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Central venulitis in liver allografts: Considerations of differential diagnosis
Editorials
Central Venulitis in Liver Allografts: Considerations of Differential Diagnosis
SEE ARTICLE ON PAGE 1141
The histopathologic manifestations of various hepatic insults and diseases appear the same in liver allografts as they do in nontransplanted livers. Final determination of an etiology in either setting requires clinicopathologic correlation. There are, however, two major differences. First, some diseases or insults are unique to the allograft or extremely uncommon in native livers, such as rejection, preservation injury, iatrogenic mechanical complications, and adverse reactions to immunosuppressive medications. Second, timing of the complication after transplantation is an extremely important consideration in the interpretation of allograft biopsies. Thus, the differential diagnosis for “central venulitis,” as defined by Krasinskas et al. in this issue of HEPATOLOGY1 should include all insults associated with similar lesions in native livers, plus those unique to the allograft. Centrilobular or perivenular hepatocyte necrosis in native livers can be caused by viral and autoimmune hepatitis, adverse drug reactions, and compromised afferent or efferent blood flow; rejection is added to the list in allografts. In an allograft, further histopathologic characterization can help narrow the possibilities. If the necrosis is accompanied by perivenular mononuclear inflammation, an immune-mediated or associated etiology is often suspected. Involvement of a majority of central veins suggests a global insult such as an adverse drug reaction, vascular compromise, or rejection, whereas patchy involvement is more common with viral and autoimmune hepatitis. The focus of any coexistent portal necroinflammatory activity can provide additional useful information. Inflammatory damage to bile ducts and portal veins suggests coexistent rejection, as in the study of Krasinskas et al.,1 whereas prominent interface activity indicates coexistent viral or autoimmune hepatitis.2 Mechanical compromises to blood flow are most common early after transplantation, usually involve the hepatic artery, and are uncommonly associated with an inflammatory infiltrate; they are also more common with segmental liver allografts. It is not surprising that Krasinskas et al.1 found no association with altered blood flow in their study given the timing of onset. Centrilobular confluent necrosis is also associated with ad-
From the Division of Transplant Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA. Received March 1, 2001; accepted March 6, 2001. Address reprint requests to: Anthony Jake Demetris, M.D., Division of Transplant Pathology, University of Pittsburgh Medical Center, E1548 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261. E-mail: [email protected]; fax: 412-624-6654. Copyright © 2001 by the American Association for the Study of Liver Diseases. 0270-9139/01/3305-0039$35.00/0 doi:10.1053/jhep.2001.24315
verse reactions to a number of drugs including both predictable and idiosyncratic hepatotoxins. Included are acetaminophen, halothane, and other halogenated anesthetic agents; isoniazid, methyldopa, ketoconazole, and hydralazine; as well as toxins such as Amanita mushrooms, carbon tetrachloride, and copper sulfate, most of which can be effectively excluded in liver allograft recipients. Hytiroglou et al.3 raised the possibility that central venulitis might represent an adverse reaction to tacrolimus (FK506), even though the lesion was more common in cyclosporine-treated patients in their study.3 Evidence against this hypothesis includes (1) the presence of an indistinguishable lesion in liver allograft recipients who have never received tacrolimus, (2) the lack of an association with tacrolimus blood levels, (3) the timing of the appearance of the lesion, and (4) a better alternative explanation. It would be unusual for an adverse reaction to a medication to first appear at a mean of 2 months after first exposure in 16% of patients when the dose of the suspect medication is much lower than early after transplantation, particularly when the insult stabilizes or resolves without any further change in the dosage of the suspect drug, as seen in the study of Krasinskas et al.1 Nevertheless, the possibility that tacrolimus caused centrilobular necrosis and inflammation was very seriously considered during drug development in experimental animals and in the early human trials: the question was directly addressed and the interpretation reported.4-6 The native liver of murine, canine, and primate renal allograft recipients was systematically examined. The possibility of rejection can be excluded in this setting. Centrilobular hepatocellular swelling was the only liver toxicity, and this change was seen only in dogs, which are exquisitely sensitive to gastrointestinal side effects of tacrolimus.4-6 A convincing but unpublished observation occurred during a weekly clinicopathologic conference at the University of Pittsburgh more than 10 years ago. Three of 20 to 25 first tacrolimus-treated patients who underwent liver biopsy that week showed central venulitis, and concern of an adverse reaction was raised. Convinced that central venulitis was a manifestation of rejection, as originally described by Porter,7 the program chief, Dr. Starzl, ordered a doubling of the tacrolimus dosage in these particular patients. Review of follow-up biopsies from affected patients the following week showed resolution of the changes. Finally, the lack of reports of significant hepatic toxicity or central venulitis in tacrolimus-treated kidney and heart allograft recipients is reassuring, but more follow-up is needed. Porter7 first described central venulitis and subendothelial inflammation of both central and portal veins, as a manifestation of acute rejection in untreated liver allograft recipients. Rejection targets this region because the venular and perivenular connective tissue contains potent donor antigen-presenting cells (dendritic cells and precursors), which stimulate recipient lymphocyte blastogenesis, proliferation, and cyto-
1329
1330 DEMETRIS
kine release in allografts, but not in syngeneic controls.8 When loaded with viral or other antigens, these antigen-presenting cells can also stimulate syngeneic lymphocytes, and larger hepatic veins contain small lymphatic vessels that drain to inferior venal caval nodes. Thus, it is not surprising that foci central venulitis appear also in native livers with viral or autoimmune hepatitis. In an allograft, cytokines produced as a result of recurrent diseases or infections have the potential to up-regulate adhesion, costimulatory, and donor major histocompatibility complex antigens, which can then stimulate allo-recognition and rejection. Thus, foci central venulitis can appear during recurrent viral or autoimmune hepatitis either as part of the underlying disease or as a manifestation of coexistent rejection. Distinguishing between these two possibilities can be difficult and subjective: when a majority of central veins are involved, we favor a coexistent rejection reaction. The histopathologic manifestations and incidence of various complications are similar in adults and pediatric liver allograft recipients with the exception of vascular complications, which are more frequent in pediatric livers because of smaller caliber vessels; and “oportunistic” viral infections such as EBV, CMV, and adenovirus to which children have less preexisting immunity. Recurrent disease is also a less frequent problem in children, but they may show heightened immune reactivity leading to a higher incidence of chronic rejection. Previous studies of central venulitis in adults show a later onset compared with traditional portal-based rejection,9 and a survey of our adult liver allograft recipients showed a remarkably similar incidence of isolated central venulitis (17%; unpublished observation, A.D. Demetris). The most ominous outcome of central venulitis is the development of chronic changes, which occurred in 29% of the patients in the study of Krasinskas et al.1 but in less than 10% of our adult patients. This difference could be related to consistent treatment of central venulitis as a manifestation of rejection9 or to the propensity of certain individuals to develop fibrosis. The chronic changes can manifest as severe perivenular fibrosis and a veno-occlusive syndrome,10 complete with refractory ascites, or as more traditional chronic rejection with bile duct loss, or both.11,12 The congestion and ascites are likely attributable to disruption and fibrosis of the delicate junction between the sinusoids and the central veins. It is worth noting that the incidence of severe perivenular fibrosis in liver allografts with chronic rejection11,12 and venoocclusive disease in bone marrow recipients13 is less in those maintained on tacrolimus compared with cyclosporine. Thus, when central venulitis is encountered in a liver allograft recipient, it is my opinion that rejection should be given primary consideration; several studies,9,10,14 including the one by Krasinskas et al.,1 have come to a similar conclusion. However, depending on subtle histopathologic cues outlined
HEPATOLOGY May 2001
above and the circumstances surrounding the biopsy, a reasonable search for other possible causes should be performed, which takes into consideration the best interests of the patient. ANTHONY JAKE DEMETRIS, M.D. Division of Transplant Pathology University of Pittsburgh Medical Center Pittsburgh, PA REFERENCES 1. Krasinskas AM, Ruchelli ED, Rand EB, Chittams MS, Furth EE. Central venulitis is pediatric liver allografts. HEPATOLOGY 2001;33:1141-1147. 2. Nakazawa Y, Walker NI, Kerlin P, Steadman C, Lynch SV, Strong RW, Clouston AD. Clinicopathological analysis of liver allograft biopsies with late centrilobular necrosis: a comparative study in 54 patients. Transplantation 2000;69:1599-1608. 3. Hytiroglou P, Lee R, Sharma K, Theise ND, Schwartz M, Miller C, Thung SN. FK506 versus cyclosporine as primary immunosuppressive agent for orthotopic liver allograft recipients. Histologic and immunopathologic observations. Transplantation 1993;56:1389-1394. 4. Todo S, Ueda Y, Demetris JA, Imventarza O, Nalesnik M, Venkataramanan R, Mazowka L, et al. Immunosuppression of canine, monkey, and baboon allografts by FK 506: with special reference to synergism with other drugs and to tolerance induction. Surgery 1988;104:239-249. 5. Todo S, Murase N, Ueda Y, Podesta L, ChapChap P, Kahn D, Okuda K, et al. Effect of FK506 in experimental organ transplantation. Transplant Proc 1988;20(Suppl 1):215-219. 6. Demetris AJ, Fung JJ, Todo S, McCauley J, Jain A, Takaya S, Alessiani M, et al. Conversion of liver allograft recipients from cyclosporine to FK506 immunosuppressive therapy—a clinicopathologic study of 96 patients. Transplantation 1992;53:1056-1062. 7. Porter KA. Pathology of liver transplantation. Transplant Rev 1969;2: 129-170. 8. Demetris AJ, Qian S, Sun H, Fung JJ, Yagihashi A, Murase N, Iwaki Y, et al. Early events in liver allograft rejection. Delineation of sites of simultaneous intragraft and recipient lymphoid tissue sensitization. Am J Pathol 1991;138:609-618. 9. Tsamandas AC, Jain AB, Felekouras ES, Fung JJ, Demetris AJ, Lee RG. Central venulitis in the allograft liver: a clinicopathologic study. Transplantation 1997;64:252-257. 10. Sebagh M, Debette M, Samuel D, Emile JF, Falissard B, Cailliez V, Shouval 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;30:1144-1150. 11. Blakolmer K, Seaberg EC, Batts K, Ferrell L, Markin R, Wiesner R, Detre K, et al. Analysis of the reversibility of chronic liver allograft rejection implications for a staging schema. Am J Surg Pathol 1999;23:1328-1339. 12. Blakolmer K, Jain A, Ruppert K, Gray E, Duquesnoy R, Murase N, Starzl TE, et al. Chronic liver allograft rejection in a population treated primarily with tacrolimus as baseline immunosuppression: long-term follow-up and evaluation of features for histopathological staging. Transplantation 2000;69:2330-2336. 13. Woo M, Przepiorka D, Ippoliti C, Warkentin D, Khouri I, Fritsche H, Korbling M. Toxicities of tacrolimus and cyclosporin A after allogeneic blood stem cell transplantation. Bone Marrow Transplant 1997;20:10951098. 14. Ludwig J, Gross JB, Perkins JD, Moore SB. Persistent centrilobular necroses in hepatic allografts. Hum Pathol 1990;21:656-661.
Central Venulitis in Liver Allografts: Considerations of Differential Diagnosis
SEE ARTICLE ON PAGE 1141
The histopathologic manifestations of various hepatic insults and diseases appear the same in liver allografts as they do in nontransplanted livers. Final determination of an etiology in either setting requires clinicopathologic correlation. There are, however, two major differences. First, some diseases or insults are unique to the allograft or extremely uncommon in native livers, such as rejection, preservation injury, iatrogenic mechanical complications, and adverse reactions to immunosuppressive medications. Second, timing of the complication after transplantation is an extremely important consideration in the interpretation of allograft biopsies. Thus, the differential diagnosis for “central venulitis,” as defined by Krasinskas et al. in this issue of HEPATOLOGY1 should include all insults associated with similar lesions in native livers, plus those unique to the allograft. Centrilobular or perivenular hepatocyte necrosis in native livers can be caused by viral and autoimmune hepatitis, adverse drug reactions, and compromised afferent or efferent blood flow; rejection is added to the list in allografts. In an allograft, further histopathologic characterization can help narrow the possibilities. If the necrosis is accompanied by perivenular mononuclear inflammation, an immune-mediated or associated etiology is often suspected. Involvement of a majority of central veins suggests a global insult such as an adverse drug reaction, vascular compromise, or rejection, whereas patchy involvement is more common with viral and autoimmune hepatitis. The focus of any coexistent portal necroinflammatory activity can provide additional useful information. Inflammatory damage to bile ducts and portal veins suggests coexistent rejection, as in the study of Krasinskas et al.,1 whereas prominent interface activity indicates coexistent viral or autoimmune hepatitis.2 Mechanical compromises to blood flow are most common early after transplantation, usually involve the hepatic artery, and are uncommonly associated with an inflammatory infiltrate; they are also more common with segmental liver allografts. It is not surprising that Krasinskas et al.1 found no association with altered blood flow in their study given the timing of onset. Centrilobular confluent necrosis is also associated with ad-
From the Division of Transplant Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA. Received March 1, 2001; accepted March 6, 2001. Address reprint requests to: Anthony Jake Demetris, M.D., Division of Transplant Pathology, University of Pittsburgh Medical Center, E1548 Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, PA 15261. E-mail: [email protected]; fax: 412-624-6654. Copyright © 2001 by the American Association for the Study of Liver Diseases. 0270-9139/01/3305-0039$35.00/0 doi:10.1053/jhep.2001.24315
verse reactions to a number of drugs including both predictable and idiosyncratic hepatotoxins. Included are acetaminophen, halothane, and other halogenated anesthetic agents; isoniazid, methyldopa, ketoconazole, and hydralazine; as well as toxins such as Amanita mushrooms, carbon tetrachloride, and copper sulfate, most of which can be effectively excluded in liver allograft recipients. Hytiroglou et al.3 raised the possibility that central venulitis might represent an adverse reaction to tacrolimus (FK506), even though the lesion was more common in cyclosporine-treated patients in their study.3 Evidence against this hypothesis includes (1) the presence of an indistinguishable lesion in liver allograft recipients who have never received tacrolimus, (2) the lack of an association with tacrolimus blood levels, (3) the timing of the appearance of the lesion, and (4) a better alternative explanation. It would be unusual for an adverse reaction to a medication to first appear at a mean of 2 months after first exposure in 16% of patients when the dose of the suspect medication is much lower than early after transplantation, particularly when the insult stabilizes or resolves without any further change in the dosage of the suspect drug, as seen in the study of Krasinskas et al.1 Nevertheless, the possibility that tacrolimus caused centrilobular necrosis and inflammation was very seriously considered during drug development in experimental animals and in the early human trials: the question was directly addressed and the interpretation reported.4-6 The native liver of murine, canine, and primate renal allograft recipients was systematically examined. The possibility of rejection can be excluded in this setting. Centrilobular hepatocellular swelling was the only liver toxicity, and this change was seen only in dogs, which are exquisitely sensitive to gastrointestinal side effects of tacrolimus.4-6 A convincing but unpublished observation occurred during a weekly clinicopathologic conference at the University of Pittsburgh more than 10 years ago. Three of 20 to 25 first tacrolimus-treated patients who underwent liver biopsy that week showed central venulitis, and concern of an adverse reaction was raised. Convinced that central venulitis was a manifestation of rejection, as originally described by Porter,7 the program chief, Dr. Starzl, ordered a doubling of the tacrolimus dosage in these particular patients. Review of follow-up biopsies from affected patients the following week showed resolution of the changes. Finally, the lack of reports of significant hepatic toxicity or central venulitis in tacrolimus-treated kidney and heart allograft recipients is reassuring, but more follow-up is needed. Porter7 first described central venulitis and subendothelial inflammation of both central and portal veins, as a manifestation of acute rejection in untreated liver allograft recipients. Rejection targets this region because the venular and perivenular connective tissue contains potent donor antigen-presenting cells (dendritic cells and precursors), which stimulate recipient lymphocyte blastogenesis, proliferation, and cyto-
1329
1330 DEMETRIS
kine release in allografts, but not in syngeneic controls.8 When loaded with viral or other antigens, these antigen-presenting cells can also stimulate syngeneic lymphocytes, and larger hepatic veins contain small lymphatic vessels that drain to inferior venal caval nodes. Thus, it is not surprising that foci central venulitis appear also in native livers with viral or autoimmune hepatitis. In an allograft, cytokines produced as a result of recurrent diseases or infections have the potential to up-regulate adhesion, costimulatory, and donor major histocompatibility complex antigens, which can then stimulate allo-recognition and rejection. Thus, foci central venulitis can appear during recurrent viral or autoimmune hepatitis either as part of the underlying disease or as a manifestation of coexistent rejection. Distinguishing between these two possibilities can be difficult and subjective: when a majority of central veins are involved, we favor a coexistent rejection reaction. The histopathologic manifestations and incidence of various complications are similar in adults and pediatric liver allograft recipients with the exception of vascular complications, which are more frequent in pediatric livers because of smaller caliber vessels; and “oportunistic” viral infections such as EBV, CMV, and adenovirus to which children have less preexisting immunity. Recurrent disease is also a less frequent problem in children, but they may show heightened immune reactivity leading to a higher incidence of chronic rejection. Previous studies of central venulitis in adults show a later onset compared with traditional portal-based rejection,9 and a survey of our adult liver allograft recipients showed a remarkably similar incidence of isolated central venulitis (17%; unpublished observation, A.D. Demetris). The most ominous outcome of central venulitis is the development of chronic changes, which occurred in 29% of the patients in the study of Krasinskas et al.1 but in less than 10% of our adult patients. This difference could be related to consistent treatment of central venulitis as a manifestation of rejection9 or to the propensity of certain individuals to develop fibrosis. The chronic changes can manifest as severe perivenular fibrosis and a veno-occlusive syndrome,10 complete with refractory ascites, or as more traditional chronic rejection with bile duct loss, or both.11,12 The congestion and ascites are likely attributable to disruption and fibrosis of the delicate junction between the sinusoids and the central veins. It is worth noting that the incidence of severe perivenular fibrosis in liver allografts with chronic rejection11,12 and venoocclusive disease in bone marrow recipients13 is less in those maintained on tacrolimus compared with cyclosporine. Thus, when central venulitis is encountered in a liver allograft recipient, it is my opinion that rejection should be given primary consideration; several studies,9,10,14 including the one by Krasinskas et al.,1 have come to a similar conclusion. However, depending on subtle histopathologic cues outlined
HEPATOLOGY May 2001
above and the circumstances surrounding the biopsy, a reasonable search for other possible causes should be performed, which takes into consideration the best interests of the patient. ANTHONY JAKE DEMETRIS, M.D. Division of Transplant Pathology University of Pittsburgh Medical Center Pittsburgh, PA REFERENCES 1. Krasinskas AM, Ruchelli ED, Rand EB, Chittams MS, Furth EE. Central venulitis is pediatric liver allografts. HEPATOLOGY 2001;33:1141-1147. 2. Nakazawa Y, Walker NI, Kerlin P, Steadman C, Lynch SV, Strong RW, Clouston AD. Clinicopathological analysis of liver allograft biopsies with late centrilobular necrosis: a comparative study in 54 patients. Transplantation 2000;69:1599-1608. 3. Hytiroglou P, Lee R, Sharma K, Theise ND, Schwartz M, Miller C, Thung SN. FK506 versus cyclosporine as primary immunosuppressive agent for orthotopic liver allograft recipients. Histologic and immunopathologic observations. Transplantation 1993;56:1389-1394. 4. Todo S, Ueda Y, Demetris JA, Imventarza O, Nalesnik M, Venkataramanan R, Mazowka L, et al. Immunosuppression of canine, monkey, and baboon allografts by FK 506: with special reference to synergism with other drugs and to tolerance induction. Surgery 1988;104:239-249. 5. Todo S, Murase N, Ueda Y, Podesta L, ChapChap P, Kahn D, Okuda K, et al. Effect of FK506 in experimental organ transplantation. Transplant Proc 1988;20(Suppl 1):215-219. 6. Demetris AJ, Fung JJ, Todo S, McCauley J, Jain A, Takaya S, Alessiani M, et al. Conversion of liver allograft recipients from cyclosporine to FK506 immunosuppressive therapy—a clinicopathologic study of 96 patients. Transplantation 1992;53:1056-1062. 7. Porter KA. Pathology of liver transplantation. Transplant Rev 1969;2: 129-170. 8. Demetris AJ, Qian S, Sun H, Fung JJ, Yagihashi A, Murase N, Iwaki Y, et al. Early events in liver allograft rejection. Delineation of sites of simultaneous intragraft and recipient lymphoid tissue sensitization. Am J Pathol 1991;138:609-618. 9. Tsamandas AC, Jain AB, Felekouras ES, Fung JJ, Demetris AJ, Lee RG. Central venulitis in the allograft liver: a clinicopathologic study. Transplantation 1997;64:252-257. 10. Sebagh M, Debette M, Samuel D, Emile JF, Falissard B, Cailliez V, Shouval 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;30:1144-1150. 11. Blakolmer K, Seaberg EC, Batts K, Ferrell L, Markin R, Wiesner R, Detre K, et al. Analysis of the reversibility of chronic liver allograft rejection implications for a staging schema. Am J Surg Pathol 1999;23:1328-1339. 12. Blakolmer K, Jain A, Ruppert K, Gray E, Duquesnoy R, Murase N, Starzl TE, et al. Chronic liver allograft rejection in a population treated primarily with tacrolimus as baseline immunosuppression: long-term follow-up and evaluation of features for histopathological staging. Transplantation 2000;69:2330-2336. 13. Woo M, Przepiorka D, Ippoliti C, Warkentin D, Khouri I, Fritsche H, Korbling M. Toxicities of tacrolimus and cyclosporin A after allogeneic blood stem cell transplantation. Bone Marrow Transplant 1997;20:10951098. 14. Ludwig J, Gross JB, Perkins JD, Moore SB. Persistent centrilobular necroses in hepatic allografts. Hum Pathol 1990;21:656-661.