Successful Liver Transplantation for Hyperammonemic Fibrolamellar Hepatocellular Carcinoma.

Fibrolamellar hepatocellular carcinoma is a rare hepatocellular tumor usually arising in noninfected and noncirrhotic livers. Only 2 cases accompanied by hyperammonemia due to intrahepatic shunting have been reported. A 23-year-old white woman presented with a 2-week history of nausea, vomiting, generalized weakness, and intermittent right upper quadrant pain. Abdominal computerized tomography revealed a 13 x 9-cm hepatic mass. Core-needle biopsy revealed fibrolamellar hepatocellular carcinoma. She presented with coma due to hyperammonemia levels (peak at 437 mcg/dL) but without metastatic disease. She was urgently transplanted, started on daily sorafenib 8 weeks after transplantation, and was free of disease at 1 year after transplantation.

Can sorafenib increase survival for recurrent hepatocellular carcinoma after liver transplantation? A pilot study.

Recurrence of hepatocellular carcinoma (HCC) remains a main detriment to long-term survival in liver transplants (LTx) for HCC. The study aims to review the use of sorafenib in recurrent HCC LTx in the Model End Stage Liver Disease era. Two hundred forty-seven patients with HCC LTx from 2002 to 2013 were included. Survival was calculated by the Kaplan-Meier (KM) method and Cox multivariate model. Twenty-two patients recurred (11%). By KM, overall survival was 27 months (standard deviation [SD], 3.2 months; median, 28.4 months). Mean time to recurrence was 16.9 months (SD, 2.8 months; median, 12 months). Nine patients were treated with sorafenib after recurrence. Median survival for sorafenib-treated patients was 42 months compared with a median of 16.2 months without sorafenib (-2 log likelihood ratio, P = 0.0582). By Cox, only sorafenib (P = 0.0233; hazard ratio, 8.528) and pathologic stage had a significant impact on survival. The recurrence rates of HCC LTx remain acceptable considering understaging and expansion of beyond Stage A. This pilot study of sorafenib in recurrent HCC demonstrates improved survival over historic controls. Many other factors affecting improved survival are explained. However, treatment remains palliative. Quality-of-life years and cost analysis need to be performed in this population.

Nonalcoholic fatty liver disease epidemic and its implications for liver transplantation.

Nonalcoholic steatohepatitis (NASH) is increasingly recognized as the most common chronic liver disease worldwide. The aim of this study is to investigate the transplantation trends of liver transplant (LT) recipients with NASH. Using the United Network for Organ Sharing database, we found a steady increase in LT rate especially in those more than 65 years old. We identified differences across ethnic groups and United Network for Organ Sharing regions. This study highlights the impact of the rising prevalence of NASH on the demand for LT and provides invaluable information to healthcare policymakers and the transplant community about the target groups and geographic location for focused and early intervention.

Obesity portends increased morbidity and earlier recurrence following liver transplantation for hepatocellular carcinoma.

BACKGROUND: Obesity has been associated with poor oncologic outcomes following pancreatoduodenectomy for pancreatic cancer. However, there is a paucity of evidence on the impact of obesity on postoperative complications, oncologic outcome and survival in patients with hepatocellular carcinoma (HCC) undergoing orthotopic liver transplantation (OLT). METHODS: From a database of over 1000 patients who underwent OLT during 1996-2008, 159 patients with a diagnosis of HCC were identified. Demographic data, body mass index (BMI), perioperative parameters, recurrence and survival were obtained. Complications were grouped according to Clavien-Dindo grading (Grades I-V). RESULTS: There were increased incidences of life-threatening complications in overweight (58%) and obese (70%) patients compared with the non-obese patient group (41%) (P < 0.05). Furthermore, the incidence of recurrence of HCC was doubled in the presence of overweight (15%) and obesity (15%) compared with non-obesity (7%) (P < 0.05). Time to recurrence also decreased significantly. Differences in mean ± standard deviation survival in the overweight (45 ± 3 months) and obese (41 ± 4 months) groups compared with the non-obese group (58 ± 6 months) did not reach statistical significance. CONCLUSIONS: These findings indicate that BMI is an important surrogate marker for obesity and portends an increased risk for complications and a poorer oncologic outcome following OLT for HCC.

A therapeutic DNA vaccination strategy for autoimmunity and transplantation.

De novo autoimmunity induced by an allograft may play a significant role in chronic organ rejection, which remains a major barrier to successful transplantation. Accordingly, immunization with non-polymorphic antigens found in both donor allograft and recipient would be an attractive means to prevent long-term graft rejection, because it would rely on recipient mechanisms of immune homeostasis and could minimize the need to identify appropriate donor polymorphic antigens for induction of graft tolerance. Here we show that intradermal injection of plasmid DNA encoding glutamic acid decarboxylase (GAD) polypeptide, which is synthesized in both pancreatic islet and skin tissue, ameliorated new-onset type 1 diabetes in NOD mice and increased skin allograft survival in a BALB/c-C57BL/6 model system in a donor-specific manner. Successful therapy of autoimmune diabetes required CpG-methylation of plasmid DNA and co-delivery of a cDNA coding for the pro-apoptotic BAX protein, which was shown previously to induce Foxp3(+) regulatory T cells in NOD mice. In contrast, significantly increased skin allograft survival after immunization of recipient only required CpG-methylation of plasmid DNA coding for GAD alone. Injection of unmethylated plasmid DNA coding for BAX alone near the allograft also promoted graft survival, but induced a pro-inflammatory response to self-antigens. Our results reveal a promising potential for autoimmunity-targeting DNA vaccination to be applied to transplantation.

Increased plasma nitric oxide, L-arginine, and arginase-1 in cirrhotic patients with progressive renal dysfunction.

BACKGROUND AND AIMS: Increased levels of nitric oxide (NO) are hypothesized to contribute to renal dysfunction in patients with decompensated cirrhosis. In this study, we examined whether splanchnic and/or peripheral NO levels and L-arginine (L-Arg) correlate with progressive renal dysfunction in cirrhotics. METHODS: Serum NO metabolites (NOx) and L-Arg were measured in: controls (n = 10); organ donors (n = 12); compensated cirrhotics (n = 17), cirrhotics with ascites (n = 25), refractory ascites (n = 11) or hepatorenal syndrome type II (HRS) (n = 11) and chronic renal failure patients (n = 18). RESULTS: Plasma NOx and L-Arg levels rose progressively with worsening renal function in decompensated cirrhotics. Both NOx and L-Arg levels were highest in patients with HRS (P < 0.001 and P < 0.025, respectively). While there were no differences in NOx levels related to the site of sampling, L-Arg levels were lowest in hepatic venous blood. There were significant relationships of NOx and L-Arg with Model for End-Stage Liver Disease score and Child-Pugh scores (P < 0.04 and P < 0.01, respectively). Multivariate analysis showed a significant relationship between NOx, L-Arg and HRS. CONCLUSION: Worsening renal function in decompensated cirrhosis is accompanied by progressive elevation in plasma NOx and L-Arg. These findings support the hypothesis that NO-mediated vasodilation is probably linked with the mechanism of progressive renal failure in decompensated cirrhotics.

The impact of intercurrent EBV infection on ATP levels in CD4+ T cells of pediatric kidney transplant recipients.

ImmuKnow measures ATP (ng/mL) in PHA-activated CD4+ T cells from patient's whole blood. According to published reports, median ImmuKnow is 258 ng/mL in stable pediatric kidney transplant (PKT) recipients > or =12 yr, and 165 ng/mL in those <12 yr. However, data on the effect of infection or AR on ImmuKnow are scarce. We studied the effect of Epstein-Barr virus (EBV) viremia on ImmuKnow in PKT with GD. Twenty-eight PKT with GD were reviewed. Group 1 has 19 PKT > or =12 yr, and group 2 has nine PKT <12 yr. Mean follow-up was 19.4 +/- 12 months. All ImmuKnow values discussed in this study were measured during GD +/- fever. None had ImmuKnow pretransplant. EBV DNA was isolated from patient blood by real-time PCR. Group 1 has eight boys and 11 girls (mean age = 16.6 +/- 2.4 yr). Group 2 has two boys and seven girls (mean age = 6 +/- 3.1 yr). Median ImmuKnow was 292 ng/mL in group 1, and 370 ng/mL in group 2. Nine children developed EBV viremia: two in group 1 (median ImmuKnow = 273 ng/mL), and seven in group 2 (median ImmuKnow = 475 ng/mL). Overall mean ImmuKnow in the nine EBV viremic patients was higher than that in the 19 non-viremic ones (422 +/- 176 ng/mL, and 302 +/- 113 ng/mL, respectively, unequal variance t-test, p = 0.08). Eight children developed AR (all in G1, median ImmuKnow = 272 ng/mL). In group 1, one patient developed concurrent EBV viremia and rejection, while another patient developed EBV viremia six months following a rejection episode. In group 2, none developed simultaneous AR, CMV, or BK virus infection with EBV viremia. None developed post-transplant lymphoproliferative disease. In summary, EBV viremia was paradoxically associated with high ImmuKnow in PKT <12 yr. This suggests strong co-stimulation of PHA-activated CD4+ T cells by EBV-transformed B cells.

Monitoring peripheral blood CD4+ adenosine triphosphate activity in a liver transplant cohort: insight into the interplay between hepatitis C virus infection and cellular immunity.

Peripheral blood CD4+ adenosine triphosphate [ATP (ng/mL)] release [ImmuKnow Immune Cell Function Assay (ATP)] correlates to immunoreactivity. We hypothesized that ATP levels could provide insight into hepatitis C virus (HCV) infection and recurrent liver disease in liver transplantation (LT). We studied our center's LT cohort, in which ATP levels had been measured off protocol from February 2005 through July 2006. Of the 280 LTs performed since 1993, 114 (58.2%) fit the selection criteria, with a mean age of 49 +/- 10 years. LT (alone/combination) indications included HCV (58%), alcoholic liver disease (41%), hepatocellular carcinoma (16%), and other (33%). Four hundred seventy-seven ATP levels were obtained: 3 (1-17) per patient 25 months (4 days to 19 years) from the time from transplantation. Final diagnoses were normal allograft function (n = 166, 35%), recurrent disease (n = 199, 42%), septic event (n = 34, 7%), other (n = 51, 11%), and undetermined (n = 27, 6%). Two hundred eighty-one ATP levels were obtained [3 (1-18) per patient] in 66 HCV(+) patients. Forty-five (68%) developed biopsy-proven recurrent liver disease [188/281 (67%) ATP levels]. The median ATP level (ng/mL) was 162 (1-761); it was lower in HCV(+) patients (151 +/- 109) versus HCV(-) patients (211 +/- 139; P < 0.0001). ATP ranges in HCV(+) patients were stable from the time from transplantation. In HCV(-) patients, ATP ranges were initially high and eventually decreased to HCV(+) levels (P = 0.01). Immunosuppressant levels were low in 62% of HCV(-) patients versus 38% of HCV(+) patients (P = 0.04). In HCV(+) patients, ATP was lower in disease recurrence (139 +/- 97) versus none (181 +/- 141; P = 0.01) with similar immunosuppression, and ATP decreased with grade (P = 0.05) but not stage. Time from transplantation, aspartate aminotransferase/alanine aminotransferase >1, and low ATP were independently associated with recurrent HCV. In conclusion, after LT, global cellular immune function appears depressed at baseline in HCV(+) patients versus HCV(-) patients and more so in HCV(+) recurrent disease.

Comparison of outcomes with low-dose anti-thymocyte globulin, basiliximab or no induction therapy in pediatric kidney transplant recipients: a retrospective study.

It is unclear which induction therapy yields the best outcomes in pediatric kidney transplantation. Retrospective data of 88 children receiving a renal allograft between November 1996 and October 2003 were analyzed. Patients received ATGI (n = 12), BI (n = 29), or NAI (n = 47). The mean ATG dose was 5.1 +/- 2.1 mg/kg. At 12 months, graft survival rates were 91.7%, 100%, and 97.9% for ATGI, BI, and NAI groups, respectively. Acute rejection rates at 12 months were 0 (ATGI), 20.6% (BI), and 10.7% (NAI). The mean GFR for ATGI (42.4 +/- 25.9 mL/min) was lower than for BI (78.3 +/- 27.2 mL/min), and NAI (66 +/- 28.3 mL/min) at 12 months (p < 0.05). One ATGI patient developed CMV pneumonia but none developed post-transplant lymphoproliferative disorder. Although there was no renal allograft survival benefit with either ATGI or BI, relative to NAI, the absence of acute rejection and equivalent rates of viral infections in the higher-risk ATGI recipient group suggests that the treatment strategy is promising. A large prospective study is needed to better define the role of ATGI in pediatric kidney transplantation.

Pro-apoptotic DNA vaccination ameliorates new onset of autoimmune diabetes in NOD mice and induces foxp3+ regulatory T cells in vitro.

We have shown previously that incorporation of a cDNA coding for the pro-apoptotic protein BAX into plasmid DNA coding for a secreted form of the pancreatic beta-cell antigen glutamic acid decarboxylase (GAD) promotes prevention of type 1 diabetes in non-obese diabetic (NOD) mice. Here we present evidence indicating that injection of the same vaccine at time of early diabetes onset could ameliorate the disease with efficacy, with 42% of mice overtly diabetic by 40 weeks of age compared to 92% in control groups. In addition, immunological analysis revealed that the DNA vaccine induced CD4(+)CD25(+) T cells cultured from draining lymph nodes that had immunosuppressive function in vitro. The induced regulatory T cells (Tregs) expressed the foxp3 gene and showed cell-contact-dependent as well as TGF-beta- and IL-10-independent immunosuppressive activity. Data also revealed that CD4(+)CD25(-) T cells from mice immunized with the DNA vaccine yielded a cell population that was foxp3(+), showed increased expression of CD25 compared to control, and had immunosuppressive function in vitro, indicating that Tregs could have developed from antigen-induced, peripheral T lymphocytes. In contrast, injection of DNA coding for SGAD55 or BAX alone did not induce Tregs. Altogether, our data confirm that pro-apoptotic DNA vaccination can be used as an immunosuppressive strategy and demonstrate its potential for therapy of pathological autoimmunity.

Donor intracaval thrombus formation and pulmonary embolism after simultaneous piggyback liver transplantation and aortic valve replacement.

Pulmonary embolism (PE) is a well known and serious complication that may develop after abdominal surgery. Liver transplant recipients are not immune to PE and tend to share many of the same risk factors with surgical patients who are stricken with this potential fatal complication. Liver transplantation using the piggyback (PB) technique is widely accepted, although there are reports of technique-specific-related vascular complications. We present a case of a 49-yr-old male liver transplant recipient who received his graft using the PB while simultaneously undergoing aortic valve replacement. His post-operative course was complicated by a PE 15 d after his surgery and was the result of an intracaval thrombus of the graft liver. The current case should alert clinicians to think of a donor intracaval thrombus as a complication of PB liver transplantation and a possible source of PE.