Pathology of liver transplantation

1. Pathology of liver transplantation
Moderator: Dr Udayakumar M
Presenter: Dr G Santhipriya
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2. Contents
• Introduction
• Post-transplant liver biopsy techniques
• Types of post transplant liver biopsy
• Differentials as per timing of biopsy
• Spectrum of diseases
 Liver transplant rejection
 Recurrence of primary diseases
 Post transplant lymphoproliferative disorder
 Opportunistic infections
 Vascular complications
 Biliary tract complication
 Small for size graft syndrome
 De novo autoimmune hepatitis/ plasma cell hepatitis
• References
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3. Introduction
• Biopsies of liver allografts are -gold standard.
• They play an important and integral role in the
interpretation and explanation of changes that may occur
in
 response to alterations in function tests
 in the interpretation and explanation of functional
abnormalities,
 and in the interpretation and explanation of diagnostic
images
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4. • Biopsies are also useful for monitoring and are often part
of the protocol
• The evaluation of biopsy samples after transplantation
can be difficult especially because of the very broad
spectrum of complications that may arise in the post-
transplant period.
• Histological evaluation of liver allograft biopsies is an
integral part of the management of liver transplant
patients
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5. Post-transplant liver biopsy techniques
• Percutaneous approach(US/CT)
• A transjugular approach
• A surgical/ laparoscopic approach(open/lap)
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6. Types of post transplant liver biopsy
• 7 days
• LFT are insufficient
• 6 months
• To distinguish
• Interpret LFT
• Adjust immunosuppresive doses
• Recognize current disease
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7. Spectrum of diseases seen in post transplant liver
biopsies
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• Rejection
• Recurrence of original disease
• New onset/ de novo post transplant abnormalities
 Problems with preservation and reperfusion of donor
organ
 Technical / surgical complications involving vascular and
/or biliary structures
 Complications of immunosuppressive therapy
 De novo diseases
• Recurrent or de novo neoplasma

8. Differentials as per timing of biopsy
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9. Acute rejection
• Most common form of liver allograft damage
• Mostly within first month post transplant
 20-50%: clinically significant
 Protocol bx: definitive
• Elevated some or all liver injury test
• Histopathology: diagnostic triad
1. portal inflammation
2. bile duct damage
3. venular endothelial inflammation k/a endothelitis
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10. Portal tract showing mixed inflammation
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11. Portal tract showing mixed inflammation and
bile duct damage
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12. Portal tract showing endotheliatis
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13. Hyperacute (Humoral) Rejection
• Usually seen in ABO incompatible grafts rarely in ABO
compatible grafts
• First 2 weeks of transplantation, 1-2 days in a host with
preformed anti-donor antibodies
• C4d IHC – portal stroma/ venular plexus of >50% of
tracts: dx pattern for acute humoral rejection in ABO
incompatible grafts
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14. Neutrophilic exudation, congestion and coagulative
hepatocyte necrosis leading to massive hemorrhagic
necrosis
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16. Grading and staging of acute liver allograft
rejection
• Banff scheme- consensus of eminent.
• Once the diagnosis of acute rejection is made
 Graded descriptively- Global Assessment of Rejection
Grade or
 Numerically scored by semi-quantitative scoring system-
Rejection Activity Index(RAI)
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19. • RAI scored from 0 to 9
 Indeterminate 1-2
 Mild 3-4
 Moderate 5-6
 Severe >6
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20. • Mild rejection
 No definite therapeutic approach
 Mostly no additional immunosuppression required
• Moderate- severe rejection
 Warrant treatment with increased immunosuppression
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21. Late acute rejection
• 3-6 months post.
• Raised transaminase levels instead of cholestatic liver
biochemistry
• Less responsive to immunosuppresion
• Adverse outcome- AR/ CR/ de novo
• HPE- central perivenulitis
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22. Central perivenulitis
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23. Chronic rejection
• Progressive graft dysfunction leading to graft failure
during the first 12 months following transplantation
 Early
 Late chronic rejection
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24. • Early chronic rejection:
 Bile duct atypia- eosinophilic transformation of
cytoplasm, incr N/C ratio, nuclear hyperchormasia ,
unequal nuclear spacing
 Central perivenulitis
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25. • Late chronic rejection
 Loss of small bile ducts-ductopenia
 Obliterative vasculopathy of medium to large sized
arteries- rarley needle bx
• Ductopenia - > 50% of portal tracts, absence of ductual
proliferation or significant periportal fibrosis- advanced/
irreversible
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28. Liver transplant rejection
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29. Preservation/ Reperfusion Injury (PRI)
• Injury during preservation of graft
• Cold ischemia
• Warm ischemia
• Reperfusion injury- kupffer cell activation:ROS
• HPE: balooning, polymorph, cholangiolar cholestatis
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31. Recurrence of primary diseases
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• M/c/c of graft dysfunction in pts surviving > 12 months
post
 Hep C- >90%
 PBC- 20-50 %
 PSC
 AIH-20-30 %
 NAFLD- 20-40 %
 Hep B <10%

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33. Features suggestive of HCV reoccurance
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34. Fibrosing cholestatic hepatitis (FCH)
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• HBV & HCV inf- atypical aggressive reinfection pattern
• First few months- level of imsp are highest
• l/t graft failure
• a/w massive viral replication
• HPE- marked balooning, cholestatis, ductular
proliferation, perisinusoidal/ periportal fibrosis with lack
of significant inflammation

35. Marked hepatocellular balloning and
perisinosoidal fibrosis
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36. • DD- biliary stricture
• Bile ductular reaction seen in both
• Cholestasis in both
• Balooning more prominent in FCH, where as copper
associated protein, portal edema, neutrophils in portal
tracts and presence of CK7 positive intermediate cells in
priportal region are more prominent in biliary stricture
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37. Post transplant lymphoproliferative disorder
• B cell proliferation d/t therapeutic immsp post.
• Spectrum- polyclonal to lymphoma
• EBV
• 1 month, mostly after a yr
• In sity hybidization for EBV RNA
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38. Classification- 2008
• Early hyperplastic lesions: plasmacytic hyperplasia,
infectious mononucleosis like lesion
• Polymorphic lesions- polyclonal or monoclonal
• Monomorphic lesions- B cell neoplasms, T cell
neoplasma
• Classic Hodgkin type lymophomas
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39. • HPE- portal tracts are enlarged and densely infiltrated by
atypical L with large nuclei and prominent nucleoli
• Infiltrate – sinusoids, central venules and portal vein
• Late stage- densely packed monomorphic cells in the
enlarged portal tracts
• CD 20,kappa and lambda light chains, and EBV antigens
reveals predominantly or exclusively B cells in
lymphoproliferative disease
• RX- reduction or withdrawl in immsp with addition of
antiviral agents
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40. Opportunistic infections
• Cytomegaloviral hepatitis
• Herpes simplex viral hepatitis
• Epstein- Barr viral(EBV) Hepatitis
• Adenoviral hepatitis
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41. Cytomegaloviral hepatitis
• Mc opportunistic inf
• Absence of prophylaxis, first 3 months
• Types – reactivation, primary and super infection
• CMV syndrome- flu or inf mononucleosis syn, often with
neutropenia
• Tissue invasive dis- nephritis, hepatitis, carditis,
pneumonitis, pancreatitis, retinitis or colitis with the
transplanted orgn usually showing the greatest infl
pathology
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42. • Liver biopsy
 Lobules show microabscess- N
 Microgranuloma- mac,l, surrounding necrotic hepatocytes
 Inclusions-endo, bile duct e or parenchymal cells
 Portal tracts- mononuclear inflammatory cells
surrounding bile ducts with inclusions
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44. Opportunistic infections
• Cytomegaloviral hepatitis
• Herpes simplex viral hepatitis- HSV 1 & 2 IHC
• Epstein- Barr viral(EBV) Hepatitis- mononucleosis sys/
HSM
 Increased S.aminotransferase, leukocytosis. Ig M anti
EBV antibodies
 Single file arrangement- sinusoids
• Adenoviral hepatitis- pediatric
 Pox like granuloma-geographic necrosis resemble HSV
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45. Hepatic Artery Thrombosis (HAT)
• Several days to 1-3 yr
• Paediatric population, complex, technically demanding
anastomosis are created
• Biliary tract epithelial lining of allograft
• Ischemia and resultant strictures, necrosis and biliary
sludge syndrome= Ischemic cholangitis or ischemic
cholangiopathy
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46. • Hepatic arteiogram
• Bx-rare
• HPE- coagulative necrosis, ballooning degeneration of
centrilobular heptocytes, sinusoidal dilation, ductular
reaction with or without ductular cholestasis and
cholangitis
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47. Hepatic artery stenosis
• Can progress to HAT
• Surgical anastomosis and is linked to technical factors,
clamp injury, kinked vessels, fibrosis, edema and
thrombus formation
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48. Portal vein stenosis/ Thrombosis
• Cm seen in small for size graft syndrome
• Complete- massive hepatic necrosis/ failure or portal
hypertention with massive ascites and edema
• Partial – liver atrophy, zonal or panlobular steatosis,
nodualar regenerative hyperplasia , or seeding by
intestinal bac resulting in miliary/ small abscesses and
intermittent fever
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49. Biliary tract complication
• Biliary strictures
• Bile leakage
• Hepatobiliary iminodiacetic acid scan and
cholangiography
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50. • Liver biopsy
 Centrilobular cholestatis
 Changes in portal tracts- edema, ductal reaction-N, acute
cholangitis
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53. “Small- For- Size” Graft Syndrome
• To minimize the risk for living donors, transplant
surgeons aim at procuring the least necessary liver
volume, also l/t potentially small grafts
• Unable to meet the fun/met demands
• LDLT, a graft to recipient body weight ration>= 0.8 % or
graft weight ratio >= 30 %
• Portal hyperperfusion l/t portal vein and periportal
sinusoidal endothelial denudation
• Increased portal venous flow diminishes hepatic artery
flow, predisposing to arteria thrombosis and ischemic
cholangitis
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54. • Clinical features:
 Cholestatis
 Coagulopathy
 Ascites
 1-2 weeks post transplantaion
 d/t splanchnic congestion
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55. • Liver biopsy
 Sinusoidal cell injury, endothelial cell damage
 Biliary ischemia- nonspecific changes- centrilobular
canalicular cholestatis, steatosis, hepatic atrophy,
congestion, mild ductular reaction and ductular
cholestatis
 Obliterative venopathy and nodular regenerative
hyperplasia- small portal vein branch occlusion
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56. De novo auto immune heptitis/ plasma cell
hepatitis
• Allograft dysfunction with clinical, serologic, and
histologic features resembling AIH may dev in paediatric
and adult patients who have received LT for end stage
disease other than AIH
• Hypergammaglobulinemia
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58. References
1. Gupta NB. Liver biopsy made easy. 2017.
2. Varma V, Mehta N, Kumaran V, Nundy S. Indications and Contraindications for
Liver Transplantation. Int J Hepatol. 2011;2011:1–9.
3. Geramizadeh B, Malek-Hosseini SA. Role of Histopathologist in Liver
Transplantation. :6.
4. Wee A, Soon G. Liver transplantation: from a histopathologist’s perspective. Liver
Transpl. :9.
5. Neil DAH, Hübscher SG. Current views on rejection pathology in liver
transplantation: Liver transplant rejection pathology. Transpl Int. 2010
Oct;23(10):971–83.
6. R. A, R. L, J. R. Liver Biopsy After Liver Transplantation. In: Tagaya N, editor.
Liver Biopsy - Indications, Procedures, Results [Internet]. InTech; 2012
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59. • Thank you!!!
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