Progressive histological damage in liver allografts following paediatric liver transplantation Helen...

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

Background

1. Histological Findings in Late (>12 months) Post-Transplant Biopsies

2. Chronic hepatitis in the liver allograft

3. Specific issues relating to the paediatric liver allograft recipient

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

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)

Institution Time of

biopsy

No of

biopsies

No (%) Biopsies

with CH

Aetiology

Pittsburgh

(Pappo 1995)

> 5 yrs 65 19 (29) 9 HCV, 3 HBV, 1 AIH

6 (32%) cause unknown

Kings, London

(Slapak, 1997)

> 5 yrs 116 27 (23) 10 HCV, 2 HBV, 2 AIH

13 (48%) cause unknown

Paris

(Sebagh, 2003)

> 10 yrs 143 78 (54) 58 HCV, 10 HBV, 5 HBV+ HCV 4 AIH

1(1.3%) cause unknown

Birmingham

(Liver Unit Database

1998-2003)

> 1 yr 1124 527 (47) 104 (20%) – recurrent disease

423 (80%) – other/unknown cause

Factors Influencing the Assessment of Late Post-transplant biopsies

1. Nature of original liver disease

2. Indication for liver biopsy(protocol or clinically indicated)

3. Type/amount of immunosuppression used

4. Recurrent disease versus other transplant complications

5. Diagnostic criteria

Chronic Hepatitis in the Liver Allograft Possible Causes

1. VIRAL INFECTION (recurrent or acquired)- hepatitis B

- hepatitis C

2. RECURRENT AUTOIMMUNE DISEASE- autoimmune hepatitis- primary biliary cirrhosis- primary sclerosing cholangitis

3. ‘DE NOVO’ AUTOIMMUNE HEPATITIS

4. DRUG TOXICITY

5. UNKNOWN (?REJECTION)



- hepatitis C


In some cases histological features of “non-specific” chronic hepatitis may precede development of more typical biochemical, serological or histological changes


4. DRUG TOXICITY




- hepatitis C



4. DRUG TOXICITY


‘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 ).

1. Classical biochemical, serological and histological features of AIH may develop in patients transplanted for other diseases

2. Higher incidence in paediatric population (up to 5-10%)

3. In adult population commonest underlying diseases are PBC and PSC.

4. Most cases respond to increased immunosuppression. Occasional cases have progressed to graft failure

• 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 al Hepatology 2001 ;34 :464-70)

‘De Novo’ Autoimmune Hepatitis in the Liver AllograftProblems with Classification



- hepatitis C



4. 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)




- hepatitis C



4. DRUG TOXICITY


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)

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

Methods Patients & Biopsies

210 children transplanted between 1983 and 1996158 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-transplantOther 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)

Indications for transplantation (158 cases)

Indication for transplantation Number % • Cholestatic disorders 85 53.4

Extra hepatic biliary atresia 77 48.4Other 8 5.0

• Fulminant hepatic failure 23 15.1Non-A, non-B, non-C acute hepatitis 15 9.5Viral hepatitis (HAV -3, Echovrus -1) 4 2.5Drug-induced 4 2.5

• Metabolic disorders 23 15.1Alpha-1-antitrypsin deficiency 8 5.0Tyrosinaemia type 1 5 3.1Wilson’s disease 6 3.8Other 4 2.5

• Autoimmune diseases 8 5.0Autoimmune hepatitis 3 1.9Sclerosing cholangitis 5 3.1

• Miscellaneous 19 11.9Cryptogenic cirrhosis 7 4.4Cystic fibrosis 6 3.8Hepatoblastoma 4 2.5Other 2 1.2

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)

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

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

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)

Main Histological Findings at 1, 5 and 10 years

Histological Diagnosis 1 year (n=113)

5 years (n=135)

10 years (n=64)

Normal/ near normal (1) 68.2% 45.2% 31.3%

Chronic hepatitis (2) 22.1% 43.0% 64.0%

Rejection (acute or chronic) 2.7% 2.2% 0

Biliary obstruction 6.2% 7.4% 1.6%

Recurrent Disease 0.9% 0.7% 1.6%

Other 0 1.3% 1.6%

(1) & (2) p < 0.0001

Normal/near-normal biopsies

1 year

(n=77)

5 years

(n=61)

10 years

(n=20)

Normal 9% 16% 5%

Mild-non specific changes

88% 75% 75%

Mild fibrosis

(all stage 1)

3% 9% 20%

Chronic Hepatitis 124 biopsies 25 – 1 year, 58 – 5 years, 41 – 10 years

Necroinflammatory Activity

None Mild Moderate Severe

Interface hepatitis 6% 76% 16% 2%

Lobular inflammation/ necrosis

49% 33% 15% 3%

Overall grade 0 59% 33% 8%

Chronic Hepatitis Severity of Necro-inflammatory Activity at Different Times

0

10

20

30

40

50

60

70

80

%

1 year 5 years 10 years Overall

Time post-OLT

mild

moderate

severe

Chronic Hepatitis – Histological FindingsInflammatory Changes

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

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

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

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

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

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

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

Chronic Hepatitis (moderate) – Zone 3 necro-inflammation Male, age 3, 2.5 years post-transplant for biliary atresia

Normal Hepatic Vein

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

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

Chronic Hepatitis (severe) – bridging necrosis

Female, age 30, 3 years post-transplant for fibrolamellar HCC

Chronic Hepatitis (severe) – panacinar necrosis

Female, age 30, 3 years post-transplant for fibrolamellar HCC

Chronic Hepatitis versus

Late Cellular Rejection

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

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

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

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

Chronic Hepatitis – Histological FindingsFibrosis

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

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

Chronic Hepatitis Severity of Fibrosis at Different Times

05

101520253035404550

%

1 year 5 years 10 years

Time post-OLT

none

mild

moderate

severe

(P<0.0001)

Correlation between AST levels and Histology

AST levels

Median (range)

Histology 1 year 5 years 10 years

Normal 43 (8 – 136) 44 (16 – 155) 38 (21 – 105)

Chronic hepatitis

52 (17 – 110) 63 (22 – 103) 48 (25 – 128)

Other histology 81 (24 – 138) 63 (28 – 248) 65 (16 – 142)

P < 0.005 Other histology vs normal/chronic hepatitis at 1 year

Correlation between Autoantibodies and Histology

Autoantibody positivity

(no positive/total number of biopsies)

Histology 5 years 10 years

Normal/near-normal 8/61 (13%) 2/20 (10%)

Chronic hepatitis 42/58 (72%) 33/41 (80%)

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)

Correlation between Autoantibodies and Histology

Autoantibody positivity

(no positive/total number of biopsies)

Histology 5 years 10 years

Normal/near-normal 8/61 (13%)ANA 1 in 25 = 4

ANA 1 in 40 = 4

2/20 (10%)ANA 1 in 25 = 1

ANA 1 in 40 = 1

Chronic hepatitis 42/58 (72%)ANA 1 in 25 = 8

ANA 1 in 40 = 7

ANA 1 in 100 = 10

ANA 1 in 400 = 9

ANA 1 in 1600 = 4

SMA = 12

LKM = 2

Mixed Abs = 10

33/41 (80%)ANA 1 in 25 = 5

ANA 1 in 40 = 11

ANA 1 in 100 = 8

ANA 1 in 400 = 3

ANA 1 in 1600 = 3

SMA = 8

LKM = 2

Mixed Abs = 7

Chronic Hepatitis Causes Identified

Possible cause Number of cases Time of diagnosis

Hepatitis C 2 1 year

De novo AIH 4 1 @ 5 years

3 @ 10 years

52/58 cases – no cause identified

Factors Correlating with Chronic Hepatitis

Univariate Analysis


• Sex mismatch

• AST/ALT levels

Multivariate Analysis


Late Biopsies from Paediatric Liver Allograft Recipients Summary & Conclusions

• Histological abnormalities commonly present in biopsies taken > 1 year post-transplant

• Many occur in children who are clinically well with normal LFTs

• Commonest histological diagnosis is chronic hepatitis:– Prevalence increases with time (20% at 1 year, >60% at 10 years)

– Inflammatory activity typically mild, may increase with time

– Fibrosis increases with time (50% have bridging fibrosis or cirrhosis at 10 years)

• In the majority of cases (52/58) no definite cause for chronic hepatitis can be identified.

• Many cases of chronic hepatitis are associated with autoantibodies, but rarely fulfil other diagnostic criteria for de novo autoimmune hepatitis

• Potential clinical implications:– Graft monitoring (autoantibody testing)

– Treatment ( to prevent development/progression of fibrosis)

Sunday May 15 2005, 4.19 pm

Sunday May 15 2005, 4.51 pm

Chronic Hepatitis Severity of Necro-inflammatory Activity at Different Times

0

10

20

30

40

50

60

70

80

%

1 year 5 years 10 years Overall

Time post-OLT

mild

moderate

severe

Progressive histological damage in liver allografts following paediatric liver transplantation Helen...

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