Liver and Biliary

Sheffield Diagnostic Histopathology Course 2010
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
1. Is this acute or chronic damage?
2. How severe is the damage?
3. What is the cause?

Sheffield Diagnostic Histopathology Course
Liver – Case 1
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
– Spotty lobular inflammation, associated with

• Ballooning
• Acidophil body formation
• Lobular disarray
• Small foci of confluent necrosis
• Bilirubinostasis (mild)
Liver – Case 1
Diagnosis
•Acute hepatitis – probably autoimmune
Autoimmune Hepatitis
Acute Presentation
(up to 40% of cases – Czaja and Freese

2002)
Autoimmune Hepatitis - Acute Presentation
Acute “flare” of chronic liver disease (Nikias 1994, Burgart 1995)

– > 50% of patients with apparently acute presentation have
bridging fibrosis or cirrhosis
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
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
Stain Material Distribution In Changes In Liver Disease

Demonstrated Normal Liver
Reticulin Type III collagen Portal tracts, Collapse of reticulin

fibres hepatic sinusoids framework in areas of
recent liver cell necrosis.
(few days)
Haematoxylin Type I collagen fibres Portal tracts, walls Increased in hepatic fibrosis
Van Gieson of hepatic veins (weeks/months)
Orcein Elastic fibres Portal tracts, Found in long-standing

walls of hepatic fibrosis/cirrhosis
veins (months/years)
Liver – Case 2
– Large areas of panacinar necrosis (multi-acinar necrosis)
• Periportal ductular reaction
• Inflammation of hepatic veins
– Surviving areas of liver parenchyma

• Nodular regeneration
• Severe bilirubinostasis
• Zonal necrosis
• Little inflammation
Liver – Case 2
Diagnosis
• Severe acute hepatitis with multiacinar necrosis
(submassive hepatic necrosis)
• No strong aetiological pointers ( “seronegative
hepatitis”)

• severe acute hepatitis versus decompensated chronic liver disease

Severe Acute Hepatitis (e.g. case 2)
Acute versus Chronic Damage

• Areas of bridging necrosis & nodular regeneration can resemble changes occurring
in cirrhosis
• Areas of multiacinar necrosis can resemble inflamed fibrous septa in cirrhosis
Acute versus Chronic Damage - Helpful pointers

• Clinical context
• Identification of normal vascular relationships
• Use of connective tissue stains to determine age of lesions

Liver Cell Death in Acute (and Chronic) Hepatitis
PATTERN OF HISTOLOGICAL FEATURES

CELL DEATH
Spotty necrosis Apoptosis of individual hepatocytes (acidophil
bodies)
Confluent necrosis Loss of groups of adjacent liver cells
(zone 3)
Bridging necrosis Confluent necrosis linking vascular structures
(central-central or central-portal bridging)
Panacinar necrosis Loss of hepatocytes in an entire acinus
Multiacinar necrosis Panacinar necrosis involving several adjacent acini

Liver Cell Death in Acute (and Chronic) Hepatitis
Severity of liver cell necrosis correlates with:

• Progression to liver failure (acute hepatitis)
• Progression to fibrosis (acute and chronic hepatitis)
• Response to therapy
– In AIH bridging necrosis associated with poor response to immunosuppression
– (interface hepatitis generally more responsive)

Acute Hepatitis – Possible Causes
(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
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
– Portal inflammation (mainly mononuclear, moderately dense
with occasional lymphoid aggregates)
– Bile duct inflammation (mild)
– Lobular inflammation (mild, spotty)
– Siderosis (hepatocellular, grade 2-3/4)

Liver – Case 3
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
• Establishing a histological diagnosis

• Identifying or confirming the aetiology (including co-
existent disease)
• Assessing disease severity
– necro-inflammatory activity (grading)
– fibrosis (staging)
• Identifying additional lesions

– fatty change
– siderosis
Hepatitis C – Histological Features
• Portal inflammation predominates, mainly mononuclear

• Lymphoid aggregates
• also seen in autoimmune diseases (AIH, PBC)
• Interface hepatitis
• Typically mild. Important in disease progression
• Lobular inflammation
• Generally mild
• Confluent bridging/necrosis not seen with HCV alone (except in
immunocompromised individuals e.g. post-transplant). When
present, consider other causes (e.g. co-existent AIH)
• Fatty change
• Typically mild, mainly macrovesicular
Hepatitis C – Grading and Staging
• Several systems described

– METAVIR and Ishak most widely used
• System used doesn’t matter so long as clinician reading report
understands the scores and uses them appropriately
• Histological scores are not numerical measurements and should not
be used as a substitute for conventional histological reporting
• Problems with
– Observer variation
– Sampling variation
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
Sampling variation
• Histological concordance (e.g. studies using paired biopsies)
– Generally good for inflammation
– Less good for fibrosis
Factors influencing sampling variability

– Biopsy length
– Biopsy diameter
• Short or narrow biopsies tend to underestimate both disease grade and stage
Grading and Staging in Chronic Liver Disease (HCV and NASH)
Sampling Variability
(Regev 2002, Bedossa 2003, Janiec 2005, Mendez 2005, Goldstein 2005, Ratziu 2005, Merriman
2006, Arun 2007, Cholongitas 2007)
• What is an “adequate biopsy”?

– At least 20 - 25 mm long
– At least 1.4 mm diameter
– At least 11 complete portal tracts
• Liver biopsies increasingly obtained by radiologists,

who favour using narrow gauge biopsies
– Reduce risk of complications
– Still produce “adequate diagnostic material”
Identifying Additional Lesions
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
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)
• More severe siderosis with pure hepatocellular distribution

raises possibility of genetic haemochromatosis
• Presence of siderosis has adverse influence on response to

antiviral therapy
Cases 4 & 5
Chronic Biliary Disease
Liver – Case 4
Clinical Summary
• Female, age 53.
• Chronic cholestatic liver disease
• Anti-mitochondrial antibody positive
Macroscopic Findings
• enlarged liver (weight > 1550g)
• generally finely nodular and green
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
• 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
Liver – Case 4
Diagnosis
Primary biliary cirrhosis
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 – Case 5
• 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)
Feathery degeneration, ballooning, Mallory-Denk bodies

What term describes this combination of changes?
What other changes should we look for in and
around large ducts in PSC?
PSC + Cholangiocarcinoma
• 0.6-1.5% per year
• Overall risk 20%
• Premalignant changes
Liver – Case 5
• Established cirrhosis with “biliary features”
• Spectrum of bile duct lesions

• SMALL reduced in number
(“vanishing bile duct syndrome”)
• MEDIUM-SIZED nodular scars

(fibrous cholangitis)
• LARGE dilated, inflamed & ulcerated

Liver – Case 5
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
- bile duct lesions
2. Role of staging
Bile Duct Lesions - PBC And PSC
Ducts Involved
PBC Small (interlobular)
PSC Small (interlobular)

Medium (septal) *
Large (hilar)
Extrahepatic
* NOTE: Fibrosing duct lesions mainly involve medium-sized ducts

Granulomatous Cholangitis - Other Causes
Sarcoidosis
Hepatitis C
Autoimmune cholangitis (AMA-negative PBC)
Sclerosing Cholangitis - Other Causes
Abdalian R, Heathcote EJ. Hepatology 2006;44:1063-1074
Vascular - hepatic artery occlusion

- portal vein occlusion (portal biliopathy)
Infective - bacterial
- viral
- protozoal
Neoplastic - Langerhans cell histiocytosis
- systemic mastocytosis
Autoimmune - autoimmune sclerosing cholangitis
(IgG4-associated sclerosing cholangitis)
Idiopathic - idiopathic adult ductopenia
Bile Duct Lesions in PBC and PSC
PBC – granulomatous cholangitis PSC –fibrous cholangitis
Rarely seen in needle biopsy specimens
• Granulomatous cholangitis in 85/258 (32%) PBC biopsies
• Fibrous cholangitis in 7/60 (12%) PSC biopsies
• Histological distinction only possible in 92/318 (28%) cases

(Wiesner RH, La Russo NF, Ludwig J, Dickson ER, Gastroenterology 1985;88:108-114)
Chronic Biliary Disease
Bile duct loss and ductular reaction
Ductular Reaction With Neutrophils (Cholangiolitis)
Primary Biliary Cirrhosis
Ductular Fibrosis (HVG)
Ductular reaction – CK 7 immunostaining
What other stain is most helpful in the diagnosis of

mild/early chronic biliary disease?
- bile duct lesions
2. Role of staging
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
Cirrhotic area No fibrosis

Proposal of a new staging and grading system for primary biliary cirrhosis
Hiramatsu, K., Aoyama, H., Zen, Y., Aishima, S., Kitagawa, S., Nakanuma, Y..
Histopathology 2006;49:466-78.
Factor analysis and correlational analysis

17 histological features in liver biopsies from 188 PBC patients – graded on a
scale of 0-3
Correlated with other clinical and laboratory data (Mayo Clinic Prognostic
Model)
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)
- bile duct lesions
2. Role of staging
- Part of normal disease spectrum
PRIMARY BILIARY CIRRHOSIS
portal inflammation
Primary Biliary Cirrhosis
portal inflammation with interface hepatitis
PBC (and PSC)
Severity of interface hepatitis:

• Predicts subsequent development of fibrosis/cirrhosis
(chronic active hepatitis versus chronic persistent hepatitis)
• May guide therapeutic decisions
– Cases with prominent inflammatory activity present in combination with
autoantibodies (e.g. ANA, SMA) and/or hepatitic LFTS (AST/ALT)
may be classified as “autoimmune overlap syndromes”
– Treatment with immunosuppression (in addition to UDCA) may result
in biochemical improvement and prevent fibrosis progression
PBC and PSC – Changing Role Of Liver Biopsy
• Cases with typical clinical features and appropriate

serological or radiological findings may not require liver
biopsy confirmation
• Liver biopsy still useful to detect atypical cases

– AMA-negative PBC (“autoimmune cholangitis”)
– Small duct-PSC
– Autoimmune overlap syndromes
• May have a role is assessing disease severity

Case 6
Vascular Disease
Liver – Case 6
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 – Case 6
• liver normal size (weight > 1200g)
• generally finely nodular
• wire stent connecting right hepatic vein to portal vein
Liver – Case 6
• 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
• NO features of alcoholic liver disease

Liver – Case 6
Diagnosis
Vascular/architectural changes, in keeping with portal venous
insufficiency (“non-cirrhotic portal hypertension”)
“Non-Cirrhotic Portal Hypertension”
Problems with Liver Biopsy Diagnosis
(1) Uncommon (compared with hepatic fibrosis/cirrhosis)
(2) Subtle Changes
(3) Sampling Variation
(4) Problems with Terminology/Classification

“Non-Cirrhotic Portal Hypertension”
Histological Features (+ alternative terms)
• Normal vascular relationships

• Parenchymal atrophy
• Nodular regeneration without fibrosis (nodular regenerative
hyperplasia)
• Delicate non-linking fibrous septa (incomplete septal
fibrosis/cirrhosis)
• Portal vein obliteration (hepatoportal sclerosis)
• Portal vein ectasia (shunt vessels)
• Sinusoidal dilatation/congestion
Non-cirrhotic portal hypertension (hepatoportal sclerosis)
Pathogenesis + Histological Features
Occlusion of small PV branches

(portal vein sclerosis)
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.
Roskams T, Baptista A, Bianchi L, Burt A, Callea F, Denk H, De

Groote J,Desmet V, Hubscher S, Ishak K, MacSween R, Portmann
B, Poulson H, Scheuer P,Terracciano L, Thaler H.
Histopathology. 2003;42:2-13.
Case 7
Fatty Liver Disease
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
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
Liver – Case 7
Diagnosis
Steatohepatitis (presumed non-alcoholic)
Role of Liver Biopsy in Fatty Liver Disease
1. Establishing a morphological diagnosis

• Distinction between steatosis and steatohepatitis
• Recognition of portal tract changes
2. Aetiological pointers
• AFLD versus NAFLD
• cases with a dual pathology (e.g. HCV and NAFLD)
3. Assessing disease severity

• grading of fat, ballooning, inflammation
• staging of fibrosis
Steatohepatitis
Hepatocyte ballooning
Mallory’s hyaline
Mixed inflammatory cell infiltrate (including neutrophils)
Steatohepatitis – Pericellular Fibrosis
Steatohepatitis – Ballooning and Mallory’s Hyaline
Hepatitis C – Fatty Change and ? Ballooning
Mallory’s Hyaline – Ubiquitin Immunohistochemistry
Portal/Periportal Changes in (Non-Alcoholic) Fatty Liver Disease
1. Portal inflammation +/- interface hepatitis

(chronic hepatitis-like)
2. Biliary features
(resembling low-grade biliary obstruction)
3. Isolated portal fibrosis
(without features of steatohepatitis)
Portal Changes in NAFLD - Chronic Hepatitic Features
• 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)
• Interface hepatitis likely to be important in the pathogenesis of progressive

periportal fibrosis
• Portal inflammation and fibrosis particularly important in paediatric NAFLD
>50% have steatosis, portal inflammation/fibrosis without typical lobular
features of steatohepatitis (Schwimmer Hepatology 2005;42;641-649)
Portal Changes in NAFLD - Biliary Features
Possible mechanisms
(Roskams 2003, Yang 2004, Clouston 2005, Richardson
2007)
Steatosis impairs hepatocellular replication
CK 7 Progenitor cell activation
Ductular reaction

• distinction between steatosis and steatohepatitis
• Recognition of portal tract changes
• cases with a dual pathology (e.g. HCV and NAFLD – see case 3 discussion)

Non-Alcoholic Fatty Liver - Nuclear vacuolation
Incidence: NAFLD 70-80%, ALD <10%
Itoh et al Am. J. Gastroenterol 1987; 82: 650-654, Diehl et al Gastroenterology 1988; 95: 1056-1062

• distinction between steatosis and steatohepatitis
• cases with a dual pathology (e.g. HCV and NAFLD)

Grading and Staging of Steatohepatitis
1. Brunt EM et al . Nonalcoholic steatohepatitis: a proposal for grading and

staging the histological lesions. Am J Gastroenterol. 1999; 94: 2467-74.
2. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis:

summary of an AASLD Single Topic Conference. Hepatology
2003;37:1202-19.
3. Kleiner DE et al Design and validation of a histological scoring system

for nonalcoholic fatty liver disease. Hepatology. 2005 Jun;41(6):1313-21.
NIDDK NASH Clinical Research Network
NAFLD Scoring System
Activity Score (0-8) Fibrosis Score (Masson’s

Trichrome)
Steatosis (0-3) 1a, b: Zone 3 PSF

– <5%; 5-33%; 33-66%; >66% 1c: Portal only
Lobular Inflam (0-3) 2: Zone 3 + portal/periportal
– 0; <2; 2-4; >4 foci/20x
3: Bridging
Ballooning (0-2) 4: Cirrhosis
– None, few, many/prominent
Kleiner et al. Hepatology 2005; 41: 1313-1321

NASH Activity Score vs Steatohepatitis Diagnoses
(Kleiner et al 2005 - courtesy of EM Brunt)
100
80
% of All Scores
Steatohepatitis
60 No
Probable
40 Yes
20
0
0 1 2 3 4 5 6 7 8
Activity Score
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
Liver – Case 8
Clinical Summary
• Male, age 39.
• Acute liver failure. Recent history of depression.
• Paracetamol overdose
Liver – Case 8
• liver normal size (weight > 1200g)
• zonal red/brown colour (“nutmeg” appearance)
CK 7
Liver – Case 8
• Recent zonal necrosis
– Coagulative pattern
– Uniform distribution
– Lack of inflammation
• Sublethal injury in surviving periportal hepatocytes

– Ballooning, fatty change, spotty acidophil body formation
– ( Bilirubinostasis commonly also present )
• Mild portal tract changes

– Inflammation
– Ductular reaction
Liver – Case 8
Diagnosis
Recent zonal necrosis (paracetamol toxicity)
Liver – Case 8
Discussion points
1. Toxic versus hepatitic injury in acute liver failure
2. Differential diagnosis of zonal coagulative necrosis

Toxic versus hepatitic injury in acute liver failure
(compare Case 8 with Case 2)
TOXIC HEPATITIC
(e.g. paracetamol) (e.g. viral, drugs,
autoimmune)
Pattern of necrosis Coagulative Lytic
(may appear lytic
later)
Distribution of Uniform Patchy
necrosis
Inflammation +/- ++/+++

Liver – Case 8
Discussion points
1. Toxic versus hepatitic injury in acute liver failure
2. Differential diagnosis of zonal coagulative necrosis

• “ischaemic hepatitis” (necrosis less uniform)
• Toxic injury &ischaemia are two main causes of massively

elevated serum transaminases
Liver – Case 9
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.
Liver – Case 9
• Bilirubinostasis ++
• Minimal inflammation (portal and parenchymal)
• No features to suggest biliary obstruction or any underlying
chronic liver disease
Liver – Case 9
Diagnosis
Intrahepatic cholestasis ?cause
(exclude drug reaction)
Liver – Case 9
Discussion points
Differential diagnosis of “pure” intrahepatic cholestasis
Histological diagnosis of drug-induced liver damage

Causes of “Pure” Intrahepatic Cholestasis
• 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
(1) Most of the common morphological patterns of liver

damage may be caused by drugs
(2) Histological distinction from other causes of liver damage
is frequently difficult or impossible
(3) Many patterns of liver injury usually have an alternative
mechanism
(4) For some patterns of liver injury drugs should be
considered near the top of the differential diagnosis
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
ZONAL NECROSIS * - paracetamol, carbon tetrachloride
* Histological findings with high index of suspicion for drug aetiology

Drug-Induced Liver Disease - Patterns of Liver Injury
ACUTE HEPATITIS* - anti-TB drugs, NSAIDs, herbal remedies

• classical (with spotty necrosis)
• severe (with confluent necrosis)
• atypical features*
CHRONIC HEPATITIS - methyldopa, isoniazid, NSAIDs

• with autoimmune features
• without autoimmune features
GRANULOMAS*
• epithelioid - allopurinol, carbamazepine, phenylbutazone
• fibrin-ring - allopurinol
• mineral-oil - mineral oil ingestion
• foreign body - chronic metal exposure, IV drug abuse
* Histological findings with high index of suspicion for drug aetiology

Drug-induced Acute Hepatitis
Many cases indistinguishable from

other causes of acute hepatitis
Features favouring a drug aetiology :

• Well circumscribed zonal necrosis
• Lack of lobular inflammation
• Prominent canalicular cholestasis
• Lack of portal reaction
• Abundant eosinophils
• Fatty change
• Granulomas
Cases 10 & 11
Focal Liver Lesions
Liver – Case 10
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
Liver – Case 10
- central scar with abnormal blood vessels
- fibrous septa
- hepatocyte nodules
- ductular reaction without bile ducts
- copper associated protein
Liver – Case 10
Diagnosis
Focal nodular hyperplasia
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
(1) TYPICAL FNH

Cirrhosis-like changes
Chronic biliary disease with bile duct loss
Nearby space-occupying lesion
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.)
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
• Localised area of hyperplasia related to increase in blood

supply compared to surrounding liver tissue.
• Primary FNH
– congenital arterial malformation
• Secondary FNH
– associated with acquired vascular abnormalities
• Haemangioma / other neoplasms
• Venous thrombosis
• Cirrhosis
Liver – Case 11
Clinical Summary
• Male, age 65.
• Cirrhosis ? cause
• Hepatectomy specimen contained 4 larger nodules, up
to 2.5cm diameter.
• Slide submitted contains one of these nodules.
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
Large Dysplastic Dysplastic

Cirrhotic
Regeneration Nodule Nodule Early HCC
Nodule
Nodule (low-grade) (high-grade)
Nuclear changes
Ki 67
Trabecular architecture
Features suggestive of clonal expansion
“Nodule-in-nodule” growth pattern
Vascular Changes
CCD 34
CCD 34
Infiltrative Growth Pattern
• Periphery - capsular or vascular invasion

• Within lesion - stromal invasion
Tumour Markers
Calpha FP
Dysplastic Nodules versus Early/Small HCC - Molecular Approaches
(Llovet 2006, Shibata 2006,Di Tommaso 2007, Wong 2007,Wurmbach 2007, Seimaya 2008,
Kojiro 2009, Sakamoto 2009, Di Tommaso 2009 )
Many genes / proteins upregulated in early HCC

Some can be demonstrated immunohistochemically
– e.g. Glypican-3, HSP 70, Glutamine Synthetase,
– None has 100% specificity or sensitivity individually
– Panel of antibodies improves diagnostic accuracy
• > 2/3 positive - 100% specificity & 60% sensitivity for HCC (Di Tommaso 2009)
Benign Versus Malignant Nodules in Cirrhotic Livers
Features Favouring a Diagnosis of Malignancy
Nuclear changes Pleomorphism, multinucleation

Increased N/C ratio, nuclear crowding (“small cell change”)
Increased proliferation (mitoses, Ki67 index)
Trabecular architecture Cell plates > 2-3 cells thick
Loss of reticulin fibres
Features suggestive of Phenotypic changes cf. surrounding cirrhotic nodules

clonal expansion (e.g. fat, ballooning, hyaline inclusions, iron)
“Nodule-within-nodule” growth pattern
Vascular Changes Arterialisation
Acquisition of vascular phenotype in tumour sinusoids
Infiltrative Growth Stromal invasion

Pattern Capsular invasion
Vascular invasion (satellite nodules in surrounding liver)
Tumour Markers Alpha fetoprotein
Glypican-3, HSP 70, Glutamine Synthetase
Liver – Case 11
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 )
• “For sure ------- Di ------ will do a good job. He is half

Swiss, half Italian – the best combination”
1. Who was Luigi referring to?

– Roberto di Matteo, who was appointed as manager of West
Bromwich Albion on July 1 2009
2. Was Luigi’s prediction correct?

– YES!!

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Sheffield Diagnostic Histopathology Course 2010

1. Is this acute or chronic damage?

2. How severe is the damage?

3. What is the cause?

– Spotty lobular inflammation, associated with

(up to 40% of cases – Czaja and Freese

Acute “flare” of chronic liver disease (Nikias 1994, Burgart 1995)

Stain Material Distribution In Changes In Liver Disease

Reticulin Type III collagen Portal tracts, Collapse of reticulin

Orcein Elastic fibres Portal tracts, Found in long-standing

– Surviving areas of liver parenchyma

1. Is this acute or chronic damage?

2. How severe is the damage?

3. What is the cause?

Acute versus Chronic Damage

Acute versus Chronic Damage - Helpful pointers

1. Is this acute or chronic damage?

2. How severe is the damage?

3. What is the cause?

PATTERN OF HISTOLOGICAL FEATURES

Multiacinar necrosis Panacinar necrosis involving several adjacent acini

Severity of liver cell necrosis correlates with:

1. Is this acute or chronic damage?

2. How severe is the damage?

3. What is the cause?

– Bile duct inflammation (mild)

– Lobular inflammation (mild, spotty)

– Siderosis (hepatocellular, grade 2-3/4)

• Establishing a histological diagnosis

• Identifying additional lesions

• Portal inflammation predominates, mainly mononuclear

• Several systems described

Factors influencing sampling variability

• What is an “adequate biopsy”?

• Liver biopsies increasingly obtained by radiologists,

• More severe siderosis with pure hepatocellular distribution

• Presence of siderosis has adverse influence on response to

Feathery degeneration, ballooning, Mallory-Denk bodies

• Spectrum of bile duct lesions

• MEDIUM-SIZED nodular scars

• LARGE dilated, inflamed & ulcerated

PBC Small (interlobular)

PSC Small (interlobular)

* NOTE: Fibrosing duct lesions mainly involve medium-sized ducts

Vascular - hepatic artery occlusion

PBC – granulomatous cholangitis PSC –fibrous cholangitis

Rarely seen in needle biopsy specimens

• Granulomatous cholangitis in 85/258 (32%) PBC biopsies

• Fibrous cholangitis in 7/60 (12%) PSC biopsies

• Histological distinction only possible in 92/318 (28%) cases

What other stain is most helpful in the diagnosis of

Cirrhotic area No fibrosis

Factor analysis and correlational analysis

Severity of interface hepatitis:

• Cases with typical clinical features and appropriate

• Liver biopsy still useful to detect atypical cases

• May have a role is assessing disease severity

• NO features of alcoholic liver disease

(1) Uncommon (compared with hepatic fibrosis/cirrhosis)

(2) Subtle Changes

(3) Sampling Variation

(4) Problems with Terminology/Classification

• Normal vascular relationships