Case 6 -

Vanishing Bile Ducts and Chronic Rejection of Liver Transplant Arthur H. Cohen, Juan Lechago and Cynthia C. Nast

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The findings of case #6 are quite characteristic of the ductopenic chronic rejection picture, also known as vanishing bile duct syndrome. This is one of two possible presentations of chronic rejection, although, according to some, the rapid evolution of the condition and its appearance shortly after transplantation would place it in the category of so-called acute vanishing bile duct syndrome. There has been mounting speculation that the presence of CMV infection may be related to the appearance or to the rate of progression of this type of ductopenic rejection. Indeed, the patient illustrated in this case had documented CMV infection. Differential diagnosis of this condition includes mechanical bile duct obstruction, recurrent primary biliary cirrhosis, and recurring primary sclerosing cholangitis. Chronic Rejection Chronic rejection of the liver transplant generally takes place several weeks after transplantation, and may extend into years after the procedure. Chronic rejection leading to graft loss currently occurs in 2% to 20% of recipients and is often associated with inability to maintain baseline immunosuppression. Risk factors identified so far include primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis and infection with hepatitis B and C viruses. A recent study disclosed that chronic rejection virtually never takes place in pediatric patients subject to tacrolimus-based treatment, as long as baseline immunosuppression is maintained. An explanation offered for this difference with adults is that children rarely present the risk factors listed above. There are two forms of chronic rejection: (A) Bile duct loss (vanishing bile duct syndrome), and (B) Vascular type (obliterative arterial lesion with ischemia). These two mechanisms may be seen independently of each other, but they appear more frequently together. The diagnosis of chronic rejection with follow-up needle biopsies of the liver is fraught with difficulty, particularly in the early stages, when appropriate anti-rejection therapy may be most effective. Indeed, bile duct loss may be only partial and not involve all the portal tracts in the sample. Early damage of the bile ducts present is a good indicator, but it lacks specificity as it is also found in acute rejection. Thus, such change must be interpreted in light of other findings. Vascular rejection is characterized by occlusion of major arterial vessels at the hilum and major branches by foamy cells in the subendothelial compartment, medial fibrosis and, sometimes, thrombosis of the lumen. The manifestation of this damage at the periphery consists of pericentral hemorrhage and hepatocytic ballooning and/or necrosis, once more a finding with poor specificity that must be distinguished from acute rejection and from severe reperfusion injury. Clearly, correlation with clinical and laboratory information, as well as active communication with the treating physician is essential. Chronic rejection has been graded, together with acute rejection, by the NIDKK in the table presented below: NIDDK Liver Transplant Dabase Rejection Grades No Rejection Acute Cellular Rejection (Without Bile Duct Loss) Mild Some, not all, triads involved Moderate Most, or all, triads involved Severe Some or all triads involved, plus centrilobular hepatocyte ballooning, necrosis and dropout Chronic Rejection (With Bile Duct Loss) Mild Bile duct loss present (>50% of ducts absent in at least 4 triads) Moderate Bile duct loss present, plus one of: (a) centrilobular cholestasis, (b) centrilobular fibrosis, (c) hepatocellular ballooning or necrosis and dropout Severe Bile duct loss present, plus at least two of the findings above Cytomegalovirus Hepatitis and Contribution to Rejection. Cytomegalovirus (CMV) is the most frequent viral infection of the liver and has been detected in up to 20% of allografts. Prophylaxis and treatment with ganciclovir have improved the situation a good deal, but still it can be found in a significant number of cases. The typical lesion consists of focal destruction of hepatocytes associated with small clusters of neutrophils, or microabscesses, with or without Kupffer cell hyperplasia. Characteristic intranuclear and, sometimes, intracytoplasmic inclusions can be seen in many instances. Immunocytochemical investigation may be useful in cases where the typical inclusions cannot be seen with routine stains. There has been a good deal of interest in the fact that the genomic expression of CMV has been detected in structures involved in chronic transplant rejection, such as bile ducts and vascular endothelia. It has been suggested that CMV participates in the mechanisms of chronic liver transplant rejection, particularly in the vanishing bile duct syndrome. It has been further postulated that this participation consists of induction ofHLA antigen expression in cases where the donor/recipient HLA antigen match renders the transplanted liver susceptible. It has been determined that HLA-DR3 constitutes by itself a risk factor for chronic rejection, and that this risk is significantly increased in the presence of TNF-α and CMV infection. The presence of CMV in circulation, on the other hand, does not seem to influence the rate of acute rejection or reinfection in patients transplanted for HCV-related cirrhosis. Differential Diagnosis: Bile Duct Obstruction Bile duct strictures occur with diminishing frequency as surgical technology improves and experience in the field of liver transplantation accrues. In some instances, the stricture occurs at the place of anastomosis. In others, it takes place at a distance and in such cases it may be secondary to ischemic injury caused by vascular compromise to the bile ducts. The typical findings of bile duct obstruction include portal edema and fibrosis, ductular proliferation, periductular neutrophilic infiltration and canalicular cholestasis. Acute cholangitis may be present in some instances. Ductular proliferation may also be seen in acute cellular rejection, but in the latter the predominating inflammatory infiltrate tends to be chronic rather than acute. Differential diagnosis of bile duct obstruction, particularly when it occurs later, includes recurrent primary sclerosing cholangitis and chronic allograft rejection. Primary Biliary Cirrhosis Primary biliary cirrhosis (PBC) has been shown to recur in the transplanted liver in some cases. Serum titers of antimitochrondrial antibodies, which drop after the transplant, rise again in conjunction with the appearance of histological findings of recurrent disease, generally one year or more after transplantation. Recurrence of PBC has been noted in up to 50% of recipients by 10 years. The recurrent disease reenacts the findings of the primary condition, namely dense chronic inflammatory infiltrates in portal areas with formation of lymphoid aggregates, progressive bile duct destruction, and appearance of portal granulomas. Chronic rejection with ductopeniaposes the most serious differential diagnosis quandary with recurrent PBC. This condition, however, tends to be accompanied by pericentral necrosis and cholestasis, neither generally found in PBC. Primary Sclerosing Cholangitis Liver transplantation is regarded as an effective therapy for primary sclerosing cholangitis. Although it is believed that primary sclerosing cholangitis (PSC) may recur following liver transplantation, the differential diagnosis of the histologic and radiologic findings with other forms of bile duct obstruction with fibrosis may be nearly impossible. Nonetheless, it has been observed that patients who are transplanted because of PSC have a significantly higher incidence of biliary strictures post transplantation than non-PSC transplanted individuals. Long term follow-up and absence of clear evidence of chronic rejection may be needed to clearly substantiate a diagnosis of recurrent PSC. References Arnold JC, Portmann BC, O'Grady JG, Naoumov NV, Alexander GJM, Williams R. Cytomegalovirus infection persists in the liver graft in the vanishing bile duct syndrome. Hepatology 1992;16:285-292. Blakolmer K, Seaberg EC, Batts K, et al. Analysis of the reversibility of chronic liver allograft rejection. Implications for a staging schema. Am J Surg Pathol 1999;23:1328-1341. 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