post-transplant centrilobular hepatitis - rejection or autoimmune-like?

Post-transplant centrilobular hepatitis- rejection or autoimmune-like?

Andrew Clouston & Catherine CampbellPrincess Alexandra Hospital, Australia

University of Queensland, Australia

Outline

• introduction

• pathology of CLH

• evolution

• possible pathogenesis

Centrilobular hepatitis

• Acute rejection

• Chronic rejection

• Vascular

• Autoimmune hepatitis

• “Central venulitis”

Centrilobular hepatitis

• Acute rejection portal

changes

• Chronic rejection duct changes

• Vascular imaging

• Autoimmune hepatitis histo & autoAb

• “Central venulitis”

Allo- vs Auto-immunity

Allo- vs Auto-immunity

Allo- vs Auto-immunity

De novo AIH post-OLT

• elevated transaminases• typical histology

– interface hepatitis ++– plasma cells

De novo AIH post-OLT

• elevated transaminases• typical histology

– interface hepatitis ++– plasma cells

• late – median 24 months• autoantibodies• response to pred / aza

40 - 50%

Salcedo Hepatology 2002

CV CV

Allo- vs Auto-immunity

Late centrilobular hepatitis

• Tsamandas 1997– AR -- prognosis good

• Nakazawa 2000– hepatitis -- prognosis OK

• Hassoon 2004– AR (50%) – prognosis poor– >> evolution into CR

IS THIS A FORM OF AR or AIH?

Case

• 28 yr old man previous farm worker• 1994 cryptogenic cirrhosis• March 2003 OLTx ; uneventful post op course

Case

• 28 yr old man previous farm worker• 1994 cryptogenic cirrhosis• March 2003 OLTx ; uneventful post op course

• June 2004 abnormal LFTs – Transaminitis, BR normal

• Immunosuppression stable– prednisolone 5mg, tacrolimus

• Biopsy ?AR

Liver function tests

0

100

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500

Fe

b-0

4

Ma

r-0

4

Ap

r-0

4

Ma

y-0

4

Ju

n-0

4

Ju

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Au

g-0

4

Se

p-0

4

Oc

t-0

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No

v-0

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De

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4

Ja

n-0

5

Fe

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Ma

r-0

5

ALK PALT AST BILT GGT

Liver function tests

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500

Fe

b-0

4

Ma

r-0

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Ap

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4

Ju

n-0

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Au

g-0

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Se

p-0

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Oc

t-0

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No

v-0

4

De

c-0

4

Ja

n-0

5

Fe

b-0

5

Ma

r-0

5

ALK PALT AST BILT GGT

No treatment

“Darrell”

2005 Draft statement on late liver allograft dysfunction (Banff working group)

• “Central venulitis” • “Centrilobular inflammation +/- hepatocyte

necrosis/dropout”

– Peri-venular inflammation– Peri-venular hepatocyte necrosis/dropout– Haemorrhage– Pigmented macrophages

Ddx “central venulitis” (Banff)

• Acute rejection as isolated central venulitis – Perivenular inflammation with

hepatocyte dropout and haemorrhage– Grading system provided– “severe” – damage of >3 hepatocyte

layers in some central veins– Variable outcome

Hypothesis – centrilobular hepatitis

? Pure centrilobular form of AR

? Form of autoimmune- like hepatitis

Aims

1. Characterise “centrilobular hepatitis” - Nature of the histological changes- Associated clinical features

2. Document the natural history

3. Investigate possible mechanism

Methods

• Prospectively accrued cases from 1999• Prominent “centrilobular hepatitis” on biopsy• No portal tract changes of AR or CR

• Clinical details – baseline, biopsy and follow up LFTs– baseline immunosuppression– change in treatment– auto-antibody status

Methods

• Histological assessment

CL portal

Results

• Seen in 24 pts (182 transplants) – 13%• 30 - 2850 days post-OLT• Mean 1066 days (~ 3 years) i.e. “late

allograft dysfunction”

n=24

Autoimmune-like hepatitis

Centrilobular

hepatitis n=13

Recurrent AIH n=5 Denovo AI-like hepatitis

n=5

Moderate interface hepatitis & typical autoAb

Rejection n= 1

Original disease

Mean score portal inflammation (0-4)

0

1

2

3

4

Recurrent AIH Denovo AIH CLH

**

Mean score interface activity (0-4)

0

1

2

3

4

Recurrent AIH Denovo AIH CLH

**

Mean score portal plasma cells (0-4)

0

1

2

3

4

Recurrent AIH Denovo AIH CLH

**

Mean score portal eosinophils (0-4)

0

1

2

3

4

Recurrent AIH Denovo AIH CLH

**

Mean score duct injury (0-3)

0

1

2

3

Recurrent AIH Denovo AIH CLH

p=0.063

Mean score lobular sum (0-10)- inflammation + dropout

0

2

4

6

8

10

Recurrent AIH Denovo AIH CLH

ns

Mean score lobular centrilobular dropout (0-6)

0

1

2

3

4

5

6

Recurrent AIH Denovo AIH CLH

*

Mean score lobular plasma cells (0-4)

0

1

2

3

4

Recurrent AIH Denovo AIH CLH

* p=0.051

Mean score CV endothelialitis (0-3)

0

1

2

3

Recurrent AIH Denovo AIH CLH

ns

Histology - summary

• Milder portal infiltrates• Milder interface hepatitis• Fewer portal plasma cells• Minimal duct injury

PT

Histology - summary

• Milder portal infiltrates• Milder interface hepatitis• Fewer portal plasma cells• Minimal duct injury

• Milder degree of CL dropout• Similar inflammatory infiltrate (↓ PC)• Overall lobular scores similar• Minimal endothelialitis

PT

Lob

CL portal

HCV

Clinical features

• No differences in LFTs between 3 groups• LFT pattern variable

– BR usually normal– raised transaminases or cholestatic enzymes

• Autoantibodies– Recurrent 5/5– De-novo 5/5– CLH 7/13

Treatment

De-novo AI-like hepatitis

Recurrent AIH

AIH protocol AIH protocol

Treatment

De-novo AI-like hepatitis

Recurrent AIH CLH

AIH protocol AIH protocol

5 - AIH protocol 8 - no change

4-HCV+ 2-fluctuate 2-resolve

No episodes CR or VOD

Liver function tests

0

100

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600

700Ja

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-00

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-01

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-02

ALK PALT AST BILT GGT

CLH on biopsy

Liver function tests

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600Ja

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r-02

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ALK P

ALT AST

BILT GGTP pred / aza

Evolution (n=8 multiple biopsies)

De-novo AI-like hepatitis

Recurrent AIH CLH

1

1

2 + 3

1

Centrilobular hepatitis & AI-like hepatitis

1. Histological overlap CLH & AIH-DN & AIH-R

2. Similar clinical presentation

3. Histological evolution between the lesions

4. No episodes CR or VOD

Centrilobular hepatitis & AI-like hepatitis

1. Histological overlap CLH & AIH-DN & AIH-R

2. Similar clinical presentation

3. Histological evolution between the lesions

4. No episodes CR or VOD

? Does CLH represent a form of de novo autoimmune-like hepatitis with no or mild portal tract changes

Issues

De-novo AI-like hepatitis

ARRecurrent AIH

CLH

How to save money at Christmas

Do AutoAb mean AIH?

NO

• Animal models of Tx• 71% OLT recipients

– 2/3 patients by 3 years– M > F Salcedo J Hepatol 2001

Abstr.

• 30% non-OLT cirrhotics

AutoAb - classical AIH

% Age AutoAb

Type 1 80% Adult ANA , aSMA

Type 2 4-20% Child anti-LKM-1

Type 3 10-20% Adult anti-SLA/LP

Autoantibodies

• variable• late – 6 mo after hepatitis

• atypical anti-LKM– cytosolic antigen Salcedo 2002 Hepatology

– anti-GST-T1 Aguilera 2001 Clin Exp Immunol

Autoantibodies

• variable• late – 6 mo after hepatitis

• atypical LKM– cytosolic antigen Salcedo 2002 Hepatology

– anti-GST-T1 Aguilera 2001 Clin Exp Immunol

Denovo AI-like hepatitis

• GSTT1 detoxification enzyme preferentially expressed liver and kidney cells (centrilobular hepatocytes)

• 20% popn deletion GSTT1 gene non-expression

• Potential for organ mismatch

Aguilera I et al, Liver Transplantation 2004; 10: 1166-1172

Denovo AI-like hepatitis

Aguilera I et al, Liver Transplantation 2004; 10: 1166-1172

Denovo AI-like hepatitis

Aguilera I et al, Liver Transplantation 2004; 10: 1166-1172

110 OLT patients

15 pos neg recipient

12/15 anti-GSTT1 Ab

6/15 de-novo AIH

Denovo AI-like hepatitis

Aguilera I et al, Liver Transplantation 2004; 10: 1166-1172

• Immune response to GSST1 in donor liver

• Targeted peptide not a self-Ag

• Immune response oligo-specific

GSTT-1 expression – PAH cohort

Recipient negative GSTT1

• Controls 0/15• AIH-R 3/5• AIH-DN 2/4• CLH 4/12

ns

p = 0.004

Allo- vs Auto-immunity

Conclusions - CLH

• Common late finding in OLTx biopsies (13%)

• Shares clinical and histological features that overlap with autoimmune type hepatitis (milder)

• Responds to re-introduction of steroids • Untreated may resolve or persist• No progression to CR or VOD

• Shares potential pathogenic mechanism with de novo AI-like hepatitis (GSTT-1 mismatch)

Conclusions - CLH

• ? re-consider “isolated central venulitis” as form of acute rejection

(Banff 2005)

“Autoimmune-like centrilobular hepatitis”

Acknowledgments

• Dr Catherine Campbell• Ms Glenda Balderson• Ms Alba Vanelli-Rees• Dr Julie Jonsson• Dr Darrell Crawford