Familial Chylomicronaemia Syndrome

Familial chylomicronaemia syndrome (FCS) is a rare recessive disorder of chylomicron clearance that causes persistent severe hypertriglyceridaemia and recurrent acute pancreatitis. Plasma triglycerides (TG) are usually over 10 mmol/L (880 mg/dL), often 20 to 100 mmol/L.

Prevalence is about 1 in 100,000 to 1 in 1,000,000. Presentation is usually in childhood or adolescence, with abdominal pain or pancreatitis.

Causes are biallelic loss-of-function variants in LPL (most common), APOC2, APOA5, LMF1 or GPIHBP1, or anti-LPL or anti-GPIHBP1 antibodies in rare autoimmune cases. Multifactorial chylomicronaemia (heterozygous or polygenic with secondary factors) is far more common and should be distinguished.

Pancreatitis risk rises steeply when TG exceed 10 mmol/L and is particularly high over 20 mmol/L.

Pathophysiology.

Lipoprotein lipase, activated by apoC-II and anchored by GPIHBP1, hydrolyses TG in chylomicrons and VLDL. When this fails, chylomicrons accumulate and TG rise to extreme levels even after a very low fat intake.

Pancreatitis is driven by free fatty acid release from TG within the pancreatic capillaries by pancreatic lipase, causing local inflammation and injury. Because FCS is a defect in chylomicron clearance, atherosclerotic risk is lower than in other severe dyslipidaemias, though not absent.

Presentation includes recurrent abdominal pain, acute pancreatitis, eruptive xanthomas (crops of yellow papules on buttocks, shoulders and extensor surfaces), lipaemia retinalis, hepatosplenomegaly, and in infants failure to thrive and colic. Neurocognitive fog and fatigue are described.

Blood samples are milky; a creamy supernatant forms over a clear infranatant after standing at 4 degrees Celsius overnight.

Features: fasting TG persistently over 10 mmol/L (880 mg/dL) on repeated testing despite dietary control and treatment of secondary causes; history of pancreatitis; no response to fibrates; onset in childhood or young adulthood; family history of consanguinity.

Tests:

• Fasting lipid profile with the lipaemic sample handled appropriately (laboratory interference with sodium, amylase and glucose).
• Pancreatic assessment: lipase or amylase (amylase can be falsely low in severe lipaemia), CT or MRI.
• Secondary causes: diabetes, hypothyroidism, alcohol, nephrotic syndrome, pregnancy, drugs (oestrogen, tamoxifen, retinoids, propofol, protease inhibitors, thiazides, atypical antipsychotics).
• Genetic testing for biallelic variants in LPL, APOC2, APOA5, LMF1, GPIHBP1. Post-heparin LPL activity (under 20% of normal) where available.

Differential diagnosis.

• Multifactorial chylomicronaemia (the commonest cause of severe hypertriglyceridaemia).
• Familial combined hyperlipidaemia and dysbetalipoproteinaemia.
• Secondary hypertriglyceridaemia (diabetes, alcohol, drugs).
• Lipodystrophy and acquired antibody mediated LPL deficiency.

Core therapy: diet. Fat intake under 10 to 15% of energy (about 20 g daily or less), with no alcohol, complex carbohydrate emphasis, and medium chain triglyceride substitution under dietitian supervision. Fat soluble vitamin (A, D, E, K) and essential fatty acid supplementation. Fibrates, omega-3 fatty acids and statins are largely ineffective.

Disease modifying drugs.

• Volanesorsen (licensed in some regions): 285 mg subcutaneously once weekly for 3 months, then every 2 weeks, long term; platelet count before starting (do not start if under 140 x 10^9/L), every 2 weeks during treatment, hold if under 75 x 10^9/L and stop if under 25 x 10^9/L; avoid in severe renal impairment and with antiplatelet or anticoagulant drugs unless monitored.
• Olezarsen: 80 mg subcutaneously once monthly, long term; maximum 80 mg monthly; monitor TG, ALT, and injection site reactions; no renal adjustment; platelets are not usually affected.
• Plozasiran: 25 mg subcutaneously every 3 months, long term; monitor TG, glucose and liver tests.

Acute pancreatitis due to hypertriglyceridaemia.

• Fast, analgesia, and intravenous crystalloid (balanced solution, 10 mL/kg bolus if hypovolaemic, then about 1.5 mL/kg/h, adjusted to response).
• Intravenous insulin: regular insulin 0.1 to 0.3 units/kg/h with dextrose, titrated to glucose of 8 to 10 mmol/L (150 to 180 mg/dL), checked hourly; potassium monitored. Aim for TG under 11.3 mmol/L (1000 mg/dL) within 48 hours and under 5.6 mmol/L (500 mg/dL) by 72 hours.
• Plasmapheresis (plasma exchange) is used for TG over 22.6 mmol/L (2000 mg/dL), or over 11.3 mmol/L with severe pancreatitis, organ failure or no response; evidence is limited.
• Early enteral nutrition with low fat intake once the pain settles.

Monitoring. TG every 1 to 3 months (every 2 weeks initially on volanesorsen with platelets), amylase or lipase at presentations with pain, annual liver ultrasound for steatosis, glucose, and vitamin levels.

Referral and escalation. All suspected FCS should be referred to a lipid specialist. Admit any patient with TG over 10 mmol/L and abdominal pain, or TG over 20 mmol/L at any time. Severe or persistent epigastric pain with organ dysfunction (hypotension, hypoxia, renal impairment) indicates acute pancreatitis needing high dependency care.

Special groups.

• Pregnancy: TG rise sharply; strict fat restriction, specialist care, omega-3 as adjunct, and plasmapheresis for pancreatitis or TG over 22.6 mmol/L. Volanesorsen and olezarsen are avoided.
• Children: medium chain triglyceride formula in infants; growth and vitamin monitoring.
• Region specific: access to antisense therapy is limited, so dietary control and avoidance of precipitants are the mainstay.