|Ahead of print
|A comparative histological analysis of early and late graft dysfunction in different time zones following living donor liver transplantation
Archana Rastogi1, Nayana Patil1, Sphurti Srivastava1, Gayatri Ramakrishna2, Rakhi Maiwal3, Guresh Kumar4, Ashok K Choudhary3, Seema Alam5, Chhagan Bihari1, Viniyendra Pamecha6
1 Department of Pathology, Institute of Liver and Biliary Sciences, Delhi, India
2 Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, Delhi, India
3 Department of Hepatology, Institute of Liver and Biliary Sciences, Delhi, India
4 Department of Statisics, Institute of Liver and Biliary Sciences, Delhi, India
5 Department of Paediatric Hepatology, Institute of Liver and Biliary Sciences, Delhi, India
6 Department of Liver Transplantation and HPB Surgery, Institute of Liver and Biliary Sciences, Delhi, India
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|Date of Submission||26-Apr-2021|
|Date of Decision||07-Dec-2021|
|Date of Acceptance||09-Dec-2021|
|Date of Web Publication||24-May-2022|
| Abstract|| |
Background: Liver biopsy plays a crucial role in evaluating allograft dysfunction. Comprehensive analysis of the histological spectrum of complications, particularly rejection, in different time zones is lacking. Aim: To evaluate the histological spectrum of rejection, in four time zones, in a large Living donor liver transplant series. Patients and Methods: Retrospective analysis of 313 biopsies for the last 10 years of living donor liver transplantation (LDLT) recipients. 123 of which had rejection as diagnosis, were redistributed in four time zones [1-early (<3), 2-intermediate (3–6), 3 and 4-late (6–12 and > 12) months] and were assessed for sixteen histological parameters. Results: Biopsies in time zone 1 (26.5%), 2 (20.7%), 3 (24.6%), and 4 (28.1%)] were nearly equal. Multiple coexistent complications existed in 12% of the cases. Rejection diagnosed in time zone groups: 1 = 22 (17.9%), 2 = 27 (22%), 3 = 36 (29.3%), and 4 = 38 (30.9%). Portal inflammation mixed type (P < 0.000), portal vein (P = 0.001) and hepatic vein endothelialitis (P < 0.000), portal eosinophils (P = 0.001), and lymphocytic bile duct damage (P = 0.01) were most pronounced in group 1. Perivenulitis without hepatic vein endothelialitis was observed (P = 0.03) in groups 3, whereas bile duct atypia (P = 0.01) and duct loss (P < 0.000) were observed in group 4. Multiple episodes of rejection displayed significant association with central perivenulitis (P = 0.002) and bile duct loss (P < 0.001). Conclusions: Histological analysis in large series of LDLT recipients highlights the spectrum of complications in different time zones. Late acute and chronic rejection occurred as early as 3 months posttransplant. Central perivenulitis and bile duct atrophy were associated with repeated episodes of rejection and deterioration.
Keywords: Acute rejection, chronic rejection, late acute rejection, liver allograft biopsy, spectrum
|How to cite this URL:|
Rastogi A, Patil N, Srivastava S, Ramakrishna G, Maiwal R, Kumar G, Choudhary AK, Alam S, Bihari C, Pamecha V. A comparative histological analysis of early and late graft dysfunction in different time zones following living donor liver transplantation. Indian J Pathol Microbiol [Epub ahead of print] [cited 2022 Jul 4]. Available from: https://www.ijpmonline.org/preprintarticle.asp?id=345870
| Introduction|| |
Liver transplantation is the main therapeutic option for patients with irreversible acute or chronic liver disease. Graft dysfunction can occur in the early and late posttransplant periods., The main complications in immediate posttransplant period are related to surgical techniques, infections, and rejection. Long-term complications include rejection, recurrence of original disease, de novo diseases, malignancies, biliary complications, and organ toxicity.,,
Liver allograft dysfunction has been described as early and late, based on the posttransplant duration, i.e., less than 3 months and more than 6 months, respectively Certain complications display overlapping clinical manifestations and laboratory abnormalities, and many times there are multiple coexisting pathologies. Correct diagnosis and delineation of dominant cause are of utmost important in view of different therapies for these complications.,
Liver allograft biopsy assessment plays a very important role in evaluating graft dysfunction. In certain conditions, such as graft rejection and disease recurrences, biopsy is the gold standard. Also, biopsy plays crucial role in confirming or detecting an alternate, additional or dominant cause of dysfunction.,,,
Liver allograft rejection is still the most important problem after living donor liver transplantation (LDLT). Rejection is further subdivided into antibody-mediated rejection (AMR), acute cellular rejection (ACR), late acute rejection (LAR), and chronic rejection (CR). Rejection histology shows certain characteristic features., LAR may show overlaps in the time of occurrence and rejection histology with ACR. In view of poor compliance, more refractoriness to treatment, higher risk of repeat episodes and progression to CR, accurate diagnosis of LAR, and rejection in general, is warranted.,,,,
This study was therefore conducted to evaluate the histological spectrum of complications in early as well as late graft dysfunction and comparative assessment of rejection histology in different time zones following LDLT.
| Patients and Methods|| |
This is a retrospective single-institutional study of liver allograft biopsies of LDLT recipients, performed in the last 10 years. There were in total 567 (LDLT) recipients. 366 clinically indicated graft biopsies were received in the Department of Pathology. 313 biopsies obtained from 159 patients, fulfilling the inclusion and exclusion criteria, were retrieved for the study.
- Liver allograft biopsies obtained from LDLT recipients.
- Deceased donor liver transplant recipients
- Incomplete clinical and lab information
- Liver allograft biopsy with less than 6 portal tracts
- Follow-up period of less than 6 months.
Clinico pathological assessments of 313 allograft biopsies (from 159 LDLT recipients) for which the database of clinical and laboratory details were retrieved from the hospital information system. Histological diagnoses of posttransplant complications recorded were: ACR, LAR, CR, recurrence, drug toxicity, sepsis, preservation-reperfusion injury, biliary or vascular pathology, and miscellaneous causes. Histological diagnosis was based upon the standard criteria, as recommended in the published literature.,,,,, Histology slides of these cases were retrieved to record the dominant and coexisting pathologies, along with the period of their occurrence after LDLT.
Single histological diagnosis of graft dysfunction (rejection)
Patients with posttransplant graft dysfunction with histological diagnosis of rejection and without any other coexistent complications were further analyzed. 123 rejection graft biopsies obtained from 69 patients constituted the study group for histological reassessment. These allograft biopsies were further subdivided into various posttransplant periods and reviewed for occurrence and severity of histological parameters of ACR, LAR, and CR.
Patients were classified based on posttransplant period: group 1 (<3 months), group 2 (3–6 months), group 3 (6–12 months), and group 4 (>12 months).
Reassessment of histological parameters
Sixteen histological parameters were reassessed, their presence/absence was recorded, and semiquantitative scores and frequency of occurrence in different time zone groups were calculated.
Histological parameters: inflammation predominant location-predominant portal (1), portal with central inflammation (2); predominant central (3); severity of portal inflammation (PI)-0–3; type of PI-mixed (1), mononuclear (2); portal eosinophils-0–2; portal plasma cells-0–2; portal vein endotheliitis-0–3; hepatic vein endothelialitis-0–3; lymphocytic bile duct damage-0–3; centrilobular bile-0–3; ballooning degeneration of hepatocytes-0–3; bile duct epithelial atypia-0–3; bile duct atrophy and duct loss-0–2; lobular inflammation (LI)-0–3; central perivenulitis (CP)-0–3; interface activity-0–3; CP without hepatic vein endothelialitis- present (0), absent (1).
This study was approved by the Institutional Review Board (IEC/2019/68/MA14).
Immunosuppression regime in the first 3 months of transplant included triple-drug therapy, i.e., tacrolimus, mycophenolate, and steroids. The steroid was tapered over a period of 3 months. By the end of first year, most of the patients were maintained on a single agent, i.e., tacrolimus. With deranged Liver function test (LFT), history of drug compliance, exclusion of Cytomegalovirus (CMV) infection and exclusion of biliary or vascular complication, a liver biopsy was performed.
In descriptive statistics, categorical variables were presented as proportions, while continuous variables were either presented as mean with standard deviation (SD) or median with range. Comparison of parametric data was performed using the Student's t-test and one-way ANOVA with post hoc comparisons by Bonferroni method; or Mann–Whitney and Kruskal–Wallis test for nonparametric data. Categorical variables were compared by Fisher's exact test or Pearson's Chi-square test. P value < 0.05 was considered as significant. All statistical tests were performed using SPSS for Windows version 22 (Armonk IBM Corp).
| Results|| |
Baseline characteristics: in a total of 553 LDLT, 313 liver allograft biopsies were obtained from 159 recipients were studied. Their baseline characteristics are summarized in [Table 1]. The median age was 41 years, with male predominance (M: F = 3.9:1). 134 (84.3%) had end-stage chronic liver disease (CLD) and 25 (15.7%) had acute liver failure (17/159) or acute-on-chronic liver failure (8/159) as an indication for transplant. Among the CLD, alcohol related and cryptogenic cirrhosis constituted 61% of the cases; other etiologies were HCV and HBV related cirrhosis (8%), hepatocellular carcinoma (8%), nonalcoholic steatohepatitis (4%), autoimmune liver disease (11%) and the remaining etiologies were biliary atresia, and Wilson's disease.
Distribution analysis of the 313 clinically indicated liver allograft biopsies in different time zone groups—group 1 (<3 months)-83 (26.5%), group 2 (3–6 months)-65 (20.7%), group 3 (6–12 months)-77 (24.6%), and group 4 (>12 months)-88 (28.1%)—revealed uniform distribution across the groups.
Among these 313 biopsies, most common histologic diagnosis of dysfunction was rejection (n = 137; 44%), followed by dual pathologies in which rejection and other pathology coexisted (n = 37), drug toxicity (n = 18), recurrence of original disease (n = 18), biliary complication (n = 14), unremarkable biopsy (n = 37), and miscellaneous causes (n = 52) which included sepsis, CMV infection, acute hepatitis, idiopathic chronic hepatitis, de novo AIH, AMR, preservation reperfusion injury, primary graft dysfunction and small for size.
Liver allograft pathology favoring rejection (61.3%), biliary complication (64.3%), and recurrence (77.8%) were higher in the late posttransplant period (>6 months) [Table 2].
Multiple coexistent complications: the majority of the cases with histological evidence of multiple complications showed rejection as one of the causes of graft dysfunction. Coexistent causes were biliary complication, HCV recurrence, sepsis, preservation-reperfusion injury, steatosis, or CMV-related pathology.
Recurrence of original disease was confirmed in 18 biopsies obtained from 10 recipients. These were attributable to ethanol-related CLD in 8 biopsies, HCV recurrence in 6, recurrence of Primary biliary cholangitis (PBC) in 2, and recurrence of HCC and HBV in one case each.
Graft dysfunction due to rejection: out of 137 cases, 14 biopsies were reported to be indeterminate for rejection. The remaining 123 cases from 69 LDLT recipients' patients were distributed in the four time zone groups according to the time of occurrence of graft dysfunction: group 1–22 (17.9%), group 2–27 (22%), group 3–36 (29.3%), and group 4–38 (30.9%). Baseline characteristics were recorded for each group and are compiled in [Table 3]. Serum ALT and AST levels were significantly higher in the early period (P < 0.000), whereas the rest of the lab parameters showed no statistically significant difference.
|Table 3: Baseline characteristics of the recipients with histological diagnosis of rejection|
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Assessment of rejection-related histological parameters: sixteen parameters that were reassessed and compared among the four groups [Table 4] revealed significant findings.
Predominant portal-based inflammation was the most common in group 1; however, it was not statistically different in other groups (P = 0.09). Severity of PI was highest in group 1, whereas CP was most pronounced in group 3; however, no statistical difference was found.
Histopathology analysis in the 4 groups revealed PI of mixed type in group 1 (P < 0.000), whereas mononuclear type in groups 2 to 4. Portal vein and hepatic vein endothelialitis were most striking in group 1 (P = 0.001 and P < 0.000, respectively) and were of lesser degree in groups 2–4. Portal eosinophils and lymphocytic bile duct damage were also most pronounced in group 1 (P = 0.001 and P = 0.01, respectively). Perivenulitis without hepatic vein endothelialitis was the most significant (P = 0.03) in group 3 (>6 months posttransplant) [Figure 1] and [Figure 2]. Portal plasma cells, zone 3 hepatocellular and canalicular bile, interface activity and LI did not reveal any significant difference among the four groups. Thus, portal tract-based features of classical ACR were most pronounced in the allograft biopsies performed in the first 3 months and atypical features describing LAR were frequent in the rest of the biopsies, including those received in the intermediate period (group 2) [Figure 3].
|Figure 1: Histological characteristics in different time zones: features of classical acute rejection|
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|Figure 2: Histological characteristics in different time zones: features of early classical and late rejection|
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|Figure 3: Microphotograph depicting classical early acute rejection with portal mixed inflammation (including eosinophils), portal vein endothelialitis, bile duct damage, and periportal spillover of inflammation (a-c); atypical acute rejection with mononuclear portal tract inflammation with interface activity, minimal portal vein endothelialitis, bile duct damage, and CP with perivenular congestion (d-f)|
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Bile duct atypia and duct loss were most common and severe in group 4 (>12 months posttransplant) and least evident in group 1 (P = 0.01 and P < 0.000, respectively) [Figure 4] and [Figure 5].
|Figure 4: Microphotograph depicting chronic rejection with bile duct atypia and atrophy (a), perivenular bile and foam cells (b), and small ghost-like tracts with minimal inflammation and duct atrophy (c)|
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|Figure 5: Histological characteristics in different time zones: biliary changes in rejection|
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Out of 69 patients from whom 123 biopsies were retrieved, 35 patients had a single episode of rejection and 34 patients had dual or multiple episodes of rejection. The presence of CP and bile duct loss were compared in both groups. Patients with multiple episodes of rejection were found to have a significantly higher incidence of CP (P = 0.002) and bile duct loss (P < 0.001) [Table 5].
|Table 5: Incidence of central perivenulitis and bile duct loss in patients with single/multiple episodes of rejection|
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| Discussion|| |
Liver allograft biopsy plays a very important role in posttransplant management. Besides being the gold standard for rejection and disease recurrence—the most important complications of early and late graft dysfunction—biopsy assists in many other ways. Pathology interpretation is required for the assessment of severity and progression of damage, monitoring of the course, and confirmation of diagnosis. A biopsy can guide in such challenging situations toward the dominant cause of graft dysfunction or even appraise an unsuspected or additional confounding factor.
This is a retrospective study of clinically indicated posttransplant liver biopsies performed in a large series of LDLT recipients. Several reviews ,,, and a few original articles have delineated the histology in early and later periods,,, whereas a few are focused only on late graft dysfunction.,,, The novelty of this study is the analysis of the histological spectrum of both early and late graft dysfunction divided in four different time zones with critical analysis of rejection histology, studied in a large number of LDLT allograft liver biopsies (n = 313).
The most frequent indication for LDLT was alcohol related and cryptogenic decompensated cirrhosis. Alcohol has become the most prevalent indication for liver transplant, leaving behind HCV, which was the major indication earlier., Majority of the patients were males, in accord with existing studies. In our series, liver allograft biopsies received in the different time zones were nearly equal. The most common histological diagnosis of dysfunction was rejection, which is in agreement with the published literature.,
69.2% of rejection biopsies were received within 1 year of LT which is similar to other studies. Late graft dysfunction is often attributable to several potential causes, making biopsy examination essential. In our series, graft dysfunction was attributable to multiple offenders in 37 cases; 62% of them occurred in late posttransplant period, with acute cellular rejection and biliary pathology being the most frequent combination. This is in compliance with other studies. In our series, recurrence of ethanol-related liver disease was the most common, followed by HCV infection. Many studies have shown HCV as the most frequent cause of recurrence.,,,
Rejection pathology differs with respect to the type, severity and distribution of inflammation as well as the predominant immune targets.,,,,, Histology of ACR differs from LAR. However, a single biopsy might display features of ACR as well as signs of progressive liver injury with bile duct loss in different tracts., There is increasing awareness and concern about timely and correct diagnosis of LAR. It shows variable behavior but more often it is associated with poor response to immunosuppression, greater risk of recurrence of ACR, progression to CR, and graft loss., LAR has no unanimous definition and is arbitrarily defined to occur after 1, 3, 6, or 12 months after transplantation.,,,,, LAR is characterized by portal-based inflammatory changes, which are less intense, predominantly mononuclear, with prominent interface activity, bile duct atypia and CP, seen in the same biopsy.
Sine qua non and overlaps in rejection histology in different periods posttransplantation is the highlight of this study. Comprehensive assessment of 16 histomorphological parameters in these time zones ratifies such distribution and complex histomorphology. Rejection biopsies retrieved in the period of 3–12 months posttransplant, particularly exhibited amalgamation of the typical early acute and chronic rejection features. Early biopsies showed predominant portal involvement by mixed inflammation, portal eosinophils, portal vein and hepatic vein endothelialitis, and lymphocytic bile duct damage. Bile duct atypia and duct loss were most common and severe in the biopsies obtained after 1 year. CP without hepatic vein endothelialitis was frequent in intermediate and late posttransplant biopsies. Thus, portal tract-based features of ACR were most prominent in the allograft biopsies performed in the first 3 months and atypical features describing late acute rejection were frequent in the rest of the biopsies, including those received in the intermediate period (group 2). Interestingly, LAR and CR were noted in the early and intermediate periods also in our study. Such early occurrence has rarely been reported by others as well.
In the present study, patients with multiple episodes of rejection were found to have a significantly greater incidence of CP as well as bile duct loss. This agrees well with the published literature that affirms CP and bile duct loss as poor prognostic features.
| Conclusion|| |
This comprehensive analysis of the histological spectrum of graft dysfunction in 313 allograft biopsies elucidates the frequency and time of occurrence of various complications as well as distribution and overlap of rejection histological characteristics in different time zones posttransplant. The most frequent diagnosis of graft dysfunction was rejection followed by recurrence of original disease. Complex histomorphology attributable to multiple complications was seen in 12% of the biopsies. Portal-based features of rejection were most common in early dysfunction, whereas perivenular changes were most pronounced in 6–12 months and biliary atrophy after 1 year. Features characterizing LAR were noted in a significant number of cases in 3–6 months period; similarly, CR was found as early as 3 months posttransplant. Rejection affecting zone 3 or bile ducts was found to be associated with repeated episodes of rejection or further deterioration. Histological assessment in different time zones after transplant in a large series of LDLT recipients provides critical overview of histology in rejection.
Prof. Shiv K Sarin, Director, ILBS, Delhi, India, for his continuous guidance and support during all the stages of this study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Professor (Pathology), Institute of Liver and Biliary Sciences (ILBS), D-1, Vasant Kunj, New Delhi - 110 070
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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