BEYOND THE JOURNALAssociate Editors: Guadalupe Garcia-Tsao,

Ronald Oude Elferink, and Didier SamuelCommittee: James Boyer, Jean-Francois Dufour,

Hartmut Jaeschke, Luigi Pagliaro, Jorge Rakela,

Tania Roskams and Christian Trautwein

Centrilobular changes in acute rejection: a severe acute rejection oralready an early chronic rejection?

Acute hepatic allograft rejection: a comparison of

patients with and without centrilobular alterations

during first rejection episode. Lovell MO, Speeg KV,

Halff GA, Molina DK, Sharkey FE.

The histologic diagnosis of acute hepatic allograft

rejection is usually based upon the identification of

characteristic portal tract features. In addition to these,

centrilobular alterations such as central vein endothe-

lialitis, zone 3 inflammation, and hepatocyte necrosis

may also be seen during episodes of acute rejection. The

purpose of this study was to identify any differences in

the subsequent clinical course of patients with and

without centrilobular alterations during their first

biopsy-proven episode of acute rejection. Acute rejection

was diagnosed at least once in 35 liver recipients who had

undergone allograft biopsy. Of these, 15 (43%) had

centrilobular alterations in their first posttransplant

biopsy. These 15 patients developed ductopenia (60% vs.

30%) and subsequent episodes of acute rejection (53%

vs. 25%) more often than did the 20 patients who lacked

centrilobular alterations in their first posttransplant

biopsy. Time to first episode of acute rejection and rates

of subsequent recurrent hepatitis and death were similar

between the 2 groups. Patients with centrilobular

alterations during a first episode of acute rejection are

more likely to have subsequent episodes of acute

rejection and to develop features of chronic rejection

than are patients without these changes. These patients

may benefit from more vigilant clinical follow-up and/or

higher levels of immunosuppression.

[Abstract reproduced by permission of Liver Transpl

2004;10:369–73]

Acute rejection (AR) is a common (64%) complica-

tion after liver transplantation [1]. This condition is

histologically well characterized, with the use of inter-

nationally accepted Banff classification in terms of its

description and grading [2]. Some histological findings have

been reported to have a predictive value for the graft

outcome. A recent study by Lovell et al. [3] draws attention

to a particular form of AR that is associated with

centrilobular alterations (CA). The CA was observed on

the liver biopsies during the first AR episode in 43% of their

patients with AR. The patients with CA at first AR episode

had a significantly increased risk for developing recurrent

episodes of AR and signs consistent with chronic rejection

(CR) when compared to patients without CA. Although the

importance of CA during the development of CR has been

previously implicated [4–6], this is the first study directly

comparing the prognosis of AR with and without associated

CA during the first episode of AR. Thus, the work by Lovell

et al. [3], allows to highlight again this finding as a

pejorative prognostic factor and to question a shortcoming

of the Banff classification for AR.

The CA, also named ‘centrilobular necroinflammation’

[6] or ‘centrilobular venulitis’ [7] is a term coined to refer

the complex of hepatic vein endothelial inflammation with

or without spill over of inflammatory cells into the zone 3

hepatocytes and varying degrees of centrilobular necrosis. It

may result from various pathological processes including

ischemia (hepatic artery thrombosis/insufficiency, hepatic

vein obstruction, preservation injury), viral and autoimmune

hepatitis, drugs, acute and CR. Some of them may be easily

ruled out using the clinical data, the pattern of CA and other

associated histological findings. In the context of AR, CA

may be present with or without the presence of the portal

features of AR. In the latter situation—which was the case

in one of the patients in the study by Lovell et al. [3]—the

morphologic and clinical evidence of other potential causes

for this lesion should be ruled out.

It has been well described previously that the incidence

and severity of CA are higher in AR that ultimately evolves

Journal of Hepatology 41 (2004) 356–358

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0168-8278/$30.00 q 2004 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

doi:10.1016/j.jhep.2004.06.006

into CR [6,8] and the article by Lovell et al. [3] confirms

these observations. Based on our experience and published

work we also suggest that AR with centrilobular predilec-

tion may present a special subset of AR or may even

represent an unusual form of early CR [9]. The data by

Lovell et al. [3] does not allow verification if the CA

were associated with lower rates of ductopenia (i.e. between

20 and 50%), as they diagnosed ductopenia in the absence

of bile ducts in more than 50% of portal tracts. In this case,

it is possible that early CR was under diagnosed in their

work.

The Banff Schema for grading AR represents the

consensus opinion of a group of recognised liver transplant

pathologists, hepatologists and surgeons [2]. The schema

includes a descriptive grade: none, indeterminate, mild,

moderate and severe, and a semi-quantitative scoring (RAI)

of the three key histological features: portal inflammation,

bile duct damage, and venous subendothelial inflammation,

which are used to establish the diagnosis. In patients with

AR, the worst grade is reported to be mild in 73%, and

moderate and severe in 17% of the patients [1]. In most

centres, patients with mild AR are generally treated with

increased immunosupression only if there is concomitant

increase in liver injury tests or a dissatisfactory clinical

course that is not explained by other causes. Moderate and

severe AR are the most clinically relevant forms, and in fact

patients having moderate or severe AR during the first

episode are reported to be at increased risk of graft failure

from acute and CR [1].

In the original Banff Schema the diagnosis of AR

required the presence of at least two of the portal triad

elements, irrespective of the presence of CA. However, the

accumulating data have suggested that CA without or with

only mild portal inflammatory features can represent a

rejection related process [6,7,10]. Ongoing CA, despite

increased immunosupression enough to diminish/abolish

the portal inflammation, has been reported during the

development of CR and CA has been reported to be a

predictor of graft loss from CR [6,10]. Accordingly, the

most recent Banff report concerning CR [11] has incorpor-

ated CA without portal features of rejection as diagnostic of

AR in the proper clinical setting. But this has not been

reflected well in the descriptive grading schema of AR [2],

which classifies CA (accompanied by at least moderate

portal tract rejection changes), directly into the severe

grade. Nevertheless for CA without or with minimal portal

rejection there is uncertainty as to how they should be

graded. The work by Lovell et al. [3] shows that, when the

original descriptive Banff grade was assigned without

taking into account the CA, 33% of patients were falling

into mild grade, 33% were falling into moderate grade, and

33% were remaining in severe grade. This finding should

draw the attention to central veins in order not to under

diagnose CA when the rejection infiltrate in portal tracts is

mild or moderate.

With respect to the predictive value of individual scores

of RAI, it has been reported that the RAI score for bile duct

damage does not correlate with subsequent bile duct loss,

and the portal RAI score of $2 is a predictor of portal

fibrosis in subsequent biopsies [1]. In fact venous endo-

thelial inflammation is the RAI component which is the

most predictive of graft failure because of acute or CR [1].

Combining these results with those of the study by Lovell

et al. [3], we suggest the incorporation of separated scores

for portal veins and terminal hepatic veins into the Banff

Schema. This could allow us to evaluate the importance of

CA according to its severity. To our experience, severe

centrilobular endothelialitis is a pejorative finding that can

cause the obliteration of the vein lumen and evolution

towards a veno-occlusive disease and poor prognosis in

its highly severe form [9]. In the transplant setting, patho-

logical processes may be encountered in combination. This

also includes the combination of AR and early CR. The

correlation of a future score of centrilobular venulitis, of

CA, and the rate of ductopenia may also identify whether if

this identity represents a form of AR or the beginning of an

early CR independent of AR.

Mylene Sebagh1, Funda Yilmaz2,3

1Department of Pathology, Paul Brousse Hospital,

12, avenue Paul Vaillant Couturier,

94800 Villejuif Cedex, France2Faculty of medecine, University of Paris XI,

Kremlin Bicetre, France3Department of Pathology, Faculty of medecine,

University of Ege,

Izmir, Turkey

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