role of liver biopsy in assessing disease severity in autoimmune … · 2016. 10. 25. · •the...
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Role of liver biopsy in assessing disease severity in autoimmune
hepatitis
Dr Asha K DubéSheffield Teaching Hospitals NHS
Foundation Trust
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Autoimmune hepatitis
• Relapsing and remitting disease process in some, progressive in others.
• Unknown triggers, but sometimes drug-induced.
• Genetic risk associated with HLA type– HLA-DRB1*03:01 and HLA-DRB1*04:01
• Female preponderance.
• Diagnosed by scoring the constellation of features (simplified IAIHG criteria).
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What constitutes severe disease ?
• Clinical or biochemical decompensation.
• High stage fibrosis.
• But only about 10% of patients present with decompensation.
• Histological activity.
• About 40% as a clinically acute hepatitis.
• About 90% will have a liver biopsy.
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Drawbacks of liver biopsy
• Complications.
• Invasive procedure.
• Sampling error.
• Intra- and inter-observer variability in interpretation.
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Justification for biopsy
• Presence of ANA or ASMA positivity does not correlate with clinical or histological severity, or predict response to antibody therapy (52 patients). Mehendiratta et al. Clin Gastroenterol Hepatol 2009 7: 98- 103
• Patients presenting with acute hepatitis or atypically (eg. male) may be missed. Miyake et al. Dig Liver Dis 2010 42: 210- 5
• Half with normal serum parameters still showed histological activity HAI 4 or 5, but these were at lower risk of fibrosis progression than those with scores of ≥6. Lüth et al. J Clin Gastroenterol 2008 42: 926- 30
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Activity
• Histological activity index.
• Portal inflammation – type and amount
• Interface hepatitis – extent and amount
• Lobular activity
• More extensive necrosis
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Acute hepatitic presentation
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Normal portal area
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Portal inflammation
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Interface hepatitis
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Interface hepatitis
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Interface hepatitis
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Other interface findings
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Hepatocyte rosettes
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Lobular hepatitis
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Lobular hepatitis
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Lobular hepatitis
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Confluent necrosis
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Bridging necrosis
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Emperipolesis
• More recently recognised as a feature.
• 65.3% of 101 patients with AIH vs. 17.9% PBC, 14.9% chronic hepatitis and 25.6% DILI. Miao et al. Clin Rev Allergy Immunol 2015 48: 226- 35
• Where present, significantly higher transaminases, more severe necroinflammatory features and more advanced fibrosis.
• CD8+ lymphocytes in hepatocytes.
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Emperipolesis• We looked at first AIH biopsies for emperipolesis.
• Graded as None, Rare (1- 4 in 15hpf), Few (5- 10 in 15hpf or many >10 in 15 hpf)
• Present in 83 of 84 biopsies. All had lymphocytes in hepatocytes, but also occasional plasma cells or neutrophils involved. 30% had lymphocytes in biliary epithelial cells.
• 40% Many and 39% Few.
• Grade positively correlated with portal tract number, necroinflammatory score and presenting serum IgG.
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Emperipolesis
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Emperipolesis
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Emperipolesis
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Not emperipolesis
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Cholestasis
• Can be seen in acute presentation cases.
• Found by some to be more indicative of drug-induced injury.
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Differential diagnosis – drug-induced liver injury
• Includes patients who have AIH already and in whom an exacerbation is triggered by a drug/ herbal medication.
• Includes patients whom the drug/ herbal medication triggers AIH in those with a predisposition to developing it.
• Some patients will develop progressive disease if not treated.
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Is biopsy severity important ?
• Half with normal serum parameters still showed histological activity HAI 4 or 5, but these were at lower risk of fibrosis progression than those with scores of ≥6. Lüth et al. J CLinGastroenterol 2008 42: 926- 30
• Compared outcome of histological remission with HAI 0- 3 with HAI 4- 5. Latter less likely to achieve fibrosis regression (27% vs 60%).
• Liver-related death and transplant independently associated with persisting histological activity (HR 9.7).
Dhaliwal et al. Am J Gastroenterol 2015 110: 993- 9
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Non-invasive assessment of inflammation
• Inflammatory score = 17.0 + 0.0049 AST [U/L] – 3.40 total albumin [g/dl] + – 0.4128 total bilirubin [mg/dl] + 0.2527 CRP [mg/L]
• ≥3.57 differentiates HAI >4 from <4.• Sensitivity 100%, specificity 85%.
• Gutkowski et al. Liver Int 2013 33: 1370- 7
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Non-invasive assessment of inflammation - drawbacks
• Training and validation sets – small numbers.
• Mixed active/ remission groups in differing proportions.
• CRP not specific for type of inflammation, so not suitable if co-morbidity.
• Remains to see if it will catch on and if it is good enough.
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Prediction of relapse ?
• Only the presence of portal plasma cells in the biopsy prior to withdrawal was associated with relapse (31% vs 7%). PPV 92%.
Czaja & Carpenter Liver Int 2003 23: 116- 23
• Grading of interface hepatitis not significantly associated with relapse. More patients treated with prednisolone only had relapse. Yokokawa et al. Hepatol Res 2011 41: 641- 6
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Prediction of relapse ?• Compared the outcomes of histological remission
HAI 0- 3with HAI 4- 5. Latter less likely to achieve fibrosis regression (60% vs 27%).
• Persisting histological activity independently associated with liver-related death/ Tx (HR 9.7).
Dhaliwal et al. Am J Gastroenterol 2015 110: 993- 9
• Higher ALT and IgG levels (but within N range) were associated with time to relapse. All patients maintaining remission had ALT < half ULN and IgG <12g/L at the time of withdrawal.
Hartl et al. J Hepatol 2015 62: 642- 6
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Prediction of relapse ?
• >90% probability of relapse if time to remission ≥5mths, portal plasma cell score ≥3 and number of times ALT/AST abnormal per year ≥2 (PPV 100%).
Verma et al. Am J Gastroenterol 2004 99: 1510- 6
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Is there fibrosis ?
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Is there fibrosis ?
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Is there fibrosis ?
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Is there fibrosis ?
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Fibrosis ?
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Yes
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Fibrosis
• Acute loss of hepatocytes causes collapse of the reticulin framework.
• Hepatic stellate cells produce collagen.
• Stimulated by activated kupffer cells and inflammatory cells, including plasma cells.
• Remodelled by collagenases.
• Increased collagen type I in fibrosis and cirrhosis.
• Elastin deposition later than collagen.
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Drivers of fibrosis in AIH
• Increased hepatic stellate cell population in AIH, mainly activated phenotype.
• Co-localisation of plasma cells and activated stellate cells.
• Positive correlation between stellate cells, fibrosis scores and number of plasma cells.
• Successful Rx gave reduced numbers of plasma cells, HSCs and fibrosis (those with 2nd
bx).Brandão et al. Pathol Res Pract 2010 206: 800- 4
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Non-invasive assessment of fibrosis in autoimmune hepatitis
• Hartl et al. J Hepatol 2016 65: 769- 775
• Diagnosis of cirrhosis optimal cut-off of 16kPa.
• Performance impaired when TE performed within 3 months of start of Rx, where there was correlation with histological grade, but not stage.
• Cut-off excellent in patients treated for 6mths or longer.
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Non-invasive assessment of fibrosis
• Fibroscan
• ELF (enhanced liver fibrosis)
• Acoustic radiation force imaging
• Supersonic shear wave imaging
• Other imaging
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Non-invasive assessment of fibrosis
• AST-Platelet Ratio Index, APRI=[ (AST/upper limit of normal)*100/platelet count]
• Fibrotest – (Fibrosure) alph-2-macroglobulin, haptoglobin, total bilirubin, apolipoprotein-A, GGT, age and gender. 0.0- 1.0.
• FIB4 = (age*AST)/(plts*√ALT)
• Fibroindex – plt count , AST and GGT
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Non-invasive assessment of fibrosis
• Hyaluronic acid – may correlate with activity and fibrosis
• PIIINP – amino terminal of serum pro-collagen III peptide
• TIMP-1
• YKL-40 – chondrex. Bacterial chitinase family
• ELF – Enhanced Liver Fibrosis – HA, PIIINP, TIMP-1
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Conclusions
• The liver biopsy is still important.
• Classical features of AIH occur in an acute setting, but individually are not specific.
• Histological activity illustrates one aspect of severity.
• Degree of fibrosis illustrates another.
• Non-invasive tests remain complementary at present and timing is important.
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References
• Clinical phenotypes Wang et al. J Autoimmun2016 66: 98- 107
• HLA types Genes Immun 2015 16: 247- 52
World J Gastroenterol 2006 12: 5513- 6
• Statin toxicity Hepatol 2014 60: 679- 86
• Drug-induced AIH Dig Liver Dis 2014 46: 1116- 20
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References
• Grading and staging Ishak et al. J Hepatol1995 22: 696- 699
• Simplified criteria for diagnosis IAIHG Hepatology 2008 48(1):169-76.
• Non-invasive markers of inflammation in AIH (Editorial) Liver Int 2013 33: 1295- 97
• Non-invasive diagnosis of advanced fibrosis/ cirrhosis World J Gastroenterol 2014 20: 16820- 30
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Not quite West Bromwich Albion…