Recurrence of subsquamous dysplasia and carcinoma after successful endoscopic and radiofrequency ablation therapy for dysplastic Barrett's esophagus.

Barrett's esophagus with dysplasia is commonly treated with radiofrequency ablation (RFA). Despite its effectiveness, a concern of any ablative technique is the development of subsquamous intestinal metaplasia, which could have potential for future neoplastic progression. To date, 34 cases of subsquamous neoplasia have been described in the literature after various ablation therapies. However, only three cases of subsquamous neoplasia have been reported after successful RFA treatment of dysplastic Barrett's esophagus. In this case series, we report on four additional cases of subsquamous neoplasia detected after successful endoscopic resection and RFA for neoplastic and dysplastic Barrett's esophagus. All four patients were treated successfully with endoscopic resection of their recurrent subsquamous neoplastic and dysplastic lesions. This case series highlights the need for continued surveillance following successful treatment of dysplastic Barrett's esophagus with RFA.

Liver transplantation in Langerhans' cell histiocytosis (histiocytosis X).

Two children with biopsy-proven LCH underwent successful hepatic transplantation for end-stage liver disease. These patients were thought not to have active LCH disease at the time of transplantation, although one had developed a new osteolytic lesion a few months before the operation and the other had suspicious osteolytic lesions at the time of transplantation. The histologic examination of the excised liver showed features consistent with primary sclerosing cholangitis. The two patients had an excellent recovery with no evidence of progression of LCH or recurrence of the underlying disease in the hepatic allograft at 1 and 3 years after organ transplantation.

Expression of cytokines and immune mediators during chronic liver allograft rejection.

To determine the immune processes involved in chronic liver allograft rejection (CR) we examined in situ cytokine production in tissue from 15 patients with both clinical and histopathological diagnoses of CR. Total RNA was isolated from liver samples, reverse-transcribed and analyzed by RT-PCR for the production of proinflammatory cytokines and immunoregulatory mediators. Transcripts for the Th1-like cytokines IL-2 and IFN-gamma were detected in 53.3% and 46.7% of CR grafts, while they were detected in only 16% and 0% of stable grafts, respectively. The cytotoxic T cell mediator granzyme B was expressed in the majority of liver grafts undergoing CR, but was expressed only in a minority of stable grafts (80% vs. 16%, P < 0.05). The T cell product IL-5 was also significantly upregulated in CR as compared with stable livers (80% vs. 16%, P < 0.01). Other Th2 cytokines--IL-4 and IL-10--and macrophage products--IL-1 beta, IL-6, IL-8, TGF-beta, and TNF-alpha--were not substantially upregulated in CR grafts as compared with stable grafts. PDGF-beta transcripts were detected in the majority of the CR grafts, but were not detected in stable liver grafts (73% vs. 0, P < 0.05). By immunohistochemical staining, we observed that CD3+CD4+, and CD3+CD4- T cells were detected in CR grafts along with CD20+ B cells and CD68+ macrophages. There was, however, a predominant infiltration of CD3+CD4+ lymphocytes. Taken together, these data suggest that infiltrating cells produce proinflammatory and immunoregulatory cytokines that have a role in mediating graft damage in CR.

Rapid development of hepatocellular siderosis after liver transplantation for neonatal hemochromatosis.

A male infant with neonatal iron storage disease, also known as neonatal hemochromatosis (NH), underwent orthotopic liver transplantation (OLT) at the age of 55 days. The native liver contained an incidental hepatocellular carcinoma. Scant iron accumulation was found in a biopsy specimen of the implanted liver on the seventh postoperative day (POD); successive biopsies showed increasing siderosis. On POD 62, the patient died of a cardiac arrhythmia. Autopsy showed siderosis at many sites, including the implanted liver. We discuss the possibility that hemochromatosis recurred in the liver allograft and review possible factors contributing to the siderosis.

Apoptosis as a mechanism of cell death in liver allograft rejection.

It is generally recognized that there are two mechanisms of cell death, apoptosis and necrosis. Apoptosis--programmed cell death--is involved in numerous states of physiological cell deletion. Recent studies have demonstrated that hepatocytes, under certain conditions, undergo apoptosis. The purpose of this work was to determine if apoptotic cell death is involved in liver allograft rejection. Groups of Lewis (RT1l) rats underwent orthotopic liver transplantation (OLT) from disparate DA (RT1a) or syngeneic Lewis rats. Liver samples were harvested at 1, 2, 3, 4, and 7 days posttransplant and analyzed for apoptotic cell death. Since the characteristics of apoptosis are difficult to discern using routine hematoxylin and eosin staining, we utilized a novel method that detects the classic indicator of apoptosis, nonrandom DNA degradation. Paraffin-embedded tissue sections were end-labeled with nonradioactive dUTP and detection of apoptotic bodies accomplished by immunoassay. The incidence of apoptotic cells increased steadily over time in allografts, in contrast to syngeneic grafts. In this study apoptotic cell death paralleled standard indicators of liver allograft rejection including pathology, mononuclear cell infiltration, and increases in liver enzymes. Moreover, increased expression of TGF-beta 1 correlated with apoptosis in liver allografts, supporting the previously described role for this cytokine in hepatocyte apoptosis. Our results demonstrate, for the first time, that apoptosis may be a mechanism of cell death in liver allograft rejection.

An increased incidence of Epstein-Barr virus infection and lymphoproliferative disorder in young children on FK506 after liver transplantation.

The incidence of Epstein-Barr virus (EBV) infection and lymphoproliferative disorder (LPD) was determined in a pediatric liver transplant population consisting of 51 children treated with FK506 and 91 treated with cyclosporine. The incidence of symptomatic EBV infection was 21.9% (23 of 105 cases) in children < 5 yr old and 10.8% (4 of 37 cases) in children 5 to 17 yr old as compared with 2.7% (9 of 323 cases) in adults (P < 0.0001). In the under 5 yr old group on cyclosporine, the incidences of EBV infection and LPD were 9 of 68 (13.2%) and 2 of 68 children, (2.9%), respectively. In contrast, in children under 5 yr old group on FK506, the incidences of EBV infection and LPD in the FK506 group were 14 of 37 (37.8%) and 7 of 37 children (18.9%), respectively. The difference between these two groups was statistically significant (P < 0.02). There were no cases of LPD in the 5-17 yr-old children on either cyclosporine (n = 23) or FK506 (n = 14). The incidence of EBV infections in the 5 to 17 yr age group, 17.4% on cyclosporine and 0% on FK506, was less than for the younger children on FK506 (37.8%). A total of 39% (9 of 23) of children under 5 yr old who had symptomatic EBV infections developed LPD, and 44% (4 of 9) with LPD died. The higher incidence of EBV infections and LPD in the younger children treated with FK506 was probably related to a greater intensity of immunosuppression for patients on FK506 than those on cyclosporine.

Graft involvement by Legionella in a liver transplant recipient.

Legionella pneumophila, serogroup 1, was identified by direct immunofluorescence in the lung and liver graft from a 2 1/2-month-old infant who underwent orthotopic liver transplantation because of fulminant hepatic failure secondary to neonatal hepatitis. The patient died of respiratory failure owing to this infection 22 days after transplantation despite treatment with erythromycin lactobionate. To our knowledge, this represents the first reported case of hepatic infection with Legionella in liver transplant recipients.

Orthotopic liver transplantation for hepatocellular carcinoma. Factors affecting long-term patient survival.

OBJECTIVE: To determine the influence of several clinicopathologic factors on the 3-year actuarial survival of patients with nonfibrolamellar hepatocellular carcinoma (HCC) following orthotopic liver transplantation (OLT). DESIGN: A case series of 26 consecutive patients with HCC treated with OLT, with a maximum follow-up of 90 months. SETTING: A tertiary care center. PATIENTS: Between March 1988 and December 1993, 521 OLTs were performed in 480 patients, 27 of whom had HCC. One patient was excluded because of donor-transmitted melanoma. Of the remaining 26 patients, there were 18 adults and 8 children, with a mean age of 41 years (range, 0.2-67.4 years). Fourteen patients (54%) had either hepatitis B (n = 6) or hepatitis C (n = 8), while 15 (58%) had coincidental tumor. INTERVENTION: OLT was performed using standard techniques. MAIN OUTCOME MEASURES: The effect of several clinicopathologic factors on 3-year actuarial patient survival. RESULTS: The overall actuarial survival rates for the 26 patients with HCC were 73%, 65.4%, and 65.4%, at 1, 2, and 3 years, respectively. Sixteen patients (62%) were alive at the time of this report, with 14 (54%) free of disease. None of the clinicopathologic factors significantly affected the 3-year patient survival rate. However, the rate of recurrent HCC was significantly higher in nonincidental vs coincidental tumors and in solitary vs multiple tumors. CONCLUSION: Our results suggest that HCC should not contraindicate OLT, as long-term patient survival and cure can be achieved. While patient selection is important, survival in patients with HCC after OLT is not always predictable using the usual clinicopathologic prognostic factors.

Hepatocellular carcinoma and liver cell dysplasia in children with chronic liver disease.

The histology of 72 livers from 72 children who underwent liver transplantation was reviewed. Nine children (12.5%) had hepatocellular carcinoma (HCC) and/or liver cell dysplasia (LCD) in their native livers. Ages at the time of transplantation ranged from 2 months to 11 years. Primary liver diseases included tyrosinemia (3), biliary atresia (2), chronic active hepatitis B (1), chronic active non-A non-B non-C hepatitis (1), idiopathic neonatal hepatitis (1), and neonatal iron storage disease (1). Explanted livers showed large multifocal HCC in two cases, incidental HCC in three, and dysplastic nodules in four. LCD also was present in three cases in conjunction with HCC. All patients had cirrhosis. Alpha-fetoprotein was measured in six children and was elevated in all six (range, 300 to 1,770,000 ng/mL; normal, 0 to 15 ng/mL). Abdominal computed tomography, ultrasonography, and/or magnetic resonance imaging showed large masses in two cases, but did not detect the tumors of less than 2 cm or the dysplastic nodules in the other seven children. After a follow-up period of 2 months to 3 years (mean, 19.8 +/- 12.1 months), eight children are alive and have no evidence of recurrence. The patient with neonatal iron storage disease died 2 months after transplantation, without evidence of tumor recurrence. The authors conclude that children with end-stage liver disease of diverse causes referred for liver transplantation may have LCD and/or HCC. Serial determination of alpha-fetoprotein and images studies may detect early lesions curable by liver transplantation.

Primary sclerosing cholangitis and Hodgkin's disease.

Three patients with primary sclerosing cholangitis and Hodgkin's disease, a previously unrecognized association, are reported. All three patients were men, and one patient had Crohn's disease of the colon. Primary sclerosing cholangitis was diagnosed 2, 11 and 17 yr before diagnosis of Hodgkin's disease in the three patients, and all three had advanced biliary cirrhosis prompting referral for liver transplantation. The symptoms of Hodgkin's disease were often masked by similar manifestations of primary sclerosing cholangitis, particularly symptoms of recurrent biliary sepsis. Hodgkin's disease is another disorder that may occur in patients with primary sclerosing cholangitis, particularly in the setting of advanced disease, and may be masked by the underlying hepatobiliary disease.

Hepatic failure due to massive iron ingestion successfully treated with liver transplantation.

A 3-year-old female had fulminant hepatic and renal failure due to massive iron ingestion, despite gastric lavage, deferoxamine administration, hemodialysis and continuous arteriovenous hemofiltration. She underwent a successful emergency liver transplantation on 5th day after ingestion and was discharged 25 days later with excellent liver and renal function.

Liver transplantation from non-heart beating donors in rats: influence of viscosity and temperature of initial flushing solutions on graft function.

BACKGROUND: We evaluated the effect of warm (37 degrees C) versus cold (4 degrees C) solutions as the initial flush for liver preservation from non-heart beating donors in rats. METHODS: An initial flush was performed just before donor hepatectomy with cold or warm University of Wisconsin solution (UW), UW without hydroxyethyl starch, sodium lactobionate sucrose solution, or lactated Ringer's solution as the control group. A separate group also used as control received no initial flushing. Liver transplantation was performed, and the graft function was determined by survival and assessment of enzyme release. The viscosity of each solution and the vascular resistance of the graft were measured. RESULTS: The 7-day survival rate was 83% and 100% in the warm and cold sodium lactobionate sucrose solution groups and 60% and 50% in the warm and cold lactated Ringer's solution groups, respectively. In the no-initial-flush group, rats did not survive. The 7-day survival rate was 67% and 0% in the warm and cold UW groups, respectively. Eliminating the hydroxyethyl starch from the cold UW improved the survival to 67%. Serum alanine aminotransferase levels 1 day after transplantation in the no-initial-flush and the cold UW groups were significantly higher than those of the remaining groups. At 4 degrees C the viscosity was higher in the UW (86.2 cp) compared to hydroxyethyl starch-free UW solution (30.9 cp), lactated Ringer's solution (24.5 cp), and sodium lactobionate sucrose solution (32.7 cp). The viscosity of UW at 37 degrees C was 34.7 cp. Vascular resistance correlated well with the viscosity. Livers flushed with solutions with a low viscosity showed lower vascular resistance than those flushed with cold UW and led to better survival. CONCLUSIONS: These data suggest that the viscosity of the initial flushing solution may play an important role in determining the outcome of organ procurement from non-heart beating donors.

Outcome of liver transplantation in patients with hemochromatosis.

Recent preliminary reports suggest a poor outcome of orthotopic liver transplantation for patients with hemochromatosis. We analyzed an institutional experience with orthotopic liver transplantation for hemochromatosis, focusing on factors contributing to increased morbidity and mortality. Between March 1988 and October 1992, nine of 249 adults (3.6%) undergoing orthotopic liver transplantation had hemochromatosis. Mean age was 53 yr (range, 42 to 62 yr), and eight of nine patients were men. The diagnosis of hemochromatosis was based on transferrin saturation > 62% and hepatic iron index > 2.0. Only two patients were known to have hemochromatosis before liver transplantation. All nine patients underwent standard cardiac evaluation before transplantation, and no patient had detectable pre-existing cardiac disease. One patient had a major operative cardiac complication as a result of pulmonary embolism and made a full recovery. Postoperatively, congestive heart failure developed in three patients and four patients had arrhythmias. One patient is undergoing phlebotomy for post-transplant cardiac complications from hemochromatosis. Two patients had primary hepatic tumors in the explant liver. There were four deaths caused by multiorgan failure with congestive heart failure (1), infection (2), and/or malignancy (2). Five patients are alive 3 to 25 mo post-transplant. The actuarial survival of the nine patients was 53% at 25 mo vs. 89% for 18 age- and sex-matched control transplant recipients (p = 0.1) and 81% for all other adult liver transplant recipients (p < 0.01). In five of seven patients, post-transplant liver biopsies revealed hepatic iron accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

GB virus C (GBV-C/HGV) and E2 antibodies in children preliver and postliver transplant.

The association of GB virus type C (GBV-C) virus and clinical disease is uncertain. The role of GBV-C and (Envelope) E2 antibody in children with liver transplants has not been determined. This study's aim is to examine the prevalence of GBV-C in children with liver transplants, to assess the relationship of GBV-C to posttransplant hepatitis, and to determine the role of E2 antibodies. Sera from 34 children, preliver and postliver transplant, between 1989-1996 were tested for GBV-C (Ribonucleic acid) RNA by the automated Abbott LCx PCR assay. Anti-E2 antibodies were detected by an Abbott immunoassay. Recent posttransplant liver biopsies were examined for hepatitis. The results of the study determined that pretransplant, four children (12%) were GBV-C RNA positive. Posttransplant, 14 (42%) children were GBV-C RNA positive. The GBV-C RNA positive conversion rate was 33% (CI 17.2-55.7%). Patients received blood products from a mean of 68 +/- 34 donors, which correlated with GBV-C acquisition. There was no difference in the incidence (32%versus 36%; p = 0.726) or severity (grade 2.00 versus 0.68; p = 0.126) of posttransplant hepatitis in the liver biopsies of GBV-C RNA negative and/or positive children, respectively. Pretransplant, nine of 32 children were anti-E2 positive. Posttransplant, eight of 32 children were anti-E2 positive, including five children who were anti-E2 positive pretransplant. Of nine children who were anti-E2 positive and GBV-C RNA negative pretransplant, three became GBV-C RNA positive posttransplant. The results of this study conclude that the prevalence of GBV-C infection in children postliver transplantation is high and that blood product transfusions correlate with GBV-C acquisition. Also, no correlation was found between GBV-C RNA and the incidence or severity of posttransplant hepatitis. Finally, E2 antibody presence before transplantation failed to provide complete protection from GBV-C acquisition.

Intramuscular hepatitis B immune globulin combined with lamivudine for prophylaxis against hepatitis B recurrence after liver transplantation.

Immunoprophylaxis using intravenous (IV) hepatitis B immune globulin (HBIG) decreases the recurrence of hepatitis B virus (HBV) infection after orthotopic liver transplantation (OLT). However, IV HBIG is expensive, has significant side effects, and is inconvenient to administer. An alternative approach for prophylaxis using intramuscular (IM) HBIG and oral lamivudine was prospectively evaluated in this study. Ten consecutive patients with cirrhosis with HBV infection who underwent OLT were included in this study. Nine of 10 patients received lamivudine, 150 mg/d, for an average duration of 8.6 months before OLT. Two of 10 patients with detectable HBV DNA at the time of OLT received 10,000 U (45 mL) of IV HBIG daily for 7 consecutive days, followed by 5 mL of IM HBIG weekly for the next 3 weeks, then every 3 weeks. The other 8 patients were HBV DNA negative at OLT and received one dose of IV HBIG (45 mL) during surgery, followed by 5 mL of IM HBIG weekly for 4 weeks, then every 3 weeks. All patients received lamivudine, 150 mg/d, after OLT. During a mean follow-up of 15.6 months, 9 of 10 patients achieved a protective hepatitis B surface antibody (HBsAb) titer greater than 200 IU/L and had no evidence of HBV recurrence. One patient failed to develop an adequate HBsAb titer and developed histological and virological evidence of recurrence. One patient died unrelated to HBV recurrence. Our preliminary data suggest that this combination prophylaxis with IM HBIG and lamivudine is effective and potentially cost saving.

Ganciclovir treatment of hepatitis B virus infection in liver transplant recipients.

To determine the safety and efficacy of ganciclovir treatment of hepatitis B virus (HBV) infection after liver transplantation, nine patients (seven males, two females; mean age, 38 years) with posttransplant HBV infection were treated with ganciclovir for 3 to 10 months. Ganciclovir was administered intravenously at an initial dose of 5 mg/kg/d and then increased to 10 mg/kg/d. Immunosuppressive drug therapy was maintained at low levels. There were no major side effects of ganciclovir therapy. Serum HBV DNA levels decreased by a mean of 90% (range, 42% to 100%), and four of nine patients had no measurable HBV DNA at the completion of therapy. Mean serum alanine aminotransferase levels decreased by 83%. Hepatic expression of HBV antigens and HBV DNA was assessed before and after therapy in six patients and found to be reduced in three patients. The histology activity index was also stabilized or improved in all patients. After discontinuation of therapy, four of nine patients underwent retreatment for 4- to 12-fold elevation of serum HBV DNA and/or biochemical and clinical relapse, that was severe in one patient. This pilot study shows the safety and efficacy of ganciclovir therapy for reducing HBV replication in patients with HBV infection after liver transplantation.

Clinical and pathological features of bacillary peliosis hepatis in association with human immunodeficiency virus infection.

BACKGROUND: Peliosis hepatis is characterized by cystic, blood-filled spaces in the liver and is seen in patients with chronic infections or advanced cancer and as a consequence of therapy with anabolic steroids. Cutaneous bacillary angiomatosis is a bacterial infection that occurs in patients with human immunodeficiency virus (HIV) infection; its histologic appearance is that of a pseudoneoplastic vascular proliferation. METHODS: We studied liver tissue from eight HIV-infected patients with peliosis hepatis, two of whom also had cutaneous bacillary angiomatosis. For comparison we examined tissue from four patients who had peliosis hepatis without HIV infection. Tissues were examined histologically on routine sections and with special stains and electron microscopy. RESULTS: The histologic features seen in peliosis hepatis associated with HIV infection, but not in the four cases unrelated to HIV infection, were myxoid stroma and clumps of a granular purple material that on Warthin-Starry staining and electron microscopy proved to be bacilli. The bacilli, which could not be cultured, were morphologically identical to those found in the skin lesions of cutaneous bacillary angiomatosis. The clinical courses of two of the patients with this "bacillary peliosis hepatis" indicate that it responds to antibiotic treatment. CONCLUSIONS: HIV-associated bacillary peliosis hepatis is an unusual, treatable opportunistic infection, probably caused by the same organism that causes cutaneous bacillary angiomatosis. Our failure to find bacilli in non-HIV-associated cases implies that other pathogenetic mechanisms may also be responsible for peliosis hepatis.