- Email: [email protected]
Transient Elastography in Acute Cellular Rejection Following Liver Transplantation: Systematic Review
Transient Elastography in Acute Cellular Rejection Following Liver Transplantation: Systematic Review L.S. Nacifa,*, C.d.C. Gomesa, M.N. Mischiattib, V. Kimb, D. Paranaguá-Vezozzob, G.L. Reinosob, F.J. Carrilhob, and L.C. D’Albuquerquea a
Liver and Gastrointestinal Transplant Division, Department of Gastroenterology, University of São Paulo School of Medicine, Brazil; and bGastroenterology and Hepatology Division, Department of Gastroenterology, University of São Paulo School of Medicine, Brazil
ABSTRACT Background. Transient elastography (TE) is a noninvasive technique that measures liver stiffness. When an inflammatory process is present, this is shown by elevated levels of stiffness. Acute cellular rejection (ACR) is a consequence of an inflammatory response directed at endothelial and bile epithelial cells, and it is diagnosed through liver biopsy. This is a systematic review of the viability of TE in ACR following liver transplantation. Methods. The Cochrane Library, Embase, and Medline PubMed databases were searched and updated to November 2016. The MESH terms used were “Liver Transplantation,” “Graft Rejection,” “Elasticity Imaging Techniques” (PubMed), and “Elastography” (Cochrane and Embase). Results. Seventy studies were retrieved and selected using the PICO (patient, intervention, comparison or control, outcome) criteria. Three prospective studies were selected to meta-analysis and evaluation. A total of 33 patients with ACR were assessed with TE. One study showed a cutoff point of >7.9 kPa to define graft damage and <5.3 kPa to exclude graft damage (receiver operating characteristic 0.93; P < .001). Another study showed elevated levels of liver stiffness in ACR patients. However, in this study, no cutoff point for ACR was suggested. The final prospective study included 27 patients with ACR at liver biopsy. Cutoff points were defined as TE > 8.5 kPa, moderate to severe ACR, with a specificity of 100% and receiver operating characteristic curve of 0.924. The measurement of TE < 4.2 kPa excludes the possibility of any ACR (P ¼ .02). Conclusions. TE may be an important tool for the severity of ACR in patients following liver transplantation. Further studies should be performed to better define the cutoff points and applicability of the exam.
L
IVER transplantation (LT) is one of the most complex procedures in medicine, and despite all the basic research for this therapeutic method, the procedure still has many complications that require scientific models to improve the final results [1]. Although all of these advances contribute to increased transplant safety, rejection still occurs in at least 50% of transplanted individuals. Acute cellular rejection (ACR) is the most common and is characterized as a lymphocyte-mediated immune reaction against in the graft. Transient elastography (TE) is a noninvasive technique for liver stiffness measurement (LSM) and is useful to show
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the degree of liver fibrosis and portal hypertension [2]. The gold standard for fibrosis and ACR is still the liver biopsy. However, this procedure is invasive and carries some risks. ACR is a consequence of an inflammatory response directed at endothelial and bile epithelial cells. It is
*Address correspondence to Lucas Souto Nacif, MD, PhD, Liver and Gastrointestinal Transplant Division, Department of Gastroenterology, University of São Paulo School of Medicine, Brazil. Tel: (55 11) 2661-3323, Fax: (55 11) 2661-9007. E-mail: [email protected] ª 2018 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 772e775 (2018)
LIVER TRANSPLANTATION AND TRANSIENT ELASTOGRAPHY
773 Imaging Techniques” (Medline PubMed) and “Elastography” (Cochrane and Embase). The review methodology followed the recommendations published by PRISMA guidelines [4]. The terms and MESH terms used on PubMed database search were developed using the PICO (patient, intervention, comparison or control, outcome) structure. The terms for each group were used in combination with the “OR” operator. The results for the search terms that formed the P (patients) group were combined with the result that formed the I (intervention) group using “AND” and terms were excluded with “NOT.” The Medline search was performed through PubMed (www.ncbi. nlm.nih.gov/pubmed) and was adapted by using the terms and MESH terms: ("Liver Transplantation" [MESH] AND "Graft Rejection" [MESH]) AND "Elasticity Imaging Techniques" [MESH]. The same strategy was used in the Embase (www.embase.com) with “liver transplantation” AND “graft rejection” AND “elastography.” The Cochrane Library Database (http://www.cochrane.org) was searched for both registered and already published systematic reviews and clinical trials on the management of “Liver Liver Transplantation” AND “Graft Rejection” AND “Elastography” (Fig 1).
Inclusion and Exclusion Criteria Selection criteria were performed within the research question with the PICO structure. Therefore, only randomized controlled trials, nonrandomized controlled trials, or comparative clinical studies were included. Furthermore, only studies that evaluated the graft rejection with elastography in LT were included. Fig 1. Characteristics of all search and databases selection.
diagnosed through liver biopsy [2,3]. Recent study suggests that LSM can help in the assessment of the severity of ACR in LT [3]. So, this systematic review aims to evaluate all studies and the viability of TE in ACR following LT. METHODS Study Identification and Selection A systematic review of the literature was performed on the management of graft rejection with elastography in LT. The Cochrane library, Embase, and Medline PubMed databases were electronically search and updated to November 2016. The MESH terms used were “Liver Transplantation,” “Graft Rejection,” “Elasticity
Data Collection, Statistical Analysis, and Critical Evaluation Two reviewers independently assessed the studies quality and extracted data. The quality and selection of the studies were evaluated by 2 independent researchers (L.S.N. and M.N.M.). In case of disagreement, the researchers held a consensus meeting to reach a final decision. Data were extracted from the text, tables, and figures of the original published articles. Data were synthesized using Review Manager Version 5.3 software provided by the Cochrane Collaboration (RevMan; The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark). Continuous data were expressed as mean difference and 95% confidence intervals. Heterogeneity was examined using I2 statistic, where I2 values of 70% or more represented an indicator of substantial heterogeneity. In the absence of significant heterogeneity, we pooled data using a fixed-effect model (I2 < 50%); otherwise we used a random effects
Fig 2. Flowchart of the study selection. Abbreviation: PICO, patient, intervention, comparison or control, outcome.
774
NACIF, GOMES, MISCHIATTI ET AL Table 1. Characteristics of All Selected Studies Study
Type
n
Population
Rigamonti et al 2012 [6] Prospective 69 Liver transplant
ACR
3
Crespo et al 2016 [3]
Prospective 87 Liver transplant
27
Inoue et al 2009 [7]
Prospective 87 Liver transplant
3
Intervention
Outcome
Assess the presence of graft damage of other non-HCV etiologies Association between liver stiffness and the severity of ACR TE evaluation
TE < 5.3 kPa not liver biopsy; If >7.4 kPa mandatory liver biopsy TE is associated with the severity of the ACR All cases with ACR with higher TE measurements
Abbreviations: ACR, acute cellular rejection; HCV, hepatitis C virus; LT, liver transplantation; TE, transient elastography.
Fig 3. Meta-analysis done of these 3 selected articles. Abbreviations: ACR, acute cellular rejection; CI, confidence interval. model (I2 > 50%) [5]. Results were considered statistically significant at P < .05. Publication bias was evaluated using a funnel plot.
RESULTS Study Selection
Initially, we found 70 studies that were retrieved and selected using the PICO criteria, demonstrated in Fig 2. Of the articles selected, 11 were from PubMed/Medline, 2 Cochrane, and 57 Embase. Three prospective studies were selected to demonstrate the applicability of TE in ACR. A total of 33 patients with ACR were assessed with TE (Table 1). We used the overall characteristics of all these selected 3 studies (Table 1) to evaluate and perform a meta-analysis (Fig 3). The Newcastle-Ottawa Scale for assessing the quality of nonrandomized studies is demonstrated on Table 2. The elastography Fibroscan (FibroScan, EchoSens, Paris, France) (kPa) value on ACR after LT of all 3 articles selected is demonstrated on Table 3. Study Results
One study showed a cutoff point of >7.9 kPa to define graft damage (recurrence of the underlying disease; autoimmune de novo; idiopathic hepatitis; steatohepatitis; ARC; cholangitis) and <5.3 kPa to exclude graft damage (receiver operating characteristic 0.93; P < .001) [6]. Another prospective study showed elevated levels of liver stiffness in ACR patients, which decreased following successful immunosuppression. However, in this study, no cutoff point for ACR was suggested [7]. The final prospective study included a total of 27 patients with ACR at liver biopsy. ACR was subclassified into mild ACR (n ¼ 08) and moderate to severe ACR (n ¼ 19). Cutoff points were defined as TE > 8.5 kPa defining moderate to severe ACR, with a specificity of 100% and receiver operating characteristic
curve of 0.924. The measurement of TE < 4.2 kPa excludes the possibility of any ACR (P ¼ .02). A linear regression analysis was performed, which verified that the elastography values are associated with the severity of the ACR (P < .001) [3]. DISCUSSION
The present systematic review shows the progress in the current articles with the measurements of a noninvasive method for ACR evaluation after LT. Furthermore, we performed a meta-analysis for this specific topic. However, as a limitation of this study, we did not find randomized controlled clinical trials, and the selections of the articles were presented in the general post-transplant context (which needs to exclude other causes such as hepatitis, cholangitis, and autoimmune or cholestatic recurrence, virus recurrence, thrombosis), and only 1 article evaluated the Table 2. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Non-Randomized Studies [8] Non-Randomized Studies Author, Year
Population
Total Score
Quality
C. Rigamonti Prospective et al. 2012. [6]
Study
69
2C
G. Crespo Prospective et al. 2016. [3]
87
Y. Inoue Prospective et al. 2009. [7]
87
Selection: *** Comparability: * Outcome: *** Total: 7 Selection: *** Comparability: ** Outcome: *** Total: 8 Selection: *** Comparability: * Outcome: *** Total: 7
2B
2C
Note: Ottawa Hospital Research Institute. The Newcastle-Ottawa Scale (NOS) for assessing the quality of non-randomized studies in meta-analysis [8].
LIVER TRANSPLANTATION AND TRANSIENT ELASTOGRAPHY
775
Table 3. The Elastography Fibroscan (kPa) Value on ACR After Liver Transplant Non-Randomized Studies Author, Year
Rigamonti et al. 2012 [6] Patients Fibroscan Crespo et al 2016 [3] Patients Fibroscan Inoue et al 2009 [7] Patients Fibroscan
ACR
Without ACR
n¼3 7.8 kPa (range 5.4e27.4)
n ¼ 27 5.3 kPa (range 3.1e7.4)
n ¼ 27 11 kPa (range 4.8e18.5 kPa)
n ¼ 30 4.2 kPa (range 2e7 kPa)
n¼3 4.2 (range 3.0e6.4 kPa)
n ¼ 16 4.6 (range 3.0e6.4 kPa)
Note: Results are median and range. Abbreviation: ACR, acute cellular rejection.
specific topic of ACR. So, we know that need more controlled articles and multicentric studies on the topic. The real benefit of this meta-analysis is to show that we are moving toward better evaluation of these patients with less invasive methods. CONCLUSION
TE may be an important tool for the definition and classification of the severity of ACR in patients following LT. It decreases the number of liver biopsies and makes the follow-up of these patients safer. Further studies should be performed to better define the cutoff points and applicability of the exam. REFERENCES [1] Martınez SM, Crespo G, Navasa M, Forns X. Noninvasive assessment of liver fibrosis. Hepatology 2011;53:325e35. [2] Nacif LS, Pinheiro RS, de Arruda Pécora RA, et al. Retransplantation, higher creatinine levels in hepatitis c virus patients, and donor age are predictors of mortality in long-term analysis of
late acute rejection in liver transplantation. Ann Transplant 2017;22:9e16. [3] Crespo G, Castro-Narro G, García-Juárez I, et al. Usefulness of liver stiffness measurement during acute cellular rejection in liver transplantation. Liver Transpl 2016;22:298e304. [4] Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009;6:e1000100. [5] Higgins JP, Thompson SG. Quantifying heterogeneity in a metaanalysis. Stat Med 2002;21:1539e58. [6] Rigamonti C, Fraquelli M, Bastiampillai AJ, et al. Transient elastography identifies liver recipients with nonviral graft disease after transplantation: a guide for liver biopsy. Liver Transpl 2012;18:566e76. [7] Inoue Y, Sugawara Y, Tamura S, et al. Validity and feasibility of transient elastography for the transplanted liver in the peritransplantation period. Transplantation 2009;88:103e9. [8] Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa: Ottawa Hospital Research Institute. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford. asp. Accessed July 2017.
Liver and Gastrointestinal Transplant Division, Department of Gastroenterology, University of São Paulo School of Medicine, Brazil; and bGastroenterology and Hepatology Division, Department of Gastroenterology, University of São Paulo School of Medicine, Brazil
ABSTRACT Background. Transient elastography (TE) is a noninvasive technique that measures liver stiffness. When an inflammatory process is present, this is shown by elevated levels of stiffness. Acute cellular rejection (ACR) is a consequence of an inflammatory response directed at endothelial and bile epithelial cells, and it is diagnosed through liver biopsy. This is a systematic review of the viability of TE in ACR following liver transplantation. Methods. The Cochrane Library, Embase, and Medline PubMed databases were searched and updated to November 2016. The MESH terms used were “Liver Transplantation,” “Graft Rejection,” “Elasticity Imaging Techniques” (PubMed), and “Elastography” (Cochrane and Embase). Results. Seventy studies were retrieved and selected using the PICO (patient, intervention, comparison or control, outcome) criteria. Three prospective studies were selected to meta-analysis and evaluation. A total of 33 patients with ACR were assessed with TE. One study showed a cutoff point of >7.9 kPa to define graft damage and <5.3 kPa to exclude graft damage (receiver operating characteristic 0.93; P < .001). Another study showed elevated levels of liver stiffness in ACR patients. However, in this study, no cutoff point for ACR was suggested. The final prospective study included 27 patients with ACR at liver biopsy. Cutoff points were defined as TE > 8.5 kPa, moderate to severe ACR, with a specificity of 100% and receiver operating characteristic curve of 0.924. The measurement of TE < 4.2 kPa excludes the possibility of any ACR (P ¼ .02). Conclusions. TE may be an important tool for the severity of ACR in patients following liver transplantation. Further studies should be performed to better define the cutoff points and applicability of the exam.
L
IVER transplantation (LT) is one of the most complex procedures in medicine, and despite all the basic research for this therapeutic method, the procedure still has many complications that require scientific models to improve the final results [1]. Although all of these advances contribute to increased transplant safety, rejection still occurs in at least 50% of transplanted individuals. Acute cellular rejection (ACR) is the most common and is characterized as a lymphocyte-mediated immune reaction against in the graft. Transient elastography (TE) is a noninvasive technique for liver stiffness measurement (LSM) and is useful to show
0041-1345/18 https://doi.org/10.1016/j.transproceed.2018.02.008
772
the degree of liver fibrosis and portal hypertension [2]. The gold standard for fibrosis and ACR is still the liver biopsy. However, this procedure is invasive and carries some risks. ACR is a consequence of an inflammatory response directed at endothelial and bile epithelial cells. It is
*Address correspondence to Lucas Souto Nacif, MD, PhD, Liver and Gastrointestinal Transplant Division, Department of Gastroenterology, University of São Paulo School of Medicine, Brazil. Tel: (55 11) 2661-3323, Fax: (55 11) 2661-9007. E-mail: [email protected] ª 2018 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 772e775 (2018)
LIVER TRANSPLANTATION AND TRANSIENT ELASTOGRAPHY
773 Imaging Techniques” (Medline PubMed) and “Elastography” (Cochrane and Embase). The review methodology followed the recommendations published by PRISMA guidelines [4]. The terms and MESH terms used on PubMed database search were developed using the PICO (patient, intervention, comparison or control, outcome) structure. The terms for each group were used in combination with the “OR” operator. The results for the search terms that formed the P (patients) group were combined with the result that formed the I (intervention) group using “AND” and terms were excluded with “NOT.” The Medline search was performed through PubMed (www.ncbi. nlm.nih.gov/pubmed) and was adapted by using the terms and MESH terms: ("Liver Transplantation" [MESH] AND "Graft Rejection" [MESH]) AND "Elasticity Imaging Techniques" [MESH]. The same strategy was used in the Embase (www.embase.com) with “liver transplantation” AND “graft rejection” AND “elastography.” The Cochrane Library Database (http://www.cochrane.org) was searched for both registered and already published systematic reviews and clinical trials on the management of “Liver Liver Transplantation” AND “Graft Rejection” AND “Elastography” (Fig 1).
Inclusion and Exclusion Criteria Selection criteria were performed within the research question with the PICO structure. Therefore, only randomized controlled trials, nonrandomized controlled trials, or comparative clinical studies were included. Furthermore, only studies that evaluated the graft rejection with elastography in LT were included. Fig 1. Characteristics of all search and databases selection.
diagnosed through liver biopsy [2,3]. Recent study suggests that LSM can help in the assessment of the severity of ACR in LT [3]. So, this systematic review aims to evaluate all studies and the viability of TE in ACR following LT. METHODS Study Identification and Selection A systematic review of the literature was performed on the management of graft rejection with elastography in LT. The Cochrane library, Embase, and Medline PubMed databases were electronically search and updated to November 2016. The MESH terms used were “Liver Transplantation,” “Graft Rejection,” “Elasticity
Data Collection, Statistical Analysis, and Critical Evaluation Two reviewers independently assessed the studies quality and extracted data. The quality and selection of the studies were evaluated by 2 independent researchers (L.S.N. and M.N.M.). In case of disagreement, the researchers held a consensus meeting to reach a final decision. Data were extracted from the text, tables, and figures of the original published articles. Data were synthesized using Review Manager Version 5.3 software provided by the Cochrane Collaboration (RevMan; The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark). Continuous data were expressed as mean difference and 95% confidence intervals. Heterogeneity was examined using I2 statistic, where I2 values of 70% or more represented an indicator of substantial heterogeneity. In the absence of significant heterogeneity, we pooled data using a fixed-effect model (I2 < 50%); otherwise we used a random effects
Fig 2. Flowchart of the study selection. Abbreviation: PICO, patient, intervention, comparison or control, outcome.
774
NACIF, GOMES, MISCHIATTI ET AL Table 1. Characteristics of All Selected Studies Study
Type
n
Population
Rigamonti et al 2012 [6] Prospective 69 Liver transplant
ACR
3
Crespo et al 2016 [3]
Prospective 87 Liver transplant
27
Inoue et al 2009 [7]
Prospective 87 Liver transplant
3
Intervention
Outcome
Assess the presence of graft damage of other non-HCV etiologies Association between liver stiffness and the severity of ACR TE evaluation
TE < 5.3 kPa not liver biopsy; If >7.4 kPa mandatory liver biopsy TE is associated with the severity of the ACR All cases with ACR with higher TE measurements
Abbreviations: ACR, acute cellular rejection; HCV, hepatitis C virus; LT, liver transplantation; TE, transient elastography.
Fig 3. Meta-analysis done of these 3 selected articles. Abbreviations: ACR, acute cellular rejection; CI, confidence interval. model (I2 > 50%) [5]. Results were considered statistically significant at P < .05. Publication bias was evaluated using a funnel plot.
RESULTS Study Selection
Initially, we found 70 studies that were retrieved and selected using the PICO criteria, demonstrated in Fig 2. Of the articles selected, 11 were from PubMed/Medline, 2 Cochrane, and 57 Embase. Three prospective studies were selected to demonstrate the applicability of TE in ACR. A total of 33 patients with ACR were assessed with TE (Table 1). We used the overall characteristics of all these selected 3 studies (Table 1) to evaluate and perform a meta-analysis (Fig 3). The Newcastle-Ottawa Scale for assessing the quality of nonrandomized studies is demonstrated on Table 2. The elastography Fibroscan (FibroScan, EchoSens, Paris, France) (kPa) value on ACR after LT of all 3 articles selected is demonstrated on Table 3. Study Results
One study showed a cutoff point of >7.9 kPa to define graft damage (recurrence of the underlying disease; autoimmune de novo; idiopathic hepatitis; steatohepatitis; ARC; cholangitis) and <5.3 kPa to exclude graft damage (receiver operating characteristic 0.93; P < .001) [6]. Another prospective study showed elevated levels of liver stiffness in ACR patients, which decreased following successful immunosuppression. However, in this study, no cutoff point for ACR was suggested [7]. The final prospective study included a total of 27 patients with ACR at liver biopsy. ACR was subclassified into mild ACR (n ¼ 08) and moderate to severe ACR (n ¼ 19). Cutoff points were defined as TE > 8.5 kPa defining moderate to severe ACR, with a specificity of 100% and receiver operating characteristic
curve of 0.924. The measurement of TE < 4.2 kPa excludes the possibility of any ACR (P ¼ .02). A linear regression analysis was performed, which verified that the elastography values are associated with the severity of the ACR (P < .001) [3]. DISCUSSION
The present systematic review shows the progress in the current articles with the measurements of a noninvasive method for ACR evaluation after LT. Furthermore, we performed a meta-analysis for this specific topic. However, as a limitation of this study, we did not find randomized controlled clinical trials, and the selections of the articles were presented in the general post-transplant context (which needs to exclude other causes such as hepatitis, cholangitis, and autoimmune or cholestatic recurrence, virus recurrence, thrombosis), and only 1 article evaluated the Table 2. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Non-Randomized Studies [8] Non-Randomized Studies Author, Year
Population
Total Score
Quality
C. Rigamonti Prospective et al. 2012. [6]
Study
69
2C
G. Crespo Prospective et al. 2016. [3]
87
Y. Inoue Prospective et al. 2009. [7]
87
Selection: *** Comparability: * Outcome: *** Total: 7 Selection: *** Comparability: ** Outcome: *** Total: 8 Selection: *** Comparability: * Outcome: *** Total: 7
2B
2C
Note: Ottawa Hospital Research Institute. The Newcastle-Ottawa Scale (NOS) for assessing the quality of non-randomized studies in meta-analysis [8].
LIVER TRANSPLANTATION AND TRANSIENT ELASTOGRAPHY
775
Table 3. The Elastography Fibroscan (kPa) Value on ACR After Liver Transplant Non-Randomized Studies Author, Year
Rigamonti et al. 2012 [6] Patients Fibroscan Crespo et al 2016 [3] Patients Fibroscan Inoue et al 2009 [7] Patients Fibroscan
ACR
Without ACR
n¼3 7.8 kPa (range 5.4e27.4)
n ¼ 27 5.3 kPa (range 3.1e7.4)
n ¼ 27 11 kPa (range 4.8e18.5 kPa)
n ¼ 30 4.2 kPa (range 2e7 kPa)
n¼3 4.2 (range 3.0e6.4 kPa)
n ¼ 16 4.6 (range 3.0e6.4 kPa)
Note: Results are median and range. Abbreviation: ACR, acute cellular rejection.
specific topic of ACR. So, we know that need more controlled articles and multicentric studies on the topic. The real benefit of this meta-analysis is to show that we are moving toward better evaluation of these patients with less invasive methods. CONCLUSION
TE may be an important tool for the definition and classification of the severity of ACR in patients following LT. It decreases the number of liver biopsies and makes the follow-up of these patients safer. Further studies should be performed to better define the cutoff points and applicability of the exam. REFERENCES [1] Martınez SM, Crespo G, Navasa M, Forns X. Noninvasive assessment of liver fibrosis. Hepatology 2011;53:325e35. [2] Nacif LS, Pinheiro RS, de Arruda Pécora RA, et al. Retransplantation, higher creatinine levels in hepatitis c virus patients, and donor age are predictors of mortality in long-term analysis of
late acute rejection in liver transplantation. Ann Transplant 2017;22:9e16. [3] Crespo G, Castro-Narro G, García-Juárez I, et al. Usefulness of liver stiffness measurement during acute cellular rejection in liver transplantation. Liver Transpl 2016;22:298e304. [4] Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 2009;6:e1000100. [5] Higgins JP, Thompson SG. Quantifying heterogeneity in a metaanalysis. Stat Med 2002;21:1539e58. [6] Rigamonti C, Fraquelli M, Bastiampillai AJ, et al. Transient elastography identifies liver recipients with nonviral graft disease after transplantation: a guide for liver biopsy. Liver Transpl 2012;18:566e76. [7] Inoue Y, Sugawara Y, Tamura S, et al. Validity and feasibility of transient elastography for the transplanted liver in the peritransplantation period. Transplantation 2009;88:103e9. [8] Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa: Ottawa Hospital Research Institute. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford. asp. Accessed July 2017.