What type of Primary Bile Acid Malabsorption is associated with Familial Type 3 Hyperlipoproteinemia?

Type III Hyperlipoproteinemia and Bile Acid Malabsorption

Familial Type III Hyperlipoproteinemia is associated with Type 3 Primary Bile Acid Malabsorption, characterized by defects in the MDR3 (ABCB4) gene. This specific genetic defect leads to impaired phospholipid transport and subsequent bile acid handling abnormalities.

Pathophysiology of Type III Hyperlipoproteinemia and Bile Acid Malabsorption

Type III Hyperlipoproteinemia (also called dysbetalipoproteinemia) is characterized by:

• Accumulation of cholesterol-rich VLDL remnants and chylomicron remnants 1
• Near-equivalent cholesterol and triglyceride values due to impaired receptor-mediated clearance 1
• Homozygosity for the rare apoE2 isoform, which displays defective binding to LDL receptors 1, 2
• Additional factors required for expression (obesity, diabetes mellitus, hypothyroidism) 1

The connection to bile acid malabsorption involves the MDR3 deficiency (PFIC Type 3), which:

• Results from defects in the class III multidrug resistance P-glycoprotein (MDR3) or ATP binding cassette subfamily B member 4 (ABCB4) gene 1
• Causes impaired phospholipid transport into bile, leading to bile acid handling abnormalities 1
• Creates a phenotypic continuum from mild to severe cholestasis 1

Clinical Manifestations

Patients with Type III Hyperlipoproteinemia and associated bile acid malabsorption may present with:

• Palmar or tuboeruptive xanthomas 1
• Increased cardiovascular and peripheral vascular disease risk 1, 3
• Chronic diarrhea (from bile acid malabsorption) 4
• Cholestatic features that may present later in life beyond childhood 1
• Coronary heart disease (occurs in approximately 41.7% of patients) 3

Diagnostic Approach

Diagnosis requires:

• Lipid profile showing elevated total cholesterol and triglycerides with near-equivalent values 1, 5
• Elevated remnant cholesterol (RLP-C) levels above 30 mg/dL 3
• High plasma RLP-C/plasma TG ratio above 0.1 3
• Genetic testing for ABCB4 mutations 1
• Apolipoprotein B measurement (not routinely performed but valuable for diagnosis) 5

Treatment Considerations

For patients with this combined disorder:

• Low-carbohydrate diet is particularly effective 1
• Ursodeoxycholic acid (UDCA) is recommended for those with at least one missense variant in ABCB4 1
• Fibrates and nicotinic acid are ideal for treating the combined lipid abnormalities 1
• Statins may be used with lifestyle modifications, with addition of fibrates for more extreme triglyceride elevations 1
• Plasmapheresis using dextran sulfate-cellulose columns may be effective in severe cases 6

Important Clinical Pearls

• Despite the association with bile acid malabsorption, Type III Hyperlipoproteinemia is often underdiagnosed because apoB is not routinely measured 5
• The cardiovascular risk associated with Type III Hyperlipoproteinemia is significant but responds well to treatment 5
• Women are generally protected from Type III Hyperlipoproteinemia until after menopause due to estrogen effects on LDL receptor expression and lipolytic processing 2
• Bile acid malabsorption may present with chronic diarrhea that responds to cholestyramine 4

Early identification and aggressive management of both the lipid abnormalities and bile acid malabsorption are essential to prevent cardiovascular complications and improve quality of life in affected individuals.