Persistent Chylomicronemia

Mini Review

Abstract

Persistent chylomicronemia is a rare but serious metabolic disorder characterized by extremely high triglyceride levels - often surpassing 1,000 mg/dL - and the abnormal presence of fasting chylomicrons. This results from severely impaired clearance of chylomicrons, leading to their continuous accumulation and posing a major risk for recurrent, potentially fatal acute pancreatitis. Its etiology includes monogenic and polygenic forms. The monogenic form, known as familial chylomicronemia syndrome, is extremely rare and caused by biallelic mutations in genes essential for lipoprotein lipase function, such as lipoprotein lipase, APOC2, APOA5, GPIHBP1, and LMF1. In contrast, the polygenic/multifactorial form is far more common and results from the combined effect of multiple genetic variants together with secondary factors such as uncontrolled diabetes, obesity, hypothyroidism, alcohol intake, nephrotic syndrome, and certain medications. Clinically, the most severe consequence is acute pancreatitis, triggered by capillary obstruction and toxic free fatty acid release within the pancreas. Other manifestations include eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and neurological symptoms linked to hyperviscosity. Diagnosis involves identifying markedly elevated triglycerides (typically >885 mg/dL) and fasting chylomicrons, sometimes evident as lactescent plasma. Genetic testing is useful when familial chylomicronemia syndrome is suspected. Management requires lifelong intervention, with strict dietary fat restriction (10-15% of daily calories), avoidance of simple sugars and alcohol, and lifestyle measures such as weight loss and smoking cessation. Traditional triglyceride-lowering drugs - fibrates, omega-3 fatty acids, and niacin—are often ineffective in familial chylomicronemia syndrome due to absent lipoprotein lipase activity. Emerging therapies focus on lipoprotein lipase - independent pathways. APOC-III inhibitors, including volanesorsen, olezarsen, and plozasiran, produce substantial triglyceride reductions across various forms of chylomicronemia. Patients with residual lipoprotein lipase activity may also benefit from ANGPTL3 inhibitors. Improved recognition, education, and personalized treatment based on clinical phenotype - not solely genetics - are essential to reduce complications and mortality.