Antibodies

to hepatitis C virus in patients with hepatocellular

carcinoma

To study the potential relationship between the hepatitis C virus (HCV), the majo: etiologic agent of parenterally trans. mitted non-A. non-B hepatitis. and the development of bepatowllular carcinoma (HCC), we tested the presence of antiHCV antibodies in sera from a large panel of HCC patients of different racial and geogqhical origins. Anti-HCV antibodies were delected in 82 out of I14 (71.9%) HBsAg-negative HCC patients and in 15 oat of 53 (28.3%) HBsAg-positive patients. No aipnificaot difference in the prevalence of anti-HCV antibodies was found in the HBsAg-negative HCC patients when they were divided according to presence of anti-HBs and/or anti-HBc antibodies, or absence of all hepatitis B virus (HBV) serological markers. The prevalence of anti-HCV antibodies was similar in HCC patients of Caucasian and African ongin. No d!fferences were noted when the patients were grouped according to sex. The mechanisms by which HCV might contribute to the development of HCC need to be further investigated. As for HBV infection. the necro-inflammation associated with HCV infection may induce cirrhosis, regeneration and eventually malignant transformation. The finding that few anti-HCV patients had HCC which is not superimposed on cirrhosis suggests that HCV could, however, exert some direct effect oo the development of HCC.

The availability, in the 1970’s, of specific diagnostic tests for the known hepntotrope agents. i.e., hepatitis A virus (HAVI. heoatms B vxus IHBW. cvtomeealovirus (CM;) andihe Epstein Barr vi,;, (EBb),ied tobe iden-

don, at least half of the non-A, non-B infections result in chronic hepatitis, which in torn progress to cirrhosis in approx. 20% of cases (12). Recently Houghton and coworkers isolated a cDNA clone encoding pan of a viral

tificatlon. from the epidemiological point of view, of one or more viruses, termed non-A, non-B. as the main caoscs of posi-trancfusian hepatitis (l-4). About 90% of trsnsfuSian-associated hepatitis cases worldwide are attributed to non-A. non-B hepatitis virus and an estimated 10% of all transfusions are thought to result in a non-A, non-B

antigen associated with non-A, non8 hepatitis (13) and soon after they developed solid-phase tests for the detection of circulating antt-HCV antibodies (14). Non-A, non-B infections have been proposed, in addirion to HBV and alcohol, as another important contributing factor for HCC development (15) and more recently a high prevalence of anti-HCV antibodies has been described in Ital-

hepatitis (5.6). Moreover non-A, non-B accounts for an important proportion of hepatitis cases among haemophiliacs (7). drug addicts (8) and haemodialysis patients (9) and more than 25% of the cases of sporadic hepatitiswithout nhviow pr;cotanmuserposule (lU.11). Although the acute dxseese i\ mild and often subclimcal in its presenta-

ian (16.17) and Spanish (IS) patients affected by HCC. To further assess the potential relationship between HCV infection and the development of HCC, sera from a large panel of HCC patients of different racial and geographical origins have been tested for anti-HCV antibodies.

ma, anrigcnr

Materiolsand MetbwJr

detected by mdirect

WCTC

crnce on the appropriate

Sera

irom

1980-1988

lh7

HCC

paruns.

to the I Climca

admitted

Mcdica

between

of the Uruversity

Rome and to the Gastroenterology

of

Unit of the University

of Modena,

or referred to the Laboratoire

gie-Virologie

of the Faculty of Medicine

m,munonuore\-

wbrtrxe

The j-xtwic m anti-HCV

test was used to analycr the d,fkrcncci prevalence in the various patient groups.

de Bacterioloin Dakar.

were

included in this study. The patients included 135 men and 32 women.

15-72

yrs of see (mean 62 vrs)

parients were hat&n One hundred

and1)3‘patients

and fifty-three

intake

(males,

(31.7%)

>80

The prevalence of anti-HCV

patients had asso-

had a hlstory cd high alcohol

g/day;

were chronicallv

were from Africa

(91.6%)

ciated cirrhosis, 33 (19.7%)

Seventv-four

females

>SO

infected bv HBV

giday).

53

as determined

by the positivity of HBsAg

m the se&

were positive for arsi-delta

antibodies in their sera and for

HDAg

and three (I .R%)

in their livers. lo 81 patients

liver disease was not determined.

the etiology

Twenty-three

had received at least one blood tramfusion sis of HCC.

The diaenosis of HCC

gically or by autops;in 74 Italian

before diagno-

was conhrmed

all patient..

patients (64.8%)

patients (69.8%)

of the patients

Forty-etght

hirtolo-

out of the

and 65 out of the 93 African

had elevated (400 @ml)

serum a-feto-

from

100

ltaliail

patents

chronic hepatttis or actiw

with

biopsy-proven

cirrhosns were atso included

in

this study. Patients included 61 men and 39 women. ritnging from 20-75 non-A,

non-8

years of age. Fifty patients had developed chronic hepatitis following

ized post-transfusional

non-A,

wetl-character-

eon-B acute hepatitis.

ty patients were aifected by the so-called community quired or cryptogenic chronic hepatitis.

The non-A.

B infection was diagnosed when all the serological ers of HAV,

HBV,

CMV

abuse OI autoimmune

Anti-HCV

All

addaon,

HCV

were detected Antibodies

the sera were stored

at -80

aicchol

sera

Test System.

was avoided.

Sera

were diluted I:10 and tested under code in duplicare. sults were considered turer’s instructions.

positive

according

All serologic HBV,

markers were tested using curnms&dly immunwssay ad

anti-EBV

by indirect RIA

kits from Abbott antibodies

of the igM

immunofluores~ence.

(Abbott

Laboratories).

smooth muscle, mitochondrial

Re-

to manufac-

HAV

and HDV

avaitatlc

Laboratories.

radio

AntKMV

class were drtrc~d

AFP

was measured by

Antibodies

to

and hver-kidney

m pa-

antibodies

were de-

reeled m Xi out of It4 (71 9%) HBsAg-negatwe

are shown

m Table 1. Anti-HCV

HCC pil-

tlents. but only I” I5 out uf 53 (28.3%) HCC

eeticntr

of anti-HCV

No sienificant difference m the orevalence antihodierwv

group of HCC

to presence of anti-HBr annhndws

and/or anti-HBc

markers.

VP. 68.3%)

origin.

group (Fig. (Fix.

antibodies.

prevalence

or

of anti-

natients of Cau-

barb in the HBsAg-negative

or in the HBsAg-posirive

(30.0

I). No differences were n&d

the patients were grouped statu

The

was similar m the HCC

casian and Afrwm (75.9

found in rhe HBqAg-ncgnuvu

patients when they were diwded according

absence of all HBV HCV

flBsAp_posnive

vs.

when

according to sex a,.d HBsAg

1). In the 14 oatzents who develooed HCC

m

the abscncc of detectable cirrhosis the prevalence of anttHCV

antibodies

between

was 57.1%

HBsAg-positive

with no obvious differences

and HBsAg-negative

patients.

patients showed no statistically

“C. all shippmgs were

done on dry ice and freeze-thawing

and the rrla-

and anti-HCV

acnon-

mark-

in patwttr

ELISA

antibodies.

markers

The analysis of the age structure of the different groups of

processes.

anttbodies

using the ORTHO

of drug

HBV

Fif-

and EBV viruses were negative.

and there was no evidence

bctweco

tients wtth CICC and m thoce with chronic liver disuse.

27.3%)

protein levels. Sera

rmnships

nuclear. microso-

significant difhrcncr

tween the patients infected with WV with HBV

(Fig.

2). Among

hc-

and those infected

the 33 HCC

patients with a

eat

Asia”,

rub-Lhara”

poQulatio”s

Atncim

show the highrat

and South Afnca rates (more

than

100 000 per ye;ir in males) (19). I” southern

black 211 per

Europe

and

iapan as many a, 10 to 20 new cases per 100 000 per year are ieported

(I’)).

In Italy. a dell 8s in many other co”,,-

tries. a staistically

significant median increase in the i”u-

dence of HCC has bee” shown (20-22). B virus infection. tion of HCC

which is implicated

world-wide

exists with HCC

(23).

in hll-90%)

Chronic hepatitis I” a very large frac-

and cirrhosis.

of p.die”ts

which co-

in both high and

low incidence region5 (24). are the two major canal ciations. HCC ate

The

sequenttal

in oatients with “on-A. (25-27).

ty acquired

Moreover.

“on-A,

cases of HCC prevalence different portion

11outof

“on-B

HCV

compared

Italian

patients

post-tmn~lusior ‘cr)propc”ic’

with chronic “on-A.

antiboaies

liver disease was 94%

“on-El

hrpatili,

and 62%

in

HCC

QOsitiVe.

were both

and anti-HCV

of anti-HCV

antibodies patients

Since

for

demiology,

in HBV

of

of anti-HBc patients

witbout

as

HCC.

and HCV

it epi-

doer not suggest a possiolr co-operation

of the two viral agents in the devetopnwr~t 01 HCC.

fection is one of the most common

There are striking geagaphlcal

patients

and anti-HCV

in HCC

patients

mechanisms by which HCV of HCC

gation. The necro-inflammation

carcinoma

many

I” a large pro-

the co-occurrence

might simply reflect similarities

1h:usuion

bee” in HCC

in I-ICC

origin!,. anti-H&

to chronic hepatitis ad

with

with cirrhosis of

I” this study we confirm the high

lated to the development

CIIIICCIISI” the aorld.

hepatitis

in patients

for

chronic hepatitis or cirrhosis.

HcQ~too~lular

hepatitis evidence

is not more frequent

Tbe potential

rx~al wriwo”~

“on-B

racial and geographical of our

und

seems to indi-

there is indirect

chronic

development

of anti-HCV

18 patients urith a history of blood transfusions were antipositwe. The prrvalcncr

PTH

in Italy which correlate commu”~.

unknown origin (28-30).

positive;

“WI-B

asso-

of cirrhosis

B link between bloud borne “on-A.

and HCC

from studies performed

h:gh alcohol intake tc” zcrc anti-HCV

development

and

Incidence: Chinese. South-

may induce

different

evidcncc

between populations HCC.

(31).

of patients

and eventually

Cirrhosis

carcinOma

regions (31 I. Dcspne

that its relation

in

this :here is

to the tumor

differs

having a high and low incidence of

I” high-risk populations

in Africa and Asia the two

diseases appear to share a common

aetiology,

and, according to recent findings, HCV

and HBV

seem to represent

the most likely etiolagical

factors.

only function

of hepatocarcinogenesis,

as initiators

‘The viruses may not

may “Is” ca”se the “ecro-inilasmatory that acts as a promoter in which KC

in-

malig-

occurs in a similar

heQatOcehiar

with

geographical

mounting

associated with HCV

regeneration

nant transformation proportion

could be re-

deserrc forther investi-

hepatic

of carcinogen&

is less common.

but

disease

In populations

cirrhosis usually precedes

the onset of the tumor by several years and see”ts to reprehent the major aetiological

association with the tumor.

I” these cases chronic alcohol abuse is the most frequently encountered

cause of cirrhosas. Whether

HCC

table consequence of cirrhosis or whether ders the hepatocytrs ronmental

is a” ioevi-

curhosis ren-

mo:e susceptible to ubiquitous

carcinopens remai”~ to be determined.

c”vi-

Thr discovery whout exert

uf a few HCC cases in :a”,~-t ICV

carrhosis could. dirccr

effects

howrre,.

duing

suggest tlmt

long-lasting

patienls

HCV

~“fccuo”

may which

may play B ,ole in the pathogenesis

vf WC.

Although

the available

il DNA

ixermcdmte

information

in the replicstive porubdity into

exclude5

cycle of HCV

of inscrtional

Ihe host cellular

(14).

mutagrnrsk gcnume.

thus encludin$ by “IT.!

the powbdity

idl

the

~“regrauo” that

HCV