Relapsing hepatitis A infection with immunological sequelae

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

A patient with relapsing hepatitis A infec tio n, po lyarchritis, vasculitis and peripheral neuroparhy, who had persbtent anti-I IA V lgM for nine months is described.PaH med ica l history inc lud ed a blood tra nsfusion 111 1983 for anemia of unknown ct in logy.There was no previous drug or alcohnl use.

Deparrmen1. , of
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, v ihracion a nd p111pn ck sensation were impaired in a stoc king distnhlllion and ankle reflexes were ah-~cn t. 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.H oweve r, in one series, five of 37 patients h,1d pe rsiste nce of this marker for 200 Jays a nd anti-HA V lgM has been documented 14 months after HAV infection ( 1,6).P ersistent anti-HA V lgM may also accom pa n y relapsing h epati tis A (4).
T he rransam inases 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 rheum atoid tactor, preabsn rp ti on of rhc se ra with an tirh eumato id facror w,is performed, which did nnt reduce the counts, cnnf'irrning persistence of th is marker.

HAVlgG
Six wee k s later, th e patie nt presented with epiga,tric pain and a hemoglobin of 73 g/L.Exa min at ion revealed a re~olving lower extremity rash.No red ce ll fragment s or crvoglohulins were noreJ; h aptoglo 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 a minn-1r,1mferase 48 iu/ L, gamma glurnmyl tran ferase 166 iu/L a nd 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 Relapsing HA V is often heralJed by an increase in transaminases, fllthough original attacks of h epatitis 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 n egative in th is case, antecedent pose transfusion non-A non-B hepatitis, frequently associated with multiphasic aminotmnsfcrase patterns, cannot he ahsolutcly excl uded (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, nitrofurantoin or ocher drugs assoc iated 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 o r case control st udies (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<.:ntswith ncute hepatitis A, two liver biopsies performed before six months had daps<.:dshowed changes com1~aciblc with chronic active hepatitis (8); histologic features of chronic hepatitis ha ve also been noted in pat iencs a ffli ctt.!d by foodborne outbreaks of hep,Hitis A (9). H owever, 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.with relapsing HA V infection, arthrn,, and cryoglobulincmia, one of whl11n had c utaneous 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 likel y sewndary to vasculitis in chb case.Eleltromyography was not performed.
However, no other ca use of self linrncJ peripheral neuropath y was idennfirJ.