase, typically not expressing until adulthood due to environmental factors like obesity and stress. 1

Genetic Basis and Inheritance

• FHTG has a polygenic inheritance pattern, not the simple autosomal dominant pattern once believed, with the phenotype determined by multiple genetic variants combined with environmental factors 2
• The disorder results from heterozygous loss-of-function mutations in genes encoding proteins involved in triglyceride metabolism, including variants in the APOA5 gene 1
• More than 300 genetic loci have been identified for association with triglyceride levels, and polygenic scores demonstrate that many hypertriglyceridemia phenotypes previously attributed to monogenic inheritance actually have a polygenic basis 3

Pathophysiology

• The primary mechanism involves VLDL overproduction and reduced VLDL catabolism, which results in saturation of lipoprotein lipase 1
• Apolipoprotein B (apo B) levels are not elevated in FHTG, which distinguishes it from familial combined hyperlipidemia (FCHL) 1
• Environmental factors such as obesity, alcohol consumption, and metabolic syndrome heavily influence phenotype expression 4

Clinical Presentation and Lipid Profile

• Triglyceride levels typically range from 200-1000 mg/dL with elevated VLDL particles 1, 5
• The disorder usually does not express until adulthood because environmental factors like obesity and physical inactivity are required for clinical manifestation 1
• When secondary triggers occur (medications, alcohol, uncontrolled diabetes, pregnancy), triglycerides can exceed 1000 mg/dL, creating risk for acute pancreatitis 1

Cardiovascular Risk

• FHTG is usually not associated with coronary heart disease unless metabolic syndrome features are present or baseline triglyceride levels are high (≥200 mg/dL) 1
• This contrasts with FCHL, which is strongly represented in survivors of myocardial infarction, especially those under 40 years of age 1
• The cardiovascular risk in FHTG is primarily mediated through associated metabolic abnormalities rather than the triglyceride elevation itself 1

Differential Diagnosis

FHTG must be distinguished from other familial hypertriglyceridemic syndromes 1:

• Familial combined hyperlipidemia (FCHL): characterized by elevated apo B levels (>90th percentile) and multiple lipoprotein abnormalities affecting first-degree relatives 1
• Type III dysbetalipoproteinemia: near-equivalent cholesterol and triglyceride values with defective apo E 1
• Rare monogenic disorders: LPL deficiency, apo CII deficiency, apo AV homozygosity, GPIHBP1 deficiency—these present with much more severe hypertriglyceridemia (often >1000 mg/dL) and chylomicronemia syndrome 1

Clinical Significance and Complications

• The most clinically relevant complication is acute pancreatitis, which occurs when triglycerides exceed 1000 mg/dL, though only 20% of subjects with these extremely high levels develop pancreatitis 1
• Secondary factors that can precipitate severe hypertriglyceridemia in FHTG patients include: hypothyroidism, pregnancy (especially third trimester), poorly controlled diabetes, alcohol excess, and numerous medications (oral estrogens, beta-blockers, thiazides, steroids, protease inhibitors) 1
• Family screening is essential when FHTG is identified, even when a secondary cause is present 1

Management Approach

• Treatment focuses on controlling environmental factors and implementing lifestyle modifications: cessation of alcohol consumption, reduced intake of rapidly metabolized carbohydrates, weight loss, and blood sugar control 6
• Pharmacological therapy is reserved for reducing cardiovascular risk in moderate hypertriglyceridemia or preventing acute pancreatitis in severe cases 2
• The need to lower LDL cholesterol must be determined based on cardiovascular risk, independently of triglyceride management 6

Key Clinical Pitfalls

• Do not confuse FHTG with FCHL: FHTG has normal apo B levels, while FCHL has elevated apo B (>90th percentile) and requires at least 2 lipid abnormalities segregating among first-degree relatives 1
• Always screen for secondary causes before attributing hypertriglyceridemia solely to genetic factors, as acquired conditions frequently unmask or exacerbate the genetic predisposition 1
• Recognize that patients with baseline FHTG remain at risk for pancreatitis even after treatment if they experience exacerbation due to secondary factors or treatment interruption 1