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Acute hypertriglyceridemic pancreatitis during pregnancy due to homozygous lipoprotein lipase gene mutation
Clinica Chimica Acta 400 (2009) 137–138
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Clinica Chimica Acta j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c l i n c h i m
Letter to the Editor Acute hypertriglyceridemic pancreatitis during pregnancy due to homozygous lipoprotein lipase gene mutation
Dear Editor, Acute pancreatitis during pregnancy, when caused by hyperlipidemia in lipoprotein lipase (LPL [MIM 609708]) deficient patients [1– 4], is a life-threatening disease for both the fetus and the mother. During pregnancy, plasma triglyceride (TG) levels normally increase, often as much as 3-fold [5], but this is usually of little clinical consequence. When lipoprotein lipase activity is compromised, however, marked hypertriglyceridemia may result in severe pancreatitis [2]. LPL (EC 3.1.1.34) is a key enzyme for the hydrolysis of TG from chylomicrons and VLDL particles of blood plasma [6]. LPL deficiency (type I hyperlipoproteinemia), a recessive genetic disease, has a prevalence about one in a million, except in Quebec, Canada where it is more frequent [6]. It usually presents in childhood with hypertriglyceridemia causing lactescent blood. No mutations in the LPL gene have been identified in the Hungarian population. The T/ C substitution in codon 86 of exon 3 that replaced the original tryptophan with arginine (W86R) and produced the characteristic symptoms of LPL deficiency has been observed only in three (apparently unrelated) cases: one having English ancestry [7], another in the Seattle (USA) area [8], and one from Croatia [9]. The first two were reported as compound heterozygotes, with only the W86R mutation in common, and the third case a male patient found homozygous without the enzyme activity level documented.
third trimester of her third pregnancy and diagnosed as pancreatitis. After two days of conservative therapy a severe septicotoxic condition necessitated immediate surgery during which diffuse peritonitis was found with 3 L of purulent fluid originating from necrotizing pancreatitis. The dead fetus was removed with the uterus, the pancreas was resected. Following this, a number of reoperations were performed due to omental abscesses and progressive intraabdominal sepsis. Her gall-bladder was also removed and the abdominal wound treated in a semi-open way. Because of her continuous septic condition and progression of disease, the patient was later transported to the Institute of Surgery, University of Debrecen, where a total of 4 scheduled surgeries were performed in order to treat the extremely aggressive pancreatitis. Our interventions included necrectomies, placement of a jejunostomy tube and programmed lavages. The patient was treated at our Intensive Care Unit throughout her hospital stay. Blood-tests revealed an extreme hyperlipidemia (19.5 mmol l− 1 [normal range: 0.0–1.7 mmol l− 1]). Hypocalcemia and significant hemostatic disorder also made the course of disease more complicated. Repeated cultures yielded several bacteria and Candida species. After 32 strenuous days she was discharged from the ward. This is the first report of the LPL W86R mutation causing serious exacerbation of the hyperlipidemia symptoms during pregnancy and
Here we report a case of an ethnic Hungarian pregnant woman with a nearly fatal hyperlipidemic pancreatitis in whom we identified mutations in the LPL gene. After approval by the Ethical Review Board of University of Debrecen and informed consent, the proband's DNA was screened for LPL mutations by sequencing of the PCR amplifications of LPL exons 1–9 (and portions of introns) in two directions using LPL gene specific primers. We identified a homozygous W86R variant, a T to C transition at codon 86 resulting in a tryptophan to arginine change. After the identification of the mutation in the proband, five other family members were tested for this LPL variant. Four of them were found to be heterozygous for the same mutation (Fig. 1). Both parents were heterozygous and the mode of inheritance corresponded to the expected autosomal recessive. Post-heparin LPL activity was determined in plasma drawn 20 min after the injection of heparin (250 IU/kg body weight) after an overnight fast. Lipoprotein lipase activity was assayed as formerly described [10]. The results represent the average of three determinations. The patient's post-heparin plasma LPL activity was found 5.3 ± 1. 9 μmol ml− 1 h− 1, that represented an average of 29% of normal control values (18.44 ± 3.01 μmol ml− 1 h− 1). The 25-year-old woman was admitted to her local hospital several times due to recurrent episodes of acute abdominal pain during the 0009-8981/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2008.10.016
Fig. 1. Pedigree of the LPL W86R mutation. The female III/2 (arrow) was the proband. Family members were tested for this mutation, except for persons I/2, III/3, and IV/2 (were not available for testing). Labels: shaded symbol – homozygous mutant; halfshaded – heterozygous for the mutation; open – not containing the mutation; open symbol with question mark – not tested.
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the first case in which the level of residual activity in a homozygous W86R mutation could be clearly documented. The residual LPL activity of the W86R variant (29% of normal) accounts for why the severe pancreatitis appeared only during pregnancy, when the burden of lipid metabolism was significantly challenged. Fat depots increased during early pregnancy later break down causing an accumulation of TGs [5]. The presence of lipoprotein receptors in the placenta together with LPL and intracellular lipase activities, allow the release of fatty acids to the fetus [5]. Acknowledgements Contribution of G. Vargha was supported by the Széchenyi István Fellowship of the Ministry of Education, Hungary. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.cca.2008.10.016. References [1] Henderson H, Leisegang F, Hassan F, Hayden M, Marais D. A novel Glu421Lys substitution in the lipoprotein lipase gene in pregnancy-induced hypertriglyceridemic pancreatitis. Clin Chim Acta 1998;269:1–12. [2] Hsia SH, Connelly PW, Hegele RA. Successful outcome in severe pregnancyassociated hyperlipemia: a case report and literature review. Am J Med Sci 1995;309:213–8. [3] Murugasu CG, Armstrong G, Creedon G, Cavanna JS, Galton DJ, Tomkin GH. Acute hypertriglyceridaemic pancreatitis in a pregnant Indian: a new lipoprotein lipase gene mutation. J R Soc Med 1998;91:205–7. [4] Suga S, Tamasawa N, Kinpara I, et al. Identification of homozygous lipoprotein lipase gene mutation in a woman with recurrent aggravation of hypertriglyceridaemia induced by pregnancy. J Intern Med 1998;243:317–21. [5] Herrera E. Lipid metabolism in pregnancy and its consequences in the fetus and newborn. Endocrine 2002;19:43–55. [6] Gagne C, Brun LD, Julien P, Moorjani S, Lupien PJ. Primary lipoprotein-lipaseactivity deficiency: clinical investigation of a French Canadian population. CMAJ 1989;140:405–11. [7] Ishimura-Oka K, Faustinella F, Kihara S, Smith LC, Oka K, Chan L. A missense mutation (Trp86-Arg) in exon 3 of the lipoprotein lipase gene: a cause of familial chylomicronemia. Am J Hum Genet 1992;50:1275–80.
[8] Reina M, Brunzell JD, Deeb SS. Molecular basis of familial chylomicronemia: mutations in the lipoprotein lipase and apolipoprotein C-II genes. J Lipid Res 1992;33:1823–32. [9] Pasalic D, Jurcic Z, Stipancic G, et al. Missense mutation W86R in exon 3 of the lipoprotein lipase gene in a boy with chylomicronemia. Clin Chim Acta 2004;343:179–84. [10] Kalmar T, Seres I, Balogh Z, Kaplar M, Winkler G, Paragh G. Correlation between the activities of lipoprotein lipase and paraoxonase in type 2 diabetes mellitus. Diabetes Metab 2005;31:574–80.
Iván Bartha Tamás Dinya Institute of Surgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary Ildikó Seres György Paragh 1st Department of Internal Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary Colin Ross Michael R. Hayden Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada Sándor Biró György Vargha⁎ Department of Human Genetics, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary ⁎Corresponding author. Department of Human Genetics, Medical and Health Science Center, University of Debrecen, 4032 Debrecen, Nagyerdei krt. 98., Hungary. Tel./fax: +36 52 416531. E-mail address: [email protected] (G. Vargha). 15 October 2008
Contents lists available at ScienceDirect
Clinica Chimica Acta j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c l i n c h i m
Letter to the Editor Acute hypertriglyceridemic pancreatitis during pregnancy due to homozygous lipoprotein lipase gene mutation
Dear Editor, Acute pancreatitis during pregnancy, when caused by hyperlipidemia in lipoprotein lipase (LPL [MIM 609708]) deficient patients [1– 4], is a life-threatening disease for both the fetus and the mother. During pregnancy, plasma triglyceride (TG) levels normally increase, often as much as 3-fold [5], but this is usually of little clinical consequence. When lipoprotein lipase activity is compromised, however, marked hypertriglyceridemia may result in severe pancreatitis [2]. LPL (EC 3.1.1.34) is a key enzyme for the hydrolysis of TG from chylomicrons and VLDL particles of blood plasma [6]. LPL deficiency (type I hyperlipoproteinemia), a recessive genetic disease, has a prevalence about one in a million, except in Quebec, Canada where it is more frequent [6]. It usually presents in childhood with hypertriglyceridemia causing lactescent blood. No mutations in the LPL gene have been identified in the Hungarian population. The T/ C substitution in codon 86 of exon 3 that replaced the original tryptophan with arginine (W86R) and produced the characteristic symptoms of LPL deficiency has been observed only in three (apparently unrelated) cases: one having English ancestry [7], another in the Seattle (USA) area [8], and one from Croatia [9]. The first two were reported as compound heterozygotes, with only the W86R mutation in common, and the third case a male patient found homozygous without the enzyme activity level documented.
third trimester of her third pregnancy and diagnosed as pancreatitis. After two days of conservative therapy a severe septicotoxic condition necessitated immediate surgery during which diffuse peritonitis was found with 3 L of purulent fluid originating from necrotizing pancreatitis. The dead fetus was removed with the uterus, the pancreas was resected. Following this, a number of reoperations were performed due to omental abscesses and progressive intraabdominal sepsis. Her gall-bladder was also removed and the abdominal wound treated in a semi-open way. Because of her continuous septic condition and progression of disease, the patient was later transported to the Institute of Surgery, University of Debrecen, where a total of 4 scheduled surgeries were performed in order to treat the extremely aggressive pancreatitis. Our interventions included necrectomies, placement of a jejunostomy tube and programmed lavages. The patient was treated at our Intensive Care Unit throughout her hospital stay. Blood-tests revealed an extreme hyperlipidemia (19.5 mmol l− 1 [normal range: 0.0–1.7 mmol l− 1]). Hypocalcemia and significant hemostatic disorder also made the course of disease more complicated. Repeated cultures yielded several bacteria and Candida species. After 32 strenuous days she was discharged from the ward. This is the first report of the LPL W86R mutation causing serious exacerbation of the hyperlipidemia symptoms during pregnancy and
Here we report a case of an ethnic Hungarian pregnant woman with a nearly fatal hyperlipidemic pancreatitis in whom we identified mutations in the LPL gene. After approval by the Ethical Review Board of University of Debrecen and informed consent, the proband's DNA was screened for LPL mutations by sequencing of the PCR amplifications of LPL exons 1–9 (and portions of introns) in two directions using LPL gene specific primers. We identified a homozygous W86R variant, a T to C transition at codon 86 resulting in a tryptophan to arginine change. After the identification of the mutation in the proband, five other family members were tested for this LPL variant. Four of them were found to be heterozygous for the same mutation (Fig. 1). Both parents were heterozygous and the mode of inheritance corresponded to the expected autosomal recessive. Post-heparin LPL activity was determined in plasma drawn 20 min after the injection of heparin (250 IU/kg body weight) after an overnight fast. Lipoprotein lipase activity was assayed as formerly described [10]. The results represent the average of three determinations. The patient's post-heparin plasma LPL activity was found 5.3 ± 1. 9 μmol ml− 1 h− 1, that represented an average of 29% of normal control values (18.44 ± 3.01 μmol ml− 1 h− 1). The 25-year-old woman was admitted to her local hospital several times due to recurrent episodes of acute abdominal pain during the 0009-8981/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2008.10.016
Fig. 1. Pedigree of the LPL W86R mutation. The female III/2 (arrow) was the proband. Family members were tested for this mutation, except for persons I/2, III/3, and IV/2 (were not available for testing). Labels: shaded symbol – homozygous mutant; halfshaded – heterozygous for the mutation; open – not containing the mutation; open symbol with question mark – not tested.
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Letter to the Editor
the first case in which the level of residual activity in a homozygous W86R mutation could be clearly documented. The residual LPL activity of the W86R variant (29% of normal) accounts for why the severe pancreatitis appeared only during pregnancy, when the burden of lipid metabolism was significantly challenged. Fat depots increased during early pregnancy later break down causing an accumulation of TGs [5]. The presence of lipoprotein receptors in the placenta together with LPL and intracellular lipase activities, allow the release of fatty acids to the fetus [5]. Acknowledgements Contribution of G. Vargha was supported by the Széchenyi István Fellowship of the Ministry of Education, Hungary. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.cca.2008.10.016. References [1] Henderson H, Leisegang F, Hassan F, Hayden M, Marais D. A novel Glu421Lys substitution in the lipoprotein lipase gene in pregnancy-induced hypertriglyceridemic pancreatitis. Clin Chim Acta 1998;269:1–12. [2] Hsia SH, Connelly PW, Hegele RA. Successful outcome in severe pregnancyassociated hyperlipemia: a case report and literature review. Am J Med Sci 1995;309:213–8. [3] Murugasu CG, Armstrong G, Creedon G, Cavanna JS, Galton DJ, Tomkin GH. Acute hypertriglyceridaemic pancreatitis in a pregnant Indian: a new lipoprotein lipase gene mutation. J R Soc Med 1998;91:205–7. [4] Suga S, Tamasawa N, Kinpara I, et al. Identification of homozygous lipoprotein lipase gene mutation in a woman with recurrent aggravation of hypertriglyceridaemia induced by pregnancy. J Intern Med 1998;243:317–21. [5] Herrera E. Lipid metabolism in pregnancy and its consequences in the fetus and newborn. Endocrine 2002;19:43–55. [6] Gagne C, Brun LD, Julien P, Moorjani S, Lupien PJ. Primary lipoprotein-lipaseactivity deficiency: clinical investigation of a French Canadian population. CMAJ 1989;140:405–11. [7] Ishimura-Oka K, Faustinella F, Kihara S, Smith LC, Oka K, Chan L. A missense mutation (Trp86-Arg) in exon 3 of the lipoprotein lipase gene: a cause of familial chylomicronemia. Am J Hum Genet 1992;50:1275–80.
[8] Reina M, Brunzell JD, Deeb SS. Molecular basis of familial chylomicronemia: mutations in the lipoprotein lipase and apolipoprotein C-II genes. J Lipid Res 1992;33:1823–32. [9] Pasalic D, Jurcic Z, Stipancic G, et al. Missense mutation W86R in exon 3 of the lipoprotein lipase gene in a boy with chylomicronemia. Clin Chim Acta 2004;343:179–84. [10] Kalmar T, Seres I, Balogh Z, Kaplar M, Winkler G, Paragh G. Correlation between the activities of lipoprotein lipase and paraoxonase in type 2 diabetes mellitus. Diabetes Metab 2005;31:574–80.
Iván Bartha Tamás Dinya Institute of Surgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary Ildikó Seres György Paragh 1st Department of Internal Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary Colin Ross Michael R. Hayden Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada Sándor Biró György Vargha⁎ Department of Human Genetics, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary ⁎Corresponding author. Department of Human Genetics, Medical and Health Science Center, University of Debrecen, 4032 Debrecen, Nagyerdei krt. 98., Hungary. Tel./fax: +36 52 416531. E-mail address: [email protected] (G. Vargha). 15 October 2008