Hypertriglyceridaemic Pancreatitis

Acute pancreatitis caused by very high serum triglycerides, almost always more than 11.3 mmol/L (1000 mg/dL).

The risk rises from about 5% at levels of 5.6 to 11.3 mmol/L to 10 to 20% at more than 11.3 mmol/L, and is higher with levels of more than 22.6 mmol/L (2000 mg/dL).

• Accounts for about 1 to 10% of acute pancreatitis and up to 50% in the third trimester of pregnancy. The clinical course is often more severe than other causes (higher rates of organ failure and necrosis).
• Causes: primary (familial chylomicronaemia syndrome from lipoprotein lipase, APOC2, APOA5, GPIHBP1 or LMF1 mutations; multifactorial chylomicronaemia) and secondary (uncontrolled diabetes mellitus, obesity, alcohol, hypothyroidism, nephrotic syndrome, pregnancy, drugs such as oestrogens, tamoxifen, propofol, isotretinoin, corticosteroids, thiazides, beta blockers, protease inhibitors, asparaginase, sirolimus, and clozapine).
• Mechanism: hydrolysis of excess triglycerides by pancreatic lipase releases free fatty acids that injure acinar cells and capillary endothelium. Hyperviscosity impairs the microcirculation.

Epigastric pain radiating to the back, nausea and vomiting; often a history of previous episodes, high triglycerides or diabetes.

• Signs of hypertriglyceridaemia: eruptive xanthomata, lipaemia retinalis (milky vessels), milky serum, hepatosplenomegaly, abdominal pain episodes in childhood; features of obesity and diabetes.
• Signs of severity: tachypnoea, hypotension, oliguria, hypocalcaemia (tetany), lactic acidosis.
• Differential diagnosis: gallstone pancreatitis, alcohol related pancreatitis, diabetic ketoacidosis with abdominal pain, mesenteric ischaemia, perforated ulcer, bowel obstruction, acute fatty liver of pregnancy, pre-eclampsia (haemolysis, elevated liver enzymes and low platelets), inferior myocardial infarction.
• Complications: pancreatic necrosis and infection, organ failure, acute respiratory distress syndrome, acute kidney injury, hypocalcaemia, pseudocyst, recurrent pancreatitis (up to 20 to 40% when triglycerides are not controlled), diabetes, and in pregnancy fetal loss and premature delivery.

Triglycerides of more than 11.3 mmol/L (1000 mg/dL), or 5.6 to 11.3 mmol/L with milky serum and no other cause; measure before treatment or fasting later; lipaemic serum may interfere with amylase and lipase assays (lipase may be falsely normal).

• Lipase (more than 3 times normal in most), glucose, HbA1c, ketones, creatinine, urea, calcium, liver tests, thyroid function, urinary protein, full blood count, C-reactive protein, lactate, and arterial blood gas.
• Ultrasound to exclude gallstones; CT after 72 hours for necrosis or complications.
• Secondary cause evaluation: drug review, alcohol history, pregnancy test, thyroid and renal function, and diabetes assessment.
• Primary disorder: fasting lipid profile at least 4 weeks after recovery, genetic testing in early onset or familial disease (LPL, APOC2, APOA5, GPIHBP1, LMF1), and family screening.

Initial treatment of pancreatitis: lactated Ringer solution 5 to 10 mL/kg/hour for 12 to 24 hours, with reassessment every 6 hours (urine output more than 0.5 mL/kg/hour, mean arterial pressure of 65 to 85 mmHg). Avoid excess fluid.

Give analgesia with paracetamol 1 g every 6 hours and morphine 2 to 5 mg IV every 2 to 4 hours as needed or fentanyl 25 to 50 micrograms IV. Give oxygen and enoxaparin 40 mg SC daily.

• Withhold oral fat and stop causative drugs. Allow oral low fat diet or enteral feeding only after triglycerides are falling, and avoid lipid-containing parenteral nutrition and propofol.
• Lowering triglycerides (aim for less than 5.65 mmol/L (500 mg/dL) within 48 to 72 hours):
  • Intravenous insulin infusion 0.1 to 0.3 units/kg/hour (start 0.1 units/kg/hour; 50 units in 50 mL saline) with 5% to 10% dextrose to keep glucose at 8 to 11 mmol/L (140 to 200 mg/dL). Check glucose hourly and potassium every 4 hours.
  • Continue insulin until triglycerides are less than 5.65 mmol/L (usually 2 to 4 days); also for patients without diabetes.
  • Plasma exchange (plasmapheresis) is considered with triglycerides of more than 22.6 mmol/L (2000 mg/dL) or more than 11.3 mmol/L with severe features, hypocalcaemia, lactic acidosis, or no improvement in 24 to 48 hours.
  • One session of 1 to 1.5 plasma volumes with albumin replacement lowers triglycerides by 50 to 80% (evidence for outcome benefit is limited). It is also used in pregnancy when insulin fails.
  • Heparin infusions and insulin-alone with no diet adjustment are not routine; heparin lowers triglycerides briefly but depletes lipase, so it is not recommended.
• Long-term lipid lowering:
  • Fenofibrate 145 mg daily (or 160 mg micronised; 48 to 145 mg in renal impairment) started when oral intake is possible. Monitor liver tests and creatinine; avoid combination with gemfibrozil and statin without caution.
  • Bezafibrate 400 mg daily is an alternative.
  • Omega-3 fatty acids: icosapent ethyl 2 g twice daily or omega-3 acid ethyl esters 4 g daily with food.
  • Statin (atorvastatin 20 to 80 mg daily) when low density lipoprotein cholesterol is raised, once triglycerides are under control.
  • Niacin 500 mg at night rising to 2 g daily is a second-line option (flushing, glucose, uric acid).
  • Very low fat diet (less than 10 to 15% of energy, or 20 g fat/day in familial chylomicronaemia) with medium chain triglycerides, no alcohol, weight loss and exercise.
  • Familial chylomicronaemia syndrome (does not respond to fibrates): volanesorsen 285 mg SC weekly (platelet monitoring every 2 weeks; specialist use only), or olezarsen as available; evidence limited.
• Treat secondary causes: glucose control (insulin, metformin 500 mg to 1 g twice daily), levothyroxine for hypothyroidism (50 micrograms daily increasing to 100 to 150 micrograms), stop oestrogens and the offending drugs, stop alcohol.
• Hypocalcaemia: calcium gluconate 10% 10 to 20 mL IV over 10 minutes only if symptomatic or QT prolongation.
• Pancreatic collections and necrosis: delay intervention to 4 weeks.
• Then treat infected or obstructing necrosis with endoscopic transluminal drainage using a lumen-apposing metal stent or percutaneous drainage, followed by necrosectomy if there is no improvement. Give meropenem 1 g IV every 8 hours for infected necrosis.
• Special groups: pregnancy (triglycerides rise in the third trimester; insulin infusion, plasmapheresis, strict low fat diet, omega-3 fatty acids 2 to 4 g daily, avoid fibrates and statins where possible; discuss early delivery in severe disease with obstetric and critical care teams).
• Children: very low fat diet, medium chain triglycerides, genetic testing; plasma exchange when severe. Elderly: screen for secondary causes and drugs.
• Renal impairment: fenofibrate dose reduction, avoid in severe renal disease. Diabetes: tight glycaemic control and insulin.
• Red flags: triglycerides of more than 22.6 mmol/L, lactic acidosis, hypocalcaemia with tetany, organ failure, pregnancy, rapid deterioration, no response in 48 hours.
• Follow-up: repeat triglycerides every 24 hours in hospital, then at 2 weeks and 4 to 6 weeks, then every 3 months for a year; lipid and glucose clinic review; family screening; dietitian follow-up; HbA1c every 3 months in diabetes.