Hepatitis delta infections in Toronto , Ontario

ABSTRAr::'T: This study assessed the prevalence of hepatitis delta virus infection, rhe relation of this infection to the clinical and histo logical status and ro the geographic origin of216 patients with hepatitis B virus infection in Toronto, Ontario. Evidence of delta infectio n was present in 13 of the 2 16 patients ( 6.0%). It was more common in patients wirh acure hepatitis ( 11.1 %) and with chronic hepatitis ( 16.7%) tha n in asymptomatic carriers (3.6%). It was not present in rhe three patients with hepatocellular carcinoma. The clinical course of the two patients with acute hepatitis and delta markers was si milar to patients with hepatitis B alone and both made a complete recovery. Of the five patients with chronic liver disease a nd delra markers, three had severe chronic active hepatitis. Three of the 13 patients with delta infection were born in Canada. All three patients were intravenous drug abusers. Of the 10 patients not born in Canada, eight were immigrants from countries where de lta infection is endemic. The remaining rwo were from West Germa ny and China. From this study irwasconcluded that, in Toronto. delta infection was mo re common in patienrs with acute and chronic hepatitis B than in asymptomatic carriers. Patients with both acute hepatitis Band delta in fection had a similar clinical course to patient~ with acute hepatitis B alo ne. Patients with ch ronic hepatitis B and delta infection frequently had severe chronic active hepatitis. In Canadian-born patients delta infection was present in intravenous drug abusers o nly. Most imm igrants with evidence o f delta mfcction came from countries where delta is endemic. Can J Gastroen terol 1988; 2(4): 151-5

T HE HEPATITIS DELTA VlRUS (HDV) lS an incomplete virus requiring the helper function of the hepati tis B virus (HBV) for its expression ( 1.2).HOV can infect a nonimmune host sim ul taneously with H BV (coinfection) or infect an hepatitis B surface an tigen (HBsAg) carrier causing an acute, ch ronic or asymptomatic illness (superinfection).Following the introduction of sensitive methods for detecting HOV antigen and its antibodies it became apparent that HDV infections originally described in southern Italia ns arc worldwid e (2.3).Endemic areas of HDV exist in the eastern Mediterranean a rea, the Middle East, some areas of Africa (4).among the Yucpa Indians in Venezuela (5) and in th e Nauru and oche r isla nds of the western Pac ifi c (6).In western and northern Europe and in the Un ited States, HDV infec ti ons occur mostly in pa renteral drug abusers and hemoph ili acs (7-ll ).
HDV infections arc rare among Chinese, despite a high HBsAg carrier rate ( 12).
The a ims o f th is study were to estimate the prevalence of HOV infection in patients with various types of HBV related liver disease in Toronto, On ta rio and to correlate the presence of HOV infection with the cl inical and histological status of the patients and with their geographic origins.

PATIENTS AND METHODS
Two hundred and sixteen H BsAg positive patients were included in the study (Table 1).Of the 216, 18 had acute h epatitis B. 30 had chronic liver disease, th ree patients had hepatocellular carcinoma and 165 were asymp tomatic HBsAg carrier:,.Of the patients with chronic liver disease, seven had chro nic persistent hepatitis, 17 chronic active hepatitis and six patients had cirrhosis.
Of the 18 patients with acute hepatitis, two were intravenous drug abusers and one of them was homosexual.All patients with chronic hepati tis, cirrh osis and hepatocellular carcinoma had liver b iopsies.H istological interpretation was in accordance with the Fogerty classification ( 13 ).All the asymptomatic carrie rs had no cl inica l evidence of live r disease and had persisten tly normal liver fu nction tests for at least six mon ths.and those with chronic liver disease were :,een monthly.Liver biopsies were performed wh en clinically indicated and delta determinations were done within three to six months of the liver biopsy.Labo ratory tests: Hepatitis B surface antigen, anti-HBsAg .anti-HB core antigen, hepatitis Be antigen, anti-hepatitis Be and lgM anti-H Bc tests were done by commercially available RIA kits (Abbott Pharmaceutical.North Chicago, Ill inois).
Antidelta was measured by the comme rcially avai lable antidelta RIA k it (Abbott P harmaceutical Laboratories) and by blocking RIA in the Division of Molecular Biology and Immuno logy, Georgetown U n iversity.The delta a n tigen was measured by a blocking RIA also at Georgetown Un iversity.A ll sam p les were ana lyzed under code.

RESULTS
Thirteen of th e 216 patients (6.0%) were found to have antidelta in their sera.The distribution of antidelta in the various types of HBV liver disease is shown in Table 2.
rwo were found to have delta coinfection One had delta antigen in th e scrum in the first week of illness and one had high levels of antidelta in the second week of the illness.Both we re Canadian-born and both were intravenous drug abusers; one was homosexual.There wasno difference between the clinical presemation of the two patients who were anndelta positive and the 16 who had no evidence of HOV infection.There were no chronic sequelae in either the 16 patients with acute hepa titis B or the two patients with coincident HOV infcc• cion.The only fatal case was negative for H OV infection.Patie nts w ith c hronic live r disease: Five of th e 30 patients ( 16.7°'o) with ch ronic liver disease had evidence of del ta infection .One of seven patients wi th ch ronic persistent hepatitis had antidelta in the serum; this patient had immigrated from Africa.T hree of the I) patients with chronic active hepatitis had antidclta in the serum; one w::i.sfrom Italy, one from Malta and one was Canadian• born.The Canadian-born patient was an intravenous drug abuser.All three patients had very severe chronic active hepatitis on liver biopsy.One of the six patients with cirrhosis had an tidclta in th e serum.This patient came from Ger• many, a country where H OV is not e ndemic.The patient denied intravc• nous drug abuse.
A symptom atic c arrie rs: Six of 165 carriers (3 .6%)had evidence of HOV infection.Five of the six carriers were from a group of 108 who were born in areas where HO V is endemic.Two were T he patients selected for study h ad all been referred to the Liver Study Un it at Mount Sinai Hospital, Toron to.The 165 asymptomatic carriers were selected from an HBsAg carrier clinic which has been following 600 carriers for many years.A ll patients who attended the clinic over a period o f n ine mo n ths were tested for antibody to HOV.T hese patients were evaluated every fou r mon ths and have been followed for at least three years.The patients with acute and ch ronic liver d isease were th ose seen in the liver clinic over a period of nin e mo nths.Patients with acute hepatitis were seen weekl y

DISCUSSION
The prevalence of HOV infection was 6':o in the 216 patients studied.The three patients in this study who had evidence of HOV infection and who were born in Canada we re all intravenous drug abusers.The majority of patients (eight of 10) with HOV infection who were born outside of Canada came from cou ntries where HOV infection is endemic.None of these were drug abusers.A previous Canadian study also fo u nd ch at, where HOV infection was present, it was almost exclusively in immigrants from countries where HOV infection is en-demic{l4).ln chacscudy, serum ancidclca was done in 326 HBsAg positive patients.The group consisted of 216 Indochinese refugees, 46 patients with acute hepatitis, 39 blood donors and 25 patie n ts at high risk fo r hepatitis (homosexuals, patients with hemoph ilia and drug abusers).Eight serum samples were positive for antidel,., (2.4%).Seven were from Indochinese refugees whose samples were obtained on arrival in Can ada and one from a homosexual male with no history of drug abuse.This was a serological survey only and the cli n ical and histological status of the immigrants was not mentioned in the report ( 14).
The high prevalence of antibody to  In endemic areas HOV is also common in the absence of intravenous drug abuse and in these areas transmission may be by inapparent permucosal or percutaneous routes (20).
The acute ill ness in the patients in th is study with HBV and HOV coinfeccion was not more severe than in che 16 patients who had hepatitis B alone and no patient in either group developed ch ron ic hepatitis.Oth er studies have shown that acute coinfeccion with HBV and HOV does not result in chronic hepatitis more commonly than in patients who have acute hepatitis B alone ( 18,21).The reason for chis is chat when HBV and HDV infection are acqui red simultaneously, che HDV infection cannot outlast the HBV infection (22).ln this study, the patient with fulminanc hepatitis had no markers of HOV infection.However, other studies have shown a h igh prevalence of delta markers in patients with fulm inant hepatitis (5,23).This is not a universal fi nding.In a report from the Mayo Clinic none of eigh t patie n ts with fulminant hepatitis had delta markers ( 15).Chronic HOV infection is seen more commonly when HOV infection is superimposed on chron ic HBV infections than when coinfection occurs.Superinfection in an H BsAg carrier may be subclinical or present as acute hepatitis.It frequen tly causes progression of liver injury and an asymptomatic carrier or one with chronic persistent hepatitis can be converted to a carrier with chronic active hepatitis and cirrhosis (24).ln patients with chronic delta hepatitis, chronic active hepatitis is che most common histological lesion seen (22.25).In the present.studyfive of 30 patients with ch ronic hepatitis B had evidence of delta infectio n .Three of the five had chronic active hepatitis and all three had severe disease o n liver biopsy (Table 2).
There is considerable difference in the prevalence of delta infection in ch ro ni c live r disease in different pares of th e world (Table 3).ln countries with a low prevale n ce of delta infection, such as West Germany ( 19) and C h ina ( 12,26), delta infection in patients with chron ic liver disease due co HBV is uncommon, while in endemic areas, such as Italy (27), it is common.The reasons fo r the difference in prevalence of HOV markers in patients with chronic acti ve hepati tis in ch e reported studies are not known.They may be related to difference in freq uency of drug abuse, the geographic origin of the patients or the extent of liver damage prior co the delta superinfection.le is evident chat HOV superinfection of patien ts with ch ronic hepatitis B is an im portant contribu tor to chronic liver d isease in some pares of the world but plays a negligible role in ocher areas.
The n umber of patien ts with cirrhosis and hepatocellu lar carcinoma in chis study was too small to estimate the importance of HOV in fectio n in thei r pathogenesis.In a nother stu dy, coincident HDV infection did not appear to increase FEINMAN ct a/ rhc frequency of hepati tis B rdatcd carcinoma (28).
In the asymptomatic carriers in this study, 3.6% haJ HDV markers.The p revalence of HD V markers in !08 patients born in countries with a high prevalence of H OV was 4.6"(,.This approximates the pn:valcncc in asymptomatic HBsAg carriers in an en d em ic a rea suc h ns I ta ly (6.4''.,) (28).In 57 patien ts born in countries wirh a low prevale nce it was on ly l. 7"t ACKNOWLEDGEMENTS: The authors thank the Mount Sinai Research lm titutc for their supr on, Joan Freeman and Florence Strain for secretarial assistance and Thelma Berris for editorial advice.

TABLE 1
Geographic origin of 216 patients and type of hepatitis B virus liver disease Geographic origin Number AS CAR ACHEP-B CPH-B CAH-B CIRR-B HCC-B Prevalence of delta infection in various types of hepatitis B virus liver disease CPH Chronic oersistent hepo/1/is.CAH Chronic active hepotifis

TABLE 3
Comparison of prevalence of delta infection in various c ountries Swed en (7 ).Germany ( l9), the USA (4,22) an d Ch in a ( 12,29) (Table3).Th e asymptomat ic Elle ecait p lus coura ncc chez Jes pa tients Sou ffrant d'hepatite a igue ( JI.! %) Ct d'hepati te chro n ique ([6.7%) que parmi Jes porteurs asy m ptomatiques (3.6%).Elle e ta it absentc chez les trois patients atteints d e carcinomc hcpatoccllu laire.L'cvolurion cliniq ue des deux patients attein ts d'hepati te aiguc er porccurs de marque u rs delta eta it similai re a ccllc des patients atteints d 'hepatite B se ulemcnt et tous deux se sontco mplerc me nt re ta blis.Des cinq patients attein ts de maladie chron iq uc du foie avec marque urs delta, troi::, souffraient d'hepatite severe Th e two patients with acute hepatitis B and delta infection had a si mila r clinical course to the patients with hepatitis B alone and had no seque lac.ln patients with chronic hepatitis B, HOV infection was fre-Epide mio logic reports: Prevalence of delta agent infection in Canada.Can Med Assoc J 1986; !'34:375.15.Shiels MT.Czaja AJ, Taswcll HF. et al Frequency and significance of delta antibody 111 acute and ch ronic hcrmitis B A United States experience.De Cock KM, Govind araja n S. Chin KP.Redccker AG.Delta hepatitis 1n the Los Angeles area.A rcpurt of 126 cases.Ann Intern Med 1986; 105: 108-14 18. Mocstrup T, Hansson BG, Widell A, Norden felt E. Clinical aspects of delta A low p reva lence of H OV infection in asymptomati c carriers ha s been reported from France (6), patients atteints a la fo is d'hepatite a ig ue B ct d'infection delta, la maladic suiv aic unc evolu tion clin iquc se mblable a cellc des sc ules he patitcs B aigues.Les patients souffranc a la fo is d'hcpatite chroniqu c B ct d'infeccion delta avaien t fre qu emme nt une hepatitc evolutive chronique severe.Parm i Jes patie nts ca nadi e n s d'origine, !'infection delta n'eca it presence que chcz les d rogu es u rilisant !es inrraveneuses.La plu parc des immigrants ch ez qui se manifcstait unc infectio n delta venaient d e pays ou e lle est c nde miqu c. 154 asympto m atic car riers.l 4 infection.Br Med J (Clin Res ) 1983;286:87-90.19.RoggendorfM.Gmelin K. Zoulek C. et al Epidemiological studies on the prevalence of hepatitis delta virus