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Progressive histological damage in liver allografts following paediatric liver transplantation

Progressive histological damage in liver allografts following paediatric liver transplantation. Helen M Evans 1 , Deirdre A Kelly 1 , Patrick J McKiernan 1 and Stefan G Hübscher 2

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Progressive histological damage in liver allografts following paediatric liver transplantation

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  1. Progressive histological damage in liver allografts following paediatric liver transplantation Helen M Evans1, Deirdre A Kelly1, Patrick J McKiernan1 and Stefan G Hübscher2 1The Liver Unit, Birmingham Children’s Hospital, United Kingdom and 2Department of Pathology, University of Birmingham, United Kingdom

  2. Background • Histological Findings in Late (>12 months) Post-Transplant Biopsies • Chronic hepatitis in the liver allograft • Specific issues relating to the paediatric liver allograft recipient

  3. Histological Findings in Late (>12 months) Post-Transplant Biopsies(Nakhleh 1990, Hübscher1990, Hübscher 1993, Pappo 1995 Rosenthal 1997, Slapak 1997, Pessoa 1998, Davison 1998,Sebagh 2003, Heneghan 2003, Rifai 2004, Nakhleh 2005) • Studies in adults suggest that the majority (70-90%) develop histological abnormalities • Many seen in protocol biopsies obtained from people who are clinically well with good graft function • Recurrent disease (particularly HCV) is the commonest aetiological factor. • Rejection relatively uncommon. May have different features to those seen in the early post-transplant period. • Many biopsies have features of chronic hepatitis. • In a varying proportion of cases no obvious cause for chronic hepatitis can be identified

  4. Histological Findings in Late (>12 months) Post-Transplant Biopsies(Nakhleh 1990, Hübscher1990, Hübscher 1993, Pappo 1995 Rosenthal 1997, Slapak 1997, Pessoa 1998, Davison 1998,Sebagh 2003, Heneghan 2003, Rifai 2004, Nakhleh 2005)

  5. Factors Influencing the Assessment of Late Post-transplant biopsies • Nature of original liver disease • Indication for liver biopsy (protocol or clinically indicated) • Type/amount of immunosuppression used • Recurrent disease versus other transplant complications • Diagnostic criteria

  6. Chronic Hepatitis in the Liver Allograft Possible Causes • VIRAL INFECTION (recurrent or acquired) - hepatitis B - hepatitis C • RECURRENT AUTOIMMUNE DISEASE - autoimmune hepatitis - primary biliary cirrhosis - primary sclerosing cholangitis • ‘DE NOVO’ AUTOIMMUNE HEPATITIS • DRUG TOXICITY • UNKNOWN (?REJECTION)

  7. Chronic Hepatitis in the Liver Allograft Possible Causes • VIRAL INFECTION (recurrent or acquired) - hepatitis B - hepatitis C • RECURRENT AUTOIMMUNE DISEASE - autoimmune hepatitis - primary biliary cirrhosis - primary sclerosing cholangitis • ‘DE NOVO’ AUTOIMMUNE HEPATITIS • DRUG TOXICITY • UNKNOWN (?REJECTION)

  8. Chronic Hepatitis in the Liver Allograft Possible Causes • VIRAL INFECTION (recurrent or acquired) - hepatitis B - hepatitis C • RECURRENT AUTOIMMUNE DISEASE - autoimmune hepatitis - primary biliary cirrhosis - primary sclerosing cholangitis In some cases histological features of “non-specific” chronic hepatitis may precede development of more typical biochemical, serological or histological changes • ‘DE NOVO’ AUTOIMMUNE HEPATITIS • DRUG TOXICITY • UNKNOWN (?REJECTION)

  9. Chronic Hepatitis in the Liver Allograft Possible Causes • VIRAL INFECTION (recurrent or acquired) - hepatitis B - hepatitis C • RECURRENT AUTOIMMUNE DISEASE - autoimmune hepatitis - primary biliary cirrhosis - primary sclerosing cholangitis • ‘DE NOVO’ AUTOIMMUNE HEPATITIS • DRUG TOXICITY • UNKNOWN (?REJECTION)

  10. ‘De Novo’ Autoimmune Hepatitis in the Liver Allograft(Kerkar 1998, Jones 1999, Gupta 2001, Heneghan 2001, Salcedo 2002, Czaja 2002, Vergani 2002, Mieli-Vergani 2004). • Classical biochemical, serological and histological features of AIH may develop in patients transplanted for other diseases • Higher incidence in paediatric population (up to 5-10%) • In adult population commonest underlying diseases are PBC and PSC. • Most cases respond to increased immunosuppression. Occasional cases have progressed to graft failure

  11. ‘De Novo’ Autoimmune Hepatitis in the Liver Allograft Problems with Classification • Antibodies directed against graft antigens rather than self antigens (alloimmune rather than autoimmune disease?) • Autoantibodies arising de novo following transplantation also described transiently in association with episodes of rejection. (Lohse 1999, Duclos-Vallee 2000) • Acute rejection episodes have predictive value for development of de novo AIH (D’Antiga 2002,Miyagawa-Hayashino 2004) • “De novo” AIH may represent a form of late cellular rejection • “Graft dysfunction mimicking autoimmune hepatitis“ may be a better term (Heneghan et alHepatology 2001 ;34 :464-70)

  12. Chronic Hepatitis in the Liver Allograft Possible Causes • VIRAL INFECTION (recurrent or acquired) - hepatitis B - hepatitis C • RECURRENT AUTOIMMUNE DISEASE - autoimmune hepatitis - primary biliary cirrhosis - primary sclerosing cholangitis • ‘DE NOVO’ AUTOIMMUNE HEPATITIS • DRUG TOXICITY - chronic hepatitis not typical of immunosuppressive drug toxicity - 7/31 cases of post-transplant hepatitis (patients at low risk for disease recurrence) = probable drug toxicity (Nakhleh Transplant Proc. 2005 Mar;37(2):1240-2) • UNKNOWN (?REJECTION)

  13. Chronic Hepatitis in the Liver Allograft Possible Causes • VIRAL INFECTION (recurrent or acquired) - hepatitis B - hepatitis C • RECURRENT AUTOIMMUNE DISEASE - autoimmune hepatitis - primary biliary cirrhosis - primary sclerosing cholangitis • ‘DE NOVO’ AUTOIMMUNE HEPATITIS • DRUG TOXICITY • UNKNOWN (?REJECTION)

  14. Late Cellular Rejection Different Histological Features(Snover 1988, Kemnitz 1989, Cakaloglu 1995, Pappo 1995) • Bile duct inflammation and venular endothelial inflammation less conspicuous • More prominent interface hepatitis • More prominent lobular hepatitis with spotty necrosis • Overall features resemble those seen in chronic hepatitis (e.g. viral or autoimmune)

  15. Late Post-Transplant Histology in the Paediatric Population • Few studies have specifically assessed late post-transplant biopsies in children undergoing liver transplantation • Most of the diseases for which transplantation carried out in children do not recur. Chronic hepatitis in the paediatric liver allograft recipient not due to recurrent disease • Children more susceptible than adults to develop ‘de novo’ autoimmune hepatitis

  16. Methods Patients & Biopsies 210 children transplanted between 1983 and 1996 158 alive with graft survival > 5 years - age 0.0- 15.9 years (median 2.9, mean 4.7) - 69 (44%) whole livers, 89 (56%) reduced size (81 cut down, 8 split) Protocol biopsies at 1, 5 and 10 years post-transplant Other investigations: - standard LFTs (AST, bilirubin, Alk Phos) - immunoglobulins A, G, M - autoantibodies (ANA, SMA, AMA, LKM) - ≥ 1:25 = positive - CMV and EBV serology - HBV, HCV and HGV serology (if biopsy showed chronic hepatitis)

  17. Indications for transplantation (158 cases) Indication for transplantation Number % • Cholestatic disorders 85 53.4 Extra hepatic biliary atresia 77 48.4 Other 8 5.0 • Fulminant hepatic failure 23 15.1 Non-A, non-B, non-C acute hepatitis 15 9.5 Viral hepatitis (HAV -3, Echovrus -1) 4 2.5 Drug-induced 4 2.5 • Metabolic disorders 23 15.1 Alpha-1-antitrypsin deficiency 8 5.0 Tyrosinaemia type 1 5 3.1 Wilson’s disease 6 3.8 Other 4 2.5 • Autoimmune diseases 8 5.0 Autoimmune hepatitis 3 1.9 Sclerosing cholangitis 5 3.1 • Miscellaneous 19 11.9 Cryptogenic cirrhosis 7 4.4 Cystic fibrosis 6 3.8 Hepatoblastoma 4 2.5 Other 2 1.2

  18. Methods Histological Assessments • Histological data recorded using a long-term biopsy proforma (since 1989) • Range of portal and parenchymal features assessed, some semi-quantitatively graded • Final diagnostic category assigned • Statistical analyses • Chi-squared test to demonstrate differences in frequencies of observations at 1, 5 and 10 years • Logistic regression to investigate factors associated with histological abnormalities at 5 years (time at which most biopsies available)

  19. Methods Assessment of Inflammatory Activity and Fibrosis(cases with chronic hepatitis) Inflammatory Activity Grade • Interface hepatitis (0-3) • Lobular necro-inflammation (0-3) • Overall inflammatory grade (0-3) Fibrosis Stage • 0 = none • 1 = mild (fibrous expansion without bridging) • 2 = moderate (bridging fibrosis) • 3 = cirrhosis

  20. Methods Variables Assessed Statistically Demographic variables • Underlying liver disease • Age (recipient and donor) • Sex (recipient and donor) • Blood group (recipient and donor) • CMV status (recipient and donor) • Cold ischaemic time • Type of allograft (whole, reduced or split) Dynamic variables (at time of biopsy) • Transaminase levels (ALT and AST) • Immunoglobulin levels • Autoantibody positivity

  21. ResultsBiopsies at Different Time Points 1 year 113/158 (72%) biopsied (10-17 months, mean 14 months) • No graft loss or death between 1-5 years 5 years 135/158 (85%) biopsied (49-87 months, mean 62 months) • 11 graft losses between 5-10 years • 7 deaths (rec disease-4, bacterial sepsis-2, SAH-1) • 4 retransplanted (biliary obstruction-2, chronic rejection-1, de novo AIH-1) 10 years 64/81 (79%) biopsied (102-132 months, mean 117 months) Configuration of patients similar at 3 time points (no drop-out bias)

  22. Main Histological Findings at 1, 5 and 10 years (1) & (2) p < 0.0001

  23. Normal/near-normal biopsies

  24. Chronic Hepatitis 124 biopsies 25 – 1 year, 58 – 5 years, 41 – 10 yearsNecroinflammatory Activity

  25. Chronic Hepatitis Severity of Necro-inflammatory Activity at Different Times

  26. Chronic Hepatitis – Histological FindingsInflammatory Changes

  27. Chronic Hepatitis (mild)- Portal inflammation, mild interface hepatitisMale, age 8, 1 year post-transplant for cryptogenic cirrhosis

  28. Chronic Hepatitis (mild) – Portal lymphoid follicleFemale, age 6, 5 years post-transplant for acute liver failure (seronegative hepatitis)

  29. Chronic Hepatitis (mild) - Spotty lobular inflammation (zone 3)Female, age 44, 8 years post-transplant for PBC

  30. Chronic Hepatitis (mild) - Zone 3 inflammation with dropout Female, age 24, 1 year post-transplant for acute liver failure (seronegative hepatitis)

  31. Chronic Hepatitis - Isolated zone 3 inflammation Female, age 24, 1 year post-transplant for acute liver failure (seronegative hepatitis)

  32. Chronic Hepatitis (moderate) – portal and lobular (zone 3) inflammationMale, age 3, 2.5 years post-transplant for biliary atresia

  33. Chronic Hepatitis (moderate) – Portal inflammtion with interface hepatitisMale, age 3, 2.5 years post-transplant for biliary atresia

  34. Chronic Hepatitis (moderate) – Zone 3 necro-inflammationMale, age 3, 2.5 years post-transplant for biliary atresia Normal Hepatic Vein

  35. Chronic Hepatitis (moderate) - Portal plasma cells Female,age 58, 1 year post-transplant for PBC (no other autoantibodies)

  36. Chronic Hepatitis (severe) – Portal inflammation with interface hepatitisFemale, age 57, 12 years post-transplant for PBC

  37. Chronic Hepatitis (severe) – bridging necrosisFemale, age 30, 3 years post-transplant for fibrolamellar HCC

  38. Chronic Hepatitis (severe) – bridging necrosis Female, age 30, 3 years post-transplant for fibrolamellar HCC

  39. Chronic Hepatitis (severe) – panacinar necrosisFemale, age 30, 3 years post-transplant for fibrolamellar HCC

  40. Chronic Hepatitis versusLate Cellular Rejection

  41. Chronic Hepatitis (mild) Female, age 28, 3 years post-transplant for acute liver failure (paracetamol)

  42. Chronic hepatitis (mild) ? Cellular rejection - Bile duct inflammationFemale, age 28, 3 years post-transplant for acute liver failure (paracetamol)

  43. Chronic hepatitis (mild) ? Cellular rejection – Portal venulitis Female, age 28, 3 years post-transplant for acute liver failure (paracetamol)

  44. Chronic hepatitis (mild) ? Cellular rejection – Bile duct loss Female, age 28, 3 years post-transplant for acute liver failure (paracetamol)

  45. Chronic Hepatitis – Histological FindingsFibrosis

  46. Chronic Hepatitis - Bridging FibrosisFemale, age 53, 4 years post-transplant for acute liver failure (seronegative hepatitis)

  47. Chronic Hepatitis – CirrhosisMale, age 21, 8 years post-transplant for cystic fibrosis

  48. Chronic Hepatitis Severity of Fibrosis at Different Times (P<0.0001)

  49. Correlation between AST levels and Histology P < 0.005 Other histology vs normal/chronic hepatitis at 1 year

  50. Correlation between Autoantibodies and Histology P< 0.0001 (normal vs CH) 4 children with chronic hepatitis and autoantibodies (1 at 5 years + 3 at 10 years) had other features supporting a diagnosis of de novo AIH (AST>1.5xN, raised immunoglobulins)

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