Tietz syndrome

A 34-year-old Hispanic man with a history of human immunodeficiency virus (HIV) infection was admitted to our hospital with a viral load of more than 170000 copies and an absolute CD4 cell count of 18 cells/(mu)L. He complained of headaches and was found to have cryptococcal meningitis. He was treated with intravenous amphotericin B for 2 weeks, and his headaches improved significantly. However, during his hospital stay, he developed right upper quadrant pain and fever. No diarrhea or jaundice was found. The liver panel showed the following marked abnormalities: alkaline phosphatase, 1227 U/L (normal, 36-- 126 U/L); alanine aminotransferase, 323 U/L (normal, 17-- 63 U/L); aspartate aminotransferase, 228 U/L (normal, 15-- 41 U/L); total bilirubin, 21.1 mg/dL (normal, 0.2-1.2 mg/ dL); and direct bilirubin, 8.2 mg/dL (normal, 0.1-0.3 mg/ dL). Serum amylase levels were within the normal range. No ova or parasites were detected in the stool sample. Endoscopic retrograde cholangiopancreatography (ERCP) revealed mild beading of the intrahepatic bile ducts with mucosal irregularity (arrows), but no significant dilation, consistent with sclerosing cholangitis (Figure 1). A bile duct biopsy specimen obtained by ERCP showed multiple small, basophilic spheres (arrowheads) closely attached to the luminal border of the bile duct epithelium (Figure 2). These microorganisms (protozoans) were approximately 3 (mu)m in diameter and were positive with periodic acid-Schiff, Giemsa, and Gram stains, but negative with acid-fast and methenamine silver stains. A liver core biopsy specimen demonstrated focal concentric periductal fibrosis, giving the stroma an onionskin-like cuffing appearance. The lumen of one of the bile ducts was obliterated by the proliferating bile duct epithelium, but no significant inflammation was identified (Figure 3). The sclerosed intrahepatic bile duct was removed from the paraffin tissue, deparaffinized, and imbedded in plastic for examination by electron microscopy. Protozoans (arrow) were found tightly adherent to the surface of the bile duct epithelium and focally replaced bile duct cilia (Figure 4). There was a dense band at the interface between the trophozoites and the ductal epithelial cells at the point of attachment.

What is your diagnosis?

Pathologic Diagnosis: Sclerosing Cholangitis Secondary to Biliary Cryptosporidiosis

The protozoan parasite, Cryptosporidium parvum, is a causative agent of human gastroenteritis worldwide. Infection is usually self-limited, but in immunocompromised hosts, severe diarrhea and wasting may result, which is resistant to therapy. Protozoan parasite infection is a substantial threat to HIV-infected patients. Cryptosporidiosis is found in 6% of all patients with acquired immunodeficiency syndrome (AIDS) and in 21% of AIDS patients with diarrhea1-3 When the encysted C parvum are ingested, after exposure to acid in the stomach and digestive enzymes in the proximal duodenum, sporozoites are released from the exocyst. These motile organisms then infect epithelial cells of the intestinal tract and cause severe diarrhea. C parvum sporozoites also travel up the biliary tree to infect the epithelial cells that line the gallbladder and bile ducts. Acalculous cholecystitis and/or sclerosing cholangitis may then develop. Two published reports4,5 found that sclerosing cholangitis developed in 1 in 6 cases of biliary cryptosporidiosis in HIV-infected patients.

To our knowledge, the present case is the first case that showed direct morphologic evidence of Cryptosporidium presence in a sclerosing cholangitic lesion. The proliferating ductal epithelium, which was parasitized by the protozoan, occluded the bile duct lumen.

Various pathogenic mechanisms may be involved in biliary cryptosporidiosis in immunocompromised patients. For instance, there may be a direct cytopathic effect of HIV on the biliary tract mucosa. However, recent in vitro and in vivo data support the theory that the Cryptosporidium organisms are themselves cytopathic and directly produce the sclerosing cholangiole lesion.6 One in vivo study7 suggests that T-cell cytokines such as interferon-gamma might be mechanically involved in stimulating the inflammatory and sclerosing responses of Cryptosporidium in immuno-- deficient mice. This study supports the hypothesis that cell-mediated immunity contributes to the pathogenesis of Cryptosporidium-related biliary tract disease and argues against a nonspecific biliary toxicity occurring in HIV infection.

Another study,8 using in vitro cultured human biliary epithelium, demonstrated specific attachment and invasion of biliary epithelium by Cryptosporidium. The infection resulted in a direct cytopathic effect of the protozoans via apoptosis. However, in the case reported herein, the biliary ductal cells were proliferating and piling up to obstruct the lumen rather than undergoing apoptosis as was observed in the in vitro experiments. The difference between our observation in vivo and the laboratory observation in vitro may be due to several possibilities. The immune system in vivo could play a role in the toxicity of the protozoan, which would be absent in the in vitro environment. The HIV viral load and the stage of the viral infection could also play a role in the in vivo situation. In addition, the proliferative bile duct lesion described herein may represent the early stage of disease process, whereas the final apoptotic event may represent a later stage of the disease. This may be followed by condensation into a collagen scar in place of the destroyed bile duct.

The clinical features of HIV-associated sclerosing cholangitis include right upper quadrant pain (which is usually dull or colicky and nonradiating), nausea, vomiting, and fever. Jaundice is uncommon. Laboratory test results may disclose a marked increase in liver function. Cholangiography, which is usually achieved via ERCP, is necessary to define the precise anatomic biliary irregularities. Multiple strictures throughout the intrahepatic ducts are the most common manifestation.9 Since others have demonstrated that Cryptosporidium is one of the most common causative microorganisms associated with sclerosing cholangitis in HIV patients, Cryptosporidum infection in the biliary tract should always be excluded in patients with HIV who have abnormal liver laboratory findings and cholangiography, even in the absence of chronic diarrhea.

The serologic tests and stool smears stained with acid fast are the conventional methods for detection of Cryptosporidium infection. However, morphologic diagnosis of Cryptosporidium by hematoxylin-eosin and electron microscopy has also been used. By electron microscopy, the characteristic morphologic findings of Cryptosporidium and its attachment to the luminal bile duct epithelium are diagnostic.

References

1. Godwin TA. Cryptosporidiosis in the acquired immunodeficiency syndrome: a study of 15 autopsy cases. Hum Pathol. 1991;22:1215-1223.

2. Hamour AA, Bonnington A. Hawthorne B, Wilkins E. Successful treatment of AIDS-related cryptosporidial sclerosing cholangitis. AIDS. 1993;7:1449-1451.

3. Petersen C. Cryptosporidiosis in patients infected with the human immunodeficiency virus. Clin Infect Dis. 1992;15:903-909.

4. Dowsett JF, Miller R, Davidson R, Vaira D, et al. Sclerosing cholangitis in acquired immunodeficiency syndrome. Scand J Gastroenterol. 1988;23:1267-- 1274.

5. Cello JP. Acquired immunodeficiency syndrome cholangiopathy: spectrum of disease. Am J Med. 1989;86:539-546.

6. Owen RL. New perspectives on the pathogenesis of Cryptosporidium biliary disease. Hepatology 1998;28:1159-1160.

7. Stephens J, Cosyns M, Jones M, Hayward A. Liver and bile duct pathology following Cryptosporidium parvum infection of immunodeficient mice. Hepatology. 1999;30:27-35.

8. Chen XM, Levine SA, Tietz P, et al. Cryptosporidium parvum is cytopathic for cultured human biliary epithelia via an apoptotic mechanism. Hepatology. 1998;28:906-913.

9. Forbes A, Blanshard C, Gazzard B. Natural history of AIDS related sclerosing cholangitis: a study of 20 cases. Gut. 1993;34:116-121.

Chen Chen, MD, PhD; Priya Gulati, MD; Samuel W French, MD

Accepted for publication April 16, 2002.

From the Department of Pathology, Harbor-UCLA Medical Center, Torrance, Calif.

Corresponding author: Chen Chen, MD, PhD, Department of Pathology, Harbor-UCLA Medical Center, 1000 W Carson St, Torrance, CA 90502 (e-mail: cchen09o08@yahoo.com).

Reprints not available from the author.

Copyright College of American Pathologists Feb 2003
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