View Patient Website
Actor portrayal of acute pancreatic patient on a hospital bed talking to a doctor

Severe hypertriglyceridemia (sHTG) has many causes

For most people with sHTG, a combination of factors can affect the production and/or clearance 
of plasma triglycerides (TGs).1

Primary & Secondary Causes of sHTG

Plasma levels of TG are largely determined by:1

  • The production of very low-density lipoproteins (VLDL) and chylomicrons, which carry most plasma TGs
  • The removal of TGs from the circulation by lipolysis

Therefore, elevated TG levels may arise from increased VLDL production, increased chylomicron production, and/or reduced clearance of these lipoproteins by lipolysis or the liver.  If TG levels exceed 500 mg/dL (sHTG), the dominant metabolic abnormality is reduced lipolysis of circulating VLDL and chylomicrons.1

Diagram showing the production of VLDL and the removal of TGs from the circulation by lipolysis

Most cases of sHTG have a genetic component, but secondary factors usually contribute.23

In some cases, genetic factors may explain high TG levels that are refractory to lifestyle changes and guideline-directed therapy.4,12

Lifestyle and medical factors icon

Lifestyle and Medical Factors9,4,2

Lifestyle & Medical Causes of sHTG
Medications icon

Medications9,4,2

Medications That Can Cause sHTG
Genetic causes icon

Genetic Causes4

Genetic Causes of sHTG
learn about the clinical presentation of shtg >

REFERENCES

  1. Ginsberg HN, Packard CJ, Chapman MJ, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. Eur Heart J. 2021;42(47):4791-4806.
  2. Virani SS, Morris PB, Agarwala A, et al. 2021 ACC Expert Consensus Decision Pathway on the Management of ASCVD Risk Reduction in Patients With Persistent Hypertriglyceridemia: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2021.
  3. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet. 2014;384(9943):626-635.
  4. Laufs U, Parhofer KG, Ginsberg HN, et al. Clinical review on triglycerides. Eur Heart J. 2020;41(1):99-109c.
  5. Packard CJ. Remnants, LDL, and the Quantification of Lipoprotein-Associated Risk in Atherosclerotic Cardiovascular Disease. Curr Atheroscler Rep. 2022;24(1534-6242 (Electronic)):133-142.
  6. Wang Y. Higher fasting triglyceride predicts higher risks of diabetes mortality in US adults. Lipids Health Dis. 2021;20(1):181.
  7. Paquette M, Bernard S. The Evolving Story of Multifactorial Chylomicronemia Syndrome. Front Cardiovasc Med. 2022;9:886266.
  8. Christian JB, Bourgeois N, Snipes R, et al. Prevalence of severe (500 to 2,000 mg/dl) hypertriglyceridemia in United States adults. Am J Cardiol. 2011;107(6):891-897.
  9. Sandesara PB, Virani SS, Fazio S, et al. The Forgotten Lipids: Triglycerides, Remnant Cholesterol, and Atherosclerotic Cardiovascular Disease Risk. Endocr Rev. 2019;40(2):537-557.
  10. Pedersen SB, Langsted A, Nordestgaard BG. Nonfasting Mild-to-Moderate Hypertriglyceridemia and Risk of Acute Pancreatitis. JAMA Intern Med. 2016;176(12):1834-1842.
  11. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111-188.
  12. Chyzhyk V, Brown AS. Familial chylomicronemia syndrome: A rare but devastating autosomal recessive disorder characterized by refractory hypertriglyceridemia and recurrent pancreatitis. Trends Cardiovasc Med. 2020;30(2):80-85.
  13. Santos-Baez LS, Ginsberg HN. Hypertriglyceridemia-Causes, Significance, and Approaches to Therapy. Front Endocrinol (Lausanne). 2020;11:616.
  14. Moulin P, Dufour R, Averna M, et al. Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS): Expert panel recommendations and proposal of an “FCS score”. Atherosclerosis. 2018;275:265-272.
  15. Hegele RA, Ginsberg HN, Chapman MJ, et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol. 2014;2(8):655-666.
  16. Brahm AJ, Hegele RA. Chylomicronaemia–current diagnosis and future therapies. Nat Rev Endocrinol. 2015;11(6):352-362.
  17. Borén J, Chapman MJ, Krauss RM, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2020;41(24):2313-2330.
  18. Semenkovich CF. Disorder of Lipid Metabolism. In: Goldman LaS, A.I., editor. Goldman-Cecil Medicine, 25th Edition. Philadelphia, PA: Elsevier Saunders; 2016. p. 1389-1397.
  19. Nordestgaard BG. Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease: New Insights From Epidemiology, Genetics, and Biology. Circ Res. 2016;118(4):547-563.
  20. Nordestgaard BG, Benn M, Schnohr P, et al. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. Jama. 2007;298(3):299-308.
  21. Stroes E, Moulin P, Parhofer KG, et al. Diagnostic algorithm for familial chylomicronemia syndrome. Atheroscler Suppl. 2017;23:1-7.
  22. Davidson M, Stevenson M, Hsieh A, et al. The burden of familial chylomicronemia syndrome: Results from the global IN-FOCUS study. J Clin Lipidol. 2018;12(4):898-907.e892.
  23. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019;73(24):e285-e350.
  24. Belhassen M, Van Ganse E, Nolin M, et al. 10-Year Comparative Follow-up of Familial versus Multifactorial Chylomicronemia Syndromes. J Clin Endocrinol Metab. 2021;106(3):e1332-e1342.
  25. Nawaz H, Koutroumpakis E, Easler J, et al. Elevated serum triglycerides are independently associated with persistent organ failure in acute pancreatitis. Am J Gastroenterol. 2015;110(10):1497-1503.
  26. Bedogni G, Bellentani S, Miglioli L, et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol. 2006;6:33.
  27. Koehler EM, Schouten JN, Hansen BE, et al. External validation of the fatty liver index for identifying nonalcoholic fatty liver disease in a population-based study. Clin Gastroenterol Hepatol. 2013;11(9):1201-1204.
  28. Nivukoski U, Niemelä M, Bloigu A, et al. Combined effects of lifestyle risk factors on fatty liver index. BMC Gastroenterol. 2020;20(1):109.
  29. Maltais M, Brisson D, Gaudet D. Non-Alcoholic Fatty Liver in Patients with Chylomicronemia. J Clin Med. 2021;10(4).
  30. O’Dea LSL, MacDougall J, Alexander VJ, et al. Differentiating Familial Chylomicronemia Syndrome From Multifactorial Severe Hypertriglyceridemia by Clinical Profiles. J Endocr Soc. 2019;3(12):2397-2410.
  31. Handelsman Y, Jellinger PS, Guerin CK, Bloomgarden ZT, Brinton EA, Budoff MJ, Davidson MH, Einhorn D, Fazio S, Fonseca VA, Garber AJ, Grunberger G, Krauss RM, Mechanick JI, Rosenblit PD, Smith DA, Wyne KL. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Management of Dyslipidemia and Prevention of Cardiovascular Disease Algorithm – 2020 Executive Summary. Endocr Pract. 2020;26(10):1196-224.
  32. Hopkins PN, Wu LL, Hunt SC, Brinton EA. Plasma triglycerides and type III hyperlipidemia are independently associated with premature familial coronary artery disease. J Am Coll Cardiol. 2005;45(7):1003-12.
  33. Toth PP, Grabner M, Ramey N, Higuchi K. Clinical and economic outcomes in a real-world population of patients with elevated triglyceride levels. Atherosclerosis. 2014;237(2):790-7.
  34. Williams L, Rhodes KS, Karmally W, Welstead LA, Alexander L, Sutton L. Familial chylomicronemia syndrome: Bringing to life dietary recommendations throughout the life span. J Clin Lipidol. 2018;12(4):908-19.
  35. ClinicalTrials.gov A Study of Olezarsen (ISIS 678354) in Participants With Hypertriglyceridemia and Atherosclerotic Cardiovascular Disease, or With Severe Hypertriglyceridemia. ClinicalTrials.gov identifier: NCT05610280. Accessed March 13, 2024. Updated March 1, 2024. https://clinicaltrials.gov/ct2/show/NCT05610280
  36. Jacobson TA, Ito MK, Maki KC, et al. National lipid association recommendations for patient-centered management of dyslipidemia: part 1–full report. J Clin Lipidol. 2015;9(2):129-169. PMID:25911072
  37. Newman CB, Blaha MJ, Boord JB, et al. Lipid Management in Patients with Endocrine Disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2020;105(12). PMID:32951056
  38. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes-2024. Diabetes Care. 2024;47 (Suppl 1):S179-s218. PMID:38078592
  39. Symptoms and Diagnosis of Metabolic Syndrome. American Heart Association. 2023; cited  January 23, 2024. Available from: https://www.heart.org/en/health-topics/metabolic-syndrome/symptoms-and-diagnosis-of-metabolic-syndrome.
  40. Lee AH. The role of CREB-H transcription factor in triglyceride metabolism. Curr Opin Lipidol. 2012;23(2):141-146. PMID:22262056
  41. Carrasquilla GD, Christiansen MR, Kilpeläinen TO. The genetic basis of hypertriglyceridemia. Curr Atheroscler Rep. 2021;23(8):39. PMID:34146174
  42. Dron JS, Dilliott AA, Lawson A, et al. Loss-of-function CREB3L3 variants in patients with severe hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 2020;40(8):1935-1941. PMID:32580631
  43. Burnett JR, Hooper AJ, Hegele RA. Familial Lipoprotein Lipase Deficiency. In: Adam MP, Ardinger HH, Pagon RE, et al editors GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 2017.
  44. ClinicalTrials.gov A Study of Olezarsen Administered Subcutaneously to Participant With Severe Hypertriglyceridemia, etc. Identifier: NCT05079919. https://clinicaltrials.gov/ct2/show/NCT05079919
  45. Dron JS, Hegele RA. Genetics of hypertriglyceridemia. Front Endocrinol (Lausanne). 2020;11:455.
  46. Tripathi M, Wong A, Solomon V, et al. The prevalence of probable familial chylomicronemia syndrome in a southern California population. Endocr Pract. 2021;27(1):71-76.
  47. Pallazola VA, Sajja A, Derenbecker R, et al. Prevalence of familial chylomicronemia syndrome in a quaternary care center. Eur J Prev Cardiol. 2020;27(19):2276-2278.
  48. Definition of autosomal recessive inheritance. National Cancer Institute. 2024; cited  April 30, 2024. Available from: https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/autosomal-recessive-inheritance
  49. Śliwińska-Mossoń M, Bil-Lula I, Marek G. The Cause and Effect Relationship of Diabetes after Acute Pancreatitis. Biomedicines. 2023;11(3).