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Management of Severe Hypertriglyceridemia Due to Lipoprotein Lipase Deficiency in Children

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Management of Severe Hypertriglyceridemia Due to Lipoprotein Lipase Deficiency in Children ID: 19-0052 -19-0052 S W Y Poon and others Management of severe ID: 19-0052; July 2019 hypertriglyceridemia DOI: 10.1530/EDM-19-0052 Management of severe hypertriglyceridemia due to lipoprotein lipase deficiency in children Correspondence Sarah W Y Poon, Karen K Y Leung and Joanna Y L Tung should be addressed to J Y L Tung Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong, Email Hong Kong [email protected] Summary Severe hypertriglyceridemia is an endocrine emergency and is associated with acute pancreatitis and hyperviscosity syndrome.Wedescribeaninfantwithlipoproteinlipasedeficiencywithseverehypertriglyceridemiawhopresentedwith acute pancreatitis. She was managed acutely with fasting and intravenous insulin infusion, followed by low-fat diet with no pharmacologicalagent.Subsequentfollow-upuntiltheageof5 yearsshowedsatisfactorylipidprofileandshehasnormal growth and development. Learning points: • Hypertriglyceridemia-inducedacutepancreatitishassignificantmorbidityandmortality,andprompttreatmentis imperative. • Whennosecondarycausesarereadilyidentified,geneticevaluationshouldbepursuedinhypertriglyceridemiain children. • Intravenousinsulinisasafeandeffectiveacutetreatmentforhypertriglyceridemiainchildren,evenininfants. • Long-termmanagementwithdietarymodificationsalonecouldbeeffectiveforprimaryhypertriglyceridemiadue tolipoproteinlipasedeficiency,atleastinearlychildhoodphase. Background Hypertriglyceridemia is defined as fasting plasma The clinical severity and rate of complications with triglyceride (TG) level above an age and gender – adjusted hypertriglyceridemic pancreatitis are generally higher, 95th percentile. Monogenic hypertriglyceridemia include thus appropriate treatment and prevention of disease genetic defects in triglyceride metabolism, whereas recurrence is essential. As such, there is no consensus polygenic hypertriglyceridemia are often due to interplay on the acute and long-term management of severe between genetic, hormonal and environmental factors hypertriglyceridemia in the pediatric population. Our including uncontrolled diabetes, obesity, metabolic case highlights the use of insulin as an adjunct to lower syndrome and medications in the pediatric age group. the TG, followed by medium-chain triglyceride (MCT)- Severe hypertriglyceridemia, defined as triglyceride based diet, and subsequently, strict dietary fat restrictions concentration of greater than 1000 mg/dL, can present as long-term management in a young infant with familial with pancreatitis in the first decade of life and should chylomicronemia syndrome (FCS) due to lipoprotein prompt consideration of monogenic hypertriglyceridemia. lipase (LPL) deficiency. This work is licensed under a Creative Commons © 2019 The authors https://edm.bioscientifica.com/ Attribution-NonCommercial-NoDerivatives 4.0 PublishedbyBioscientificaLtd International License. Downloaded from Bioscientifica.com at 09/28/2021 07:39:27PM via free access S W Y Poon and others Management of severe ID: 19-0052; July 2019 hypertriglyceridemia DOI: 10.1530/EDM-19-0052 Case presentation compatible with type I hyperlipidemia with LPL deficiency. Subsequent genetic testing confirmed two heterozygous A 38-day-old Chinese girl presented to the emergency LPL variants, p.Cys54 (p.Cys27 in mature protein) (C27X) department for vomiting, irritability and suspected and p.Leu279Val (L279V), which have been reported to seizure. She was born full term with a birth weight of be pathogenic mutations (1, 2). Parents declined genetic 2.8 kg with uneventful postnatal course. She was on studies due to personal reasons. mixed feeding (breast milk supplemented with normal formula) and was growing along the 25th centile. Her parents are non-consanguineous Chinese and her father Treatment has hypertriglyceridemia with triglyceride (TG) level at She was kept fasted and started on intravenous dextrose. 250–300 mg/dL and diabetes mellitus requiring TG level dropped to 9232 mg/dL after 11 h of fasting. medication since the age of 40 years. There is otherwise Intravenous insulin infusion was then started at no family history of dyslipidemia or pancreatitis. 0.05 unit/kg/h around 12 h after admission. TG level On admission, she was noted to have decreased slowly to 106 mg/dL after 84 h before the hepatosplenomegaly. Physical examination was infusion was stopped. Octreotide infusion at 0.3 µg/kg/h unremarkable otherwise and there were no skin lesions was started for acute pancreatitis and serum lipase or abnormal body fat distribution. During venesection, gradually normalized (Fig. 2). milky serum was noted (Fig. 1A and B). Feeding was resumed after 1 week of fasting with Monogen, a low-fat, high-MCT infant milk formula Investigation (84% MCT, 16% long-chain triglyceride) containing 12.9 g fat per 100 g, with total fat intake of 9–12 g per day. TG levels were found to be >13,290 mg/dL with the total cholesterol level at 919 mg/dL. Serum lipase was elevated at 2534 µ/L (normal 23–300 µ/L), while amylase level Outcome and follow-up was normal. Serum sodium was 129 mEq/L, potassium She recovered uneventfully and weaning diet was started 5.1 mEq/L, adjusted calcium 8.12 mg/dL and bicarbonate at 6 months of age with low-fat diet (fat calorie 15% of 18 mEq/L. Computed tomography of the abdomen total calories). Until the age of 5 years, triglyceride level showed indistinct pancreatic head with loss of glandular was maintained at 195–265 mg/dL, while high-density structure, while the uncinated process, pancreatic body lipoprotein cholesterol remained low at 11.5–19 mg/dL. and tail displayed homogenous enhancement, suggestive She was later found to have mild vitamin D deficiency of pancreatitis. and was put on calciferol supplement, while vitamin B12, Agarose gel electrophoresis showed a dense folate and zinc levels were satisfactory and clotting profile chylomicron band, while the intensity of the very low- was normal. density lipoprotein (VLDL) band was mildly increased, There were no further episodes of acute pancreatitis. Her growth is along the 25th centile and she has normal development. Discussion We describe an infant who had acute pancreatitis resulting from hypertriglyceridemia due to LPL deficiency, the most common cause of FCS. Other mutations include apolipoprotein C2 (APOC2), apolipoprotein A5 (APOA5), glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GP1HBP1) and lipase maturation factor 1 (LMF1), which are important co-factors of LPL. LPL hydrolyzes triglyceride of chylomicrons and VLDLs after fat intake. Mutation in genes encoding LPL Figure 1 and its co-factors thus result in impaired lipolytic cascade (A and B) Milky serum noted on blood taking. and accumulation of chylomicrons in the plasma. https://edm.bioscientifica.com/ 2 Downloaded from Bioscientifica.com at 09/28/2021 07:39:27PM via free access S W Y Poon and others Management of severe ID: 19-0052; July 2019 hypertriglyceridemia DOI: 10.1530/EDM-19-0052 Triglyceride level with time 13290 14000 Insulin infusion started 12000 ) 10000 9232 8000 6000 4000 TG level (mg/dL Insulin infusion stopped 1656 1506 2000 549 124 106 0 0612 18 24 30 36 42 48 54 60 66 72 78 84 90 Time (Hour) Figure 2 Trend of triglyceride level with time after treatment initiated. As in our patient, affected individuals typically degradation into fatty acid and glycerol and facilitates present with lipemia plasma during blood sampling. storage in adipocytes (3). Therefore, insulin would only While abdominal pain is suggestive of pancreatitis in be useful if there is residual LPL activity. In a number older children, presentation during infancy is non- of case reports in adults, insulin has been shown to be specific and heterogeneous. Other physical findings effective in reducing TG levels. However, case report on may include eruptive xanthomas, lipemic retinitis and insulin use in patients with FCS, in particular due to hepatosplenomegaly, but it may not be present in all LPL deficiency, is limited. While our case demonstrated cases and could be non-specific. Due to interference by sustained decline in TG level with insulin infusion, one markedly elevated plasma triglyceride level, amylase cannot ascertain if similar effect could be achieved by level may be spuriously normal even with pancreatitis. fasting alone. Indeed, functional data related to both Thus, measurement of serum lipase level is essential in L279V and C27X mutations are limited. Theoretically, this situation. C27X creates a premature termination in the translation Management of hypertriglyceridemia in children is of the LPL peptide, and the very short truncated peptide challenging as there is lack of established guideline. with only 26 amino acids is expected to carry no As such, we aim to review the acute and long-term catalytic function (2). Therefore, insulin may have only management in children. contributed modest effect in our case. However, at the initial presentation, such information was not available. The clinical decision to initiate insulin infusion was Acute management mainly based on the balance between the potential risks Fasting and benefits. Intravenous insulin given as continuous Since chylomicrons are produced in the small intestine infusion, at 0.1–0.3 units/kg/h, allows easier titration and are dependent on dietary fat for formation, fasting of doses compared to subcutaneous boluses. The major results in robust decline in TG levels and allows gradual risk with intravenous insulin, especially in
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