Centrilobular histopathologic changes in liver transplant biopsies

Centrilobular Histopathologic Changes in Liver Transplant Biopsies URMILA KHETTRY, MD, AMY BACKER, MD, GAMZE AYATA, MD, W. DAVID LEWIS, MD, ROGER L. JENKINS, MD, AND FREDRIC D. GORDON, MD We evaluated centrilobular histologic changes seen on post-orthotopic liver transplantation (OLT) biopsies to refine the pathologic diagnosis by systematic study of morphologic and clinical data with possible identification of prognostic criteria. A total of 110 biopsies with zone 3 pathology from 59 patients were reviewed and correlated with clinical findings. Within the first 6 months post-OLT (group I), 39 of 47 patients had combinations of centrilobular hepatocytic dropout, ballooning, and cholestasis on single or multiple biopsies attributed to perioperative ischemic/perfusion injury; 12 of 39 patients with all 3 features present had increased incidence of biliary complications and sepsis and decreased 1-year patient and graft survival; 17 of 39 patients with 2 of the 3 features had increased biliary complications but not decreased 1-year survival; and the remaining 8 of 47 patients had central venulitis associated with acute cellular rejection. After 6 months post-OLT (group II),

14 patients, including 2 from group I, had biopsies with centrilobular pathology; 8 of 14 had central venulitis related to rejection (acute, 4; chronic, 4), and fibrosis was seen in 8 (rejection, 6; cardiac problems, 2). In conclusion, combinations of centrilobular hepatocytic ballooning, dropout, and cholestasis are seen in association with reversible or irreversible ischemic/perfusion damage in the early post-OLT period. The presence of all 3 features is associated with a poor outcome. Central venulitis as a feature of acute/chronic rejection is seen at any time post-OLT and is not a predictor of poor graft/patient survival. HUM PATHOL 33:270-276. Copyright 2002, Elsevier Science (USA). All rights reserved. Key words: liver allograft, zone 3, inflammation, necrosis. Abbreviations: OLT, orthoptic liver transplantation; CLN, centrilobular necrosis.

The zonal organization of the liver facilitates classification of disorders affecting this organ, a characteristic with immense histologic diagnostic utility.1 In the past 2 decades, during routine evaluation of transplant liver biopsies, we have observed cases with findings either limited to or prominently centered around zone 3. This is the zone of a hepatic acinus, also referred to as the centrilobular area, which is farthest from the supply of incoming blood and thus prone to vascular insults and is also considered the site of most metabolic processes.2 Reports in the literature describe persistent centrilobular necrosis and central venulitis in liver allograft biopsies with some debate regarding the underlying pathogenetic mechanisms.2-9 We analyzed our cases with prominent centrilobular pathology to define the pathogenetic processes involving this zone, to develop differential diagnostic clues, and to describe features with potential prognostic value.

(OLT) in our program. No split or live-donor liver grafts were implanted during this period. There were 12 perioperative deaths. A computer scanning of the post-OLT liver pathology database of the remaining 313 patients was performed for 1 or more of the key terms “centrilobular,” “central,” and “lobular.” Because the cases were signed out by the same pathologist (U.K.), in a consistent manner, this method of retrieval was considered adequate. Of the post-OLT specimens retrieved, cases with distinctive centrilobular pathology without panlobular changes were included for this study. The presence or absence of portal changes did not affect case selection.

PATIENTS AND METHODS Study Population During the period from January 1990 to June 1998, 325 patients underwent cadaveric orthotopic liver transplantation From the Departments of Pathology, Surgery and Medicine, Lahey Clinic Medical Center, Burlington, MA; Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA; and Harvard Medical School, Boston, MA. Accepted for publication December 5, 2001. Parts of this article were presented as a poster at the United States and Canadian Academy of Pathology Meeting, San Francisco, CA, March 24, 1999. Address correspondence and reprint requests to Urmila Khettry, MD, Department of Anatomic Pathology, Lahey Clinic Medical Center, 41 Mall Road, Burlington, MA. Copyright 2002, Elsevier Science (USA). All rights reserved. 0046-8177/02/3303-0002$35.00/0 doi:10.1053/hupa.2002.32225

Histologic Evaluation Two or 3 hematoxylin and eosin–stained slides per biopsy were reviewed independently by 2 pathologists (U.K., A.B.) without any clinical information. Differences in interpretation were resolved by consensus review of the biopsies in question. The following histopathologic features were evaluated: adequacy of specimen, the number of central veins included in the specimen, central vein endothelitis (present/absent), perivenular inflammation (graded semiquantitatively: absent/mild/moderate/severe and type), centrilobular hepatocytic ballooning (present/absent), centrilobular hepatocytic dropout or necrosis (graded semiquantitatively: absent/mild/moderate/severe), sinusoidal congestion (present/absent), perivenular fibrosis (present/absent), centrilobular cholestasis (graded semiquantitatively: absent/mild/moderate/severe), other changes, and any portal findings. Biopsy diagnoses were made based on previously published criteria.1 After this assessment of each biopsy included in this study, all previous and subsequent OLT biopsies from all study patients were reviewed to define the evolution and course of the disease process.

Clinical Evaluation Medical records were reviewed in detail for each of the study cases with regard to the pre-, intra-, and post-OLT

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TABLE 1. Findings in Patients Within 6 Months Post-OLT No. of Patients/ Biopsies

Biopsy/ Day Median

Hepatocytic dropout

6/10

9

Cholestasis Hepatocytic ballooning Hepatocytic ballooning and cholestasis Hepatocytic dropout and cholestasis

3/4 1/2 4/5

Centrilobular Findings

Hepatocytic dropout, ballooning, and cholestasis Central venulitis

Ischemia Times (Hours) Range/Mean/ No. With ⬎9 Hours

Patients with Perioperative Complications

2.87–10.18/5.9/1

0

9 14 14

4.72–12.35/5.3/2 5.37/5.37/0 10.62–15.55/12.4/4

0 0 1

13/20

30

1.47–14.42/9.6/9

2

12/30

30

3.38–10.27/6.5/3

7

8/15

37

5.98–11.62/8.5/2

0

Outcome (No.), Days (Cause of Death) Alive (3): 1200–3352 Dead (3): 14 (sepsis); 448 (HBV); 2496(PTLD) Alive (3): 873–1393 Alive (1): 3261 Alive (2): 2611–2998 Dead (2): 435 (HCV); 1371 (HCV) Alive (8): 1533–3351 Dead (5): 126,265 (sepsis); 415,2193 (HCV); 545 (cardiac) Alive (4): 1101–3012 Dead (8): 30,45, 73, 351, 482 (sepsis); 166 (PTLD and sepsis); 337 (biliary problems and HCV); 936(colon carcinoma) Alive (6): 804–3268 Dead (2): 32 (sepsis); 2159 (aspiration)

Abbreviations: HBV, hepatitis B virus; PTLD, Posttransplant lymphoproliferative disorder; HCV, Hepatitis C virus.

donor and recipient clinical parameters. These included the pre-liver transplantation status of the donor, the donor operation, preservation and transportation of the donor liver, and the recipient’s intraoperative and postoperative status, course, and outcome. In this way, a clinicopathologic correlation was achieved on each of the study cases. Ischemic/perfusion damage to the graft was defined as post-OLT graft dysfunction ascribed to either prolonged ischemia during harvesting, transport, and implantation of the graft, or excessive intraoperative or postoperative bleeding or complicated vascular or biliary anastomosis. The damage was considered reversible if the graft function returned to normal in the early postoperative period. Irreversible damage was associated with progressive graft dysfunction with increasing biliary complications, resulting in retransplantation or death with or without sepsis.

Statistical Evaluation The relationship between the pathologic findings and post-OLT complications and outcome was tested using the Pearson ␹2 test for independence for contingency tables.

RESULTS One hundred and ten biopsies from 59 patients were selected as the study group and were notable for having prominent zone 3 (centrilobular) changes. The cases were initially divided into 4 categories, depending on the post-OLT period during which the biopsies were obtained: (A) within 1 month post-OLT, (B) 1 to 6 months post-OLT, (C) 6 to 12 months post-OLT, and (D) more than 12 months post-OLT. Because categories A and B shared a majority of common cases with either similar or progressive or regressive pathologic findings of same underlying pathogenesis, they were combined to form group I (cases within 6 months post-OLT). With the exception of 1, all biopsies in category C were obtained at 1 year and in most cases

depicted pathologic processes that were also seen in biopsies from category D. Therefore, these two categories (C and D) were combined to form group II (cases more than 6 months post-OLT). Although no attempt was made to make the 2 groups mutually exclusive, only 2 patients were represented in both groups I and II. Group I (Patients Within 6 Months Post-OLT) Histopathologic and Clinical Evaluation. This group consisted of 86 biopsies from 47 patients. Thirty-nine patients had various combinations of hepatocytic ballooning, dropout/necrosis, and cholestasis. Table 1 lists the median biopsy day and outcome for these 39 patients. Hepatocytic dropout alone was seen in 10 biopsies from 6 patients in association with ischemia (2), cholangitis (1), sepsis (1), severe dehydration with hypotension (1), and as a nonspecific finding (1). Cholestasis alone was seen in 3 patients, 1 with bile leak, 1 with acute cellular rejection, and in 1 as a nonspecific finding. Hepatocellular ballooning alone (Fig 1) was seen in 1 patient with severe gastrointestinal bleeding in the early post-OLT period. The combination of hepatocytic dropout and cholestasis (Fig 2) was seen in 13 patients: bile leak and biliary obstruction in 3, biliary stricture in 1, ischemic cholangiopathy in 3 (2 with infection), bile leak and ischemic cholangiopathy in 2 (1 with infection), acute cellular rejection in 2, and as a nonspecific finding in 1. The thirteenth patient also had zone 3 sinusoidal congestion and dilatation, possibly related to a significant history of hypertension in the donor. Hepatocytic ballooning and cholestasis was seen in 4 cases, 3 with sepsis and 1 with bile leak and stricture. All 3 features (Fig 3) were present in 12 cases: 5 with bile leak (3 with sepsis), 4 with sepsis, and 3 with ischemic cholangiopathy. In severe cases with 2 or all 3 findings present, portal changes including acute

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FIGURE 1. Liver transplant biopsy (post-OLT day 13) from a patient with centrilobular hepatocytic ballooning. (Hematoxylin and eosin; original magnification ⫻25.)

cholangitis, edema, and biliary ductular proliferation were also seen. In cases of progressive ischemic cholangiopathy, portal fibrosis with attenuation of bile ducts and degenerative epithelial changes were present. In all 39 cases, the findings were attributed to ischemic damage to the graft with a multitude of underlying mechanisms occurring at some point during graft procurement, transport, implantation, and in the early postoperative period. The total ischemia times (range and mean) are listed in Table 1. The range of ischemia times was similar for each combination of pathologic findings. The differences in mean ischemia times were not statistically significant because of the low number of cases with 4 of the combinations. Furthermore, ischemia time exceeding 9 hours was seen in

FIGURE 2. Post-OLT day 12 biopsy showing centrilobular hepatocytic dropout and cholestasis. The bile plugs are noted in the canaliculi. The hepatocytes around the central vein are degenerative with small foci of dropout, giving this zone a paler staining characteristic compared to the remainder of the lobule. No significant inflammation is seen. This patient had a bile leak that was successfully repaired. (Hematoxylin and eosin; original magnification ⫻25.)

FIGURE 3. Centrilobular hepatocytic degeneration with single-cell necrosis, foci of liver cell dropout, ballooning of some hepatocytes, and cholestasis with canalicular bile plugs seen on post-OLT day 6 liver allograft biopsy from a patient who had biliary tract complications and eventually died of sepsis. (Hematoxylin and eosin; original magnification ⫻40.)

association with all different combinations of findings. The patient with the longest ischemia time of 15.55 hours had postoperative infectious complications but has survived long-term without biliary problems. A closer scrutiny of the clinical findings revealed graft perfusion damage related to either excessive bleeding or complications with vascular and/or biliary anastomosis in some patients, either intraoperatively or within the first week post-OLT (Table 1). Although poor graft perfusion at some point during OLT was present in all 39 patients, 7 of the 12 with all 3 features and 2 of the 13 with hepatocytic dropout and cholestasis had documented vascular or biliary anastomotic complications and/or excessive bleeding either during the late stages of OLT or in the early postoperative period. Causes of these complications included coagulopathy, capsular tear, hilar fibrosis, and adhesions with difficult biliary anastomosis, possibly accompanied by damage to peribiliary plexus, and hepatic arterial dissection in 1 case. A distinctly different finding that was reported previously as “central venulitis”4 was seen in 8 cases, involving perivenular inflammation, mostly lymphocytic, in association with hepatocytic degeneration or dropout (Fig 4). All 8 had portal changes of acute cellular rejection of varying grades. After appropriate therapy, centrilobular dropout without inflammation was seen in biopsies of 6 patients. The rejection was deemed refractory in the other 2, requiring retransplantation in 1 and further manipulations in therapy in the other. The findings of central venulitis varied in severity and were seen at variable periods following the transplant (8 to 155 days). Some patients had multiple episodes with similar pathologic changes. Although 2 of the 8 patients had total ischemia times exceeding 9 hours, none had perioperative anastomotic or bleeding complications.

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trend for increased biliary complications with a greater number of pathologic features, this trend was much less strong for 1-year survival and incidence of infection. Patients with central venulitis responded either partially or completely to modifications in immunosuppressive regimen. In 2 of the 8 cases, rejection was deemed refractory, requiring retransplantation in 1 case. For most cases, this feature did not correlate with adverse patient outcome or increased biliary complications or sepsis. One patient (LT-229) in this group died of sepsis on post-OLT day 32, but with adequate graft function. The other death late in the post-OLT period was due to aspiration pneumonia. Group II (Patients More Than 6 Months Post-OLT) FIGURE 4. Central venulitis seen on post-OLT day 20 as a part of acute cellular rejection. There is lymphocytic phlebitis of the terminal venule (central vein) with hepatocellular necrosis in zone 3. (Hematoxylin and eosin; original magnification ⫻40.)

Patient Outcome and Clinicopathologic Correlation

Table 1 lists the outcome of patients in group I. Overall 1-year survival for the group was 81%. This was identical to 1-year survival rate for our entire patient population that underwent OLT during the study period. Of the 9 deaths occurring within 1 year post-OLT, 8 were due to sepsis and 1 was a result of posttransplant lymphoproliferative disorder. Table 2 depicts stratification of patients with ischemic/perfusion injury according to their histologic findings and correlation with 1-year survival, biliary complications, and infection. The findings of centrilobular hepatocytic dropout along with cholestasis and ballooning seen in 12 patients was associated with decreased 1-year patient survival (50%) and a higher incidence of biliary complications (75%) and infections (75%). Sepsis was the underlying cause of death in 5 of these 12 patients, with 4 of the 5 occurring during the first year post-OLT. The presence of 2 of the features was associated with a higher incidence of biliary complications (53%), but the 1-year survival was similar to the overall survival for the entire group. Presence of all 3 pathologic features (12 of 39 patients) significantly decreased 1-year survival (P ⫽ 0.029) and increased the incidence of biliary complications (P ⫽ 0.036) and infections (P ⫽ 0.023). Although there was a linear

Histopathologic Evaluation and Clinicopathologic Correlation

Twenty-four biopsies from 14 patients showed predominantly centrilobular pathologic changes with relatively minor or no involvement of the remainder of the lobule. These changes are listed in Table 3. Of all zone 3 pathology, central venulitis with hepatocytic dropout with or without fibrosis was the most common finding during this period, seen in 8 of 14 patients. The degree of central venulitis was variable, but in all cases it was seen in association with some form of rejection. In 4 of the 8 cases, the degree of inflammatory and degenerative changes was mild, and because of the associated paucity of bile ducts as well as the clinical course, a diagnosis of chronic rejection was made. In the other 4 cases, central venulitis was ascribed to acute cellular rejection on the basis of response to increased immunosuppression. In 2 of these 4 (LT-246 and LT-208), the changes of central venulitis were severe, with patient noncompliance the underlying reason in 1 patient (LT-246) and decreased absorption of tacrolimus due to poorly controlled colitis in the other patient (LT-208). In the other 2 (LT-161 and LT-256), the episodes of acute cellular rejection were superimposed on a background of recurrent HCV. In both, the immunosuppression was deliberately kept low, and the changes were not severe. One patient with chronic rejection (LT-383) did not have central venulitis. Sclerosis or fibrosis around the central vein was seen in 8 cases. Three of the 8 had progressive chronic rejection, and 3 had acute cellular rejection. The 3

TABLE 2. Clinicopathologic Correlation for Patients With Ischemic/Perfusion Injury Centrilobular Hepatocytic Dropout, Ballooning Cholestasis

Total No. of Patients

1-Year Patient Survival

Biliary Complications

Infections/Sepsis

1 feature only

10

2 Features

17

All 3 Features

12

9/10 90% 15/17 88% 6/12 50%

2/10 20% 9/17 53% 9/12 75%

2/10 20% 6/17 35% 9/12 75%

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TABLE 3. Findings in Patients More Than 6 Months Post-OLT Pathologic Findings Centilobular Patient No. (Original Diagnosis) LT-109 (PSC) LT-118 (ETOH) LT-161 (ETOH) LT-189 (A1AT) LT-208 (PSC) LT-224 (PSC) LT-226 (PSC) LT-228 (ETOH) LT-246 (Acute HBV) LT-256 (A1AT and HCV) LT-316 (PBC) LT-319 (HBV and HCV) LT-329 (ETOH) LT-383 (PSC)

Biopsy Time Post-LT (Months)

Hepatocytic Ballooning

Hepatocytic Dropout

41

⫺

84

⫺

⫹ Fatty change ⫺

12

⫺

36,48,49

⫺

12

⫺

12

Clinicopathologic Diagnosis

Outcome (cause) (Days)

None

Poor nutrition

⫺

None

⫹

⫹

ACR

Severe cardiac disease ACR

⫹⫹

⫹

⫹

⫺

⫹

⫺

⫹

⫹

⫺

⫹

⫹

⫹

⫺

⫾

⫺

⫺

⫺

⫺

Bile duct paucity Injured bile ducts Bile duct paucity None

Dead (renal) 2,437 Dead (cardiac) 2,828 Dead (HCV) 1,701 Dead (Sepsis) 1,317 Alive 3,346

12, 13

⫺

⫹

⫺

⫹

⫹

⫹

38, 54, 58, 70, 78 36

⫹

⫹

⫺

⫹⫹⫹

⫹/⫺

⫹

Bile duct paucity None

⫺

⫹

⫺

⫹

⫹

⫹

None

24, 25, 31

⫺

⫹

⫺

⫹

⫺

⫹

12

⫹/⫺

⫺

⫹

⫺

⫺

⫺

Bile duct paucity None

9

⫺

⫺

⫺

⫹/⫺

⫹

⫺

Mild ACR

18, 24

⫺

⫹

⫹

⫹/⫺

⫺

⫺

Bile duct paucity

Cholestasis

Inflammation

Fibrosis

Central Venulitis

⫺

⫺

⫺

⫺

⫺

⫺

⫹

⫺

⫹⫹

⫺

⫹ Hemorrhagic

⫺

24

⫹ Hemorrhagic ⫹

Portal

Chronic rejection ACR Chronic rejection Nonspecific Chronic rejection and stricture ACR noncompliant Rec. HCV ?ACR Chronic rejection Stricture Severe cardiac disease Chronic rejection and stricture

Dead (PTLD) 2,496 Alive 3,191 Alive 3,145 Alive 2,988 Alive 2,885 Alive 2,292 Dead (HBV) 448 Alive 2,207 Alive 1,623

Abbreviations: ETOH, alcoholic liver disease; PBC, primary biliary cirrhosis; ACR, acute cellular rejection; HBV, hepatitis B; HCV, hepatitis C; PTLD, posttransplant lymphoproliferative disorder.

patients with acute cellular rejection had multiple episodes related to noncompliance (LT-246) and low maintenance immunosuppression (LT-161 and (LT256), with minimal perivenular fibrosis in all 3. Two of the 8 patients with zone 3 fibrosis had no other findings on the biopsy. Both had severe cardiac problems due to atherosclerosis (LT-118) and iron overload (LT-329). Centrilobular cholestasis was observed in biopsies from 2 of the 3 cases with biliary stricture. Predominant zone 3 hepatocytic degeneration with dropout was observed in 11 of the 14 cases, and by itself did not have any diagnostic significance. In 1 patient (LT-226), the findings of minimal centrilobular hepatocytic degeneration at 24 months were considered nonspecific. This patient later developed chronic rejection with ductopenia. Patient LT109, with zone 3 hepatocytic degeneration and fatty changes, was clinically frail with poor nutritional status. Two of the 14 patients (LT-224 and LT-319) in this group also had centrilobular histologic changes ascribed to ischemia seen in their biopsies during the first 6 months post-OLT. At this time, although it was difficult to completely rule out residual changes from earlier ischemic injury, a diagnosis of chronic rejection was rendered in 1 patient (LT-224) because of the additional findings of central venulitis and paucity of interlobular bile ducts. In the other (LT-319), cholestasis

with minimal hepatocytic ballooning was associated with biliary stricture. Patient Outcome

Six of the 14 patients from group II died of causes unrelated to their centrilobular liver biopsy findings. Three of the 5 with chronic rejection are alive and well with modifications in their immunosuppressive regimen. The causes of death in the other 2 with chronic rejection were sepsis and posttransplant lymphoproliferative disorder. Two patients died of recurrent viral hepatitis, and 2 died of cardiac and infectious etiologies. DISCUSSION Although centrilobular necrosis and venulitis in liver allograft biopsies have been described before,2-10 a comprehensive analysis of morphologic changes involving zone 3, their clinicopathologic significance, and time course have not been previously reported. By developing a systematic approach to assessing the centrilobular region that has diagnostic (and also perhaps prognostic) importance, we hope to increase the value of the liver allograft biopsy. In our study, 59 of 313 patients (19%) had prom-

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inent centrilobular pathologic changes seen on liver allograft biopsies at variable time frames post-OLT. The changes could be broadly divided into 2 types, 1 type related to ischemic/perfusion injury and the other as a part of rejection reaction. The former, as expected, was seen during the first 6 months and accounted for most of the zone 3 pathologic changes. The latter, on the other hand, could be seen (albeit in a minority of cases) at any time during the post-OLT period. The ischemic/harvest injury results from nonimmunologic damage occurring during the procedures involved in harvesting, transporting, and reperfusing the donor liver and is usually reversible.1,11 Prolongation of any of the stages of procurement and vascular anastomosis is reflected in ischemia times recorded during OLT. However, graft damage due to poor perfusion secondary to excessive bleeding or anastomotic complications can also occur with ischemia times within the acceptable range. These perfusion problems occur intraoperatively, usually in the late stages, or in the early post-OLT period, and may not have a measurable index to predict the severity of graft damage. In addition, because of the shortage of donor organs, many previous criteria of unacceptability have been relaxed, resulting in the use of borderline hepatic allografts in both emergent and elective situations.12 Newer techniques using split liver grafts or live partial liver donation may be associated with injury to the peribiliary arterial plexus at the time of surgery.13 Such diverse underlying mechanisms, some clear-cut and others somewhat obscure, can inflict graft injuries due to poor perfusion. From our study, it appears that liver grafts can usually recover from ischemic/harvest injury associated with moderate to severe increases in total ischemia times; but damage due to excessive bleeding and anastomotic complications in the early perioperative period have a more significant impact on graft and patient survival. The biliary tract is most sensitive to perfusion insults, and the resultant ischemic cholangiopathy is associated with bile leaks and stricture formation. The ischemic damage can vary in severity and can be associated with lobular and portal changes. The portal changes often reflect damage to the extrahepatic biliary tree as well. The lobular changes resulting from poor perfusion usually involve zone 3, and in our cases consisted of combinations of hepatocytic ballooning, dropout, and cholestasis. The presence of all 3 findings signified a severe form of ischemic/perfusion injury and was associated with biliary complications and poor patient survival, with death invariably due to graft dysfunction and/or sepsis. The presence of 2 of the 3 features also correlated with biliary complications with or without sepsis. However, it was not associated with significantly poor outcome and their biliary complications were corrected by radiologic and/or surgical modalities. This finding is of importance, particularly in patients in whom either partial or borderline liver grafts are implanted, who are at an increased risk for ischemia/perfusion-related complications.14 Although the focus of this study was on zone 3 pathology, one observation regarding portal changes merits

consideration and further study. Some patients with ischemic damage did show attenuation and paucity of bile ducts mimicking changes of chronic rejection15 in the later post-OLT biopsies. A case in point was patient LT224, who had ischemic changes earlier and then developed paucity of bile ducts on post-OLT liver biopsies. Similarly, the role of possible earlier ischemic damage in causing stricture and loss of interlobular bile ducts in patients LT-319 and LT-383 cannot be definitely delineated. Further studies are required to clarify this issue. The rejection-related zone 3 pathology seen in our cases was the so-called “central venulitis,” which is a distinctive lesion and has been a source of considerable controversy.2-10 In 2 reports from 1 group, changes somewhat similar to this lesion were attributed to FK506 toxicity,5,6 but this conclusion was refuted in other studies that demonstrated central venulitis as a component of acute cellular rejection.2,4,7,8 In the 2 former studies, FK506-induced hepatotoxicity involved primarily the centrilobular region, specifically inducing hepatocytic dropout and necrosis, which could be seen weeks to months after transplantation. It was unclear whether these changes were due to difference in the mechanism of rejection in allograft livers treated with FK506 versus those treated with cyclosporine or whether they reflected FK506 specific hepatotoxicity independent of rejection mechanism. If indeed the findings of central venulitis are seen only in rejection, then changes interpreted as those due to FK506 toxicity might represent refractory rejection not responding to increased immunosuppression. The efficacy of FK506 in combating rejection in most OLT recipients is well documented.16-20 In a clinical setting, on a given biopsy it is of utmost importance to make the distinction between rejection versus FK506 hepatotoxicity because of the diametrically opposite therapeutic approach. Central venulitis in our study was seen both early and late after OLT and varied in severity with respect to the inflammatory component and hepatocytic dropout. The changes were well developed and moderate to severe in cases of acute cellular rejection. Most of these cases were seen within the first 6 months. After 6 months, it was seen as a component of acute cellular rejection only when the immunosuppressive therapy was suboptimal. In some patients, all episodes of acute rejection had central venulitis, leading us to suspect differences in target cell(s) of immune attack in these individuals. With the exception of 2 cases that progressed to refractory rejection requiring retransplantation in 1 case, all others were responsive to therapy and did not herald progression to chronic rejection. This finding is keeping in line with those reported in a recent series,2 and is unlike those of an older series3 in which this lesion was associated with progression to chronic rejection. A milder form of central venulitis was seen in 4 of 5 cases of chronic rejection, all occurring later than 6 months post-OLT and associated with interlobular bile duct loss. However, it is important to point out that the delayed deaths in 2 of the 5 were not due to graft malfunction, a finding different than reported in pre-

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viously mentioned series.2,3 In our cases, the lack of progression of chronic rejection could be attributed to FK506 rescue,17-19 which was not available at the time the earlier series was published (although it must be noted that the study did not contain data regarding graft or patient survival). The prognostic difference between our cases and those reported in the more recent series2 that does include the patient and graft survival is not readily apparent. Centrilobular necrosis (CLN) in liver allografts, which includes cases of central venulitis, has been the subject of many reports.2,3,9,10 As mentioned before, Ludwig et al3 linked it to vascular rejection and an indicator of poor patient outcome, because most of their patients progressed to chronic rejection. In a series10 consisting exclusively of pediatric liver allograft recipients, CLN was seen early in the post-OLT period in association with ischemia or rejection and was a histologic marker of poor prognosis. Late CLN, defined in a recent series2 as that appearing after post-OLT day 15, was classified into 4 groups. In 2 of their groups, rejection was the underlying pathogenetic mechanism (acute, group 1; chronic, group 3), whereas hepatitis, predominantly of autoimmune etiology, constituted group 2. Group 4 included diverse, mostly vascular causes of CLN. From the pathologic descriptions, it is apparent that all these reports include cases with features of central venulitis; however, the latter 2 studies also include cases of CLN without significant endothelitis of the central/hepatic venules. To avoid confusion and for the institution of proper therapy, we endorse use of the term “central venulitis” for rejectionrelated CLN. As reported in 1 of the series,2 it is possible to distinguish between the central venulitis type of CLN and ischemia-related CLN. Among our cases, the latter was associated with varying grades of ballooning and cholestasis and lacked an inflammatory infiltrate. We purposely excluded cases with panlobular pathology, typical of a hepatitic process.21-23 Centrilobular fibrosis in our cases was seen after 6 months post-OLT and did not represent persistent or chronic changes of earlier ischemic damage. Most cases of ischemic damage either resolved completely or, if severe, led to complications resulting in the patient’s demise or retransplantation. In addition to chronic rejection, severe cardiovascular disease infrequently resulted in pericentral scarring. In summary, prominent centrilobular findings are most common during the first 6 months post-OLT. Combinations of centrilobular hepatocytic ballooning, dropout, and cholestasis in these cases are associated with reversible or irreversible ischemic/perfusion injury, and when occurring together are associated with increased biliary complications and a poor outcome. Central venulitis is seen at any time post-OLT as a feature of either acute or chronic rejection. Centrilobular fibrosis is uncommon, occurring as a sequelae of multiple refractory or chronic rejection or reflecting an underlying chronic cardiac disease.

REFERENCES 1. Demetris AJ, Tsamandas AC, Delaney CP, et al: Pathology of liver transplantation, in Busuttil RW, Klintmalm GB (eds): Transplantation of the Liver. Philadelphia, PA, Saunders, 1996, pp 681-723 2. Nakazawa Y, Walker NI, Kerlin P, et al: Clinicopathological analysis of liver allograft biopsies with late centrilobular necrosis. Transplantation 69:1599-1608, 2000 3. Ludwig J, Gross JB, Perkins JD, et al: Persistent centrilobular necroses in hepatic allografts. HUM PATHOL 21:656-661, 1990 4. Tsamandas AC, Jain AB, Felekouras ES, et al: Central venulitis in the allograft liver: A clinicopathologic study. Transplantation 64: 252-257, 1997 5. Hytiroglou P, Lee R, Sharma K, et al: FK506 versus cyclosporine as primary immunosuppressive agent for orthotopic liver allograft recipients. Transplantation 56:1389-1394, 1993 6. Fisher A, Mor E, Hytiroglou P, et al: FK506 hepatotoxicity in liver allograft recipients. Transplantation 59:1631-1632, 1995 7. Krasinskas AM, Ruchelli ED, Rand EB, et al: Central venulitis in pediatric liver transplantation. Mod Pathol 13:186A, 2000 8. Minamiguchi S, Haga H, Sakurai T, et al: Prognostic implications of central venulitis in acute cellular rejection following liver transplantation. Mod Pathol 13:188A, 2000 9. Demetris AJ: Spectrum of chronic hepatic allograft rejection and arteriopathy and the controversy of centrilobular necrosis. Liver Transpl 6:102-103, 2000 10. Allen KJ, Rand EB, Hart J, et al: Prognostic implications of centrilobular necrosis in pediatric liver transplant recipients. Transplantation 65:693-698, 1998 11. Khettry U: Surgical pathology of the liver, in McDermott WV Jr (ed): Surgery of the Liver. Cambridge, MA, Blackwell Scientific, 1988, pp 63-109 12. Washburn WK, Johnson LB, Lewis WD, et al: Graft function and outcome of older (⬎ or ⫽ 60 years) donor livers. Transplantation 61:1062-1066, 1996 13. Bucuvalas JC, Ryckman FC: The long- and short-term outcome of living-donor liver transplantation. J Pediatr 134:259-261, 1999 14. Cronin DC II, Alonso EM, Piper JB, et al: Biliary complications in living donor liver transplantation. Trans Proc 29:419-420, 1997 15. Demetris A, Adams D, Bellamy C, et al: Update of the international Banff schema for liver allograft rejection: working recommendations for the hisopathologic staging and reporting of chronic rejection. Hepatology 31:792-799, 2000 16. Demetris AJ, Fung JJ, Todo S, et al: Conversion of liver allograft recipients from cyclosporine to FK506 immunosuppressive therapy—A clinicopathologic study of 96 patients. Transplantation 53:1056-1062, 1992 17. Rucay P, Samuel D, Farges O, et al: FK506 as treatment of late acute rejection in liver transplant patients. Trans Proc 27:11051106, 1995 18. Hebert MF, Ascher NL, Lake JR, et al: Efficacy and toxicity of FK506 for the treatment of resistant rejection in liver transplant patients. Trans Proc 23:3109-3110, 1991 19. Chen CL, Eng HL, Chen YS, et al: FK506 used as rescue therapy for refractory liver allograft rejection. Trans Proc 26:19271929, 1994 20. Millis JM, Cronin, DC, Newell KA, et al: Successful use of tacrolimus for initial rejection episodes after liver transplantation. Trans Proc 30:1407-1408, 1998 21. Khettry U, Robiou C, Jenkins R, et al: Recurrent hepatitis C in liver allografts: Early histologic indicators and correlation with HCV-RNA in liver tissue. Int J Surg Path 6:197-204, 1998 22. Khettry U, Anand N, Gordon FD, et al: Recurrent hepatitis B, hepatitis C, and combined hepatitis B and C in liver allografts: A comparative pathological study. HUM PATHOL 31:101-108, 2000 23. Ayata G, Gordon FD, Lewis WD, et al: Liver transplantation for autoimmune hepatitis: A long-term pathologic study. Hepatology 32:185-192, 2000

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