What s new in liver transplantation? Romil Saxena, MD, FRCPath (UK) Indiana University School of Medicine, Indianapolis

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1 What s new in liver transplantation? Romil Saxena, MD, FRCPath (UK) Indiana University School of Medicine, Indianapolis A combination of improved surgical techniques, donor organ preservation, selection criteria and immunosuppressive drugs have all markedly decreased short term complications in the liver allograft, leading to longer graft and patient survival. Current diagnostic and therapeutic challenges therefore revolve around long-term complications in the allograft which include rejection, recurrent disease, tumor occurrence and poorly characterized lesions such as architectural alterations and fibrosis. This talk will focus on recently characterized patterns of rejection occurring in the late post-transplantation period. Rejection in the liver allograft Rejection in the liver allograft has been historically classified into acute and chronic rejection. The former is characterized by infiltration of the allograft by immune cells which represent a reaction of the host immune system against donor antigens located on the graft. This cellular process can be abrogated by administration of immunosuppressive drugs which suppress the host response. Chronic rejection, which is characterized by obliterative arteriopathy and damage to bile ducts, does not show a similar infiltration of the allograft by donor host cells; administration of immunosuppressive drugs, therefore does not have a major role, if any, in chronic rejection. Acute rejection Inspite of the moniker acute, this type of rejection may occur anytime, including many years, after transplantation. It is thus better labeled as cellular rejection with the terms acute/early or late being used to define the timing of cellular rejection after transplantation. The histological appearance of cellular rejection occurring within the first 3 6 months of transplantation (acute/ early cellular rejection) is well recognized and consists of the classic triad of mixed portal inflammatory infiltrate, bile duct damage, and endothelitis. In contrast, the histological features of cellular rejection occurring 3 6 months after transplantation (late cellular rejection) do not show this classical triad. At this stage, the inflammatory infiltrate is not mixed and consists predominantly of mature appearing lymphocytes without as many neutrophils and eosinophils. Endothelitis is not present and bile duct damage is mild. The features may thus resemble chronic hepatitis. Distinct patterns of late cellular rejection Three additional patterns of injury are now increasingly believed to represent late rejection; these are central perivenulitis, plasma cell hepatitis and chronic hepatitis. Although these are mainly cellular patterns of rejection, there is some evidence that antibody mediated mechanisms may also be at play, at least partially. Unhappily, all three patterns of injury may be caused by a variety of non-rejection etiologies, including recurrent hepatitis C. The challenge lies in establishing a diagnostic distinction between late rejection and other competing causes, especially recurrent hepatitis C. Central perivenulitis Central perivenulitis (CP) is a necroinflammatory process localized to the central veins and the perivenular zone of hepatocytes. The lesion is characterized by variable degrees of inflammatory infiltrate, endothelitis, hepatocyte loss, extravasation of red blood cells and perivenular fibrosis. The inflammatory infiltrate consists of variable combinations of plasma cells, lymphocytes, and eosinophils. Central perivenulitis may occur with or without concomitant portal tract changes. When accompanying portal changes are present, they may provide clues to the underlying process causing central perivenulitis. When CP occurs without portal tract changes, the lesion is referred to as isolated central perivenulitis 1

2 (ICP) and the underlying etiology is more difficult to tease out. CP with portal tract changes may occur both early and late after transplantation whereas ICP occurs most often 6 months to 1 year after transplantation. Cases presenting initially as ICP may show portal changes in subsequent biopsies. ICP has been reported in approximately one-third of both adult and pediatric transplant recipients. A subset of patients who present with ICP on their biopsies have been transplanted for autoimmune hepatitis or primary biliary cirrhosis and progress to typical portal changes of recurrent disease in subsequent biopsies. In the remaining cases, the differential diagnosis includes late cellular rejection, recurrent hepatitis C infection, and drug-induced hepatitis. The distinction of recurrent hepatitis C from late cellular rejection cannot be overemphasized. The diagnosis of rejection can be reliably made only when the majority, or at least 50%, of central veins are involved; a localized reaction involving only a minority of central veins is not indicative of rejection. In addition, patients with ICP due to rejection have had prior episodes of acute rejection, many with central perivenulitis. Serum levels of viral nucleic acids and recent history of immunosuppression aid in the differential diagnosis. Evidence that central perivenulitis represents late cellular rejection includes decreased incidence of perivenular fibrosis in patients treated with immunosuppression, progression of untreated patients to chronic ductopenic rejection and increased incidence of prior episodes of rejection in patients with ICP. Clinically patients may be asymptomatic or there may be mild elevations of liver tests; in contrast to portal-based rejection, transaminases are elevated more than the biliary enzymes. Some patients may miss clinical detection altogether and present with ascites and clinical suspicion of Budd-Chiari syndrome or veno-occlusive disease. While minimal or mild cases of CP resolve spontaneously, an increased incidence of perivenular fibrosis has been observed in patients with moderate to severe CP who are not treated with immunosuppression. CP is more resistant to therapy than portal based rejection and it is believed that this lesion indicates transition from acute to chronic rejection. Acetaminophen toxicity, venous outflow block and ischemic hepatitis all affect the perivenular zone of the liver. However, none of these conditions is characterized by an inflammatory response similar to that seen in CP. Acetaminophen toxicity and ischemic hepatitis demonstrate coagulative necrosis of zone 3 hepatocytes in the absence of significant inflammation. Venous outflow block shows sinusoidal dilatation and congestion with or without hepatic plate compression in the absence of significant inflammation. Not uncommonly, central perivenulitis, whether isolated or occurring with portal tract changes, may consist of a predominantly plasma cell infiltrate. This lesion is discussed next. 2

3 Diagnostic approach to central perivenulitis (Saxena R. Practical Hepatic Pathology, 2011) Plasma cell hepatitis A distinctive inflammatory process resembling autoimmune hepatitis (AIH) in the native liver occurs in liver allografts in the late posttransplant period. The inflammatory infiltrate consists predominantly of plasma cells, and it may involve the central veins (central perivenulitis), the portal tracts or both. Not infrequently, central perivenulitis may precede the appearance of a plasma cell-rich portal inflammatory infiltrate. 3

4 When involved, the portal tracts are expanded by an inflammatory infiltrate consisting predominantly of plasma cells; variable degrees of interface activity and portal fibrosis are seen. When involving the central veins, there is a rich plasma cell infiltrate around the central veins, accompanied by cell loss and extravasation of red blood cells. When occurring in patients transplanted for AIH, this pattern of injury is generally considered to represent recurrent disease. When occurring in patients not transplanted for AIH, the lesion has been referred to as de novo AIH, plasma cell hepatitis, and plasma cell-rich AIH-like hepatitis. The term plasma cell hepatitis is preferred by this author for its brevity and for being accurately descriptive without any etiologic implications. Plasma cell hepatitis has been reported most often in pediatric patients, patients transplanted for autoimmune diseases such as primary biliary cirrhosis and primary sclerosing cholangitis, and patients transplanted for chronic hepatitis C. Whereas some patients may demonstrate increased levels of serum immunoglobulins and autoimmune antibodies, this is certainly not the norm. Treatment with steroids leads to biochemical and histological improvement in most cases. However, this therapeutic option is potentially risky in patients transplanted for hepatitis C; the finding of plasma cell hepatitis in this group of patients therefore presents considerable diagnostic and therapeutic challenges. The interplay between the hepatitis C virus and the host immune response, already complex and not well understood, becomes even more so complex in the setting of transplantation and the effects of modulation of the host immune response by interferon therapy on one hand and immunosuppressive regimens on the allograft cannot always be predicted. Thus, plasma cell hepatitis occurring in patients transplanted for hepatitis C has been variously thought to represent an atypical morphological variant of recurrent hepatitis C infection, rejection following rearming of the body s immunological system following interferon treatment with and a drug (interferon)-induced auto immune hepatitis. In nontransplanted individuals, chronic hepatitis C infection has been associated with autoimmune phenomenon such as increased serum immunoglobulins, autoantibodies, mixed cryoglobulinemia, and extrahepatic autoimmune diseases. Autoimmune features may also be triggered by interferon treatment. The liver disease in these patients pursues a more aggressive course and the prognosis is worse. In transplanted individuals, plasma cell hepatitis may occur following interferon therapy for treatment of hepatitis C. These patients may also develop extrahepatic autoimmune disorders and respond favorably to prednisone. Interferon therapy has been associated with an increased risk of progressing to chronic rejection. These data suggest that plasma cell hepatitis represents an alloimmune response triggered by interferon, probably due to re-arming of the host immune response; the distinction between rejection and auto immune hepatitis being somewhat moot. A case controlled study of patients transplanted for hepatitis C infection found that plasma cell hepatitis was associated suboptimal immunosuppression and resolved when immunosuppression was increased, strengthening the view that interferon treatment triggers rejection, especially if the patient is not adequately immunosuppressed. 4

5 Diagnostic approach to plasma cell hepatitis (Saxena R. Practical Hepatic Pathology) Idiopathic posttransplant chronic hepatitis Chronic hepatitis in the liver allograft may be caused by recurrent autoimmune or viral hepatitis, de novo viral hepatitis or drug-induced hepatitis. Some cases of chronic hepatitis may evolve into recurrent primary biliary cirrhosis on subsequent biopsies. However, a significant subset of patients do not have a well-defined cause and constitute the group of cases with idiopathic posttransplant chronic hepatitis (IPTH). The incidence of IPTH varies widely between centers and is more prevalent in those that routinely perform protocol biopsies in long-term allografts, revealing that IPTH is most often a subclinical condition. Overall, IPTH has been reported in one-third to one-half of all liver biopsies taken 12 months after transplantation. The incidence is higher in children than in adults. No correlation has been found between the incidence of IPTH and the original indication for transplantation Histologically, there is a mononuclear inflammatory infiltrate in portal tracts with variable degrees of spillover/interface hepatitis and fibrosis. There is no endothelitis. Mild bile duct damage may be present in some cases but bile ducts are not lost. Varying degrees of lobular inflammation may be seen but is usually mild. There may be mild central perivenulitis. The severity of IPTH may increase or decrease over time or remain unchanged. 5

6 Evidence that IPTH represents a form of late cellular rejection comes from the increased incidence of graft failure due to cirrhosis in patients with IPTH. The incidence of cirrhosis is less in those centers that treat IPTH with immunosuppression. IPTH appears to be more common in patients who have had previous episodes of acute cellular rejection, including CP. The diagnosis of IPTH necessitates the exclusion of all known causes of hepatitis which includes recurrent viral and autoimmune hepatitis and de novo viral hepatitis. Diagnostic approach to posttransplant chronic hepatitis (Saxena R. Practical Hepatic Pathology, 2011) 6

7 References 1. Abraham SC, Freese DK, Ishitani MB, et al: Significance of central perivenulitis in pediatric liver transplantation. Am J Surg Pathol 2008;32: Krasinskas AM, Demetris AJ, Poterucha JJ, et al: The prevalence and natural history of untreated isolated central perivenulitis in adult allograft livers. Liver Transpl 2008;14: Krasinskas AM, Ruchelli ED, Rand EB, et al: Central venulitis in pediatric liver allografts. Hepatology 2001;33: Sebagh M, Debette M, Samuel D, et al: Silent presentation of veno-occlusive disease after liver transplantation as part of the process of cellular rejection with endothelial predilection. Hepatology 1999;30: Sebagh M, Rifai K, Feray C, et al: All liver recipients benefit from the protocol 10-year liver biopsies. Hepatology 2003;37: Tsamandas AC, Jain AB, Felekouras ES, et al: Central venulitis in the allograft liver: A clinicopathologic study. Transplantation 1997;64: Hubscher SG: Central perivenulitis: a common and potentially important finding in late posttransplant liver biopsies. Liver Transpl 2008;14: Evans HM, Kelly DA, McKiernan PJ, et al: Progressive histological damage in liver allografts following pediatric liver transplantation. Hepatology 2006;43: Miyagawa-Hayashino A, Haga H, Egawa H, et al: Outcome and risk factors of de novo autoimmune hepatitis in living-donor liver transplantation. Transplantation 2004;78: Syn WK, Nightingale P, Gunson B, et al: Natural history of unexplained chronic hepatitis after liver transplantation. Liver Transpl 2007;13: Shaikh OS, Demetris AJ: Idiopathic posttransplantation hepatitis? Liver Transpl 2007;13: Ekong UD, Melin-Aldana H, Seshadri R, et al: Graft histology characteristics in long-term survivors of pediatric liver transplantation. Liver Transpl 2008;14: Mells G, Mann C, Hubscher S, et al: Late protocol liver biopsies in the liver allograft: a neglected investigation? Liver Transpl 2009;15: Mells G, Neuberger J: Protocol liver allograft biopsies. Transplantation 2008;85: Fiel MI, Agarwal K, Stanca C, et al: Posttransplant plasma cell hepatitis (de novo autoimmune hepatitis) is a variant of rejection and may lead to a negative outcome in patients with hepatitis C virus. Liver Transpl 2008;14: Khettry U, Huang WY, Simpson MA, et al: Patterns of recurrent hepatitis C after liver transplantation in a recent cohort of patients. Hum Pathol 2007;38: Garcia-Buey L, Garcia-Monzon C, Rodriguez S, et al: Latent autoimmune hepatitis triggered during interferon therapy in patients with chronic hepatitis C. Gastroenterology 1995;108: Berardi S, Lodato F, Gramenzi A, et al: High incidence of allograft dysfunction in liver transplanted patients treated with pegylated-interferon alpha-2b and ribavirin for hepatitis C recurrence: possible de novo autoimmune hepatitis? Gut 2007;56: Stanca CM, Fiel MI, Kontorinis N, et al: Chronic ductopenic rejection in patients with recurrent hepatitis C virus treated with pegylated interferon alfa-2a and ribavirin. Transplantation 2007;84: Yoshitomi M, Koshiba T, Haga H, et al: Requirement of protocol biopsy before and after complete cessation of immunosuppression after liver transplantation. Transplantation 2009;87: Berenguer M, Aguilera V, Prieto M, et al: Significant improvement in the outcome of HCVinfected transplant recipients by avoiding rapid steroid tapering and potent induction immunosuppression. J Hepatol 2006;44: Berenguer M, Rayon JM, Prieto M, et al: Are posttransplantation protocol liver biopsies useful in the long term? Liver Transpl 2001;7: Nakhleh RE, Krishna M, Keaveny AP, et al: Review of 31 cases of morphologic hepatitis in liver transplant patients not related to disease recurrence. Transplant Proc 2005;37: