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Liver and Biliary
Liver and Biliary
Liver Cases
Stefan Hübscher
Department of Pathology, University of Birmingham,
Birmingham B15 2TT
Cases 1 & 2
Acute Hepatitis
Liver Biopsy in Acute Hepatitis
Histological Approach
Clinical Summary
– Male, age 52.
– Recent onset of jaundice and abnormal LFTs.
– AST 793 (normal 5-43), ALP 655 (70-330), bilirubin 172 (1-22).
– ANA positive (1:100), SMA positive, IgG19.5 (normal 6-16).
– Liver biopsy
Liver – Case 1
Liver – Case 1
Liver – Case 1
Liver – Case 1
Liver – Case 1
Liver – Case 1
Liver – Case 1
Liver – Case 1 (PAS-diastase)
Liver – Case 1 (PAS-diastase)
Liver – Case 1 (Perl’s)
Liver – Case 1 (HVG)
Liver – Case 1
Histological Findings
– Portal inflammation (mainly mononuclear with plasma cells)
– Bile ductular reaction
Diagnosis
•Acute hepatitis – probably autoimmune
Autoimmune Hepatitis
Acute Presentation
Acute lobular hepatitis (Te 1997, Singh 2002, Misdraji 2004, Hofer 2006)
– Classical features of acute lobular hepatitis
– Mainly centrilobular distribution
– Initially have little or no portal inflammation, before
subsequently progressing to more classical features of
chronic AIH
Sheffield Diagnostic Histopathology Course
Liver – Case 2
Clinical Summary
• Female, age 34.
• Subacute liver failure.
• Viral serology negative. ANA weakly positive
• Liver transplantation
Liver - Case 2. Macroscopic Appearances
Shrunken liver, weight 700g. Wrinkled capsular surface
Liver - Case 2
Macroscopic Appearances
Could this be cirrhotic?
Is this liver cirrhotic?
1. Yes
2. Probably
3. Unsure – more histological stains required
4. Probably not
5. No
Use Of Connective Tissue Stains In Liver Biopsy Assessment
Histological Findings
– Large areas of panacinar necrosis (multi-acinar necrosis)
• Periportal ductular reaction
• Inflammation of hepatic veins
Diagnosis
• Severe acute hepatitis with multiacinar necrosis
(submassive hepatic necrosis)
• No strong aetiological pointers ( “seronegative
hepatitis”)
Liver Biopsy in Acute Hepatitis
Histological Approach
(1) Viral
• A,B,C,E
• Other
(2) Drugs
(3) Autoimmune
• acute presentation of AIH
• autoantibodies as non-specific response to acute liver injury
(4) Other/Unknown
• 70% of patients undergoing liver transplantation for acute
liver failure in Birmingham have “seronegative hepatitis”
Severe Acute Hepatitis Presenting with Acute Liver Failure
Aetiological Considerations
• Appearances similar irrespective of the underlying cause (viral, drug
autoimmune)
• Many cases undergoing liver biopsy have no identifiable cause
• Liver biopsy may identify causes of acute liver failure not due to acute
hepatitis
• Decompensated chronic liver disease (e.g. Wilson’s disease)
• Acute exacerbation of chronic liver disease (e.g. autoimmune hepatitis)
• Hepatic infiltration (usually lymphoma, rarely carcinoma)
Case 3
Chronic Hepatitis
Sheffield Diagnostic Histopathology Course
Liver – Case 3
Clinical Summary
– Male, age 35.
– Hepatitis C positive.
– Splenomegaly, coarse liver texture on ultrasound ? cirrhosis.
– LFTs – AST 94, ALP 485, Bilirubin 13.
– Liver biopsy.
Liver – Case 3
Liver – Case 3
Liver – Case 3
Liver – Case 3
Haematoxylin Van Gieson
Brown granules in periportal hepatocytes
What are they?
Liver – Case 3
Perls’ stain
Liver – Case 3
Histological Findings
– Portal inflammation (mainly mononuclear, moderately dense
with occasional lymphoid aggregates)
Diagnosis
1. Chronic hepatitis (HCV positive)
• Hepatitis Activity Index (Ishak) = 4/18 (A1, B0, C1, D2)
• Fibrosis Stage = 1
2. Siderosis ? cause
Role of Liver Biopsy in Chronic Hepatitis C
• Problems with
– Observer variation
– Sampling variation
Hepatitis C – Grading and Staging
Observer variation
• Agreement (e.g. measured by Kappa scores)
– generally good for fibrosis
– less good for inflammation
• Improved with:
– Observer experience
– Pathologists working in pairs
Hepatitis C – Grading and Staging
Sampling variation
• Histological concordance (e.g. studies using paired biopsies)
– Generally good for inflammation
– Less good for fibrosis
1. Fatty change
• Severity of steatosis correlates with
– Risk factors for metabolic syndrome/NAFLD (non-genotype 3 cases)
– Viral RNA levels (genotype 3 cases)
• Both pathways of steatosis (metabolic and HCV-related) may
lead to steatohepatitis
• Severity of steatosis influences response to antiviral therapy
Role of Liver Biopsy in Chronic Hepatitis C
Identifying additional lesions
2. Siderosis
• Minor degrees commonly present in HCV
– may be secondary to necro-inflammatory activity
– Typically have a mixed distribution (hepatocytes & Kupffer cells)
Clinical Summary
• Female, age 53.
• Chronic cholestatic liver disease
• Anti-mitochondrial antibody positive
• Liver transplantation
Macroscopic Findings
• enlarged liver (weight > 1550g)
• generally finely nodular and green
Sheffield Diagnostic Histopathology Course
Liver – Case 4
Architecture
Is this liver cirrhotic?
Liver – Case 4
Liver Architecture (Reticulin)
Liver – Case 4
Liver Architecture (HVG)
Liver – Case 4
Liver – Case 4
Orcein
Liver – Case 4
Liver – Case 4
Liver – Case 4
Portal Inflammation with Interface Hepatitis
Bilirubinostasis (periportal)
Interface Hepatitis
? Significance in PBC (and PSC)
Liver – Case 4
Histological Findings
• Variable fibrosis, in places amounting to early cirrhosis
• Features of chronic cholestasis (ductular reaction,CAP)
• Bile duct loss
• Inflammatory bile duct lesions, including granulomatous cholangitis
• Portal inflammation with interface hepatitis
Sheffield Diagnostic Histopathology Course
Liver – Case 4
Diagnosis
Primary biliary cirrhosis
Sheffield Diagnostic Histopathology Course
Liver – Case 5
Clinical Summary
• Male age 42
• Recurrent cholangitis. History of ulcerative colitis.
• Chronic cholestatic liver disease.
• Cholangiography showed beading and strictures
typical of PSC
• Liver transplantation
Sheffield Diagnostic Histopathology Course
Liver – Case 5
Macroscopic Findings
• enlarged liver (weight > 2200g)
• generally green and finely nodular
• large bile ducts dilated and filled with biliary sludge
Cholate Stasis
(toxic effects of retained bile acids)
PSC + Cholangiocarcinoma
• 0.6-1.5% per year
• Overall risk 20%
• Premalignant changes
Liver – Case 5
Histological Findings
• Established cirrhosis with “biliary features”
Diagnosis
Primary sclerosing cholangitis
Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis
1. Histological Features
- bile duct lesions
- other features of chronic cholestasis
2. Role of staging
3. Hepatitic features
- part of normal disease spectrum
- More severe changes ? Overlap syndrome
Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis
1. Histological Features
- bile duct lesions
- other features of chronic cholestasis
2. Role of staging
3. Hepatitic features
- part of normal disease spectrum
- More severe changes ? Overlap syndrome
Bile Duct Lesions - PBC And PSC
Ducts Involved
Sarcoidosis
Hepatitis C
Autoimmune cholangitis (AMA-negative PBC)
Sclerosing Cholangitis - Other Causes
Abdalian R, Heathcote EJ. Hepatology 2006;44:1063-1074
1. Histological Features
- bile duct lesions
- other features of chronic cholestasis
2. Role of staging
3. Hepatitic features
- part of normal disease spectrum
- More severe changes ? Overlap syndrome
Which staging system do you use for the assessment
of PBC in routine clinical/pathological practice?
Scheuer
Ludwig
Other staging system
Don’t use staging
Primary Biliary Cirrhosis – Variable Fibrosis
Grading Staging
Chronic cholangitis (0-3) Bile duct loss (0-3)
Interface hepatitis (0-3) Fibrosis (0-3)
Lobular hepatitis (0-3) Orcein-positive granules (0-3)
Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis
1. Histological Features
- bile duct lesions
- other features of chronic cholestasis
2. Role of staging
3. Hepatitic features
- Part of normal disease spectrum
- More severe changes ? Overlap syndrome
PRIMARY BILIARY CIRRHOSIS
portal inflammation
Primary Biliary Cirrhosis
portal inflammation with interface hepatitis
PBC (and PSC)
Clinical Summary
• Female, age 62.
• Presumed alcoholic liver disease with cirrhosis.
• Recurrent variceal bleeds. Patent portal vein.
• Transjugular intrahepatic porto-systemic shunts inserted (x2).
• No previous biopsy
• Liver transplantation
Sheffield Diagnostic Histopathology Course
Liver – Case 6
Macroscopic Findings
• liver normal size (weight > 1200g)
• generally finely nodular
• wire stent connecting right hepatic vein to portal vein
Sheffield Diagnostic Histopathology Course
Liver – Case 6
Histological Findings
• Normal vascular relationships
• Parenchymal atrophy
• Nodular regeneration without fibrosis
• Delicate non-linking fibrous septa
• Portal vein obliteration
• Portal vein ectasia (shunt vessels)
• Sinusoidal dilatation/congestion
Diagnosis
Vascular/architectural changes, in keeping with portal venous
insufficiency (“non-cirrhotic portal hypertension”)
“Non-Cirrhotic Portal Hypertension”
Problems with Liver Biopsy Diagnosis
Atrophy of perivenular
Collapse + passive septum
hepatocytes Formation of shunt vessels formation
(portal vein ectasia) (incomplete septal fibrosis)
Hyperplasia of periportal
hepatocytes
Sinusoidal dilatation +/- Severe cases may develop
(Nodular regenerative progressive fibrosis/cirrhosis
hyperplasia) congestion
Histopathology of portal hypertension: a practical
guideline.
Histopathology. 2003;42:2-13.
Case 7
Fatty Liver Disease
Sheffield Diagnostic Histopathology Course
Liver – Case 7
Clinical Summary
• Female age 53.
• Potential donor liver for transplantation.
• Not used because of macroscopic fatty appearance.
• Wedge biopsy taken to assess severity of liver disease
Ubiquitin
CK 7
Liver – Case 7
Histological Findings
Liver Parenchyma (mainly zone 3)
• Moderate fatty change (mainly macrovesicular)
• Hepatocyte ballooning, Mallory’s hyalin
• Mixed inflammatory cell infiltrate, including neutrophils
• Pericellular fibrosis
Portal/Periportal Regions
• Portal inflammation (with mild interface hepatitis)
• Ductular reaction
• Periportal and bridging fibrosis
Sheffield Diagnostic Histopathology Course
Liver – Case 7
Diagnosis
Steatohepatitis (presumed non-alcoholic)
Role of Liver Biopsy in Fatty Liver Disease
2. Aetiological pointers
• AFLD versus NAFLD
• cases with a dual pathology (e.g. HCV and NAFLD)
• May become more prominent during the later stages of the disease
• Some cases associated with development of auto-antibodies
(usually in low titre, functional significance uncertain)
Possible mechanisms
(Roskams 2003, Yang 2004, Clouston 2005, Richardson
2007)
Steatosis impairs hepatocellular replication
Ductular reaction
Role of Liver Biopsy in Fatty Liver Disease
2. Aetiological pointers
• AFLD versus NAFLD
• cases with a dual pathology (e.g. HCV and NAFLD – see case 3 discussion)
2. Aetiological pointers
• AFLD versus NAFLD
• cases with a dual pathology (e.g. HCV and NAFLD)
100
80
% of All Scores
Steatohepatitis
60 No
Probable
40 Yes
20
0
0 1 2 3 4 5 6 7 8
Activity Score
Role of Liver Biopsy in Fatty Liver Disease
Assessing disease severity
Problems with:
Observer variability
• Agreement good for fibrosis & steatosis
• Less good for ballooning & inflammation
Sampling variability
• Reproducibility good for steatosis
• Less good for fibrosis and inflammation
Cases 8 & 9
Drug-induced liver disease
Sheffield Diagnostic Histopathology Course
Liver – Case 8
Clinical Summary
• Male, age 39.
• Acute liver failure. Recent history of depression.
• Paracetamol overdose
• Liver transplantation
Sheffield Diagnostic Histopathology Course
Liver – Case 8
Macroscopic Findings
• liver normal size (weight > 1200g)
• zonal red/brown colour (“nutmeg” appearance)
CK 7
Sheffield Diagnostic Histopathology Course
Liver – Case 8
Histological Findings
• Recent zonal necrosis
– Coagulative pattern
– Uniform distribution
– Lack of inflammation
Diagnosis
Recent zonal necrosis (paracetamol toxicity)
Sheffield Diagnostic Histopathology Course
Liver – Case 8
Discussion points
1. Toxic versus hepatitic injury in acute liver failure
TOXIC HEPATITIC
(e.g. paracetamol) (e.g. viral, drugs,
autoimmune)
Pattern of necrosis Coagulative Lytic
(may appear lytic
later)
Distribution of Uniform Patchy
necrosis
Discussion points
1. Toxic versus hepatitic injury in acute liver failure
Clinical Summary
Male age 62.
Presented with jaundice 9 weeks ago.
ERCP 6 weeks ago – sphincterotomy and gallstone removal
No improvement in jaundice or liver biochemistry.
Repeat ERCP 2 weeks ago – no stones in biliary tree.
Still jaundiced
Liver biopsy.
Sheffield Diagnostic Histopathology Course
Liver – Case 9
Histological Findings
• Bilirubinostasis ++
• Minimal inflammation (portal and parenchymal)
• No features to suggest biliary obstruction or any underlying
chronic liver disease
Sheffield Diagnostic Histopathology Course
Liver – Case 9
Diagnosis
Intrahepatic cholestasis ?cause
(exclude drug reaction)
Sheffield Diagnostic Histopathology Course
Liver – Case 9
Discussion points
• Drugs
• Sepsis
• Benign recurrent intrahepatic cholestasis
• Intrahepatic cholestasis of pregnancy
• Occult malignancy (especially lymphoma)
• Total parenteral nutrition
• Preservation-reperfusion injury in liver allograft
“Pure” cholestasis can also be seen during early stages of large duct obstruction
Drug-induced Liver Disease
Patterns Of Liver Injury
FATTY CHANGE
• macrovesicular - corticosteroids, methotrexate
• microvesicular * - tetracycline, valproate, zidovudine
STEATOHEPATITIS - amiodarone,tamoxifen
CHOLESTASIS
• acute (“pure”) * - oral contraceptive pill
• chronic (with duct loss) - chlorpromazine, augmentin
GRANULOMAS*
• epithelioid - allopurinol, carbamazepine, phenylbutazone
• fibrin-ring - allopurinol
• mineral-oil - mineral oil ingestion
• foreign body - chronic metal exposure, IV drug abuse
Clinical Summary
• Female, age 38.
• Incidental lesion noted in segment 6 of liver during
investigations for haematuria.
• Previous history of steroids for proctitis and oral contraceptive
use.
• Liver resection.
• Well circumscribed lesion 5.5cm diameter with central scar.
Liver biopsy diagnosis?
CK 7
Sheffield Diagnostic Histopathology Course
Liver – Case 10
Histological Findings
- central scar with abnormal blood vessels
- fibrous septa
- hepatocyte nodules
- ductular reaction without bile ducts
- copper associated protein
Sheffield Diagnostic Histopathology Course
Liver – Case 10
Diagnosis
Focal nodular hyperplasia
Sheffield Diagnostic Histopathology Course
Liver – Case 10
Discussion points
(1) Problems With Liver Biopsy Interpretation
Typical FNH
Atypical FNH
(2) Pathogenesis
Primary FNH
Secondary FNH
Focal Nodular Hyperplasia
Problems with Liver Biopsy Interpretation
2. ATYPICAL FNH
• Without central scar (esp smaller lesions <1cm)
• Without prominent ductular reaction
• Telangiectatic
• Mixed hyperplastic and adenomatous
• Atypia of large cell type
Focal nodular hyperplasia of the liver: a comprehensive pathologic study of 305 lesions and
recognition of new histologic forms. Nguyen et al Am J Surg Pathol 1999 Dec;23(12):1441-54
Recent studies suggest that telangiectatic FNH may be variant of liver cell adenoma ( Paradis
2004, Bioulac-Sage 2005, Zucman-Rossi 2006, Bioulac-Sage - J Hepatol. 2007;46(3):521-7.)
Sheffield Diagnostic Histopathology Course
Liver – Case 10
Discussion points
(1) Problems With Liver Biopsy Interpretation
Typical FNH
Atypical FNH
(2) Pathogenesis
Primary FNH
Secondary FNH
Focal Nodular Hyperplasia - Pathogenesis
• Primary FNH
– congenital arterial malformation
• Secondary FNH
– associated with acquired vascular abnormalities
• Haemangioma / other neoplasms
• Venous thrombosis
• Cirrhosis
Sheffield Diagnostic Histopathology Course
Liver – Case 11
Clinical Summary
• Male, age 65.
• Cirrhosis ? cause
• Liver transplantation
• Hepatectomy specimen contained 4 larger nodules, up
to 2.5cm diameter.
• Slide submitted contains one of these nodules.
Sheffield Diagnostic Histopathology Course
Liver – Case 11
Discussion points
Classification and diagnosis of large nodules in cirrhotic livers
Evolution of HCC in Cirrhosis
Hepatocellular Carcinogenesis
• Multi-step process
• Successive stages associated with increase in: size of nodules
molecular abnormalities
risk of progression to HCC
• Overlapping morphological spectrum
→ Increasing consensus regarding
Hepatology diagnostic
2009:49: 658-664criteria
Diagnosis
Cirrhosis (with alpha-1-antitrypsin globules)
+ hepatocellular carcinoma
And finally……
A Football-Related Quote - from Luigi Terraciano
(The person in question was appointed to a new position on July 1 2009 )