What are the distinctive types of familial dyslipidemias?

Distinctive Types of Familial Dyslipidemias

Familial dyslipidemias are classified into four major categories based on the primary lipid abnormality: disorders causing isolated hypercholesterolemia, isolated hypertriglyceridemia, combined hyperlipidemia, and low HDL cholesterol. 1

Primary Hypercholesterolemia Disorders

Familial Hypercholesterolemia (FH)

Familial hypercholesterolemia is the most critical genetic dyslipidemia to identify, occurring in approximately 1 in 200-500 individuals in North America and Europe. 1

• Heterozygous FH causes markedly elevated LDL cholesterol levels, typically ≥190 mg/dL, due to deficient or defective LDL receptors from mutations in LDLR, APOB, or PCSK9 genes 1, 2
• Homozygous FH results in extremely elevated LDL cholesterol (often >500 mg/dL) with both alleles affected, presenting at birth with severe manifestations 1
• The diagnosis can be made clinically when LDL cholesterol exceeds the 95th percentile for age and gender in families with premature cardiovascular disease history and tendon xanthomata 1
• An LDL cholesterol level ≥135 mg/dL (3.5 mmol/L) predicts FH presence with 0.98 posttest probability in children from affected kindreds 1

Familial Defective Apolipoprotein B

• This disorder causes elevated LDL cholesterol through abnormalities in apolipoprotein B100, which is recognized by the LDL receptor 1
• It accounts for approximately 3% of FH cases and produces a milder phenotype than LDLR-mediated FH 2

Polygenic Hypercholesterolemia

• Characterized by elevated LDL cholesterol from multiple genetic variants of small effect combined with environmental factors 1
• Typically presents with less severe LDL elevations than monogenic FH 1

Combined Hyperlipidemia Disorders

Familial Combined Hyperlipidemia (FCHL)

FCHL is the most common genetic dyslipidemia, affecting 1-2% of white populations, and is characterized by variable elevations in both cholesterol and triglycerides with elevated apolipoprotein B levels. 2, 3, 4

• The defining feature is elevated apolipoprotein B (>90th percentile) with triglycerides ≥1.5 mmol/L, affecting at least two first-degree relatives 5, 4
• The lipid phenotype fluctuates between Type IIa (elevated LDL cholesterol), Type IIb (elevated LDL and VLDL), and Type IV (elevated VLDL and triglycerides) 1, 6
• HDL cholesterol is often reduced in Types IIb and IV presentations 1
• FCHL carries similar cardiovascular risk to FH despite lower cholesterol levels, due to insulin resistance, small dense LDL particles, hepatic steatosis, and systemic inflammation 4, 6
• The disorder is polygenic rather than monogenic, requiring accumulation of multiple genetic variants plus environmental triggers 4, 6

Critical distinction: FCHL has elevated apolipoprotein B (>90th percentile), while familial hypertriglyceridemia has normal apolipoprotein B levels—this is the key differentiating feature. 5

Primary Hypertriglyceridemia Disorders

Familial Hypertriglyceridemia (FHTG)

Familial hypertriglyceridemia is characterized by triglyceride levels of 200-1000 mg/dL with elevated VLDL particles but normal apolipoprotein B levels, distinguishing it from FCHL. 5

• The disorder has polygenic inheritance with heterozygous loss-of-function mutations in genes like APOA5 affecting triglyceride metabolism 5
• The pathophysiology involves VLDL overproduction and reduced VLDL catabolism, saturating lipoprotein lipase 5
• Clinical expression typically does not occur until adulthood because environmental factors (obesity, physical inactivity) are required for manifestation 5
• When secondary triggers occur (medications, alcohol, uncontrolled diabetes, pregnancy), triglycerides can exceed 1000 mg/dL, creating acute pancreatitis risk 5
• FHTG is usually not associated with coronary heart disease unless metabolic syndrome features coexist or baseline triglycerides are ≥200 mg/dL 5

Severe Hypertriglyceridemia (≥1000 mg/dL)

• Characterized by markedly elevated chylomicrons and VLDL with triglycerides ≥1000 mg/dL 1
• The most clinically relevant complication is acute pancreatitis, though only 20% of subjects with these extremely high levels develop pancreatitis 5
• Often results from familial hypertriglyceridemia unmasked by secondary factors 5

Familial Chylomicronemia Syndrome (FCS)

• This rare monogenic disorder (OMIM #238600) causes severe impairment of triglyceride-containing lipoprotein metabolism 7
• Characterized by markedly elevated chylomicrons with extremely high triglyceride levels and recurrent pancreatitis 7

Disorders of HDL Cholesterol

Familial Hypoalphalipoproteinemia

• Characterized by decreased HDL cholesterol levels as the primary abnormality 1
• May occur as an isolated finding or in combination with other lipid abnormalities 1

Rare Disorders

Dysbetalipoproteinemia (Type III Hyperlipoproteinemia)

• Characterized by elevated intermediate-density lipoprotein (IDL) cholesterol and chylomicron remnants 1
• Typical lipid profile shows total cholesterol 250-500 mg/dL and triglycerides 250-600 mg/dL 1

Lipodystrophy Syndromes

• Congenital generalized lipodystrophy presents at birth with nearly complete absence of subcutaneous adipose tissue and severe hypertriglyceridemia with eruptive xanthomas and pancreatitis risk 1
• Familial partial lipodystrophy (Dunnigan variety) involves fat loss from extremities more than trunk, with severe hypertriglyceridemia particularly in women 1
• HIV-associated lipodystrophy causes increased VLDL triglycerides due to reduced clearance of triglyceride-rich lipoproteins 1

Critical Clinical Pitfalls

The most dangerous error is failing to distinguish FCHL from familial hypertriglyceridemia—measure apolipoprotein B levels, as FCHL has elevated apoB (>90th percentile) while FHTG has normal apoB. 5

• Always screen for secondary causes (hypothyroidism, medications, diabetes, alcohol) before attributing dyslipidemia solely to genetic factors, as these frequently unmask or exacerbate genetic predisposition 5, 2
• Do not miss familial hypercholesterolemia in children—LDL cholesterol ≥135 mg/dL in a child from an affected family warrants aggressive evaluation and treatment to prevent premature cardiovascular death 1, 2
• Screen first-degree relatives when any familial dyslipidemia is identified, as these disorders cluster in families and early identification enables preventive intervention 1, 4