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Background. Patients with hereditary hemochromatosis are known to have an increased risk for morbidity and mortality after orthotopic liver transplantation. Methods. The clinical, histological, and genetic findings were examined in a series of seven adult patients with marked iron accumulation in their liver explants and cardiac failure despite the absence of HFE mutations. Results. Causes for cirrhosis were alcohol and hepatitis C virus (HCV) (n=2), HCV (n=1), alcohol (n=1), and cryptogenic cirrhosis (n=3). Ages at transplantation ranged from 46 to 62 years. Genetic studies confirmed all seven cases were negative for HFE mutations C282Y and H63D. The liver explants showed marked iron accumulation that predominately involved hepatocytes, with more than 90% of the iron in hepatocytes. Two patients required cardiac transplantation and four died of cardiac failure. Cardiac tissues obtained from autopsies (n=3), endomyocardial biopsy (n=1), or cardiac transplants (n=2) showed marked myocyte hypertrophy and iron deposits with or without interstitial fibrosis. Conclusions. This study highlights a unique set of liver transplant patients with marked iron deposition in their cirrhotic liver who developed severe cardiac failure and have iron deposits in the heart, despite the absence of major HFE gene mutations. The cause of the systemic iron overload remains to be discovered.

Background. Bone marrow transplantation (BMT) is the only known cure for a variety of inherited diseases and requires the administration of high doses of immunosuppressive and myeloablative therapy. Because the fetus is immunoincompetent early in gestation, in utero stem cell transplantation (IUT) could avoid the need for this toxic conditioning. A major limitation to date of IUT is the low level of engraftment and failure to induce tolerance. Dendritic cells (DC) are considered very potent antigen-presenting cells, but DC progenitors (pDC) are strongly tolerogenic. Methods. We examined the effect of donor pDC on the degree of engraftment and tolerance induction after IUT. Bone marrow-derived pDC (CD80 low , CD86 - ) from male C57BL/6 mice (H2 b ) were injected with and without donor bone marrow (BM) intraperitoneally into 13 to 15-day BALB/c (H2 d ) fetuses. Engraftment was determined by flow cytometry and quantitative polymerase chain reaction and tolerance by skin grafts and the mixed lymphocyte reaction. Results. At 1-month posttransplant, mice that received BM+pDC showed a higher degree of engraftment (29±46%) than mice that received pDC-enriched cells or BM cells alone (0.11±0.70% and 1.71±1.66%, respectively, P

The presence of anti-GOR was determined in paired pre-orthotopic liver transplantation (pre-OLT) and post-OLT sera from 87 OLT patients with hepatitis C virus infection. Before OLT, 48/87 patients were seropositive for anti-GOR, but this marker had no relationship with the clinical and biochemical parameters, or viremia level. Anti-GOR was less commonly detected in patients infected with genotype 3a, compared with genotypes 1 and 2, which might be related to the less conserved nature of the proposed shared epitope (amino acid sequence 9-18) in genotype 3a isolates. After OLT (median follow-up 16 months), anti-GOR was detected in 31/87 patients and it had no correlation with the clinical and biochemical parameters, viremia level, histologic disease activity, and clinical outcome. Changes in anti-GOR status (before OLT versus after OLT) were also not related to any of the clinical parameters. Although anti-GOR is commonly detected in OLT patients infected with hepatitis C virus genotypes 1 and 2, it has no clinical or prognostic significance.

Reports of early success with cryopreserved saphenous veins (CSV) as arterial conduits led us to develop cryopreserved iliac veins (CIV) as interposition grafts for portal vein reconstruction in living-related liver transplantation (LRLT) (4). Despite encouraging short-term results, retrospective analysis of long-term cryopreserved vein graft performance in LRLT at our institution has revealed a high rate of late graft failure. Between July 1992 and July 1994, interposition grafts (CIV for portal vein interposition n=4, CSV for portal vein interposition n=3, and CSV for hepatic artery interposition n=2) were utilized in 7 LRLT. (Two transplanted organs had both CIV and CSV grafts.) Recipients included 5 children and two small adults (median : 3.5 years, range : 0.5-59 years). Posttransplant follow-up in excess of 36 months revealed portal vein (PV) and hepatic artery (HA) complications of cryopreserved grafts in each patient. PV complications included aneurysm (n=4) diagnosed at 28, 24, 18, and 1.5 mo, stricture (n=l) diagnosed at 11 mo, and thrombosis (n=l) diagnosed at 18 mo posttransplant. All portal vein complications have been managed without retransplantation, but one (PV thrombosis) necessitated surgical shunt therapy. Each CSV hepatic artery interposition graft has been complicated by thrombosis (diagnosed at 11 days and 24 mo posttransplant) necessitating retransplantation. Based upon these observations, we have adopted alternative strategies for HA and PV reconstruction. At present, 11 LRLT have been performed without cryopreserved vein conduits over 17 mo with no vascular complications. While this study does not permit statistical analysis, these results discourage the use of cryopreserved iliac veins for portal interposition and cryopreserved saphenous veins for arterial interposition in liver transplantation.

Liver granulomas have long been known to pose diagnostic problems for pathologists; however, their prevalence and associated etiologic factors have not been studied in liver transplant patients. We reviewed 3632 liver biopsy specimens from 563 patients at two institutions and identified 42 patients with posttransplant granulomas. A possible or probable etiologic factor was identified in 30 (71%) cases. Most were epithelioid granulomas and microgranulomas located in the parenchyma associated with hepatocyte necrosis (21 cases, 50%). Portal-based granulomas were associated with recurrent primary biliary cirrhosis (5 cases, 12%), acute cellular rejection (2 cases, 4.8%), and a foreign body-type reaction (1 case, 2.4%). One case was associated with tuberculosis (2.4%), 4 cases occurred in a fatty liver (9.5%), and 8 patients had liver granulomas but no other significant abnormality. The granulomas were most frequent in the first 7 months after transplantation when the patients were biopsied more often and underwent episodes of rejection or acute hepatitis. Portal-based granulomas in this period were usually associated with acute cellular rejection. After 7 months, the frequency of granulomas as well as the number of biopsies decreased and portal-based granulomas associated with recurrent primary biliary cirrhosis were most common (5 cases, 12%). Rare, late-appearing parenchymal granulomas were also seen (3 cases) and consisted of 1 lipogranuloma and 2 cases of epithelioid granuloma. The latter were thought, in 1 patient, to be associated with parenchymal hepatocyte necrosis; the others were of unknown etiology.

A potential approach to avoid the complications of systemic immunosuppression is to deliver immunosuppressive agents locally to the site of the allograft. Liposomes are phospholipid particles that allow delivery of drugs preferentially to the reticuloendothelial system. Since the liver is a primary component of the RES, we hypothesized that liposome technology could be utilized to deliver immunosuppressive agents locally to a transplanted liver, thereby avoiding the complications of systemically delivered immunosuppression. We evaluated this hypothesis with a prototypic cyclosporine liposome in a rat model

The role of IL-5 and eosinophils in allograft rejection was studied in human liver allograft recipients. Liver allograft biopsies were analyzed for intragraft IL-5 gene expression, and the percentages of eosinophils and plasma cells within the portal infiltrate as well as peripheral eosinophil levels were determined. The majority of allografts with evidence of rejection had concomitant IL-5 mRNA and eosinophilia, while no resolving or nonrejecting allografts had simultaneous IL-5 mRNA and eosinophilia. In fact, rejecting liver allografts that contain IL-5 mRNA and eosinophils also contain infiltrating cells that produce the cytotoxic mediator major basic protein. In contrast, intragraft plasma cell and peripheral eosinophil levels did not correlate with the histopathologic status of the allograft. Cyclosporine and FK506 had similar effects on the frequency of IL-5 gene expression in rejecting and nonrejecting allografts. However, OKT3 appeared to profoundly modulate IL-5 gene expression, since 0 of 11 biopsies obtained during OKT3 treatment for rejection contained IL-5 transcripts. These observations raise the possibility of a cellular pathway of liver allograft rejection mediated by IL-5-activated eosinophils.

Forty-three human liver allograft biopsies and normal liver were directly analyzed for inflammatory and immunoregulatory cytokine gene expression by polymerase chain reaction (PCR). IL-5 gene expression was predominantly present in biopsies from liver allografts with histopathological evidence of acute rejection. IL-2 gene expression was rarely observed in rejecting allografts or allografts without evidence of rejection. In contrast, IL-4 message was readily detectable in the majority of liver allografts regardless of clinical status. The inflammatory mediators IL-1 beta, TNF-alpha, and IL-6 were detected with similar frequency in rejecting allografts and allografts without evidence of rejection. These findings suggest that inflammatory and immunoregulatory cytokines are produced within the allograft. Moreover, IL-5 may play a role in the local mechanisms of liver allograft rejection.

Fibrosing cholestatic hepatitis is a specific histologic manifestation of hepatitis B virus infection consisting of periportal fibrosis, hepatocyte ballooning, cholestasis, a relatively scant inflammatory infiltrate, and marked overexpression of hepatitis B viral antigens in hepatocytes. Until recently, fibrosing cholestatic hepatitis had been reported only in recipients of liver allografts. In this report, we present two patients in whom this lesion developed following renal transplantation. Both patients had previous liver biopsies showing relatively mild histologic changes. In one patient, the lesion developed early after retransplantation, during the period of maximal immunosuppression. However, in the second patient this lesion developed after withdrawal of immunosuppression. In both cases, death occurred within a few months because of progressive liver disease. Since this lesion can develop in “relatively healthy” hepatitis B carriers following transplantation of organs other than liver, these patients should have careful monitoring of their liver disease. Moreover, since the disease may progress despite withdrawal of immunosuppression, these patients would clearly benefit from the development of more effective therapies for posttransplant hepatitis B.