hep belfast talk hubscher - path · cholangiography and exclusion of secondary causes of sclerosing...

21/07/2017

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Update on Autoimmune Biliary Disease

Changing Role of Liver Biopsy in PBC and PSC

Stefan HübscherInstitute of Immunology & Immunotherapy, University of Birmingham

Department of Cellular Pathology, Queen Elizabeth Hospital, Birmingham, UK

Primary Biliary Cirrhosis Cholangitis

Change in Nomenclature for PBC : From “Cirrhosis” to “Cholangitis”(EASL Panel, Beuers et al – J Hepatol Nov 2015, Gut Nov 2015, Hepatology Nov 2015)

• Most patients don’t have cirrhosis at the time of diagnosis and some never develop cirrhosis

• Patient groups (mostly female, non-alcohol drinkers) dislike the stigma attached to the term “cirrhosis”

• Other terms proposed to describe PBC (e.g. chronic non-suppurativedestructive cholangitis, autoimmune cholangitis) have failed to gain widespread acceptance

• “Primary biliary cholangitis” now accepted as the term to describe the disease

PBC & PSC- Diagnostic CriteriaAASLD Practice Guidelines – Hepatology 2009, EASL Clinical Practice Guidelines – J Hepatol 2009, AASLD Practice Guidelines - Hepatology 2010, EASL Clinical Practice Guidelines – J Hepatol 2017

Liver biopsy no longer required for routine diagnosis:

• PBC diagnosed by cholestatic liver biochemistry (raised Alk Phos) and immunology (anti-mitochondrial antibodies, raised IgM)

• PSC diagnosed by cholestatic liver biochemistry (raised Alk Phos), cholangiography and exclusion of secondary causes of sclerosing cholangitis

Consequences:

1. Fewer biopsies obtained from PBC & PSC patients

2. Biopsies obtained more complex and challenging

Role of Liver Biopsy in PBC and PSC

1. Establishing a diagnosis in atypical cases

2. Identifying early disease

3. Assessing inflammatory activity (“overlap syndromes”)

4. Assessing disease progression (staging)



• AMA-negative PBC

• Small duct PSC




AMA – negative PBC (‘Autoimmune Cholangitis’)

Prevalence • Approximately 5-10% cases

Diagnostic Features• Typically have other autoantibodies (ANA,

SMA)• Cholestatic biochemistry and histology

Some differences compared with AMA+ PBC• e.g. less severe pruritus, higher AST, lower

IgM levels, more plasma cells, more T cells, more CD5+ cells, more CD20+ cells

Overall behaviour similar to AMA+ PBC• Including similar response to treatment with

UDCA (Lindor 2009)

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AMA-Positivity in Asymptomatic Patients with Normal Alk Phos

• AMA-positivity present in 0.07% - 9.9% of apparently healthy individuals (Dahlqvist 2017)

• Functional significance uncertain

1. Mitchison (Hepatology 1986), Metcalf (Lancet 1996) – 29 cases

• 24 (83%) had histological features compatible with or diagnostic of PBC• 24 developed cholestatic liver biochemistry (median follow-up 17.8 years)

• 22 progressed to symptomatic PBC (none became cirrhotic)

2. Dahlqvist (Hepatology 2017) - 130 cases

• Liver biopsies obtained from 28 patients – none reported as showing features suggestive of PBC

• Follow-up data from 92 patients - 9 progressed to PBC (median 16% at 5yrs)

Small Duct PSC

Prevalence• approximately 5-15 % of PSC patients have disease confined to small ducts

Diagnostic Features• Normal/near-normal cholangiogram• Histological features of sclerosing cholangitis

BUT • Histological features required not clearly defined or uniformly applied

– Fibrosing duct lesions only present in 4/25 (16%) of cases (Singal 2011)• Remainder had features of chronic biliary disease compatible with PSC

Small Duct PSC - Natural History( La Russo 2006, Bjornsson 2008)

Outcome variable• 20 - 30% of cases progress to large duct involvement:

• typically associated with IBD− more frequently Crohn’s disease (Bjornsson 2008, Halliday 2012, Fevery 2016)

• probably represent early stages or mild form of true PSC

• 70 - 80% of cases don’t progress to large duct disease• usually occur without IBD,• have a different HLA genotype to large duct PSC (Naess 2014)

• may represent a different disease



2. Identifying early disease• Subtle histological features of chronic cholestasis may identify early

chronic biliary disease before this has been recognised clinically

• Studies of biopsies sent for expert review suggest that chronic biliarydisease is frequently not recognised histologically (Bejarano 2001, Colling2014, Paterson 2016)



Referred Biopsy – Diagnosis Chronic Hepatitis ? CauseRaised AST & Alk Phos. Autoantibody screen negative.

• Portal inflammation and interface hepatitis• Biliary features not conspicuous

OrceinPeriportal copper-associated protein

Keratin 7 Immunostaining“intermediate hepatobiliary cells”

Repeat autoantibody testing = AMA-positive

Early Chronic Biliary Disease – Changes in Periportal Hepatocytes

RhodanineStaining for Copper

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Loss of Canals of Hering in “Minimal Change” Primary Biliary Cirrhosis(Khan, Hepatology 2012 )

10 Cases (PBC supected on clinical/biochemical grounds)• Nearly normal or mildly inflamed biopsies, with no features to suggest PBC• Loss of canals of Hering (CoH) demonstrated by K19 immunostaining• Outcome similar to control population of histologically confirmed early PBC

“Minimal change PBC” “Minimal change PBC” Normal control

Loss of CoH may also be a feature associated with disease progression (Kakuda 2015)

• Lower CoH density/parenchymal area associated with fibrosis stage, duct loss and orcein-positive granule deposition

• Also associated with higher “hepatitis activity” score , suggesting possible inflammatory destruction of canals of Hering

Primary Sclerosing Cholangitis – Early Small Bile Duct LesionsBile Duct Inflammation

Periductal Fibrosis (early)Some inflammatory cells also present

Florid Duct Lesion(rarely seen in PSC)

Periductal InflammationFocal infiltration of bile duct epithelium

Primary Sclerosing Cholangitis – Early Small Bile Duct LesionsBasement Membrane Thickening

(Mattila – Liver 1992, Colling - Histopathology 2015)

• Basement membrane thickness assessed in bile ducts using DPAS sections• Thickening graded on scale of 0-3• Grade 2/3 thickening more frequent in PSC cases (47%) than non-PSC cases (12%)

G0 G1

G2 G3






Autoimmune “Overlap Syndromes”Problems with Classification / Terminology

• Approximately 5-15% of patients with PBC and PSC have additional features supporting a diagnosis of autoimmune hepatitis (AIH)

• Most cases with “overlap features” (PBC/AIH or PSC/AIH) are best regarded as variants of PBC or PSC, rather than as distinct entities

• Terms such as “PBC/PSC with hepatitic features” or “PBC/PSC with AIH features” may be more appropriate

Assessing Inflammation in PBC and PSC

• Portal inflammation and interface hepatitis = part of normal disease spectrum− Usually mild, more prominent in PBC than PSC

• Lobular inflammatory changes may also be present− Usually mild, more prominent in PBC than PSC

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Assessing Inflammation in PBC and PSC

Unusually Severe Inflammation ? “Overlap Syndrome”• Dense plasma-cell rich portal inflammation• Prominent interface hepatitis

• Hepatocyte ballooning, rosetting, emperipolesis• Lobular inflammation associated with confluent/bridging necrosis

PBC & PSC Clinical Relevance of Assessing Inflammatory Activity

PBC• Presence/severity of inflammatory activity in baseline biopsies predicts

progession to fibrosis/cirrhosis & liver failure (Degott 1999, Corpechot 2002, Corpechot 2008, Carbone 2015)

PSC

• Relevance of inflammatory activity for predicting disease progression less clearly established

• One study of 46 PSC patients showed “widespread” versus “mild” piecemeal necrosis more frequent in patients who died (Aadland, Scand J Gastroenterol 1987)

Diagnostic Criteria for AIH (Chazouilleres 1998, IAHG guidelines 2011, EASL Guidelines 2017)

1. ALT >5x upper limit of normal (ULN) 2. IgG levels >2x ULN OR SMA positive3. Liver biopsy with at least moderate interface hepatitisØ Histological confirmation of interface hepatitis “mandatory for diagnosis”

• less rosettes, emperipolesis and lobular hepatitis than “pure” AIH (Kobayashi 2014)

Presentation • Usually simultaneously• Occasional cases have sequential presentation

– usually PBC AIH (intervals up to 13 years)

Clinical Significance• PBC with “hepatitic features” - worse outcome than “pure” PBC

˗ Reduced 5 year adverse outcome free survival in 46 PBC/AIH patients compared with 277 “pure” PBC patients (58% vs 81%) (Yang 2016)

• May benefit from treatment with immunosuppression (+UDCA)˗ Less fibrosis progression, better short-term outlook

PBC/AIH “overlap syndrome” (PBC with “hepatitic features”)PSC/AIH Overlap Syndrome

(Beuers 2009, Chapman 2010, Boberg 2011, Czaja 2012, Schulze 2015 )

Diagnostic Criteria

• Similar to those used for PBC/AIH overlap (but less clearly defined)

• Demonstration of histological inflammatory activity important

Presentation

“Sequential syndrome” more common than in PBC, particularly in children/young adults

• Usually AIH PSC (intervals 6 months -13 years)

• Extent to which PSC excluded at the time of diagnosing AIH uncertain

– Using routine cholangiography up to 50% of children presenting with AIH have features compatible with PSC – “Autoimmune Sclerosing Cholangitis” (ASC) (Gregorio 2001)

– Features compatible with PSC detected in 2-10% of adults undergoing cholangiography at the time of first presenting with AIH (Abdalian 2008, Lewin 2009)

Autoimmune Sclerosing Cholangitis in Children - Natural History

• Initial study suggested a favourable outcome with good response to immunosuppression – similar to paediatric AIH (Gregorio 2001)

• Further follow-up showed that many children developed features of progressive chronic biliary disease (Scalori 2007, Mieli-Vergani 2009)

• Another study from U.S. suggested that children with ASC have a distinct phenotype, different to typical PSC or AIH (Deneau 2013)

PSC/AIH “Overlap Syndrome” in AdultsTreatment & Prognosis

• Current guidelines documents (AASLD, EASL, IAIHG) recommend treatment with UDCA and immunosuppression

• Less favourable response to immunosuppression than cases of pure AIH

• Overall prognosis better than pure PSC

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Histological Staging of PBC and PSC

Several staging systems described (Rubin 1965, Scheuer 1967, Popper & Schaffner 1970, Ludwig 1978, Ludwig 1981)

• Based on various combinations of portal/periportal inflammation, ductularreaction & fibrosis

• Stage 4 = cirrhosis• Widely used in the assessment of patients with PBC and PSC

Problems with sampling variability• Studies of paired liver biopsies and hepatectomy specimens obtained at LT

showed variation in stage in 27-52% of cases (Olsson 1995, Garrido & Hubscher 1996)

• No longer used in routine assessment

Chronic Biliary Disease – Progression of Periportal Fibrosis

Moderate - bridging fibrosis (Ludwig stage 3)

All 3 images are from the same block of a PSC liver obtained at transplantation

Mild – periportal fibrosis (Ludwig stage 2)

Severe –cirrhosis (Ludwig stage 4)

PBC – Role of Biopsy in Staging

Histological features predictive of poor outcome in PBC (including HCC ) (Vleggar 2000, Bergasa 2004, Mayo 2008, Cavazza 2009, Kumagi 2010,

Floreani 2011, Harada 2013, Kakuda 2013, Chan 2014)

• Advanced fibrosis/established cirrhosis• Marked ductopenia• Orcein-positive granules

Proposal of a new staging and grading system for primary biliary cirrhosis (Hiramatsu 2006, Nakanuma 2010)

Grading Features1. Cholangitis Activity (0-3)2. Hepatitis Activity (0-3)

Staging Features1.Bile duct loss (0-3)2.Fibrosis (0-3)3.Orcein-positive granules (0-3)

Total Staging Score (0-9)0 = stage 1 (no progression)1-3 = stage 2 (mild progression)4-6 = stage 3 (moderate progression)7-9 = stage 4 (advanced disease)

Staging features correlated with biochemical abnormalities and with Mayo Risk Score(grading features – no correlation)

(Staging features could also be applied to PSC)

Japanese (Nakanuma) System for Grading & Staging PBC – Further Studies

• Subsequent studies have shown that Nakanuma system for staging PBC correlated better with adverse outcomes than other scoring systems such as Scheuer (1967) and Ludwig (1978) (Harada 2013, Kakuda 2013, Chan 2014)

‒ CAP deposition score is most powerful prognostic feature (Kakuda 2013, Chan 2014)

• Nakanuma scoring system also predicts response to treatment with UDCA (Nakamura, Hepatol Res 2015)

• Higher bile duct loss score = risk factor for worse Alk Phos response• Higher hepatitis score = risk factor for worse IgM response

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Another Histological Scoring System for PBC(Wendum, Liver International 2015)

• Liver biopsies from 33 newly diagnosed PBC patients

• Semi-quantitative scoring of features thought to be prognosticallyimportant:

1. Fibrosis (F0 – F4)2. Interface hepatitis ( 0-3)3. Bile duct ratio (number of PTs with BD/total number of PTs)

• Results (compared with Scheuer & Ludwig systems)• Better inter-observer agreement for each of the 3 features assessed• Similar correlation with biochemical abnormalities • No liver-related events to assess prognostic value

64 patients with PSC (Dutch cohort), median follow-up 9.3 years• Baseline liver biopsies assessed by two observers in tandem

‒ Ludwig stage, Ishak grade & stage, Nakanuma grade & stage

Staging components of all 3 scoring systems associated with adverse outcomes:

Scoring System Hazard RatiosTransplant-free Survival Time to LT

Ludwig 1.94 3.13Ishak 2.56 4.18Nakanuma 6.53 7.05

Journal of Hepatology 2015: 63:1212–1219

119 patients from 7 European centres, median follow- up 11.8 years• Baseline liver biopsies assessed by two observers in tandem

‒ Ludwig stage, Ishak grade & stage, Nakanuma grade & stage

→ Staging components of all 3 scoring systems associated with adverse outcomes:

Scoring System

Hazard Ratios

PSC-related death/liver transplantation

Liver transplantation Liver-related events

Ludwig NS 2.62 2.06

Ishak NS 1.55 1.43

Nakanuma 2.14 3.16 2.05

Interobserver Agreement StudySame 119 biopsies assessed by 6 other liver pathologists• Agreement substantial for Nakanuma fibrosis (κ = 0.67), Ishak stage (κ = 0.64), Ludwig stage (κ = 0.62)• Αgreement moderate for Nakanuma overall stage (κ = 0.56)

Role of Liver Biopsy in Monitoring Outcomes in PBC/PSC Clinical Trials

• PBC and PSC are both relatively uncommon diseases with long natural histories • Need to have surrogate endpoints to determine treatment outcomes

Liver biopsy still viewed as “gold standard” for assessing disease severity

• Diagnostic/prognostic utility of non-invasive markers less clearly established in chronic biliary diseases (PBC and PSC) than in non-biliary diseases (e.g. HCV, NAFLD) (Poupon 2015, Corpechot 2016, Stasi 2016)

• Non-invasive markers of fibrosis unable to detect other histological staging features relevant in disease progression (e.g. ductopenia, CAP deposits)

Advantages of Liver Biopsy in Monitoring Outcomes in PBC/PSC Trials Role of Liver Biopsy in PBC and PSC – Summary & Conclusions

1. For cases of PBC and PSC with other typical findings, liver biopsy no longer required for diagnosis.

2. Liver biopsy continues to be important in establishing a diagnosis in atypical cases (e.g. AMA-negative PBC, small duct PSC).

3. Identifying subtle features of chronic cholestasis may point to a diagnosis of chronic biliary disease in cases where this has not yet been identified clinically.

4. Assessing inflammatory activity is important prognostically and may have implications for treatment with immunosuppression.

5. Staging of PBC and PSC is relevant prognostically and may be useful in monitoring treatment outcomes in clinical trials.

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And, finally….......

Barclay’s Premier League – Saturday March 18th 2017West Bromwich Albion 3 – Arsenal 1

Craig Dawson scores second headed goal from a corner to clinch a well-deserved victory

hep belfast talk hubscher - path · cholangiography and exclusion of secondary causes of sclerosing...

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