Portal vein thrombosis

Context.-Chronic hepatic allograft rejection is characterized by arteriopathy and bile duct loss. Pathology of the portal vein or its branches is not considered to play a major role in chronic rejection.

Objective.-A recent case of chronic rejection with total fibrous obliteration of the portal vein at the hilum and graft loss prompted us to retrospectively analyze cases of failed allografts for portal vein changes.

Design.-Six cases of failed hepatic allograft recorded in our files from 1994 to 1998 were selected for the study. For comparison, 4 cases of hepatitis C cirrhosis were included. Clinical features, including arteriograms or Doppler studies, were reviewed whenever available. Sections taken from the hilum and random parenchyma stained with routine hematoxylin-eosin, elastic van Gieson, and Massen trichrome were examined by 3 experienced liver pathologists in a randomized, blinded fashion.

Results.-Significant hepatic artery occlusion with foam cell change and bile duct loss was seen in all cases of chronic rejection (3/3), but not in the other cases. Foam cell change in the portal vein at the hilum (3/3) and occasionally into the distal branches (2/3) with variable occlusion of the lumen was seen only in cases of chronic hepatic allograft rejection. Mild luminal narrowing was observed in all the cases of cirrhosis (4/4) as a result of phlebosclerosis, most likely representing a change secondary to portal hypertension. Total obliteration of the portal vein at the hilum was seen in the index case (case 1) only.

Conclusion.-Portal venopathy can be a significant finding in chronic hepatic allograft rejection and may contribute to graft dysfunction or failure. Two-vessel disease must be considered in cases of chronic hepatic allograft rejection, and pathologists should thoroughly examine the hilum in explanted hepatic allografts.

Chronic hepatic allograft rejection is defined as an irreversible form of injury characterized by bile duct loss and/or obliterative vasculopathy.1-4 With better graft survival largely due to improved surgical techniques, better immunosuppression, and early treatment of infections, the incidence of chronic rejection has been decreasing. The principal form of obliterative vasculopathy seen in chronic rejection is foam cell arteriopathy and usually involves the large and medium-sized arteries close to the hilum. Similar changes in the portal vein (PV) or its branches as a feature of chronic rejection have been described only rarely and are not considered graft threatening.5,6 We recently encountered a case of chronic rejection in which total obliteration of the PV at the hilum was the most impressive pathologic finding. This observation led us to examine all resected specimens of graft loss seen at our institution and to evaluate changes in the PV and its radicals.

MATERIALS AND METHODS

All cases of failed hepatic allografts were identified from the files of the Liver Transplant Unit at Yale New Haven Hospital (New Haven, Conn). Only those cases in which the explants were available for histologic examination were included in the study. The cases were classified as chronic rejection based on established criteria.7 All the other explants were put in the non-chronic hepatic allograft rejection category. Two hilar sections and 2 random sections from the parenchyma stained with hematoxylineosin, elastic van Gieson, and Masson trichrome stains were reviewed independently by 3 pathologists in a randomized, blinded fashion. All portal tracts, including those at the hilum, were examined for histologic evaluation of the hepatic artery (HA), PV, and bile ducts. Percent occlusion in the HA or PV in the hilar and septal vessels and percent bile duct loss in the portal tracts were graded on a quartile scale (1, 0%-25%; 2, 26%-50%; 3, 51%-75%, and 4, 76%-100%). Foam cell change, intimal fibroplasia, and inflammation were also recorded and graded as mild, moderate, or severe. The mean parameter scores of the 3 observers were used to calculate the mean ± SD for each explant group. The vascular changes in the chronic rejection group are thought to be related to chronic rejection; therefore, 2 groups that do not have any components of chronic rejection were selected for comparison, namely, (1) cases of acute allograft failure for which explants were available and (2) cases of non-allograft-related chronic inflammatory liver disorder with portal hypertension, which are subjected to the same rapid specimen processing in the surgical pathology suite and rigorous morphologic evaluation as are failed hepatic allografts. The second category consisted of 4 primary explants for hepatitis C cirrhosis. Clinical features, including appropriate radiographic imaging studies (angiograms, Doppler study), were evaluated in all cases.

RESULTS

Seventy-four orthotopic liver transplantations were performed between 1994 and 1999 at Yale New Haven Hospital; of these cases, 6 were identified as failed hepatic allografts. Three of these 6 cases required retransplantation for non-rejection-related graft loss (ie, non-chronic rejection), and 3 required retransplantation because of chronic rejection. All orthotopic liver transplantations were performed according to the standard techniques, using venovenous bypass in most cases. The clinical details of the non-chronic rejection and chronic rejection cases are shown in Table 1. All the patients presented with gradually increasing liver enzymes and worsening liver functions. The patient in the index case (case 1) developed ascites and evidence of portal hypertension.

The means ± SDs of scores in each category are shown in Table 2. Severe HA occlusion with foam cell change was encountered in the hilum and larger septal vessels in all cases of chronic rejection but not in hepatitis C cirrhosis or non-chronic rejection cases. Foam cell portal venopathy was also encountered in all of the chronic rejection cases at the hilum (Figure 1) and occasionally in other septal vessels and smaller portal tracts (Figure 2). In the smaller portal tracts, the changes were often limited to a collection of a few foam cells only. The degree of luminal narrowing was much more pronounced in the arteries than in the PVs, except in case 1. These changes were not seen in the non-chronic rejection and hepatitis C cirrhosis cases. Significant bile duct loss was also seen only in the chronic rejection cases. In case 1, the PV at the hilum was fibrosed and completely obliterated, with marked disruption of the elastic laminae (Figures 3 and 4). The HA in the same case showed about 80% narrowing of the lumen, with foam cell arteriopathy. Foam cells were not seen in the hepatic veins or in the sinusoids. Patchy areas of centrizonal necrosis and parenchymal fibrosis were noted. This patient had developed portal hypertension, and Doppler ultrasound showed the occlusive lesion in the main PV. Acute necrosis was not evident in any of the other chronic rejection cases, and parenchymal fibrosis in those cases was also milder. Extensive acute ischemic necrosis was seen in case 6, in and around the hilar area. Clinically, thrombosis of the hepatic artery close to the anastomotic site was suspected in this case; however, no thrombus was identified in the resection specimen.

COMMENT

Chronic hepatic allograft rejection is mainly characterized by foam cell arteriopathy and bile duct loss.1-4,7 The parenchymal lesions (eg, cholestasis, centrizonal necrosis, and bile duct loss) are believed to be secondary to ischemia, although direct immunologic damage to the ducts has also been implicated.8 Interestingly, the impact of arteriopathy in the transplanted liver is much greater than that observed in normal liver, which is protected largely because of a dual blood supply. It is believed that additional hemodynamic alterations involving the portal circulation predispose the transplanted livers to ischemic damage. It should also be realized that these changes may be insidious, having no acute component, and individual contributions from HA occlusion or portal venopathy may be difficult to differentiate.

Portal vein thrombosis is a complication of orthotopic liver transplantation, mostly seen as an early complication.9-12 It has been described secondary to surgical complications, aspergillosis, or ABO-incompatible allografts. On the other hand, venous changes in chronic rejection are thought to be inconsequential and are rarely described in detail.5,6,13,14 In a careful study of the vascular pathology of the secondary liver explants, foam cell venopathy was observed in the PV radicals (3/3 cases), as well as in hepatic veins (2/3 cases).5 It is also noteworthy that these authors observed progression of foam cell lesions to fibrous lesions with time. One could argue that the complete fibrous obliteration seen in our case possibly represents a similar phenomenon. In this study, we did not see foam cell vasculopathy involving the central veins, although a prior study showed frequent veno-occlusive changes involving the central veins, as well as sclerotic changes in the hepatic and portal venous radicals independent of foam cell arteriopathy.6 In this large study, foam cell venopathy involving the portal or hepatic venous radicals was not identified as a significant finding. From these studies, as well as ours, it appears that although the histologic changes in the venous radicals are less impressive than those in the accompanying arteries, they are very frequent and most likely also contribute to hepatic dysfunction. Also, to the best of our knowledge, complete fibrous obliteration of the PV associated with chronic rejection has never been described before. Although immunologic and hemodynamic alterations have been implicated, the exact mechanisms underlying the vasculopathy, including the foam cell change, remain unclear.14-17

In summary, we conclude that fibrous obliteration is a feature of chronic rejection, and a possibility of 2-vessel disease must be considered clinically in cases of chronic rejection. Furthermore, when looked for carefully, foam cell changes are not that infrequent in the PV radicals and may contribute to hepatic dysfunction. From the biopsy diagnosis point of view, it should be noted that in our study foam cell venopathy was occasionally seen in the smaller portal tracts, although it was not as prominent quantitatively as in the large arteries. Therefore, a careful study looking for such changes in biopsies is needed to evaluate the diagnostic utility of foam cell venopathy in chronic rejection. Pathologists should also thoroughly examine hilar vessels, including the PV, in explanted hepatic allografts.

References

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2. Demetris AJ, Seaberg EC, Barts KP, et al. Chronic liver allograft rejection. Am J Surg Pathol. 1998;22:28-39.

3. Rubin R, Munoz SJ. Clinicopathologic features of late hepatic dysfunction in orthotopic liver transplants. Hum Rathol. 1993;24:643-651.

4. Pappo O, Ramos H, Starzl TE, Fung JJ, Demetris AJ. Structural integrity and identification of causes of liver allograft dysfunction occurring more than 5 years after transplantation. Am J Surg Pathol. 1995;19:192-206.

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6. Nakazawa y, Jonsson JR, Walker NI, et al. Fibrous obliterative lesions of veins contribute to progressive fibrosis in chronic liver allograft rejection. Hepatology. 2000;32:1240-1247.

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8. Thrombosis of the portal vein secondary to invasive aspergillosis following liver transplantation [in Spanish], Enferm Infec Microbiol Clin. 1998;16:127-129.

9. Samuel D, Gillet D, Reynes M, Bismuth H. Portal and arterial thrombosis in liver transplantation: a frequent event in severe rejection. Transplant Proc. 1989;21:2225-2227.

10. Zajko AB, Bron KM, Starzl TE, et al. Angiography of liver transplantation patients. Radiology. 1985;157:305-311.

11. Kok T, Slooff MJ, Thijin CI, et al. Routine Doppler ultrasound for the detection of clinically unsuspected vascular complications in the early postoperative phase after orthotopic liver transplantation. Transpt Int. 1998;11:272-276.

12. Ludwig I, Wiesner RH, Batts KP, et al. The acute vanishing bile duct syndrome (acute irreversible rejection) after orthotopic liver transplantation. Hepatology. 1987;7:476-483.

13. Grand J, Gouw S, Poppema S, Sloofff MJH, Gips CH. Chronic rejection in liver transplants: a histopathologic analysis of failed grafts and antecedent serial biopsies. Transplant Proc. 1986;18(suppl 4):128-135.

14. Demetris AJ, Lasky S, Van Thiel DH, et al. A review of 62 adult allograft recipients immunosuppressed with a cyclosporin/steroid regimen. Am J Pathol. 1985;118:151-161.

15. Oguma S, Zerbe T, Banner B, et al. Chronic liver allograft rejection and obliterative arteriopathy: possible pathogenetic mechanisms. Transplant Proc. 1989;21:2203-2207.

16. O'Connell JB, Renlund DG, Bristow MR, et al. Detection of allograft endothelial cells of recipient origin following ABO-compatible non-identical cardiac transplantation. Transplantation. 1991;51:438-442.

17. Oguma S, Belle S, Starzl TE, et al. A histometric analysis of chronically rejected human liver allografts: insights into the mechanisms of bile duct loss: direct immunologic and ischemic factors. Hepatology. 1989;9:204-209.

Dhanpat Jain, MD; Marie E. Robert, MD; Victor Navarro, MD; Amy L. Friedman, MD; James M. Crawford, MD, PhD

Accepted for publication August 8, 2003.

From the Departments of Pathology (Drs Jain and Robert), Medicine (Dr Navarro), and Liver Transplant Unit (Dr Friedman), Yale University School of Medicine, New Haven, Conn; and the Department of Pathology, University of Florida College of Medicine, Gainesville (Dr Crawford).

Reprints: Dhanpat Jain, MD, Department of Pathology, Yale University School of Medicine, PO Box 208023, New Haven, CT 06520-8023 (e-mail: dhanpat.jain@yale.edu).

Copyright College of American Pathologists Jan 2004
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