HepatitisGvirusinfectioninchronicliverdisease
MGuilera,JCSáiz,FXLópez-Labrador,EOlmedo,SAmpurdanés,XForns,JBruix,
AParés,JMSánchez-Tapias,MTJiménezdeAnta,JRodés
Abstract
Background?The hepatitis G virus
(HGV), a recently identified member of
theFlaviviridaefamily,cancausechronic
infectioninmanbuttheroleofthisagent
in chronic liver disease is poorly under-
stood.
Aims?To evaluate the prevalence and
meaningofHGVinfectioninalargeseries
ofpatientswithchronicliverdisease.
Subjects?Two hundred volunteer blood
donors,179patientswithchronichepatitis
C, 111 with chronic hepatitis B, 104 with
alcoholicliverdisease,136withhepatocel-
lular carcinoma,and 24 with cryptogenic
chronicliverdiseasewerestudied.
Methods?HGV RNA was investigated in
serum samples by reverse transcription
andpolymerasechainreactionamplifica-
tion of the 5' non-coding region of HCV
andhybridisationtoaspecificprobe.The
main features of HGV RNA seropositive
andseronegativepatientswerecompared.
Results?TheprevalenceofHGVinfection
was 3% in blood donors, 7% in chronic
hepatitisC,8%inchronichepatitisB,2%
inalcoholicliverdisease,4%inhepatocel-
lular carcinoma, and 8% in cryptogenic
chronic liver disease. HGV infected pa-
tients tended to be younger than non-
infected patients but no diVerences
concerning sex, possible source of infec-
tion, clinical manifestations, biochemical
and virological parameters,or severity of
liverlesionswerefound.
Conclusions?The prevalence of HGV in-
fectioninchronicliverdiseaseseemstobe
relatively low in our area. Infection with
HGV does not seem to play a significant
pathogenic role in patients with chronic
liver disease related to chronic HBV or
HCV infection or to increased alcohol
consumption,orinthosewithcryptogenic
chronicliverdisease.
(Gut1998;42:107?111)
Keywords:chronicliverdisease;hepatitisGvirus
The hepatitis G virus (HGV) is a recently
identified member of the Flaviviridae family
distantlyrelatedtohepatitisCvirus(HCV).
12
This virus can be transmitted eYciently by
blood transfusion and by other parenteral
mechanisms
2?5
and transient and long lasting
infectionswithHGVhavebeendocumentedin
man.
24
HGVRNAsequenceshavebeendetectedin
ahighproportionofvolunteerblooddonors.
26
HGV RNA positive donors may present with
minor increases in serum alanine aminotrans-
ferase(ALT)butatleast50%ofthemdonot
present with any evidence of liver disease.On
this basis, HGV does not appear to be highly
pathogenic.
InfectionwithHGVhas,however,alsobeen
detected in a high proportion of patients with
idiopathic fulminant hepatitis,
78
suggesting
that HGV may be highly pathogenic in some
cases.This possibility is still open to question
sinceotherstudieshavenotdisclosedasignifi-
cant prevalence of HGV infection in this
condition.
910
There is also controversy about the role of
HGV infection in the pathogenesis of chronic
liver disease. Preliminary surveys of patients
withchronicliverdiseaseshowedthatHGVis
often detected in patients chronically infected
with other hepatotropic viruses such as the
hepatitis B virus (HBV) or HCV but more
rarely in patients with cryptogenic liver
disease.
21112
Somestudieshavehoweverfound
arelativelyhighprevalenceofHGVinfectionin
patients with cryptogenic chronic hepatitis,
suggestingthatthisvirusmaybeimportantin
thiscondition.
13 14
To elucidate further the pathogenic role of
HGV in chronic liver disease we investigated
the prevalence of HGV infection and its
associatedfeaturesin554patientswithdiVer-
ent chronic liver diseases including represent-
ative series of patients with alcoholic liver
diseaseandhepatocellularcarcinoma.
Patientsandmethods
PATIENTS
Five hundred and fifty four patients with
chronic liver disease and 200 consecutive first
donationvolunteerblooddonorswerestudied.
According to clinical, serological, and his-
topathologicalfeatures,patientswereseparated
intothefollowingcategories.
ChronichepatitisC
This group included 179 patients (109 male
and 70 female; mean age 50 years, range
19?83). Chronic hepatitis C was assessed by
sustained elevation of ALT, histologically
proved chronic inflammation of the liver,and
positive tests for anti-HCV antibodies and for
HCV-RNA in serum.Other causes of chronic
liverdiseasewereexcluded.
ChronichepatitisB
Thisgroupincluded111patients(92maleand
19 female; mean age 41 years, range 14?69)
with chronic hepatitis B virus infection, as
assessed by long lasting hepatitis B surface
(HBsAg) antigenaemia and elevated ALT.
Liverbiopsywasperformedin71cases.
Gut1998;42:107?111 107
LiverUnit,
Departmentof
Medicine,University
ofBarcelonaMedical
School,Barcelona,
Spain
MGuilera
JCSáiz
FXLópez-Labrador
EOlmedo
SAmpurdanés
XForns
JBruix
AParés
JMSánchez-Tapias
JRodés
Serviceof
Microbiology,Hospital
Clínic,Departmentof
Medicine,University
ofBarcelonaMedical
School,Barcelona,
Spain
MTJiménezdeAnta
Correspondenceto:
DrJMSánchez-Tapias,
LiverUnit,HospitalClínic,
Villarroel170,08036
Barcelona,Spain.
Acceptedforpublication
16July1997
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Alcoholicpatients
Thisgroupincluded104patients(70maleand
34 female; mean age 43 years, range 22?76)
whohadconsumedmorethan80gofethanol
perdayforatleastfiveyears.HBsAgandanti-
HCV were negative in all cases. Liver biopsy
showedminimalabnormalitiesorfattyinfiltra-
tionin43(41%),fattyinfiltrationandfibrosis
in 14 (13.5%), alcoholic hepatitis in 23
(22.1%),hepatic cirrhosis in 21 (20.2%),and
chronichepatitisinthree(3%).
Hepatocellularcarcinoma
Thisgroupincluded136patients(91maleand
45 female; mean age 64 years, range 40?93)
with hepatocellular carcinoma and underlying
cirrhosis. The diagnosis of hepatocellular
carcinoma was based on data from imaging
techniques?ultrasonography, computed tom-
ography, and/or hepatic arteriography?and
confirmed by histopathological and/or cyto-
logical examinations. The aetiology of pre-
existingcirrhosiswasknownin125cases.
Cryptogenicchronicliverdisease
Thisgroupincluded24patients(12maleand
12 female; mean age 45 years, range 19?75)
years.Allpresentedwithabnormalitiesofliver
functiontestsconsistingmainlyofelevationof
aminotransferaseserumlevels1.5timesabove
the upper normal limit lasting for at least one
year. None were obese or alcoholic, and all
denieduseofpotentiallyhepatotoxicdrugs.All
hadnegativetestsforHBsAg,anti-HCV,HCV
RNA, and autoantibodies (antinuclear, antis-
moothmuscle,antimitochondrial,andantiliver
andkidneymicrosomes).Serumlevelsofiron,
ferritin, caeruloplasmin, and Ć
1
-antitripsin
were normal in all cases.Liver biopsy showed
minimalchangesin10cases,fattyliverinfour,
minimalcholestasisintwo,chronichepatitisin
two,portal and periportal fibrosis in two,and
micronodularcirrhosisinfour.
Blooddonors
Two hundred consecutive volunteer blood
donors(114maleand86female;meanage39
years,range18?65)werestudiedatthetimeof
theirfirstdonation.
SEROLOGICAL METHODS
HBsAg,anti-HCV,and anti-HDV were tested
with commercially available enzyme linked
immunosorbent assay (ELISA) kits. HBV-
DNAinserumwasinvestigatedbypolymerase
chain reaction (PCR) amplification of HBV
core sequences according to a simplified
protocolreportedpreviously.
15
HCV RNA in serum was determined by
reversetranscription(RT)andamplificationby
nested PCR of the 5' non-coding region
(5'NCR) region of HCV, as described
previously.
16
HCV RNA serum levels were
measured by a competitive PCR method
recentlydevelopedinourlaboratory.
17 18
HCV
genotype was determined according to
Okamoto et al
19
with some modifications, as
describedpreviously.
20
HGV RNA in serum was determined as
described previously.
10 18
In brief, RNA was
extracted from 140 µl of serum using a
commercially available kit (QiAmp, Qiagen,
Hilden,Germany).ComplementaryDNAwas
synthesisedfrom15µlofextractedRNAby60
minutes incubation at 37°C with 300 U of
Moloneyleukaemiavirusreversetranscriptase
(Gibco-BRL, Gaithersburg, Maryland, USA),
random primers, and 20 U of ribonuclease
inhibitorinafinalvolumeof30µlofRTbuffer
(50mMTris-HCl,pH8.3,75mMKCl,3mM
MgCl
2
,10mMDTT,0.01%gelatine,200mM
each deoxynucleotide). Specific PCR amplifi-
cation and hybridisation of the 5'NCR of the
HGVgenomewascarriedoutusingacommer-
cial kit (Hepatitis G virus-Primer and capture
probe set, Boehringer, Mannheim GmbH,
Mannheim,Germany)accordingtothemanu-
facturer?s instructions.One positive and three
negative controls were included in each run.
The background signal of negative controls
rangedbetween0.084and0.113.Samplesgiv-
ing a signal five times above the mean
background signal were considered positive.
Results were accepted on agreement on
repeatedtesting.
STATISTICAL ANALYSIS
Comparisons between groups were made by
the  
2
orFisher?sexacttestforcategoricalvari-
ables and by the Mann-Whitney test or
Student?sttestwhenappropriateforquantita-
tivevariables.Apvaluelessthan0.05wascon-
sideredsignificant.
Results
HGV INFECTION IN BLOOD DONORS
HGV RNA was detected in six of 200 blood
donors (3%). Anti-HCV was positive in two
(1%)andHBsAginone(0.5%).HGVinfected
donorswereyoungerthannon-infecteddonors
(27(5)versus39(14)years,p=0.03).Noneof
the HGV infected donors had past history or
clinical evidence of liver disease. ALT values
weresimilarinHGVinfected(32(8)IU/l)and
non-infecteddonors(29(14)IU/l).Aminimal
elevationofALT(45IU)wasdetectedinone
of six (17%) HGV infected and in 28 of 194
(14%)non-infecteddonors.
HGV INFECTION IN PATIENTS WITH CHRONIC
HEPATITIS C
HGVRNAsequenceswerefoundin12of179
patients (6.7%). Although the prevalence of
HGVinfectioninthisgroupwashigherthanin
blooddonorsthediVerencedidnotreachsta-
tistical significance. No significant diVerences
between HGV infected and non-infected pa-
tients were observed concerning the demo-
graphicfeatures,thepresumedsourceofinfec-
tion, the biochemical or haematological
abnormalities, the degree of severity of liver
lesions, the infecting HCV genotype, or the
levelofHCVviraemia(table1).
HGV INFECTION IN PATIENTS WITH CHRONIC HBV
INFECTION
HGV RNA was detected in nine of 111
patients (8.1%). Although the prevalence of
HGVinfectioninthisgroupwashigherthanin
blood donors the diVerence was not statisti-
108 Guilera,Sáiz,López-Labrador,etal
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callysignificant.Asshownintable2compari-
sonofHGVinfectedandnon-infectedpatients
didnotshowsignificantdiVerencesconcerning
demographic features, biochemical and hae-
matological abnormalities, severity of liver
lesions,levelofdetectableHBVreplication,or
infection with other hepatotropic viruses such
as HDV and HCV. The presumed source of
infectionwasalsosimilar.However,ahighrate
of HGV infection (four of 10) was observed
amongHBVinfectedmalehomosexuals.
HGV INFECTION IN PATIENTS WITH ALCOHOLIC
LIVER DISEASE
HGVRNAwasdetectedintwoof104patients
(1.9%). Statistical analysis was not possible
duetothesmallnumberofHGV-RNApositive
patients.Onewasa39yearoldwomanwithout
clinical evidence of liver disease and slightly
abnormalliverfunctiontests(serumaspartate
aminotransferase(AST)60IU/l,ALT38IU/l,
alkaline phosphatase 149 IU/l, Ş-glutamyl
transferase76IU/l,bilirubin0.8mg/dl,serum
albumin 42 g/l, prothrombin time 100%) in
whom liver biopsy showed mild fatty infiltra-
tion of the liver. The other was a 51 year old
manwithhepaticcirrhosisandabnormalliver
function tests. None had a history of blood
transfusion or intravenous drug misuse.Eight
of 102 HGV-RNA negative patients had
receivedbloodtransfusionsinthepast.
HGV INFECTION IN PATIENTS WITH
HEPATOCELLULAR CARCINOMA
HGVRNAwasdetectedinfiveof136patients
(3.7%).This prevalence is almost identical to
that found in blood donors. HGV infected
patients tended to be younger than non-
infected patients. A history of blood transfu-
sionpriortodiagnosisofliverdiseasewasmore
frequent in HGV infected patients. However,
statisticalanalysisdidnotshowsignificantdif-
ferences between the two groups of patients
concerning demographic features, presumed
aetiology of underlying cirrhosis, presumed
sourceofinfection,orhaematologicalandbio-
chemical features (table 3). HGV-RNA was
detected in association with HCV infection in
fourofthefivecases.
HGV INFECTION IN PATIENTS WITH CRYPTOGENIC
CHRONIC LIVER DISEASE
HGVRNAwasdetectedintwoof24patients
(8.3%).Onewasanasymptomatic55yearold
woman with slight ALT elevation lasting for
seven years after recovery from an episode of
fulminanthepatitisofunknownaetiology.The
patient had received blood products at that
time. The other was a 19 year old man with
abnormal liver function tests in whom liver
biopsy showed evidence of chronic hepatitis
withmildactivityandminimalfibrosis.Apos-
sible source of infection was not identified in
this patient.Further analysis was not possible
due to the small number of HGV infected
patientsdetectedinthisgroup.
Discussion
HGV,orGBV-C,isarecentlyidentifiedmem-
ber of the Flaviviridae family that can cause
Table1 BaselinefeaturesofpatientswithchronichepatitisCaccordingtothepresenceor
absenceofHGV-RNAsequencesinserum
Characteristics
HGV-RNA
negative(n=167)
HGV-RNA
positive(n=12) pValue
Age(y) 50(14) 49(17) NS
Sex(male/female) 102/65 7/5 NS
Presumedsourceofinfection NS
Bloodtransfusion 51(30%) 3(25%)
Addictiontoi.v.drugs 15(9%) 2(17%)
Unknown 101(61%) 7(58%)
WBCcount(×10
9
/l) 5.6(1.8) 4.1(2.3) NS
Plateletcount(×10
9
/l) 152(55) 125(65) NS
AST(IU/l) 92(61) 95(80) NS
ALT(IU/l) 151(115) 186(151) NS
Ş-glutamyltransferase(IU/l) 52(44) 32(15) NS
Bilirubin(mg/dl) 0.9(1.01) 1.0(0.7) NS
Degreeofhistologicalseverity NS
Mildhepatitis 55(33%) 2(16%)
Moderatehepatitis 50(30%) 4(33%)
Severehepatitis 18(11%) 2(16%)
Cirrhosis 44(26%) 4(33%)
Virologicalfeatures
Genotype1b 131(80%) 8(67%) NS
Othergenotypes 33(20%) 4(33%) NS
HCVviraemia(copies/ml ×10
6
) 0.418(0.873) 1.105(1.719) NS
Quantitativevariablesareexpressedasmean(SD).Categoricalvariablesareexpressedasn(%).
Table2 BaselinefeaturesofpatientswithchronicHBVinfectionaccordingtothepresence
orabsenceofHGV-RNAsequencesinserum
Characteristics
HGV-RNA
negative(n=102)
HGV-RNA
positive(n=9) pValue
Age(y) 41(13) 36(5) NS
Sex(male/female) 86/16 6/3 NS
Presumedsourceofinfection NS
Bloodtransfusion 1(1%) 1(11%)
Addictiontoi.v.drugs 2(2%) 1(11%)
Intrafamilial 19(19%) 1(11%)
Malehomosexuality 6(5%) 4(44%)
Unknown 74(67%) 2(22%)
WBCcount(×10
9
/l) 5.9 (1.8) 5.5(1.7) NS
Plateletcount(×10
9
/l) 156(47) 163(61) NS
AST(IU/l) 70(54) 63(29) NS
ALT(IU/l) 125(118) 111(91) NS
Ş-glutamyltransferase(IU/l) 45(47) 28(7) NS
Bilirubin(mg/dl) 0.8(0.3) 0.6 (0.4) NS
Degreeofhistologicalactivity NS
Mildhepatitis 16(23%) 2(29%)
Moderatehepatitis 22(31%) 1(14%)
Severehepatitis 22(31%) 3(43%)
Livercirrhosis 8(11%) 1(14%)
Othervirologicalmarkers NS
HBV-DNApositive 64(63%) 4/9(44%) NS
Anti-HDVpositive 2(2%) 1/9(11%) NS
Anti-HCVpositive 11(13%) 2/9(22%) NS
Quantitativevariablesareexpressedasmean(SD).Categoricalvariablesareexpressedasn(%).
Table3 Baselinefeaturesofpatientswithlivercirrhosisandhepatocellarcarcinoma
accordingtothepresenceorabsenceofHGV-RNAsequencesinserum
Characteristics
HGV-RNA
negative(n=131)
HGV-RNA
positive(n=5) pValue
Age(y) 64(9) 57(9) NS
Sex(male/female) 88/43 3/2 NS
Aetiologyofcirrhosis NS
Alcoholic 11(8%) 1(20%)
HCVinfection 78(60%) 2(40%)
HBVinfection 4(3%) 0
HCVandHBVinfection 5(4%) 0
AlcoholicandHCVinfection 20(15%) 1(20%)
AlcoholicandHBVinfection 2(2%) 0
PBCandHCVinfection 0 1(20%)
Cryptogenic 11(8%) 0
Presumedsourceofinfection NS
Bloodtransfusion 35(27%) 4(80%)
Unknown 96(73%) 1(20%)
WBCcount(×10
9
/l) 5.9(4.1) 5.4(2.4) NS
Plateletcount(×10
9
/l) 107(53) 107(58) NS
AST(IU/l) 115(130) 149(120) NS
ALT(IU/l) 106(117) 158(121) NS
Alkalinephosphatase(IU/l) 290(239) 247(119) NS
Ş-glutamyltransferase(IU/l) 118(145) 149(114) NS
Bilirubin(mg/dl) 2.2(2.2) 3.3(3) NS
Quantitativevariablesareexpressedasmean(SD).Categoricalvariablesareexpressedasn(%).
PBC,primarybiliarycirrhosis.
HepatitisGvirusinfectioninchronicliverdisease 109
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acute and chronic infection in man.
12
The
recent development of sensitive laboratory
techniques for determination of HGV RNA
sequences in clinical specimens has led to
intensive investigation of the frequency and
meaningofHGVinfectionindiVerentclinical
conditions. Despite many eVorts, however,
important aspects of the epidemiology and
pathogenicityofHGVinfectionanditsrolein
acute and chronic liver diseases still remain
obscure.
In the current study we investigated the
presence of HGV RNA infection in a large
seriesofpatientswithavarietyofchronicliver
diseases and in a group of volunteer blood
donors living in the same geographical area.
Themaindemographic,epidemiological,clini-
cal, and histopathological features in HGV
infected and non-infected patients were ana-
lysed.
It is now clear that patients heavily exposed
to blood and blood products,such as haemo-
philiacs, thalassaemics, and liver transplanted
patients,
610132122
aswellasthoseathighriskof
parenteral exposure, such as patients on
haemodialysis
23 24
and intravenous drug
users,
325
have the highest prevalence of HGV
infection. These data suggest that parenteral
exposure plays an important role in the
transmission of HGV. This study showed,
however,thatasubstantialproportionofHGV
infectedpatientswithchronicliverdiseasedid
nothaveahistoryofovertparenteralexposure,
suggestingthatHGVcouldalsobetransmitted
by other routes. Furthermore, irrespective of
the clinical or histological diagnosis, most of
thesepatientsalsohadevidenceofinfectionby
other parenterally transmitted hepatotropic
viruses,suchasHCV,HBV,orboth,suggesting
that HGV may also spread through non-
apparent parenteral exposure. Interestingly,
fouroftheninepatientscoinfectedwithHGV
andHBVweremalehomosexualsanddidnot
have associated risk factors. This observation
suggests that HGV may be sexually transmit-
ted,asrecentlyreported.
25
Despite a similar epidemiological back-
ground, the prevalence of HGV infection in
patients with chronic hepatitis C observed in
thisstudywasapproximatelytwotimeshigher
than that in those with hepatocellular carci-
noma, most of whom were also infected with
HCV.ThereasonforthisdiVerenceisunclear.
Onepossibleexplanationcouldbethatchronic
HGVinfectionmaysubsidewithtime,leading
toclearanceofHGVRNA,asseemstooccurin
patientswithhaematologicaldisorders
6
andin
intravenousdrugmisusersinfectedwithHIV.
25
This is likely because the patients with cancer
wereolderand,possibly,hadmorelonglasting
viral infection than those with chronic hepati-
tis. The observation that HGV RNA was
detected in young rather than in middle aged
blooddonors,furthersupportsthishypothesis.
Data on the pathogenic eVects of HGV are
controversial.HGVinfectionistheonlyagent
identifiedinsomepatientswithacutesporadic
non-A, non-E hepatitis,
2
idiopathic fulminant
hepatitis,
78
or cryptogenic chronic liver
disease.
14
Studies in blood donors
2
and in
haemodialysis patients,
423
however, have
clearlyshownthatHGVinfectionisfrequently
foundinsubjectswithoutclinicalorbiochemi-
calevidenceofliverdisease.Inarecentstudyin
haemodialysispatients,HGVinfectedpatients
didnotusuallypresentwithliverabnormalities
except if coinfected with other hepatotropic
viruses.
24
Mild elevation of ALT is often found in
HGV infected blood donors.
2
In this study, a
minimalelevationofALTwasobservedinone
of the six blood donors in whom HGV RNA
was detected in serum, but this abnormality
was also observed in a similar proportion of
HGV non-infected donors and may be a
non-specificfinding.
In agreement with previous observa-
tions,
18 26 27
infectionwithHGVdidnotappear
to increase the severity of liver lesions in
patients with chronic liver disease resulting
from HBV or HCV infection. On the other
hand, there is increasing evidence indicating
thatcoexistingHGVinfectiondoesnotappear
tomodifytheresponsetointerferoninpatients
withchronichepatitisC.
18 26 27
Thesedatasup-
portthehypothesisthatHGVcoinfectiondoes
not play a relevant role in the pathogenesis of
HBV or HCV induced chronic liver disease.
Further evidence against the pathogenicity of
HGV was recently provided by a study of
patientswithacutepost-transfusionalhepatitis,
showing that combined infection with HGV
andHCVdidnotproducemoreseverehepati-
tisthaninfectionwithHCValone.
28
Although HGV infection often becomes
chronic, chronic hepatitis does not appear to
develop in subjects persistently infected with
HGValone,asrecentlyshowninpatientswith
acute non-A,non-E hepatitis.
29
In the current
study,theprevalenceofHGVRNAinpatients
withchronicliverdiseaseunrelatedtoHCVor
HBV infection, including patients with cryp-
togenic disease and patients with cryptogenic
cirrhosis and hepatocellular carcinoma, was
similar to that observed in healthy volunteer
blood donors and in patients with alcoholic
liverdisease.Thus,HGVdoesnotseemtobe
involved in cryptogenic liver diseases in our
geographicalarea.
Supportedinpartbygrants94/098fromFISoftheMinisterio
de Sanidad and SAF97-0103 from CICYT. M Guilera, F X
López-Labrador, E Olmedo, and S Ampurdanés were sup-
portedbyFundacióPrivadaClínic.
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HepatitisGvirusinfectioninchronicliverdisease 111
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doi: 10.1136/gut.42.1.107
 1998 42: 107-111Gut
 
M Guilera, J C Sáiz, F X López-Labrador, et al.
 
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Hepatitis G virus infection in chronic liver
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