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Heparin Treatment for Severe Hypertriglyceridemia in Diabetic Ketoacidosis

Heparin Treatment for Severe Hypertriglyceridemia in Diabetic Ketoacidosis Abstract In a patient with diabetic ketoacidosis complicated by severe elevation of plasma triglyceride concentrations, treatment with low-level intravenous unfractionated heparin led to prompt reduction in plasma triglyceride concentration and may have prevented the development of hypertriglyceridemia-associated acute pancreatitis. This article reviews the rationale for this treatment and surveys prior publications using heparin in this and similar settings. In a patient with newly diagnosed diabetic ketoacidosis, routine admission laboratory tests revealed grossly lipemic plasma level and a markedly elevated serum triglyceride concentration. In an attempt to prevent the development of triglyceride-induced pancreatitis, treatment was started with intravenous heparin along with intravenous insulin. The rationale, previous experience, and potential adverse effects for this therapy are reviewed herein. Report of a case A 45-year-old man with a history of hyperglycemia identified after a motor vehicle crash, complicated by deep venous thrombosis, sought medical attention 1 year previously after developing increasing polyuria and polydipsia and after a borrowed capillary blood glucose meter reading was critically high. Examinations at admission revealed a heart rate of 117/min, a blood pressure of 127/85 mm Hg, respiration rate of 18/min, normal mental status, and an abdominal examination with no cutaneous signs of hyperlipidemia. Findings from laboratory tests showed a bicarbonate level of 16 mEq/L (to convert to millimoles per liter, multiply by 1.0), anion gap of 22 mEq/L (to convert to millimoles per liter, multiply by 1.0), glucose level of 695 mg/dL (to convert to millimoles per liter, multiply by 0.0555), normal amylase and lipase levels, positive serum ketones, triglyceride concentration of 8701 mg/dL (to convert to millimoles per liter, multiply by 0.0113), and total cholesterol level of 753 mg/dL (to convert to millimoles per liter, multiply by 0.0259). There was no evidence of systemic infection or acute vascular event. Subsequent C-peptide concentration was 0.8 ng/mL (reference range, 0.9-4.3 ng/mL) (to convert to nanograms per liter, multiply by 0.331), and hemoglobin A1c level was 13.8% (to convert to proportion of hemoglobin, multiply by 0.01). He was treated with intravenous fluids and insulin initially and was allowed nothing by mouth. The time course of serum triglyceride concentration is shown in the Figure. After repeated triglyceride concentration measurements were basically unchanged, intravenous regular heparin therapy was started at 600 U/h, with prompt rapid reduction in triglyceride concentration. Assuming exponential decay kinetics, the half-time for triglyceride reduction was 7.3 hours. On the third hospital day he was started on therapy with atorvastatin, fenofibrate, and omega-3 ethyl ester. He remained without evidence of acute pancreatitis throughout the hospital course. Figure. View LargeDownload Plasma triglyceride concentration during low-dose heparin therapy. To convert triglycerides to millimoles per liter, multiply by 0.0113. Comment The acute clearing action of intravenous heparin on alimentary lipemia has been known for decades.1,2 The use of heparin in the treatment of hypertriglyceridemia has for the most part been reserved for patients with markedly elevated triglyceride plasma concentrations with accompanying pancreatitis.3-11 This caution may be related to the reported longer-term effects of heparin on depletion of lipoprotein lipase activity with development of secondary paradoxical hypertriglyceridemia.12-15 In recent reviews, the use of heparin to help with the acute management of even severe hypertriglyceridemia has been rarely advocated.16-18 Although severely elevated triglyceride concentrations can be seen in asymptomatic patients, when discovered in acutely ill patients, aggressive therapy is usually warranted to prevent complications like pancreatitis. The risk of pancreatitis increases when plasma triglyceride concentration exceeds 1000 mg/dL.16,18 In these situations, the time course of triglyceride concentration improvement may be important. In the setting of acute hyperglycemia or diabetic ketoacidosis, therapy would usually include fasting, intravenous fluid and electrolyte replacement, and intravenous insulin. In our patient, the institution of these measures from initial assessment in the acute care setting had no appreciable effect on serum triglyceride concentration. Only after institution of intravenous heparin did triglyceride concentration diminish. Heparin works to reduce serum triglyceride concentration via the release of lipoprotein lipase and hepatic lipase from the endothelium.2,19 The Table gives the published experience with heparin treatment for severe hypertriglyceridemia. The mean (SD) half-time for the studies listed was 17.5 (8.8) hours, based on the baseline triglyceride concentrations, the time of repeated triglyceride level measurements during heparin administration, and exponential decay kinetics: Table. View LargeDownload Previous Reports of Heparin Treatment for Severe Hypertriglyceridemia With Estimates of Plasma Triglyceride Clearance Rates where C(t) indicates the triglyceride concentration at time t; C(0), the triglyceride concentration at time t = 0; t, time (in hours); e, the base of the natural logarithm; and λ, the exponential decay constant (in inverse hours) and where ln2 indicates the natural log of 2; and t½, half-time (in hours). With continued longer-term heparin administration, a potential adverse effect on lipoprotein metabolism arises. Lipoprotein lipase and hepatic lipase that is released into plasma can be taken up and degraded by the liver. Thus with continued heparin administration, plasma lipoprotein concentration may actually decrease if hepatic metabolism and degradation is greater than the rate of production and release of lipoprotein lipase and hepatic lipase from tissue sites.12-15,19 This must be appreciated when heparin is used to treat severe hypertriglyceridemia especially when extended duration of heparin therapy is considered. Finally, complications of heparin therapy must be recognized including the development of heparin-induced thrombocytopenia and bleeding. Development of pancreatitis despite heparin therapy is possible including pancreatic necrosis with hemorrhagic features. In this case, imaging of the pancreas and possible withholding of heparin would be necessary. Correspondence: Randolph P. Cole, MD, Department of Medicine, Holy Name Hospital, 718 Teaneck Rd, Teaneck, NJ 07666 (rc18@columbia.edu). Accepted for Publication: April 13, 2009. Financial Disclosure: None reported. References 1. Hahn PF Abolishment of alimentary lipemia following injection of heparin. Science 1943;98 (2531) 19- 20PubMedGoogle ScholarCrossref 2. Bensadoun A Lipoprotein lipase. Annu Rev Nutr 1991;11217- 237PubMedGoogle ScholarCrossref 3. Hsia SHConnelly PWHegele RA Successful outcome in severe pregnancy-associated hyperlipidemia: a case report and literature review. Am J Med Sci 1995;309 (4) 213- 218PubMedGoogle ScholarCrossref 4. Henzen CRöck MSchnieper CHeer K Heparin and insulin in the treatment of acute hyperglyceridemia-induced pancreatitis. Schweiz Med Wochenschr 1999;129 (35) 1242- 1248PubMedGoogle Scholar 5. Berger ZQuera RPoniachik JOksenberg DGuerrero J Heparin and/or insulin treatment of acute pancreatitis caused by hypertriglyceridemia. Rev Med Chil 2001;129 (12) 1373- 1378PubMedGoogle ScholarCrossref 6. Loo CCTan JYL Decreasing the plasma triglyceride level in hypertriglyceridemia-induced pancreatitis in pregnancy: a case report. Am J Obstet Gynecol 2002;187 (1) 241- 242PubMedGoogle ScholarCrossref 7. Monga AArora AMakkar RPGupta AK Hypertriglyceridemia-induced acute pancreatitis—treatment with heparin and insulin. Indian J Gastroenterol 2003;22 (3) 102- 103PubMedGoogle Scholar 8. Sleth JCLafforgue EServais R et al. A case of hypertriglyceridemia-induced pancreatitis in pregnancy: value of heparin [in French]. Ann Fr Anesth Reanim 2004;23 (8) 835- 837PubMedGoogle ScholarCrossref 9. Alagözlü HCindoruk MKarakan TÜnal S Heparin and insulin in the treatment of hypertriglyceridemia-induced severe acute pancreatitis. Dig Dis Sci 2006;51 (5) 931- 933PubMedGoogle ScholarCrossref 10. Jain PRai RRUdawat HNijhawan SMathur A Insulin and heparin in treatment of hypertriglyceridemia-induced pancreatitis. World J Gastroenterol 2007;13 (18) 2642- 2643PubMedGoogle Scholar 11. Röggla GFasan MKapiotis S Treating hypertriglyceridemia. CMAJ 2007;177 (6) 603PubMedGoogle ScholarCrossref 12. Watts GFCameron JHenderson ARichmond W Lipoprotein lipase deficiency due to long-term heparinization presenting as severe hypertriglyceridemia in pregnancy. Postgrad Med J 1991;67 (794) 1062- 1064PubMedGoogle ScholarCrossref 13. Weintraub MRassin TEisenberg S et al. Continuous intravenous heparin administration in humans causes a decrease in serum lipolytic activity and accumulation of chylomicrons in circulation. J Lipid Res 1994;35 (2) 229- 238PubMedGoogle Scholar 14. Näsström BOlivecrona GOlivecrona TStegmayr B Lipoprotein lipase during continuous heparin infusion: tissue stores become partially depleted. J Lab Clin Med 2001;138 (3) 206- 213PubMedGoogle ScholarCrossref 15. Al Riyami NBFrohlich J Extreme hypertriglyceridemia following intravenous heparin infusion. Clin Biochem 2008;41 (10-11) 907- 909PubMedGoogle ScholarCrossref 16. Dunbar RLRader DJ Demystifying triglycerides: a practical approach for the clinician. Cleve Clin J Med 2005;72 (8) 661- 680PubMedGoogle ScholarCrossref 17. Smellie WSA Hypertriglyceridemia in diabetes. BMJ 2006;333 (7581) 1257- 1260PubMedGoogle ScholarCrossref 18. Yuan GAl-Shali KZHegele RA Hypertriglyceridemia: its etiology, effects and treatment. CMAJ 2007;176 (8) 1113- 1120PubMedGoogle ScholarCrossref 19. Ng D Heparin in hypertriglyceridemia: friend or foe? J Lab Clin Med 2001;138 (6) 356- 358PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

Heparin Treatment for Severe Hypertriglyceridemia in Diabetic Ketoacidosis

Archives of Internal Medicine , Volume 169 (15) – Aug 10, 2009

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American Medical Association
Copyright
Copyright © 2009 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinternmed.2009.221
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Abstract

Abstract In a patient with diabetic ketoacidosis complicated by severe elevation of plasma triglyceride concentrations, treatment with low-level intravenous unfractionated heparin led to prompt reduction in plasma triglyceride concentration and may have prevented the development of hypertriglyceridemia-associated acute pancreatitis. This article reviews the rationale for this treatment and surveys prior publications using heparin in this and similar settings. In a patient with newly diagnosed diabetic ketoacidosis, routine admission laboratory tests revealed grossly lipemic plasma level and a markedly elevated serum triglyceride concentration. In an attempt to prevent the development of triglyceride-induced pancreatitis, treatment was started with intravenous heparin along with intravenous insulin. The rationale, previous experience, and potential adverse effects for this therapy are reviewed herein. Report of a case A 45-year-old man with a history of hyperglycemia identified after a motor vehicle crash, complicated by deep venous thrombosis, sought medical attention 1 year previously after developing increasing polyuria and polydipsia and after a borrowed capillary blood glucose meter reading was critically high. Examinations at admission revealed a heart rate of 117/min, a blood pressure of 127/85 mm Hg, respiration rate of 18/min, normal mental status, and an abdominal examination with no cutaneous signs of hyperlipidemia. Findings from laboratory tests showed a bicarbonate level of 16 mEq/L (to convert to millimoles per liter, multiply by 1.0), anion gap of 22 mEq/L (to convert to millimoles per liter, multiply by 1.0), glucose level of 695 mg/dL (to convert to millimoles per liter, multiply by 0.0555), normal amylase and lipase levels, positive serum ketones, triglyceride concentration of 8701 mg/dL (to convert to millimoles per liter, multiply by 0.0113), and total cholesterol level of 753 mg/dL (to convert to millimoles per liter, multiply by 0.0259). There was no evidence of systemic infection or acute vascular event. Subsequent C-peptide concentration was 0.8 ng/mL (reference range, 0.9-4.3 ng/mL) (to convert to nanograms per liter, multiply by 0.331), and hemoglobin A1c level was 13.8% (to convert to proportion of hemoglobin, multiply by 0.01). He was treated with intravenous fluids and insulin initially and was allowed nothing by mouth. The time course of serum triglyceride concentration is shown in the Figure. After repeated triglyceride concentration measurements were basically unchanged, intravenous regular heparin therapy was started at 600 U/h, with prompt rapid reduction in triglyceride concentration. Assuming exponential decay kinetics, the half-time for triglyceride reduction was 7.3 hours. On the third hospital day he was started on therapy with atorvastatin, fenofibrate, and omega-3 ethyl ester. He remained without evidence of acute pancreatitis throughout the hospital course. Figure. View LargeDownload Plasma triglyceride concentration during low-dose heparin therapy. To convert triglycerides to millimoles per liter, multiply by 0.0113. Comment The acute clearing action of intravenous heparin on alimentary lipemia has been known for decades.1,2 The use of heparin in the treatment of hypertriglyceridemia has for the most part been reserved for patients with markedly elevated triglyceride plasma concentrations with accompanying pancreatitis.3-11 This caution may be related to the reported longer-term effects of heparin on depletion of lipoprotein lipase activity with development of secondary paradoxical hypertriglyceridemia.12-15 In recent reviews, the use of heparin to help with the acute management of even severe hypertriglyceridemia has been rarely advocated.16-18 Although severely elevated triglyceride concentrations can be seen in asymptomatic patients, when discovered in acutely ill patients, aggressive therapy is usually warranted to prevent complications like pancreatitis. The risk of pancreatitis increases when plasma triglyceride concentration exceeds 1000 mg/dL.16,18 In these situations, the time course of triglyceride concentration improvement may be important. In the setting of acute hyperglycemia or diabetic ketoacidosis, therapy would usually include fasting, intravenous fluid and electrolyte replacement, and intravenous insulin. In our patient, the institution of these measures from initial assessment in the acute care setting had no appreciable effect on serum triglyceride concentration. Only after institution of intravenous heparin did triglyceride concentration diminish. Heparin works to reduce serum triglyceride concentration via the release of lipoprotein lipase and hepatic lipase from the endothelium.2,19 The Table gives the published experience with heparin treatment for severe hypertriglyceridemia. The mean (SD) half-time for the studies listed was 17.5 (8.8) hours, based on the baseline triglyceride concentrations, the time of repeated triglyceride level measurements during heparin administration, and exponential decay kinetics: Table. View LargeDownload Previous Reports of Heparin Treatment for Severe Hypertriglyceridemia With Estimates of Plasma Triglyceride Clearance Rates where C(t) indicates the triglyceride concentration at time t; C(0), the triglyceride concentration at time t = 0; t, time (in hours); e, the base of the natural logarithm; and λ, the exponential decay constant (in inverse hours) and where ln2 indicates the natural log of 2; and t½, half-time (in hours). With continued longer-term heparin administration, a potential adverse effect on lipoprotein metabolism arises. Lipoprotein lipase and hepatic lipase that is released into plasma can be taken up and degraded by the liver. Thus with continued heparin administration, plasma lipoprotein concentration may actually decrease if hepatic metabolism and degradation is greater than the rate of production and release of lipoprotein lipase and hepatic lipase from tissue sites.12-15,19 This must be appreciated when heparin is used to treat severe hypertriglyceridemia especially when extended duration of heparin therapy is considered. Finally, complications of heparin therapy must be recognized including the development of heparin-induced thrombocytopenia and bleeding. Development of pancreatitis despite heparin therapy is possible including pancreatic necrosis with hemorrhagic features. In this case, imaging of the pancreas and possible withholding of heparin would be necessary. Correspondence: Randolph P. Cole, MD, Department of Medicine, Holy Name Hospital, 718 Teaneck Rd, Teaneck, NJ 07666 (rc18@columbia.edu). Accepted for Publication: April 13, 2009. Financial Disclosure: None reported. References 1. Hahn PF Abolishment of alimentary lipemia following injection of heparin. Science 1943;98 (2531) 19- 20PubMedGoogle ScholarCrossref 2. Bensadoun A Lipoprotein lipase. Annu Rev Nutr 1991;11217- 237PubMedGoogle ScholarCrossref 3. Hsia SHConnelly PWHegele RA Successful outcome in severe pregnancy-associated hyperlipidemia: a case report and literature review. Am J Med Sci 1995;309 (4) 213- 218PubMedGoogle ScholarCrossref 4. Henzen CRöck MSchnieper CHeer K Heparin and insulin in the treatment of acute hyperglyceridemia-induced pancreatitis. Schweiz Med Wochenschr 1999;129 (35) 1242- 1248PubMedGoogle Scholar 5. Berger ZQuera RPoniachik JOksenberg DGuerrero J Heparin and/or insulin treatment of acute pancreatitis caused by hypertriglyceridemia. Rev Med Chil 2001;129 (12) 1373- 1378PubMedGoogle ScholarCrossref 6. Loo CCTan JYL Decreasing the plasma triglyceride level in hypertriglyceridemia-induced pancreatitis in pregnancy: a case report. Am J Obstet Gynecol 2002;187 (1) 241- 242PubMedGoogle ScholarCrossref 7. Monga AArora AMakkar RPGupta AK Hypertriglyceridemia-induced acute pancreatitis—treatment with heparin and insulin. Indian J Gastroenterol 2003;22 (3) 102- 103PubMedGoogle Scholar 8. Sleth JCLafforgue EServais R et al. A case of hypertriglyceridemia-induced pancreatitis in pregnancy: value of heparin [in French]. Ann Fr Anesth Reanim 2004;23 (8) 835- 837PubMedGoogle ScholarCrossref 9. Alagözlü HCindoruk MKarakan TÜnal S Heparin and insulin in the treatment of hypertriglyceridemia-induced severe acute pancreatitis. Dig Dis Sci 2006;51 (5) 931- 933PubMedGoogle ScholarCrossref 10. Jain PRai RRUdawat HNijhawan SMathur A Insulin and heparin in treatment of hypertriglyceridemia-induced pancreatitis. World J Gastroenterol 2007;13 (18) 2642- 2643PubMedGoogle Scholar 11. Röggla GFasan MKapiotis S Treating hypertriglyceridemia. CMAJ 2007;177 (6) 603PubMedGoogle ScholarCrossref 12. Watts GFCameron JHenderson ARichmond W Lipoprotein lipase deficiency due to long-term heparinization presenting as severe hypertriglyceridemia in pregnancy. Postgrad Med J 1991;67 (794) 1062- 1064PubMedGoogle ScholarCrossref 13. Weintraub MRassin TEisenberg S et al. Continuous intravenous heparin administration in humans causes a decrease in serum lipolytic activity and accumulation of chylomicrons in circulation. J Lipid Res 1994;35 (2) 229- 238PubMedGoogle Scholar 14. Näsström BOlivecrona GOlivecrona TStegmayr B Lipoprotein lipase during continuous heparin infusion: tissue stores become partially depleted. J Lab Clin Med 2001;138 (3) 206- 213PubMedGoogle ScholarCrossref 15. Al Riyami NBFrohlich J Extreme hypertriglyceridemia following intravenous heparin infusion. Clin Biochem 2008;41 (10-11) 907- 909PubMedGoogle ScholarCrossref 16. Dunbar RLRader DJ Demystifying triglycerides: a practical approach for the clinician. Cleve Clin J Med 2005;72 (8) 661- 680PubMedGoogle ScholarCrossref 17. Smellie WSA Hypertriglyceridemia in diabetes. BMJ 2006;333 (7581) 1257- 1260PubMedGoogle ScholarCrossref 18. Yuan GAl-Shali KZHegele RA Hypertriglyceridemia: its etiology, effects and treatment. CMAJ 2007;176 (8) 1113- 1120PubMedGoogle ScholarCrossref 19. Ng D Heparin in hypertriglyceridemia: friend or foe? J Lab Clin Med 2001;138 (6) 356- 358PubMedGoogle ScholarCrossref

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Aug 10, 2009

Keywords: heparin,triglycerides,hypertriglyceridemia,diabetic ketoacidosis,ketoacidosis,pancreatitis, acute,unfractionated heparin,plasma

References