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

Fatty liver disease

• Is there fatty change ?

• Is there a fatty liver hepatitis?

• What is the cause of the fatty liver disease?

Clinical Liver Disease Volume 2, April 2013, Pages 64–67

(http://onlinelibrary.wiley.com/doi/10.1002/cld.172/full)

Clinical Liver Disease Volume 1, September 2012, Pages 108–111

(http://onlinelibrary.wiley.com/doi/10.1002/cld.31/full)

Types of fatty change:Large droplet

“mesovesicular fatty change”

Causes of large droplet fatty change

• Obesity and Diabetes Mellitus

• Protein-calorie malnutrition

• TPN

• Drugs and toxins (e.g. alcohol, corticosteroids)

• Metabolic disorders ( e.g. Wilson’s Disease)

• Infections ( e.g. hepatitis C)

Types of fatty change:Small droplet

Causes of small droplet fatty change

• Alcohol

• Fatty liver of pregnancy

• Drugs (e.g. nucleoside analogues)

• Toxins (e.g. Jamaican vomiting disease)

• Inborn errors of metabolism (e.g. urea cycle disorders).

• Reye’s syndrome

• Infections (e.g. Hepatitis A)

Fatty liver disease: More than just fat

• Is there fibrosis?

• Is there a fatty liver hepatitis?

Ballooning and inflammation

(B) Normal hepatocytes,

ballooning,

grade 0. Cytoplasm is pink and

granular and liver cells have

sharp angles.

(C) Ballooning, grade 1.

Hepatocytes have rounded

contours with clear reticular

cytoplasm. Size is quite similar

to that of normal hepatocytes.

(D) Ballooning, grade 2.

Cells are rounded with clear

cytoplasm and twice as large as

normal hepatocytes.

Recognising ballooning

Hepatology Volume 56, November 2012 Pages 1751–1759

Nuclear vacuolation

Causes of nuclear vacuolation

• Physiological

• Insulin resistance

• Wilson’s disease

• Glycogen storage disease

Gastroenterology, Volume 146,

Issue 5, 2014, 1231 - 1239

A Histologic Scoring System for

Prognosis of Patients With

Alcoholic Hepatitis

Histologic features independently associated with 90-day survival included in the Histologic AHHS. ( A – C ) Degree of fibrosis

(Masson trichrome staining): portal fibrosis, expansive areas of liver fibrosis, and cirrhosis, respectively. H&E s...

Histologic features independently associated with 90-day survival included in the Histologic AHHS. ( A ) Hepatocellular and

canalicular bilirubinostasis ( arrow ). ( B ) Ductular bilirubinostasis ( arrow ). ( C ) Megamitochondria ( arrows ). ( D and E) Mild and

severe PMN infiltration, respectively (arrow). H&E stain.

Gastroenterology, Volume 146, Issue 5, 2014, 1231 - 1239

Points

Stage of fibrosis

No fibrosis or portal fibrosis 0

Expansive fibrosis 0

Bridging fibrosis or cirrhosis +3

Bilirubinostasis

No 0

Hepatocellular only 0

Canalicular or ductular +1

Canalicular or ductular plus hepatocellular +2

PMN infiltration

No/Mild +2

Severe 0

Megamitochondria

No megamitochondria +2

Megamitochondria 0

The AHHS categories are as follows: mild, 0–3; intermediate, 4–5; severe, 6–9.

AHHS for Prognostic Stratification of AH

Chronic viral hepatitis

• Assess disease severity:

Grade (necro-inflammation)

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:

HBV: Ground glass cells

HCV: Lymphoid follicles, hepatitic bile duct damage, fatty change

HDV: Increased lobular activity

• Large cell changeClinical Liver Disease Volume 1, April 2012 , Pages 32–35

(http://onlinelibrary.wiley.com/doi/10.1002/cld.30/full)

Clinical Liver Disease Volume 2, February 2013, Pages 49–51

(http://onlinelibrary.wiley.com/doi/10.1002/cld.139/full)

HBV: Ground glass hepatocytes

Orcein

HCV: Lymphoid aggregate/follicle

HCV: Hepatitic bile duct damage

HCV genotype 3: Fatty change

HDV

Something else going on

• Drug reaction

• Another virus

• Fatty liver disease

fatty liver hepatitis in 5% of liver biopsies of patients with chronic liver disease

Mod Pathol 2003; 16: 49

• Iron overload

In patients with HCV:

stainable iron in 16%,

grade 2 and 3 (out of 4) iron in 7%.

J Gastroenterol Hepatol 2005; 20: 243

Large cell change (or is it dysplasia?)

Iron overload

• What is the pattern if iron overload?

• Grade the degree of iron overload

• Assess fibrosis

• ? Send tissue for biochemical iron measurement

Mod Pathol 2007; 20: S31–S39.

What is the pattern of iron overload?

• Parenchymal • Macrophage

Patterns of iron overload

• Parenchymal overload

– gut derived iron.

• Macrophage iron

– transfusion derived iron

• Mixed

Mixed pattern of iron overload:Sickle cell anaemia Ferroportin deficiency

Autoimmune hepatitis

• Help in making the diagnosis

• Help in assessing the response to treatment

Clinical Liver Disease Volume 3, February 2014, Pages 38–41

(http://onlinelibrary.wiley.com/doi/10.1002/cld.321/full)

Simplified histological criteria for the diagnosis of AIH

• “Typical”

1. Interface hepatitis

2. lymphocytic / lympho-plasmacytic 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.

Autoimmune Hepatitis

The Overlap Syndromes of Autoimmune Hepatitis

Clinical Liver Disease Volume 3, January 2014, Pages 2–5

(http://onlinelibrary.wiley.com/doi/10.1002/cld.294/full)

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

Clinical Liver Disease Volume 4, Issue 1, July 2014, Pages 12–16

(http://onlinelibrary.wiley.com/doi/10.1002/cld.371/full)

Injury Patterns of Selected Drugs in Common Use

Drug Pattern of Injury

Paracetamol Zone 3 necrosis (with little additional inflammation)

Amiodarone Steatohepatitis-like, with numerous Mallory-Denk bodies

and fibrosis

Amoxicillin-clavulanate Cholestatic hepatitis (with prominent duct injury)

Anabolic steroids Acute cholestasis to cholestatic hepatitis with little duct

injury

Azithromycin Variable: Hepatitis with or without cholestasis

Diclofenac Zone 3 necrosis with lymphocytic inflammation

Isoniazid Acute or chronic hepatitis

Methotrexate Steatosis and fibrosis, sometimes steatohepatitis-like

Minocycline Acute or chronic hepatitis

Nitrofurantoin Acute or chronic hepatitis

Oxaliplatin Hepatoportal sclerosis, sinusoidal dilation, nodular

regenerative hyperplasia

Drug reaction

Drug reaction

Drug reaction

Histological predictors of severity in drug-induced liver disease.

• More severe disease associated with: 1. necrosis2. fibrosis stage3. microvesicular steatosis4. cholangiolar cholestasis 5. bile duct damage

• Milder disease associated with: 1. granulomas2. increased eosinophils

http://livertox.nih.gov/

Biliary tract disease

Biliary tract disease: Orcein stain

Biliary tract disease: CK7

Causes of Disappearing Bile Ducts

• PBC* (and its variants)

• PSC (and its variants)

• Drugs and Toxins

• Chronic transplant rejection

• Graft Vs. Host

• Hodgkin’s Disease, Histiocytosis X

• Sarcoid

• Paucity of interlobular bile ducts

• HIV

• Idiopathic

Primary Biliary Cholangitits

= the name for Primary Biliary Cirrhosis

Vascular Disease:Non-cirrhotic portal hypertension

Vascular Disease:Non-cirrhotic portal hypertension

Causes of Nodular Regenerative Hyperplasia

• Connective tissue disorders

• Myeloproliferative disorders

• Chronic vascular congestion

• Drugs e.g. steroids, anticancer drugs, anticonvulsants, immunosuppressive agents

Clinical Liver Disease, Volume 6, October 2015, Pages 103–106 (http://onlinelibrary.wiley.com/doi/10.1002/cld.505/full)

Discrepancy rates in liver biopsy reporting

• fibrosis staging

• recognising and interpreting bile duct disorders

• misdiagnoses of autoimmune hepatitis

J Clin Pathol 2014;67:825-827

Histopathology. 2016 Jan 30. doi: 10.1111/his.12940

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

Example of not very useful clinical information

• “Liver biopsy”

• “Abnormal LFTs”

• “Complex medical history”

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http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)2046-2484