Open Access Review Article

Drug Treatment of Hypertriglyceridemia in Children

Ana Paula Marte Chacra1, Anita LR Saldanha2, Ana Paula Pantoja Margeotto2, André LV Gasparoto3 and Tania Leme da Rocha Martinez2*

1Heart Institute, Faculty of Medicine, University of São Paulo, Brazil

2Nephrology Department, BP - A Beneficência Portuguesa de São Paulo, Brazil

3Intensive Care Unit, BP - A Beneficência Portuguesa de São Paulo, Brazil

Corresponding Author

Received Date: March 21, 2022;  Published Date: April 06, 2022

Treatment of severe hypertriglyceridemia aims to treat and prevent complications including acute pancreatitis, mesenteric ischemia, and recurrent abdominal pain. The risk of pancreatitis increases with serum triglyceride levels above 1000 mg/dL. The aim of treatment is the reduction of triglycerides to values less than 1000 mg/dL. The indication of hospitalization should be for patients with symptoms and triglycerides values above 1000 mg/dL. Laboratory evaluation should include lipid, metabolic profile, renal function, electrolytes, liver function, glycemic profile, thyroid hormone and urine type I. Patients with severe hypertriglyceridemia and abdominal pain or pancreatitis should be kept fasting and intravenous hydration. The average fasting time is 48 hours. Insulin activates lipoprotein lipase and thus the lipolytic pathway of plasma triglycerides, facilitating the removal of these particles from the circulation, reducing their serum values. The use of plasmapheresis in children with severe hypertriglyceridemia is rare. Being an invasive procedure, it requires specialized centers. The efficacy of plasmapheresis in rapidly reducing plasma triglycerides is 70%. There are no triglycerides -reducing drugs approved for use in children and adolescents. Even without approval for children and adolescents, some of these drugs are used in the presence of fasting serum triglycerides concentrations above 500 mg/dL. Omega-3-fatty acids (omega-3-FA) can be used as adjuvant therapy when the triglycerides concentration is exceeded at 500 mg/dL. Omega-3-FA reduce the hepatic secretion of VLDL cholesterol and increase the catabolism of chylomicron. A new medication for familial chylomicronemia syndrome has been recently approved for adults in many European and South American countries, volanesorsen, an antisense oligoprotein that inhibits apoprotein CIII, a co-activator of lipoprotein lipase. This brings a lot of hope that can in the future be proved safe for children aswell.

Keywords:Familial Chylomicronemia Syndrome; Hypertriglyceridemia; Lipoprotein Lipase; Omega-3-Fatty Acids; Severe Hypertriglyceridemia;Triglycerides

Abbreviations:FCS: Familial Chylomicronemia Syndrome; HTG: Hypertriglyceridemia; LPL: Lipoprotein Lipase; Omega-3-FA: Omega-3-Fatty Acids; SHTG: Severe Hypertriglyceridemia; TG: Triglycerides

Treatment of acute complications of severe hypertriglyceridemia

The clinical picture of familial chylomicronemia syndrome (FCS) affects children and adolescents, with a higher prevalence in children younger than 1 year of life. With breastfeeding and accumulation of chylomicron in the circulation, severe hypertriglyceridemia (SHTG) and onset of symptoms may develop in a period of days to months. In the age groups less than 1 year, the clinical presentation is heterogeneous. In addition to classic symptoms such as abdominal pain, irritability may be present, especially during breastfeeding, pallor, fever, nausea, vomiting, diarrhea, low intestinal bleeding, and hypotension. In asymptomatic patients, lipemic serum is one of the diagnostic criteria. Initial clinical examination may be normal or present with abdominal pain, hepatospelnomegaly, lipemia retinalis, and eruptive xanthomas [1-4].

Hospitalization

The indication of hospitalization should be for patients with symptoms and TG values above 1000 mg/dL. In asymptomatic patients, hospitalization should take into account previous episodes of pancreatitis.

Laboratory evaluation

Laboratory evaluation should include lipid, metabolic profile, renal function, electrolytes, liver function, glycemic profile, thyroid hormone and urine type I. Depending on the methodology, SHTG may interfere with electrolyte dosages such as sodium, potassium and chloride, reducing its serum values [5-7]. Similarly, levels of amylase and lipase may be normal, even in the presence of pancreatitis [1]. Abdominal imaging tests are recommended for diagnostic confirmation of acute pancreatitis [1].

Treatment

Fasting

Patients with SHTG and abdominal pain or pancreatitis should be kept fasting and intravenous hydration. The average fasting time is 48 hours [8].

Insulin

Insulin activates lipoprotein lipase and thus the lipolytic pathway of plasma TG, facilitating the removal of these particles from the circulation [9], reducing their serum values. Case reports with insulin use in children with FCS are rare. In patients with or without residual LPL activity, the use of continuous intravenous insulin, dextrose solution and fasting were effective in reducing HTG. As these measures were associated with fasting, it cannot be quantified whether the effect of plasma TG reduction is the result of insulin, fasting or both. The indication of intravenous insulin in FCS should be considered in the presence of acute complications of SHTG and in the risk and benefit of this therapy. Intravenous insulin administered continuously infusion, at 0.1-0.3 units/kg/h, allows easier titration of doses compared to subcutaneous bolus. The risk especially in newborns is hypoglycemia. Concomitant infusion of dextrose along the same intravenous line as insulin infusion is important to maintain euglycemia and ensure endogenous insulin secretion. Blood glucose should be monitored in the blood frequently during insulin infusion. The therapeutic response is observed in the first 24 hours [10].

Plasmapheresis

The use of plasmapheresis in children with SHTG is rare. Being an invasive procedure, it requires specialized centers. Therefore, the indication of plasmapheresis in the pediatric population is restricted to cases of refractory HTG, for treatment and prevention of complications such as acute pancreatitis. There are case reports of newborns with SHTG and acute pancreatitis complicated by lactic acidosis, respiratory distress syndrome, and organ failure where immediate reduction of TG with plasmapheresis was beneficial [11-14]. The use of plasmapheresis in newborns is of great concern due to the potential risks related to the extracorporeal procedure, mainly due to hemodynamic effects and hemorrhagic events. Plasma filtration would be preferred in very young babies because it requires a smaller volume of extracorporeal circulation than plasma exchange, but seems to be less effective in SHTG, as chylomicrons remain trapped in the primary plasma filter because of its larger diameter and high molecular weight [11,15]. Stefanutti et al. reported two cases of SHTG in very young babies successfully treated with plasmapheresis without adverse events. These authors introduced modifications to the standard procedure to minimize risks [16]. The efficacy of plasmapheresis in rapidly reducing plasma TG is 70% [17]. Plasmapheresis can technically be the challenge, depending on the age of the child and the availability of the procedure is quite limited [18]

Exchange transfusion (ET)

Was introduced in the late 1940s and has since been applied to many diseases (such as high levels of unconjugated hyperbilirubinemia in the newborn due to any cause, severe anemia, disseminated intravascular coagulation, neonatal sepsis). It is a common procedure performed by neonatologists [19]. The most common related adverse effects include thrombocytopenia, hypocalcaemia, hyperkalemia, apnea, bradycardia, hypotension and catheter-related complications. The first case report of the use of ET in a patient with less than 1 month of life, with FCS and high risk of pancreatitis, resulted in a significant and immediate decrease in plasma TG levels, without adverse events [20]. This effect is by the procedure itself and possibly by the presence, in transfused blood, of the LPL enzyme released from mononuclear blood cells [21, 22]. The ET procedure should be considered for the treatment of SHTG in infants with FCS in order to decrease the risk of potentially fatal pancreatitis.

Drug treatment

Fibrates are the drugs of choice to treat HTG, but with limited evidence of efficacy and safety in the pediatric population. They are not effective if LPL activity is absent, or with very high plasma TG values. They reduce plasma TG by activation of PPAR-alpha receptors (peroxisome proliferator agonists activated receptoralpha) and decreased liver production VLDL (very low-density lipoprotein). Fibrates may cause the development of gallstones and are contraindicated in patients with altered renal function [1,24,25]. There are no TG-reducing drugs approved for use in children and adolescents [23]. Even without approval for children and adolescents, some of these drugs are used in the presence of fasting serum TG concentrations above 500 mg/dL.

Omega 3

Omega-3-fatty acids (omega-3-FA) can be used as adjuvant therapy when the TG concentration is exceeded at 500 mg/dL. Omega-3-FA reduce the hepatic secretion of VLDL cholesterol and increase the catabolism of chylomicron. Gastrointestinal side effects among them “fish taste” eructations hinder adherence [26,27]. Pediatric clinical trials with omega-3 do not show significant reduction in TG [28,29].

Volanesorsen

A new medication for FCS has been recently approved for adults in many European and South American countries, volanesorsen, an antisense oligoprotein that inhibits apoprotein CIII, a co-activator of LPL [30,31]. This brings a lot of hope that can in the future be proved safe for children aswell. Inhibition of apoC3 using the antisense oligonucleotide reduces triglyceride levels by up to 77% and rates of pancreatitis while improving well-being.

Acknowledgment

None.

Conflicts of Interest

No conflict of interest.

References

  1. Schaefer EW, Leung A, Kravarusic J, Stone NJ (2012) Management of severe hypertriglyceridemia in the hospital: a review. J Hosp Med 7(5): 431-438.
  2. Tsuang W, Navaneethan U, Ruiz L, Palascak JB, Gelrud A (2009) Hypertriglyceridemic pancreatitis: presentation and management. Am J Gastroenterol 104(4): 984-991.
  3. Feoli-Fonseca JC, Lévy E, Godard M, Lambert M (1998) Familial lipoprotein lipase deficiency in infancy: clinical, biochemical, and molecular study. J Pediatr 133(3): 417-423.
  4. Wilson CJ, Priore Oliva C, Maggi F, Catapano AL, Calandra S (2003) Apolipoprotein C-II deficiency presenting as a lipid encephalopathy in infancy. Ann Neurol 53(6): 807-810.
  5. Seda G, Meyer JM, Amundson DE, Daheshia M (2013) Plasmapheresis in the management of severe hypertriglyceridemia. Crit Care Nurse 33(4): 18-23.
  6. Dimeski G (2008) Interference testing. Clin Biochem Rev 29 Suppl 1(Suppl 1): S43-S48.
  7. Kroll MH (2004) Evaluating interference caused by lipemia. Clin Chem 50(11): 1968-1969.
  8. Lopez-Miranda J, Williams C, Lairon D (2007) Dietary, physiological, genetic and pathological influences on postprandial lipid metabolism. Br J Nutr 98(3): 458-473.
  9. Eckel RH (1989) Lipoprotein lipase. A multifunctional enzyme relevant to common metabolic diseases. N Engl J Med 320(16): 1060-1068.
  10. Poon SWY, Leung KKY, Tung JYL (2019) Management of severe hypertriglyceridemia due to lipoprotein lipase deficiency in children. Endocrinol Diabetes Metab Case Rep 2019(1): 1-5.
  11. Ewald N, Kloer HU (2009) Severe hypertriglyceridemia: an indication for apheresis. Atheroscler Suppl 10(5): 49-52.
  12. Lutfi R, Huang J, Wong HR (2012) Plasmapheresis to treat hypertriglyceridemia in a child with diabetic ketoacidosis and pancreatitis. Pediatrics 129(1): e195-e198.
  13. Kohli RS, Bleibel W, Shetty A, Dhanjal U (2006) Plasmapheresis in the treatment of hypertriglyceridemic pancreatitis with ARDS. Dig Dis Sci 51(12): 2287-2291.
  14. Syed H, Bilusic M, Rhondla C, Tavaria A (2010) Plasmapheresis in the treatment of hypertriglyceridemia-induced pancreatitis: A community hospital's experience. J Clin Apher 25(4): 229-234.
  15. Stefanutti C, Lanti A, Di Giacomo S, Mareri M, De Lorenzo F, et al. (2004) Therapeutic apheresis in low weight patients: technical feasibility, tolerance, compliance, and risks. Transfus Apher Sci 31(1): 3-10.
  16. Stefanutti C, Gozzer M, Pisciotta L, D'Eufemia P, Bosco G, et al. (2013) A three-month-old infant with severe hyperchylomicronemia: molecular diagnosis and extracorporeal treatment. Atheroscler Suppl 14(1): 73-76.
  17. Stefanutti C, Di Giacomo S, Vivenzio A, Labbadia G, Mazza F, et al. (2009) Therapeutic plasma exchange in patients with severe hypertriglyceridemia: a multicenter study. Artif Organs 33(12): 1096-1102.
  18. Nasa P, Alexander G, Kulkarni A, Juneja D, Sehra S, et al. (2015) Early plasmapheresis in patients with severe hypertriglyceridemia induced acute pancreatitis. Indian J Crit Care Med 19(8): 487-489.
  19. Steiner LA, Bizzarro MJ, Ehrenkranz RA, Gallagher PG (2007) A decline in the frequency of neonatal exchange transfusions and its effect on exchange-related morbidity and mortality. Pediatrics 120(1): 27-32.
  20. Pugni L, Riva E, Pietrasanta C, Rabacchi C, Bertolini S, et al. (2014) Severe hypertriglyceridemia in a newborn with monogenic lipoprotein lipase deficiency: an unconventional therapeutic approach with exchange transfusion. JIMD Rep 13: 59-64.
  21. Stengel D, Antonucci M, Gaoua W, Dachet C, Lesnik P, et al. (1998) Inhibition of LPL expression in human monocyte-derived macrophages is dependent on LDL oxidation state: a key role for lysophosphatidylcholine. Arterioscler Thromb Vasc Biol 18(7): 1172-1180.
  22. Merkel M, Eckel RH, Goldberg IJ (2002) Lipoprotein lipase: genetics, lipid uptake, and regulation. J Lipid Res 43(12): 1997-2006.
  23. Shah AS, Wilson DP (2015) Primary hypertriglyceridemia in children and adolescents. J Clin Lipidol 9(5 Suppl): S20-S28.
  24. Wheeler KA, West RJ, Lloyd JK, Barley J (1985) Double blind trial of bezafibrate in familial hypercholesterolaemia. Arch Dis Child 60(1): 34-37.
  25. Becker M, Staab D, Von Bergman K (1992) Long-term treatment of severe familial hypercholesterolemia in children: effect of sitosterol and bezafibrate. Pediatrics 89(1): 138-142.
  26. Yuan G, Al-Shali KZ, Hegele RA (2007) Hypertriglyceridemia: its etiology, effects and treatment. CMAJ 176(8): 1113-1120.
  27. Pirillo A, Catapano AL (2015) Update on the management of severe hypertriglyceridemia--focus on free fatty acid forms of omega-3. Drug Des Devel Ther 9: 2129-2137.
  28. de Ferranti SD, Milliren CE, Denhoff ER, Steltz SK, Selamet Tierney ES, et al. (2014) Using high-dose omega-3 fatty acid supplements to lower triglyceride levels in 10- to 19-year-olds. Clin Pediatr (Phila) 53(5): 428-438.
  29. Chahal N, Manlhiot C, Wong H, McCrindle BW (2014) Effectiveness of omega-3 polysaturated fatty acids (fish oil) supplementation for treating hypertriglyceridemia in children and adolescents. Clin Pediatr (Phila) 53(7): 645-651.
  30. Esan O, Wierzbicki AS (2020) Volanesorsen in the treatment of familial chylomicronemia syndrome or hypertriglyceridaemia: Design, development and place in therapy. Drug Des Devel Ther 14: 2623-2636.
  31. Witztum JL, Gaudet D, Freedman SD, Alexander VJ, Digenio A, et al.. (2019) Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N Engl J Med 381(6): 531-542.
Citation
Keywords
Signup for Newsletter
Scroll to Top