- Email: [email protected]
Timing clinical events in the treatment of pancreatitis and hypertriglyceridemia with therapeutic plasmapheresis
Transfusion and Apheresis Science 45 (2011) 3–7
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Timing clinical events in the treatment of pancreatitis and hypertriglyceridemia with therapeutic plasmapheresis C. Stefanutti ⇑, S. Di Giacomo, G. Labbadia Therapeutic Plasmapheresis Unit – Department of Clinical and Medical Therapy, University of Rome ‘‘La Sapienza’’ – ‘‘Umberto I’’ Hospital, 155, V.le del Policlinico, I-00161 (EU) Rome, Italy
a r t i c l e
i n f o
Keywords: Severe hypertriglyceridemia Hyperlipidemic pancreatitis Therapeutic apheresis
a b s t r a c t Background: Hyperlipidemic pancreatitis (HP) is caused by severe hypertriglyceridemia (SHTG). Evidence of SHTG refractoriness to standard medical treatment but not to therapeutic apheresis has increased in the last years. Methods: Described is the timing of clinical events and the sequence of therapeutic plasma-exchange (TPE) procedures to treat pancreatitis due to SHTG in a male patient, Caucasian, aged 49 years, referred to emergency for severe epigastric pain. There was no history of alcohol consumption, a pre-existing mild hyperlipidemia was treated with diet alone, and biliary imaging was normal. Physical examination revealed epigastric tenderness. Laboratory investigation revealed marked hypertriglyceridemia (11,355 mg/dL; range: 30–150), and hypercholesterolemia (941 mg/dL; range: 80–200). Serum amylase (Amy) and lipase (Lip) were increased: 160 UI/L (range: 20–100) and 175 UI/L (range: 13–60), respectively. A computerized tomography (CT) scan of the abdomen revealed a picture compatible with acute pancreatic phlogosis. It was diagnosed as ‘‘acute secondary pancreatitis (AP) and SHTG’’. Results: The patient was successfully submitted to three sessions of TPE in emergency. He was released from hospital after 13 days of hospitalization. The levels of lipids and lipoproteins in his plasma were as follows: triglycerides (TG) 185 mg/dL; total cholesterol (TC) 179 mg/dL; HDL-cholesterol (HDLC) 22 mg/dL; LDL-cholesterol (LDLC) 120 mg/dL. Conclusions: The decision to submit the patient with clinical evidence of HP caused by SHTG to apheresis was correct. The improvement in the clinical picture was fast and the recovery was complete. Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction SHTG is a rare but well documented cause of AP (1–4%) [1]. The HP is characterized by the presence of SHTG (>1000–2000 mg/dL) in the absence of other causes [2]. Primary disorders – e.g. deficiency of lipoprotein lipase (LPL), of apoprotein C-II (apo C-II) or Familial hypertriglyceridemia – and secondary (alcohol abuse, diabetes, drugs, pregnancy, hypothyroidism) of lipid metabolism are associated with SHTG [3,4]. The clinical course of HP is similar to that ⇑ Corresponding author. E-mail address: [email protected] (C. Stefanutti). 1473-0502/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.transci.2011.06.013
of AP from other causes. However, particular attention must be given to the alteration of lipid metabolism. Standard treatment foresees: absolute diet restriction regarding fats (free-fat diet), use of hypolipidemic agents (fenofibrate, gemfibrozil, x-3 fatty acids), low weight molecular heparin, insulin in patients with diabetes frequently secondary to surgical pancreatic sectioning carried out in the past, or previous to events of AP. More recently, the non pharmacological approach has started to spread based on the removal of the triglyceride-rich lipoproteins through TPE. Today, this therapeutic approach which is registered in the III category of the ’American Society for Apheresis’ (ASFA), is being used with success in acute HP [5–7]. Case series, case reports and
4
C. Stefanutti et al. / Transfusion and Apheresis Science 45 (2011) 3–7
a multi-center study have all been published [5,7–10]. This case report highlights the fundamental importance of a precocious diagnosis and well-timed treatment with TPE in a case of secondary AP to SHTG in the area of medico-surgical urgent emergency.
hypertriglyceridemia and grave hypercholesterolemia with values of 11.355 mg/dL (range:30–150) and 941 mg/dL (range:80–200), respectively.
2. Materials and methods (case report)
An abdominal ultrasound, performed with technical difficulty as the patient was overweight and because of the intense intestinal meteorism, reported the following picture: a non assessable pancreas and an enlarged liver with steatosis. A CT scan of the abdomen revealed: liver moderately increased in dimension, steatosis and a notable increase in volume of the pancreas, that appears to be characterized by diffuse structural lack of homogeneity, especially in correspondence with the cephalic region; an abundant amount of fluid in the peri-pancreatic area, in the retro-cavity of the epiploon, through the splenic vein, in the para-renal bilateral anterior area, and in the mesenteric area with diffuse lack of homogeneity of the adipose tissue at this level. The CT picture is compatible with acute pancreatic phlogosis. It is diagnosed as ‘‘acute secondary pancreatitis and SHTG’’ (Figs. 1 and 2).
A 49 year old patient (male, Caucasian, height: 180 cm, weight: 110 kg; blood pressure: 140/80 mm Hg; pulse frequency per minute: 80) arrived on 04/08/2009, at the Emergency Department of our hospital with the appearance, starting 2 h previously, of the following symptoms: epigastric pain spreading to the posterior, in the spine, without nausea or vomiting. The clinical history was scarcely informative apart from one check-up, during a routine hematobiochemical exam in 2007, of hypertriglyceridemia (350 mg/dL) and an episode of epigastric pain in August 2008. The patient was aware of the existence of dyslipidemia in his family, but was unable to provide details. 2.1. Physical examination The physical examination showed intense pain in the epigastric area and left hypochondrium with a positive Blumberg sign. The hematobiochemical exams (04/08/ 2009 at 09.00 p.m.) highlighted chyle serum, Amy 160 UI/L (range: 20–100), Lip 175 UI/L (range: 13–60), direct bilirubin 10.46 mg/dL (range: 0.15–0.35), blood glucose 279 mg/dL (range: 74–106). The laboratory announced that it was impossible to carry out further exams due to the condition of the serum (too high a concentration of triglyceride-rich lipoproteins). Determination of the levels of lipids and lipoproteins in the plasma was requested (04/08/2009 at 11.00 p.m.). The tests showed severe
2.2. Instrumental diagnosis
3. Results 3.1. Treatment with TPE and combined drug regimen The patient underwent urgent treatment (at 04.00 a.m. on 04/09/2009) of TPE (a written informed consent was obtained). Duration of procedure: 90 min (interrupted by request of patient). 3966 ml of blood were processed with the extraction of 1281 ml of plasma, and the infusion of 923 ml of human albumin at 5% as a replacement fluid. The vascular accesses utilized were peripheral venous accesses. According to our extracorporeal treatment
Fig. 1. A CT scan of the abdomen revealed: liver moderately increased in dimension, steatosis and a notable increase in volume of the pancreas, that appears to be characterized by diffused structural lack of homogeneity, especially in correspondence with the cephalic region; abundant amount of fluid spill in the peri-pancreatic area, in the retro-cavity of the epiploon, through the splenic vein, in the para-renal bilateral anterior area, and in the mesenteric area with diffused lack of homogeneity of the adipose tissue at this level. The CT picture was compatible with acute pancreatic phlogosis. It was diagnosed as ‘‘acute secondary pancreatitis and SHTG’’. Venous phase: increase in volume and edema of the pancreas (white arrow).
C. Stefanutti et al. / Transfusion and Apheresis Science 45 (2011) 3–7
5
Fig. 2. A CT scan of the abdomen revealed: liver moderately increased in dimension, steatosis and a notable increase in volume of the pancreas, that appears to be characterized by diffused structural lack of homogeneity, especially in correspondence with the cephalic region; abundant amount of fluid spill in the peri-pancreatic area, in the retro-cavity of the epiploon, through the splenic vein, in the para-renal bilateral anterior area, and in the mesenteric area with diffused lack of homogeneity of the adipose tissue at this level. The CT picture was compatible with acute pancreatic phlogosis. It was diagnosed as ‘‘acute secondary pancreatitis and SHTG’’. Venous phase: the arrows show the cephalic region of the pancreas, and the abundant amount of fluid spill in the peri-pancreatic area.
protocol, heparin, 5000 UI intravenous as a bolus was administered at the beginning of the procedure, while continuous anticoagulation during treatment guaranteed by the use of Anticoagulant Citrate Dextrose Solution A (ACD-A). The centrifugal apheresis system used was the ‘‘Spectra’’ COBE, LRS SystemTurboVersion 7.0 (COBE Laboratories, Inc., Lakewood, Co., USA). The procedure was well tolerated with no collateral effects. After TPE, TG levels and TC levels (04/09/2009 at 06.00 a.m.) dropped respectively to 7131 and 756 mg/dL; Lip values of 1100 UI/L and Amy of 771 UI/L. In the morning (04/09/2009 at 10.40 a.m.) the patient underwent a second session of TPE with a dramatic reduction in levels of TG to 752 mg/dL and of TC to 497 mg/dL with reduction of Amy and Lip respective to 598 and 592 UI/L. The following day (04/10/2009 at 9.30 a.m.) a third session TPE was carried out of with TG values of 1726 (before) and 735 mg/dL (after). TC values were: 396 (before) and 192 mg/dL (after). After only a few days the patient became asymptomatic and acquired acceptable values of Amy and Lip, 49 and 33 UI/L, respectively. Diet and pharmacological treatment were satisfactory. In the acute phase, omeprazole (40 mg iv), scopolamine butyl bromide (20 mg iv), ketorolac (30 mg iv), paracetamol (10 mg iv), calcium gluconate (10 ml 10%), saline (sodium chloride) (3000 ml/24 h, iv) were given. As is known, the fibric acid derivatives (fibrates), such as gemfibrozil, fenofibrate or bezafibrate, are the drugs of first choice in treating hypertriglyceridemia. The lipid-lowering agent given was gemfibrozil (1800 mg/day). The drug was well tolerated and demonstrated to be effective if taken regularly along with diet restrictions. Moreover, no more TPE procedures were carried out. On release from hospital, after 13 days of hospitalization, the levels of lipids and lipoproteins in the plasma were as follows: TG 185 mg/dL; TC 179 mg/dL; HDLC 22 mg/dL; LDLC 120 mg/dL.
3.2. Dietary and drug treatment (ward) During the emergency phase, it was absolutely necessary for the patient to remain in the fasting state. Once transferred to the ward following clinical improvement, the diet prescribed was ‘fat-free’. The drugs administered were: gemfibrozil (1800 mg/day), aspartate/insulin (VIII UI x 3 sc), insulin glargine (V UI sc in the evening 10.00 p.m.), glucose solution 5% (1000 ml/day) buffered with aspartate/insulin (VII UI sc), saline (sodium chloride) 500 ml (1000 ml/day), potassium chloride KCL (40 mEq/ day), ceftriaxon (2 g iv), omeprazole (40 mg iv) and ketorolac (30 mg iv). 4. Discussion A dyslipidemia of type I, IV and V according to Fredrickson’s classification (modified by Beaumont, World Health Organization) is usually associated with SHTG [11]. Types I–V hyperlipidemia can arise with AP without causing factors, while type IV generally requires predisposing factors [4]. Numerous therapeutic approaches have been adopted in the management of a patient with HP secondary to SHTG. Initial treatment of AP is the same in the various forms and includes staying on fasting, intravenous hydration and analgesics. In the case of parenteral nutrition in HP, lipid infusions should be avoided. The main aim of therapy of SHTG in HP is the reduction of TG levels in plasma to below 500 mg/dL [12]. A lipid-lowering diet (fat-free diet) and drugs are utilized in reducing hypertriglyceridemia. The infusion of heparin and/or insulin stimulates activity of the LPL and accelerates the degradation of chylomicrons [13]. Case reports [14–16] and case series [17,18] have utilized both these drugs to reduce levels of
6
C. Stefanutti et al. / Transfusion and Apheresis Science 45 (2011) 3–7
TG. However, where standard medical approaches fail to promote the clearance of TG from plasma and a high risk of first or secondary HP persists, TPE provides a valuable therapeutic option for preventing life threatening SHTG. Different plasmapheresis methods have been used in the treatment of HP. However, TPE is undoubtedly superior to double filtration and adsorption techniques in the removal of excessive TG because the membrane of the plasma fractionators is usually blocked by the larger particles of chylomicrons, remnants, and other TG-rich lipoproteins. Yeh et al. in 2003 reported that the removal rates of plasma lipids and lipoproteins were strongly associated with a lower level of maximal transmembrane pressure (TMP). This was a consequence of early saturation of the plasma fractionators blocked by the extremely high level of TGrich lipoproteins. They concluded that TPE was more suitable for the initial treatment of SHTG [20]. ASFA has categorized the use of TPE in HP due to hypertriglyceridemia as a Category III indication: ‘‘suggestion of benefit for which existing evidence is insufficient, either to establish the efficacy of therapeutic apheresis or to clarify the risk/benefit (or sometimes the cost/benefit) ratio’’ [7]. According to Winters et al., this decision was based on a January 2006 literature review [19]. At that time no randomized controlled trial, one controlled trial involving 29 patients, seven case series involving 57 patients, and 23 single patient case reports, were identified. The committee scored the available literature as Type III evidence, ‘‘opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees’’ despite the presence of a controlled trial due to limitations of that trial. Recently, to evaluate the therapeutic efficacy of TPE in treating patients with SHTG, 17 patients who had not responded to conventional medical therapy (fat-free diet plus pharmacological interventions) were referred for TPE in a multicenter case series study. Two hundred seventeen TPE sessions were performed. The removal of TG-rich lipoproteins prevented relapses of acute pancreatitis (AP) [10]. According to this experience and the latest case reported here it is clear, at least in our opinion, that the outcome of each case may be quite different according to the timing of intervention with TPE. It is consistently helpful during the acute inflammatory phase. However, TPE may even be an effective therapeutic measure. TPE (with a contribution of heparin and insulin that is difficult to quantify but not resolved) is the active instrument in rapid reduction of TG. Subsequent check-ups of the levels of lipid and lipoprotein in plasma, follows the progressive recovery of pancreatic tissue function, which is not immediate. It is highly probable that the rapid clearance of macromolecular lipids in plasma obtained from TPE, represents the difference in therapeutic terms. The mechanism of action may be desuppressing a key enzyme involved in the pathogenesis of SHTG: LPL. The essential aspect is the relative delipidation of the plasma milieu at a pancreatic capillary level and the progressive reactivation of enzyme function of LPL extra-pancreatic and pancreatic, capable of finally reacting effectively on sites of cleavage of VLDL previously ‘masked’ by excess lipoproteins of large molecular weight, which are chylomicrons and remnants of chylomicrons. Even the subsequent fibrates play an active role in
maintaining an acceptable and non risky profile of TG-rich lipoproteins in plasma. However, not in the initial phase, when it is useless and ineffective. To conclude, this case report, is, objectively, a further confirmation that TPE is a safe, efficient, and helpful method for treating patients with refractory SHTG when a severe complication, such as AP, is clinically demonstrated in an emergency. To our knowledge there is no clinical case reported in the literature where there is a detailed description of the clinical protocol applied in the chronological evolution of an emergency. It is plausible that the reported experience may be useful to those who find themselves having to intervene in similar emergency cases, which do not necessarily evolve towards remission with standard treatment. Above all, they do not receive an intervention on an etiological basis. The diagnosis is often misinterpreted by Medical Staff in the Emergency Department, when the symptomatic therapy of acute pancreatitis does not differ in relation to the pathogenetic cause of the clinical picture.
5. Conflict of interest and financial disclosure The authors certify that they have no affiliation with or financial involvement in any organization or entity with a direct financial interest in the subject matter or materials discussed in this manuscript.
References [1] Fortson MR, Freedman SN, Webster III PD. Clinical assessment of hyperlipidemic pancreatitis. Am J Gastroenterol 1995;90:2134–9. [2] Steinberg W, Tenner S. Acute pancreatitis. N Engl J Med 1994;330: 1198–210. [3] Mahley RW, Rall SC. Type III hyperlipoproteinemia. In: Seriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic basis of inherited disease, vol. I. New York: McGraw-Hill; 1989. p. 1195–213. [4] Yadav D, Pitchumoni CS. Issues in hyperlipidemic pancreatitis. J Clin Gastroenterol 2003;36:54–62. [5] Furuya T, Komatsu M, Takahashi K, Hashimoto N, Hashizume T, Wajima N, et al. Plasma exchange for hypertriglyceridemic acute necrotizing pancreatitis: report of two cases. Ther Apher 2002;6:454–8. [6] Kyriakidis AV, Raitsiou B, Sakagianni A, Harisopoulou V, Pyrgioti M, Panagopoulou A, et al. Management of acute severe hyperlipidemic pancreatitis. Digestion 2006;73(4):259–64. [7] Szczepiorkowski ZM, Shaz BH. The new approach to assignment of ASFA categories-introduction to the fourth special issue: clinical applications of therapeutic apheresis. J Clin Apher 2007;22:96–105. [8] Al-Humoud H, Alhhumoud E, Al-Hilali N. Therapeutic plasma exchange for acute hyperlipidemic pancreatitis: a case series. Ther Apher Dial 2008;12:202–4. [9] Gubensek J, Buturovic’ P, Marn-Pernat A, Kovac J, Knap B, Premru V, et al. Treatment of hyperlipidemic acute pancreatitis with plasma exchange: a single-center experience. Ther Apher Dial 2009;13(4):314–7. [10] Stefanutti C, Di Giacomo S, Vivenzio A, Labbadia G, Mazza F, D’Alessandri G, et al. Therapeutic plasma exchange in patients with severe hypertriglyceridemia: a multicenter study. Artif Organs 2009;33(12):1096–102. [11] Fredrickson DS. An international classification of hyperlipidemias and hyperlipoproteinemias. Ann Intern Med 1971;75:471–2. [12] Toskes PP. Hyperlipidemic pancreatitis. Gastroenterol Clin North Am 1990;19:783–91. [13] Henzen C, Rock M, Schnieper C. Heek: heparin and insulin in the treatment of acute hypertriglyceridemia-induced pancreatitis. Schweiz Med Wochenschr 1999;129:1242–8. [14] Alagozlu H, Cindoruk M, Karakan T, Unal S. Heparin and insulin in the treatment of hypertriglyceridemia-induced severe acute pancreatitis. Dig Dis Sci 2006;51(5):931–3.
C. Stefanutti et al. / Transfusion and Apheresis Science 45 (2011) 3–7 [15] Jain P, Rai RR, Udawat H, Nijhawan S, Mathur A. Insulin and heparin in the treatment of hypertriglyceridemia-induced pancreatitis. World J Gastroenterol 2007;13:2642–3. [16] Bolaman Z, Yavasoglu I, Kadikoylu G. Plasmapheresis in asparaginaseinduced pancreatitis. Transfusion 2009;49:185. [17] Berger Z, Quera R, Poniachik J, Oksenberg D, Guerrero J. Heparin and insulin treatment of acute pancreatitis caused by hypertriglyceri demia. Experience of 5 cases. Rev Med Chil 2001;129(12):1373–8.
7
[18] Kfour-Baz EM, Nassar RA, Tainos RF, Otrock ZK, Youssef AM, Albany C, et al. Plasmapheresis in asparaginase-induced hypertriglyceridemia. Transfusion 2008;48:1227–30. [19] Winters JL, Shaz BH, Szczepiorkowski ZM. Plasma exchange in pancreatitis due to hypertriglyceridemia. Transfusion 2009;49:1022. [20] Yeh JH, Lee MF, Chiu HC. Plasmapheresis for severe lipemia: comparison of serum-lipid clearance rates for the plasma-exchange and double-filtration variants. J Clin Apher 2003;18(1):32–6.
Contents lists available at ScienceDirect
Transfusion and Apheresis Science journal homepage: www.elsevier.com/locate/transci
Timing clinical events in the treatment of pancreatitis and hypertriglyceridemia with therapeutic plasmapheresis C. Stefanutti ⇑, S. Di Giacomo, G. Labbadia Therapeutic Plasmapheresis Unit – Department of Clinical and Medical Therapy, University of Rome ‘‘La Sapienza’’ – ‘‘Umberto I’’ Hospital, 155, V.le del Policlinico, I-00161 (EU) Rome, Italy
a r t i c l e
i n f o
Keywords: Severe hypertriglyceridemia Hyperlipidemic pancreatitis Therapeutic apheresis
a b s t r a c t Background: Hyperlipidemic pancreatitis (HP) is caused by severe hypertriglyceridemia (SHTG). Evidence of SHTG refractoriness to standard medical treatment but not to therapeutic apheresis has increased in the last years. Methods: Described is the timing of clinical events and the sequence of therapeutic plasma-exchange (TPE) procedures to treat pancreatitis due to SHTG in a male patient, Caucasian, aged 49 years, referred to emergency for severe epigastric pain. There was no history of alcohol consumption, a pre-existing mild hyperlipidemia was treated with diet alone, and biliary imaging was normal. Physical examination revealed epigastric tenderness. Laboratory investigation revealed marked hypertriglyceridemia (11,355 mg/dL; range: 30–150), and hypercholesterolemia (941 mg/dL; range: 80–200). Serum amylase (Amy) and lipase (Lip) were increased: 160 UI/L (range: 20–100) and 175 UI/L (range: 13–60), respectively. A computerized tomography (CT) scan of the abdomen revealed a picture compatible with acute pancreatic phlogosis. It was diagnosed as ‘‘acute secondary pancreatitis (AP) and SHTG’’. Results: The patient was successfully submitted to three sessions of TPE in emergency. He was released from hospital after 13 days of hospitalization. The levels of lipids and lipoproteins in his plasma were as follows: triglycerides (TG) 185 mg/dL; total cholesterol (TC) 179 mg/dL; HDL-cholesterol (HDLC) 22 mg/dL; LDL-cholesterol (LDLC) 120 mg/dL. Conclusions: The decision to submit the patient with clinical evidence of HP caused by SHTG to apheresis was correct. The improvement in the clinical picture was fast and the recovery was complete. Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction SHTG is a rare but well documented cause of AP (1–4%) [1]. The HP is characterized by the presence of SHTG (>1000–2000 mg/dL) in the absence of other causes [2]. Primary disorders – e.g. deficiency of lipoprotein lipase (LPL), of apoprotein C-II (apo C-II) or Familial hypertriglyceridemia – and secondary (alcohol abuse, diabetes, drugs, pregnancy, hypothyroidism) of lipid metabolism are associated with SHTG [3,4]. The clinical course of HP is similar to that ⇑ Corresponding author. E-mail address: [email protected] (C. Stefanutti). 1473-0502/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.transci.2011.06.013
of AP from other causes. However, particular attention must be given to the alteration of lipid metabolism. Standard treatment foresees: absolute diet restriction regarding fats (free-fat diet), use of hypolipidemic agents (fenofibrate, gemfibrozil, x-3 fatty acids), low weight molecular heparin, insulin in patients with diabetes frequently secondary to surgical pancreatic sectioning carried out in the past, or previous to events of AP. More recently, the non pharmacological approach has started to spread based on the removal of the triglyceride-rich lipoproteins through TPE. Today, this therapeutic approach which is registered in the III category of the ’American Society for Apheresis’ (ASFA), is being used with success in acute HP [5–7]. Case series, case reports and
4
C. Stefanutti et al. / Transfusion and Apheresis Science 45 (2011) 3–7
a multi-center study have all been published [5,7–10]. This case report highlights the fundamental importance of a precocious diagnosis and well-timed treatment with TPE in a case of secondary AP to SHTG in the area of medico-surgical urgent emergency.
hypertriglyceridemia and grave hypercholesterolemia with values of 11.355 mg/dL (range:30–150) and 941 mg/dL (range:80–200), respectively.
2. Materials and methods (case report)
An abdominal ultrasound, performed with technical difficulty as the patient was overweight and because of the intense intestinal meteorism, reported the following picture: a non assessable pancreas and an enlarged liver with steatosis. A CT scan of the abdomen revealed: liver moderately increased in dimension, steatosis and a notable increase in volume of the pancreas, that appears to be characterized by diffuse structural lack of homogeneity, especially in correspondence with the cephalic region; an abundant amount of fluid in the peri-pancreatic area, in the retro-cavity of the epiploon, through the splenic vein, in the para-renal bilateral anterior area, and in the mesenteric area with diffuse lack of homogeneity of the adipose tissue at this level. The CT picture is compatible with acute pancreatic phlogosis. It is diagnosed as ‘‘acute secondary pancreatitis and SHTG’’ (Figs. 1 and 2).
A 49 year old patient (male, Caucasian, height: 180 cm, weight: 110 kg; blood pressure: 140/80 mm Hg; pulse frequency per minute: 80) arrived on 04/08/2009, at the Emergency Department of our hospital with the appearance, starting 2 h previously, of the following symptoms: epigastric pain spreading to the posterior, in the spine, without nausea or vomiting. The clinical history was scarcely informative apart from one check-up, during a routine hematobiochemical exam in 2007, of hypertriglyceridemia (350 mg/dL) and an episode of epigastric pain in August 2008. The patient was aware of the existence of dyslipidemia in his family, but was unable to provide details. 2.1. Physical examination The physical examination showed intense pain in the epigastric area and left hypochondrium with a positive Blumberg sign. The hematobiochemical exams (04/08/ 2009 at 09.00 p.m.) highlighted chyle serum, Amy 160 UI/L (range: 20–100), Lip 175 UI/L (range: 13–60), direct bilirubin 10.46 mg/dL (range: 0.15–0.35), blood glucose 279 mg/dL (range: 74–106). The laboratory announced that it was impossible to carry out further exams due to the condition of the serum (too high a concentration of triglyceride-rich lipoproteins). Determination of the levels of lipids and lipoproteins in the plasma was requested (04/08/2009 at 11.00 p.m.). The tests showed severe
2.2. Instrumental diagnosis
3. Results 3.1. Treatment with TPE and combined drug regimen The patient underwent urgent treatment (at 04.00 a.m. on 04/09/2009) of TPE (a written informed consent was obtained). Duration of procedure: 90 min (interrupted by request of patient). 3966 ml of blood were processed with the extraction of 1281 ml of plasma, and the infusion of 923 ml of human albumin at 5% as a replacement fluid. The vascular accesses utilized were peripheral venous accesses. According to our extracorporeal treatment
Fig. 1. A CT scan of the abdomen revealed: liver moderately increased in dimension, steatosis and a notable increase in volume of the pancreas, that appears to be characterized by diffused structural lack of homogeneity, especially in correspondence with the cephalic region; abundant amount of fluid spill in the peri-pancreatic area, in the retro-cavity of the epiploon, through the splenic vein, in the para-renal bilateral anterior area, and in the mesenteric area with diffused lack of homogeneity of the adipose tissue at this level. The CT picture was compatible with acute pancreatic phlogosis. It was diagnosed as ‘‘acute secondary pancreatitis and SHTG’’. Venous phase: increase in volume and edema of the pancreas (white arrow).
C. Stefanutti et al. / Transfusion and Apheresis Science 45 (2011) 3–7
5
Fig. 2. A CT scan of the abdomen revealed: liver moderately increased in dimension, steatosis and a notable increase in volume of the pancreas, that appears to be characterized by diffused structural lack of homogeneity, especially in correspondence with the cephalic region; abundant amount of fluid spill in the peri-pancreatic area, in the retro-cavity of the epiploon, through the splenic vein, in the para-renal bilateral anterior area, and in the mesenteric area with diffused lack of homogeneity of the adipose tissue at this level. The CT picture was compatible with acute pancreatic phlogosis. It was diagnosed as ‘‘acute secondary pancreatitis and SHTG’’. Venous phase: the arrows show the cephalic region of the pancreas, and the abundant amount of fluid spill in the peri-pancreatic area.
protocol, heparin, 5000 UI intravenous as a bolus was administered at the beginning of the procedure, while continuous anticoagulation during treatment guaranteed by the use of Anticoagulant Citrate Dextrose Solution A (ACD-A). The centrifugal apheresis system used was the ‘‘Spectra’’ COBE, LRS SystemTurboVersion 7.0 (COBE Laboratories, Inc., Lakewood, Co., USA). The procedure was well tolerated with no collateral effects. After TPE, TG levels and TC levels (04/09/2009 at 06.00 a.m.) dropped respectively to 7131 and 756 mg/dL; Lip values of 1100 UI/L and Amy of 771 UI/L. In the morning (04/09/2009 at 10.40 a.m.) the patient underwent a second session of TPE with a dramatic reduction in levels of TG to 752 mg/dL and of TC to 497 mg/dL with reduction of Amy and Lip respective to 598 and 592 UI/L. The following day (04/10/2009 at 9.30 a.m.) a third session TPE was carried out of with TG values of 1726 (before) and 735 mg/dL (after). TC values were: 396 (before) and 192 mg/dL (after). After only a few days the patient became asymptomatic and acquired acceptable values of Amy and Lip, 49 and 33 UI/L, respectively. Diet and pharmacological treatment were satisfactory. In the acute phase, omeprazole (40 mg iv), scopolamine butyl bromide (20 mg iv), ketorolac (30 mg iv), paracetamol (10 mg iv), calcium gluconate (10 ml 10%), saline (sodium chloride) (3000 ml/24 h, iv) were given. As is known, the fibric acid derivatives (fibrates), such as gemfibrozil, fenofibrate or bezafibrate, are the drugs of first choice in treating hypertriglyceridemia. The lipid-lowering agent given was gemfibrozil (1800 mg/day). The drug was well tolerated and demonstrated to be effective if taken regularly along with diet restrictions. Moreover, no more TPE procedures were carried out. On release from hospital, after 13 days of hospitalization, the levels of lipids and lipoproteins in the plasma were as follows: TG 185 mg/dL; TC 179 mg/dL; HDLC 22 mg/dL; LDLC 120 mg/dL.
3.2. Dietary and drug treatment (ward) During the emergency phase, it was absolutely necessary for the patient to remain in the fasting state. Once transferred to the ward following clinical improvement, the diet prescribed was ‘fat-free’. The drugs administered were: gemfibrozil (1800 mg/day), aspartate/insulin (VIII UI x 3 sc), insulin glargine (V UI sc in the evening 10.00 p.m.), glucose solution 5% (1000 ml/day) buffered with aspartate/insulin (VII UI sc), saline (sodium chloride) 500 ml (1000 ml/day), potassium chloride KCL (40 mEq/ day), ceftriaxon (2 g iv), omeprazole (40 mg iv) and ketorolac (30 mg iv). 4. Discussion A dyslipidemia of type I, IV and V according to Fredrickson’s classification (modified by Beaumont, World Health Organization) is usually associated with SHTG [11]. Types I–V hyperlipidemia can arise with AP without causing factors, while type IV generally requires predisposing factors [4]. Numerous therapeutic approaches have been adopted in the management of a patient with HP secondary to SHTG. Initial treatment of AP is the same in the various forms and includes staying on fasting, intravenous hydration and analgesics. In the case of parenteral nutrition in HP, lipid infusions should be avoided. The main aim of therapy of SHTG in HP is the reduction of TG levels in plasma to below 500 mg/dL [12]. A lipid-lowering diet (fat-free diet) and drugs are utilized in reducing hypertriglyceridemia. The infusion of heparin and/or insulin stimulates activity of the LPL and accelerates the degradation of chylomicrons [13]. Case reports [14–16] and case series [17,18] have utilized both these drugs to reduce levels of
6
C. Stefanutti et al. / Transfusion and Apheresis Science 45 (2011) 3–7
TG. However, where standard medical approaches fail to promote the clearance of TG from plasma and a high risk of first or secondary HP persists, TPE provides a valuable therapeutic option for preventing life threatening SHTG. Different plasmapheresis methods have been used in the treatment of HP. However, TPE is undoubtedly superior to double filtration and adsorption techniques in the removal of excessive TG because the membrane of the plasma fractionators is usually blocked by the larger particles of chylomicrons, remnants, and other TG-rich lipoproteins. Yeh et al. in 2003 reported that the removal rates of plasma lipids and lipoproteins were strongly associated with a lower level of maximal transmembrane pressure (TMP). This was a consequence of early saturation of the plasma fractionators blocked by the extremely high level of TGrich lipoproteins. They concluded that TPE was more suitable for the initial treatment of SHTG [20]. ASFA has categorized the use of TPE in HP due to hypertriglyceridemia as a Category III indication: ‘‘suggestion of benefit for which existing evidence is insufficient, either to establish the efficacy of therapeutic apheresis or to clarify the risk/benefit (or sometimes the cost/benefit) ratio’’ [7]. According to Winters et al., this decision was based on a January 2006 literature review [19]. At that time no randomized controlled trial, one controlled trial involving 29 patients, seven case series involving 57 patients, and 23 single patient case reports, were identified. The committee scored the available literature as Type III evidence, ‘‘opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees’’ despite the presence of a controlled trial due to limitations of that trial. Recently, to evaluate the therapeutic efficacy of TPE in treating patients with SHTG, 17 patients who had not responded to conventional medical therapy (fat-free diet plus pharmacological interventions) were referred for TPE in a multicenter case series study. Two hundred seventeen TPE sessions were performed. The removal of TG-rich lipoproteins prevented relapses of acute pancreatitis (AP) [10]. According to this experience and the latest case reported here it is clear, at least in our opinion, that the outcome of each case may be quite different according to the timing of intervention with TPE. It is consistently helpful during the acute inflammatory phase. However, TPE may even be an effective therapeutic measure. TPE (with a contribution of heparin and insulin that is difficult to quantify but not resolved) is the active instrument in rapid reduction of TG. Subsequent check-ups of the levels of lipid and lipoprotein in plasma, follows the progressive recovery of pancreatic tissue function, which is not immediate. It is highly probable that the rapid clearance of macromolecular lipids in plasma obtained from TPE, represents the difference in therapeutic terms. The mechanism of action may be desuppressing a key enzyme involved in the pathogenesis of SHTG: LPL. The essential aspect is the relative delipidation of the plasma milieu at a pancreatic capillary level and the progressive reactivation of enzyme function of LPL extra-pancreatic and pancreatic, capable of finally reacting effectively on sites of cleavage of VLDL previously ‘masked’ by excess lipoproteins of large molecular weight, which are chylomicrons and remnants of chylomicrons. Even the subsequent fibrates play an active role in
maintaining an acceptable and non risky profile of TG-rich lipoproteins in plasma. However, not in the initial phase, when it is useless and ineffective. To conclude, this case report, is, objectively, a further confirmation that TPE is a safe, efficient, and helpful method for treating patients with refractory SHTG when a severe complication, such as AP, is clinically demonstrated in an emergency. To our knowledge there is no clinical case reported in the literature where there is a detailed description of the clinical protocol applied in the chronological evolution of an emergency. It is plausible that the reported experience may be useful to those who find themselves having to intervene in similar emergency cases, which do not necessarily evolve towards remission with standard treatment. Above all, they do not receive an intervention on an etiological basis. The diagnosis is often misinterpreted by Medical Staff in the Emergency Department, when the symptomatic therapy of acute pancreatitis does not differ in relation to the pathogenetic cause of the clinical picture.
5. Conflict of interest and financial disclosure The authors certify that they have no affiliation with or financial involvement in any organization or entity with a direct financial interest in the subject matter or materials discussed in this manuscript.
References [1] Fortson MR, Freedman SN, Webster III PD. Clinical assessment of hyperlipidemic pancreatitis. Am J Gastroenterol 1995;90:2134–9. [2] Steinberg W, Tenner S. Acute pancreatitis. N Engl J Med 1994;330: 1198–210. [3] Mahley RW, Rall SC. Type III hyperlipoproteinemia. In: Seriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic basis of inherited disease, vol. I. New York: McGraw-Hill; 1989. p. 1195–213. [4] Yadav D, Pitchumoni CS. Issues in hyperlipidemic pancreatitis. J Clin Gastroenterol 2003;36:54–62. [5] Furuya T, Komatsu M, Takahashi K, Hashimoto N, Hashizume T, Wajima N, et al. Plasma exchange for hypertriglyceridemic acute necrotizing pancreatitis: report of two cases. Ther Apher 2002;6:454–8. [6] Kyriakidis AV, Raitsiou B, Sakagianni A, Harisopoulou V, Pyrgioti M, Panagopoulou A, et al. Management of acute severe hyperlipidemic pancreatitis. Digestion 2006;73(4):259–64. [7] Szczepiorkowski ZM, Shaz BH. The new approach to assignment of ASFA categories-introduction to the fourth special issue: clinical applications of therapeutic apheresis. J Clin Apher 2007;22:96–105. [8] Al-Humoud H, Alhhumoud E, Al-Hilali N. Therapeutic plasma exchange for acute hyperlipidemic pancreatitis: a case series. Ther Apher Dial 2008;12:202–4. [9] Gubensek J, Buturovic’ P, Marn-Pernat A, Kovac J, Knap B, Premru V, et al. Treatment of hyperlipidemic acute pancreatitis with plasma exchange: a single-center experience. Ther Apher Dial 2009;13(4):314–7. [10] Stefanutti C, Di Giacomo S, Vivenzio A, Labbadia G, Mazza F, D’Alessandri G, et al. Therapeutic plasma exchange in patients with severe hypertriglyceridemia: a multicenter study. Artif Organs 2009;33(12):1096–102. [11] Fredrickson DS. An international classification of hyperlipidemias and hyperlipoproteinemias. Ann Intern Med 1971;75:471–2. [12] Toskes PP. Hyperlipidemic pancreatitis. Gastroenterol Clin North Am 1990;19:783–91. [13] Henzen C, Rock M, Schnieper C. Heek: heparin and insulin in the treatment of acute hypertriglyceridemia-induced pancreatitis. Schweiz Med Wochenschr 1999;129:1242–8. [14] Alagozlu H, Cindoruk M, Karakan T, Unal S. Heparin and insulin in the treatment of hypertriglyceridemia-induced severe acute pancreatitis. Dig Dis Sci 2006;51(5):931–3.
C. Stefanutti et al. / Transfusion and Apheresis Science 45 (2011) 3–7 [15] Jain P, Rai RR, Udawat H, Nijhawan S, Mathur A. Insulin and heparin in the treatment of hypertriglyceridemia-induced pancreatitis. World J Gastroenterol 2007;13:2642–3. [16] Bolaman Z, Yavasoglu I, Kadikoylu G. Plasmapheresis in asparaginaseinduced pancreatitis. Transfusion 2009;49:185. [17] Berger Z, Quera R, Poniachik J, Oksenberg D, Guerrero J. Heparin and insulin treatment of acute pancreatitis caused by hypertriglyceri demia. Experience of 5 cases. Rev Med Chil 2001;129(12):1373–8.
7
[18] Kfour-Baz EM, Nassar RA, Tainos RF, Otrock ZK, Youssef AM, Albany C, et al. Plasmapheresis in asparaginase-induced hypertriglyceridemia. Transfusion 2008;48:1227–30. [19] Winters JL, Shaz BH, Szczepiorkowski ZM. Plasma exchange in pancreatitis due to hypertriglyceridemia. Transfusion 2009;49:1022. [20] Yeh JH, Lee MF, Chiu HC. Plasmapheresis for severe lipemia: comparison of serum-lipid clearance rates for the plasma-exchange and double-filtration variants. J Clin Apher 2003;18(1):32–6.