BRI EF COMMUN l CATION Relapsing hepatitis A infection with immunological sequelae DE&.)RAIIJ. COOK, MD, FRCPC, ROBERT H. RmDELL, MD, FRCPATII, FRCPC, MAX A. CHERNESKY, PHD, RRUNl) J. SALENA, MD, FRCPC, RFNAT<\ SI Al'SYS, PI ID ABSTRACT: The cl ini ca l course of hepatitis A infection is usuall y benign. A patient with persistent anti-hepatitis A virus (HA V) lgM fo ll owing icteric hepamis A, vascu li tis, arthritis a nd peripheral ncuropathy is reported. The clinical, biochemical and serol og i ca l f eat ures of relapsing hepat itis A arc desc ri bed. Can J Gastroenterol 1989;3(4): 145-148 Key Words: C hr onic active h epa cicis, Hepatitis A virus , Relaf,sing hepatitis A Hepatite virale A recurrente et sequelles immunologiques RESUME: L'evo lution clinique d'une h cpa tite v irale A est habitue ll cmcnt benigne. O n rappnrte le cas d'un pa tient chez qui l'on continue a det ec ter Jes lgM anti -I IA V ap rcs une h epatite A icterique, une vasc ularite, unc a rthri te ct une ncuropa thie pe ripheriquc. Les caractc ri stique~ cliniqu es, biochimique6 et ,enilogiques de l'hcpatite A rec ur rentc som J ccritc~. I ?-JFE<...1I ON WIT! I l lEPATI TIS A VIRUS (HA V), unlike hcpatitb R, is unco m- monly assoc iat ed with cxcrahepat 1c manifestations (I). Th e duration of in- fection with HA V i~ variable but brief; liver function tests are usually normal within two month s and c hroni city ha s not been proven (2-4 ). However, re l apsing HA V infection has heen linked LO pcn,i stc nt HA V lgM ant1body (anti-HA V lgM) (5-8). A patient with relapsing hepatitis A infectio n, polyarchritis, vasc ulitis and peripheral neuroparhy, who had pe rsbt- ent anti- I IA V lgM for nine months is described. Deparrmen1., of Gmrroenternlogy and Pachology. Mc Master University Medical Centre; and S1Joseph's Hmprwl, Hamilwn, Ontario Correspondence: Dr D.J. Cook, H oom 1137, McM,mer UniversrL'\' Mediccrl Centre, 1200 ~lam Street We. ,c, Hami/wn , On1arro LRN 325 . Telephone ( 416) 521 -2100 Recervecl fur fmbl1cc1rron ML1rch / 989 . Acce/>ted May 25, / 989 CA~ J GASTRL)ENTl:Rtll Vo1 3 No 4 SEl'TEMlll:R 1989 CASE PRESENT A TlON A 57-year-o lJ Ca ucasian fomali.: developed pu nc.l1ce while 111 La"ire 111 Novemher 1987. Acute I IA V infecti on was confirmed hy positive HA V lgM. When asymptomatic cwo months !mer, the total b il 1rubin was 32 umol/L (nor- m al less than 21 ); asparca te aminotransferase 54 iu/L (normal less than 35); alani ne aminmransfernse 80 iu/L (norma l less than 35); and alkaline phosphaLase 195 1u/L {normal 30 co 120). Four months l ater, the patient was admllted w hospital with a one week hiswry of le ft a nkle arth rit is and lower ext remity skin ra~h. PaH med ica l hi sto ry incl ud ed a bl ood transfusi on 111 1 983 for anemia of unknown ct in logy. There was no pre- vious drug or alcohn l use. Ph ysical cxa mm ation was normal except for a left ank le effusion and pur- p un c, raised erythcmatous lesions over the lower ex t remities (F igure l ). Proprioception, vihracion a nd p111p nck sen sation were impaired in a stoc king distnhlllion and ankle re fl exes were ah- ~cn t. 145
Transcript
BRIEF COMMUNlCATION
Relapsing hepatitis A infection with immunological sequelae
DE&.)RAIIJ. COOK, MD, FRCPC, ROBERT H. RmDELL, MD, FRCPATII, FRCPC, MAX A. CHERNESKY, PHD, RRUNl) J. SALENA, MD, FRCPC, RFNAT<\ SI Al'SYS, PI ID
ABSTRACT: The cl inical course of hepatitis A infection is usually benign. A patient with persistent anti-hepatitis A virus (HA V) lgM following icteric hepamis A, vasculi tis, arthritis and peripheral ncuropathy is reported. The clinical, biochemical and sero logical features of re lapsing hepat itis A arc descri bed. Can J Gastroenterol 1989;3(4): 145-148
Key Words: Chronic active hepacicis, Hepatitis A virus , Relaf,sing hepatitis A
Hepatite virale A recurrente et sequelles immunologiques
RESUME: L'evolution clinique d'une hcpatite vira le A est habituellcmcnt benigne. O n rappnrte le cas d'un patient chez qui l'on continue a detecte r Jes lgM anti-I IA V aprcs une hepatite A ic terique, une vascularite, unc a rthrite ct une ncuropathie pe ripheriquc. Les caractcristique~ cliniques, biochimique6 et ,enilogiques de l'hcpatite A rec urrentc som J ccritc~.
I?-JFE<...1ION WIT! I l lEPATITIS A VIRUS (HA V), unlike hcpatitb R, is uncom
monly assoc iated with cxcrahepat1c manifestations (I). The duration of infection with HA V i~ variable but brief; liver funct ion tests are usually norma l within two months and c hronicity has not been proven (2-4 ). However,
re lapsing H A V infection has heen linked LO pcn,istcnt HA V lgM ant1body (anti-HA V lgM) (5-8).
A patient with relapsing hepatitis A infec tion, po lyarchritis, vasculitis and peripheral neuroparhy, who had persbtent anti- I IA V lgM for nine months is described.
Deparrmen1., of Gmrroenternlogy and Pachology. Mc Master University Medical Centre; and S1Joseph's Hmprwl, Hamilwn, Ontario
Correspondence: Dr D.J. Cook, Hoom 1137, McM,mer UniversrL'\' Mediccrl Centre, 1200 ~lam Street We.,c, Hami/wn , On1arro LRN 325 . Telephone ( 416) 521 -2100
CA~ J GASTRL)ENTl:Rtll Vo1 3 No 4 SEl'TEMlll:R 1989
CASE PRESENT A TlON A 57-year-o lJ Ca ucasian fomali.:
developed p unc.l1ce while 111 La"ire 111
Novemher 1987. Acute I IA V infect ion was confi rmed hy positive HA V lgM. W he n asymptomatic cwo months !mer, the total bil1rubin was 32 umol/L (norm al less than 21 ); asparca te aminotransferase 54 iu/L (normal less than 35); alanine aminmransfernse 80 iu/L (normal less than 35); and al ka line phosphaLase 195 1u/L {normal 30 co 120). Four months later, the patient was admllted w hospital with a one week hiswry of le ft ankle arthrit is and lower extremity skin ra~h.
PaH med ica l history inc luded a blood tra nsfusion 111 1983 for anemia of unknown ct in logy. There was no previous drug or alcohnl use.
Physica l cxammation was normal except for a left ank le effusion and purpunc, raised erythcmatous lesions over the lower ex t remities (F igure l ). Proprioception, vihracion a nd p111pn ck sensation were impaired in a stocking distnhlllion and ankle reflexes were ah~cn t.
145
ClX)Ket al
Figure 1) Confluent /mr/mnc l'nthemawus lesiom over both lower e.xtremllles
Laboratory mvesugawms mcluded hemoglobin of 109 g/L with a mean corpuscular volume of 90.6 IL The platelets, white blrn,d cell count ,ind differential, electrolytes, urea and crcatinin· were normal. Asp,urnte ammorrnnsierase was 3.3 3 iu/L; al.mine ammorransfcrase 2 75 1u/L; gamma glucamyl tramfcrnse 268 iu/L; alkaline pho~phatasc 386 iu/L; and hilirubin 15 umol/L. Scrum iron, fcrritin, vitamin Bl 2, rec.I cell folate, copper and comple-
... • , #
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.. ••
.. ' ' •
Figure 3) The liver biopsy per[ orined four months after the omet of 1a1md1ce shows infiltratwn of a portal tract by nwnonuclear cells with piecemeal necrnm and foci of mfiltrnuon by chrome m{lam, mawry cells wl[hm the lobule~. llemawxylm and eo.1in X 145
ment levels were normal. Rheumatoid factor was positive at 2060 tu/ml hut antinuclear antibody, ant1mitnchondrial antibody, ancismooch muscle antibody and cryoglohulins were negative. Serum lgA wa~ 3.46 g/L (normal O. l 7 to 3.45 ), IgG 33. 3 g/L (normal 6.5 to 15.0) and lgM 2.87 (normal 0.42 to 2.1 ). Hepatitis R surface antigen and antibodies co hepatitis B surface antigen, hepatitis B core antigen, human immunodeficiency virus, cytnmegalo-
' •"' . -' .
••
virus and Epstein Barr virus were negative. The anu-HAV lgM raJ1011nmunoa ssay was positive (Abhntt Laboratories, Chicago, Illinois).
Skm biopsy revealed an intact epidermis; several small dermal arteries showed the features of a leukocycoclas· tic vasculitis with endothelial swelling infiltrated by neutroph1ls. Extravasation of erythrocytes in the perivascular connective tissue was noted (Figure 2).
An abdominal ultrasound and li\'cr spleen scan were unremarkable. A liwr biopsy revealed normal archicecwre,although the portal tracts were expanded by a chronic inflammatory infi ltrate Ill· eluding lymphocytes, plasma cells and histiocytes. There was inflammation across che limiting place with isolation of hepatocytes (Figure 3). The lohules also contained a foca l infiltrate of similar in flammacory eel Is and ncidophi l bodies were identified (Figure 4 ). There was no pericentral loss of
hepatocyres or cholcstasis. Mmimal iron was prcsenr and the diastase-PAS stain showed no evidence of alpha1 anti trypsin deficiency. Sections of li\'er and epidermis stnined for hepac,us A antigen with fluorescenc reagent were negative.
Figure 2) Skm bwpsy showmg leuk11cywc/a1,t1C t•,t1rn/1us Th<! tluckened t'essel wall is mfiltrnted h,, newrnphil /)()lymor{>h.1, some of which are /ra.~mentcd Prnvcisrnlczr extmvasoticm of erwhrncyces i.1 nored. Hemawxylm and e11.1111 X 140
O ne week after hnsp1tal admission, a right wmt and left knee eff us1nn Jcveltlped. The aspartatc amino-
146 CAN J GAsTRt lENTEROL VOi 1 NO 4 Stl'Tl:.1'.llll:R 1989
Figure 4) Pericentral region showingloh11lar infkimmarion w1t/1 chronic injlammmawry cells between ~pawcyte~ and in the sinHS()lili hut wirh nu loss of li.:pawcyre.1 annmd che central t'em. Occasional aculophil hodie.1 are (>re~enc. I lemacoxylin ,md ecmn X 95 5
transferase and abnine aminotransferase increased to greater than 500 iu/L. Prednisone 30 mg daily wa,
prescrihed, symptorm 11nproved nnd th e transamina,e~ hegan to decrease.
rhcum::itnid facror ahsorbent (Cull
Laboratories, Sal t L::ike City, Urnh) faded to reduce the positive counts in the anti -HA V lgM radioimmunoassay. In August l 988, nine months after the onset of jaundice, the anti -HA V lgG
became positive while the anti-HA V
HAVlgM
vasculitis arthritis
Relapsing he patitis. A infec tion
lgM hccame negative ;ind the
rheumatoid foctor disappcmed. Liver function tests in Janua ry 1989 were .ill within norma l limns (Figure 5). The
pa tie n t cont inued tn feel well and returned LO Africa.
DISCUSSION Acute vira l hepatitis A usual ly has a
brief clin ical course. Less than 10% of patients reportedly have elevated transaminases after l 4 weeb and anu -H A V lgM usually disappears hy 120 days (6). H oweve r, in one series, five of 37 patients h,1d persiste nce of this marker
for 200 Jays and anti-HA V lgM has been documented 14 months after HAV infection ( 1,6). Persistent antiHA V lgM may also accompany relapsing hepati tis A (4).
T he rransaminases in the presen t patient rema in e d <! levateJ e ight months after jaundice developed and inc reased dramatical ly with the onset of
arthritis a nd vascul itis. The detection uf anti-HA V lgM (m nme montb strongly suggests th::it relapsing HA V
was responsible. T o exclude the po:,sibility of a fa lse positive anti-H A V lgM test d ue to rheumatoid tactor, preabsn rp ti on of rhc se ra with an ti rheumato id facror w,is performed, which did nnt reduce the counts, cnnf'irrning persistence of th is marker.
HAVlgG
Six wee ks later, th e patie nt presented with epiga,tric pain and a hemoglobin of 73 g/L. Examinat ion revealed a re~olving lower extremity rash. No red ce ll fragment s or
crvoglohulins were noreJ; haptoglo bin ~cnJing was greater than 0.3 g/L a nd Coomb's test was ncg;nive. Endoscopy revealed a large duodenal ulce r. Scrum concentrations were: alanine amino-1ransfcrase 59 iu/L, asparrare aminn-1r,1mferase 48 iu/ L, gamma glurnmyl tran ferase 166 iu/L and a lka line pho,
rharase 177 iu/L. The repeat anti-HA V lgM wa, positive. Prednisonc was dbcontinued, two units tif blood were
transfu,ed and rnnitidine was rrescribed . The pa tient recovered fully ,mJ liver function tests re turned tn n ormal.
jaundice liver biopsy
The anti-HA V lgM pe rsisted umil July 1988, providing reac t inm ahnve
1000 counts/min (pos itive c ut-off 660 counts/min).
AST (U/L)
600
500
400
300
200
100
'
0 1 2 3
Repeated treatment o t sc rn with Figure 5) C ' /inrrnl co1ff1e of l1wr discme
C~N J GASTROENTEROL VL)L , Nu 4 SErTEt--lBER I 989
'
4 5 6 7 8 9 10 11 12 TIME (months)
147
CCX1K er al
Relapsing HA V is often heralJed by an increase in transaminases, fllthough original attacks of hepatitis may he duplicated in a milder form (8). It has been postulated that the virus may nOL be eliminated during the first hepatitis episode, thus producing ,l ~econd infection or inducing an autoimmune response (7). However, relapsing hepatitis appears to he more common following exposure to more than one hep,1t itis virus, suggesting two distinct infections rather than relapse of an origina l infection (8). Although hepatit is B, cytomcgalovirus, Epstein Barr \'irus and human i,nmunodeficicncy virus serology were negative in th is case, antecedent pose transfusion non-A non-B hepatitis, frequently associated with multiphasic aminotmnsfcrase patterns, cannot he ahsolutcly excluded (8).
1-lepatms B was excluded ~c rologica lly. Autoimmune or lupoid hepatitis is possible in this patient; a polyclonal gammopathy b common and the antinuclear antibody and ancismooth muscle antibody may he negative in up to 50% L' cases (2). This patient had not ab used alcohol or ingesred oxyphenacetin, methyldopfl, isonia:id,
ACKNOWLEDGEMENTS: The ,H1thllr, thank Dr, 11. R,1,hog1 anJ R. Adach i, Department o( Medicine, and Dr J.M. Kay, [)eparrment of Pathology, St Joseph's I lo,pital, Hamilrlln, Ontario for his help with thi, case.
REFERENCES I. Wright R, Millward-Sadlcr Gll, Bull
FG. Acurc viral heparins. In: Wright R, Millward-S,1Jlcr G I l, Alherti KGMM, ct al, eds. Liver and Bi liary Di~case, 2nd edn. London: WB S;iundcrs, I 9H5:677-767.
2. Wright R, M11lwarJ -Sadlcr GI I. Chronic hepatitis. In: Wrighr R, Millward-Sadler GI I, Alhcni KGMM, er al, L'<.b. Liver and Biliary Disca,-c, 2nd L-dn. Lond,m: WB Saunder,, 1985: 769-820.
148
nitrofurantoin or ocher drugs associated with abnormal liver function tests or chronic hepatitis.
The progression of HA V infection to chron ic liver disease has nor been proven by retrospective or case control studies (2). Changes in liver morphology after hepatitis A usuall y last two to
four weeks and nlmo~t always resolve without distortion of liver architecture ( 4 ). In a series of 25 pati<.:nts with ncute hepatitis A, two liver biopsies performed before six months had daps<.:d showed changes com1~aciblc with chronic active hepatitis (8); histologic features of chronic hepatitis have also been noted in pat iencs a fflictt.!d by foodborne outbreaks of hep,Hitis A (9). However, a lternate etiologic~ of chronic active hepatitis in thc~c cases were not adequately evalumed and hiscologic follow-up was nm widely availahk at ~ix month~. Bccm1,c th is patient had crnwcrccd co HA V lgG and had normal ll\·cr functl(ll1 tests l O mnnths after the onset nf jaundice, and remained in gond health five months thereafter, a repeat liver biopsy was J,(ficult to justify.
Relapsing hepatitis A appears w be uncommon, with two of 25 patients
4. Friedman LS, Dicn,rng J L. The db,c,1,c and it, pmhugcne.,is. 111: Gerety RJ, ed. I lcparir1, A. Orlando: Ac;idcmil l'rc", I 984:5 5-79.
5. Inman RD, I lodge M, Jnhnswn MEA, Wright J, l lcarl1e,irc J. Arthri tis , \'m,culi t1s and crynglohul incm1a associated wirh re lapsing hcpautb A , ·1rus 1nfccrinn. Ann Intern Med [986; 105:700-3.
6. Kan I IW. A,hca\'ai M, Redeker AG. The pcrsi,tcncc uf heparit i, A lgM antih{1dy afrer acute c linical heparirb A. l lepamlogy I 9H4;4:933-6.
99 patients reported in another (11). The association of arthriu s and leukocytoclast ic vnscul iti s with hepatitis A in thi:; patient is extrcmd, rare. On ly two other patients have hren reported by lnman and co-worker, (5) with relapsing HA V infection, arthrn,, and cryoglobulincmia, one of whl11n had cutaneous vasculitis. Although peripheral neuropathy has been Jocu, mented during acute I IA V infection 11
has not previously been associated w1tl1 relapsing I IA V and was likely sewndary to vasculitis in chb case. Eleltromyography was not performed. However, no other cause of self linrncJ peripheral neuropath y was idennfirJ.
The persistence of anti-HA V ]gM for nine months, the unusual presence of vasculiris, arthritis, peripheral neuropathy and fluc tuat ing ammo, trnmkrnses m ch is pat icnt, as well a, the pr<.:scnc<.: of an unresolved acute v1r.il ht.!pat iti, lour months after the inllial presentat11m, are C1)mpatihlc 111th
relapsing H A V infection. Although rch,pse~ 1)f hepatitis A arc ol van,thle ~everity (8), conscrvauve managemrnt appear~ to bL' ju~tif°ied by ultimate resolution of t his condition.
.i,s11c1at1.:d \\'ith hcparitb A v1ru,. Laneel 1982;ii:163. (Letter)
8. Jacuh,nn IM, Nath BJ, D1cn,1,1gJL. Rcla1Nng ,·ir.11 hcpat 1rb A. J Med Vm1I 1985;16:163-9.
9. R11utcnherg JA, l)1cnsrag J L, I larmnn WO, ct al. Fn,1dhornc outhreak ol hcp,lltlls A: C lini cal and lah1iratur} fr.iturc, of .icutc and prnrrnclL'd illness. Am J !\led Sc, 1979;278: 121-17.
10. Weir WR, Mdlnr JA. Smirh 11, Tyrell DA. S1gntl1cancc of hep,n1u, cn:ymt level, m discharge in ;1cure viral hep<1t 11 is. J lnku 198 1; 3: 309- 15.
I I. Ramh<:r M, Thuma, I IC. Rann"tcr B, Sherlock S. A.:ute 1ypc A, B. :md rn>n· A, non-B hcpatttt, in a ho,p1t.1l popula-1 wn 111 LpnJun : C l1n1 cal and e111dcmwlug1c,1l fcatun:s. Ciur 1983;24:561 -4.
