When and how to suspect and diagnose familial hypertriglyceridemia?

When to Suspect and How to Diagnose Familial Hypertriglyceridemia

Suspect familial hypertriglyceridemia when fasting triglyceride levels are 200-1000 mg/dL with normal apolipoprotein B levels, particularly in adults with a family history of dyslipidemia who lack secondary causes of hypertriglyceridemia. 1

When to Suspect FHTG

Clinical Presentation

• Triglyceride levels typically range from 200-1000 mg/dL with elevated VLDL particles but normal apolipoprotein B levels 1, 2
• The disorder usually does not manifest until adulthood because environmental factors (obesity, physical inactivity) are required for clinical expression 1
• Suspect FHTG when triglycerides exceed 1000 mg/dL in the presence of secondary triggers such as medications (thiazides, beta-blockers, estrogen, corticosteroids, protease inhibitors), alcohol excess, uncontrolled diabetes, or pregnancy 3, 1

Family History Red Flags

• Evaluate for family history of dyslipidemia and premature cardiovascular disease in all patients with primary hypertriglyceridemia 3
• Multiple family members with elevated triglycerides but variable lipid phenotypes suggest FHTG rather than other familial dyslipidemias 1

Associated Risk Factors

• Central obesity, hypertension, abnormal glucose metabolism, and liver dysfunction should be assessed as these increase cardiovascular risk 3
• Physical inactivity and diet rich in simple carbohydrates are common contributing factors 3

How to Diagnose FHTG

Initial Diagnostic Testing

• Obtain fasting serum triglyceride levels as the primary diagnostic test 3, 4
• Measure a complete lipid panel including total cholesterol, LDL-cholesterol, HDL-cholesterol, and calculate non-HDL cholesterol 3
• Measure apolipoprotein B levels to distinguish FHTG from familial combined hyperlipidemia (FCHL) 1, 2

Diagnostic Criteria Using Endocrine Society Classification

The diagnosis should be based on fasting triglyceride levels with the following cutoffs 3:

• Mild hypertriglyceridemia: 150-199 mg/dL (1.7-2.3 mmol/L)
• Moderate hypertriglyceridemia: 200-999 mg/dL (2.3-11.3 mmol/L)
• Severe hypertriglyceridemia: 1000-1999 mg/dL (11.3-22.6 mmol/L)
• Very severe hypertriglyceridemia: ≥2000 mg/dL (≥22.6 mmol/L)

Key Distinguishing Features of FHTG

• Normal apolipoprotein B levels (<90th percentile) distinguish FHTG from FCHL 1, 2
• FHTG shows elevated VLDL particles without the multiple lipoprotein abnormalities seen in FCHL 1
• The primary mechanism involves VLDL overproduction and reduced VLDL catabolism with saturation of lipoprotein lipase 1

Exclude Secondary Causes Before Diagnosing Primary FHTG

All patients with elevated fasting triglycerides must be evaluated for secondary causes 3:

• Excessive alcohol intake
• Uncontrolled diabetes mellitus
• Endocrine conditions (hypothyroidism, Cushing's syndrome)
• Renal or liver disease
• Pregnancy (especially third trimester)
• Autoimmune disorders
• Medications: thiazides, beta-blockers, estrogen, isotretinoin, corticosteroids, bile acid-binding resins, antiretroviral protease inhibitors, immunosuppressants, antipsychotics 3, 1

Genetic Considerations

• FHTG has a polygenic inheritance pattern with the phenotype determined by multiple genetic variants combined with environmental factors 1
• Associated with heterozygous loss-of-function mutations in genes encoding proteins involved in triglyceride metabolism, including APOA5 gene variants 1
• Genetic testing is not routinely required for diagnosis but may be considered in severe cases or when monogenic disorders are suspected 1

Critical Pitfalls to Avoid

Do Not Confuse FHTG with FCHL

• FHTG has normal apolipoprotein B levels, while FCHL has elevated apo B (>90th percentile) 1, 2
• FCHL requires at least 2 lipid abnormalities segregating among first-degree relatives, whereas FHTG typically shows isolated triglyceride elevation 1, 2
• FCHL carries similar cardiovascular risk to familial hypercholesterolemia despite lower cholesterol levels, while FHTG is usually not associated with coronary heart disease unless metabolic syndrome features are present 2

Always Screen for Secondary Causes First

• Do not attribute hypertriglyceridemia solely to genetic factors without excluding acquired conditions, as secondary factors frequently unmask or exacerbate the genetic predisposition 1
• Treating secondary causes (e.g., improving glycemic control in diabetes) may obviate the need for specific lipid-lowering therapy 5

Recognize Pancreatitis Risk

• Severe and very severe hypertriglyceridemia (>1000 mg/dL) significantly increase the risk of acute pancreatitis 3, 6
• Patients with baseline FHTG remain at risk for pancreatitis even after treatment if they experience exacerbation due to secondary factors or treatment interruption 1
• Only 20% of subjects with triglycerides exceeding 1000 mg/dL develop pancreatitis, but the risk is clinically significant 1

Cardiovascular Risk Assessment

• The cardiovascular risk in FHTG is primarily mediated through associated metabolic abnormalities rather than the triglyceride elevation itself 1
• Baseline triglyceride levels predict subsequent cardiovascular mortality among relatives in FHTG families, particularly when baseline triglycerides are ≥200 mg/dL 1, 7