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Fatal cholestatic hepatitis in aninfant: An unusual etiology

MARK R OLIVER MBBS, ALFREDO PINTO MD, R BRENT SCOTT MDCM

OBSTRUCTIVE JAUNDICE REQUIRES

prompt investigation to identifyan etiology and institute specific sup-portive and/or therapeutic measures toprevent morbidity and mortality. Wereport a three-month-old infant girlwho presented with cholestatic jaun-dice and hepatitis that progressed tofulminant hepatic failure due to adeno-

virus type 5 infection. Postmortem di-agnosis of severe combinedimmunodeficiency syndrome (SCIDS)was made. Infection, viral or bacterial,can be a recognized but less commoncause of this clinical picture in infancy(1,2). However, neither adenovirus in-fection nor immunodeficiency hasbeen included as a cause of hepatitis or

cholestasis during infancy in compre-hensive summaries of the differentialdiagnosis (1-3).

CASE PRESENTATIONClinical history: A three-month-oldfemale born to unrelated Mennoniteparents was transferred from a regionalcentre (following a one-week admis-sion) to the Alberta Children’s Hospi-tal in Calgary, Alberta with cholestaticjaundice and hepatitis as indicated bytotal bilirubin of 68 �mol/L (normalless than 32) with a conjugated biliru-bin of 57 �mol/L and elevated liver en-zymes (aspartate aminotransferase 542U/L [normal 0 to 30] and alkaline phos-phate 1721 U/L [normal 75 to 400]). Atentative diagnosis of biliary atresia hadbeen made at the referring institutionon the basis of absent excretion of bileinto the small intestine during a nuclearmedical hepatobiliary scan. However,there were some unusual features thatweighed against the transfer diagnosisand suggested an infectious etiology.First, the child had also presented withfever, leukopenia (total white bloodcell count 3.2x109 cells/L, normal 5 to18.5) and microcytic, hypochromicanemia (hemoglobin 59 g/L, normal 95to 155). Second, the infant also had ahistory of failure to thrive, with a recentonset of otitis externa. Before transferthe infant commenced a course of bothbroad spectrum intravenous antibioticsand an oral antifungal agent. Cultures ofurine and blood obtained before treat-ment was initiated did not subsequently

BRIEF COMMUNICATION – HEPATOLOGY

MR OLIVER, A PINTO, RB SCOTT. Fatal cholestatic hepatitis in an infant: Anunusual etiology. Can J Gastroenterol 1995;9(4):217-220. An infant girl whopresented with cholestasis and hepatitis that rapidly progressed to fulminant liverfailure is reported. Postmortem examination yielded a diagnosis of demonstratedextensive hepatic necrosis due to adenovirus type 5 infection which had devel-oped in the setting of an occult primary immunodeficiency (severe combined im-munodeficiency). The aim of this report is to alert the physician to a rare cause ofcholestasis and hepatitis in infancy. Recognition of the combination of adenovi-ral infection with underlying primary immunodeficiency is a prerequisite tothe provision of genetic counselling.

Key Words: Adenovirus, Cholestasis, Hepatitis, Immunodeficiency

Hépatite choléstatique fatale chez un nourrisson : étiologieinhabituelle

RÉSUMÉ : Le cas d’un nourrisson de sexe féminin qui a présenté une choléstaseet une hépatite ayant progressé vers une insuffisance hépatique fulminante estrésumé ici. L’autopsie a permis de poser un diagnostic de nécrose hépatique éten-due attribuable à une infection à adénovirus de type 5 qui s’était développée dansle contexte d’une immunodéficience primitive occulte (immunodéficience com-binée grave). Le but de ce rapport est de sensibiliser les médecins à une cause rarede choléstase et d’hépatite chez les nourrissons. L’observation d’une infectionadénovirale combinée à une immunodéficience primitive sous-jacente est essen-tielle à tout counselling génétique.

Department of Pediatrics and Pathology, Alberta Children’s Hospital and University ofCalgary, Calgary, Alberta

Correspondence and reprints: Dr R Brent Scott, Department of Pediatrics, Health ScienceCentre, 3330 Hospital Drive NW, Calgary, Alberta T2N 4N1. Telephone 403-220-4556,Fax 403-283-3028, e-mail [email protected]

CAN J GASTROENTEROL VOL 9 NO 4 JUNE 1995 217

grow either bacterial or fungal patho-gens.

On admission to the Alberta Chil-dren’s Hospital, the following addi-tional information was obtained. Thepatient had been born at term (weight2.8 kg) and at home, in a Mennonite

colony in Mexico. She had been exclu-sively bottle-fed with Enfalac (MeadJohnson Canada) since birth and apartfrom poor weight gain, which the par-ents attributed to ‘difficult feeding’, shehad been relatively well until twoweeks before admission to the referring

hospital, at which time she was jaun-diced and passing both acholic stoolsand dark urine. These symptoms wereaccompanied by a discharging right earand pallor. She had never been immu-nized or been given any prescribed ornonprescribed medications. The pati-ent’s 19-month-old sibling was well.Several unexplained deaths in the firstyears of life were reported on the mater-nal side of the family.

Physical examination confirmedfailure to thrive; both the patient’sheight and weight were below the fifthpercentile. She was afebrile, and ap-peared pale, jaundiced and poorlynourished. There was a yellow dis-charge from her right ear due to otitisexterna and mild oral candidiasis. Bothtonsillar and lymphoid tissue wereclinically present. She was noticeablyirritable on stimulation; however,there was no evidence of focal neuro-logical signs. Her liver was 7 cm in spanand her spleen was palpable 2 cm belowthe left costal margin. There was noother clinical evidence of chronic liverdisease.

Laboratory investigations per-formed on admission are summarized inTable 1. Within 12 h of admission thepatient suffered a significant deteriora-tion characterized by the clinical find-ings of shock, bleeding diathesis anddeteriorating liver function. She re-ceived supportive care including vol-ume expansion with fresh frozenplasma, antibiotics, pooled immuno-globulin and vitamin K. Serologicalinvestigations for hepatitis A, B and C,cytomegalovirus, toxoplasmosis, herpessimplex and human immunodeficiencyvirus-1 were negative. Plasma aminoacids and urinary organic acid profilefailed to detect an underlying meta-bolic disorder. Repeat blood and urinecultures were negative for bacterial orfungal organisms. Rotavirus was iso-lated from the stools and adenoviruscultured from the patient’s nasopha-rynx eight days following admission tothe Children’s Hospital. Despite allsupportive efforts the patient’s coagu-lopathy persisted (uncorrected byblood products and vitamin K) andher liver function continued to deterio-rate (Table 1). In addition, she devel-

TABLE 1Laboratory investigations

On admission Before death Normal values

Hemoglobin (g/L) 94 75 110-147

White blood cells (x109/L) 3 4.9 6-18

Lymphocytes (x109/L) 0.5 1.8 2.8-14.4

Platelets (x109/L) 167 75 150-550

Prothrombin time (s) 15.1 28 11.9-17.7

Activated partial thromboplastin time

(s)

33 >150 23.7-37.9

Fibrinogen (g/L) 2.0 1.4 2-4

D-dimers (fibrinogen equivalent units) <0.05 <0.05 <0.5

Total bilirubin (�mol/L) 55 108 5-23

Conjugated bilirubin (�mol/L) 25 76 0-10

Gamma glutamyltransferase (U/L) 1518 652 16-43

Aspartate aminotransferase (U/L) 1656 23,250 12-50

Alanine transaminase (U/L) 480 1740 5-40

Albumin (g/L) 24 22 35-50

Immunoglobulin G (U/L) 0.73 – 3.45-12.36

Immunoglobulin A (U/L) <0.07 – 0. 14-1.23

Immunoglobulin M (U/L) 0.17 – 0.43-1.73

Alpha-1 antitrypsin (U/L) – 3.48 0.85-2.65

Urinary reducing substances Negative

Figure 1) Light microscopy demonstrates extensive necrosis of the hepatocytes without a significantinflammatory response. Some hepatocytes contain intranuclear inclusions consistent with viral infec-tion (hematoxylin and eosin x262)

218 CAN J GASTROENTEROL VOL 9 NO 4 JUNE 1995

OLIVER et al

oped significant neurological dysfunc-tion characterized by irritability,opisthotonos, apnea and seizures in theabsence of evidence of an intracranialbleed on cerebral computed tomo-graphic scan (or later at autopsy). Shedied eight days following admission.Autopsy findings: Autopsy revealed adiffuse granular liver, which on his-tological assessment showed exten-sive areas of necrosis with minimal in-flammation and normal portal tracts.Hepatocytes at the periphery of ne-crotic areas contained round nucleiwith acidophilic inclusions sugges-tive of viral infection (Figure 1). Elec-tron microscopic examination of livertissue revealed the presence of adenovi-rus particles (Figure 2). The adenoviruswas serotyped as type 5 by standard neu-tralization tests using adenovirus type 5reference antisera (4). At the time ofautopsy, adenovirus was cultured fromstools, heart, lungs, liver, cerebrospinalfluid and throat, reflecting terminalviremia. There was no evidence of in-flammation or viral inclusion bodiesdetected in other organs apart from theliver. Examination of the reticuloendo-thelial system disclosed a small thymuswith complete depletion of lympho-cytes, dysplastic epithelium and ab-sence of Hassall’s corpuscles. Thelymph nodes, spleen and Peyer’spatches were depleted in lymphocytesand showed no evidence of germinalcentres. These histological findings arecharacteristic of severe combined im-munodeficiency (5).

DISCUSSIONA diagnosis of SCIDS, a heteroge-

nous group of disorders characterizedby a gross functional impairment ofboth T and B lymphocytes, was madein our patient. This diagnosis is sup-ported by both laboratory and autopsyfindings including the presence of lym-phocytopenia, hypogammaglobuline-mia, thymic dysplasia and generalizedlymphoid hypoplasia. There is usually apositive family history obtained in 50%of patients with SCIDS which may re-flect an autosomal recessive, dominantor X-linked pattern of inheritance (6).It is possible that in this patient’s Men-nonite background there is an unrecog-

nized basis for recessive inheritance;however, the precise inheritance of herdisease remains to be elucidated.

Adenovirus can, like many other vi-ruses, take advantage of an abnormalimmune system and produce either per-sistent or generalized infections(4,7-11). In the immunocompromisedpatient with adenoviral infection thereis a case fatality rate of over 50% inthose who present with hepatitiscompared with less than 10% in theimmunocompetent patient (9). Whenadenoviral infection occurs as a resultof a primary immunodeficiency, over90% of cases are associated with SCIDS

(9). Of the 19 reported adenoviral in-duced fatalities in patients with SCIDS,there has been only one previously re-ported case with adenovirus type 5 in-fection, and in that patient the clinicalpicture and outcome was similar to thatdescribed for our patient (10).

There is no specific treatment forSCIDS although a variety of natural andsynthetic products have been used withminimal success, including thymic hu-moral factor, pooled immunoglobulinG (which was used unsuccessfully inour patient) and interferon (9). Morerecently ganciclovir has shown somepromise in disseminated adenoviral in-fection after liver transplantation (12).

Lastly, successful treatment of fulmi-nant viral hepatitis (ECHO virus type11) by orothotopic liver transplanta-tion has been reported in an infant(13). Despite post-transplant immu-nosuppressive drug therapy, this latterpatient’s ECHO viral hepatitis did notrecur. Such aggressive treatment war-rants further assessment in the case ofcertain viral-induced hepatic infec-tions. However, because of our pati-ent’s underlying severe immunodefi-ciency syndrome we do not believe thatliver transplantation would have beenan appropriate therapeutic option.

CONCLUSIONSThe aim of this report was to alert

the physician to a rare cause of cho-lestasis and hepatitis in infancy. Whileadenoviral hepatitis and cholestasis ininfants with SCIDS is rare, and usuallylethal even with early recognition andtreatment, it should not go unrecog-nized because of the need to providegenetic counselling to the family.

ACKNOWLEDGEMENTS: The authorsthank Roberta Funk for typing the manu-script. Mark Oliver is a recipient of an Al-berta Children’s Hospital FoundationFellowship.

Figure 2) Hepatocyte showing the typical crystalline array of adenovirus particles withinthe nucleus (uranyl acetate-lead citrate x5216)

CAN J GASTROENTEROL VOL 9 NO 4 JUNE 1995 217

Fatal cholestatic hepatitis

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