persistent haemolysis after infectious hepatitis · persistent haemolysis after infectious...

Gut, 1969, 10, 516-521

Persistent haemolysis after infectious hepatitisMARCEL E. CONRAD

From the Department ofHematology, Walter Reed Army Institute of Research, Washington, DC

Viral hepatitis is a pantropic disease which oftenhas haematological manifestations (Lucke, 1944;Conrad, Schwartz, and Young, 1964; Conrad,Weintraub, Schwartz, and Young, 1965). Fre-quently there is transient suppression of bonemarrow function or a mild haemolytic disorder(Kjellberg, 1941; Havens, 1948; Neumann andHommer, 1949; Hirscher, 1950; Bornemann andMichel, 1955; Kalk, 1955; Miescher, 1958; Horvathand Ivanyi, 1959; Kivel, 1961; Fodor and Tanasescu,1962; Sansone, Rovei, and Rasore-Quartino, 1963;Conrad et al, 1964 and 1965; Frick and Schmid,1965). Rarely, patients with hepatitis developeither a fatal aplastic anaemia or moderatelysevere haemolytic anaemia (Kjellberg, 1941; Lorenzand Quaiser, 1955; Kivel, 1961; Sansone et al, 1963;Rubin, Gottlieb, and Vogel, 1968).The mild haemolytic disorder associated with viral

hepatitis is often undetected because bilirubinaemiais attributed solely to liver disease, the rate of haemo-lysis is usually insufficient to cause anaemia, andreticulocytosis does not occur until most patientsrecover from the acute symptoms of hepatitis.The compensated haemolytic disorder of viral

hepatitis is usually brief in duration and abateswithin a few months after the onset of jaundice(Conrad et al, 1965). Only a few patients have apersistent haemolytic disorder which may last forlonger intervals. The aetiology of this haemolyticstate is difficult to establish unless the acute hepatitiswas well documented.

This communication reports three patients withviral hepatitis who had a compensated haemolyticdisorder long after recovery from liver disease.

SUBJECTS AND METHODS

The subjects of this study were three US servicemen whohad persistent reticulocytosis and indirect bilirubinaemiafor more than one year after recovery from viral hepatitis.These patients were found among a group of 68 soldierswho developed icteric hepatitis in Korea and had labora-tory studies performed at intervals for one year after theonset of jaundice. Each of the patients was maintainedon modified bed rest and a regular hospital diet during

516

the acute stage of the disease (Chalmers, Eckhardt,Reynolds, Cigarroa, Deane, Reifenstein, Smith, andDavidson, 1955). No other treatment was employed.The diagnosis of viral hepatitis was established in each

patient by observation of the clinical illness and by thedemonstration of elevated serum direct bilirubin andtransaminase levels. The diagnosis was confirmed in eachpatient by examination ofa liver biopsy specimen obtainedduring the first week of admission to hospital forhepatitis (Menghini, 1958; Smetana, 1963). It wasbelieved unlikely that the three patients had serum-trans-mitted hepatitis. One patient received parenteral injec-tions of penicillin for gonococcal urethritis four weeksbefore admission to the hospital (case 3) and another hada smallpox vaccination two weeks before the onset ofjaundice (case 1). No other inoculations or drugs werereceived during the six months before admission to thehospital with hepatitis.

Clinical symptoms, physical findings, and laboratorytests were quantified by previously described methods(Conrad et al, 1964). Heterophile agglutination studiesand microagglutination tests showed no evidence ofinfectious mononucleosis or leptospirosis.The red blood cell life span was measured by transfusion

of both autologous and homologous 61Cr-labelled cells(Ebaugh, Emerson, and Ross, 1953). The range ofnormal values for the ti of 5"Cr-transfused erythrocytesin this laboratory was 27 to 35 days. Homologous bloodwas obtained for these studies from a normal compatibledonor whose blood had been transfused into numerousrecipients without the occurrence of hepatitis. This donorhad a ti of 29 days following autotransfusion of 5"Cr-labelled red blood cells.

Haematological laboratory studies were performedas described by Dacie and Lewis (1963).

RESULTS

Serial observations in 68 patients with viral hepatitisshowed that most patients had a significant decreasein the haematocrit during the second and thirdweek after the onset of jaundice and developedreticulocytosis during the third or fourth week ofadmission to hospital (Fig. 1). Previously reportedstudies in a group of these patients showed that 25%had a shortened survival of 15Cr-labelled red bloodcells during the acute stage of illness (Conrad et al,1965).

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Persistent haemolysis after infectious hepatitis

AnorexiaMalaiseAbdominal discomfortNauseaCigarette distasteDark urineFeverSplenomegalyHepatomegaly

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-10 0 10 20 30 40 100 360 720Days in hospital

FIG. 1. Schematic representation of the median clinicaland laboratory findings in 68 US soldiers with icteric viralhepatitis. The median patient admitted for study was illfor five days andjaundicedfor one day. Usually the diseasestarted with symptoms of fever and malaise which werebelieved to represent the prodromal symptoms of an upperrespiratory infection. Subsequently the patients developedanorexia, nausea, abdominal discomfort, and a distastefor cigarettes. Most patients became asymptomatic duringthe second week in hospital. The liver was enlarged in all butone patient. The splenic tip was palpated during the firstfewdays in hospital in more than half the subjects. Laboratorytests showed a significant decrease in the haematocrit duringthe first two weeks and reticulocytosis during the third weekafter admission. The maximal elevation in the serum trans-aminase was usually observed in the admission specimen.In contrast, the serum bilirubin increased during the firstweek after admission. Laboratory tests became normalduring the fourth week.

In most patients with hepatitis, the serum bili-rubin returned to normal values before the serumtransaminase. However, 14 patients had both in-direct bilirubinaemia and reticulocytosis two monthsafter the clinical onset of jaundice and the serumtransaminase values were abnormal in only two ofthese subjects. In 11 of these patients, the serumbilirubin values and reticulocyte count becamenormal during the next month. The remaining threepatients had indirect bilirubinaemia and reticulo-cytosis six months and one year after the onset ofjaundice (Figs. 2 to 5). Laboratory tests indicativeof liver disease were normal at these intervals. Liverbiopsy specimens obtained one year after the onsetof jaundice showed no histological abnormalities.Follow-up laboratory studies at yearly intervalsshowed that two subjects had evidence of haemolysistwo years after the onset of jaundice and their reti-culocyte counts and serum bilirubin levels becamenormal during the next year (Figs. 2 to 4).The survival of transfused 51Cr-labelled auto-

logous and homologous red blood cells was mea-sured in each subject one year after the onset ofjaundice (Table I). The rapid disappearance of boththe patients' cells and donor cells indicated thathaemolysis was caused by extracorpuscular factorsand not by the production of abnormal, defectiveerythrocytes.

Blood specimens obtained from the three patientswith persistent posthepatitical haemolysis six monthsand one year after the onset of jaundice showednormal haematological studies. These included haema-tocrit, red blood cell indices, white blood count,differential smear of the peripheral blood, plateletcount, direct antiglobulin (Coombs) test, studiesfor cold agglutinins and haemolysis, the acidifiedserum (Ham's) test, the Donath-Landsteiner test,incubated osmotic fragility studies, haemoglobinelectrophoresis, measurements of A2 and foetalhaemoglobin, and assays for glucose-6-phosphate-dehydrogenase in red blood cell haemolysates.

DISCUSSION

Marked anaemia is an infrequent finding in patientswith viral hepatitis (Havens, 1948; Neumann andHommer, 1949; Bornemann and Michel, 1955;

TABLE ILABORATORY STUDIES IN PATIENTS WITH HAEMOLYSIS ONE YEAR AFTER HEPATITIS

Case White Blood Platelet Red Blood Haenmatocrit Haemoglobin Reticulocytes Serum Bilirubin `Cr-Red Blood CountNo. Count Count Count (',) (gliQ0 ml) (% Red Blood (mg/100 ml) TI days

(cells/lcnni) (cells/cmm) (million Count) - - - _ _cells/cmm) Direct Total Autologous Homologous

Cells Cells

6,700 345,000 5.29,400 325,000 4-88,200 290,000 5-0

474445

15-414-515-1

2-6 02 1-3 202-2 0-1 1-1 172-4 0-1 1-7 18

23

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FIG. 2. Case 1 A 19-year-oldsoldier had a typical clinical courseof viral hepatitis except for apersistent reticulocytosis and in-creased indirect serum bilirubinvalues for two years after the onsetofjaundice.

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FIG. 3. Case 2 A 23-year-oldman had a moderately prolongedacute illness. Symptoms, physicalfindings, and laboratory abnorm-alities indicative of liver diseaselasted for two months. Indirectbilirubinaemia and reticulocytosiswere found in blood specimens forone year after the onset ofjaundice.

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Persistent haemolysis after infectious hepatitisAnorexiaMalaiseAbdominal discomfortNauseaCigarette distasteDark urineFeverSplenomegalyLirv...i..

45% HAEMATOCRIH40

6 REETICULOCYTE,imm,

BILIRUBIN

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FIG. 4. Case 3 A19-year-old soldierhad anorexia andmalaisefor two weeksbefore he became ic-teric. Clinical symp-toms and laboratorystudies suggestive ofliver disease becamenormal within amonth after admis-sion but evidence ofhaemolysis persistedfor two years.

T- TI Ir

-20 -10 0 10 20Days in hospital

30 40 100 360 720

FIG. 5. Liver biopsy specimenobtained from case 1 on the secondday after admission for hepatitisshowing the characteristic changesobserved in specimens from eachpatient during the acute phase ofillness. There was a mononuclearinfiltration of the portal areas andsinusoids with foci of hepatic cellnecrosis. There was distortion of thehepatic architecture due to irregul-arity in the liver cells forming theparenchymal columns. B enucleatedliver cells were more frequent thanballoon cells and acidophilic bodies.Haemotoxylin and eosin.

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520 Marcel E. Conrad

Kalk, 1955; Horvath and Ivanyi, 1959; Kivel, 1961;Fodor and Tanasescu, 1962; Conrad et al, 1965).However, in most patients the haematocrit decreasesgradually during the first three weeks of clinicalillness (Conrad et al, 1964). Subsequently, amoderatereticulocytosis develops and the haematocrit returnsto normal values. In part these changes may beattributed to a temporary suppression of bonemarrow production which is manifested by amegaloblastoid maturation in about one-third ofpatients (Conrad et al, 1965). The anaemia asso-ciated with a maturation arrest of the bone marrowdevelops more slowly than leucopenia becausecirculating red blood cells have a longer life span(Dacie and Lewis, 1963).

In approximately a quarter of patients with acuteviral hepatitis the red blood cell survival time isslightly shortened (t1, 15 to 23 days) (Bornemann andMichel, 1955; Kalk, 1955; Horvath and Ivanyi,1959; Conrad et al, 1965; Frick and Schmid, 1965).This rate of haemolysis is insufficient to causeanaemia without the simultaneous decrease in pro-duction of erythrocytes (Crosby, 1954). Althoughhaemolysis can enhance bilirubinaemia, it does notcause reticulocytosis until patients recover from bonemarrow hypofunction (Conrad et al, 1965).Measurements of red blood cell life span with

autologous and homologous labelled erythrocytesindicated that haemolysis was caused by extra-corpuscular factors (Miescher, 1958; Conrad et al,1965; Frick and Schmid, 1965). Thus, we could notattribute excessive haemolysis to the production ofdefective erythrocytes or to a previously undetectedhereditary haemolytic disorder. However, the co-existence of an additional cause for haemolysismight worsen the haematological manifestations ofhepatitis and explain certain previously reportedcases with a moderately severe anaemia (Sansoneet al, 1963).The aetiology of the haemolytic disorder of viral

hepatitis is unknown. It is difficult to attributehaemolysis to the liver disease because in mostpatients with viral hepatitis red blood cells have anormal survival time and some patients have per-sistent haemolysis long after the disappearance of allstigmata of liver disease (Flood and James, 1947;Kalk, 1955; Fodor and Tanasescu, 1962; Conradet al, 1964; Conrad et al, 1965; Frick and Schmid,1965). It has been postulated that the haemolyticstate is caused either by a circulating antibody or isthe direct effect of a virus upon red blood cells.Failure to identify the aetiological virus and specificantibodies of hepatitis has made it impossible toprove this hypothesis (Flood and James, 1947;Kalk, 1955; Miescher, 1958; Horvath and Ivanyi,1959; Wright and Gardner, 1960; Kivel, 1961;

Fodor and Tanasescu, 1962; Conrad et al, 1964and 1965; Frick and Schmid, 1965).

SUMMARY

Serial clinical and laboratory studies in 68 soldierswith viral hepatitis revealed three patients with acompensated haemolytic disorder which lasted fromone to three years. Each patient had clinical andlaboratory studies and histological findings in a liverspecimen which were compatible with a diagnosis ofinfectious hepatitis. One year after the clinical onsetof hepatitis these three patients were asymptomaticbut had reticulocytosis and indirect bilirubinaemia.Laboratory tests suggestive of liver damage hadbecome normal. A shortened 51Cr survival of boththe patients' red blood cells and labelled donor cellsindicated that the haemolytic disorder was extra-corpuscular. Red blood cell antibodies were notdemonstrated in blood specimens from these patients.That the haemolytic state was caused by hyper-splenism seemed unlikely because the spleen did notremain palpable, and there were normal numbers ofcirculating white blood cells and platelets. The per-sistence of a haemolytic disorder could not berelated either to the severity or duration of acuteliver disease or relapsed hepatitis.

REFERENCES

Bornemann, K., and Michel, C. (1955). Hepatitis epidemica undHamolyse-Neigung. Arztl. Wschr., 10, 813-817.

Chalmers, T. C., Eckhardt, R. D., Reynolds, W. E., Cigarroa, J. G.,Jr, Deane, N., Reifenstein, R. W., Srnith, C. W., and Davidson,C. S. (1955). The treatment of acute infectious hepatitis.Controlled studies of the effects of diet, rest, and physicalreconditioning on the acute course of the disease and on theincidence of relapses and residual abnormalities. J. clin.Invest., 34, 1163-1235.

Conrad, M. E., Schwartz, F. D., and Young, A. A. (1964). Infectioushepatitis-a generalized disease. A study of renal, gastro-intestinal and hematologic abnormalities. Amer. J. Med.,37, 789-801.Weintraub, L. R., Schwartz, F. D., and Young, A. A. (1965).Viral hepatitis in Korea: Clinical observations and studiesperformed during prospective studies to obtain specimens forvirologic culture. Progr. Liver Dis., 2, 395-415.

Crosby, W. H. (1954). The hemolytic states. Bull. N. Y. Acad. Med.,30, 27-42.

Dacie, J. V., and Lewis, S. M. (1963). Practical Haematology, pp. 133-206, Grune and Stratton, New York.

Ebaugh, F. G., Jr, Emerson, C. P., and Ross, J. F. (1953). The useof radioactive chromium5' as an erythrocyte tagging agent forthe determination of red cell survival in vivo. J. clin. Invest.,32, 1260-1276.

Flood, C. A., and James, E. M. (1947). Clinical and pathologicalfindings in prolonged hepatitis. Gastroenterology, 8, 175-184.

Fodor, 0., and Tanasescu, R. (1962). Post-hepatitis immunologicalhaemolytic anaemia (In Rumanian). Med. interna (Buc.),14, 1469-1478.

Frick, P. G., and Schmid, J. R. (1965). Das hamolytische Syndrombei der akuten und chronischen Hepatitis. Klin. Wschr. 43,305-309.

Havens, W. P., Jr (1948). Infectious hepatitis. Medicine (Baltimore),27, 279-326.

Hirscher, H. (1950). Erworbene hamolytische Anamie bei Hepatitis.Dtsch. Gesundh.-Wes., 5, 814-819.

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Horvath, G., and Ivanyi, J. (1959). Hamolyse bei derakutenVirus-hepatitis. Wien. med. Wschr., 109, 101-102.

Kalk, H. (1955). 1Yber die posthepatitische Hyperbilirubinamie.Gastroenterologia (Basel), 84, 207-225.

Kivel, R. M. (1961). Hematologic aspects of acute viral hepatitis.Amer. J. dig. Dis., 6, 1017-1031.

Kjellberg, K. (1941). Ein Fall von akuter hamolytischer Anamie beiakuter Hepatitis. Kinderarztl. Prax., 12, 296-299.

Lorenz, E., and Quaiser, K. (1955). Panmyelopathie nach Hepatitisepidemica. Wien. med. Wschr., 105, 19-22.

Luck6, B. (1944). The pathology of fatal epidemic hepatitis. Amer. J.Path., 20, 471-593.

Menghini, G. (1958). One-second needle biopsy of the liver. Gastro-enterology, 35, 190-199.

Miescher, P. (1958) cited by Keiderling, W., Lee, M., and Schmidt,

H. A. E. Eisenstoffwechselstudien bei Leberzellschadigung.Strahlentherapie, suppl. 38, 182-196.

Neumann, H., and Hommer, E. (1949). Akute splenohepatischeHepatitiden von aussergew%ohnlichem serohamatologischemVerhalten. Klin. Wschr., 27, 747-749.

Rubin, E., Gottlieb, C., and Vogel, P. (1968). Syndrome of hepatitisand aplastic anemia. Amer. J. Med., 45, 88-97.

Sansone, G., Rovei, S., and Rasore-Quartino, A. (1963). Anemiaemolitica in glucosio-6-fosfato deidrogenasi erithrocitaria.G. Mal. infett., 15, 550-556.

Smetana, H. F (1963). Pathology of hepatitis. In Disease of theLiver, 2nd ed., edited by L. Schiff, pp. 369-424. Lippincott,Philadelphia. Pitman, London.

Wright, C. S., and Gardner, E., Jr (1960). A study of the role of acuteinfections in precipitating crises in chronic hemolytic states.Ann. intern. Med., 52, 530-537.

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