Hypertriglyceridaemia

Hypertriglyceridaemia is a raised fasting triglyceride concentration of 1.7 mmol/L (150 mg/dL) or more. It carries an increased risk of atherosclerotic disease, and at very high levels it carries a risk of acute pancreatitis. It is most often secondary to obesity, insulin resistance, diabetes and alcohol, on a background of a genetic tendency.

• Severity: mild 1.7 to 2.3 mmol/L (150 to 199 mg/dL); moderate 2.3 to 5.6 mmol/L (200 to 499 mg/dL); severe 5.6 to 11.2 mmol/L (500 to 999 mg/dL); very severe 11.2 mmol/L (1000 mg/dL) or more. Pancreatitis risk rises sharply above 10 mmol/L and especially above 20 mmol/L.
• Causes: obesity and metabolic syndrome, type 2 diabetes (poor control), alcohol, high refined carbohydrate and fat diet, hypothyroidism, nephrotic syndrome, chronic kidney disease, pregnancy (third trimester), Cushing syndrome, lipodystrophy, and lymphoma or paraproteins.
• Drugs: oral oestrogen, tamoxifen, thiazides, loop diuretics, non-selective beta blockers, corticosteroids, isotretinoin and acitretin, protease inhibitors, atypical antipsychotics (olanzapine, clozapine), sirolimus, ciclosporin, propofol, and bile acid sequestrants.
• Genetic: familial hypertriglyceridaemia, familial combined hyperlipidaemia, familial chylomicronaemia syndrome (lipoprotein lipase, apolipoprotein C-II, GPIHBP1 deficiency), dysbetalipoproteinaemia.

• Usually none when moderate. Severe: recurrent abdominal pain, acute pancreatitis (epigastric pain radiating to the back, vomiting), eruptive xanthomata (crops of yellow papules on buttocks, shoulders, extensors), lipaemia retinalis, hepatosplenomegaly, lipaemic (milky) serum, memory impairment and dyspnoea (chylomicronaemia syndrome).
• Palmar crease xanthomata in dysbetalipoproteinaemia.
• Features of the underlying cause: central adiposity, acanthosis nigricans, hypothyroidism features, heavy alcohol use, polyuria.
• Family history of pancreatitis, early cardiovascular disease, or lipid disorders.

• Fasting (9 to 12 hours) lipid profile, repeated to confirm; non-fasting triglycerides above 5 mmol/L should be rechecked fasting.
• Check for secondary causes: HbA1c or fasting glucose, thyroid stimulating hormone, liver function tests (and gamma glutamyl transferase), creatinine and eGFR, urine albumin to creatinine ratio, calcium, and urine protein; pregnancy test in women; paraprotein screen if unexplained.
• Calculate non-HDL cholesterol and apolipoprotein B (high when atherogenic particles are increased).
• When triglycerides are above 10 mmol/L: serum amylase or lipase if abdominal pain, and review urgently.
• Genetic testing for suspected familial chylomicronaemia (severe at a young age, recurrent pancreatitis, no secondary cause, triglycerides above 10 mmol/L repeatedly).
• Pre-analytical errors: very high triglycerides cause pseudohyponatraemia and artefacts in other laboratory tests.
• Differentials: severe hypertriglyceridaemia secondary to uncontrolled diabetes (including ketoacidosis), alcohol related, oestrogen induced pancreatitis, hypothyroidism, familial disorders.

All patients

• Weight loss: 5 to 10 percent reduces triglycerides by 20 percent or more.
• Diet: restrict refined carbohydrate, added sugar and fruit juice; limit saturated and trans fats; limit alcohol to under 14 units weekly (none if triglycerides above 5.6 mmol/L); include fish twice weekly; fat limited to 10 to 15 percent of energy for severe levels.
• Exercise 150 minutes weekly.
• Optimise glycaemic control: metformin, a GLP-1 receptor agonist (semaglutide, liraglutide), pioglitazone or insulin when needed; insulin lowers triglycerides rapidly.
• Treat hypothyroidism with levothyroxine; treat nephrotic syndrome.
• Stop or change causative drugs where possible (oral oestrogen to transdermal, change thiazide or beta blocker, review retinoid and antipsychotic).

Mild to moderate (1.7 to 5.6 mmol/L)

• Lifestyle and cardiovascular risk management first. Atorvastatin 20 to 40 mg or rosuvastatin 10 to 20 mg at night when 10 year risk is raised, or diabetes (statins reduce triglycerides by 10 to 30 percent).
• Icosapent ethyl 2 g orally twice daily with food in high risk patients on a statin with triglycerides 1.5 to 5.6 mmol/L (watch for atrial fibrillation and bleeding; check fish and shellfish allergy).
• Fenofibrate 145 mg orally daily (48 mg with eGFR 30 to 59; avoid below 30) if triglycerides remain above 2.3 mmol/L with low HDL-C and high risk; it can be combined with a statin (avoid gemfibrozil with statins).

Severe or very severe (5.6 mmol/L or more)

• Aim for below 5.6 mmol/L and ideally below 2.3 to 4.5 mmol/L. Alcohol abstinence, fat restriction to 10 to 15 percent of energy (or 20 g per day in chylomicronaemia), medium chain triglyceride substitution, no refined sugar.
• Fenofibrate 145 mg daily (or 200 mg micronised) as first drug; add omega-3 fatty acid ethyl esters 2 to 4 g daily; gemfibrozil 600 mg twice daily if fenofibrate is not suitable (not with statins).
• Statin only after triglycerides are below 5.6 mmol/L, or low dose atorvastatin when cardiovascular risk is high.
• Familial chylomicronaemia syndrome: strict dietary fat control; volanesorsen 285 mg subcutaneously weekly (specialist, with platelet monitoring) or olezarsen under specialist care; fibrates and omega-3 are often ineffective.

Acute pancreatitis or triglycerides above 20 mmol/L with symptoms

• Admit: nil by mouth, intravenous fluids, analgesia, and an intravenous insulin infusion (0.1 to 0.3 units/kg/hour, with glucose 5 to 10 percent) until triglycerides are below 5.6 mmol/L; plasmapheresis in selected cases at specialist centres.

Special groups

• Pregnancy: triglycerides rise 2 to 3 times; severe levels need dietary fat restriction, omega-3 and rarely plasmapheresis; avoid statins and fibrates; refer to obstetric medicine.
• Children: refer to specialist; dietary control.
• Diabetes: improve control; fenofibrate may reduce microvascular complications.

Follow up

• Repeat fasting lipids at 4 to 12 weeks after a change, then every 6 to 12 months; check liver function, creatinine (fenofibrate can raise creatinine), and creatine kinase for muscle symptoms.
• Refer for triglycerides above 10 mmol/L despite treatment, pancreatitis, suspected genetic disease, or pregnancy.