LIVER TRANSPLANTATION 21:1091–1095, 2015
ORIGINAL ARTICLE
Living Donor Liver Transplantation for Echinococcus Alveolaris: Single-Center Experience Fatih Ozdemir, Volkan Ince, Bora Barut, Asim Onur, Cuneyt Kayaalp, and Sezai Yilmaz _ on € u€ University, Malatya, Turkey Liver Transplantation Institute, Department of Surgery, In
Echinococcus alveolaris (EA) causes a hepatic zoonotic infection and behaves like a malignant tumor during invasion. Liver transplantation (LT) is the only curative treatment option for this unresectable disease. Here, we share our experience with living donor liver transplantation (LDLT) due to EA from the time between March 2002 and November 2014 at the Liver _ o €nu € University. Ten patients (mean age, 38.6 years) undergoing LDLT because of unresectable Transplantation Institute of In EA were evaluated preoperatively, and the operative and follow-up data were analyzed retrospectively. The mean time interval between diagnosis and LT was 27 months. The mean operation time and mean intraoperative blood requirement were 613 minutes and 4 units of packed red blood cells, respectively. Diaphragmatic resections were performed in 3 patients, and vena cava replacement was performed in 2 patients because of difficulties in removing the extended disease. The local recurrence and distant metastasis rates were 10% and 20%, respectively. The mean survival time was 19.5 months (range, 0-54 months), and the mortality rate was 30%. Unresectable hepatic alveolar echinococcosis is a rare indication for LT and presents some technical difficulties during surgery because diaphragmatic resection, vascular reconstruction, or multiple blood transfusions may be needed. LDLT can be performed successfully in patients with this rare infectious disease, with careful follow-up for potential recurrence and metastasis and administration of low-dose immunosuppressive agents. Liver C 2015 AASLD. Transpl 21:1091-1095, 2015. V Received January 30, 2015; accepted May 5, 2015.
See Editorial on Page 1013 The larval stage of Echinococcus alveolaris (EA) causes hepatic zoonotic infection and behaves like a malignant tumor during invasion in humans who are accidental intermediate hosts.1 If patients remain untreated after diagnosis, the mortality rate is approximately 90% within 10 years.2,3 The disease invades neighboring structures when it is located primarily in the liver, and distant organ metastasis may occur hematogenously. Early diagnosis and treatment are
the main goals to prevent complications, such as biliary tract infection, liver abscess, bleeding due to portal hypertension (PHT; related to secondary biliary cirrhosis or parasitic involvement of the portal vein), and chronic Budd-Chiari syndrome, in cases of parasitic involvement of the suprahepatic veins. Curative surgery can be performed in only 35% of patients,4 and a liver transplantation (LT) is the only curative treatment option for unresectable liver disease5 (Fig. 1). Here, we share our experience with living donor liver transplantation (LDLT) due to EA from the time between March 2002 and November 2014 at the Liver Transplantation _ o € n€ Institute of In u University.
Abbreviations: EA, Echinococcus alveolaris; ICU, intensive care unit; LDLT, living donor liver transplantation; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; MMF, mycophenolate mofetil; PHT, portal hypertension. Potential conflict of interest: Nothing to report. Financial support: Nothing to report. _ o €nu € University, Elazig Road 15th Address reprint requests to Fatih Ozdemir, M.D., Liver Transplantation Institute, Department of Surgery, In kilometer, Malatya, Turkey 44280. Telephone: 190 422 341 06 60/3701; E-mail: [email protected] DOI 10.1002/lt.24170 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
1092 OZDEMIR ET AL.
LIVER TRANSPLANTATION, August 2015
TABLE 1. Patient Demographic Characteristic Value
Figure 1.
Explanted liver with EA.
PATIENTS AND METHODS In total, 1114 LDLTs were performed at our center between March 2002 and November 2014, and 10 patients (0.9%; 2 females and 8 males; age, mean, 38.6 years; range, 19-61 years) who underwent LDLT due to EA were analyzed retrospectively. The patient’s demographic characteristics are summarized in Table 1. The mean time interval between diagnosis and LT was 27 months (range, 3-108 months). The symptoms at diagnosis were nonspecific upper abdominal pain, jaundice, and fever. The mean patient Model for EndStage Liver Disease (MELD) score was 15 (range, 723). Four patients received interventional procedures before transplantation, including percutaneous biliary drainage and biliary stenting by endoscopic retrograde cholangiography. Four patients had undergone surgery previously, including segmental liver resection for hepatic EA. Six patients received a round of albendazole therapy before LT but were not treated regularly with the drug. One patient had splenic and pulmonary metastases before LDLT and experienced septic biliary complications and liver failure during the evaluation period; thus, we performed palliative LDLT. Our indications for LDLT were extensive liver disease, hilar involvement, recurrent cholangitis, cholestasis, and recurrent disease after surgical resection (Table 2). Staging according to the World Health Organization classification is shown in Table 2.
RESULTS All surgeries performed were LDLTs. Mean operation time was 613 minutes (range, 386-835 minutes), and the mean intraoperative blood requirement was 4 units (range, 0-15 units) of packed red blood cells. Two patients required replacement of the vena cava because of difficulties removing the extended disease. One of these patients had a vascular reconstruction with a cadaveric caval graft, and the other had a vascular reconstruction with a cadaveric aortic graft.6,7 Three patients required diaphragmatic resections
Age, years, mean (range) Sex, female/male MELD score, mean (range) Intraoperative blood requirement, units of packed red blood cells, mean (range) Operation time, minutes, mean (range) Postoperative ICU stay, days, mean (range) Length of hospital stay, days, mean (range) Time interval between diagnosis and transplantation, months, mean (range) Medical therapy before transplantation (albendazole), n (%) Hepatic resection before transplantation, n (%) Interventional procedures before transplantation, n (%) Follow-up, months, median (range) Local recurrence, n (%) Distant metastasis, n (%) Survival time, months, mean (range) Mortality, n (%)
38.6 (19-61) 2/8 15 (7-23) 4 (0-15)
613 (386-835) 4.7 (1-10) 32 (17-94) 27 (3-108)
6 (60)
4 (40) 4 (40)
14.5 (2-54) 1 (10) 2 (20) 19.5 (0-54) 3 (30)
because of diaphragmatic invasion. Five patients had hepatic hilar invasion (Table 2). Findings of the explanted grafts are provided in Table 3. Only 2 patients received a hepaticojejunostomy anastomosis, and the remainder received a duct-to-duct anastomosis to reconstruct the biliary tract. The vascular graft anastomoses had no extraordinary features. All living donors were in good physical condition without any complications.
Follow-Up Data One patient died on postoperative day 1 because of hepatic arterial thrombosis. Another patient, who was receiving oral anticoagulant therapy for mitral valve prolapse, died 6 months postoperatively because of a pulmonary hemorrhage. One patient died suddenly at home 2 months after LDLT. The remaining 7 patients are alive. Median follow-up was 14.5 months (range, 2-54 months). All patients received the same immunosuppressive protocol, consisting of prednisolone, mycophenolate mofetil (MMF), and tacrolimus, from the time of diagnosis. The steroid was discontinued after 3 months, and MMF was discontinued after 6 months. One of the patients, who received a hepaticojejunostomy anastomosis, developed a biliary leak
LIVER TRANSPLANTATION, Vol. 21, No. 8, 2015
OZDEMIR ET AL. 1093
TABLE 2. Patients’ Data, Intraoperative Findings, and PNM Classification Patients,
Distant
Age (years),
Organ
Diaphragma
Hilum
Vena Cava
Cause of LT
Metastasis
Invasion
Invasion
Invasion
PNM
Stage
Extensive disease at the liver, PHT, hilum invasion Extensive disease at the liver, PHT, hilum invasion Liver abscess, cholangitis, PHT
—
—
1
—
P3N0M0
IIIA
—
—
1
—
P3N0M0
IIIA
Lung and splenic metastasis —
—
—
—
P3N0M1
IV
1
1
—
P3N1M0
IIIB
—
1
—
1
P4N1M0
IV
—
—
1
1
P4N1M0
IV
—
—
—
—
P3N0M0
IIIA
—
—
1
—
P3N0M0
IIIA
—
—
—
—
P1N0M0
I
—
1
—
—
P1N1M0
IIIB
Sex 58, male
61, male
19, male
33, male 49, female 21, male
29, male 51, male 37, female 28, male
Hilum invasion, cholangitis Chronic cholestasis, PHT Extensive disease at the liver, hilum invasion Extensive disease at the liver, cholestasis Hilum invasion, cholestasis Extensive disease at the liver Extensive disease at the liver, cholestasis
NOTE: 1, present; —, absent.
TABLE 3. Histopathological Findings of the Explanted Livers Patients, Age (Years),
Weight of the Explanted Liver,
Largest Tumor
Largest Tumor
Grams
Size, cm
Localization
Histological Diagnosis
58, male
2500
17 3 13 3 11
Right lobe
61, male
2000
13 3 8 3 7
Right lobe
19, male
2285
83533
Right lobe
33, male
1490
63434
Right lobe
49, female
2960
19 3 18 3 11
Right lobe
21, male
3746
18 3 16 3 10
Left lobe
29, male
1186
11.5 3 5 3 5
Right lobe
51, male
2106
12.5 3 8.2 3 6
Right lobe
37, female 28, male
3500 1930
21 3 17 3 12 63535
Right lobe Right lobe
Liver parancyme necrosis due to extensive EA Cholestatic liver destruction due to extensive EA Secondary biliary cirrhosis due to extensive EA Cholestatic liver destruction due to extensive EA Cholestatic liver destruction due to extensive EA Cholestatic liver destruction due to extensive EA Cholestatic liver destruction due to extensive EA Cholestatic liver destruction due to extensive EA Nodular cirrhosis Cholestatic liver destruction due to extensive EA
Sex
1094 OZDEMIR ET AL.
from the anastomosis. He was treated by percutaneous internal-external biliary drainage catheterization, which was performed by an interventional radiologist in the first month after LDLT. Another patient developed ascites because of hepatic venous stenosis during postoperative month 11. He was treated by hepatic vein stent replacement. Brain metastasis occurred in 1 patient 2 months after LDLT and was treated surgically. This patient had pulmonary and splenic metastases before LDLT. The same patient was diagnosed with liver allograft reinfection 3 years after LDLT. He is still alive and has been receiving albendazole for the past 3 months. Another patient, who developed a brain metastasis 1 year after LDLT, received albendazole after the diagnosis. The local recurrence, distant metastasis, and mortality rates in our series were 10%, 20%, and 30%, respectively. Mean survival time was 19.5 months (range, 0-54 months; Table 1).
DISCUSSION Hepatic EA is an infectious disease that grows and spreads like a malignant tumor. If curative surgery is not possible in cases of extended disease or because of hilar involvement, the only treatment option is LT. Removing the liver during LT is a major problem in patients with this disease. The long operation times and multiple blood transfusion requirements are the result of technical difficulties related to the extrahepatic extension of the disease (mostly because of the diaphragm but also because of adjacent structures) during surgery.5 We treated 3 patients who required a diaphragmatic resection because of invasion. We also had technical difficulties while removing the liver, and we removed the retrohepatic vena cava with the liver and replaced the vena cava in 2 patients.6,7 A prior surgery can make the operation more complicated. Thus, it is important for future transplant candidates to avoid unnecessary abdominal surgery and to undergo endoscopic or percutaneous radiological interventions for unresectable EA.8 Most of our patients with hepatic EA had advanced disease when diagnosed and had undergone various interventional and surgical procedures before admission to our center. However, their problems persisted. If hepatic EA spreads to the liver hilum, neither an interventional procedure nor medical treatment is adequate to manage the recurrent cholangitis. Patients with extensive disease and recurrent cholangitis require LT. Our series contained only 1 patient with early stage EA, who underwent LT because of concomitant liver failure caused by hepatitis B infection. Bresson-Hadni et al.8 showed that extrahepatic dissemination, medical treatment before and after transplantation for EA, and immunosuppressive therapy are the major factors responsible for recurrence and mortality in patients with EA. One of our patients developed splenic and pulmonary metastases during the LT evaluation period. Bresson-Hadni et al.9 reported that potential recur-
LIVER TRANSPLANTATION, August 2015
rence of the disease, particularly in patients with residual or metastatic EA lesions, should not be considered a contraindication to LT because EA is lethal in the short term. Our patient had septic biliary complications and liver failure at the time of LDLT, so we performed palliative LDLT. Brain metastasis occurred in the same patient 2 months after LDLT and was treated surgically. He is now receiving albendazole for reinfection of the liver allograft, which was diagnosed 3 years after LDLT. Extrahepatic dissemination seems to be the main reason for morbidity and mortality. Benzimidazole derivates, such as mebendazole and albendazole, are the drugs used to treat EA. However, they have a parasitostatic rather than a parasitosidal effect with an overall success rate of 55%-97%.10 Patients must receive long-term benzimidazole therapy to reach these success rates and, occasionally, despite severe side effects and intolerability.11 In addition, an increase in liver enzyme levels can make follow-up difficult after transplantation. Six patients diagnosed with hepatic EA received short-term albendazole therapy before LT in our series. We do not use benzimidazole derivates after curative resection and successful transplantation for hepatic EA unless recurrent disease develops or distant metastasis occurs. Heavy immunosuppressive treatment after LT is related to the possible recurrence of EA.5 Our immunosuppression protocol included prednisolone, tacrolimus, and MMF. We stopped the steroid treatment after 3 months and continued the tacrolimus and MMF. We only administered tacrolimus at the beginning of month 6. Our aim with immunosuppression is to use the minimum levels of these drugs at which they are most effective. It seems important to reduce the immunosuppressive treatment as early as possible in this particular indication for LT.5 Cases of LDLT for EA have only been published as case reports since 1989 (the first LDLT) according to PubMed records.6,7,12-14 We have performed one of the largest LDLT case series due to EA. In conclusion, unresectable hepatic EA is a rare indication for LT. The surgical procedures for this condition are technically complex, including difficult dissections and vascular reconstruction during surgery, such that multiple blood transfusions may be required. In addition, diaphragmatic resection because of disease invasion may be necessary. Cadaveric or artificial vascular grafts should be available for vascular reconstruction during surgery. LDLT can be performed successfully for this rare infectious disease with careful follow-up for potential recurrence and metastasis and administration of low-dose immunosuppressive agents.
REFERENCES 1. Gottstein B. Molecular and immunological diagnosis of echinococcosis. Clin Microbiol Rev 1992;5:248-261. 2. Moreno-Gonz alez E, Loinaz Segurola C, Garcıa Ure~ na MA, Garcıa Garcıa I, G omez Sanz R, Jim enez Romero C, et al. Liver transplantation for Echinococcus granulosis hydatid disease. Transplantation 1994;58: 797-800.
LIVER TRANSPLANTATION, Vol. 21, No. 8, 2015
3. Xia D, Yan LN, Li B, Zeng Y, Cheng NS, Wen TF, et al. Orthotopic liver transplantation for incurable alveolar echinococcosis: report of five cases from west China. Transplant Proc 2005;37:2181-2184. 4. Bresson-Hadni S, Vuitton DA, Bartholomot B, Heyd B, Godart D, Meyer JP, et al. A twenty-year history of alveolar echinococcosis: analysis of a series of 117 patients from eastern France. Eur J Gastroenterol Hepatol 2000; 12:327-336. 5. 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. 6. Mamedov R, Novruzov N, Baskiran A, Yetisir F, Unal B, Aydın C, et al. Living donor liver transplantation with replacement of vena cava for Echinococcus alveolaris: A case report. Int J Surg Case Rep 2014;5:169-171. 7. Yetis¸ir F, Dogan SM, Mamedov R, Kayaalp C, Yilmaz S. Replacement of vena cava up to the right atrium during living donor liver transplantation for Echinococcus alveolaris. Case Rep Transplant 2014;2014:801657. 8. Bresson-Hadni S, Koch S, Miguet JP, Gillet M, Mantion GA, Heyd B, Vuitton DA; for European group of clinicians. Indications and results of liver transplantation
OZDEMIR ET AL. 1095
for Echinococcus alveolar infection: an overview. Langenbecks Arch Surg 2003;388:231-238. 9. Bresson-Hadni S, Blagosklonov O, Knapp J, Grenouillet F, Sako Y, Delabrousse E, et al. Should possible recurrence of disease contraindicate liver transplantation in patients with end-stage alveolar echinococcosis? A 20-year followup study. Liver Transpl 2011;17:855-865. 10. Reuter S, Jensen B, Buttenschoen K, Kratzer W, Kern P. Benzimidazoles in the treatment of alveolar echinococcosis: a comparative study and review of the literature. J Antimicrob Chemother 2000;46:451-456. 11. Reuter S, Buck A, Manfras B, Kratzer W, Seitz HM, Darge K, et al. Structured treatment interruption in patients with alveolar Echinococcosis. Hepatology 2004;39:509-517. 12. Moray G, Shahbazov R, Sevmis S, Karakayali H, Torgay A, Arslan G, et al. Liver transplantation in management of alveolar echinococcosis: two case reports. Transplant Proc 2009;41:2936-2938. 13. Kantarci M, Pirimoglu B, Aydinli B, Ozturk G. A rare reason for liver transplantation: hepatic alveoloar echinococcosis. Transpl Infect Dis 2014;16:450-452. 14. Hatipoglu S, Bulbuloglu B, Piskin T, Kayaalp C, Yilmaz S. Living donor liver transplantation for alveolar echinococcus is a difficult procedure. Transplant Proc 2013;45:1028-1030.
ORIGINAL ARTICLE
Living Donor Liver Transplantation for Echinococcus Alveolaris: Single-Center Experience Fatih Ozdemir, Volkan Ince, Bora Barut, Asim Onur, Cuneyt Kayaalp, and Sezai Yilmaz _ on € u€ University, Malatya, Turkey Liver Transplantation Institute, Department of Surgery, In
Echinococcus alveolaris (EA) causes a hepatic zoonotic infection and behaves like a malignant tumor during invasion. Liver transplantation (LT) is the only curative treatment option for this unresectable disease. Here, we share our experience with living donor liver transplantation (LDLT) due to EA from the time between March 2002 and November 2014 at the Liver _ o €nu € University. Ten patients (mean age, 38.6 years) undergoing LDLT because of unresectable Transplantation Institute of In EA were evaluated preoperatively, and the operative and follow-up data were analyzed retrospectively. The mean time interval between diagnosis and LT was 27 months. The mean operation time and mean intraoperative blood requirement were 613 minutes and 4 units of packed red blood cells, respectively. Diaphragmatic resections were performed in 3 patients, and vena cava replacement was performed in 2 patients because of difficulties in removing the extended disease. The local recurrence and distant metastasis rates were 10% and 20%, respectively. The mean survival time was 19.5 months (range, 0-54 months), and the mortality rate was 30%. Unresectable hepatic alveolar echinococcosis is a rare indication for LT and presents some technical difficulties during surgery because diaphragmatic resection, vascular reconstruction, or multiple blood transfusions may be needed. LDLT can be performed successfully in patients with this rare infectious disease, with careful follow-up for potential recurrence and metastasis and administration of low-dose immunosuppressive agents. Liver C 2015 AASLD. Transpl 21:1091-1095, 2015. V Received January 30, 2015; accepted May 5, 2015.
See Editorial on Page 1013 The larval stage of Echinococcus alveolaris (EA) causes hepatic zoonotic infection and behaves like a malignant tumor during invasion in humans who are accidental intermediate hosts.1 If patients remain untreated after diagnosis, the mortality rate is approximately 90% within 10 years.2,3 The disease invades neighboring structures when it is located primarily in the liver, and distant organ metastasis may occur hematogenously. Early diagnosis and treatment are
the main goals to prevent complications, such as biliary tract infection, liver abscess, bleeding due to portal hypertension (PHT; related to secondary biliary cirrhosis or parasitic involvement of the portal vein), and chronic Budd-Chiari syndrome, in cases of parasitic involvement of the suprahepatic veins. Curative surgery can be performed in only 35% of patients,4 and a liver transplantation (LT) is the only curative treatment option for unresectable liver disease5 (Fig. 1). Here, we share our experience with living donor liver transplantation (LDLT) due to EA from the time between March 2002 and November 2014 at the Liver Transplantation _ o € n€ Institute of In u University.
Abbreviations: EA, Echinococcus alveolaris; ICU, intensive care unit; LDLT, living donor liver transplantation; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; MMF, mycophenolate mofetil; PHT, portal hypertension. Potential conflict of interest: Nothing to report. Financial support: Nothing to report. _ o €nu € University, Elazig Road 15th Address reprint requests to Fatih Ozdemir, M.D., Liver Transplantation Institute, Department of Surgery, In kilometer, Malatya, Turkey 44280. Telephone: 190 422 341 06 60/3701; E-mail: [email protected] DOI 10.1002/lt.24170 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
1092 OZDEMIR ET AL.
LIVER TRANSPLANTATION, August 2015
TABLE 1. Patient Demographic Characteristic Value
Figure 1.
Explanted liver with EA.
PATIENTS AND METHODS In total, 1114 LDLTs were performed at our center between March 2002 and November 2014, and 10 patients (0.9%; 2 females and 8 males; age, mean, 38.6 years; range, 19-61 years) who underwent LDLT due to EA were analyzed retrospectively. The patient’s demographic characteristics are summarized in Table 1. The mean time interval between diagnosis and LT was 27 months (range, 3-108 months). The symptoms at diagnosis were nonspecific upper abdominal pain, jaundice, and fever. The mean patient Model for EndStage Liver Disease (MELD) score was 15 (range, 723). Four patients received interventional procedures before transplantation, including percutaneous biliary drainage and biliary stenting by endoscopic retrograde cholangiography. Four patients had undergone surgery previously, including segmental liver resection for hepatic EA. Six patients received a round of albendazole therapy before LT but were not treated regularly with the drug. One patient had splenic and pulmonary metastases before LDLT and experienced septic biliary complications and liver failure during the evaluation period; thus, we performed palliative LDLT. Our indications for LDLT were extensive liver disease, hilar involvement, recurrent cholangitis, cholestasis, and recurrent disease after surgical resection (Table 2). Staging according to the World Health Organization classification is shown in Table 2.
RESULTS All surgeries performed were LDLTs. Mean operation time was 613 minutes (range, 386-835 minutes), and the mean intraoperative blood requirement was 4 units (range, 0-15 units) of packed red blood cells. Two patients required replacement of the vena cava because of difficulties removing the extended disease. One of these patients had a vascular reconstruction with a cadaveric caval graft, and the other had a vascular reconstruction with a cadaveric aortic graft.6,7 Three patients required diaphragmatic resections
Age, years, mean (range) Sex, female/male MELD score, mean (range) Intraoperative blood requirement, units of packed red blood cells, mean (range) Operation time, minutes, mean (range) Postoperative ICU stay, days, mean (range) Length of hospital stay, days, mean (range) Time interval between diagnosis and transplantation, months, mean (range) Medical therapy before transplantation (albendazole), n (%) Hepatic resection before transplantation, n (%) Interventional procedures before transplantation, n (%) Follow-up, months, median (range) Local recurrence, n (%) Distant metastasis, n (%) Survival time, months, mean (range) Mortality, n (%)
38.6 (19-61) 2/8 15 (7-23) 4 (0-15)
613 (386-835) 4.7 (1-10) 32 (17-94) 27 (3-108)
6 (60)
4 (40) 4 (40)
14.5 (2-54) 1 (10) 2 (20) 19.5 (0-54) 3 (30)
because of diaphragmatic invasion. Five patients had hepatic hilar invasion (Table 2). Findings of the explanted grafts are provided in Table 3. Only 2 patients received a hepaticojejunostomy anastomosis, and the remainder received a duct-to-duct anastomosis to reconstruct the biliary tract. The vascular graft anastomoses had no extraordinary features. All living donors were in good physical condition without any complications.
Follow-Up Data One patient died on postoperative day 1 because of hepatic arterial thrombosis. Another patient, who was receiving oral anticoagulant therapy for mitral valve prolapse, died 6 months postoperatively because of a pulmonary hemorrhage. One patient died suddenly at home 2 months after LDLT. The remaining 7 patients are alive. Median follow-up was 14.5 months (range, 2-54 months). All patients received the same immunosuppressive protocol, consisting of prednisolone, mycophenolate mofetil (MMF), and tacrolimus, from the time of diagnosis. The steroid was discontinued after 3 months, and MMF was discontinued after 6 months. One of the patients, who received a hepaticojejunostomy anastomosis, developed a biliary leak
LIVER TRANSPLANTATION, Vol. 21, No. 8, 2015
OZDEMIR ET AL. 1093
TABLE 2. Patients’ Data, Intraoperative Findings, and PNM Classification Patients,
Distant
Age (years),
Organ
Diaphragma
Hilum
Vena Cava
Cause of LT
Metastasis
Invasion
Invasion
Invasion
PNM
Stage
Extensive disease at the liver, PHT, hilum invasion Extensive disease at the liver, PHT, hilum invasion Liver abscess, cholangitis, PHT
—
—
1
—
P3N0M0
IIIA
—
—
1
—
P3N0M0
IIIA
Lung and splenic metastasis —
—
—
—
P3N0M1
IV
1
1
—
P3N1M0
IIIB
—
1
—
1
P4N1M0
IV
—
—
1
1
P4N1M0
IV
—
—
—
—
P3N0M0
IIIA
—
—
1
—
P3N0M0
IIIA
—
—
—
—
P1N0M0
I
—
1
—
—
P1N1M0
IIIB
Sex 58, male
61, male
19, male
33, male 49, female 21, male
29, male 51, male 37, female 28, male
Hilum invasion, cholangitis Chronic cholestasis, PHT Extensive disease at the liver, hilum invasion Extensive disease at the liver, cholestasis Hilum invasion, cholestasis Extensive disease at the liver Extensive disease at the liver, cholestasis
NOTE: 1, present; —, absent.
TABLE 3. Histopathological Findings of the Explanted Livers Patients, Age (Years),
Weight of the Explanted Liver,
Largest Tumor
Largest Tumor
Grams
Size, cm
Localization
Histological Diagnosis
58, male
2500
17 3 13 3 11
Right lobe
61, male
2000
13 3 8 3 7
Right lobe
19, male
2285
83533
Right lobe
33, male
1490
63434
Right lobe
49, female
2960
19 3 18 3 11
Right lobe
21, male
3746
18 3 16 3 10
Left lobe
29, male
1186
11.5 3 5 3 5
Right lobe
51, male
2106
12.5 3 8.2 3 6
Right lobe
37, female 28, male
3500 1930
21 3 17 3 12 63535
Right lobe Right lobe
Liver parancyme necrosis due to extensive EA Cholestatic liver destruction due to extensive EA Secondary biliary cirrhosis due to extensive EA Cholestatic liver destruction due to extensive EA Cholestatic liver destruction due to extensive EA Cholestatic liver destruction due to extensive EA Cholestatic liver destruction due to extensive EA Cholestatic liver destruction due to extensive EA Nodular cirrhosis Cholestatic liver destruction due to extensive EA
Sex
1094 OZDEMIR ET AL.
from the anastomosis. He was treated by percutaneous internal-external biliary drainage catheterization, which was performed by an interventional radiologist in the first month after LDLT. Another patient developed ascites because of hepatic venous stenosis during postoperative month 11. He was treated by hepatic vein stent replacement. Brain metastasis occurred in 1 patient 2 months after LDLT and was treated surgically. This patient had pulmonary and splenic metastases before LDLT. The same patient was diagnosed with liver allograft reinfection 3 years after LDLT. He is still alive and has been receiving albendazole for the past 3 months. Another patient, who developed a brain metastasis 1 year after LDLT, received albendazole after the diagnosis. The local recurrence, distant metastasis, and mortality rates in our series were 10%, 20%, and 30%, respectively. Mean survival time was 19.5 months (range, 0-54 months; Table 1).
DISCUSSION Hepatic EA is an infectious disease that grows and spreads like a malignant tumor. If curative surgery is not possible in cases of extended disease or because of hilar involvement, the only treatment option is LT. Removing the liver during LT is a major problem in patients with this disease. The long operation times and multiple blood transfusion requirements are the result of technical difficulties related to the extrahepatic extension of the disease (mostly because of the diaphragm but also because of adjacent structures) during surgery.5 We treated 3 patients who required a diaphragmatic resection because of invasion. We also had technical difficulties while removing the liver, and we removed the retrohepatic vena cava with the liver and replaced the vena cava in 2 patients.6,7 A prior surgery can make the operation more complicated. Thus, it is important for future transplant candidates to avoid unnecessary abdominal surgery and to undergo endoscopic or percutaneous radiological interventions for unresectable EA.8 Most of our patients with hepatic EA had advanced disease when diagnosed and had undergone various interventional and surgical procedures before admission to our center. However, their problems persisted. If hepatic EA spreads to the liver hilum, neither an interventional procedure nor medical treatment is adequate to manage the recurrent cholangitis. Patients with extensive disease and recurrent cholangitis require LT. Our series contained only 1 patient with early stage EA, who underwent LT because of concomitant liver failure caused by hepatitis B infection. Bresson-Hadni et al.8 showed that extrahepatic dissemination, medical treatment before and after transplantation for EA, and immunosuppressive therapy are the major factors responsible for recurrence and mortality in patients with EA. One of our patients developed splenic and pulmonary metastases during the LT evaluation period. Bresson-Hadni et al.9 reported that potential recur-
LIVER TRANSPLANTATION, August 2015
rence of the disease, particularly in patients with residual or metastatic EA lesions, should not be considered a contraindication to LT because EA is lethal in the short term. Our patient had septic biliary complications and liver failure at the time of LDLT, so we performed palliative LDLT. Brain metastasis occurred in the same patient 2 months after LDLT and was treated surgically. He is now receiving albendazole for reinfection of the liver allograft, which was diagnosed 3 years after LDLT. Extrahepatic dissemination seems to be the main reason for morbidity and mortality. Benzimidazole derivates, such as mebendazole and albendazole, are the drugs used to treat EA. However, they have a parasitostatic rather than a parasitosidal effect with an overall success rate of 55%-97%.10 Patients must receive long-term benzimidazole therapy to reach these success rates and, occasionally, despite severe side effects and intolerability.11 In addition, an increase in liver enzyme levels can make follow-up difficult after transplantation. Six patients diagnosed with hepatic EA received short-term albendazole therapy before LT in our series. We do not use benzimidazole derivates after curative resection and successful transplantation for hepatic EA unless recurrent disease develops or distant metastasis occurs. Heavy immunosuppressive treatment after LT is related to the possible recurrence of EA.5 Our immunosuppression protocol included prednisolone, tacrolimus, and MMF. We stopped the steroid treatment after 3 months and continued the tacrolimus and MMF. We only administered tacrolimus at the beginning of month 6. Our aim with immunosuppression is to use the minimum levels of these drugs at which they are most effective. It seems important to reduce the immunosuppressive treatment as early as possible in this particular indication for LT.5 Cases of LDLT for EA have only been published as case reports since 1989 (the first LDLT) according to PubMed records.6,7,12-14 We have performed one of the largest LDLT case series due to EA. In conclusion, unresectable hepatic EA is a rare indication for LT. The surgical procedures for this condition are technically complex, including difficult dissections and vascular reconstruction during surgery, such that multiple blood transfusions may be required. In addition, diaphragmatic resection because of disease invasion may be necessary. Cadaveric or artificial vascular grafts should be available for vascular reconstruction during surgery. LDLT can be performed successfully for this rare infectious disease with careful follow-up for potential recurrence and metastasis and administration of low-dose immunosuppressive agents.
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3. Xia D, Yan LN, Li B, Zeng Y, Cheng NS, Wen TF, et al. Orthotopic liver transplantation for incurable alveolar echinococcosis: report of five cases from west China. Transplant Proc 2005;37:2181-2184. 4. Bresson-Hadni S, Vuitton DA, Bartholomot B, Heyd B, Godart D, Meyer JP, et al. A twenty-year history of alveolar echinococcosis: analysis of a series of 117 patients from eastern France. Eur J Gastroenterol Hepatol 2000; 12:327-336. 5. 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. 6. Mamedov R, Novruzov N, Baskiran A, Yetisir F, Unal B, Aydın C, et al. Living donor liver transplantation with replacement of vena cava for Echinococcus alveolaris: A case report. Int J Surg Case Rep 2014;5:169-171. 7. Yetis¸ir F, Dogan SM, Mamedov R, Kayaalp C, Yilmaz S. Replacement of vena cava up to the right atrium during living donor liver transplantation for Echinococcus alveolaris. Case Rep Transplant 2014;2014:801657. 8. Bresson-Hadni S, Koch S, Miguet JP, Gillet M, Mantion GA, Heyd B, Vuitton DA; for European group of clinicians. Indications and results of liver transplantation
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