Formulation and Application of a Numerical

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HEPATOLOGY

Copyright 1981by the American Association for the Study of Liver Diseases

Vol.

1,

No.

p.

431,

1981

Printed in U S A .

Formulation and Application of a Numerical

Scoring System for Assessing Histological

Activity

in Asymptomatic Chronic

Active

Hepatitis

ROBERTG. KNODELL,KAMAL

G.

ISHAK, ILLIAM

C.

BLACK, HOMAS.

CHEN,

ROBERT

CRAIG,

NEIL

KAPLOWITZ,

HOMAS

.

KIERNAN, ND JEROMEOLLMAN

Gastroenterology Section Veterans Administration Medical Center Minneapolis Minnesota

5541

7;Department of Hepatic Pathology Armed Forces Institute of Pathology Washington

D.C.

20306; University of New Mexico School o Medicine Albuquerque New Mexico

8714 ;

Veterans Administration Medical Center East Orange New Jersey 0701 9; Lakeside Veterans

Administration Medical Center Chicago Illinois 60612; Wadsworth Veterans

Administration Medical Center Los Angeles California 90073

A Histology Activity Index has been developed which generates a numerical score for liver biopsy

specimens obtained from patients with asymptomatic chronic active hepatitis. Biopsies are graded

in four categories: periportal necrosis, intralobular necrosis, portal inflammation, and fibrosis.

Under code, three pathologists and three hepatologists evaluated 4 iver biopsy specimens obtained

from five patients with asymptomatic chronic active hepatitis. Good correlation was seen between

severity of liver biopsy lesions as judged by conventional histological descriptions and Histology

Activity

Index

scores.

Significant differences in Histology Activity Index score occurred in only

2

of

28 duplicate scorings of biopsy specimens by two observers. This system provides definitive

endpoints for statistica l analysis of serial changes in liver histology and offers an alternative to the

use of conventional pathological descriptions in following the natural history and trea tment

responses of asymptomatic chronic active hepatitis.

Chronic active hepatitis (CAH) is

a

necroinflammatory

lesion of the liver diagnosed by characteristic pathologic

changes in the liver biopsy specimen. Early reports of

patients with CAH emphasized the profound clinical and

biochemical alterations often accompanying this condi-

tion, described the poor prognosis associated with severe

CAH, and outlined treatment regimens which signifi-

cantly decreased mortality and morbidity

2-5).

Recently

it has become apparent that patients with severe CAH

represent only a small percentage of the total population

whose liver biopsy specimen is interpreted as showing

CAH ( 6 , 7 ) .Many such patients a re totally free of clinical

Received January 23,1981; accepted June 17, 1981.

This study was supported by th e Veterans Administration Cooper-

ative Studies Program. Results

of

this study were presented at the

annual meetingof the American Society for the Study of Liver Disease,

Chicago, Illinois, November 1980, and have appeared in abstr act form

(1).

Address reprint requests to: Robert

G.

Knodell, M.D., Gastroenter-

ology

Section (111D),VA Medical Center, 54th Stree t and 48th Avenue

South, Minneapolis, Minnesota 55417.

symptoms and have only mild alterations in serum ami-

notransferases, bilirubin, and y-globulin. The natural his-

tory of asymptomatic CAH is not known and guidelines

for treatment have not yet been established. The rate of

clinical progression of asymptomatic CAH appears to be

slower than for severe CAH. Conventional clinical events

used in evaluating the natural history and response to

trea tment of severe CAH (such as death and develop-

ment or disappearance of jaundice, ascites, and enceph-

alopathy)

will

not be applicable in the study of asymp-

tomatic CAH. Rather it appears that pathological study

of serial liver biopsy specimenswill be the most valuable

parameter to follow the short-term course of this disease.

Conventional pathological descriptions of histology of

serial liver biopsy specimens are often extremely detailed

or very broad and minimally descriptive. Such descrip-

tions also do not readily provide definitive endpoints for

statistical analysis. This report describes a Histology

Activity Index (HAI) which generates a numerical score

for asymptomatic CAH liver biopsy specimens. This scor-

ing system is both objective and reproducible, and it may

431


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HEPATOLOGY

32

KNODELL ET

AL.

be useful as either an alternative or supplement to the

use of conventional pathological terminology in the study

and management of asymptomatic CAH patients in

whom histological changes in serial liver biopsy speci-

mens may be the only prognostic indicator available for

evaluation.

MATERIALS AND METHODS

Liver biopsy specimens for analysis were obtained from

five patients whose serum aminotransferases had been

elevated a mean period of

17 8

months (range

8

to

27

months). Mean levels of serum SGOT and SGPT eleva-

tions were

58 k 43

and

140 178

mIU per ml respectively

(range

18

to

130

and

25

to

497

mIU per ml respectively).

No patient had persistent malaise, fatigue, or anorexia.

None of the patients had jaundice, ascites, or encepha-

lopathy, and y-globulin elevations, if present, were mini-

mal (mean

2.0

&

0.4

gm per dl, range

1.4

to

2.6

gm per

dl). One patient's serum was positive for HBsAg, HBeAg,

and DNA polymerase, while the remaining four patients

are presumed to be cases of non-A, non-B chronic hepa-

titis. The initial biopsy specimen was interpreted by one

of the authors K.

G.

I.) and a diagnosis of CAH was

made. From one to three subsequent liver biopsy speci-

mens were obtained in the patients over periods of 1 to

3

years. A total of

14

biopsy specimens was used in testing

the applicability and reproducibility of the HA1 scoring

system.

Liver biopsies were performed percutaneously or at

laparoscopy using a Travenol Tru-cut biopsy needle

(Travenol Laboratories, Inc., Deerfield,

Ill. . ll

biopsy

specimens except two were

2 2

cm

in

length and con-

tained

2 6

portal areas for examination. Specimens were

fixed in

10

buffered formalin.

Six

to eight sections were

cut from each biopsy for routine and special stains, but

only sections stained with hematoxylin and eosin and

Masson's trichrome stain were used in evaluating the

scoring system. After coding, specimens were submitted

to three hepatic pathologists and to three clinical hepa-

tologists for their conventional interpretation and for

numerical scoring according to the HAI. No training in,

or discussion of, the HA1 was provided to readers prior

to scoring the biopsy specimens.All s x readers saw the

same sections of each liver biopsy specimen. To test the

HA1 scoring system for intraobserver variation, two of

the authors (R. G. K. and K. G. I.) scored the coded

biopsies on two occasions separated by a period of 1 to

2

months. Consistent differences in interobserver and in-

traobserver HA1 scoring were tested for significance by

analysis of variance

8) .

A description of the HA1 is given in Table

1.

Biopsy

TABLE.HA1

FOR

NUMERICALCORINGF LIVER

IOPSY

SPECIMENS

Score

. Periportal +/- bridg-

ing necrosis

I.

Intralobular degenera- score III. Portal inflammation score

IV.

Fibrosis score

tion and focal

necrosisb

A.

None

B. Mild piecemeal

necrosis

C.

Moderate piece-

meal necrosis (in-

volves

less

than

50%

of the cir-

cumference of

most portal

tracts)

necrosis (involves

more

than 50%of

the circumference

of most portal

tracts)

E.

Moderate piece-

meal necrosis p us

bridging necrosis''

F. Marked piecemeal

necrosis p us

bridging necrosis"

G . Multilobular ne-

crosis"

D.

Marked piecemeal

1

3

4

5

6

I 0

A

None

B. Mild (acidophilic

bodies, ballooning

degeneration and/

or sca ttered foci of

hepatocellular ne-

crosis in

<

of

lobules or nodules)

volvement of

-??

of lobules or nod-

ules)

C. Modera te (in-

D.

Marked (involve-

ment of

>

of lob-

ules or nodules)

A. No

portal inflam-

mation

B.

Mild (sprinkling of

inflammatory cells

in

<

of portal

tracts)

C. Moderate (in-

creased inflamma-

tory cells in

%-?h

of portal tracts)

D.

Marked (dense

packing of inflam-

matory cells in

>

of portal tracts)

A No

fibrosis

0

B. Fibrous portal ex- 1

pansion

C. Bridging fibrosis

3

(portal-portal or

portal-central

linkage)

D.

Cirrhosis'

4

HA1 score is t he combined scores for necrosis, inflammation, an d fibrosis.

Degeneration-acidophilic

bodies, ballooning; focal necrosis-scattered foci of hepatocellular necrosis.

oss

of normal hepatic lobular architecture with fibrous septae separating and surrounding nodules.

''Bridging is defined as 2 2 bridges in the liver biopsy specimen; no distinction is made between portal-portal and portal-central linkage.

wo

or

more contiguous lobules with panlobular necrosis.


3/5

Vol. 1,

No.

5,

1981

NUMERICAL SCORING

OF

ASYMPTOMATIC CAH LIVER BIOPSIES

433

specimens were graded in four categories: (a) periportal

+/- bridging hepatocellular necrosis; (b) intralobular

degeneration and focal hepatocellular necrosis;

c )

portal

inflammation, and (d) fibrosis. A numerical score for

each category was assigned to each liver biopsy specimen,

and the combined score of the four categories formed the

HA1 score for that biopsy specimen. The numerical score

assigned each component in the

HA1

represented a con-

sensus of the authors and was based on clinical experi-

ence and .a review and critical analysis of literature

pertinent to CAH histology

(9-11).

Periportal necrosis

bridging necrosis

was

weighted more heavily than

other parameters since it appears to be more influential

in determining the activity and severity of severe CAH

(10,ll).Also sampling variability for fibrosis, particularly

in regard to cirrhosis, may be marked with serial liver

biopsies (12).

RESULTS

Good correlation was seen between conventional his-

tological descriptions for liver biopsy specimens from

patients with asymptomatic CAH and HA1 numerical

scores (Figure 1 .Liver biopsy specimens which were

interpreted as showing chronic persistent hept kitis or

nonspecific changes had low numerical scores, while

biopsies with more severe liver lesions including CAH,

CAH with bridging, and active cirrhosis had higher HA1

scores.

No

examiner had difficulty adapting to the HA1

scoring system. Mean standard deviation for interob-

server differences in HA1 scoring of the 14 biopsies was

2.4

and differences in scoring by the six readers did not

approach statistical significance when tested by analysis

of variance (df, =

5,

dfi

78,

F

=

0.788). Intraobserver

variation in HA1 scores when biopsy specimens were

interpreted on two different occasions by the same ob-

server was also small (Figure 2). Mean difference in HA1

2 4 8

10 12 14

16

18 20

H A 1 S COR E -R e a d i n g 2

Reader 2

6

.s

14

-

1

U

a

2

W

s

v

U

U

/

2

4

6

8

10 12

14 16 18

2

:

I

I

I

I I

I

I

N o rm o l N on - C P H C A H C A H t C A H t A c t iv e

Specific B r i d g i n g M L N C ir rh o s i s

C h a n g e s

C O N V E N T I O N A L D I AG N OS IS

FIG.1. Comparisonof conventional readings for liver biopsy speci-

mens with HA1 scores. HA1 values represent the mean score of

s x

individual readers. The conventional diagnosis plotted was used for

that particular liver biopsy specimen by four or more of the s x exam-

iners; in one instance, both chronic persistent hepatitis (CPH) and

CAH were selected by three examiners and the biopsy result is plotted

between these two conventiond diagnoses.

H A 1

SCORE -Reading 2

FIG.2 . Comparison of HA1 scoring of liver biopsy specimens on

duplicate determinations by two different readers. Biopsy scores for the

initial reading are plotted against biopsy scores obtained at the second

reading. Biopsies which were scored identically on the two determina-

tions fall on the solid diagonal line. Reader 1,K. G. I.; Reader 2 R. G

K.

score for

28

duplicate readings was

1.3

and the magnitude

of this difference was not related to the size of the biopsy

score. A difference of >3 in HA1 score was seen in only

2 of

28

duplicate determinations (7 )and was paralleled

by differences in the conventional reading (CAH vs.

chronic persistent hepatitis for higher and lower scores,

respectively). Both specimens with HA1 scoring differ-

ences

>3

had marginally adequate tissue available for

examination; one specimen was fragmented and had only

three portal areas for examination, while the second

specimen was

1.5

cm in length and contained four portal

triads. Differences in duplicate

HA1

scoring of biopsy


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HEPATOLOGY

34 KNODELL ET AL.

specimens by the same individual were not statistically

significant (paired

t

test).

DISCUSSION

The importance of initial liver histology in predicting

the evolution and response to treatment in severe CAH

has been addressed by Baggenstoss and coworkers (10,

13). Severe histological disease activity (CAH

+

bridging,

CAH

+

multilobular necrosis, and active cirrhosis) is

associated with higher mortality ra te and trea tment fail-

ure. It

is

reasonable to assume tha t histological changes

in serial liver biopsy specimens will also be an important

parameter to follow in evaluating patients with asymp-

tomatic CAH. Indeed, it may be the only parameter

available for analysis in many such patients in whom no

clinical or physical signs of chronic liver disease are

present and whose liver biochemistries are minimally

abnormal. If disease activity in asymptomatic CAH is to

be assessed by changes in histology of serial liver biopsy

specimens, such changes should be simply and objec-

tively quantitated and should be easily amenable to

statistical analysis. Conventional terminology used to

describe severe CAH would be difficult to analyze statis-

tically in asymptomatic CAH because it tends to use very

detailed descriptive terms (14) or combines all lesions

into four broad categories of CAH, CAH + bridging,

CAH

+

multilobular necrosis, and active cirrhosis (10,

13).

The HA1 developed in this paper provides an alterna-

tive to use of traditional terminology to describe liver

histology in asymptomatic CAH. Numerical HA1 scores

paralleled severity of liver lesions as described by con-

ventional terminology. High HA1 scores were seen for

liver biopsy specimens whose conventional diagnoses

were CAH, CAH with bridging, and active cirrhosis,

while low scores were seen with diagnoses of CPH and

nonspecific changes. Overall HA1 scores can also be

broken into individual components of necrosis, inflam-

mation, and fibrosis to yield additional information not

provided by conventional composite scales for grading

necroinflammatory liver disease (10,

11 .

Total unanimity

of

liver biopsy assessment was not

achieved by the six individual readers with conventional

interpretation. All six readers made the same conven-

tional diagnosis for only one of the 14 biopsies. Th e same

diagnosis was made by four or more readers for 12

additional biopsies, while three readers selected the same

diagnosis for the remaining biopsy specimen. The four

categories chosen for inclusion in the HA1 were piecemeal

necrosis, intralobular degeneration and hepatocellular

necrosis, portal inflammation, and fibrosis. Recently

Theodossi e t al. assessed

27

pathologic features for inter-

observer variation using Kappa statistics (15). High sig-

nificance and strong evidence of agreement were seen

between readers for piecemeal necrosis, intralobular ne-

crosis and fibrosis, thus supporting the choice of catego-

ries included in the HA1 scoring system. Standard devia-

tion in HA1 scoring of the 14 biopsies by the six readers

was 2.4, and degree of variation in HA1 scoring did not

correlate well with magnitude of mean HA1 scores ( =

0.31). Interobserver variation in interpretation of liver

biopsy histology using the HA1 compares favorably with

that seen using conventional terminology.

The degree of reproducibility of multiple interpreta-

tions of the same biopsy by one individual is an important

characteristic of any system for describing liver histology.

Intraobserver variability using the HA1 scoring system

approximated th at of conventional interpretation both in

this study and in the study by Soloway

12).

Thirty-four

slides of liver tissue obtained from patients with severe

CAH were compared in Soloway’s study, and overall

severity of hepatitis was reproduced in 88% of duplicate

interpretations using a grading scale of 0 (normal) to 3

(most severe). Standard deviation for intraobserver dif-

ferences in HA1 score between 28 duplicate readings in

this study was 1.3. HA1 scores for 24 of

28

duplicate

determinations (86%) fell within

2

times the standard

deviation

(k2.6)

of each other and 100% of 14 duplicate

HA1 interpretations by the more experienced reader K.

G.

I.) differed by

k 2

or less.

If liver histology does not change in asymptomatic

CAH patients during a reasonable period of observation,

then histology will not be a helpful parameter to follow

in the assessment of this disease. The fourteen serial

biopsy specimens obtained over a 1- to 3-year period

from the five asymptomatic CAH patients are grouped

by patient in Table

2. A

+4 change in HA1 scoring of

biopsy specimens by the same observer, 3 times the

standard deviation seen for 28 duplicate liver biopsy

readings, was chosen as the level indicating a high prob-

ability that actual improvement or worsening in liver

histology had occurred. Liver histology in 4 of the

5

asymptomatic CAH patients showed a >+4 change

in

HA1 scoring over the

1-

to 3-year period of observation.

No data are available as to whether HA1 scores more

accurately predict clinical prognosis of asymptomatic

CAH than conventional pathological descriptions. An-

ecdotally, HA1 scoring suggested a progressing liver le-

TABLE

.

HA1 SCORESOR SE R I A L I VE R I O PSY PE C I ME N SROM

PATIENTS

ITH

ASYMPTOMATICAH“

Patient Date of biopsy

HA1

score

N.

P.

1977 15

1978 13

1979 9

R.M.

P . c

A . A.

E. G .

1977

19781

19782

1979

1975

1976

1978

1977

1979

1978

1979

8

9

11

14

7

10

8

7

1

2

5

“Biopsy specimens scored by R. G. K. Biopsies were coded and

scorer was blinded as to patient identity, time sequence of biopsy, and

treatment regimens at time of biopsy interpretation.


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Vol.

1 ,

No.

5,

1981

NUMERICAL SCORING

OF

ASYMPTOMATIC CAH LIVER BIOPSIES

435

sion in R. M. (Table

2)

in 1979, while conventional

readings of serial biopsies were unchanged. A liver biopsy

performed at another hospital approximately

1

year later

was interpreted conventionally as showing deterioration

from the 1979 biopsy (Dr. Matthew Janin, personal com-

munication). It does appear that changes in liver histol-

ogy are an appropriate “gold standard” by which disease

activity can be measured in patients with asymptomatic

CAH. The HA1 system outlined allows for easy, objec-

tive, and reproducible quantitation of histological change

in serial liver biopsy specimens from patients with

asymptomatic CAH.

It

provides data which are readily

amendable to statistical analysis. While conventional

readings of biopsies can also be available for evaluation,

employment of a system to score numerically liver biop-

sies appears to be a concept worthy of consideration in

following and studying patients with asymptomatic CAH.

Acknowledgments:

The constructive comments of

Yick Kwong Chan, Ph.D., and Gary R . Johnson from the

Cooperative Studies Program Coordinating Center, West

Haven, Connecticut during formulation

of

the HA1 and

the help of Valarie Wesley in preparation of this manu-

script are gratefully acknowledged.

REFERENCES

1. Knodell R G, Ishak KG, Craig R, et al.Histology activi ty index for

numerical scoring and assessment of asymptomatic chronic active

hepa tit is liver biopsies. Gastroenterology 1980; 79:1031.

2. Mistilis

SP,

Blackburn CRB. Active chronic hepatitis. Am

J

Med

1970; 48:484-495.

3. Geall MG, Schoenfield LJ, Summerskill WHJ. Classification and

treatment

of

chronic active liver disease. Gastroenterology 1968; 55:

724-729.

4. Mackay IR. Chronic hepatitis: effect of prolonged suppressive

treatment and comparison of azathioprine with prednisolone.

Q

J

Med 1968; 37:379-392.

5. Soloway RD, Summerskill WHJ, Baggenstoss AH, et al. Clinical,

biochemical and histological remission

of

severe chronic active liver

disease:

a

controlled study of treat men t and early prognosis. Gas-

troenterology 1972; 63:820-833.

6. Koretz RL, Lewin KJ, Fagen ND, et al. Chronic active hepatitis:

who meets treatment criteria. Gastroenterology 1978; 75:971.

7. Knodell RG, Conrad ME, Ishak KG. Development of chronic liver

disease after acute non-A, non-B posttransfusion hepatitis. Gastro-

enterology 1977; 72:902-909.

8. Snedecor GW, Cochran WG. Statistica l Methods. Ames, Iowa: Iowa

Stat e University Press, 1967.

9. DeGroote

J ,

Desmet VJ, Gedigk P, e t al.

A

classification of chronic

hepatitis. Lancet 1968; 2626-628.

10.

Baggenstoss AH, Soloway

RD,

Summerskill WHJ, et al. Chronic

active liver disease. T he range of histologic lesions, their response

to t reatment, and evaluation. Human Patho l 1972; 3:183-198.

11. Scheuer PJ . Liver biopsy in chronic hepatitis: 1968-1978. Gut 1978;

12. Soloway RD, Baggenstoss AH, Schoenfield

LJ

t al. Observer error

and sampling variability tested in evaluation of hepatitis and cir-

rhosis by liver biopsy. Dig Dis 1971; 161082-1086.

13. Ammon HV, Summerskill WHJ, Baggenstoss AH. Initial morpho-

logic appearances determine responses to treatment of chronic

active liver disease. Gastroenterology 1973; 65526.

14.

Ishak KG. Viral hepatitis: the morphologic spectrum. In:Gall EA,

Mostofi FK, eds. International academy of pathology monograph

no. 13. Baltimore: Williams and Wilkins, 1972: 218-226.

15. Theodossi A, Skene AM, Portmann

B,

et

al.

Observer variation in

assessment of liver biopsies including analysis by Kappa statistics.

Gastroenterology 1980; 79:232-241.

191554-557,

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