Posttransplant centrilobular hepatitis rejection or autoimmunelike

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

• Andrew Clouston Catherine Campbell
• Princess Alexandra Hospital, Australia
• University of Queensland, Australia

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Outline

• introduction
• pathology of CLH
• evolution
• possible pathogenesis

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Centrilobular hepatitis

• Acute rejection
• Chronic rejection
• Vascular
• Autoimmune hepatitis
• Central venulitis

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Centrilobular hepatitis

• Acute rejection portal changes
• Chronic rejection duct changes
• Vascular imaging
• Autoimmune hepatitis histo autoAb
• Central venulitis

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Allo- vs Auto-immunity
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Allo- vs Auto-immunity
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Allo- vs Auto-immunity
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De novo AIH post-OLT

• elevated transaminases
• typical histology
• interface hepatitis
• plasma cells

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De novo AIH post-OLT

• elevated transaminases
• typical histology
• interface hepatitis
• plasma cells
• late median 24 months
• autoantibodies
• response to pred / aza

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40 - 50 Salcedo Hepatology 2002
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CV
CV
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Allo- vs Auto-immunity
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Late centrilobular hepatitis

• Tsamandas 1997
• AR -- prognosis good
• Nakazawa 2000
• hepatitis -- prognosis OK
• Hassoon 2004
• AR (50) prognosis poor
• gtgt evolution into CR
• IS THIS A FORM OF AR or AIH?

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Case

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

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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

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No treatment
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Darrell
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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

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Ddx central venulitis (Banff)

• Acute rejection as isolated central venulitis
• Perivenular inflammation with hepatocyte dropout
  and haemorrhage
• Grading system provided
• severe damage of gt3 hepatocyte layers in some
  central veins
• Variable outcome

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Hypothesis centrilobular hepatitis
? Pure centrilobular form of AR
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Aims

• Characterise centrilobular hepatitis
• Nature of the histological changes
• Associated clinical features
• Document the natural history
• Investigate possible mechanism

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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

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Methods

• Histological assessment

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CL portal
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Results

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

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Rejection n 1
n24
Moderate interface hepatitis typical autoAb
Autoimmune-like hepatitis
Centrilobular hepatitis n13
Original disease
Recurrent AIH n5
Denovo AI-like hepatitis n5
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p0.063
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ns
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p0.051
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ns
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Histology - summary

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

PT
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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
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CL portal
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HCV
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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

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Treatment
De-novo AI-like hepatitis
AIH protocol
AIH protocol
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Treatment
De-novo AI-like hepatitis
AIH protocol
AIH protocol
5 - AIH protocol
8 - no change
4-HCV
2-fluctuate
2-resolve
No episodes CR or VOD
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CLH on biopsy
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pred / aza
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Evolution (n8 multiple biopsies)
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1
De-novo AI-like hepatitis
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2 3
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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

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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
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Issues
De-novo AI-like hepatitis
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How to save money at Christmas
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Do AutoAb mean AIH?

• NO
• Animal models of Tx
• 71 OLT recipients
• 2/3 patients by 3 years
• M gt F Salcedo J Hepatol 2001 Abstr.
• 30 non-OLT cirrhotics

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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

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Autoantibodies

• variable
• late 6 mo after hepatitis
• atypical anti-LKM
• cytosolic antigen Salcedo 2002 Hepatology
• anti-GST-T1 Aguilera 2001 Clin Exp Immunol

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Autoantibodies

• variable
• late 6 mo after hepatitis
• atypical LKM
• cytosolic antigen Salcedo 2002 Hepatology
• anti-GST-T1 Aguilera 2001 Clin Exp Immunol

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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
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Denovo AI-like hepatitis
Aguilera I et al, Liver Transplantation 2004 10
1166-1172
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Denovo AI-like hepatitis

• 110 OLT patients
• 15 pos ? neg recipient
• 12/15 anti-GSTT1 Ab
• 6/15 ? de-novo AIH

Aguilera I et al, Liver Transplantation 2004 10
1166-1172
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Denovo AI-like hepatitis

• Immune response to GSST1 in donor liver
• Targeted peptide not a self-Ag
• Immune response oligo-specific

Aguilera I et al, Liver Transplantation 2004 10
1166-1172
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GSTT-1 expression PAH cohort

• Recipient negative GSTT1
• Controls 0/15
• AIH-R 3/5
• AIH-DN 2/4
• CLH 4/12

p 0.004
ns
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Allo- vs Auto-immunity
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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)

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Conclusions - CLH

• ? re-consider isolated central venulitis as
  form of acute rejection
• (Banff 2005)

Autoimmune-like centrilobular hepatitis
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Acknowledgments

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

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