ORIGINAL ARTICLE: HEPATOLOGY
AND
NUTRITION
US-Guided Percutaneous Liver Biopsy in Pediatric Liver Transplant Recipients
Soma Mandal, yRoberto Miraglia, yLuigi Maruzzelli, yRosa Liotta, zFabio Tuzzolino, § Marco Spada, jjSilvia Riva, and yAngelo Luca
ABSTRACT Objectives: The present study assesses the safety of ultrasound (US)-guided percutaneous liver biopsies (PLBs) within pediatric liver allograft recipients, describes the pathological results according to early (12 months) and late (>12 months) posttransplantation periods, and analyzes the value of liver function tests (LFTs) and Doppler US variables in determining these results. Methods: A total of 219 US-guided PLBs in 85 pediatric patients with liver transplant (mean age 7 5 years, range: 6 months to 18 years) performed between March 2005 and May 2012 were retrospectively evaluated at a single institution. Doppler US and LFT evaluation (including total bilirubin, alanine aminotransferase, aspartate aminotransferase, g-glutamyl transferase, alkaline phosphatase) occurred within 1 day of early (n ¼ 92, 42%) and late term (n ¼ 127, 58%) posttransplantation biopsies. Results: The rate of major complications (hemorrhage requiring blood transfusion) was 0.91% (n ¼ 2). The early versus late term biopsy results, respectively, included: cholestasis at 36% versus 18% (P ¼ 0.003), minimal changes 16% versus 24% (not significant [NS]), acute rejection 13% versus 5% (P ¼ 0.027), inflammatory diseases 15% versus 15% (NS), indeterminate acute rejection 11% versus 7% (NS), chronic rejection 4% versus 14% (P ¼ 0.017), fibrotic diseases 4% versus 12% (NS), and other 0% versus 5% (NS). Neither LFT nor US variables were correlated with pathological outcomes. Conclusions: The rate of complications in pediatric patients after US-guided liver biopsy is low. A range of pathological results exists between early and late posttransplantation liver biopsies. LFT and Doppler US findings are not predictors of pathological results. Key Words: acute rejection, chronic rejection, pediatric liver transplantation, percutaneous liver biopsy, ultrasound guidance
(JPGN 2014;58: 756–761)
T
he use of ultrasound (US)-guided percutaneous liver biopsies (PLBs) in pediatric liver transplant recipients is routinely motivated by the possibility of allograft dysfunction, specifically
Received and accepted January 30, 2014. From the Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, yDiagnostic and Therapeutic Services, the zDepartment of Information Technology, §Transplantation Surgery, and jjPediatric Hepatology, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IsMeTT), Palermo, Italy. Address correspondence and reprint requests to Roberto Miraglia, Diagnostic and Therapeutic Services, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IsMeTT), Via Tricomi 1, Palermo 90127, Italy (e-mail: [email protected]). The authors report no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000328
rejection and infection. Acute rejection occurs at a rate of 20% to 40% in patients within 1 month postoperatively (1), whereas there is a 2% rate of chronic rejection with all liver allografts (1). Although it is logical to monitor graft function shortly after transplantation, US-guided PLBs during the later stages (eg, after 12 months) of the posttransplant period are questionable because of the risks the procedure carries, with reported complications ranging from 2.8% to 9.2% in children (2–5). Because of the invasive nature of US-guided PLB, there has been interest in obviating its use by relying on the value of liver function tests (LFTs) to predict histological outcomes—specifically clinical judgment has been used in place of conducting a biopsy (2). What is understood in adult cohorts is that standard LFTs do not correlate well in many cases of grading the severity of liver graft dysfunction (6–8). Similarly, Doppler US variables have been investigated as predictors of posttransplantation liver rejection, but these studies have used mostly or exclusively adult cohorts, focused on the time period within 2 weeks or shortly after transplantation, and/or preceded an international consensus of defining rejection (9–16). The aims of the present study were to describe the pathological results within pediatric liver allograft recipients according to the early (12 months) and late (>12 months) posttransplantion periods, to analyze the role of LFTs and Doppler US in determining these results, and to evaluate the safety of real-time US-guided PLB.
METHODS Patient Characteristics A single-center retrospective evaluation of biopsies was approved by institutional review board and ethics committee. Informed consent was waived for the present study. From March 2005 to May 2012, 85 patients underwent real-time US-guided PLB after liver transplantation (mean age: 7 5 years, range: 6 months to 18 years). The indications for liver transplantation are reported in Table 1. A total of 66 patients (77%) underwent left lateral split liver transplantation, 15 patients (17%) had whole liver transplantation, and 4 patients (6%) underwent extended right graft transplantation. Indications for US-guided PLB are shown in Table 1. In patients with normal LFTs, a protocol biopsy is typically performed annually posttransplantation for 2 years within our institution. Furthermore, for patients with chronic rejection or previous biliary complications, a biopsy is typically performed every 2 years; for all other patients, biopsies are reserved for every 5 years. A total of 219 real-time US-guided PLBs were conducted in the early (n ¼ 92, 42%) and late (n ¼ 127, 58%) posttransplantation periods. All of the patients underwent LFT (total bilirubin, alanine aminotransferase, aspartate aminotransferase, g-glutamyl transferase [GGT], alkaline phosphatase), coagulation parameter testing (prothrombin time [PT], international normalized ratio [INR]), a baseline complete blood count, and Doppler US on or the day before the US-guided PLB.
756 JPGN Volume 58, Number 6, June 2014 Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN
Volume 58, Number 6, June 2014
US-Guided PLB in Pediatric Liver Transplant Recipients
TABLE 1. Characteristics of 85 patients post-LT who underwent 219 US-guided PLB and graft/procedure characteristics Mean age at biopsy, y (range) Median time after LT to biopsy for patient, days (range) Average number of biopsies per patient Number of passages (% of total PLB) Single Double More than double Mean sample length, cm Type of LT (%) Split segments 2 and 3 Whole liver Extended right graft Reasons for LT (%) Biliary atresia Acute liver failure Genetic Cryptogenic cirrhosis Autoimmune Genetic cholestatic Metabolic Other Indications for biopsy (% of total PLB) Alteration in LFT alone Suspected rejection Suspected rejection with cholestasis Protocol
7.1 5.4 (0.5–17.9) 165 (10–4161) 2.58 (1–8) 211 (96) 6 (3) 2 (1) 1.7 .4 (0.2–2.5) 66 (77) 15 (17) 4 (6) 47 9 8 6 4 4 4 3
(55) (11) (9) (7) (5) (5) (5) (3)
59 52 94 14
(27) (24) (43) (6)
LFT ¼ liver function test; LT ¼ liver transplantation; PLB ¼ percutaneous liver biopsy.
Doppler US and PLB Techniques LOGIQ 7 and LOGIQ E9 US units (GE Healthcare, Milwaukee, WI) using a 3.5-MHz sectorial transducer and/or a 6- to 15-MHz multifrequency linear transducer were used for evaluation of the liver, biliary tree, and hepatic vasculature before or on the day of liver biopsy. All examinations were performed by 4 radiologists with >5 years of experience in abdominal Doppler US. For the purpose of the present study, all images were reviewed by a radiologist with 11 years of experience who was blind to both biochemical and histological results. US parameters analyzed were portal vein velocity, main hepatic arterial resistance index, hepatic vein flow pattern (calculated by imaging during at least 2 cardiac cycles), and presence of bile duct dilatation. Liver biopsies were performed by 2 abdominal interventional radiologists with 11 and 8 years of experience. Procedures were performed with a percutaneous substernal approach using an 18-gauge spring-loaded automatic biopsy needle with a 19-mm sample notch (Tru-Core II; Angiotech Pharmaceuticals Inc, Gainesville, FL) advanced under real-time US guidance using GE LOGIQ 7 or GE LOGIQ E9 US units using a 3.5-MHz sectorial transducer or a 6- to 15-MHz linear transducer. In all procedures, a sterile disposable needle guide (Ultra-Pro II Needle Guide; CIVCO, Kalona, IA) was placed over a sterile probe cover on the specific transducer bracket. The biopsy needle was followed, by the operator, within the US screening software guidelines. All procedures were performed in accordance with the American College of Radiology and Society of Interventional Radiology guidelines for image-guided percutaneous needle biopsy in adults, because no specific guidelines exist for children (17). All of the procedures were performed in monitored anesthesia www.jpgn.org
care with spontaneous respirations and additional local anesthesia at puncture site. If coagulation defects were present (platelets
AND
NUTRITION
US-Guided Percutaneous Liver Biopsy in Pediatric Liver Transplant Recipients
Soma Mandal, yRoberto Miraglia, yLuigi Maruzzelli, yRosa Liotta, zFabio Tuzzolino, § Marco Spada, jjSilvia Riva, and yAngelo Luca
ABSTRACT Objectives: The present study assesses the safety of ultrasound (US)-guided percutaneous liver biopsies (PLBs) within pediatric liver allograft recipients, describes the pathological results according to early (12 months) and late (>12 months) posttransplantation periods, and analyzes the value of liver function tests (LFTs) and Doppler US variables in determining these results. Methods: A total of 219 US-guided PLBs in 85 pediatric patients with liver transplant (mean age 7 5 years, range: 6 months to 18 years) performed between March 2005 and May 2012 were retrospectively evaluated at a single institution. Doppler US and LFT evaluation (including total bilirubin, alanine aminotransferase, aspartate aminotransferase, g-glutamyl transferase, alkaline phosphatase) occurred within 1 day of early (n ¼ 92, 42%) and late term (n ¼ 127, 58%) posttransplantation biopsies. Results: The rate of major complications (hemorrhage requiring blood transfusion) was 0.91% (n ¼ 2). The early versus late term biopsy results, respectively, included: cholestasis at 36% versus 18% (P ¼ 0.003), minimal changes 16% versus 24% (not significant [NS]), acute rejection 13% versus 5% (P ¼ 0.027), inflammatory diseases 15% versus 15% (NS), indeterminate acute rejection 11% versus 7% (NS), chronic rejection 4% versus 14% (P ¼ 0.017), fibrotic diseases 4% versus 12% (NS), and other 0% versus 5% (NS). Neither LFT nor US variables were correlated with pathological outcomes. Conclusions: The rate of complications in pediatric patients after US-guided liver biopsy is low. A range of pathological results exists between early and late posttransplantation liver biopsies. LFT and Doppler US findings are not predictors of pathological results. Key Words: acute rejection, chronic rejection, pediatric liver transplantation, percutaneous liver biopsy, ultrasound guidance
(JPGN 2014;58: 756–761)
T
he use of ultrasound (US)-guided percutaneous liver biopsies (PLBs) in pediatric liver transplant recipients is routinely motivated by the possibility of allograft dysfunction, specifically
Received and accepted January 30, 2014. From the Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center (UPMC), Pittsburgh, PA, yDiagnostic and Therapeutic Services, the zDepartment of Information Technology, §Transplantation Surgery, and jjPediatric Hepatology, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IsMeTT), Palermo, Italy. Address correspondence and reprint requests to Roberto Miraglia, Diagnostic and Therapeutic Services, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (IsMeTT), Via Tricomi 1, Palermo 90127, Italy (e-mail: [email protected]). The authors report no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000328
rejection and infection. Acute rejection occurs at a rate of 20% to 40% in patients within 1 month postoperatively (1), whereas there is a 2% rate of chronic rejection with all liver allografts (1). Although it is logical to monitor graft function shortly after transplantation, US-guided PLBs during the later stages (eg, after 12 months) of the posttransplant period are questionable because of the risks the procedure carries, with reported complications ranging from 2.8% to 9.2% in children (2–5). Because of the invasive nature of US-guided PLB, there has been interest in obviating its use by relying on the value of liver function tests (LFTs) to predict histological outcomes—specifically clinical judgment has been used in place of conducting a biopsy (2). What is understood in adult cohorts is that standard LFTs do not correlate well in many cases of grading the severity of liver graft dysfunction (6–8). Similarly, Doppler US variables have been investigated as predictors of posttransplantation liver rejection, but these studies have used mostly or exclusively adult cohorts, focused on the time period within 2 weeks or shortly after transplantation, and/or preceded an international consensus of defining rejection (9–16). The aims of the present study were to describe the pathological results within pediatric liver allograft recipients according to the early (12 months) and late (>12 months) posttransplantion periods, to analyze the role of LFTs and Doppler US in determining these results, and to evaluate the safety of real-time US-guided PLB.
METHODS Patient Characteristics A single-center retrospective evaluation of biopsies was approved by institutional review board and ethics committee. Informed consent was waived for the present study. From March 2005 to May 2012, 85 patients underwent real-time US-guided PLB after liver transplantation (mean age: 7 5 years, range: 6 months to 18 years). The indications for liver transplantation are reported in Table 1. A total of 66 patients (77%) underwent left lateral split liver transplantation, 15 patients (17%) had whole liver transplantation, and 4 patients (6%) underwent extended right graft transplantation. Indications for US-guided PLB are shown in Table 1. In patients with normal LFTs, a protocol biopsy is typically performed annually posttransplantation for 2 years within our institution. Furthermore, for patients with chronic rejection or previous biliary complications, a biopsy is typically performed every 2 years; for all other patients, biopsies are reserved for every 5 years. A total of 219 real-time US-guided PLBs were conducted in the early (n ¼ 92, 42%) and late (n ¼ 127, 58%) posttransplantation periods. All of the patients underwent LFT (total bilirubin, alanine aminotransferase, aspartate aminotransferase, g-glutamyl transferase [GGT], alkaline phosphatase), coagulation parameter testing (prothrombin time [PT], international normalized ratio [INR]), a baseline complete blood count, and Doppler US on or the day before the US-guided PLB.
756 JPGN Volume 58, Number 6, June 2014 Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN
Volume 58, Number 6, June 2014
US-Guided PLB in Pediatric Liver Transplant Recipients
TABLE 1. Characteristics of 85 patients post-LT who underwent 219 US-guided PLB and graft/procedure characteristics Mean age at biopsy, y (range) Median time after LT to biopsy for patient, days (range) Average number of biopsies per patient Number of passages (% of total PLB) Single Double More than double Mean sample length, cm Type of LT (%) Split segments 2 and 3 Whole liver Extended right graft Reasons for LT (%) Biliary atresia Acute liver failure Genetic Cryptogenic cirrhosis Autoimmune Genetic cholestatic Metabolic Other Indications for biopsy (% of total PLB) Alteration in LFT alone Suspected rejection Suspected rejection with cholestasis Protocol
7.1 5.4 (0.5–17.9) 165 (10–4161) 2.58 (1–8) 211 (96) 6 (3) 2 (1) 1.7 .4 (0.2–2.5) 66 (77) 15 (17) 4 (6) 47 9 8 6 4 4 4 3
(55) (11) (9) (7) (5) (5) (5) (3)
59 52 94 14
(27) (24) (43) (6)
LFT ¼ liver function test; LT ¼ liver transplantation; PLB ¼ percutaneous liver biopsy.
Doppler US and PLB Techniques LOGIQ 7 and LOGIQ E9 US units (GE Healthcare, Milwaukee, WI) using a 3.5-MHz sectorial transducer and/or a 6- to 15-MHz multifrequency linear transducer were used for evaluation of the liver, biliary tree, and hepatic vasculature before or on the day of liver biopsy. All examinations were performed by 4 radiologists with >5 years of experience in abdominal Doppler US. For the purpose of the present study, all images were reviewed by a radiologist with 11 years of experience who was blind to both biochemical and histological results. US parameters analyzed were portal vein velocity, main hepatic arterial resistance index, hepatic vein flow pattern (calculated by imaging during at least 2 cardiac cycles), and presence of bile duct dilatation. Liver biopsies were performed by 2 abdominal interventional radiologists with 11 and 8 years of experience. Procedures were performed with a percutaneous substernal approach using an 18-gauge spring-loaded automatic biopsy needle with a 19-mm sample notch (Tru-Core II; Angiotech Pharmaceuticals Inc, Gainesville, FL) advanced under real-time US guidance using GE LOGIQ 7 or GE LOGIQ E9 US units using a 3.5-MHz sectorial transducer or a 6- to 15-MHz linear transducer. In all procedures, a sterile disposable needle guide (Ultra-Pro II Needle Guide; CIVCO, Kalona, IA) was placed over a sterile probe cover on the specific transducer bracket. The biopsy needle was followed, by the operator, within the US screening software guidelines. All procedures were performed in accordance with the American College of Radiology and Society of Interventional Radiology guidelines for image-guided percutaneous needle biopsy in adults, because no specific guidelines exist for children (17). All of the procedures were performed in monitored anesthesia www.jpgn.org
care with spontaneous respirations and additional local anesthesia at puncture site. If coagulation defects were present (platelets
