S.G. Hübscher, Department of Pathology, University of Birmingham, Birmingham B15 2TT, U.K. The...
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S.G. Hübscher, Department of Pathology, University of Birmingham, Birmingham B15 2TT, U.K.
The Spectrum of Findings in Protocol and Indicated Biopsies
in Long-term Liver Allograft Recipients(with an emphasis on diagnostic challenges)
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Histological findings in 1045 biopsies obtained > 1 year post-transplant, Liver Unit, QE Hospital, Birmingham
Main Diagnosis
Number (%) Of Cases
Comments
Normal / near normal 152 (15)
Rejection
82 (8) Many cases co-exist with other patterns of graft damage
Biliary obstruction / cholestasis
11 (1 )
Chronic hepatitis 294 (28) 59 (6%) cases related to recurrent disease 235 (22%) cases other/unknown cause
Recurrent disease 211 (20)
Other findings 295 ( 28 ) Fatty change, vascular/structural changes, fibrosis, siderosis
Data from Liver Unit Database, Jan 2004 – Jan 2009
Reason for biopsy - 720 (69%) protocol, 325 (31%) clinically indicated
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Histological findings in 1045 biopsies obtained > 1 year post-transplant, Liver Unit, QE Hospital, Birmingham
Clinically Indicated versus Protocol Biopsies
Main Diagnosis
Clinically Indicated (n = 325)
Protocol Biopsies (n = 720)
Normal / near normal 16 (5%) 136 (19%)
Rejection
76 (24%) 6 (1%)
Biliary obstruction / cholestasis
8(3%) 3 (0%)
Chronic hepatitis 68(21%) 226 (31%)
Recurrent disease 85 (26%) 126 (18%)
Other findings 72 (22%) 223 (31%)
Data from Liver Unit Database, Jan 2004 – Jan 2009
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Histological findings in late post-transplant biopsies Liver Unit, QE Hospital, Birmingham
Main Diagnosis
> 1 year ( n = 1045)
> 5 years (n = 541)
> 10 years (n = 235)
Normal / near normal 15% 12% 9%
Rejection
8% 8% 10%
Biliary obstruction / cholestasis
1% 1% 1%
Chronic hepatitis 28% 31% 29%
Recurrent disease 20% 20% 23%
Other findings 28% 27% 27%
Clinically indicated 31% 34% 39%
Data from Liver Unit Database, Jan 2004 – Jan 2009
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Long-term Liver Allograft Pathology.How Frequently Does the Graft Remain Normal?
Centre No of biopsies
Length of follow-up
Normal histology
Normal histology with:
LFTs N LFTs raised
Changing prevalence
with time
Pittsburgh(Pappo 1995)
65 >5years 34% 64% 25%
KCH London(Slapak 1997)
116 > 5years 23% 54% 13%
Valencia(Berenguer 2001)
254 > 1 year 44-58% - - 58% normal at 1 year
44% normal at 5 years
Paris(Sebagh 2003)
143 > 10years 20% 28% 10% 44 % normal at 5 years
20% normal at 10 years
Several cases classified as normal had “mild non-specific changes”
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Histological Findings in Protocol Biopsiesfrom Patients with Normal LFTs
Institution Time of
biopsy
No of
biopsies
Biopsies
Abnormal
Abormalities found
Mayo Clinic
(Abraham 2008)
3 months - 5 yrs
165 27% Fatty liver disease (11%), recurrent disease (10%), rejection/central perivenulitis (7%), other (2%)
(32% = “non-specific changes”)*
Dallas
(Khan, ILTS, Paris, July 2008)
1-20 yrs >4000 < 5% had inflammation
Acute rejection (2-3%), recurrent HCV (0.5-2%)
London (Kings)
(Bachina, ILTS, Paris, July 2008)
> 10 yrs 13 92% Fibrosis (92%) – mod/severe in 30%, lymphocytic infiltration of variable severity (54%)
Birmingham
(Mells 2009, in press)
1-10 yrs 237 76% Unexplained CH (33%), recurrent disease (23%), fatty liver disease (14%), other (5%)
* Includes portal and lobular lymphocytic infiltration
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Factors Influencing the Histology of Late Post-transplant Biopsies
1. Nature of original liver disease
2. Indication for liver biopsy(protocol or clinically indicated)
3. Duration of follow up
4. Type/amount of immunosuppression used
5. Diagnostic criteria/terminology
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Main Pathological Changes in Biopsies >12 Months Post-transplant
Rejection• Less common than in early post-transplant period• May have different histological features• Worse outcome
Recurrent disease• General issues• Assessment of biopsies from HCV-positive individuals
De novo disease• General issues• De novo autoimmune hepatitis
Other findings in late biopsies• “Idiopathic” chronic hepatitis• Vascular/structural abnormalities
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Main Pathological Changes in Biopsies >12 Months Post-transplant
Rejection• Less common than in early post-transplant period• May have different histological features• Worse outcome
Recurrent disease• General issues• Assessment of biopsies from HCV-positive individuals
De novo disease• General issues• De novo autoimmune hepatitis
Other findings in late biopsies• “Idiopathic” chronic hepatitis• Vascular/structural abnormalities
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Acute Cellular Rejection – Typical Histological Features
Portal inflammation (mixed population) Bile duct inflammation
Venous endothelial inflammation
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Late Cellular Rejection - Different Histological Features(Snover 1988, Kemnitz 1989, Cakaloglu 1995, Pappo 1995)
• Portal inflammation predominantly mononuclear
• Inflammation of bile ducts and venular endothelium less conspicuous
• More prominent interface hepatitis and lobular inflammation
• Overall features resemble chronic hepatitis (e.g. viral or autoimmune)
– (? “idiopathic” chronic hepatitis as a manifestation of late rejection)
• More recent studies suggest that central perivenulitis may also be a feature of late cellular rejection (Banff Working Party, Hepatology 2006; 44: 489-501)
• Central perivenulitis can occur without typical portal changes. Isolated CP seen in:
– 28% of adult patients (protocol biopsy) > 3years post-transplant (Krasinskas 2008)
– 22% of paediatric patients > 3 months post-transplant (Abraham 2008)
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Liver Allograft Rejection - “Isolated Central Perivenulitis”
Liver biopsy, 6 months post-transplant. Worsening LFTs (AST 2xN)
Other possible causes of zone 3 necroinflammation
Autoimmune hepatitis- recurrent AIH-de novo AIH
Viral hepatitis (recurrent or acquired)- HBV- HCV
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Central Perivenulitis in Liver Allograft Rejection – Clinical Correlations
• Present later than cases with pure portal rejection
• Often associated with raised transaminase levels
• Less responsive to immunosuppression
• Increased risk of developing “adverse outcomes”:– Further episodes of acute rejection
– Chronic (ductopenic) rejection
– De novo AIH
– Centrilobular fibrosis
(Krasinskas 2001,Gouw 2002, Neil 2002,Sebagh 2002, Lovell 2004, Hassoun 2004, Junge 2005, Riva 2006, Sundaram 2006, Krasinskas 2008, Abraham 2008, Demirhan 2008)
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Main Pathological Changes in Biopsies >12 Months Post-transplant
Rejection• Less common than in early post-transplant period• May have different histological features• Worse outcome
Recurrent disease• General issues• Assessment of biopsies from HCV-positive individuals
De novo disease• General issues• De novo autoimmune hepatitis
Other findings in late biopsies• “Idiopathic” chronic hepatitis• Vascular/structural abnormalities
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Disease Recurrence in the Liver Allograft
DISEASE FREQUENCY
HEPATITIS B < 10% (up to 85% in earlier studies)
HEPATITIS C > 80%
PBC 30-50%
PSC 20-30%
AUTOIMMUNE HEPATITIS 20-30%
ALCOHOL 10 - 30%
NASH (“cryptogenic” cirrhosis) 20-40%
Recurrent disease = commonest cause of late graft dysfunction
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Disease Recurrence in Liver Allografts -Diagnostic Problems (1) Recurrent disease and other transplant complications
(A) Histological Similarities
• Hepatitis C v Acute rejection
• PBC/PSC v Chronic rejection
• PSC v Ischaemic biliary complications
(B) Other Interactions
• Higher incidence of rejection (acute and chronic) in: – patients transplanted for autoimmune liver disease
– recurrent HCV
• Changes seen in late biopsies often reflect more than one pathological process
• Clinical picture often complex
• Histology may help to identify the dominant cause of graft damage
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Disease Recurrence in Liver Allografts -Diagnostic Problems (2) Effects of immunosuppression
LESS aggressive disease - immune - mediated disease
(e.g. AIH, PBC)
MORE aggressive disease - viral hepatitis
(atypical patterns) (e.g. HBV,HCV)
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Hepatitis C in the Liver AllograftDifferences Compared with HCV in the Native Liver
• More aggressive disease– More severe inflammatory activity (more rapid progression to fibrosis
and cirrhosis)
– Cholestatic features (fibrosing cholestatic hepatitis)
• Hepatitis C and rejection
• Hepatitis C with “autoimmune features” (? de novo AIH)
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Recurrent Hepatitis C prominent lobular inflammation with zone 3 necrosis
• Are these changes related to HCV alone?
• or HCV + another graft complication- rejection with central perivenulitis- de novo AIH
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Aggressive Recurrent HCV
• Male, age 52. 21 months post-LT for HCV
• Antiviral therapy recently stopped because of nephric abscess
• Presented with acutely deranged LFTs (AST 650)
• Became HCV-RNA positive
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Hepatitis C and Acute Rejection(Demetris Am J Surg Pathol 2004, Banff Working Party 2006)
• AR and recurrent HCV have overlapping histological features (portal inflammation, bile duct inflammation, venous endothelial inflammation)
• In most cases the time of occurrence and pattern of inflammation enable a reasonably confident diagnosis to be made
• Cases in which distinction between HCV and AR is difficult probably have a dual pathology
– In most of these cases rejection changes are mild
– HCV best considered as the primary diagnosis
– No additional immunosuppression required
• Increased immunosuppression should be considered as a treatment option if rejection changes moderate or severe
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Hepatitis C versus Acute Rejection - Other Approaches
Immunostaining for HCV Antigens (Grassi 2006, Errico-Grigioni 2008, Sadamori 2009)
• Higher frequency of staining and greater proportion of positively staining hepatocytes in HCV than rejection.
• Poor correlation with HCV-RNA levels (Errico-Grigioni 2008, Sadamori 2009).
• High tissue expression helpful in confirming diagnosis of HCV hepatitis in 16 patients with inconclusive histopathological diagnosis (Grassi 2006).
• Problems with reproducibility, tissue processing (2/3 studies used frozen sections).
Immunostaining for C4d (Schmeding, 2006, Lorho, 2006,Jain, 2006)
• Higher frequency of C4d positivity in acute rejection (45-80%) than in recurrent HCV infection (0-12%)
• BUT specificity for rejection not confirmed in other studies (e.g Bellamy 2007), nor has utility in cases with overlapping features of HCV and rejection.
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Hepatitis C versus Acute Rejection - Other Approaches
Immunostaining for Mcm-2 (Unitt Liver Transpl 2009; 15: 306-312)
Mcm-2 expression also helpful in 11 HCV-infected patients with uncertain diagnosis
• 7 eventually diagnosed as HCV, 4 as superimposed corticosteroid responsive ACR
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Hepatitis C with “Autoimmune Features” ( de novo AIH)
Following Interferon Therapy (Cholongitas 2006,Kontorinis 2006,Berardi 2007,Merli 2009)
• 14 cases – all had features compatible with de novo AIH
• 12/14 were HCV-RNA negative
• 10/14 responded to treatment with immunosuppression
Unrelated to Interferon Therapy (Khettry 2007, Fiel 2008)
• 47 patients - plasma cell rich portal and lobular infiltrates (“plasma cell hepatitis”)
• Central perivenulitis in 43/47
• Worse outcome than cases of “typical” recurrent HCV
– Progression to cirrhosis, retransplantation or death
• 75% had increased serum immunoglobulins and/or autoantibodies (Khettry 2007)
• 82% had suboptimal immunosuppression, auto-antibodies in 61% (low titre)
– probably a form of rejection (Fiel 2008)
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Main Pathological Changes in Biopsies >12 Months Post-transplant
Rejection• Less common than in early post-transplant period• May have different histological features• Worse outcome
Recurrent disease• General issues• Assessment of biopsies from HCV-positive individuals
De novo disease• General issues• De novo autoimmune hepatitis
Other findings in late biopsies• “Idiopathic” chronic hepatitis• Vascular/structural abnormalities
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De Novo Disease in the Liver Allograft
DISEASE DE NOVO OCCURRENCE
Hepatitis B YES
Hepatitis C YES
PBC NO
PSC ? (ischaemic cholangitis resembles PSC)*
Autoimmune Hepatitis YES
Alcohol Possible
NASH YES (several risk factors, including recurrent
HCV)
* One possible case, 5 years post-LT (McPartland Path Int 2009; 59: 312-316)
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‘De Novo’ Autoimmune Hepatitis in the Liver Allograft
(Kerkar 1998, Jones 1999, Gupta 2001, Heneghan 2001, Salcedo 2002, D’Antiga 2002, Miyagawa-Hayashino 2004, Mieli-Vergani 2004, Aguilera 2004 & 2005, Riva 2006, Avitzur 2007, Rodriguez-
Mahou 2007, Vernick 2007, Salcedo 2009).
1. Classical biochemical, serological and histological features of AIH may develop in patients transplanted for other diseases
2. Higher prevalence in paediatric population (5-10%), compared with adults (1-2%) ? Immunosuppressive drugs interfering with normal T cell maturation
3. Most cases respond to increased immunosuppression. Occasional cases have progressed to graft failure
4. Areas of overlap between de novo AIH and rejection - antibodies to graft antigens may indicate an alloimmune response - de novo AIH could represent a form of late cellular rejection
5. Areas of overlap/interaction between de novo AIH and hepatitis C
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Chronic Hepatitis in the Liver AllograftFeatures favouring an autoimmune aetiology
• Portal inflammation with numerous plasma cells
• Prominent interface hepatitis
• Lobular inflammation (plasma cell rich) with zone 3 necrosis
• Lobular changes in de novo AIH more prominent than in AIH in the native liver (Salcedo 2002, Aguilera 2004)
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Main Pathological Changes in Biopsies >12 Months Post-transplant
Rejection• Less common than in early post-transplant period• May have different histological features• Worse outcome
Recurrent disease• General issues• Assessment of biopsies from HCV-positive individuals
De novo disease• General issues• De novo autoimmune hepatitis
Other findings in late biopsies• “Idiopathic” chronic hepatitis• Vascular/structural abnormalities
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Main Pathological Changes in Biopsies >12 Months Post-transplant
“Idiopathic” chronic hepatitis
• Common(est) histological diagnosis in late post-transplant biopsies
• In cases where viral and autoimmune causes have been excluded, could this be a form of rejection? (late rejection may have hepatitic features)
• A potentially important cause of graft fibrosis
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Chronic Hepatitis in the Liver Allograft Portal Inflammatory Changes
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Chronic Hepatitis in the Liver Allograft Lobular Inflammatory Changes
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Chronic Hepatitis in the Liver Allograft -Periportal Fibrosis
Mild (fibrous portal expansion) Moderate (bridging fibrosis)
Severe (cirrhosis)
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Chronic Hepatitis in the Liver Allograft – Centrilobular Fibrosis
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Chronic Hepatitis in Late Post-Transplant BiopsiesIs this a form of late cellular rejection?
• In the adult population, excluding recurrent disease as a cause for chronic hepatitis is difficult
– Most of the diseases for which transplantation carried out in adults have the potential to recur, with features of chronic hepatitis
• HBV, HCV, AIH, PBC, PSC
– Histological features of “non-specific” chronic hepatitis may precede other diagnostic abnormalities of recurrent disease (AIH and PBC)
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Chronic Hepatitis (Interface Hepatitis) in Paediatric Liver Transplant Patients
Birmingham(Evans 2006)
Montreal(Herzog 2008)
Number of children 158 119
Biopsy indications Protocol biopsies at 1,5, 10 years Clinically indicated biopsies
Prevalence/time of
presentation with chronic hepatitis
22% at 1year
43 % at 5 years,
64 % at 10 years
24%
( median 2 years)
Progressive fibrosis
(by 10 years)
37% -bridging fibrosis
15% - cirrhosis
35% -bridging fibrosis
35% - cirrhosis
Other findings 70-80% had auto-antibodies
Only 6% diagnosed as de novo AIH
(AST levels < 2x normal)
No association with auto-antibodies
55% had features of chronic rejection
( Evans. Hepatology 2006; 43: 1109-1117, Herzog Liver Transpl 2008; 14: 946-955 )
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Graft Histology in Long-Term Survivors of Paediatric Liver TransplantationEkong, Liver Transplantation 2008; 14: 1582-1587 (Northwestern University, Chicago)
• 63 biopsies from children surviving > 3 years post-LT
• 39 normal LFTs, 24 clinically indicated
0 1 2 3 4
Portal inflammationBatts &Ludwig 1995
19 26 16 2 0
Fibrosis stageMETAVIR, Bedossa 1996
2 30 17 14 0
• Aetiology uncertain. Only 6/63 had features suggestive of chronic rejection.
• Factors correlating with > stage 3 fibrosis– Time post-transplant > 6years
– Inflammatory grade > 2
– NO correlation with abnormal LFTs
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Unexplained chronic hepatitis in adults following liver transplantation(Syn WK, Nightingale P, Gunson B, Hubscher SG, Neuberger JM. Liver Transplantation 2007, 13: 984-9) • 288 adults transplanted without features of disease recurrence (ALD ,
drug-induced liver failure)
• Chronic hepatitis present in 46/143 (32%) patients biopsied > 6 months post-transplant. Median time of diagnosis 15 months (6-72)
• No obvious correlation with AST levels
• 43% developed progressive fibrosis in follow-up biopsies – median 4 years (10% cirrhotic)
• Factors correlating with fibrosis progression
– High titre autoantibodies (ANA > 1:1600)
– Plasma cell rich infiltrate in index biopsy
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Graft Monitoring• Routine LFTs unreliable
• Role for protocol biopsies
• Autoantibody testing (particularly in children)
Treatment (immunosuppression to prevent disease progression?)• criteria for treatment
• monitoring therapeutic responses
• patients transplanted for hepatitis C
Many patients have mild changes with no evidence of fibrosis• Does mild (non-progressive) portal hepatitis represent a form of graft tolerance?
• Can liver biopsy help to identify patients in whom immunosuppression can be
reduced or withdrawn?
Chronic Hepatitis with “Autoimmune Features”Clinical Implications
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Protocol Liver Allograft BiopsiesMells G, Neuberger JM. Transplantation 2008; 85: 1686-1692
• Survey of 35 liver transplant centres (North America 19, Europe 13, Other 3)
– 23 (65%) protocol annual biopsies for HCV-positive patients
– 9 (25%) protocol biopsies for other patients
• Reasons for discontinuing protocol biopsies – Risk of potentially serious complications
– Cost
– Non-invasive alternatives (e.g. to assess fibrosis)
– Problems with histological interpretation
– Findings don’t influence clinical management
Healy’s Law (From Knisely & Thompson 2008)
“Don’t order a test if you lack the facts to know how to interpret the result”
Healy B, N Engl J Med 1997; 336: 1448-9
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Late Protocol Biopsies in the Liver Allograft – A Neglected Investigation?
Mells G, Mann C, Hubscher S, Neuberger J. Liver Transplantation 2009, in press
235 biopsies > 1yr post –LT from 176 patients (ALD 49, AIH 20, PBC 107)All had normal LFTs at time of biopsy
ALD
(n=60)
AIH
( n= 28)
PBC
(n=147)
TOTAL
(n=235)
Normal 18% 29% 26% 24%
Fatty liver 42% 14% 4% 14%
Idiopathic CH 28% 18% 38% 33%
Rec disease (AIH/PBC) N/A 39% 29% 23%
De novo AIH 2% N/A 3% 2%
Other 10% 0 1% 3%
Idiopathic Chronic Hepatitis Cases (n=78)• Inflammatory grade – mild 75 (96%), moderate 3 (4%), severe 0
• Fibrosis stage – none 29 (37%), mild 41 (53%), moderate 8 (10%), severe (0)
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Late Protocol Biopsies in the Liver Allograft – A Neglected Investigation?
Mells G, Mann C, Hubscher S, Neuberger J. Liver Transplantation 2009, in press
76/235 cases had change in immunosuppression after biopsy
• 11 increased (active inflammation in protocol biopsy)
• 58 reduced (lack of inflammation in protocol biopsy)
• 7 switched to CNI-sparing regime (active inflammation and renal impairment)
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Idiopathic Post-Transplantation Hepatitis Following LDLTMiyagawa-Hiyashino Transpl Int 2009: 22: 303-312
IPTH in 42/944 (4.4%) liver allograft recipients (NO protocol biopsies)
Higher prevalence in children (6.5%) than adults (1.3%)
Associated Factors • Previous acute rejection (82%)
• Positive auto-antibodies (68%)
– no differences between patients with low (< 1:160) and high (> 1: 160) titres
Outcome (serial biopsies in 29 patients)• 8 - progressive fibrosis (5 developed cirrhosis & retransplanted)
• 21 - improvement in fibrosis
(possibly due to increase in immunosuppression after diagnosis of IPTH)
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Unexplained Chronic Hepatitis or Periportal Fibrosisin Late Post-Transplant Biopsies
Are there other causes?
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Chronic Hepatitis E Virus Infection in Liver Allograft Recipients Haagsma 2008, Kamar 2008, Gerolami 2008
• 11 transplant patients (5 liver, 4 kidney, 2 kidney/pancreas)
• All 11 patients developed biochemical and histological features of chronic hepatitis, with persistently elevated serum HEV-RNA levels
• Outcome variable:
– 2 patients retransplanted with severe fibrosis/cirrhosis (Haagsma 2008)
– Other 9 patients clinically well with persistently abnormal LFTs (raised AST/ALT). 7/9 have METAVIR fibrosis stage < 2
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Graft Fibrosis after Paediatric Liver Transplantation: Ten Years of Follow-upScheenstra Hepatology 2009; 49: 880-886 (Groningen)
• 39/55 (69%) children biopsied at 10 years had fibrosis – 17 mild, 11 bridging, 16 cirrhosis
• Associated with abnormal LFTs (ALP, GGT)
• Risks Factors– Young age of recipient– High donor/recipient age ratio– Cold ischaemia time– Reduced size graft
• Factors NOT associated with fibrosis– Rejection – Chronic hepatitis (only 2 patients had unexplained CH)
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Main Pathological Changes in Biopsies >12 Months Post-transplant
• Rejection– Less common than in early post-transplant period– May have different histological features
• Recurrent disease– General issues– Assessment of biopsies from HCV-positive individuals
• De novo disease– General issues– De novo autoimmune hepatitis
• Other findings in late biopsies– “Idiopathic” chronic hepatitis– Vascular/structural abnormalities
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Nodular Regenerative Hyperplasia Male age 46 – protocol biopsy 12 months post-transplant for Wilson’s disease
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Perisinusoidal Fibrosis
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• Frequency 2% - 82%
• Possible Causes (impaired sinusoidal blood flow)– Vascular problems (portal/hepatic venous insufficiency)
– Drug toxicity (azathioprine)
– Immune mediated (rejection related damage to sinusoidal/vascular sinusoidal endothelium)
• Clinical Consequences– 6/26 cases reported from KCH London required retransplantation (Slapak
Hepatology 1997; 25: 195-202)
– 7/14 cases from Mayo Clinic symptomatic with features of portal hypertension (ascites -7, varices- 4) (Devarbhavi Liver Transpl. 2007;13:1552-6.)
– Others noted as incidental finding
Nodular changes in late post-transplant biopsies(Pappo 1995, Slapak 1997, Sebagh 2003, Devarbhavi 2007)
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Late Post-Transplant Biopsies – Future Studies
1. HCV with features of rejection or autoimmune hepatitis
2. Biopsies with (mild) unexplained inflammatory changes • Terminology (chronic hepatitis vs other terms)
• Characterising the nature of the inflammatory infiltrate (alloimmune or tolerogenic, fibrogenic cytokine profiles)
• In cases thought to be alloimmune (with fibrosis) - clinical trial of immunosuppression vs no immunosuppression.
3. Nodular changes• morphological spectrum and natural history
• ? more common in reduced-sized grafts
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Banff 2009 – The Year of the Hat