De Novo Autoimmune Hepatitis Following Liver Transplantation.

INTRODUCTION: De novo autoimmune hepatitis, also known as plasma cell hepatitis, is an increasingly recognized entity following liver transplantation. The aim of this study is to investigate the long-term outcomes of patients with de novo autoimmune hepatitis. METHODS: Using transplant liver biopsy database, we identified all patients showing plasma cell hepatitis following liver transplantation between 2008 and 2013. The diagnosis of plasma cell hepatitis was based on the histologic features from liver biopsies. RESULTS: A total of 30 patients with plasma cell hepatitis were identified. Underling liver disease were hepatitis C virus (n = 11) and non-hepatitis C virus-related disease (n = 19). The interval period from liver transplantation to development of plasma cell hepatitis was 20 (2-246) months during 6 (1.5-25.8) years after liver transplantation. The mean international autoimmune hepatitis score and frequency of acute cellular rejection episode prior to the diagnosis of plasma cell hepatitis were lower in the patients with hepatitis C virus than those underlying non-hepatitis C virus-related disease. Twenty-seven patients (90.0%) showed complete biochemical response to plasma cell hepatitis treatment, but 10 (37.0%) patients relapsed. During the median 72 months' follow-up after liver transplantation, 9 (30.0%) patients progressed to cirrhosis (median 37 months) and 10 (33.3%) patients died or were retransplanted. CONCLUSIONS: This long-term clinical observation shows that de novo autoimmune hepatitis represents one cause of graft loss in patients with or without hepatitis C virus. Although most patients exhibit a good response to medical therapy, de novo autoimmune hepatitis is likely to recur and progress to liver cirrhosis.

Liver Transplantation for Hepatitis B in Early Adulthood: Analysis of the United Network for Organ Sharing Database.

BACKGROUND: Chronic hepatitis B virus (HBV) infection has a mild course in most children that may delay initiation of treatment even when indicated. Unfortunately, a small number of cases can progress rapidly to cirrhosis, which may require liver transplantation (LT) in early adulthood. The aim of this study was to assess the characteristics of HBV-positive young adults who received LT and to evaluate post-transplant outcomes including patient and graft survival and differences between pre- and post-implementation of Model for End-stage Liver Disease (MELD) prioritization. METHODS: The United Network for Organ Sharing (UNOS) database review was conducted from 1987 to 2012, and a retrospective analysis was performed on all young adult patients (ages 18-35 years) who underwent LT in the United States with a primary diagnosis of HBV or were seropositive for HBV surface antigen at time of LT. Kaplan-Meier analysis was used to assess patient and graft survival in the pre-MELD and post-MELD eras. Factors associated with survival were identified through the use of Cox regression analysis. RESULTS: A total of 522 HBV-infected subjects were included. Average age at time of transplant was 28.4 ± 5.2 years; 60.9% were male, 48.6% were white, the mean body mass index was 25 ± 5.5 kg/m2, diabetes was present in 3.9%, hepatocellular carcinoma (HCC) was present in 4.4%, and 10.4% were on dialysis prior to LT. Median follow-up after first LT was 48.2 months [12.5, 109]. During this time, 174 (33.3%) patients died with a mean age at the time of death of 31.6 ± 7.8 years, including 144 of 522 (28%) after the first LT, 26 of 74 (35%) after the second LT, and 4 of 12 (33%) after the third LT. The most common cause of death was graft failure (27.6%), followed by infection (16.6%). Overall, only 58% of patients were alive with their first LT at last follow-up. Kaplan-Meier analysis revealed worse patient and graft survival after re-transplantation in comparison to initial LT. Three hundred thirty subjects were transplanted in the pre-MELD era and 192 were transplanted in post-MELD era. Obesity, HCC, shorter ventilation use, shorter cold ischemia time, and non-white donor race were significantly more common in the post-MELD era (all with P < .05). Importantly, 5-year patient and graft survival rates were higher in the post-MELD era compared with the pre-MELD era. CONCLUSIONS: LT in young adults for HBV has poor outcomes and can be associated with premature death. These findings should prompt more aggressive evaluation and treatment for HBV in young patients. Superior outcomes in the post-MELD era compared with the pre-MELD era may be attributed to pre-transplant factors, improved surgical technique, and better treatment options for HBV infection.

Sofosbuvir and Simeprevir for the Treatment of Recurrent Hepatitis C with Fibrosing Cholestatic Hepatitis after Liver Transplantation.

Fibrosing cholestatic hepatitis (FCH) is an aggressive form of hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT), which frequently results in graft failure and death. Treatment of FCH remains challenging, and the optimal antiviral therapy is yet to be determined. Between November 2013 and early 2015, 62 patients with HCV cirrhosis underwent OLT at our transplant center, of whom, 5 patients developed recurrence HCV in the form of severe FCH and were treated with sofosbuvir and simeprevir (SOF-SMV) for 24 weeks. All patients achieved significant improvement of HCV viral load and had undetectable viral PCR at 6-8 week of treatment. The HCV RNA remained undetectable throughout treatment course. The first two patients achieved SVR at week 12 after completion of the treatment. There were significant histologic and biomarkers improvements after initiation of the treatment. One patient developed refractory pruritus and acute pancreatitis. The second, fourth and fifth patients had very benign treatment courses with no side effects recorded. The third patient was starting the treatment with multiple comorbid conditions. His course was complicated with hepatic artery thrombosis, and later developed sepsis and renal failure. Therefore, it seems that the combination of SOF-SMV is an efficacious oral regimen in OLT recipient with recurrent hepatitis C and FCH. However, safety profile needs to be carefully evaluated.

Hepatocellular Carcinoma in the Setting of Chronic Hepatitis B Virus Infection: Tumor Recurrence and Survival Rates After Liver Transplantation.

BACKGROUND: Higher rates of hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) in patients with chronic hepatitis B virus (HBV) infection have been reported. This can influence their selection for LT and post-LT monitoring. OBJECTIVE: The aim of this work was to compare the rates of post-LT HCC recurrence and survival in HBV and non-HBV patients with the use of the United Network for Organ Sharing (UNOS) database. METHODS: After accessing the UNOS database, we analyzed patients with HCC stage T2 who underwent LT from cadaveric donors on or after August 24, 1998. Propensity score matching based on age, Model for End-Stage Liver Disease (MELD), and donor risk index was used to match HBV-HCC patients to HCC patients with other underlying liver diseases: hepatitis C virus (HCV), alcoholic liver disease (ALD), both HCV + ALD, and nonalcoholic steatohepatitis (NASH). Kaplan-Meier plots and multivariable analysis (with the use of propensity score, age, sex, and race) were used to assess post-LT HCC recurrence and overall survival. RESULTS: A total of 4,480 HCC patients were matched. Their average age was 57 ± 7.8 years and average calculated MELD score was 13. Within 5 years of LT, 5.5% of patients had HCC recurrence and 20% died. HBV-HCC patients had 1.9 and 1.8 times higher hazard of tumor recurrence compared with ALD and NASH patients, respectively, and a 32% lower hazard of death than patients with HCV + ALD. There was no evidence of any other significant difference in HCC recurrence or survival among the etiology groups. CONCLUSIONS: HCC recurrence and survival rates following LT for HCC patients with chronic HBV infection are similar to those of HCC patients with other underlying liver diseases. These findings support LT as a viable option for HCC-HBV patients.

Treatment of Recurrent Hepatitis C Genotype-4 Post-Liver Transplantation with Sofosbuvir plus Simeprevir.

Hepatitis C virus (HCV) infection remains a leading indication for orthotopic liver transplantation (OLT) worldwide. Recurrence of HCV following OLT is universal. There is scarcity of data on the post-OLT treatment of HCV genotype-4-the predominant genotype in North Africa and the Middle East. Herein, we present three patients who have experienced HCV genotype-4 recurrence post-OLT. All three patients were interferon-naive and were treated with simeprivir (SIM) and sofosbuvir (SOF) combination therapy for 12-24 weeks. The data from this case series show that SIM+SOF are well-tolerated and effective for achieving viral clearance in HCV genotype-4 post-OLT patients. Given the limited nature of a case series, further research must be pursued regarding post-OLT HCV genotype-4 responses to direct-acting anti-viral therapy.

Breathprints of childhood obesity: changes in volatile organic compounds in obese children compared with lean controls.

OBJECTIVE: The objective of this study was to investigate changes in volatile organic compounds (VOCs) in exhaled breath in overweight/obese children compared with their lean counterparts. STUDY DESIGN: Single exhaled breath was collected and analyzed per protocol using selective ion flow tube mass spectrometry (SIFT-MS). RESULTS: Sixty overweight/obese children and 55 lean controls were included. Compared with the lean group, the obese group was significantly older (14.1 ± 2.8 vs. 12.1 ± 3.0 years), taller (164.8 ± 10.9 vs. 153.3 ± 17.1 cm) and more likely to be Caucasian (60% vs. 35.2%); P < 0.05 for all. A comparison of the SIFT-MS results of the obese group with the lean group revealed differences in concentration of more than 50 compounds. A panel of four VOCs can identify the presence of overweight/obesity with excellent accuracy. Further analysis revealed that breath isoprene, 1-decene, 1-octene, ammonia and hydrogen sulfide were significantly higher in the obese group compared with the lean group (P value < 0.01 for all). CONCLUSION: Obese children have a unique pattern of exhaled VOCs. Changes in VOCs observed in this study may help to gain insight into pathophysiological processes and pathways leading to the development of childhood obesity.

The incidence and risk factors of de novo skin cancer in the liver transplant recipients.

BACKGROUND: Liver transplantation (LT) increases the risk of de novo malignancies including skin cancers. However, risk factors for this type of cancers have not been well studied. OBJECTIVE: To determine the incidence of skin cancer in LT recipients, and to identify the risk factors of this type of cancer. METHODS: We identified all adult patients who underwent LT and developed de novo skin cancer post-LT at our institution between 1996 and 2009. We excluded the patients with history of skin cancer prior to LT. We also studied a control group of patients who underwent LT during the same period but did not develop skin cancer; the control group was matched (1:2) for age, gender and geographical place of residence. RESULTS: Over a median (IQR) follow-up of 41.5 (18.0, 98.6) months, 23 (2.3%) of 998 patients developed skin cancer post-LT, of whom 10 were identified with squamous cell carcinoma, 9 with basal cell carcinoma and 4 with melanoma. After adjusting the confounding variables, subjects who had combined liver/kidney transplant had 22 (95% CI: 5.1-99) times higher hazard of skin cancer compared to subjects with LT alone. Furthermore, patients who had non-skin cancer prior to LT had 23 (95% CI: 8.6-60) times higher hazard developing skin cancer after the transplant. Patients with history of alcohol consumption, as the underlying etiology of liver disease, had 4 (95% CI: 1.2-12.9) times higher hazard of developing skin cancer after transplantation. Type or duration of immunosuppression was not associated with increased risk of skin cancer post-LT. The post-LT survival outcome was not affected by the development of de novo skin cancer post-LT. CONCLUSION: Skin cancer is relatively common in LT recipients and should be monitored, particularly in patients with a history of pretransplant malignancy, recipients of combined liver and kidney transplant or having alcoholic cirrhosis as the underlying cause of liver disease.

Rate of tumor growth predicts recurrence of hepatocellular carcinoma after liver transplantation in patients beyond Milan or UCSF criteria.

BACKGROUND: It is likely that some patients whose tumor burdens exceed the current transplant criteria have favorable tumor biology, and that these patients would have low risk of tumor recurrence after liver transplantation (LT). To assess the rate of tumor growth as selection criteria for LT in patients with hepatocellular carcinoma (HCC). METHODS: We identified all patients who underwent LT for HCC in our institution from 2002 to 2008. Total tumor volume (TTV) was calculated as the sum of the volumes of all tumors on pretransplantation imaging [(4/3)πr3, where r is the maximum radius of each HCC]. The rate of tumor growth was calculated as per-month change in TTV on sequential pretransplantation imaging before any locoregional therapy. A Kaplan-Meier plot was constructed and Cox regression analysis performed. RESULTS: Ninety-two patients were included in the study. The median follow-up was 19.5 (range 10.7-30.7) months during which 12 patients (13%) experienced recurrence of HCC. Twenty-four patients (26%) had HCC beyond the Milan criteria, and the overall survival rate of the entire group was 72%. Higher pre-LT alpha-fetoprotein (hazard ratio [HR] 1.01; P=.001), poorly differentiated tumors (HR 13; P=.039), the presence of microvascular invasion (HR 7.9; P=.001), higher TTV (HR 1.03; P<.001), and faster tumor growth (HR 1.09; P<.001) were significantly associated with the risk of recurrence. A cutoff value of tumor growth of 1.61 cm3/mo was chosen on the basis of the risk of recurrence with the use of a receiver operating characteristic curve. Patients beyond the Milan criteria with tumor growth<1.61 cm3/mo experienced less recurrence (11% vs 58%; P=.023) than those beyond the Milan criteria with tumor growth>1.61 cm3/mo. Similarly, rate of tumor growth predicted HCC recurrence in those beyond the University of California of San Francisco (UCSF) criteria. CONCLUSIONS: Patients with slowly growing tumor who would be currently excluded from LT because tumor burden exceeds traditional Milan and UCSF criteria may have a favorable posttransplantation outcome.

Recurrence of Disease Following Liver Transplantation: Nonalcoholic Steatohepatitis vs Hepatitis C Virus Infection.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is an increasing indication for orthotopic liver transplantation (OLT) in the United States and other countries. However, the incidence of disease recurrence and natural course following OLT remains incompletely understood. OBJECTIVE: To estimate the incidence of recurrent disease, outcome and identify risk factors associated with disease recurrence in patients undergoing OLT for NASH as compared to those undergoing OLT for HCV cirrhosis. METHODS: We identified all patients with end-stage liver disease secondary to NASH (n=53) or HCV (n=95) cirrhosis who underwent OLT at our institution between 1998 and 2005. Protocol liver biopsies were performed (Day 7, Month 4 and yearly) after OLT, and as clinically indicated. Kaplan-Meier survival analysis was performed to assess the fibrosis progression and survival. Cox regression analysis was performed to identify factors associated with disease recurrence. RESULTS: Five-year survival was 90.5% in NASH vs 88.4% in HCV group (p=0.97). The median (25%ile, 75%ile) follow-up to last available biopsy was 12.7 (5.9, 26.3) months, during which 17 (32%) of NASH patients developed persistent fatty infiltration in their graft, 8 (15%) of whom had accompanying histologic features of recurrent NASH. There was no difference in the prevalence of post-OLT steatosis between HCV and NASH patients after adjusting for time of histologic follow-up (p=0.33). Patients with HCV infection were more likely to develop hepatic fibrosis post-OLT than those with NASH (62.1% vs 18.9%, p<0.001). Multivariate analysis identified post-OLT diabetes (HR=2.0, 95% CI: 1.2-3.2, p=0.007) as an independent risk factor for fibrosis development. Additionally, NASH subjects who received steroids had a significantly higher risk of developing hepatic fibrosis post-OLT than NASH patients who did not receive steroids and all HCV subjects (p<0.001). CONCLUSION: Recurrence of steatosis post-OLT is common. Corticosteroid use may contribute to fibrosis progression in this population.

Total tumor volume predicts recurrence of hepatocellular carcinoma after liver transplantation in patients beyond Milan or UCSF criteria.

BACKGROUND: The aim of tumor-based selection criteria in patients with hepatocellular carcinoma (HCC) is to prevent orthotopic liver transplantation (OLT) in patients likely to experience recurrence and to maximize OLT opportunities for those with a high likelihood of cure. OBJECTIVE: Our aim was to assess total tumor volume (TTV) as a selection criterion for OLT in patients with HCC beyond Milan or University of California San Francisco criteria. METHODS: We identified patients who underwent OLT for HCC between 2002 and 2008. TTV was calculated as the sum of the volumes of all tumors on pretransplant imaging before any therapy [(4/3)πr(3), where r is the maximum radius of each HCC]. Univariable and multivariable Cox proportional hazards regression analysis was used to assess factors associated with recurrence of HCC. RESULTS: 107 patients were included in the study. The mean follow-up was 21 months (interquartile range, 11.8-32.5), during which 13 patients (12.1%) experienced recurrence of HCC. Twenty-nine patients (27.1%) had HCC beyond the Milan criteria. A TTV cutoff value of 33.5 cm(3) was chosen on the basis of the risk of recurrence by using a receiver operating characteristic curve. Patients beyond the Milan criteria with TTV <33.5 experienced less recurrence (13.3% vs 42.8%; P < .001) and higher survival (13.3% vs 57.1%; P = .006) than those who were beyond the Milan criteria with TTV ≥33.5. Similarly, TTV predicted HCC recurrence and survival in those beyond the UCSF criteria. CONCLUSION: TTV is useful in identifying patients at risk of tumor recurrence and poor survival among those with tumor burden beyond traditional criteria, and it may improve the selection of OLT candidates.

Metabolic syndrome and liver transplantation.

Non-alcoholic fatty liver disease (NAFLD), an important consequence of the global epidemic of obesity, is a common indication of orthotopic liver transplantation in the western world. Currently, NAFLD is the fourth most common indication of liver transplantation in the United Stated with prediction for increase demand of liver transplantation for NAFLD cirrhosis in the next two decades to exceed that of liver transplantation for chronic hepatitis C virus infection. Given the advances in the efficacy and tolerability of immunosuppressive agents which have reduced the incidence of chronic rejection, long-term survival rates after liver transplantation have remarkably improved. Today, long-term graft loss and death after liver transplantation are commonly related to age-related complications, such as cardiovascular disease. Features of metabolic syndrome including obesity, hypertension, hyperglycemia and dyslipidemia are very prevalent and almost universal after liver transplantation. These metabolic derangements are intricately associated with cardiovascular events and have emerged as the leading cause of morbidity and mortality after liver transplantation. In addition, the international epidemic of obesity has negatively impacted the liver transplant candidacy. Because obesity is associated with poor postoperative outcome, many transplant centers decline liver transplantation for morbidly obese individuals above certain level of body mass index.

IL-2 Receptor Antagonist (Basiliximab) Is Associated with Rapid Fibrosis Progression in Patients with Recurrent Hepatitis C after Liver Transplantation Using Serial Biopsy Specimens.

BACKGROUND: Recurrence of hepatitis C virus (HCV) infection following orthotopic liver transplantation (OLT) is universal. There is paucity of data on the safety and efficacy of interleukin (IL)-2 receptor antagonist (IL-2RA) when added to the standard immunosuppression regimen in OLT recipients with recurrent HCV infection. OBJECTIVES: To evaluate the efficacy of IL-2RA (Basiliximab) in preventing acute cellular rejection (ACR) in patients with recurrent HCV infection after OLT and to assess the impact of IL-2RA in promoting fibrosis progression in post-OLT recurrent HCV infection. METHODS: Using an electronic pathology database, we identified all OLT/HCV patients with at least 2 post-OLT liver biopsies (1998-2006). Standard immunosuppression consisted of steroids and calcineurin inhibitor with and without mycophenolate mofetil. All patients who were transplanted after May 2004 received IL-2RA induction therapy. The Ludwig-Batts system was used to stage all biopsies (593 biopsies from 124 patients). The first biopsy that showed post-OLT fibrosis or the last follow-up biopsy was used for time-to-progression analysis. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify factors associated with the progression of fibrosis. RESULTS: ACR was significantly (p<0.001) lower in patients who received IL-2RA (20 of 70, 29%) compared to those who did not (33 of 54, 61%). The median (25%ile, 75%ile) follow-up was 12.1 (6.1, 23.9) months during which 61% of patients had progression of fibrosis. Univariate analysis revealed that a higher HCV RNA load at 4 months post-OLT (p=0.002), cytomegalovirus (CMV) infection (p<0.001), use of steroid therapy for ACR (p=0.043), and use of IL-2RA (p<0.001) were associated with higher hazards for the progression of fibrosis. Viral load at 4 months post-OLT was significantly (p=0.025) higher in patients who had IL-2RA therapy (median [25%ile, 75%ile]: 2.9 [1.0, 5.0] ×10(6) vs. 1.4 [1.0, 2.3] ×10(6)). In multivariate analysis, patients who received IL-2RA therapy were 3.1 (95% CI: 1.8-5.3) times more likely to develop fibrosis than those who did not treated with IL-2RA. Steroid therapy for ACR remained significantly (Hazard Ratio=2.9, p=0.002) associated with the progression of fibrosis. CONCLUSION: IL-2RA (Basiliximab) decreases the rate of ACR. However, it may be associated with more rapid histological progression of the disease in post-OLT recurrent HCV.