immunology in heroin addicts

7/28/2019 Immunology in Heroin Addicts

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Immunological Studies of Heroin Addicts * Jitra Ratanavongsiri, M.Sc.Wattana Pan muong, B.Sc.Praphan Phanuphak, M.D., Ph.D.

Heroin addiction is one of the majo r socio-medical problems facingmany nations around the world. Infectious complications are by farthe most serious medical problemsfrequently encountered by intravenous heroin users; such complications include infective endocarditis, lung abscess and septicaemia.In addition, non-infectious complications such as vasculitides/,3 nephropathy4, s and chronic hepatitis6have been reported occasionally.The incidence of various biochemical and immunological abnormalities in a large group of otherwiseasymptomatic heroin' addicts hasbeen occasionally reported such asthe isolated reports of carrier statesofHBsAg,7 elevated liver enzymes,Shyper-IgM,9 circulating immunecomplexes,1O sterile pyuria 11 andauto-antibodiesY None 0 f theseabnormalities has ever been relatedto one another or correlated withother clinical findings .

We report here the biochemicaland immunological changes in 167asymptomatic Thai heroin addictsin relation to their preferred rou tesof heroin intake (i.e., intravenouslyor by smoking) and to their generalmedical health . The results indicatethat the choice of route for heroinintake has implications with regardto different impacts on the biochemical and immunological changes inthe addicts and these may play arole in the pathogenesis of someliver and renal complications seenin these addicts .

SUMMARY Combined clinical, biochemical and immunological studies werecarrried out on 167 heroin addicts who were attending drug dependence treatment centres in and around Bangkok. One hundred and twelve of these weretaking the drug by intravenous (I.V.) means and 55 by smoking it (i.e., theynever injected heroin). Addicts comprising the smoking group had a significantly higher incidence of past respiratory illnesses although almost all of theaddicts were quite healthy at the time they were being interviewed owing to thenature of the out-patient type clinic that they were attending. Asymptomatic(and probably sterile) pyuria was found in as high as 25.5 per cent of the smoking group and in 10.7 per cent of the I.V. group. Elevated serum glutamic oxaloacetic transaminase (SG On was found in 59.3 per cent of the I.V. group, asignificantly higher level than the 26.9 per cent of the smoking group. The reason for the asymptomatic hepatic enzymitis is at present unknown, but it persisted even after the cessation of drug usage. It may represent a form of autoimmune chronic hepatitis. Contrary to the findings of other reports, we foulUino increased incidence of hepatitis B virus infection among Thai addicts. Circulating immune complexes (CIC) as measured by liquid-phase C1 q-binding assaywere positive in 40.4 per cent of the cases in the I.V. group, but only in 13.9per cent of those in the smoking group (P < 0.01). The prevalence of CICamong the intravenous heroin users was confirmed by the higher incidence ofrheumatoid factor and cryoglobulinaemia in the I.V. group. Such complexes probably can activate complement as evidenced by the prevalence of hypocomplementaemia in the I.V. group. However, the clinical significance of these immunecomplexes remains uncertain. They may playa role in the hepatic enzymitisand inthe few cases of nephritis observed. Serum IgM levels were significantly elevatedin the I.V. group, but the incidence of other auto-antibodies was not increased.

The reason for these immu no logical dysfunctions among the intravenousheroin users remains conjectural. We postulate that parenterally administeredheroin or its impurities may act as a polyclMal B-cell activator, resulting inhyper-lgM and the formation of circulating immune complexes, rheumatoidfactor and cryoglobulins. This does not happen in the smoking group due to inadequate absorption or rapid inactivation via the respiratory tract. This hypothesis of heroin as a B-cell mitogen can be tested experimentally.

ASIAN PACIFIC J ALLERG IMMUN 1984; 2: 241246.MATERIALS AND METHODS *From the Department of Microbiology and

Patients Medicine, Faculty of Medicine, ChulalongkomUniversity, Bangkok 10500, Thailand.One hundred and sixty-seven Supported in part by a Rachadapiseksompoj-heroin addicts who were voluntarily China Medical Board Grant.241


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242attending drug dependence treatment centres in and around Bangko k were studied. 3 They were divided into two groups according tothe route of heroin intake. The intravenous (LV.) group, comprising112 patients (108 males and 4females) ranging in age from 17 to64 years (x SD = 29.6 9.0),was composed of addicts who regularly took heroin by I.V. injection. The smoking group , consisting of 55 patients (49 males and 6females) ranging in age from 14 to70 years (x SD = 35.7 17.8),comprised a ddicts who regularlytook heroin only by inhalation and/or ingestion, bu t never by injec tion.The drugs used by this latter groupwere heroin, opium and marijuanain 80 per cent, 16.4 per cent and3.6 per cent of cases respectively. 13The mean duration of heroin addiction of the LV. group was 6 .2 years(SD = 5.4) whereas that of thesmoking group was 8.3 years (SD =9.3). Patients who had been addicted for less than one month or wh ohad already stopped taking the drugfor over a week were no t studied.The money spent on drug , an indirect indicator of the amount ofdrug being consumed, was not significantly different between the twogroups of addicts (i.e., 135 115Baht per day in the LV. group ascom pared to 107 99 Baht in thesmoking group).13 Each addict wascarefully examined and interviewedabout any past medical problemsoccurring in the past two years, particularly those pro blems whichoccurred after addiction .Laboratory studies

Following medical interviews andphysical examination , urinalysiswas performed and blood sampleswere obtained for renal and liverfunction tests as well as several immu no logical s tudies.

The immunological studies consisted of qualitative and quantitativedetection of cryoglobulinaemia,14rheumatoid factor activity by latexfixation slide testiS using humangamma globulin-coated latex parti

cle (Hyland Diagnostic, Deerfield,Illinois, U.S.A.), haemolytic complemen t activity (CH50) according tothe method ofMayer,16 quantitativedetermination of C3 and C4 byradial immunodiffusion test usingantisera and standard C3 and C4 aspurchased from Hyland Diagnostic.Hepatitis B surface antigen (HBsAg)was detected by reverse passivehaemagglu tination test using hepatitis screening kits from WellcomeResearch Laboratories, Backenham,England. Circulating immune complexes (CIC) were quantified byliquid-phase C I q-binding test asdescribed by Zubler et at. 17 SerumIgG, IgA and IgM were measured byradial immunodiffusion test usingstandard antisera purchased fromHyland Diagnostic. Antibodies tonuclear antigens, smooth muscleantigens , mitochondria , reticulinand ribosome were done by indirectimmunofluorescent test as previously described. ISSera from 110 blood donors(108 males and 2 females) wereused as normal controls for variouslaboratory tests as mentionedabove. These were voluntary blooddonors and to the best of ourknolwedge, none took drug intravenously.

RESULTS1. Circulating immune complexes(CIC)

Thirty-six of the 89 LV. heroinaddicts (40.4% of the total) hadelevated CIC as determined byliquid-phase C Iq-binding test,which was significantly higher thanthe incidence in the smoking group,i.e ., five out of 36 cases or 13.9 percent of the total (p < 0.001) . Themean CIC level (% of C 1q-binding)of the LV. addicts as a groupwas also significantly higher thanthat of the smoking group; theCIC level of the latter goup was notsignificantly different from thenormal controls (Fig. 1).

RATANAVONGSIRI. ET AL.

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Fig. 1 Levels of Circulating immune complexes in heroin addicts as determined by liquid-phase Clq binding assay. Mean and standard deviation of each group are represented by the vertical bars. C 1q binding levels of more than 12.4% (mean + 2 s.d .) were considered abnormal.

2. CryoglobulinsCryoglobulins were detected in

27.3 per cent (30/110) of the LV. addicts, slightly higher than that found in the smoking group (II/54 or 20.4% of the total) . The levels of the cryoprecipitates in the two groups also were no t significantly different, i.e. , 0.140 0 . 162 mg/ ml in the l.V. group as compared with 0 .051 0 .056 mg/ ml in the smoking group. Nevertheless, the composition of the washed cr)roprecipitates differed considerably in each of the two groups. Among the 23 cryoprecipitates from the l.V. group available for analysis, 17 were composed of both IgG and IgM , one each contained only IgG or IgM whereas no immunoglobulin cou ld be id en tified in the remaining fou r. Analysis of 10 cryoglobulins from the smoking group revealed pure [gG in five of the subjects, [gG and IgA in one of them and no immunoglobulins in the other four. Rheuma toid factor activi ty could be detected in three cryoglobulins ti lfrom the LV. group, but not inthose from th e smoking group.
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243MMUNOLOGICAL STUDIES OF HEROIN ADDICTS

3. Complement levelsTotal haemolytic complementactivity (CH50) was low in 23 of

the 112 LV. addicts (20.5% of thetotal), significantly more frequentthan the smoking group (i .e., 4 ou tof 55 or 7.3% of the total, p


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244 RATANAVONGSIRI, ET AL. ,Table 1 Incidence of abnormal liver and renal function tests in heroin addicts

P value by ChiSmoking square testTests Normal values LV. addictsaddicts comparing twogroups of addicts

Liver funct ion testsTotal bilirubin 0 .2 - 1.0 mg/dl 4/108* (3.7%) 0/52 (0%) N.S.** SGOT < 20.5 u/l 64/108 (59.3%) 14/52 (26 .9%) < 0.005t Alkaline phosphatase 20 - 48 ujl 10/108 (9 .3%) 4/52 (7.7%) N.S.t t

Renal function testsBUN 15 - 38 mg/dl 0/102 (0%) 0/55 (0%) N.S.Creatinine 0 .8 - 1.5 mg/dl 3/102(2.9%) 1/55 (1.8%) N.S.Glucosuria Negtrace 0/112(0%) 0/55 (0%) N.S.Albuminuria Negtrace 10/ 117 (8.9%) 1/55 (1.8%) N.S.Microscopic haema t uria ~ 5 rbc/HD and 5/112 (4 .5%) 6/55 (10.9%) N.S.

female, notmenstruating

Microscopic pyuria ~ 5 wbc/HD 12/112 (10.7%) 14/55 (25.5%) < 0.025"number abnormal per nwnber tested.

**no significant difference. t mean S D of SGOT in the I.V. group = 34.1 27.8 u/I as compared with 21.6 14.7 u/ l in the smoking group (p


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245MMUNOLOGICAL STUDIES OF HEROIN ADDICTShigher incidence and higher level ofcirculating immune complexes(CIC) than did th e group whichnever took heroin parenterally (thesmoking grou p). This may be dueto the more direct and heavier antigenic challenge of th e immunesystem by intravenous injection ofheroin or the impurities in theheroin. Circulating immune complexes have been similarly described in 40 per cent of LV. heroinaddicts using Raji cell assay.IO Inaddition, our study indicates thatnon-parenteral a dministra tion 0 fheroin was no t associated wi th anincreased level of CIC. In many instances in our study , the presenceof CIC was further supported bythe simultaneous presence of cryoglobulins and rheumatoid factor,both of which were considered asthe indirect evidence of circulatingimmune complexes .19The l.V. addicts also had a significantly higher incidence of lowCH50 than did the smoking addicts.This may reflect complement activation by the CIC present in LV.addicts. Howe ver, a !though themean C3 level in the I. V. group wassignificantly lower than that of thenormal controls , it was significantlyhigher than that of the smokinggroup. The reason for such a discrepancy between the CH50 and C3levels is unclear. It could no t beexplained as being a result of mishandling of the serum specimensbecause six ou t of seven addictswho initially had low CH50 continued to have a low level 6-9months later. The mechanism ofhypocomplementaemia in heroinaddicts remains speculative. It maybe due to complemen t act iva tionvia the immune complexes, i.e.,classical pathway activation or viathe alterna te pa thway similar to thecase of radiocontrast media20 especially with our finding that C4levels were not decreased in any ofthe addicts. It would be of interestto measure the levels of C I q andfactor B in the heroin addicts alongwith the measurements of C3 , C4and CH50. In addition, the hypo

complementaemia may also be dueto decreased synthesis of complemen t componen ts or due to increased complement catabolism as a result of heroin administration .

The clinical significance of theaforementioned immunologicalabnormalities in heroin addictscould not be assessed in our studydue to the ambulatory type oftreatment centres from which werecruited our addicts. Most of theaddicts under study were in reasonably good health during the time ofexamination. In the LV. group,there was no increased incidence ofthe immune complex-mediated diseases such as glomerulonephritis ,arthritis or vasculitis. Nevertheless ,both patients in the l.V. group whohad a well-established history ofnephritis within two years prior tothe study were found to haveabnormal urinalysis, hypocomplementaemia, rheumatoid factor ,cryoglobulins and CIC. These findings indicated that both patientscontinued to have active immunecomplex-mediated nephritis. Theseabnormal findings persisted for upto six and eight months later whenthey returned for follow-up. It wasunfortunate that permission for akidney biopsy was not given byeither pa tient. On the other hand,another patient with a past historyof nephritis who belonged to thesmoking group did no t have anyabnormal urinary or immunologicalfindings as did those in the LV.group . Therefore , although the clinical significance of CIC and hypocomplementaemia remains unclearin most heroin addicts, CIC andhypocomplementaemia may contribute to the immunopathogenesis ofnephritis in some addicts.

Although only one addict in thel.V . group had clinical jaundice,59.3 per cent and 26 .9 per cent ofthe LV . and smoking groups respectively had elevated SCOT. Ourfindings are consistent with thoseof Ortona et afl who found that 41of their 82 LV. heroin addicts (50%)had elevated SCOT. Ten of the 14LV. addicts whose initial SCOT

levels were elevated were againfound to have elevated SCOT whenthey returned fo r follow-up 6-9months later. Seven of these10 addicts reported completeabstinence from heroin usage. Ourfindings of persistent asymptomatic hepatic enzymitis monthsafter cessation of drug abuse confirm those of previous reports. 6 ,8,22The cause of such asymptomatichepatic enzymitis in heroin addictsremains unknown . Its relation toviral hepatitis has been argued. 6To our surprise, we did no t findan increased incidence of the carrierstate of HBsAg in ou r heroinaddicts as reported by others.7This may be because Thai addictsare using more highly purifiedpreparations of heroin as a resultof easier access or it may be because they can purchase cleansyringes and needles more easilythan addicts in the U.S .A. In addition , the chronicity of abnormalliver enzymes, despite a cessation ofdrug abuse, may point to the process of auto-immune chronic hepatitis as its cause.Microscopic pyuria was found in10.7 per cent and 25 .5 per cent ofthe LV. and smoking addicts respectively. Our incidence is comparable to the 20 per cent incidenceof asymp toma tic sterile pyuria reported by Cherubin . 1I Althoughurine culture was no t performed inour study, we believe that th epyuria in our patients was alsosterile pyuria because none of ou rpatients had urethral discharge orany symptoms of urinary tract infection, no significant bacteriuriawas found and the pyuria was no t acontamination of vaginal dischargesince all the patients with pyuriabu t one were males . We did no tknow what was the cause of thepyuria although chronic interstitialnephritis was suspected . Renalbiopsy may help to answer thisquestion.

Our findings of high serum IgMlevels in th e LV. heroin addicts support the earlier findings of Brown

23et al. The smoking addicts had
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246nonnal serum IgM levels; this finding is similar to those of Blancke ta l.9 We postula te tha t heroin orthe impurities in the heroin may actas a polyclonal B cell activator onceintroduced into the circulation. InI.V. addicts, it will then inducehyper-IgM, rheumatoid factor,cryoglobulins and CIC. This wouldalso explain the high incidences ofanti-smooth muscle antibodies andanti-lymphocyt e antibodies in LV.heroin addicts reported by Husbyet at. 12 However, no increase in theincidence of various auto-antibodieswas found in our study . The possibility of heroin as a poly clonal Bcell activator is being tested in ourlaboratory.

ACKNOWLEDGEMENTSWe gratefully acknowledge sup

port provided through a Rachadapiseksompoj-China Medical BoardGrant. We deeply thank Drs. Pirayos Trongsawad, Orasa Aphaivong,Aroon Chaowanasai and ThongchaiOoneglarp for allowing us to studythe addicts at the various treatmentcentres. We also thank Miss AroonPrakobkamdee for her excellenttechnical help and Mrs. VallapaKaowmora 10 preparing the manuscript.

REFERENCES1. Louria DB, Hensle T, Rose J . The major

medical complications of heroin addiction .Ann Intern Med 1967; 67 : 1-22.

2. King] , Richards M, Tress B_ Cerebralarteritis associated with heroin abuse. Med] Aust 1978; 2:444-5.

3. Gendelman H, Linzer M, Barland P, Bezahler GH. Leukocytoclastic vasculitis in anintravenous heroin abuser . NY State] Med1983;83:984-6 .

4. Llach F, Descoeudres C, Massry SG_Heroin associated nephropathy: Clinicaland histological studies in 19 patients. ClinNephrol1979; 11 : 7-12 .

5. Cunningham EE , Brentjens ]R , ZieleznyMA, Andres GA, Venuto RC. Heroinnephropathy . A clinicopathologic and epidemiologic study . Am ] Med 1980; 68:47-53.6 . Kaplan K. Chronic liver disease in narcoticaddicts. Am] Dig Dis 1963; 8 :402-10.

7. Stimmel B, Vernace S, Schaffner F. Hepatitis B surface antige n and antibody. Aprospective study in asymptomatic drugabusers. ]AMA 1975 ; 234 : 1135-8.

8. Potter HP ]r , Cohen NN, Norris RF.Chronic hepatic dysfunction In heroinaddicts . Possible relation to carrier state ofviral hepatitis.JAtvIA 1960 ; 174:2049-51.

9_ Blanck RR, Ream N, Deegan M] . Immunoglobulins in heroin users . Am ] Epidemio11980; 111 :81-6.

10. Bayer AS, Theofilopoulos Al'l, EisenbergR, Dixon F] , Guze LB. Circulating immune complexes in infective endocardits.N Engl] Med 1976;295:1500-4.11 . Cherubin CEo Th e medical sequelae of narcotic addiction. Ann Intern Med 1967; 67:23-33.

12 . Husby G, Pierce PE, Williams RC ]r_Smooth muscle antibody in heroinaddicts. Ann Intern Med 1975;83:801-5.

13. Phanuphak P, Ratanavongsiri], PanmuongW, et aL Socioeconomy and patterns of

RAT ANAVONGS1Rl, ET AL.

drug abuse in heroin and opium addicts.Chula Med] 1982; 26:25365.

14. Mclntosh RM, Griswold WR, CherniackWB, et aL Cryoglobulins III: Furtherstudies on the nature, incidence, clinical,diagnostic, prognostic, and immunopllthologic significance of cryoproteins in renaldisease. Quart ] Med NS 1975; 44:285307.

15. Singer JM, Plotz CM. The latex fixationtest. 1. Application to the serologic diagnosis of rheumatoid arthritis. Am J Med1956;21:888-92.

16. Mayer MM . Complement and complementfixation. In : Kabat EA, ed , Experimentalimmunochemistry, 2nd ed . Springfield,lllinois: Charles C Thomas, 1971 : 133240.

17. Zubler RH, Lange G, Lambert PH, Mi es-cher PA. Detection of immune c0mr.le xesin unheated sera by a modified 12 I-Clqbinding test.] Immunol1976; 116:232-5 .

18. Phanuphak P, Tirawatnpong S, HanvanichM, et aL Autoantibodies in falciparummalaria: a sequential study in 183 Thai patients. Clin Exp Immunol 1983; 53:62733.

19. Kohler PF. Immune complexes and aller'gic disease. In: Middleton E ] r , Reed CE,Ellis E F, eds, Allergy: princip les and practice. 2nd ed. St . Louis: CV Mosby, 1983:167-99.

20. Arroyave CM, Tan EM. Mechanism of omplement activation by radiographiccontrast media . Clin Exp Immunol 1977;29 : 89-94.21. Ortona L, Laghi V, Cauda R. Immunefunction in heroin addicts. N Eng!] Med1979 ; 30 0:45 .

22. Levine RA, Payne MA. Homologus serumhepatitis in youthful heroin users. Ann Intern Med 1960 ; 53 : 164-78.

23. Brown SM, Stimmel B, Taub R.N, KochwaS. Rosenfeld RE. Immunologic dysfunction in heroin addicts. Arch Intern Med1974 ; 134: 1001-6.

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immunology in heroin addicts

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