Role of reovirus type 3 in persistent infantile cholestasis

doi:10.1016/S0022-3476(84)80076-1

The Journal of Pediatrics

Volume 105, Issue 6, December 1984, Pages 912-915

https://doi.org/10.1016/S0022-3476(84)80076-1 Get rights and content

The relationship between reovirus type 3 and persistent infantile cholestasis was studied by measuring antibody to the virus in the sera of affected and control babies younger than 1 year of age. One hundred sixty-seven infants were divided into four groups: those with extrahepatic biliary atresia, idiopathic neonatal hepatitis, or other cholestatic disorders, and controls. When available, maternal sera obtained simultaneously with infant sera were also studied. The results indicate that 62% of babies with extrahepatic biliary atresia and 52% of infants with idiopathic neonatal hepatitis have reovirus 3 antibodies. In contrast, less than 12% of either normal infants or babies with other cholestatic disorders have antibodies. These observations suggest that perinatal infection with reovirus type 3 may serve as an initiating event in the genesis of two closely related forms of infantile obstructive cholangiopathy: extrahepatic biliary atresia and idiopathic neonatal hepatitis.

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While the etiology of BA remains unclear, one proposed mechanism is a perinatal viral infection triggering a host mediated immunologic response resulting in the end phenotype of clinical biliary atresia (Landing, 1974). Evidence in support of this proposed mechanism includes the detection of multiple viruses such as rotavirus group c (Riepenhoff-Talty et al., 1996), reovirus type 3 (Glaser et al., 1984), cytomegalovirus (Domiati-Saad et al., 2000) human papillomavirus (Drut et al., 1998) and Epstein-Barr virus (Fjaer et al., 2005) in livers of infants with biliary atresia. Additional supportive evidence has been obtained using the murine model of biliary atresia where infection of BALB/c pups with rhesus rotavirus (RRV) results in portal tract inflammation and extrahepatic biliary obstruction, paralleling human biliary atresia (Riepenhoff-Talty et al., 1993).
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Perinatal cytomegalovirus (CMV) infection is a possible cause or trigger of biliary atresia though clinical evidence is scant. We hypothesised that CMV IgM+ve biliary atresia is a separate clinical entity compared to CMV IgM−ve biliary atresia.
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Citation Excerpt :
However, a distinct difference was also noticed in that complete obstruction of the bile ducts, with prominent dilatation upstream (typical of murine BA), was scarce in human BA. In light of the studies implying that BA could be caused by reovirus or another member of the Reoviridae family [4–6] and suggesting the possible etiologic relevance of group C rotavirus to human BA [24], the mouse model has seemed suitable for studying the viral etiologic mechanism of BA [17,18]; however, even though a number of recent studies have employed the RRV mouse model for clarifying the pathogenesis of BA, it has nevertheless been eagerly anticipated that researchers will eventually succeed in gathering direct evidence from BA patient samples to support the viral or rotaviral infection theory. Although group A rotavirus has been widely used in establishing BA mouse models [17,18], there have been only 3 original articles rigorously investigating the possible rotaviral link to the etiology of BA using a sensitive nested RT-PCR system [12,14,24] (Table 5).
To explore the evidence for viral infections triggering human biliary atresia (BA) by reviewing archival original articles that analyzed human samples via polymerase chain reaction (PCR) experiments, considering the recent experimental trend of extensive use of rotaviral BA animal models.
A PubMed search retrieved original articles that reported the results of PCR experiments for detecting viral DNA or RNA in patient samples as proof of past infection. Search terms included the often-debated DNA or RNA viruses and BA. Special focus was directed toward PCR analyses that targeted reovirus and rotavirus, where PCR accuracy, specimen characteristics and their interpretations were compared.
Nineteen studies were conducted on 16 different kinds of viruses using PCR, with 5 studies on reovirus, 3 on rotavirus, 10 on cytomegalovirus, 5 on Epstein-Barr virus, 4 on parvovirus B19, and so on. Among the papers suggesting a possible viral link to only BA, there was no study on reovirus, 1 on rotavirus, 3 on cytomegalovirus, 1 on EB virus, and 1 on papillomavirus. Of the 6 PCR studies on Reoviridae, 3 on reovirus and 2 on rotavirus were evaluated rigorously for experimental accuracy, including their sensitivity. Two research groups analyzed preoperative stool samples in addition to generic hepatobiliary tissue obtained at surgery. Sample collection timing varied widely, with storage period prior to PCR experimentation not revealed in most reports on Reoviridae.
Although a considerable number of PCR studies have sought to clarify a viral role in the pathogenesis of BA using human samples, the findings have been contradictory and have not succeeded in achieving an obvious differentiation between causative and accidental infection of the focused virus. Reproducible and convincing evidence for a causative Reoviridae infection has been lacking based on objective data from highly sensitive PCR experiments. Even though the possibility remains of viral disappearance at the timing of collection, to avoid further ambiguous interpretations of PCR results, rigorous and meticulous collection of large numbers of specimens at carefully planned timing, along with a strictly adjusted and finely tuned PCR system, is strongly recommended for obtaining more reliable and consistent results.

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Supported in part by The March of Dimes and by Grant AM-17702 from the National Institutes of Health.

Presented in part at the International Symposium on Biliary Atresia and Related Disorders, Sendai, Japan, 1983.

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Original articleRole of reovirus type 3 in persistent infantile cholestasis

J Pediatr Surg

J Pediatr

Biliary atresia and Reovirus type 3 infection

N Engl J Med

Comparative studies of biliary atresia in the human newborn and Reovirus-induced cholangitis in weanling mice

Lab Invest

Pathogenesis of biliary atresia and reovirus type 3 infection

A form of hepatitis in the neonatal period simulating biliary atresia

Arch Pathol

Clinical aspects of neonatal hepatitis

Am J Dis Child

Infantile obstructive cholangiopathy

Am J Dis Child

Original article
Role of reovirus type 3 in persistent infantile cholestasis