1. Dr Ian Chandler February 2013
Liver Pathology Made Easy and Understandable II – Patterns of Inflammation
Dr Ian Chandler
February 2013
With acknowledgements to Prof S Hubscher, Birmingham

2. Patterns of Inflammation in the Liver
Portal inflammation
Most chronic liver diseases (e.g. viral, autoimmune)
Also seen in acute hepatitis
Lobular inflammation
Main pattern in acute hepatitis
Varying degrees of lobular inflammation also commonly present in chronic viral and autoimmune hepatitis
Predominant pattern in some chronic liver diseases (e.g. fatty liver disease)
Mixed portal and lobular

3. Zone 3 (perivenular or centrilobular)
Normal Liver
Liver Zones
Zone 1 (periportal)
Zone 2 (mid-zonal)
Zone 3 (perivenular or centrilobular)

4. Portal Inflammation – Histological Assessment
Aetiology Known (e.g. hepatitis B & C)
Assess disease severity
inflammation grade – interface hepatitis
fibrosis stage
Identify co-existent disease (e.g. NAFLD)
Aetiology Suspected (e.g. autoimmune hepatitis)
Identify features supporting suspected diagnosis
(absence of features suggesting an alternative diagnosis)
Aetiology Uncertain/Unknown
Pattern & composition of inflammatory infiltrate (and other associated features) may provide diagnostic clues

5. Composition of Inflammatory Cells in Portal Tracts
In most conditions, most lymphocytes in portal tracts are T cells
B cell rich lymphoid aggregates will be found in HCV infection and also other conditions such as PBC and AIH
Plasma cells are characteristic of AIH, and also PBC/PSC. They are less common in HCV and NASH

6. Hepatitis C
2 cases, different severity

7. Autoimmune Hepatitis

8. Composition of Inflammatory Cells in Portal Tracts
Granulomas are common in sarcoid and PBC, but can be found in PSC, HCV and drug reactions
Portal tract neutrophils are mostly associated with a ductular reaction, in acute biliary obstruction, chronic biliary disease, and also acute hepatitis
Eosinophils: drug reaction, biliary obstruction, PBC & PSC, parasitic infestation, acute allograft rejection

9. Granuloma in HCV

10. Eosinophils in acute rejection
Eos, biliary damage, endotheliitis

11. Interface Hepatitis (“piecemeal necrosis”)
Inflammation at the interface between connective tissue (portal tract, fibrous septa) and the liver parenchyma
Severity classified according to :
extent around individual portal tracts/septa (focal vs diffuse)
proportion of portal tracts involved (e.g.<50% vs > 50%)
Autoimmune Hepatitis Chronic hepatitis with severe activity
Hepatitis C Chronic hepatitis with mild activity

12. Interface hepatitis in AIH

13. Interface Hepatitis (“piecemeal necrosis”)
Periportal hepatocyte ballooning (Autoimmune Hepatitis)
Periportal fibrosis (HVG)
Severity of interface hepatitis:
Predicts subsequent development of fibrosis/cirrhosis (HCV, AIH, PBC)
Guides therapeutic decisions (AIH, ?PBC/PSC – “overlap syndromes”)

14. PBC & PSC – Changing Role of Liver Biopsy EASL Clinical Practice Guidelines – J Hepatol 2009; 51: AASLD Practice Guidelines – Lindor. Hepatology 2009; 50:
Establishing a diagnosis
Liver biopsy no longer required in cases with other typical features
Still important in the diagnosis of atypical cases
e.g. AMA-negative PBC, small duct PSC-, IgG4-associated SC
Diagnostic duct lesions only present in liver biopsies from:
30-50% of PBC cases (Wiesner 1985, Drebber 2008)
12% of PSC cases (Wiesner 1985)

15. PBC
2 cases, more and less obvious

16. Primary Biliary Cirrhosis Significance of Inflammatory Activity
Severity of inflammatory activity (periportal and lobular)
Predictive for subsequent progession to fibrosis /cirrhosis & liver failure
Moderate or severe interface hepatitis also used as a diagnostic criterion for PBC/AIH “overlap syndrome” (PBC with “hepatitic features”) % of PBC have additional features supporting a diagnosis of AIH (biochemical, immunological and histological)
PBC with “hepatitic features” - worse outcome than “pure” PBC
May benefit from treatment with immunosuppression
Normalisation of ALT levels
Less severe fibrosis progression
Similar comments apply to PSC

17. Referred Biopsy – Diagnosis Chronic Hepatitis ? Cause
Raised Alk Phos. Autoantibody screen negative.
Portal inflammation and interface hepatitis
Biliary features not conspicuous
Orcein -
Periportal copper-associated protein
Keratin 7 Immunostaining
“intermediate hepatobiliary cells”
Repeat autoantibody testing = AMA-positive

18. Role of Liver Biopsy in Acute Hepatitis
Many of the classical morphological studies of acute hepatitis were carried out before the main causes had been discovered
Most cases of acute hepatitis now diagnosed on the basis of clinical, biochemical and serological findings and liver biopsy is rarely indicated
Liver biopsy may still be carried out in cases where the clinical presentation is atypical or the cause is uncertain
Distinguish severe acute hepatitis from decompensated chronic liver disease
Determine disease severity
Identify possible aetiological factors (including cases of acute liver injury not related to hepatitis)

19. Changes tend to be most marked in perivenular regions (zone 3)
Acute (and chronic) Hepatitis Histological Findings in Liver Parenchyma
Inflammatory Infiltration mainly lymphocytes ( T cells >> B cells) plasma cells (esp in AIH) neutrophils (esp in alcoholic hepatitis) - eosinophils (esp in drug reactions)
Hepatocellular Damage ballooning bile pigment accumulation (bilirubinostasis) - lobular disarray cell death (apoptosis and/or necrosis)
Changes tend to be most marked in perivenular regions (zone 3)

20. Liver Cell Death in Lobular Hepatitis (acute or chronic)
Pattern of Cell Death
Histological Features
Spotty necrosis
Apoptosis of individual hepatocytes (acidophil bodies)
Confluent necrosis
(zone 3)
Loss of groups of adjacent liver cells
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
Apoptosis > necrosis (in mild forms)

21. Acidophil body
AIH

22. Multiacinar Necrosis
Normal vascular relationhips
Prominent ductular reaction (resembling biliary obstruction)

23. Could this be cirrhotic?

24. Recent Post-Necrotic Collapse versus Longstanding Fibrosis - Use Of Connective Tissue Stains
Material Demonstrated
Distribution In Normal Liver
Changes In Liver Disease
Reticulin
Type III collagen fibres
Portal tracts, hepatic sinusoids
Collapse of reticulin framework in areas of recent liver cell necrosis.
(few days)
Haematoxylin
Van Gieson
Type I collagen fibres
Portal tracts, walls of hepatic veins
Increased in hepatic fibrosis
(weeks/months)
Orcein
Elastic fibres
Portal tracts,
walls of hepatic veins
Found in long-standing fibrosis/cirrhosis
(months/years)

28. Acute Hepatitis - Common Causes
Viral
Hepatitis viruses – A,B,C,D, E
Other viruses – e.g. CMV, EBV
Drugs
Autoimmune
Unknown
Seronegative hepatitis (“non-A, non-B, non-C hepatitis”)

29. Acute Hepatitis - Aetiological Considerations
Liver biopsy rarely identifies a previously unsuspected aetiology
Biopsies mostly obtained from people in whom main recognised causes have been excluded (“seronegative hepatitis”)
Biopsy sometimes provides pointers to a previously unsuspected aetiology
Aetiology
Suggestive Histological features
Drugs
Disproportionately severe necrosis/unusually prominent cholestasis
(relatively little inflammation – lobular and/or portal)
Eosinophils
Granulomas
Autoimmune hepatitis
Plasma cell rich infiltrate (also seen in hepatitis A)
Prominent periportal inflammation (interface hepatitis)
Prominent centrilobular inflammation (“central perivenulitis”)
Lymphoid aggregates

30. Role of Liver Biopsy in Fatty Liver Disease
Establishing a morphological diagnosis
Distinction between steatosis and steatohepatitis
Recognition of portal tract changes
Aetiological pointers
AFLD versus NAFLD
cases with a dual pathology (e.g. HCV and NAFLD)
Biopsy may help to identify the main cause of liver injury
Assessing disease severity
grading of fat, ballooning, inflammation
staging of fibrosis

31. Alcoholic steatohepatitis with cirrhosis
DOG IN KENNELS in capitals in the letter!!

32. HCV with fat ?cause
Fat ? ASH/NASH/HCV/methotrex from psoriasis

33. Phnom Penh