Terlipressin is a vasopressin analogue that is widely used in the treatment of hepatorenal syndrome or variceal bleeding. Because it acts mainly on splanchnic vessels, terlipressin has a lower incidence of severe ischemic complications than does vasopressin. However, it can still lead to serious complications such as myocardial infarction, skin necrosis, or bowel ischemia. Herein we report a case of severe ischemic bowel necrosis in a 46-year-old cirrhotic patient treated with terlipressin. Although the patient received bowel resection, death occurred due to ongoing hypotension and metabolic acidosis. Attention should be paid to patients complaining of abdominal pain during treatment with terlipressin

Eileen L. Yoon

Hae Rim Kim

Hyun Joo Lee

Hyun Jung Lee

Hyung Joon Yim

Ja Seol Koo

Ja Young Ryu

Jai Hyun Choi

Jong Jin Hyun

Rok Sun Choung

Sang Woo Lee

Sun Jae Lee

Sung Woo Jung

Young Sun Lee

Clinical and Molecular Hepatology

PubMed

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Copyright © 2013 by The Korean Association for the Study of the LiverThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.pISSN 2287-2728      eISSN 2287-285Xhttp://dx.doi.org/10.3350/cmh.2013.19.4.417Clinical and Molecular Hepatology 2013;19:417-420Case ReportINTRODUCTION Hepatorenal syndrome (HRS), a form of functional renal impair-ment, is one of the most serious complications in patients with advanced liver cirrhosis or acute liver failure. The main pathophysi-ology of development of HRS is reno-vascular constriction.1 In pa-tients with advanced liver cirrhosis, the development of splanchnic vasodilatation causes a reduction in effective arterial blood vol-ume, which leads to increased synthesis of several vasoactive me-diators.2,3 Terlipressin is a synthetic analogue of vasopressin, which causes vasoconstriction of splanchnic vessels and improves impaired renal function.2,4 Terlipressin is associated with a much lower incidence of ischemic complications compared with vaso-pressin, but it may still cause such problems. We report a case of severe ischemic bowel necrosis that developed after use of terlip-ressin for HRS in a patient with liver cirrhosis and hepatocellular carcinoma.CASE REPORTA 46-year-old man with underlying liver cirrhosis and hepato-cellular carcinoma (HCC) secondary to chronic hepatitis B present-ed with abdominal distension. The patient had undergone hepatic segmentectomy 1 year previously due to HCC. After HCC recur-rence, he had been receiving transarterial chemoembolization (TACE), and fifth TACE was done 1 month previously. Abdominal computed tomography (CT) which was taken 2 weeks after the last TACE showed no viable tumor in the liver. But, increased size of lymph nodes in the portocaval space and newly developed asci-tes were noted. Portal vein was patent without thrombosis.At admission, electrocardiography was normal and there was Severe ischemic bowel necrosis caused by terlipressin during treatment of hepatorenal syndromeHae Rim Kim, Young Sun Lee, Hyung Joon Yim, Hyun Joo Lee, Ja Young Ryu, Hyun Jung Lee, Eileen L. Yoon, Sun Jae Lee, Jong Jin Hyun, Sung Woo Jung, Ja Seol Koo, Rok Sun Choung, Sang Woo Lee, and Jai Hyun Choi Department of Internal Medicine, Korea University College of Medicine, Seoul, KoreaCorresponding author : Hyung Joon YimDepartment of Internal Medicine, Korea University Ansan Hospital, 123 Jeokgeum-ro, Danwon-gu, Ansan 425-707, KoreaTel. +82-31-412-6565, Fax. +82-31-412-5582E-mail; gudwns21@medimail.co.krAbbreviations: BUN, blood urea nitrogen; CT, computed tomography; HCC, hepatocellular carcinoma; HRS, hepatorenal syndrome; TACE, transarterial chemoembolizationReceived : Jun. 25, 2012 /  Revised : Sep. 22, 2012 /  Accepted : Oct. 4, 2012Terlipressin is a vasopressin analogue that is widely used in the treatment of hepatorenal syndrome or variceal bleeding. Because it acts mainly on splanchnic vessels, terlipressin has a lower incidence of severe ischemic complications than does vasopressin. However, it can still lead to serious complications such as myocardial infarction, skin necrosis, or bowel ischemia. Herein we report a case of severe ischemic bowel necrosis in a 46-year-old cirrhotic patient treated with terlipressin. Although the patient received bowel resection, death occurred due to ongoing hypotension and metabolic acidosis. Attention should be paid to patients complaining of abdominal pain during treatment with terlipressin. (Clin Mol Hepatol 2013;19:417-420)Keywords: Terlipressin; Necrosis; Hepatorenal syndrome418Clin Mol HepatolVolume_19  Number_4  December 2013http://www.e-cmh.orghttp://dx.doi.org/10.3350/cmh.2013.19.4.417no evidence of cardiac dysfunction. Initial serum creatinine was 1.2 mg/dL and blood urea nitrogen (BUN) was 12 mg/dL. Albumin lev-el was 3.6 g/dL, aspartate transaminase 136 IU/L, alanine trans-aminase 137 IU/L, alkaline phosphatase 215 IU/L and total biliru-bin 3.8 mg/dL. Hemoglobin level was 14.3 g/dL and platelet count was 284,000/uL. Prothrombin time was 12.8 seconds. A moderate amount of ascites was noted, and urine output decreased. Diag-nostic paracentesis and ascitic fluid analysis was done. Albumin was 2.2 g/dL, leukocyte count was 300/mm3 (neutrophil 61%, lymphocyte 10%, monocyte and macrophage 29%), lactate dehy-drogenase was 541 IU/L, glucose was 101 mg/dL in ascites, and bacteria was not seen on gram stain and culture of ascites. Serum-to-ascites albumin gradient (SAAG) was 1.4, suggesting ascites from portal hypertension. There was no definite evidence of spon-taneous bacterial peritonitis. Twenty mg of furosemide combined with 50 mg of spironolactone, was administered for three days.Three days after admission, serum creatinine had increased to 3.31 mg/dL and BUN had increased to 37.6 mg/dL. The fractional excretion of sodium was 0.8%. The diuretics were stopped, and a total of 80 g of albumin was administered and hydration with 1.5 L of normal saline was done for two days to rule out the possibility of pre-renal acute kidney injury. Despite such a treatment, there was no improvement of serum creatinine. No nephrotoxic drug was used and the blood pressure was generally stable. There was no evidence of parenchymal kidney disease such as marked pro-teinuria or hematuria. Abdominal sonography showed normal echogenicity on both kidney, and urinary tract abnormality was not noted. According to the criteria of International Ascites Club in 2007,5 we diagnosed the patient’s renal failure as type I HRS. One mg of terlipressin was intravenously administrated every 6 hours. Because the patient complained of severe abdominal pain after 2 doses of terlipressin, it was stopped. Serum creatinine and BUN increased to 7.95 mg/dL and 84.4 mg/dL, respectively, and hourly urine volume became further decreased (Fig. 1). Continuous renal replace therapy was applied for supporting impaired renal function. But, the patient’s abdominal pain aggravated and whole abdominal tenderness appeared. Rebound tenderness was also noted. Abdominal CT revealed that the wall of mid-ileum ap-peared to be thin and not enhanced with contrast. There were multiple air bubbles in the mesenteric veins and in the bowel wall, suggesting pneumatosis intestinalis (Fig. 2). Otherwise, there was Figure 2. Abdominal CT revealed thinning of the small-intestine wall (arrowhead) and multiple air bubbles in mesenteric veins (arrow) (A). Air bubbles were also evident in the bowel wall (arrow) (B).A BSurgeryExpiredCRRTTerlipressinTotal bilirubinCreatinineHospital day (HD)HD1121086420mg/dLHD4 HD6 HD7 HD8 HD9 HD10 HD11Figure 1. Clinical course of the patient according to changes in bilirubin and creatinine levels. CRRT, continuous renal replacement therapy.419Hae Rim Kim, et al. Severe ischemic bowel necrosis caused by terlipressinhttp://www.e-cmh.org http://dx.doi.org/10.3350/cmh.2013.19.4.417no thrombus within vessel or free air in peritoneal cavity. With these findings, the patient was diagnosed with bowel ne-crosis due to mesenteric ischemia induced by terlipressin. The pa-tient received an emergency bowel resection.Operative findings demonstrated the small bowel segment be-low the Treitz ligament to be in an ischemic state. The blood flow was improved after adjusting the direction of bowel mesentery but the infarction of ileum was severe, so approximately 30 cm of it was resected. Grossly, the resected bowel also had ischemic change on serosa and mesentery, and the mucosa was atrophied and black-pigmented on the opening of the bowel lumen (Fig. 3A). Microscopically, there were necrosis and hemorrhages in the bowel wall (Fig. 3B).There were no any immediate complications associated with surgery, but hypotension and metabolic acidosis persisted. Eventu-ally, the patient died 2 days after operation.DISCUSSIONTerlipressin, which is a synthetic long-acting analogue of vaso-pressin with intrinsic vasoconstrictor activity, is widely used in the treatment of cirrhotic patients with variceal bleeding and it im-proves renal function and short-term survival in HRS.6-9Terlipressin is a vasoconstrictor that acts preferentially on the splanchnic circulation, lowering portal venous pressure. However, all the vasoconstrictors influence the systemic circulation, which may result in ischemic complications. Although terlipressin is asso-ciated with a lower incidence of adverse events compared to vaso-pressin and other synthetic analogues as it is a selective vasocon-strictor, it also can produce systemic effects. An average incidence of adverse events is 12% of patients treated; most are cardiovas-cular or ischemic complications.3,7 Common adverse events includ-ing headache, paleness, abdominal pain and bradycardia are usu-ally mild, but serious complications such as myocardial infarction,8 skin necrosis9 or ischemic colitis may occur.10-12In this case, the patient complained of abdominal pain after treatment with terlipressin. Abdominal cramping is commonly re-ported as an adverse event of terlipressin, but most cases are mild and transient.13 However, in this case, pain was severe and contin-ued after discontinuation of terlipressin. In this situation, there were possibilities of acute mesenteric ischemia and bowel perfora-tion, so a CT scan was performed. On the basis of the CT findings, bowel necrosis with pneumatosis intestinalis was diagnosed, and mesenteric thromboembolism or bowel perforation were excluded. There are many conditions associated with pneumatosis intestina-lis including pulmonary, autoimmune, infectious, iatrogenic, drug induced, compromised immune state, gastrointestinal, or vascular disease.14 In this case, the patient had no other systemic disease except recent administration of terlipressin. And, ascitic fluid anal-ysis and culture showed no evidence of intra-abdominal infection. Therefore, we concluded that pneumatosis intestinalis developed due to mesenteric ischemia induced by terlipressin. The finding of bowel necrosis with pneumatosis intestinalis seemed to be irre-versible. So, we decided to perform a bowel resection. There are three cases that have reported intestinal ischemia af-Figure 3. Pathologic findings of the resected bowel. Grossly, the mesentery exhibited ischemic changes and the mucosa of the inner layer exhibited atrophy and black pigmentation (A), necrosis and hemorrhagic that were evident microscopically were compatible with ischemic colitis (B) (H&E stain).A B420Clin Mol HepatolVolume_19  Number_4  December 2013http://www.e-cmh.orghttp://dx.doi.org/10.3350/cmh.2013.19.4.417ter treatment of terlipressin for variceal bleeding,10-12 but those cases were unrelated to HRS. Also, the Terlipressin and Albumin for Hepatorenal Syndrome Study (TAHRS) trial, which compared the efficacy of terlipressin plus albumin and albumin alone and administered 1-2 mg of terlipressin every 4 hours, reported three cases of suspicious intestinal ischemia during terlipressin therapy for HRS.15 However, those cases were only suspicious events and there was no explanation on outcomes. An important finding in this case is that bowel ischemia developed after administration of two doses of terlipressin (total of 2 mg) and progressed after its discontinuation: The patient received bowel resection eventually. Therefore, this is the first case of severe intestinal ischemia that presented with abdominal pain at regular dose of terlipressin in HRS and progressed to severe bowel necrosis confirmed by pa-thology after surgery.Nonocclusive mesenteric ischemia is the result of splanchnic va-soconstriction occurring in response to a variety of systemic insults that diminishes mesenteric blood flow. These include decreased cardiac output (pump failure or arrhythmias), hypovolemia, hypo-tension (shock, sepsis), rapid digitalization or reaction to vasopres-sors. Early diagnosis by CT or angiography is the key to the suc-cessful management of such patients.16 Underlying causative factors should be corrected urgently, when mesenteric ischemia is diagnosed. Vasodilator therapy may be helpful, and papaverine and prostaglandin are the vasodilators most commonly used. However, referring patients for laparotomy and bowel resection should be considered when there is no response to medical thera-py and bowel necrosis is suspected.17 In conclusion, although most of the abdominal pain due to use of terlipressin is mild and resolves after discontinuation of admin-istration, it may develop as an irreversible bowel ischemic necrosis, as exemplified by the current case. Therefore, possible serious complications should be kept in mind and terlipressin needs to be used with caution.Conflicts of InterestThe authors have no conflicts to disclose. REFERENCES1. Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodés J. Peripheral arterial vasodilation hypothesis: a proposal for the initia-tion of renal sodium and water retention in cirrhosis. Hepatology 1988;8:1151-1157.2. Dagher L, Moore K. The hepatorenal syndrome. Gut 2001;49:729-737.3. Ginès P, Schrier RW. Renal failure in cirrhosis. N Engl J Med 2009;361:1279-1290.4. Ginès P, Guevara M. Therapy with vasoconstrictor drugs in cirrho-sis: The time has arrived. Hepatology 2007;46:1685-1687.5. Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, pre-vention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:1310-1318.6. Gluud LL, Christensen K, Christensen E, Krag A. Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syn-drome. Hepatology 2010;51:576-584.7. Moreau R, Lebrec D. The use of vasoconstrictors in patients with cirrhosis: type 1 HRS and beyond. Hepatology 2006;43:385-394.8. Lee MY, Chu CS, Lee KT, Lee HC, Su HM, Cheng KH, et al. Terlipres-sin-related acute myocardial infarction: a case report and literature review. Kaohsiung J Med Sci 2004;20:604-608.9. Donnellan F, Cullen G, Hegarty JE, McCormick PA. Ischaemic com-plications of Glypressin in liver disease: a case series. Br J Clin Phar-macol 2007;64:550-552.10. Schmitt W, Wagner-Thiessen E, Lux G. Ischaemic colitis in a patient treated with glypressin for bleeding oesophageal varices. Hepato-gastroenterology 1987;34:134-136.11. Hansen M, Bjerg J, Gilsaa T. Terlipressin and reversible intestinal ischaemia. Ugeskr Laeger 2007;169:1802-1803.12. Willems MG, Schoenemann J, Rey C, Schafer H, Lindecken KD. Ischemia of the cecum caused by glycylpressin. Leber Magen Darm 1985;15:165-168.13. Krag A, Borup T, Møller S, Bendtsen F. Efficacy and safety of terli-pressin in cirrhotic patients with variceal bleeding or hepatorenal syndrome. Adv Ther 2008;25:1105-1140.14. Khalil PN, Huber-Wagner S, Ladurner R, Kleespies A, Siebeck M, Mutschler W, et al. Natural history, clinical pattern, and surgical considerations of pneumatosis intestinalis. Eur J Med Res 2009;14: 231-23915. Martín-Llahí M, Pepin MN, Guevara M, Díaz F, Torre A, Monescillo A, et al. Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology 2008;134:1352-1359.16. Trompeter M, Brazda T, Remy CT, Vestring T, Reimer P. Non-occlu-sive mesenteric ischemia: etiology, diagnosis, and interventional therapy. Eur Radiol 2002;12:1179-1187.17. Brandt LJ, Boley SJ. Nonocclusive mesenteric ischemia. Annu Rev Med 1991;42:107-117.

Severe ischemic bowel necrosis caused by terlipressin during treatment of hepatorenal syndrome

Efficacy and safety of terlipressin in cirrhotic patients with variceal bleeding or hepatorenal syndrome.

Ischaemic colitis in a patient treated with glypressin for bleeding oesophageal varices.

Ischaemic complications of Glypressin in liver disease: a case series.

Ischemia of the cecum caused by glycylpressin.

Natural history, clinical pattern, and surgical considerations of pneumatosis intestinalis.

Non-occlusive mesenteric ischemia: etiology, diagnosis, and interventional therapy.

Nonocclusive mesenteric ischemia. Annu Rev Med

Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.

prevention and treatment of hepatorenal syndrome in cirrhosis.

Renal failure in cirrhosis.

Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome.

Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study.

Terlipressin and reversible intestinal ischaemia.

Terlipressin-related acute myocardial infarction: a case report and literature review.

The hepatorenal syndrome.

The use of vasoconstrictors in patients with cirrhosis: type 1 HRS and beyond.

Therapy with vasoconstrictor drugs in cirrhosis: The time has arrived.

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Severe ischemic bowel necrosis caused by terlipressin during treatment of hepatorenal syndrome

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