Fatty liver disease - Virtual Pathology at the University of Leeds

Basic patterns of liver damage – what 

information can a liver biopsy provide 

and what clinical information does the 

pathologist need? 

Rob Goldin 

r.goldin@imperial.ac.uk

What information can a liver 

biopsy provide?

Donald Rumsfeld’s guide to knowledge 

(and to liver biopsy requests) 

• “… there are known knowns; there are things 

we know we know. 

• We also know there are known unknowns; 

that is to say we know there are some things 

we do not know. 

• But there are also unknown unknowns - the 

ones we don't know we don't know."

“….there are known knowns; there 

are things we know we know.”

The clinician knows the diagnosis but 

wants to know something more 

Examples 

1. Chronic viral hepatitis 

2. Fatty liver disease 

3. Iron overload

Chronic viral hepatitis 

• Assess disease severity: 

Grade (necro-inflammation) and 

Stage (fibrosis) 

? Score (using modified Histological Activity 

Index / METAVIR) 

• Assess disease progression or response to 

treatment 

Modern Pathology 2007; 20: S3

Chronic viral hepatitis 

• Hepatitis related changes 

e.g. Large cell change, HDV 

• Something else going on? 

Modern Pathology 2007; 20: S3

Large cell change 

• A focus of large cell change is defined as: 

a group of hepatocytes with nuclear and 

cellular enlargement, normal N:C, nuclear 

pleomorphism, multinucleation, nuclear 

pseudoinclusions and prominent nucleoli 

Liver International 2005; 25: 16

Large cell change 

• A marker for developing HCC (reactive) rather 

than premalignant condition (dysplastic) 

Hepatology 1996; 23: 1112 

but … 

Hepatology 2009; 50: 752

Large cell change (or is it dysplasia?)

HDV

Drug reaction

? Something else going on 

• Fatty liver disease 

steatohepatitis in 5% of liver biopsies of 

patients with chronic liver disease 

Mod Pathol 2003; 16: 49 

• Iron overload 

In patients with HCV: stainable iron was 

detected in 16%, grade 2 and 3 iron in 7%. 

J Gastroenterol Hepatol 2005; 20: 243

Fatty change associated with 

HCV genotype 3

Fatty liver disease 

• How severe is the fatty change? 

• Is there a fatty liver hepatitis?


• How severe is the fatty change? 

Ignore less than 5% 

Mild 5-33% 

Moderate 34-66% 

Severe 67-100% 



• Is there a fatty liver hepatitis? 

Ballooning and inflammation 

• Is there fibrosis? 

Clin Liver Dis 2009; 13: 533

Fatty change: Portal tract fibrosis

Histology of NASH 

NAFLD Activity Score is the unweighted sum of: 

1. steatosis (0-3) 

2. hepatocellular ballooning (0-2) 

3. lobular inflammation (0-2) 

NAS>5 “NASH” 

NAS

Iron overload 

• What is the pattern if iron overload? 

• Grade the degree of iron overload 

• Assess fibrosis 

• ? Send tissue for biochemical iron 

measurement 

American Journal of Gastroenterology 2000; 

95: 1788

What is the pattern of iron 

overload? 

• Parenchymal 

• Macrophage

Parenchymal iron: 

Simple Scoring System 

Grade Histological Features 

0 No iron present 

1 Iron seen in periportal hepatocytes 

2 Iron seen in periportal and midzonal 

hepatocytes 

3 Iron seen in all zones with a gradient from 

the periportal to the perivenular zones 

4 Iron seen in all zones with no gradient 

from the periportal to the perivenular 

zones

“We also know there are known 

unknowns; that is to say we know 

there are some things we do not 

know.”

Clinician suspects the diagnosis 

and wants your help 

Examples: 

1. Autoimmune hepatitis 

2. Drug reaction 

3. Wilson’s disease

Autoimmune hepatitis 

• Help in making the diagnosis 

• Help in assessing the response to treatment

Revised AIH scoring system 

proposed by the IAIHG 

• Liver histology 

Interface hepatitis +3 

Lymphoplasmacytic infiltrate +1 

Rosetting of liver cells +1 

None of the above -5 

Biliary changes -3 

Other changes -3

Simplified histological criteria for 

• “Typical” 

1. Interface hepatitis 

the diagnosis of AIH 

2. lymphocytic / lymphoplasmacytic infiltrates in portal tracts 

and extending into the lobule 

3. rosetting of liver cells 

• “Compatible" a chronic hepatitis with lymphocytic 

infiltration without all the above features 

• “Atypical" for AIH when showing signs of another diagnosis. 

Am J Gastroenterol advance online publication 

3 November 2009; doi: 10.1038/ajg.2009.616

Autoimmune Hepatitis

Autoimmune Hepatitis

AIH: Treatment failure 

• Its occurrence justifies clinical reassessment to exclude 

noncompliance with therapy, alcohol consumption, or drug 

toxicity. 

• Laboratory studies to exclude a superimposed viral infection 

or a transition state to PBC or PSC, and liver tissue is 

examined to reconfirm the original diagnosis and to assess 

alternative possibilities, including fatty infiltration, PBC, or 

PSC. 


• Remission: 

Response to Treatment in 

Autoimmune Hepatitis 

Normal or minimal histological activity 

• Incomplete response 

Improved but more than minimal histological 

activity 

• Failure 

Worsening histological activity

Drug reaction

Drug reaction 

• “Any kind of liver disease can be caused by a 

drug” 

• Histological features suggesting a drug 

reaction: 

Eosinophils, plasma cells, granulomas, sharply 

demarcated necrosis, cholestatic hepatitis 

J Clin Pathol 2009; 62:481

Drug reaction

Drug reaction

Wilson’s disease

Wilson’s disease

Wilson’s Disease 

Demonstration of copper 

1. stains for Cu associated protein: orcein 

2. stains for Cu: rhodamine, rubeanic acid 

but: 

1. ease of demonstrating copper varies with 

the stage of the disease 

2. can be due to chronic cholestatic liver 

diseases

Wilson's disease: 

Diagnostic Criteria 

• Low serum caeruloplasmin levels 

• Kayser - Fleischer rings 

• High liver Cu levels > 250 micrograms/g dry weight 

• High 24 hr urinary copper levels 

• Radioisotope copper studies which assesses the 

ability to incorporate copper into caeruloplasmin 

Nature Clinical Practice Neurology 2006: 2;482-493

“But there are also unknown 

unknowns -- the ones we don't 

know we don't know."

The clinician doesn't even suspect the 

diagnosis 

• Examples: 

1. Granulomas 

2. Disappearing bile ducts

Granulomas 

• 2-10% of all liver biopsies 

• 1/3 have no known cause 

• Classification 

Adv Anat Pathol 2008; 15: 309

You can see the cause 

• Mycobacterial infection 

• Schistosomiasis

You can have an educated guess 

• Sarcoid 

• PBC

Clinician (and Pathologist) does not 

suspect the diagnosis 

• Example: 

Disappearing bile ducts

Causes of Disappearing bile ducts 

• PBC (and its variants) 

• PSC 

• Drugs and Toxins 

• Chronic transplant rejection 

• Graft Vs. Host 

• Hodgkin’s Disease, Histiocytosis X 

• Sarcoid 

• Paucity of interlobular bile ducts 

• Idiopathic

Biliary tract disease

Biliary tract disease: Orcein stain

Biliary tract disease: CK7

What clinical information does the 

pathologist need?

What clinical information does the 

pathologist need? 

• A decent clinical history!

Clinical information 

• Look at the biopsy and write the description 

without knowing any clinical information 

• Only write the conclusion when you have the 

information

Biopsy Diagnosis of Liver Disease 

Daniel Snover 

• Dedicated to 

“the multitude of patients with abnormal 

LFTs”

Proposed classification of liver 

request forms

Inadequate liver 

request form

Misleading liver request form 

• “HCV Cirrhosis”

“HCV Cirrhosis”

Surreal liver request form 

“Nodule left knee, 4cms, mobile 

? Ganglion”

Adequate liver request form

Honest request form

Fatty liver disease - Virtual Pathology at the University of Leeds

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