LIVER TRANSPLANTATION 21:1013–1015, 2015
EDITORIAL
Liver Transplantation for Alveolar Echinococcosis: Acceptable When Necessary But Is It Preventable? Jonathan Hand and Shirish Huprikar Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
See Articles on Pages 1091 and 1096 The global incidence of human alveolar echinococcosis (AE) is increasing likely as a result of ecological and social changes.1 Echinococcus multilocularis, the zoonotic parasite that causes AE, is endemic to parts of Central and Western Europe, the Middle East, Western China, Russia, and isolated areas of North America. Although foxes are considered the definitive host, domestic animals including dogs and cats also play a role in human infectivity through direct or indirect transfer of Echinococcus multilocularis eggs.1 AE is usually a chronic, asymptomatic infection with primary hepatic involvement after an incubation period of 5 to 15 years. However, it may also progress to a severe, multiorgan invasive disease involving the spleen, lungs, and brain with a mortality rate of 75% to 90% at 10 to 15 years if untreated.1,2 Lifethreatening hepatobiliary complications of AE include biliary stricture and recurrent cholangitis from hilar invasion, secondary biliary cirrhosis, gastrointestinal bleeding from portal hypertension, liver abscesses, acute inferior vena cava thrombosis, and Budd-Chiari syndrome.3 Early surgical resection of hepatic lesions is the keystone of management and may also be required for other affected organs. Existing recommendations for medical treatment of AE are low strength and based on poor quality evidence without accompanying large, controlled trials.2 The benzimidazoles, albendazole and mebendazole, are the drugs of choice for adjunctive therapy with surgical resection, and they are associated
with increased 10-year survival.2 Adjunctive benzimidazole therapy is recommended for 2 years after radical resection of AE lesions with longer, potentially lifelong, courses needed for unresectable disease.2 Given the devastating complications of AE and limited therapeutic options, liver transplantation (LT) emerged as curative and often palliative treatment in the 1980s. A case series with more than 11 years of follow-up provides insight into the long-term management and complications of patients undergoing LT in an endemic area of France.4 Although LT is presented as a legitimate option, the significant procedural complexity and high risk of recurrence despite LT suggest that the decision to proceed to LT should be carefully considered. The largest multicenter series of 45 cases of AE treated with LT from 65 European centers demonstrated a 5-year survival rate of 71%, but transplant was curative in only 50% of cases.3 In this issue of Liver Transplantation, 2 retrospective case series of AE from Turkey add to our existing knowledge of LT for AE.5,6 Both demonstrate significant survival and suggest LT as a reasonable treatment for AE involving the liver. The experience presented by Aydinli et al.5 is the largest reported single-center study and describes the clinical characteristics and outcomes of LT for AE in 27 patients. A majority of the patients underwent living donor liver transplantation (LDLT), and the overall survival was 80% after mean follow-up of 16.1 months. Two patients required urgent deceased donor LT after LDLT because of primary nonfunction. No local AE recurrence was detected, but 1 patient developed cerebral AE recurrence approximately 1 year after LT. No deaths were attributed to recurrent AE. However, the study demonstrated that invasion of the
Abbreviations: AE, alveolar echinococcosis; LDLT, living donor liver transplantation; LT, liver transplantation; WHO, World Health Organization. Address reprint requests to Shirish Huprikar, Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1090, NY 10029. Telephone: 212-241-6885; FAX: 212-534-3240; E-mail: [email protected] DOI 10.1002/lt.24197 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases C 2015 American Association for the Study of Liver Diseases. V
1014
bile duct or portal vein was associated with mortality, a finding that clinicians may consider when assessing the risks and benefits of LT for AE. In the report by Ozdemir et al.,6 10 patients underwent LDLT for AE with 70% survival after a median of 14.5 months. In contrast to the other study, local recurrence was described in 1 patient and distant metastatic lesions were described in 2 patients. The survival rates described in these studies are slightly lower but comparable to the 80% 1-year survival for LDLT recipients for all indications reported by the European Liver Transplant Registry.7 In the context of the significant morbidity and mortality caused by AE and the expected outcomes without intervention, these outcomes are acceptable. The LT procedure can be extensive and technically challenging as highlighted in both case series. These patients frequently had multiple prior abdominal surgical procedures. Additionally, intra-abdominal AE lesions are complex and may involve the diaphragm, surrounding intra-abdominal vessels, and hilar structures requiring complex resections and anastomoses.3 The favorable posttransplant outcomes described in these studies are a testament to the technical skill of the surgeons and the experience of the multidisciplinary transplant teams that provided specialized care to patients with AE. The metastatic complications of AE contribute significantly to morbidity and mortality and may be exacerbated by posttransplant immunosuppression.2 Although metastatic disease has been considered a contraindication to LT by the World Health Organization (WHO), some experts advocate that only brain involvement is an absolute contraindication.2,3 In these case series, the only patient with pretransplant metastatic lesions developed posttransplant cerebral metastasis. He was treated surgically and developed allograft reinfection 3 years later but was still alive. Notably at this center, routine posttransplant benzimidazole therapy is not given after resection or transplantation unless AE recurrence is discovered. Future studies should compare this preemptive approach with the recommended 2-year course of benzimidazole therapy after LT and assess for the risk of recurrent local or metastatic disease. The initial experience with LT for AE was reported from Besanc¸on, France in the 1980s.4 Subsequently, intensive screening with echinococcal serology and abdominal ultrasound was implemented which led to early diagnosis and surgical resection of AE lesions.8 In 1991, the group performed their last LT for AE for at least 9 years and attributed the decrease to the robust screening program.4 The studies in this issue are from the highly endemic Eastern Anatolia region of Turkey. Although neither study describes screening practices in their region, AE screening and reporting in Turkey may be inadequate.9 However, this may improve because E. multilocularis infection has become a mandatory reportable disease to the Turkish Ministry of Health.9 Given the severity of AE disease and the incomplete knowledge of the epidemiology, transmission, and life cycle of E. multilocularis as well as a lack of detailed assessments of human infection, the EurEchinoReg
LIVER TRANSPLANTATION, August 2015
project began collaborative surveillance for AE in 11 European countries in 1998. Around this time the WHO–Collaborating Center for Prevention and Treatment of Human Echinococcosis was also established in Besanc¸on, France.10 Although surveillance throughout Europe has been inconsistent,10 the FrancEchino registry in France has meticulously recorded all AE cases and has reported the highest number of well-documented cases over the past 3 decades. Using an advanced multidisciplinary approach including participating French hospitals, pharmacies dispensing albendazole, and pathology and parasitology specialists, there have been significant improvements in diagnosis and management of these patients in France.10 Additionally the FrancEchino network is developing a new, comprehensive information system for more dynamic surveillance.10 In summary, LT for AE is relatively rare and considered as a last resort to treat incurable disease or lifethreatening complications. These 2 studies in this issue demonstrate good outcomes associated with LT for AE and highlight the surgical skill and multidisciplinary care that is essential to manage these complex patients. They also highlight the need for further investigations to explore the appropriate use of posttransplant benzimidazole therapy and the risk factors for posttransplant recurrence. Perhaps the most significant factor to consider in limiting the morbidity and mortality associated with AE is the need for a concerted international effort to optimize screening practices in endemic areas as recommended by the WHO.3 The French experience provides hope that farreaching screening initiatives and potentially dynamic surveillance information systems can be implemented in all endemic regions and significantly reduce the morbidity and mortality associated with AE. The ultimate goal should be to prevent the need for LT in the management of AE.
REFERENCES 1. Moro P, Schantz PM. Echinococcosis: a review. Int J Infect Dis 2009;13:125-133. 2. Brunetti E, Kern P, Vuitton DA; for Writing Panel for the WHO-IWGE. Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans. Acta Trop 2010;114:1-16. 3. Koch S, Bresson-Hadni S, Miguet JP, Crumbach JP, Gillet M, Mantion GA, et al.; for European Collaborating Clinicians. Experience of liver transplantation for incurable alveolar echinococcosis: a 45-case European collaborative report. Transplantation 2003;75:856-863. 4. Bresson-Hadni S, Koch S, Beurton I, Vuitton DA, Bartholomot B, Hrusovsky S, et al. Primary disease recurrence after liver transplantation for alveolar echinococcosis: long-term evaluation in 15 patients. Hepatology 1999;30:857-864. 5. Aydinli B, Ozturk G, Arslan S, Kantarci M, Tan O, Ahıskalioglu A, et al. Liver transplantation for alveolar echinococcosis in an endemic region. Liver Transpl 2015; doi: 10.1002/lt.24195. 6. Ozdemir F, Ince V, Barut B, Onur A, Kayaalp C, Yılmaz S. Living donor liver transplantation for Echinococcus Alveolaris: single-center experience. Liver Transpl 2015; doi: 10.1002/lt.24170.
LIVER TRANSPLANTATION, Vol. 21, No. 8, 2015
7. Adam R, Karam V, Delvart V, O’Grady J, Mirza D, Klempnauer J, et al.; for all contributing centers (www.eltr. org) and European Liver and Intestine Transplant Association (ELITA). Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR). J Hepatol 2012;57:675-688. 8. Bresson-Hadni S, Laplante JJ, Lenys D, Rohmer P, Gottstein B, Jacquier P, et al. Seroepidemiologic screening of Echinococcus multilocularis infection in a
1015
European area endemic for alveolar echinococcosis. Am J Trop Med Hyg 1994;51:837-846. 9. Altintas N. Parasitic zoonotic diseases in Turkey. Vet Ital 2008;44:633-646. 10. Charbonnier A, Knapp J, Demonmerot F, BressonHadni S, Raoul F, Grenouillet F, et al. A new data management system for the French National Registry of human alveolar echinococcosis cases. Parasite 2014;21: 69.
EDITORIAL
Liver Transplantation for Alveolar Echinococcosis: Acceptable When Necessary But Is It Preventable? Jonathan Hand and Shirish Huprikar Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
See Articles on Pages 1091 and 1096 The global incidence of human alveolar echinococcosis (AE) is increasing likely as a result of ecological and social changes.1 Echinococcus multilocularis, the zoonotic parasite that causes AE, is endemic to parts of Central and Western Europe, the Middle East, Western China, Russia, and isolated areas of North America. Although foxes are considered the definitive host, domestic animals including dogs and cats also play a role in human infectivity through direct or indirect transfer of Echinococcus multilocularis eggs.1 AE is usually a chronic, asymptomatic infection with primary hepatic involvement after an incubation period of 5 to 15 years. However, it may also progress to a severe, multiorgan invasive disease involving the spleen, lungs, and brain with a mortality rate of 75% to 90% at 10 to 15 years if untreated.1,2 Lifethreatening hepatobiliary complications of AE include biliary stricture and recurrent cholangitis from hilar invasion, secondary biliary cirrhosis, gastrointestinal bleeding from portal hypertension, liver abscesses, acute inferior vena cava thrombosis, and Budd-Chiari syndrome.3 Early surgical resection of hepatic lesions is the keystone of management and may also be required for other affected organs. Existing recommendations for medical treatment of AE are low strength and based on poor quality evidence without accompanying large, controlled trials.2 The benzimidazoles, albendazole and mebendazole, are the drugs of choice for adjunctive therapy with surgical resection, and they are associated
with increased 10-year survival.2 Adjunctive benzimidazole therapy is recommended for 2 years after radical resection of AE lesions with longer, potentially lifelong, courses needed for unresectable disease.2 Given the devastating complications of AE and limited therapeutic options, liver transplantation (LT) emerged as curative and often palliative treatment in the 1980s. A case series with more than 11 years of follow-up provides insight into the long-term management and complications of patients undergoing LT in an endemic area of France.4 Although LT is presented as a legitimate option, the significant procedural complexity and high risk of recurrence despite LT suggest that the decision to proceed to LT should be carefully considered. The largest multicenter series of 45 cases of AE treated with LT from 65 European centers demonstrated a 5-year survival rate of 71%, but transplant was curative in only 50% of cases.3 In this issue of Liver Transplantation, 2 retrospective case series of AE from Turkey add to our existing knowledge of LT for AE.5,6 Both demonstrate significant survival and suggest LT as a reasonable treatment for AE involving the liver. The experience presented by Aydinli et al.5 is the largest reported single-center study and describes the clinical characteristics and outcomes of LT for AE in 27 patients. A majority of the patients underwent living donor liver transplantation (LDLT), and the overall survival was 80% after mean follow-up of 16.1 months. Two patients required urgent deceased donor LT after LDLT because of primary nonfunction. No local AE recurrence was detected, but 1 patient developed cerebral AE recurrence approximately 1 year after LT. No deaths were attributed to recurrent AE. However, the study demonstrated that invasion of the
Abbreviations: AE, alveolar echinococcosis; LDLT, living donor liver transplantation; LT, liver transplantation; WHO, World Health Organization. Address reprint requests to Shirish Huprikar, Department of Medicine, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1090, NY 10029. Telephone: 212-241-6885; FAX: 212-534-3240; E-mail: [email protected] DOI 10.1002/lt.24197 View this article online at wileyonlinelibrary.com. LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases C 2015 American Association for the Study of Liver Diseases. V
1014
bile duct or portal vein was associated with mortality, a finding that clinicians may consider when assessing the risks and benefits of LT for AE. In the report by Ozdemir et al.,6 10 patients underwent LDLT for AE with 70% survival after a median of 14.5 months. In contrast to the other study, local recurrence was described in 1 patient and distant metastatic lesions were described in 2 patients. The survival rates described in these studies are slightly lower but comparable to the 80% 1-year survival for LDLT recipients for all indications reported by the European Liver Transplant Registry.7 In the context of the significant morbidity and mortality caused by AE and the expected outcomes without intervention, these outcomes are acceptable. The LT procedure can be extensive and technically challenging as highlighted in both case series. These patients frequently had multiple prior abdominal surgical procedures. Additionally, intra-abdominal AE lesions are complex and may involve the diaphragm, surrounding intra-abdominal vessels, and hilar structures requiring complex resections and anastomoses.3 The favorable posttransplant outcomes described in these studies are a testament to the technical skill of the surgeons and the experience of the multidisciplinary transplant teams that provided specialized care to patients with AE. The metastatic complications of AE contribute significantly to morbidity and mortality and may be exacerbated by posttransplant immunosuppression.2 Although metastatic disease has been considered a contraindication to LT by the World Health Organization (WHO), some experts advocate that only brain involvement is an absolute contraindication.2,3 In these case series, the only patient with pretransplant metastatic lesions developed posttransplant cerebral metastasis. He was treated surgically and developed allograft reinfection 3 years later but was still alive. Notably at this center, routine posttransplant benzimidazole therapy is not given after resection or transplantation unless AE recurrence is discovered. Future studies should compare this preemptive approach with the recommended 2-year course of benzimidazole therapy after LT and assess for the risk of recurrent local or metastatic disease. The initial experience with LT for AE was reported from Besanc¸on, France in the 1980s.4 Subsequently, intensive screening with echinococcal serology and abdominal ultrasound was implemented which led to early diagnosis and surgical resection of AE lesions.8 In 1991, the group performed their last LT for AE for at least 9 years and attributed the decrease to the robust screening program.4 The studies in this issue are from the highly endemic Eastern Anatolia region of Turkey. Although neither study describes screening practices in their region, AE screening and reporting in Turkey may be inadequate.9 However, this may improve because E. multilocularis infection has become a mandatory reportable disease to the Turkish Ministry of Health.9 Given the severity of AE disease and the incomplete knowledge of the epidemiology, transmission, and life cycle of E. multilocularis as well as a lack of detailed assessments of human infection, the EurEchinoReg
LIVER TRANSPLANTATION, August 2015
project began collaborative surveillance for AE in 11 European countries in 1998. Around this time the WHO–Collaborating Center for Prevention and Treatment of Human Echinococcosis was also established in Besanc¸on, France.10 Although surveillance throughout Europe has been inconsistent,10 the FrancEchino registry in France has meticulously recorded all AE cases and has reported the highest number of well-documented cases over the past 3 decades. Using an advanced multidisciplinary approach including participating French hospitals, pharmacies dispensing albendazole, and pathology and parasitology specialists, there have been significant improvements in diagnosis and management of these patients in France.10 Additionally the FrancEchino network is developing a new, comprehensive information system for more dynamic surveillance.10 In summary, LT for AE is relatively rare and considered as a last resort to treat incurable disease or lifethreatening complications. These 2 studies in this issue demonstrate good outcomes associated with LT for AE and highlight the surgical skill and multidisciplinary care that is essential to manage these complex patients. They also highlight the need for further investigations to explore the appropriate use of posttransplant benzimidazole therapy and the risk factors for posttransplant recurrence. Perhaps the most significant factor to consider in limiting the morbidity and mortality associated with AE is the need for a concerted international effort to optimize screening practices in endemic areas as recommended by the WHO.3 The French experience provides hope that farreaching screening initiatives and potentially dynamic surveillance information systems can be implemented in all endemic regions and significantly reduce the morbidity and mortality associated with AE. The ultimate goal should be to prevent the need for LT in the management of AE.
REFERENCES 1. Moro P, Schantz PM. Echinococcosis: a review. Int J Infect Dis 2009;13:125-133. 2. Brunetti E, Kern P, Vuitton DA; for Writing Panel for the WHO-IWGE. Expert consensus for the diagnosis and treatment of cystic and alveolar echinococcosis in humans. Acta Trop 2010;114:1-16. 3. Koch S, Bresson-Hadni S, Miguet JP, Crumbach JP, Gillet M, Mantion GA, et al.; for European Collaborating Clinicians. Experience of liver transplantation for incurable alveolar echinococcosis: a 45-case European collaborative report. Transplantation 2003;75:856-863. 4. Bresson-Hadni S, Koch S, Beurton I, Vuitton DA, Bartholomot B, Hrusovsky S, et al. Primary disease recurrence after liver transplantation for alveolar echinococcosis: long-term evaluation in 15 patients. Hepatology 1999;30:857-864. 5. Aydinli B, Ozturk G, Arslan S, Kantarci M, Tan O, Ahıskalioglu A, et al. Liver transplantation for alveolar echinococcosis in an endemic region. Liver Transpl 2015; doi: 10.1002/lt.24195. 6. Ozdemir F, Ince V, Barut B, Onur A, Kayaalp C, Yılmaz S. Living donor liver transplantation for Echinococcus Alveolaris: single-center experience. Liver Transpl 2015; doi: 10.1002/lt.24170.
LIVER TRANSPLANTATION, Vol. 21, No. 8, 2015
7. Adam R, Karam V, Delvart V, O’Grady J, Mirza D, Klempnauer J, et al.; for all contributing centers (www.eltr. org) and European Liver and Intestine Transplant Association (ELITA). Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR). J Hepatol 2012;57:675-688. 8. Bresson-Hadni S, Laplante JJ, Lenys D, Rohmer P, Gottstein B, Jacquier P, et al. Seroepidemiologic screening of Echinococcus multilocularis infection in a
1015
European area endemic for alveolar echinococcosis. Am J Trop Med Hyg 1994;51:837-846. 9. Altintas N. Parasitic zoonotic diseases in Turkey. Vet Ital 2008;44:633-646. 10. Charbonnier A, Knapp J, Demonmerot F, BressonHadni S, Raoul F, Grenouillet F, et al. A new data management system for the French National Registry of human alveolar echinococcosis cases. Parasite 2014;21: 69.
