Histological

Grading and Staging of

Chronic Hepatitis

-Korean Guideline-

Sungkyunkwan Univ. School of Medicine

Kangbuk samsung hospital

Jin Hee Sohn, M.D., Ph.D.

Histologic Grading and Staging of

Chronic Hepatitis-Standardized Guideline proposed by

the korean Study Group for the

Pathology of Digestive Disease-

Young Nyun Park, Hoguen kim, Chan Yoon Chon, jae Bok Park,

Jin Hee Sohn, Seung Ha yang, Eun Sil Yu, Mi Seon Lee,

Ja June Jang, Hee kyung Chang, Jong Jae Jeong, Dae Young kang,

Yong Il Kim and Chanil Park

Korean study Group for the Pathology of Digestive Disease

대한병리학회지(Korean J Pathol) 1999; 33: 337-346

Chronic Hepatitis, Diagnosis

Saint (1953)

Chronic persistent

Chronic aggressive

De Groote et al (1968)

Chronic persistent hepatitis

Chronic active hepatitis

- periportal inflammation

and piecemeal necrosis

Chronic lobular hepatitis

- lobular necrosis and inflammation

Causes of Chronic Hepatitis

� HBV

� HCV

� HDV

� Autoimmune

� Hepatotoxic drugs

� Others

Hepatitis A

Virus

Hepatitis B

Virus

Hepatitis C

Virus

Hepatitis D

Virus

Hepatitis E

Virus

Hepatitis G

Virus*

Agent Icosahedral

capsid,

ssRNA

Enveloped

dsDNA

Enveloped

ssRNA

Enveloped

ssRNA

Unenveloped

ssRNA

ssRNA virus

Transmission Fecal-oral Parenteral;

close

contact

Parenteral;

close

contact

Parenteral;

close

contact

Waterborne Parenteral

Incubation

period

2-6 wk 4-26 wk 2-26 wk 4-7 wk 2-8 wk Unknown

Carrier state None 0.1-1.0% of

blood

donors in

0.2-1.0% of

blood

donors in

1-10% in

drug

addicts

Unknown 1-2% of

blood

donors in donors in

U.S. and

Western

world

donors in

U.S. and

Western

world

addicts

and

hemophili

acs

donors in

U.S.

Chronic

hepatitis

None 5-10% of

acute

infections

>50% <5%

coinfectio

n, 80%

upon

superinfe

ction

None None

Hepatocellula

r

carcinom

a

No Yes Yes No increase

above

HBV

Unknown,

but

unlikely

None

* At present, hepatitis G virus is not considered pathogenic.

• Active

Viral replication: HBe Ag, HBV DNA,

Sequence of Serologic

Marker of HBV hepatitis

Acute

Pathology

Viral replication: HBe Ag, HBV DNA,

DNA polymerase

• Carrier state

• Chronic replication of HBV virus

Chronic

Grading and/or Staging System

� Knodell (1981): HAI

� Scheuer (1991)

� Ishak, et al. (1995)

� Batts and Ludwig (1995)

� Bedossa and Poynard (1996, Grading of

activity in hepatitis C)

NecroinflNecroinflammatoryammatoryScoreScore

Portal Portal InflammInflammationation

Interface Interface HepatitisHepatitis

Confluent Confluent NecrosisNecrosis

Focal Focal LyticLyticNecrosis, Necrosis, Apoptosis, & Apoptosis, & Focal Focal InflammationInflammation

ModifieModified d StagingStaging

DescriptiveDescriptive

0 None Absent Absent Absent 0 No fibrosis

1 Mild (some or all

Mild (focal, few

Focal confluent necrosis

One focus or less per 10×objective

1 Fibrous expansion of some portal areas, with or without short fibrous septa

Ishak Modified Hepatitis Activity Index (HAI)

Grading and Staging of Chronic Hepatitis (1)

or all portal areas)

few portal areas)

objective short fibrous septa

2 Moderate (some or all portal areas)

Mild/moderate (focal, most portal areas)

Zone 3 necrosis in some areas

Two to four foci per 10×objective

2 Fibrous expansion of most portal areas, with or without short fibrous septa

3 Moderate/marked (all portal areas)

Moderate (continuous around <50% of tracts or septa)

Zone 3 necrosis in most areas

Five to 10 foci per 10×objective

3 Fibrous expansion of most portal areas with occasional P-P bridging

NecroinflNecroinflammatoryammatoryScoreScore

Portal Portal InflamInflammationmation

Interface Interface HepatitisHepatitis

Confluent Confluent NecrosisNecrosis

Focal Focal LyticLyticNecrosis, Necrosis, Apoptosis, & Apoptosis, & Focal Focal InflammationInflammation

ModifieModified d StagingStaging

DescriptiveDescriptive

4 Marked (all

Severe (continuous

Zone 3 necrosis + occasional P-

More than 10 foci per 10×

4 Fibrous expansion of portal areas with marked bridging

Ishak Modified Hepatitis Activity Index (HAI)

Grading and Staging of Chronic Hepatitis (2)

(all portal areas)

(continuous around >50% of tracts or septa)

+ occasional P-C bridging

foci per 10×objective

areas with marked bridging (P-P and P-C)

5 Zone 3 necrosis + multiple P-C bridging

5 Marked bridging (P-P or P-C) with occasional nodules (incomplete cirrhosis)

6 Panacinar or multiacinar necrosis

6 Cirrhosis, probable or definite

P-C, portal-central; P-P, portal-portal.

Grading Terminology Staging Terminology

Semi-quantitative

Descriptive

Interface Activity

Lobular Activity

Semi-quantitative

Descriptive

Criteria

0 Portal inflammation only;

None None 0 No fibrosis

Normal connective tissue

Batts-Ludwig Grading and Staging of Chronic

Hepatitis (1)

ion only; no activity

tissue

1 Minimal Minimal; patchy

Minimal; occasional hepatocyte apoptosis

1 Portal fibrosis

Fibrous portal expansion

2 Mild Mild; involving some or all portal tracts

Mild; little hepatocellular damage

2 Periportalfibrosis

Periportal or rare portal-portal septa

Grading Terminology Staging Terminology

Semi-quantitative

Descriptive

Interface Activity

Lobular ActivitySemi-quantitative

Descriptive

Criteria

3 Moderate Moderate; involving

Moderate; with noticeable hepatocellular

3 Septal fibrosis

Fibrous septa with architectural

Batts-Ludwig Grading and Staging of

Chronic Hepatitis (2)

involving all portal tracts

hepatocellular damage

architectural distortion; no obvious cirrhosis

4 Severe Severe; may have bridging fibrosis

Severe; with prominent diffuse hepatocellular damage

4 Cirrhosis Cirrhosis

From Batts KP, Ludwig J: Chronic hepatitis: An update on terminology and reporting. Am J Surg Pathol 19:1409-1417, 1995.

CHRONIC HEPATITIS

is defined as

- diffuse inflammatory liver disease

- hepatocellular necro-inflammation

- continuing disease without improvement for - continuing disease without improvement for at least 6 months

can be caused by

- hepatotropic viruses

- autoimmune mechanisms

- hepatotoxic drugs and hepatotoxins

Hepatitic activity

- degree of necro-inflammation

- may wax and wane.

Severity of Chronic Hepatitis

Grade

Chronicity

- degree of fibrosis

- degree of disease progression from

onset to cirrhosis

- may progress or remain stationary.

Stage

Principle of grading & staging

Etiology

Grade

Saint (1953)

Chronic persistent

Chronic aggressive

Chronic persistent hepatitis

De Groote et al (1968)

Grade

- lobular activity

(correspond to serum AST/ALT)

- portoperiportal activity

(correspond to possible prognosis)

Stage

Chronic persistent hepatitis

Chronic active hepatitis

- periportal inflammation

and piecemeal necrosis

Chronic lobular hepatitis

- lobular necrosis and inflammation

CHRONIC HEPATITIS, lobular activity

Knodell(1981) Scheuer(1991) Ishak et al(1995) Batts & Ludwig(1995)

Degeneration / N Inflammation / N Focal N / Acidophilic N Liver cell damage

None None Absent None

In <1/3 of lobules Inflam. without N 1 or less per 10x obj. Occ. spotty N.

In 1/3-2/3 of lobules Focal N / Acidophilic N 2-4 per 10x obj. Little damageIn 1/3-2/3 of lobules Focal N / Acidophilic N 2-4 per 10x obj. Little damage

In >2/3 of lobules Severe focal N 5-10 per 10x obj. Noticeable damage

Bridging N >10 per 10x obj. Prominent damage

(portal to central)

Modified HAI by Ishak et al.

Lobular activity: 4 grade focal N/acidophilic N + additional 6 grade of confluent

N, + portal 4 grade, + periportal 4 grade = total 18 grade.

CHRONIC HEPATITIS,

porto-periportal activity

Knodell(1981) Scheuer(1991) Ishak et al(1995) Batts & Ludwig(1995)

Piecemeal N Piecemeal N / Inflam. Piecemeal N Piecemeal N

< minimal portal inflam. Absent None

Portal inflam. Focal, few portal PatchyPortal inflam. Focal, few portal Patchy

6 grades Mild piecemeal N Focal, most portal Mild in all portal

(Score 0-10) Mod. piecemeal N Around <50% of Mod. in all portal

portal or septal

Severe piecemeal N Around >50% of Severe +/-

portal or septal bridging fibrosis

Knodell과 Ishak et. Al. addided additional 4 grade of portal inflammation.

Periportal N +/- Bridging N

(Knodell, 1981)

None Score 0

Mild Piecemeal N. 1

Mod. Piecemeal N ( <50% of the circum- 3

ference of most portal tracts)ference of most portal tracts)

Marked piecemeal N ( >50% of the circum- 4

ference of most portal tracts

Mod. piecemeal N + bridging N 5

Marked piecemeal N + bridging N 6

Multilobular N 10

CHRONIC HEPATITIS, fibrosis

Knodell(1981) Scheuer(1991) Ishak et al(1995) Batts & Ludwig(1995)

No fibrosis None No fibrosis

Mild fibrous portal Enlarged fibrotic Fibrous portal

expansion portal tracts expansionexpansion portal tracts expansion

Mod. fibrous portal Peripotal fibrosis 6 grades Periportal fibrosis

expansion or p-p septa (Score 0-6) or rare p-p septa

Bridging fibrosis Fibrosis with archi- Fibrous septa with

(p-p or p-c) tecture distortion architect. distort.

(no obvious cirrhosis) (No obvious cirrhosis)

Cirrhosis Cirrhosis Cirrhosis

Staging by Ishak et al(1995)

No fibrosis Score 0

Fibrosis of some portal tracts +/- short septa 1

Fibrosis of most portal tracts +/- short septa 2

Fibrosis of most portal tracts with occ. p-p 3Fibrosis of most portal tracts with occ. p-p 3

bridging

Fibrosis of portal tracts with marked p-p / p-c 4

bridging

Marked p-p / p-c bridging with occ. nodules 5

Cirrhosis, probable or definite 6

Approximate Correlation between

HAI and Descriptive Grading

Brief description HAI

Minimal chronic hepatitis 1 - 3Minimal chronic hepatitis 1 - 3

Mild chronic hepatitis 4 - 8

Moderate chronic hepatitis 9 - 12

Severe chronic hepatitis 13 - 18

Kappa Value of Various Grading/Staging Systems for Chronic Hepatitis

Knodell (1981)

PMN +/- bridging (10 등급) 0.23 fair

Interphase N

(4 등급)0.20

Confluent N

(6등급)0.01

Ishak, et al. (1995)

Lobular degeneration and

focal N (4 등급)0.16 slight

Portal inflammation (4등급) 0.25 fair

Fibrosis (4등급) 0.36 fair

(6등급)

Focal N and

apoptosis

(4등급)

0.07

Portal inflam.

(4등급)0.22

Fibrosis (6등급) 0.21

Kappa Value of Various Grading/Staging Systems for Chronic Hepatitis

Lobular activity 0.30 fair

Korean GIP study group (1999)

Portoperiportal 0.61 substantial

Stage (fibrosis) 0.64 substantial

Principle of grading & staging

� Lobular: Focal necrosis, Eosinophilic necrosis,

Confluent necrosis, Bridging necrosis arising

from THA

� Portal-periportal(>5 portal): portal-periportal

inflammation, Piecemeal necrosis, Bridging

necrosis arising from periportal area

� Staging: Fibrosis(periportal, porto-portal, porto-

terminal hepatic venule)

Grading of CH- Lobular activity

� None(score 0)

� Minimal(1): Sinusoidal lymphocytosis +/- 1 or

less necrosis per 10x objective field

Mild(2): 2~5 necrosis per 10x objective field� Mild(2): 2~5 necrosis per 10x objective field

� Moderate(3): 6~10 necrosis per 10x objective

field

� Severe(4): More than 10 necrosis per 10x

objective field or confluent necrosis (zone3)

Lobular Activity of

Chronic Hepatitis

None : No lymphocytosis

and no necrosis(N)

Minimal : Lymphocytosis

+/- 1 or less N per 100x

Focal N

Ground-glass cell

Mild : 2∼5 N per 100x

Moderate : 6 ∼10 N per 100x

Severe : More than 10 N per100x, or confluent necrosis

Acidophilic N & confluent N

C

Lobular activity fo chronic hepatitis (B viral)

A & B: no lobular activity

C & D: Minimal lobular activity

D

Mild lobular activity: 2-5 focal necrosis and acidophilic bodies

Moderate lobular activity : 6-10

focal necrosis and acidophilic bodies

Severe lobular activity: > 10 focal

necrosis &

Confluent necrosis, Acidophilic

bodies

Grading of CH:

Porto-periportal activity

� None(0): <mild portal inflammation

� Minimal(1): >mild portal inflammation +/- focal PMN

in a few portal tracts

Mild(2): PMN, focal in some or most portal tracts, or � Mild(2): PMN, focal in some or most portal tracts, or

PMN, around < 50% in a few portal tracts

� Moderate(3): PMN, around < 50% in most portal tracts

or PMN, around > 50% in a few or some portal tracts

� Severe(4): PMN, around > 50% in most portal tracts /

septal surfaces, or bridging necrosis

Porto-periportal

Activity of Chronic Hepatitis

None: < mild portal inflam.

Minimal: > mild portal inflam.

+/- focal PMN in a few poral Tr.

Mild: Focal PMN in some/ most Minimal

Mild: Focal PMN in some/ most

portal Tr. or PMN around < 50% of a few portal circum.

Moderate: PMN around < 50%

of most portal circum.

Severe: PMN around >50% of

most portal/septal circum.

or bridging PMN

Severe

A

Porto-periportal activity of chronic hepatitis

(B viral)

•Piecemeal necrosis around > 50% of portal

circumference

•Porto-portal bridging necrosis

Staging of chronic hepatitis

� No fibrosis(0): Normal connective tissue

� Portal fibrosis(1): Fibrous portal expansion

� Periportal fibrosis(2): Periportal fibrosis with short

septa extending into lobules or rare porto-portal septa septa extending into lobules or rare porto-portal septa

(intact architecture)

� Septal fibrosis(3): Fibrous septa reaching adjacent

portal tracts and terminal hepatic venules

(architectural distortion but no obvious cirrhosis)

� Cirrhosis(4): Diffuse nodular formation

Stage ofChronic Hepatitis

No fibrosis :Within normal limit

Portal fibrosis : Fibrous portal expansion

Periportal

Periportal fibrosis : Periportal fibrosis or rare porto-portal septa

Septal fibrosis : Fibrous septa with architectural distortion

Cirrhosis : Diffuse nodular formation

Septal

Stage of chronic hepatitis (B viral)

A : No fibrosis

B: Portal fibrosis

Stage of chronic hepatitis

Periportal fibrosis, short septa,

pericentrivenular fibrosis

Stage of chronic hepatitis (B viral)

Septal fibrosis reach adjacent portal

tracts with architectural distortion

Stage of chronic hepatitis

F & G: Septal fibrosis, partial

nodular formation

H & I: Cirrhosis(macro & micro)

G

I

Sample report of Chronic Hepatitis

Pathologic diagnosis significance

Chronic hepatitis, (HBV) Etiology

with (mild) lobular activity Grade of lobular activitywith (mild) lobular activity Grade of lobular activity

with (severe) porto-periportal activity Grade of porto-periportal activity;

possibility of disease progression

with (septal) fibrosis Stage

Thank you for your attention