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Vascular Complications After Orthotopic Liver Transplantation in Estonia
Vascular Complications After Orthotopic Liver Transplantation in Estonia T. Väli, A. Tein, V. Tiganik, and K. Ulst ABSTRACT The aim of this study was to analyse vascular complications (VC) accompanying the introduction in Estonia of orthotopic liver transplantation (OLT) for treatment of end-stage liver disease. We present the incidence and treatment of VC occurring among our first 23 OLT in 22 patients. The 11 female and 11 male patients were aged 12 to 67 years. Their diagnoses were cholestatic disease (n ⫽ 8); hepatitis C virus (HCV) cirrhosis (n ⫽ 6); tumor (n ⫽ 3); Budd-Chiari syndrome (n ⫽ 2); autoimmune hepatitis (n ⫽ 1); cystic fibrosis (n ⫽ 1); or fulminant hepatic failure (n ⫽ 1). Only end-to-end vascular reconstructions were used in OLT. The patients’ 1-year post-OLT survival rate was 86%. VC were confirmed using computed tomography (CT) or magnetic resonance imaging (MRI). In cases of VC, we started a 1-week course of subcutaneous anticoagulant therapy with low–molecular weight heparin (LMWH) immediately followed by permanent oral treatment. The incidence of VC was 14% (n ⫽ 3). There was no hepatic artery thrombosis. One patient developed hepatic venous thrombosis at 3 weeks after retransplantation. She was treated successfully with immediate LMWH followed by a permanent oral anticoagulation. Two patients experienced portal vein complications: 1 with pre-OLT portal vein thrombosis developed right intrahepatic portal vein thrombosis at 5 weeks after OLT requiring portal thrombectomy. He was treated successfully with immediate LMWH followed by permanent oral anticoagulation. The other subject displayed left intrahepatic portal vein thrombosis at 1 week after OLT. Despite immediate LMWH treatment followed by a permanent oral anticoagulation, he required left lobe necrectomy and Roux-Y choledochojejunostomy for recovery. The survival and recovery of all studied patients with VC allow us to recommend immediate subcutaneous anticoagulant therapy for post-OLT portal or hepatic venous thrombosis. URING the last 50 years orthotopic liver transplantation (OLT) has become a generally accepted therapeutic method of choice for several advanced liver diseases. Initially transplantation was considered to be the last therapeutic option for patients with end-stage liver insufficiency due to the high prevalence of technical complications. Considering this international experience, we started OLT for patients who were in serious clinical condition. According to literature data, the prevalence of technical complications after OLT, particularly vascular complications (VC), ranges from 7%–25%.1,2 Despite all of the advances, VC remain an important cause of morbidity, graft loss, and mortality. The aim of this study was to analyse VC accompanying the introduction in Estonia of OLT to treat endstage liver disease.
D
PATIENTS AND METHODS The data for the first 22 consecutive patients with end-stage liver disease, who were referred for 23 ABO blood group– compatible OLT between 1999 and 2011, were collected from patient records. The 11 male and 11 female patients were aged 12 to 67 years. Their diagnoses included cholestatic disease (n ⫽ 8), hepatitis C virus (HCV) cirrhosis (n ⫽ 6), tumor (n ⫽ 3), Budd-Chiari syndrome (n ⫽ 2), autoimmune hepatitis (n ⫽ 1), cystic fibrosis (n ⫽ 1), or fulminant hepatic failure (n ⫽ 1) based on established biochemical,
From the Tartu University Hospital, University of Tartu, Tartu, Estonia. Address reprint requests to Toomas Väli, Tartu University Hospital, Puusepa 8, Tartu 51014, Estonia. E-mail: toomas.vali@ kliinikum.ee
© 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.10.011
Transplantation Proceedings, 45, 1201–1203 (2013)
1201
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1202 radiological, and histopathological criteria. The disease history ranged from 1 month to 15 years; the pretransplantation liver insufficiency scores were Child-Pugh B or C. Waiting time was 1 to 36 months. The donor liver harvesting technique was based on the multiorgan extraction method as described by Starzl et al in 1984.3 Cold ischemia time in University of Wisconsin or Custodiol preservation solutions lasted 8 ⫾ 5 hours. The recipient operations, lasting 9 ⫾ 3 hours, were performed using the classical technique without hepatic veno-venous bypass, as described by Höckerstedt and Calne in 19954 only using end-to end vascular reconstructions. Posttransplantation treatment consisted of corticosteroids, cyclosporine or tacrolimus, and mycophenolate mofetil. In addition, we prescribed anti-infection prophylaxis with antimicrobial, antifungal, and antiviral drugs as well as courses of anticoagulant prophylaxis with antiaggregants or anticogulants. Posttransplantation evaluation consisted of regular biochemical, radiological, and histopathological examinations. Doppler ultrasound (DU) was performed by protocol on days 1, 3, 7, 14, and 21 after OLT as well as when clinically necessary. The patients’ post-OLT 1-year survival rate was 86% (19/22). In all cases of VC the suspected DU diagnosis was confirmed using computerized tomography (CT) or magnetic resonance imaging (MRI), as recommended by Caiado et al in 2007.5 In cases of VC, we started immediately a 1-week course of subcutaneous anticoagulation therapy using low–molecular weight heparin (LMWH), followed by a permanent oral anticoagulation as recommended by Hegenbart et al.6 The LMWH treatment included 2 subcutaneous injections of enoxaparin (clexane) 100 anti-factor Xa IU/kg daily, achieving peak concentrations of 0.5–1.0 anti-factor Xa IU/mL 3–5 hours. In the second week after the VC diagnosis the patient was placed on oral warfarin, which was dose-adjusted treatment to achieve an international normalized ratio (INR) of 2.0 to 3.0 or oral dabigatran (pradaxa; 150 mg daily). The VC patients underwent several DU and repeat CT or MRI to confirm resolution of thrombosis.
RESULTS
We identified VC in 3/22 (14%) patients. There was no hepatic artery thrombosis (HAT), but 1 subject displayed hepatic vein thrombosis (HVT) and 2 had portal vein thromboses (PVT). Case 1
A 14-year-old girl of 40 kg had a diagnosis of cystic fibrosis established as a newborn, suffering from secondary liver cirrhosis since 6 years of age. She was classified as Child C class, undergoing a successful OLT at 12 years of age. There were no complications during the first posttransplantation year. However, problems occurred due to irregular cyclosporine absorption associated with her main disease. In the second posttransplantation year a steroid- and thymoglobulinresistant late acute rejection episode required re-OLT at 14 years of age. The deceased donor was 80-kg 48-year-old man. In the third posttransplantation week the patient developed temporary ascites and renal insufficiency. The DU revealed donor venal cava thrombosis and HVT, which were confirmed using MRI and managed effectively with an immediate 1-week course of LMWH followed by permanent treatment with the oral anticoagulant dabigatran. The ascites and renal insufficiency resolved within 2 months, the
vena caval thrombosis and HVT within 6 months. No further thrombotic events occurred during the first year of follow-up. Case 2
A 31-year-old man had suffered from primary sclerosing cholangitis for more than 10 years and liver insufficiency due to PVT had worsened over the last 3 years. He experienced several episodes of septic cholangitis, intractable ascites, and primary peritonitis. He was classified as having Child C class liver insufficiency and underwent a successful OLT with a portal thrombectomy. There were no complications during the first posttransplantation month. Normal postoperative hepatic arterial, venous, and portal blood flows were verified by regular postoperative DU examination. During the second posttransplantation month he was readmitted to our hospital with a 2-day course of fever and clinical jaundice. Blood cultures revealed Klebsiella pneumoniae sepsis. The patient received 4 weeks of intravenous antibiotic therapy. The MRI revealed an intrahepatic right PVT, which was managed effectively with immediate initiation of a 1-week course of LMWH followed by permanent oral anticoagulation with warfarin. Sepsis and icterus resolved within 4 weeks and the PVT, within 2 months. No further thrombotic events have occurred during 4 years of follow-up. Case 3
A 42-year-old man who suffered from HCV-related cirrhosis displayed portal hypertension with intractable ascites and chronic encephalopathy, including episodes of hepatic coma. He was classified as having Child C liver insufficiency and underwent an OLT. In the immediate postoperative period he displayed severe cytolysis and cholestasis. Endoscopic retrograde cholangiography on postoperative day 7 revealed an anastomotic stricture that was treated with a stent placement. Liver biopsy on postoperative day 11 showed only mild preservation injury but no evidence of an acute rejection process. Normal hepatic arterial, venous, and portal blood flows were verified by regular postoperative DU over the first 2 posttransplantation weeks. In the third posttransplantation week the patient displayed Enterococcus faecium and Stenotrofomanas maltophilia sepsis. The CT showed an intrahepatic left PVT with lobas necrosis and abscess formation (Fig 1A). The patient received an 8-week course of intravenous antibiotic therapy and the left PVT was managed by an immediate, 1-week course of LMWH followed by permanent oral anticoagulant dabigatran. Despite percutaneous catheter drainage, the hepatic abscess persisted with necrosis requiring open drainage and necrectomy of liver segments II and III at 1 month after OLT. The biliary anastomotic stricture was revised to a Roux-Y choledochojejunostomy at 2 months after OLT. Sepsis and icterus resolved and the patient recovered, but left PVT did not resolve over 6 months of follow-up (Fig 1B).
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pre-OLT PVT.1,8 Our case of right PVT in the patient with pre-OLT PVT was managed effectively with immediate as well as permanent anticoagulant therapy. The major result of our study was the recanalization of the hepatic and portal veins in 2 patients with HVT and PVT who received early as well as permanent anticoagulant therapy. Our findings support a few previous reports on the use of early anticoagulant therapy with LMWH for PVT followed by permanent oral anticoagulation.6,9 In some cases of post-OLT hepatic necrosis and liver abscesses associated mainly with HAT or biliary anastomotic strictures have been treated with prolonged antibiotic therapy and percutaneous or open drainage, or even retransplantation.10 –12 The present study demonstrated that post-OLT hepatic necrosis and liver abscesses associated with PVT and biliary anastomotic stricture, can be treated successfully with prolonged antibiotic therapy combined with percutaneous and open drainage, liver resection, and biliary reconstruction. In conclusion, the survival and recovery of all studied patients with VC allowed us to recommend anticoagulant therapy for post-OLT HVT and PVT. REFERENCES
Fig 1. CT images of the patient with left PVT and hepatic necrosis. (A) Three weeks after OLT: no contrast in the left portal vein, the vein is thrombosed (black arrow), and necrosis with abscess formation of the left lobe apex is visible (white arrow). (B) Six months later: no contrast in the left portal vein, thrombosis is not resolved (black arrow). Liver segments are partly resected (white arrow).
DISCUSSION
HAT and rarely PVT or HVT show detrimental effects on patient and graft survival after OLT.1,2 There was no HAT in our series, but we detected 1 case of HVT and 2 of intrahepatic PVT. In pediatric OLT HVT has been associated with mechanical compression of hepatic veins and the interior vena cava caused by donor/recipient weight and age differences.7 Our HVT case in a pediatric re-OLT was managed effectively with immediate as well as permanent anticoagulant therapy. One of the risk factors for PVT is
1. Moreno R, Berenguer M: Post-liver transplantation medical complications. Ann Hepatol. 2006;5:77. 2. Duffy J, Hong JC, Ghobrial RM, et al: Vascular complications of orthotopic liver transplantation: experience in more than 4,200 patients. Am Coll Surg. 2009;208:896. 3. Starzl TE, Hakala T, Shaw B, et al: A flexible procedure for multiple cadaveric organ procurement. Surg Gynecol Obstet. 1984; 158:223. 4. Höckerstedt K, Calne RY: Liver transplantation. In Harjula A, Höckerstedt K (eds): 1995;, p Recallmed Ltd; 80 5. Caiado AHM, Blasbalg R, Marcelino ASZ, et al: Complications of liver transplantation: multimodality imaging approach. RadioGraphics. 2007;27:1401. 6. Hegenbarth K, Fickert P, Aschauer M, et al: Successful management of acute portal vein thrombosis by low molecular weight heparin and oral anticoagulation. AJG. 2002;97:1567. 7. Sieders E, Peeters PMJG, Vergert EMT, et al: Early vascular complications after pediatric liver transplantation. Liver Transpl. 2000;6:326. 8. Manzanet G, Sanjuan F, Orbis P, et al: Liver transplantation in patients with portal vein thrombosis. Liver Transpl. 2001;7:125. 9. Condat B, Pessione F, Denninger MH, et al: Recent portal or mesenteric venous thrombosis: increased recognition and frequent recanalization on anticoagulant therapy. Hepatology. 2000;32:466. 10. Tachopoulou OA, Vogt DP, Henderson JM, et al: Hepatic abscess after liver transplantation: 1999 –2000. Transplantation. 2003;75:79. 11. Nikeghbalian S, Salahi R, Salahi H, et al: Hepatic abscesses after liver transplantation: 1997–2008. Exp Clin Transplant. 2009; 7:256. 12. Romagnoli R, Patrono D, Mirabella S, et al: Transthoracic open window hepatostomy: a salvage approach to right lobe abscesses after liver transplantation. Liver Transpl. 2009;15:818.
D
PATIENTS AND METHODS The data for the first 22 consecutive patients with end-stage liver disease, who were referred for 23 ABO blood group– compatible OLT between 1999 and 2011, were collected from patient records. The 11 male and 11 female patients were aged 12 to 67 years. Their diagnoses included cholestatic disease (n ⫽ 8), hepatitis C virus (HCV) cirrhosis (n ⫽ 6), tumor (n ⫽ 3), Budd-Chiari syndrome (n ⫽ 2), autoimmune hepatitis (n ⫽ 1), cystic fibrosis (n ⫽ 1), or fulminant hepatic failure (n ⫽ 1) based on established biochemical,
From the Tartu University Hospital, University of Tartu, Tartu, Estonia. Address reprint requests to Toomas Väli, Tartu University Hospital, Puusepa 8, Tartu 51014, Estonia. E-mail: toomas.vali@ kliinikum.ee
© 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.10.011
Transplantation Proceedings, 45, 1201–1203 (2013)
1201
VA¨LI, TEIN, TIGANIK ET AL
1202 radiological, and histopathological criteria. The disease history ranged from 1 month to 15 years; the pretransplantation liver insufficiency scores were Child-Pugh B or C. Waiting time was 1 to 36 months. The donor liver harvesting technique was based on the multiorgan extraction method as described by Starzl et al in 1984.3 Cold ischemia time in University of Wisconsin or Custodiol preservation solutions lasted 8 ⫾ 5 hours. The recipient operations, lasting 9 ⫾ 3 hours, were performed using the classical technique without hepatic veno-venous bypass, as described by Höckerstedt and Calne in 19954 only using end-to end vascular reconstructions. Posttransplantation treatment consisted of corticosteroids, cyclosporine or tacrolimus, and mycophenolate mofetil. In addition, we prescribed anti-infection prophylaxis with antimicrobial, antifungal, and antiviral drugs as well as courses of anticoagulant prophylaxis with antiaggregants or anticogulants. Posttransplantation evaluation consisted of regular biochemical, radiological, and histopathological examinations. Doppler ultrasound (DU) was performed by protocol on days 1, 3, 7, 14, and 21 after OLT as well as when clinically necessary. The patients’ post-OLT 1-year survival rate was 86% (19/22). In all cases of VC the suspected DU diagnosis was confirmed using computerized tomography (CT) or magnetic resonance imaging (MRI), as recommended by Caiado et al in 2007.5 In cases of VC, we started immediately a 1-week course of subcutaneous anticoagulation therapy using low–molecular weight heparin (LMWH), followed by a permanent oral anticoagulation as recommended by Hegenbart et al.6 The LMWH treatment included 2 subcutaneous injections of enoxaparin (clexane) 100 anti-factor Xa IU/kg daily, achieving peak concentrations of 0.5–1.0 anti-factor Xa IU/mL 3–5 hours. In the second week after the VC diagnosis the patient was placed on oral warfarin, which was dose-adjusted treatment to achieve an international normalized ratio (INR) of 2.0 to 3.0 or oral dabigatran (pradaxa; 150 mg daily). The VC patients underwent several DU and repeat CT or MRI to confirm resolution of thrombosis.
RESULTS
We identified VC in 3/22 (14%) patients. There was no hepatic artery thrombosis (HAT), but 1 subject displayed hepatic vein thrombosis (HVT) and 2 had portal vein thromboses (PVT). Case 1
A 14-year-old girl of 40 kg had a diagnosis of cystic fibrosis established as a newborn, suffering from secondary liver cirrhosis since 6 years of age. She was classified as Child C class, undergoing a successful OLT at 12 years of age. There were no complications during the first posttransplantation year. However, problems occurred due to irregular cyclosporine absorption associated with her main disease. In the second posttransplantation year a steroid- and thymoglobulinresistant late acute rejection episode required re-OLT at 14 years of age. The deceased donor was 80-kg 48-year-old man. In the third posttransplantation week the patient developed temporary ascites and renal insufficiency. The DU revealed donor venal cava thrombosis and HVT, which were confirmed using MRI and managed effectively with an immediate 1-week course of LMWH followed by permanent treatment with the oral anticoagulant dabigatran. The ascites and renal insufficiency resolved within 2 months, the
vena caval thrombosis and HVT within 6 months. No further thrombotic events occurred during the first year of follow-up. Case 2
A 31-year-old man had suffered from primary sclerosing cholangitis for more than 10 years and liver insufficiency due to PVT had worsened over the last 3 years. He experienced several episodes of septic cholangitis, intractable ascites, and primary peritonitis. He was classified as having Child C class liver insufficiency and underwent a successful OLT with a portal thrombectomy. There were no complications during the first posttransplantation month. Normal postoperative hepatic arterial, venous, and portal blood flows were verified by regular postoperative DU examination. During the second posttransplantation month he was readmitted to our hospital with a 2-day course of fever and clinical jaundice. Blood cultures revealed Klebsiella pneumoniae sepsis. The patient received 4 weeks of intravenous antibiotic therapy. The MRI revealed an intrahepatic right PVT, which was managed effectively with immediate initiation of a 1-week course of LMWH followed by permanent oral anticoagulation with warfarin. Sepsis and icterus resolved within 4 weeks and the PVT, within 2 months. No further thrombotic events have occurred during 4 years of follow-up. Case 3
A 42-year-old man who suffered from HCV-related cirrhosis displayed portal hypertension with intractable ascites and chronic encephalopathy, including episodes of hepatic coma. He was classified as having Child C liver insufficiency and underwent an OLT. In the immediate postoperative period he displayed severe cytolysis and cholestasis. Endoscopic retrograde cholangiography on postoperative day 7 revealed an anastomotic stricture that was treated with a stent placement. Liver biopsy on postoperative day 11 showed only mild preservation injury but no evidence of an acute rejection process. Normal hepatic arterial, venous, and portal blood flows were verified by regular postoperative DU over the first 2 posttransplantation weeks. In the third posttransplantation week the patient displayed Enterococcus faecium and Stenotrofomanas maltophilia sepsis. The CT showed an intrahepatic left PVT with lobas necrosis and abscess formation (Fig 1A). The patient received an 8-week course of intravenous antibiotic therapy and the left PVT was managed by an immediate, 1-week course of LMWH followed by permanent oral anticoagulant dabigatran. Despite percutaneous catheter drainage, the hepatic abscess persisted with necrosis requiring open drainage and necrectomy of liver segments II and III at 1 month after OLT. The biliary anastomotic stricture was revised to a Roux-Y choledochojejunostomy at 2 months after OLT. Sepsis and icterus resolved and the patient recovered, but left PVT did not resolve over 6 months of follow-up (Fig 1B).
OLT IN ESTONIA
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pre-OLT PVT.1,8 Our case of right PVT in the patient with pre-OLT PVT was managed effectively with immediate as well as permanent anticoagulant therapy. The major result of our study was the recanalization of the hepatic and portal veins in 2 patients with HVT and PVT who received early as well as permanent anticoagulant therapy. Our findings support a few previous reports on the use of early anticoagulant therapy with LMWH for PVT followed by permanent oral anticoagulation.6,9 In some cases of post-OLT hepatic necrosis and liver abscesses associated mainly with HAT or biliary anastomotic strictures have been treated with prolonged antibiotic therapy and percutaneous or open drainage, or even retransplantation.10 –12 The present study demonstrated that post-OLT hepatic necrosis and liver abscesses associated with PVT and biliary anastomotic stricture, can be treated successfully with prolonged antibiotic therapy combined with percutaneous and open drainage, liver resection, and biliary reconstruction. In conclusion, the survival and recovery of all studied patients with VC allowed us to recommend anticoagulant therapy for post-OLT HVT and PVT. REFERENCES
Fig 1. CT images of the patient with left PVT and hepatic necrosis. (A) Three weeks after OLT: no contrast in the left portal vein, the vein is thrombosed (black arrow), and necrosis with abscess formation of the left lobe apex is visible (white arrow). (B) Six months later: no contrast in the left portal vein, thrombosis is not resolved (black arrow). Liver segments are partly resected (white arrow).
DISCUSSION
HAT and rarely PVT or HVT show detrimental effects on patient and graft survival after OLT.1,2 There was no HAT in our series, but we detected 1 case of HVT and 2 of intrahepatic PVT. In pediatric OLT HVT has been associated with mechanical compression of hepatic veins and the interior vena cava caused by donor/recipient weight and age differences.7 Our HVT case in a pediatric re-OLT was managed effectively with immediate as well as permanent anticoagulant therapy. One of the risk factors for PVT is
1. Moreno R, Berenguer M: Post-liver transplantation medical complications. Ann Hepatol. 2006;5:77. 2. Duffy J, Hong JC, Ghobrial RM, et al: Vascular complications of orthotopic liver transplantation: experience in more than 4,200 patients. Am Coll Surg. 2009;208:896. 3. Starzl TE, Hakala T, Shaw B, et al: A flexible procedure for multiple cadaveric organ procurement. Surg Gynecol Obstet. 1984; 158:223. 4. Höckerstedt K, Calne RY: Liver transplantation. In Harjula A, Höckerstedt K (eds): 1995;, p Recallmed Ltd; 80 5. Caiado AHM, Blasbalg R, Marcelino ASZ, et al: Complications of liver transplantation: multimodality imaging approach. RadioGraphics. 2007;27:1401. 6. Hegenbarth K, Fickert P, Aschauer M, et al: Successful management of acute portal vein thrombosis by low molecular weight heparin and oral anticoagulation. AJG. 2002;97:1567. 7. Sieders E, Peeters PMJG, Vergert EMT, et al: Early vascular complications after pediatric liver transplantation. Liver Transpl. 2000;6:326. 8. Manzanet G, Sanjuan F, Orbis P, et al: Liver transplantation in patients with portal vein thrombosis. Liver Transpl. 2001;7:125. 9. Condat B, Pessione F, Denninger MH, et al: Recent portal or mesenteric venous thrombosis: increased recognition and frequent recanalization on anticoagulant therapy. Hepatology. 2000;32:466. 10. Tachopoulou OA, Vogt DP, Henderson JM, et al: Hepatic abscess after liver transplantation: 1999 –2000. Transplantation. 2003;75:79. 11. Nikeghbalian S, Salahi R, Salahi H, et al: Hepatic abscesses after liver transplantation: 1997–2008. Exp Clin Transplant. 2009; 7:256. 12. Romagnoli R, Patrono D, Mirabella S, et al: Transthoracic open window hepatostomy: a salvage approach to right lobe abscesses after liver transplantation. Liver Transpl. 2009;15:818.