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Table of Contents
REVIEW ARTICLE
Year : 2018  |  Volume : 12  |  Issue : 2  |  Page : 78-83

Liver transplant pathology: When the things are grave!


Department of Histopathology, SRL Ltd., Fortis Escorts Heart Institute, New Delhi, India

Date of Web Publication29-Jun-2018

Correspondence Address:
Dr. Nalini Bansal
SRL Ltd., Fortis Escorts Heart Institute, Okhla Road, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_3_18

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  Abstract 


Post transplant liver biopsies (PTLB) form a cornerstone in management of transplant cases. They provide critical information regarding rejection or reoccurrence of diseases. With the development in understanding of transplant pathology new updates have come in reporting guidelines of liver transplant biopsy specimens. The recent updates also include criteria for reporting of antibody mediated rejection in liver. This review aims to cover all those aspects.

Keywords: Liver transplant, pathology, rejection


How to cite this article:
Bansal N. Liver transplant pathology: When the things are grave!. Indian J Transplant 2018;12:78-83

How to cite this URL:
Bansal N. Liver transplant pathology: When the things are grave!. Indian J Transplant [serial online] 2018 [cited 2018 Sep 25];12:78-83. Available from: http://www.ijtonline.in/text.asp?2018/12/2/78/235593




  Introduction Top


Posttransplant liver biopsies (PTLBs) form a cornerstone in the management of transplant cases. They provide critical information regarding rejection or reoccurrence of diseases. Previously, many centers were used to perform protocol biopsies at 0, 1, and 6 months to look for graft dysfunction and to predict dysfunction at a preventable stage. Currently, in most centers, biopsies are performed only when indicated. The interpretation of PTLB is an essential part of surgical pathologist trays these days and can guide therapy in many ways. This review aims at understanding of posttransplant liver pathology with an insight into 2016 Update of the Banff Working Group.

Clinical prerequisite for reporting posttransplant liver biopsies

The following information is basic minimal for reporting transplant biopsies:

  1. Timing of biopsy
  2. Primary etiology of liver disease
  3. Trends of liver function test.



  Graft Dysfunction Top


Hepatic allograft dysfunction is defined as increasing or persistent elevations in serum levels of alanine/aspartate aminotransferase, alkaline phosphatase, or bilirubin. Graft dysfunction posttransplant can be divided arbitrarily as:[1]

  • Early graft dysfunction: Occurring < or = 2-month posttransplant
  • Late graft dysfunction: Occurring >2-month posttransplant.


Early graft dysfunction

It mostly occurs due to perfusion-reperfusion injury (PRI), antibody-mediated rejection (AMR), small for size syndrome, T-cell-mediated rejection (TCMR).

Perfusion-reperfusion injury

It is injury occurring to graft during the period of preservation of graft. The graft undergoes three phases of perfusion injury as cold and warm ischemia (while it is harvested from donor) and reperfusion injury (during revascularization in recipient). Maximum injury occurs at the time of reperfusion because of formation of free radicals. A drop in mean arterial pressure >30% below the baseline value, lasting for at least 1 min, occurring during the first 5 min after reperfusion of the liver graft (unclamping of the hepatic hilum) frequently results in PRI.[2]

Histological indicators show marked hepatocyte ballooning/apoptosis, neutrophilic aggregates, and cholangiolar cholestasis [Figure 1].
Figure 1: Cholangiolar cholestasis with hepatocyte ballooning

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Antibody-mediated rejection

It is usually seen in hemolytic disease of the newborn, ABO incompatible (ABA-I) grafts rarely in ABO-compatible grafts. It presents with graft dysfunction within the first 2 weeks of transplantation mostly within 1–2 days in a host with preformed antidonor antibodies. Clinically, it shows marked rise in gamma-glutamyl transpeptidase with or without aspartate transaminase/alanine aminotransferase elevation along with gradual increase in bilirubin.[3] The criteria for AMR are now being reclassified by the 2016 Banff update with histopathology score and C4d score performed on formalin-fixed tissue [Table 1]. Based on combined h and C4d scores together with donor-specifi c antibody testing criteria for AMR are given as shown in [Table 2].
Table 1: C4d and histopathology score for acute antibody-mediated rejection

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Table 2: Diagnostic criteria of antibody-mediated rejection

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Histological indicators

Widespread neutrophilic exudation, congestion, portal hemorrhage and coagulative hepatocyte necrosis leading to massive hemorrhagic necrosis. There are bile ductular proliferation and neutrophilic cholangitis mimicking histology of biliary obstruction. Linear to granular deposition of C4d on portal vein, capillary, inlet venule, focally within sinusoids and central vein [Figure 2]. Deposition in elastic lamina of arteries, portal and perivenular elastic fibers, and necrotic and steatotic hepatocytes is a nonspecific finding and should be ignored.
Figure 2: (a and b) Portal hemorrhage (H and E, MT ×10). (c) Neutrophilic infiltrate. (d) Immunofluorescence showing C4d deposits. (e) C4d immunohistochemistry

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Role of C4d immunohistochemistry/immunofluorescence

Diffuse deposition in >50% portal tracts in >50% circumference of portal microvascular endothelium is regarded as a diagnostic pattern in an ABO incompatible graft.

Small for size syndrome

For successful transplant, donor graft-to-recipient body weight ratio should be (acceptable >0.6, preferably >0.8%). Remnant liver in donor should usually be >30%. If graft size is small compared to recipient weight, there will be portal hyperperfusion. Portal hyperperfusion leads to portal vein and periportal sinusoidal endothelial denudation. Clinically, a patient presents with rising bilirubin, ascites, and coagulopathy.

Histological indicators

Hepatocanalicular cholestasis, steatosis, hepatocyte atrophy and sinusoidal endothelial denudation.

T-cell-mediated rejection (old terminology-acute cellular rejection)

TCMR is diagnosed in 30%–60% of liver recipients and typically occurs within the first 30 days following liver transplantation. It is a most common form of liver allograft damage and will rarely cause graft loss.[4]

Histologically, changes are noted mainly at three regions – portal tract, venous endothelium (portal and central vein), and bile duct. Portal tract shows mixed inflammation comprising mainly T-lymphocytes, eosinophils, and activated blasts. Bile ducts and veins show signs of damage by these inflammatory cells called ductulitis or “endotheliitis” or “endothelialitis” [Figure 3].
Figure 3: T cell-mediated rejection. (a) Mixed portal inflammation. (b) Endotheliitis

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The degree of infl ammation at these three sites is graded as per Banff criteria to get an index called rejection activity index (RAI) [Table 3].
Table 3: Grading of acute liver allograft rejection

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Based on RAI calculated, the rejection can be graded as mild (RAI – 3-4), moderate (RAI – 5, 6), and severe (RAI − >6).

Late T-cell-mediated rejection (late acute rejection)

It occurs usually more than 6-month posttransplant. Cases of late TCMR usually present with raised transaminase levels instead of cholestatic liver biochemistry. These cases are associated with increased frequency of adverse outcomes as progression to chronic rejection (CR)/graft loss.[5]

Biopsy shows mainly perivenular changes called central perivenulitis (CP) and less of portal changes. CP is defined as necroinflammatory changes around terminal hepatic venule and surrounding liver parenchyma. CP may represent an intermediate stage before progression to irreversible CR [Figure 4].
Figure 4: Central perivenulitis

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The presence of CP is graded as severe rejection regardless of RAI score which could be low as 4, 5 or so but requires urgent intervention.

Opportunistic infections

Opportunistic infections are seen commonly after liver transplant due to immunosuppression. Common infections are cytomegalovirus (CMV), herpes simplex virus, and Epstein–Barr virus (EBV). The majority of CMV infections occur between the 6th- and 8th-week postliver transplant. Cases of herpes classically present with progressive transaminase elevation, abdominal pain, and coagulopathy, rarely jaundice. Transplant recipients who are EBV seronegative and who receive a seropositive organ are the prime targets for EBV infection and posttransplant lymphoproliferative diseases. EBV infection is very frequent in pediatric transplant cases compared to adults.[6],[7]

Histological indicators

  • CMV – Typical nuclear inclusion bodies or microabscesses are noted
  • Herpes – Areas of confluent necrosis with hepatocytes showing ground-glass nuclei and multinucleation.


Vascular and biliary complications

Vascular complications after liver transplantation include hepatic artery, portal vein, and hepatic vein stenosis and thrombosis. Hepatic artery complications are the most common vascular complications and occur in 5%–12% of adult liver recipients.

Biliary complications occur in up to 10%–20% of patients after liver transplantation and remain a significant cause of posttransplant morbidity.

Histological indicators of biliary cholangiopathy includes expanded portal tract with bile ductular proliferation and neutrophilic cholangitis along with cholestasis. CK7 will highlight bile ductular proliferation along with several regenerating hepatocytes [Figure 5].
Figure 5: (a) Bile ductular reaction. (b) Many regenerating hepatocytes with ductular reaction IHC CK 7

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Late graft dysfunction

Recurrence of primary diseases

Diseases that reoccur the following transplants are hepatitis C (>90% cases), primary biliary cirrhosis (20%–50%), primary sclerosing cholangitis (20%–30%), AIH-Autoimmune Hepatitis (20%–30%), nonalcoholic fatty liver disease (20%–40%), and hepatitis B (<10%).[8]

Major histological dilemma is to distinguish between reoccurrence and rejection, especially recurrent hepatitis C and acute rejection.

Histological indicators

Suggestive of hepatitis C virus reoccurrence: Portal tract shows mainly mononuclear cell infiltrate and occasionally lymphoid aggregate. There is a predominance of lobular unrest with hepatocytes showing ballooning degeneration and frequent apoptosis. Rejection shows mixed inflammation in tract with quiet lobules or in late rejection CP [Figure 6].
Figure 6: Hepatitis C virus reoccurrence showing portal lymphoid aggregate

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Chronic rejection

CR leads to progressive graft dysfunction leading to graft failure. CR can be TCMR or chronic AMR.

Histological indicators of chronic T-cell-mediated rejection

Features have been categorized as early and late chronic TCMR. Loss of small bile ducts (ductopenia) and obliterative vasculopathy of medium-to-large-sized arteries are important diagnostic findings [Figure 7]. Ductopenia is much more important finding as it is frequently identified in biopsy tissue. The ductopenia of TCMR is not accompanied by bile ductular reaction as opposed to biliary obstruction [Table 4].
Figure 7: (a) Ductopenia without bile ductular proliferation (H and E, ×20). (b) Immunohistochemistry CK7 highlighting duct loss

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Table 4: Histological features of early and late chronic T-cell-mediated rejection

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Ductopenia in CR is called when there is bile duct loss in more than 50% of portal tracts. The absence of ductular proliferation or signifi cant periportal fi brosis helps to differentiate CR from other recurrent or de novo cholestatic diseases. The degree of fibrosis in chronic rejection is graded as [Table 5].
Table 5: Suggested fibrosis scoring

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Chronic AMR being recognized as a distinct entity in 2016 Banff update. The criteria given for chronic AMR are shown in [Table 6].
Table 6: Criteria for Chronic AMR

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  Plasma Cell-Rich Rejection (Old Terminology-Plasma Cell Hepatitis/de Novo autoimmune Hepatitis) Top


As per 2016 Banff update, PCRR is now considered as a variant of rejection with mixed TCMR and AMR etiology overlapping with autoimmunity and is a cause of late graft loss postliver transplantation, especially in interferon-treated hepatitis C recipients. It should be part of the differential diagnosis of abnormal liver enzyme tests occurring in the late postliver transplant setting usually seen >6-month posttransplant. Portal and/or perivenular plasma cell-rich (estimated >30%) infi ltrates with easily recognizable periportal/interface and/or perivenular necroinfl ammatory activity usually involving a majority of portal tracts and/or central veins [Figure 8]. The criteria for diagnosis of PCRR are shown in [Table 7]. The criteria require the absence of original disease as autoimmune etiology. Such cases should be diagnosed recurrence of autoimmune disease and not PCRR. The authors have also recommended C4d immunohistochemistry in all cases of PCRR.[9],[10],[11]
Figure 8: Plasma cell-rich portal infiltrate with interface

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Table 7: Diagnostic criteria of plasma cell-rich rejection

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Liver transplant pathology thus is a useful tool for guiding therapy. Early diagnosis can salvage the liver graft.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Wiesner RH, Menon KV. Late hepatic allograft dysfunction. Liver Transpl 2001;7:S60-73.  Back to cited text no. 1
[PUBMED]    
2.
Siniscalchi A, Gamberini L, Laici C, Bardi T, Ercolani G, Lorenzini L, et al. Post reperfusion syndrome during liver transplantation: From pathophysiology to therapy and preventive strategies. World J Gastroenterol 2016;22:1551-69.  Back to cited text no. 2
[PUBMED]    
3.
Salah A, Fujimoto M, Yoshizawa A, Yurugi K, Miyagawa-Hayashino A, Sumiyoshi S, et al. Application of complement component 4d immunohistochemistry to ABO-compatible and ABO-incompatible liver transplantation. Liver Transpl 2014;20:200-9.  Back to cited text no. 3
[PUBMED]    
4.
Demetris A, Adams D, Bellamy C, Blakolmer K, Clouston A, Dhillon AP, et al. Update of the international Banff schema for liver allograft rejection: Working recommendations for the histopathologic staging and reporting of chronic rejection. An International Panel. Hepatology 2000;31:792-9.  Back to cited text no. 4
[PUBMED]    
5.
Akamatsu N, Sugawara Y, Tamura S, Keneko J, Matsui Y, Hasegawa K, et al. Late-onset acute rejection after living donor liver transplantation. World J Gastroenterol 2006;12:6674-7.  Back to cited text no. 5
[PUBMED]    
6.
Meru N, Davison S, Whitehead L, Jung A, Mutimer D, Rooney N, et al. Epstein-Barr virus infection in paediatric liver transplant recipients: Detection of the virus in post-transplant tonsillectomy specimens. Mol Pathol 2001;54:264-9.  Back to cited text no. 6
[PUBMED]    
7.
Razonable RR. Cytomegalovirus infection after liver transplantation: Current concepts and challenges. World J Gastroenterol 2008;14:4849-60.  Back to cited text no. 7
[PUBMED]    
8.
Hübscher SG. What is the long-term outcome of the liver allograft? J Hepatol 2011;55:702-17.  Back to cited text no. 8
    
9.
Demetris AJ, Bellamy C, Hübscher SG, O'Leary J, Randhawa PS, Feng S, et al. 2016 comprehensive update of the Banff working group on liver allograft pathology: Introduction of antibody-mediated rejection. Am J Transplant 2016;16:2816-35.  Back to cited text no. 9
    
10.
Bansal N, Rastogi M, Wadhawan M, Vij V, Kumar A. Retrospective analysis of post-transplant liver biopsies – From diagnosis to therapy – Can we guide further? Experience from a tertiary care center in India. Indian J Transplant 2017;11:138-42.  Back to cited text no. 10
  [Full text]  
11.
Bansal N. Liver Biopsy Made Easy. 1st ed. New Delhi: Jaypee Publisher; 2016.  Back to cited text no. 11
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

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