Fatal cholestatic hepatitis in an infant : An unusual etiology

OBSTRUCTIVE JAUNDICE REQUIRES prompt investigation to identify an etiology and institute specific supportive and/or therapeutic measures to prevent morbidity and mortality. We report a three-month-old infant girl who presented with cholestatic jaundice and hepatitis that progressed to fulminant hepatic failure due to adenovirus type 5 infection. Postmortem diagnosis of severe combined immunodeficiency syndrome (SCIDS) was made. Infection, viral or bacterial, can be a recognized but less common cause of this clinical picture in infancy (1,2). However, neither adenovirus infection nor immunodeficiency has been included as a cause of hepatitis or cholestasis during infancy in comprehensive summaries of the differential diagnosis (1-3).

prompt investigation to identify an etiology and institute specific supportive and/or therapeutic measures to prevent morbidity and mortality.We report a three-month-old infant girl who presented with cholestatic jaundice and hepatitis that progressed to fulminant hepatic failure due to adeno-virus type 5 infection.Postmortem diagnosis of severe combined immunodeficiency syndrome (SCIDS) was made.Infection, viral or bacterial, can be a recognized but less common cause of this clinical picture in infancy (1,2).However, neither adenovirus infection nor immunodeficiency has been included as a cause of hepatitis or cholestasis during infancy in comprehensive summaries of the differential diagnosis (1)(2)(3).

CASE PRESENTATION Clinical history:
A three-month-old female born to unrelated Mennonite parents was transferred from a regional centre (following a one-week admission) to the Alberta Children's Hospital in Calgary, Alberta with cholestatic jaundice and hepatitis as indicated by total bilirubin of 68 mmol/L (normal less than 32) with a conjugated bilirubin of 57 mmol/L and elevated liver enzymes (aspartate aminotransferase 542 U/L [normal 0 to 30] and alkaline phosphate 1721 U/L [normal 75 to 400]).A tentative diagnosis of biliary atresia had been made at the referring institution on the basis of absent excretion of bile into the small intestine during a nuclear medical hepatobiliary scan.However, there were some unusual features that weighed against the transfer diagnosis and suggested an infectious etiology.First, the child had also presented with fever, leukopenia (total white blood cell count 3.2x10 9 cells/L, normal 5 to 18.5) and microcytic, hypochromic anemia (hemoglobin 59 g/L, normal 95 to 155).Second, the infant also had a history of failure to thrive, with a recent onset of otitis externa.Before transfer the infant commenced a course of both broad spectrum intravenous antibiotics and an oral antifungal agent.Cultures of urine and blood obtained before treatment was initiated did not subsequently BRIEF COMMUNICATION -HEPATOLOGY MR OLIVER, A PINTO, RB SCOTT.Fatal cholestatic hepatitis in an infant: An unusual etiology.Can J Gastroenterol 1995;9(4):217-220.An infant girl who presented with cholestasis and hepatitis that rapidly progressed to fulminant liver failure is reported.Postmortem examination yielded a diagnosis of demonstrated extensive hepatic necrosis due to adenovirus type 5 infection which had developed in the setting of an occult primary immunodeficiency (severe combined immunodeficiency).The aim of this report is to alert the physician to a rare cause of cholestasis and hepatitis in infancy.Recognition of the combination of adenoviral infection with underlying primary immunodeficiency is a prerequisite to the provision of genetic counselling.
On admission to the Alberta Children's Hospital, the following additional information was obtained.The patient had been born at term (weight 2.8 kg) and at home, in a Mennonite colony in Mexico.She had been exclusively bottle-fed with Enfalac (Mead Johnson Canada) since birth and apart from poor weight gain, which the parents attributed to 'difficult feeding', she had been relatively well until two weeks before admission to the referring hospital, at which time she was jaundiced and passing both acholic stools and dark urine.These symptoms were accompanied by a discharging right ear and pallor.She had never been immunized or been given any prescribed or nonprescribed medications.The patient's 19-month-old sibling was well.Several unexplained deaths in the first years of life were reported on the maternal side of the family.
Physical examination confirmed failure to thrive; both the patient's height and weight were below the fifth percentile.She was afebrile, and appeared pale, jaundiced and poorly nourished.There was a yellow discharge from her right ear due to otitis externa and mild oral candidiasis.Both tonsillar and lymphoid tissue were clinically present.She was noticeably irritable on stimulation; however, there was no evidence of focal neurological signs.Her liver was 7 cm in span and her spleen was palpable 2 cm below the left costal margin.There was no other clinical evidence of chronic liver disease.
Laboratory investigations performed on admission are summarized in Table 1.Within 12 h of admission the patient suffered a significant deterioration characterized by the clinical findings of shock, bleeding diathesis and deteriorating liver function.She received supportive care including volume expansion with fresh frozen plasma, antibiotics, pooled immunoglobulin and vitamin K. Serological investigations for hepatitis A, B and C, cytomegalovirus, toxoplasmosis, herpes simplex and human immunodeficiency virus-1 were negative.Plasma amino acids and urinary organic acid profile failed to detect an underlying metabolic disorder.Repeat blood and urine cultures were negative for bacterial or fungal organisms.Rotavirus was isolated from the stools and adenovirus cultured from the patient's nasopharynx eight days following admission to the Children's Hospital.Despite all supportive efforts the patient's coagulopathy persisted (uncorrected by blood products and vitamin K) and her liver function continued to deteriorate (Table 1).In addition, she devel-

Figure 1) Light microscopy demonstrates extensive necrosis of the hepatocytes without a significant inflammatory response. Some hepatocytes contain intranuclear inclusions consistent with viral infection (hematoxylin and eosin x262)
oped significant neurological dysfunction characterized by irritability, opisthotonos, apnea and seizures in the absence of evidence of an intracranial bleed on cerebral computed tomographic scan (or later at autopsy).She died eight days following admission.Autopsy findings: Autopsy revealed a diffuse granular liver, which on histological assessment showed extensive areas of necrosis with minimal inflammation and normal portal tracts.
Hepatocytes at the periphery of necrotic areas contained round nuclei with acidophilic inclusions suggestive of viral infection (Figure 1).Electron microscopic examination of liver tissue revealed the presence of adenovirus particles (Figure 2).The adenovirus was serotyped as type 5 by standard neutralization tests using adenovirus type 5 reference antisera (4).At the time of autopsy, adenovirus was cultured from stools, heart, lungs, liver, cerebrospinal fluid and throat, reflecting terminal viremia.There was no evidence of inflammation or viral inclusion bodies detected in other organs apart from the liver.Examination of the reticuloendothelial system disclosed a small thymus with complete depletion of lymphocytes, dysplastic epithelium and absence of Hassall's corpuscles.The lymph nodes, spleen and Peyer's patches were depleted in lymphocytes and showed no evidence of germinal centres.These histological findings are characteristic of severe combined immunodeficiency (5).DISCUSSION A diagnosis of SCIDS, a heterogenous group of disorders characterized by a gross functional impairment of both T and B lymphocytes, was made in our patient.This diagnosis is supported by both laboratory and autopsy findings including the presence of lymphocytopenia, hypogammaglobulinemia, thymic dysplasia and generalized lymphoid hypoplasia.There is usually a positive family history obtained in 50% of patients with SCIDS which may reflect an autosomal recessive, dominant or X-linked pattern of inheritance (6).It is possible that in this patient's Mennonite background there is an unrecog-nized basis for recessive inheritance; however, the precise inheritance of her disease remains to be elucidated.
Adenovirus can, like many other viruses, take advantage of an abnormal immune system and produce either persistent or generalized infections (4,(7)(8)(9)(10)(11).In the immunocompromised patient with adenoviral infection there is a case fatality rate of over 50% in those who present with hepatitis compared with less than 10% in the immunocompetent patient (9).When adenoviral infection occurs as a result of a primary immunodeficiency, over 90% of cases are associated with SCIDS (9).Of the 19 reported adenoviral induced fatalities in patients with SCIDS, there has been only one previously reported case with adenovirus type 5 infection, and in that patient the clinical picture and outcome was similar to that described for our patient (10).
There is no specific treatment for SCIDS although a variety of natural and synthetic products have been used with minimal success, including thymic humoral factor, pooled immunoglobulin G (which was used unsuccessfully in our patient) and interferon (9).More recently ganciclovir has shown some promise in disseminated adenoviral infection after liver transplantation (12).
Lastly, successful treatment of fulminant viral hepatitis (ECHO virus type 11) by orothotopic liver transplantation has been reported in an infant (13).Despite post-transplant immunosuppressive drug therapy, this latter patient's ECHO viral hepatitis did not recur.Such aggressive treatment warrants further assessment in the case of certain viral-induced hepatic infections.However, because of our patient's underlying severe immunodeficiency syndrome we do not believe that liver transplantation would have been an appropriate therapeutic option.

CONCLUSIONS
The aim of this report was to alert the physician to a rare cause of cholestasis and hepatitis in infancy.While adenoviral hepatitis and cholestasis in infants with SCIDS is rare, and usually lethal even with early recognition and treatment, it should not go unrecognized because of the need to provide genetic counselling to the family.

ACKNOWLEDGEMENTS:
The authors thank Roberta Funk for typing the manuscript.Mark Oliver is a recipient of an Alberta Children's Hospital Foundation Fellowship.

Fatal
cholestatic hepatitis in an infant: An unusual etiology MARK R OLIVER MBBS, ALFREDO PINTO MD, R BRENT SCOTT MDCM O BSTRUCTIVE JAUNDICE REQUIRES