ANIMAL MODEL OF HUMAN DISEASE
Chronic Biliary Obstruiction
Animal Model: Chronic Biliary Obstruction Cauised by Reoviruis Type 3
Contributed by: Neville F. Stanley, DSc, FRCPA(Hon), and R. A. Joske, MD, PhD, FRACP, Departments of Microbiology and Medicine, University of Western Australia, Nedlands, 6009, Western Australia.
Human Disease
Nonbacterial infections prodtucing chronic biliary obstruiction in man are a clinical and pathologic enigma. Virchow 1 described an entity of catarrhal jauindice duie to chronic cholangitis. The natture of this entity remains in dispuite. Virchow's paper is, tinfortuinately, without illuistrations. It is generally considered to be a description of viral hepatitis, btut in this latter condition, changes in the external biliary tree are minimal or absent. Viral hepatitis may produice a cholestatic syndrome, with damage to the smaller interhepatic radicles resuilting in an obstruictive pictuire.2' Obstruictive jauindice in man may also resuilt from fibrouis strictuires at the lower end of the common bile dtuct in the absence of either pancreatitis or cholelithiasis. The etiology of these is uinknown, buit a local infective or inflammatory process has been invoked.4 Viruis infections may also produice external biliary obstruiction secondary to virtus pancreatitis, possibly with extension to the lower portion of the common bile duict where it traverses the head of the pancreas. This has been doctumented for muimps viruis, viruis hepatitis, and possibly also coxsackie infections in infants.'66 Generally, however, this grouip of conditions is poorly stuidied. They are not common, and viruis isolations are diffictult both to attempt and to achieve. Puiblication sponsored by the Registry of Comparative Pathology of the Armed Forces Institute of
Pathology and suipported by Ptublic Health Service Grant RR-00301 from the Division of Research
Resouirces, US Department of Health, Edtucation and Welfare, tnder the auispices of Universities As-
sociated for Research and
Edtucation
in Pathology, Inc.
185
186
STANLEY AND JOSKE
American Journal of Pathology
Biologic Features of Murine Model
Althouigh newb)orn mice are highly suisceptible to infection with reovirtls Types 1, 2, and 3, weanling mice are muich more resistant to the produiction of disease.7 10 Disease has been produiced in weanling mice only by the inocuilatioin of massive doses of reoviruis Type 3 by the intraperitoneal rouite; 40% of the mice developed chronic obstruictive jaulndice.10 Jauindice appeared 3 or more weeks after inocuilation and resuilted from the obstruiction of the common bile duict at the duiodenal end following denuidationi of the bile d(lct mtucosa. One week after inocuilation, reovirtis was observed replicating in the bile duict muicosal cells. Three weeks after infection, when jauindice was apparent, no infective viruis couild be detected in the bile duicts, livers or spleens of the mice. It appearedl that withi the higlh concentration of infective reoviruis Type 3 particles, the titer of viruis in the common bile duict became high enouigh to permit invasion of cells lining its Ilumen. Virions passed both the sinuisoidal and hepatic layers before reaching the common bile duict. Fibrosis in the terminal portion of the common bile duct came in the wake of celluilar necrosis and the inflammatory response to viruis invasion. The suibse(quent strictuire formation, and the obstruiction of flow in the common bile diuct which it cauised, was then responsible for the hepatic and pancreatic lesions seen in the later stages of the disease. Comparison With Human Disease and Potential Usefulness of the Model
This model suiggests that some cases of biliary obstruiction at the ampuilla of Vater might occuir following viruis choledochitis. Even so, establishment of this wouild be difficuilt becauise of either the absence of viruis at the time of onset of the jauindice or inability to detect it in the tissuies at this time dtue to the virostatic properties of bile. High levels of antibody might be detectable, however, buit these in tuirn wouild render detection of small amouints of persistent viruis difficuilt. A combined clinical and epidemiologic approach with attempted viruis isolation from blood and feces, as well as viral and electron microscopic stuidy of possible suirgical specimens, might aid in the stuidy of an obscuire and difficuilt grouip of diseases. The muirine infection provides a basis for a working protocol for this. Availability
Mice and viruises may be obtained from the Department of Microbiology, University of Western Auistralia.
Vol. 80, No. 1 July 1975
ANIMAL MODEL OF BILIARY OBSTRUCTION
187
References
1. Virchow R: Uber das Vorkommen uind den Nachwers des hepatogenen, insbesondere des katarrholischen Ictertus. Arch Pathol Anat 32:117-125, 1865 2. Watson CJ, Hoffbatier FW: The problem of prolonged hepatitis with partictular reference to the cholangiolitic type and to the development of cholangiolitic cirrhosis of the liver. Ann Interni Med 25:195-227, 1946 3. Joske RA, Finlay-Jones LR, Saint EG: The actite cholestatic syndrome. Med J Atist 1:609-618, 1961
4. Joske RA: The association of viral hepatitis and pancreatitis. R Melbolurne Hosp Clin Rep 25:1-8, 1955 5. Rove P: Processos inflamatorios da juneao col6doco-pancreato-duiodenal. Sao Patulo, 1953 6. Hosier DM, Newton WA Jr: Seriouis coxsackie infection in infants and childlren. J Dis Child 96:251-267, 1958 7. Stanley NF: Reovirtises. Br Med Btull 23:150-154, 1967 8. Stanley NF, Dorman DC, Ponsford J: Stuidies on the pathogenesis of a hitherto tundescribed virtus (hepatoencephalomyelitis) produicing tinuistual symptoms in suickling mice. Atist J Exp Biol Med Sci 31:147-159, 1953 9. Stanley NF, Dorman DC, Ponsford J: Stuidies on the hepatoencephalomyelitis (HEV). Aust J Exp Biol Med Sci 32:543-562, 1954 10. Phillips PA, Keast D, Papadimitriou JM, Walters MN-I, Stanley NF: Chronic obstruictive jauindice induced by reovirus type 3 in weanling mice. Pathology 1:193-203, 1969
188
STANLEY AND JOSKE
American Journal of Pathology
[End of Article]
Chronic Biliary Obstruiction
Animal Model: Chronic Biliary Obstruction Cauised by Reoviruis Type 3
Contributed by: Neville F. Stanley, DSc, FRCPA(Hon), and R. A. Joske, MD, PhD, FRACP, Departments of Microbiology and Medicine, University of Western Australia, Nedlands, 6009, Western Australia.
Human Disease
Nonbacterial infections prodtucing chronic biliary obstruiction in man are a clinical and pathologic enigma. Virchow 1 described an entity of catarrhal jauindice duie to chronic cholangitis. The natture of this entity remains in dispuite. Virchow's paper is, tinfortuinately, without illuistrations. It is generally considered to be a description of viral hepatitis, btut in this latter condition, changes in the external biliary tree are minimal or absent. Viral hepatitis may produice a cholestatic syndrome, with damage to the smaller interhepatic radicles resuilting in an obstruictive pictuire.2' Obstruictive jauindice in man may also resuilt from fibrouis strictuires at the lower end of the common bile dtuct in the absence of either pancreatitis or cholelithiasis. The etiology of these is uinknown, buit a local infective or inflammatory process has been invoked.4 Viruis infections may also produice external biliary obstruiction secondary to virtus pancreatitis, possibly with extension to the lower portion of the common bile duict where it traverses the head of the pancreas. This has been doctumented for muimps viruis, viruis hepatitis, and possibly also coxsackie infections in infants.'66 Generally, however, this grouip of conditions is poorly stuidied. They are not common, and viruis isolations are diffictult both to attempt and to achieve. Puiblication sponsored by the Registry of Comparative Pathology of the Armed Forces Institute of
Pathology and suipported by Ptublic Health Service Grant RR-00301 from the Division of Research
Resouirces, US Department of Health, Edtucation and Welfare, tnder the auispices of Universities As-
sociated for Research and
Edtucation
in Pathology, Inc.
185
186
STANLEY AND JOSKE
American Journal of Pathology
Biologic Features of Murine Model
Althouigh newb)orn mice are highly suisceptible to infection with reovirtls Types 1, 2, and 3, weanling mice are muich more resistant to the produiction of disease.7 10 Disease has been produiced in weanling mice only by the inocuilatioin of massive doses of reoviruis Type 3 by the intraperitoneal rouite; 40% of the mice developed chronic obstruictive jaulndice.10 Jauindice appeared 3 or more weeks after inocuilation and resuilted from the obstruiction of the common bile duict at the duiodenal end following denuidationi of the bile d(lct mtucosa. One week after inocuilation, reovirtis was observed replicating in the bile duict muicosal cells. Three weeks after infection, when jauindice was apparent, no infective viruis couild be detected in the bile duicts, livers or spleens of the mice. It appearedl that withi the higlh concentration of infective reoviruis Type 3 particles, the titer of viruis in the common bile duict became high enouigh to permit invasion of cells lining its Ilumen. Virions passed both the sinuisoidal and hepatic layers before reaching the common bile duict. Fibrosis in the terminal portion of the common bile duct came in the wake of celluilar necrosis and the inflammatory response to viruis invasion. The suibse(quent strictuire formation, and the obstruiction of flow in the common bile diuct which it cauised, was then responsible for the hepatic and pancreatic lesions seen in the later stages of the disease. Comparison With Human Disease and Potential Usefulness of the Model
This model suiggests that some cases of biliary obstruiction at the ampuilla of Vater might occuir following viruis choledochitis. Even so, establishment of this wouild be difficuilt becauise of either the absence of viruis at the time of onset of the jauindice or inability to detect it in the tissuies at this time dtue to the virostatic properties of bile. High levels of antibody might be detectable, however, buit these in tuirn wouild render detection of small amouints of persistent viruis difficuilt. A combined clinical and epidemiologic approach with attempted viruis isolation from blood and feces, as well as viral and electron microscopic stuidy of possible suirgical specimens, might aid in the stuidy of an obscuire and difficuilt grouip of diseases. The muirine infection provides a basis for a working protocol for this. Availability
Mice and viruises may be obtained from the Department of Microbiology, University of Western Auistralia.
Vol. 80, No. 1 July 1975
ANIMAL MODEL OF BILIARY OBSTRUCTION
187
References
1. Virchow R: Uber das Vorkommen uind den Nachwers des hepatogenen, insbesondere des katarrholischen Ictertus. Arch Pathol Anat 32:117-125, 1865 2. Watson CJ, Hoffbatier FW: The problem of prolonged hepatitis with partictular reference to the cholangiolitic type and to the development of cholangiolitic cirrhosis of the liver. Ann Interni Med 25:195-227, 1946 3. Joske RA, Finlay-Jones LR, Saint EG: The actite cholestatic syndrome. Med J Atist 1:609-618, 1961
4. Joske RA: The association of viral hepatitis and pancreatitis. R Melbolurne Hosp Clin Rep 25:1-8, 1955 5. Rove P: Processos inflamatorios da juneao col6doco-pancreato-duiodenal. Sao Patulo, 1953 6. Hosier DM, Newton WA Jr: Seriouis coxsackie infection in infants and childlren. J Dis Child 96:251-267, 1958 7. Stanley NF: Reovirtises. Br Med Btull 23:150-154, 1967 8. Stanley NF, Dorman DC, Ponsford J: Stuidies on the pathogenesis of a hitherto tundescribed virtus (hepatoencephalomyelitis) produicing tinuistual symptoms in suickling mice. Atist J Exp Biol Med Sci 31:147-159, 1953 9. Stanley NF, Dorman DC, Ponsford J: Stuidies on the hepatoencephalomyelitis (HEV). Aust J Exp Biol Med Sci 32:543-562, 1954 10. Phillips PA, Keast D, Papadimitriou JM, Walters MN-I, Stanley NF: Chronic obstruictive jauindice induced by reovirus type 3 in weanling mice. Pathology 1:193-203, 1969
188
STANLEY AND JOSKE
American Journal of Pathology
[End of Article]
