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.

Fibrosis in ulcerative colitis is directly linked to severity and chronicity of mucosal inflammation.

BACKGROUND: Fibrosis in ulcerative colitis has remained largely unexplored despite its clinical implications. AIMS: This cross-sectional study was aimed at characterising the presence, anatomical location and degree of ulcerative colitis-associated fibrosis and its possible link to clinical parameters. METHODS: Seven hundred and six individual tissue cross-sections derived every 10 cm along the length of 89 consecutive Ulcerative colitis colectomy specimens were examined and compared to Crohn's disease colitis, diverticular disease and uninvolved areas from colorectal cancer patients. Degree of inflammation, fibrosis and morphometric measurements of all layers of the intestinal wall were evaluated. Three gastrointestinal pathologists independently assessed colon sections stained with haematoxylin and eosin, Masson trichrome and Sirius red. Clinical data were collected prospectively. RESULTS: Submucosal fibrosis was detected in 100% of ulcerative colitis colectomy specimens, but only in areas affected by inflammation. Submucosal fibrosis was associated with the severity of intestinal inflammation (Spearman correlations rho (95% confidence interval): 0.58 (P < 0.001) and histopathological changes of chronic mucosal injury, but not active inflammation. Colectomy for refractory disease rather than presence of dysplasia was associated with increased fibrosis and a thicker muscularis mucosae, whereas a thinner muscularis mucosae was associated with anti-tumour necrosis factor therapy. No feature on endoscopic mucosal biopsies could predict the underlying amount of fibrosis or the thickness of the muscularis mucosae. CONCLUSIONS: A significant degree of fibrosis and muscularis mucosae thickening should be considered as common complications of chronic progressive ulcerative colitis. These features may have clinical consequences such as motility abnormalities and increased wall stiffness.

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.

Esophageal squamous cell carcinoma arising after endoscopic ablation therapy of Barrett's esophagus with high-grade dysplasia. Report of a case.

Patients with Barrett's esophagus are at risk for dysplasia and esophageal adenocarcinoma. Although surgery was the mainstay treatment for Barrett's dysplasia and cancer, patients with high-grade dysplasia and early cancers now have several nonsurgical treatment options. Most of the endoscopic therapies are relatively safe but do carry a risk for complications. Treatment failure with progression of the disease is the most severe complication, especially among patients with low surgical risk. Cryoablation has been used with promising results in both high-grade dysplasia and early esophageal cancer. A patient with a well-documented history of Barrett's esophagus with high-grade dysplasia that underwent multiple sessions of photodynamic therapy and salvage cryoablation for residual high-grade dysplasia was presented. The patient was diagnosed with squamous cell carcinoma of the distal esophagus approximately 1 year after cryoablation. This is the first complete report of squamous cell carcinoma occurring after endoscopic ablation for Barrett's neoplasia. Careful follow up is necessary in any endoscopic ablation program due to the risk of recurrent neoplasia.

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.

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.

Endoscopic water jets used to ablate Barrett's esophagus: preliminary results of a new technique.

BACKGROUND: The optimal management of Barrett's esophagus, a precursor to esophageal adenocarcinoma, remains controversial. Current therapy includes surveillance and ablative or resection techniques of varying safety and efficacy. This study aimed to determine the feasibility of a new catheter-based, endoscopic water jet ablation technique. METHODS: A high-pressure flexible catheter that can be passed through the working port of a standard gastroscope was used. The catheter had micro-drilled holes on one side near the tip. A 1-cm water jet was delivered under foot pedal control and endoscopic view at pressures adjusted from 150 to 400 psi. After approval from the authors' Institutional Review Board, tissue segments from fresh esophagectomy specimens were ablated by the catheter without use of an endoscope. Using gross appearance and histologic analysis, variable ablation pressures and times were evaluated. RESULTS: Using variable pressures and times, 11 ablation sessions were performed: 5 for normal esophagus, 4 for normal stomach, and 2 across the gastroesophageal junction in the setting of Barrett's esophagus. Ablation pressures of 150 to 300 psi for 30 to 60 s resulted in selective ablation of mucosa with preservation of the submucosa and muscularis propria. The depth of the ablation was determined by gross inspection at the time of ablation and confirmed by histologic evaluation. There was no embedding of epithelial cells in the muscularis propria. In a single normal esophagus specimen, a jet applied at 400 psi for 120 s in a confined area resulted in gross perforation. CONCLUSION: Selective ablation of esophageal and gastric epithelium using a catheter-based water jet ablation technique is feasible. The preliminary data from this study investigating a nonendoscopic technique show that the mucosa can be removed with preservation of the underlying submucosa and muscular layers. Further studies are warranted that focus on defining more precisely the pressure and duration required for optimal results and the practical application of this technique endoscopically.

Immunohistochemical distinction between primary adenocarcinoma of the bladder and secondary colorectal adenocarcinoma.

Primary adenocarcinoma of the urinary bladder sometimes causes a diagnostic dilemma because it can be indistinguishable morphologically from adenocarcinoma of colorectal origin secondarily involving the bladder by metastasis or direct extension. It is much less well studied than conventional urothelial carcinoma and colorectal adenocarcinoma because of its rarity. The current study was specifically designed to investigate whether an important mechanism involved in the pathogenesis of colorectal adenocarcinoma, beta-catenin dysregulation, was also important for the development of primary bladder adenocarcinoma and whether these two morphologically similar tumors could be distinguished immunohistochemically. Formalin-fixed, paraffin-embedded tissues from 17 primary adenocarcinomas of the urinary bladder, 16 colorectal adenocarcinomas involving the bladder, and 10 conventional urothelial (transitional) carcinomas were included in this study. Thirteen of the primary bladder adenocarcinomas were moderately to well differentiated (enteric type) and morphologically indistinguishable from colorectal cancers. The remaining four primary tumors were poorly differentiated (two cases) or of clear cell type (two cases). Immunohistochemical studies using a panel of monoclonal antibodies demonstrated positive nuclear staining for beta-catenin expression in 13 of the 16 (81%) colorectal adenocarcinomas secondarily involving the bladder but in none of the primary adenocarcinomas or the urothelial carcinomas. Instead, positive membranous (and some cytoplasmic) staining was present in all primary bladder tumors with the exception of two poorly differentiated adenocarcinomas where no beta-catenin staining was detected. All secondary colorectal adenocarcinomas stained negatively for CK7 and thrombomodulin (TM), whereas positivity for CK20 was observed in 15 (94%) cases. All urothelial carcinomas stained positively for CK7 and TM, and four of them also for CK20. Primary adenocarcinomas of the bladder showed mixed staining patterns for CK7, CK20, and TM with a positive rate of 65%, 53%, and 59%, respectively. These data indicate that dysregulation of beta-catenin, an important aberration seen in colorectal carcinogenesis, does not appear to play a role in the pathogenesis of the bladder adenocarcinoma. In addition, our data demonstrate that a panel of immunostains, including CK7, CK20, TM, and beta-catenin, is of diagnostic value in differentiating primary bladder adenocarcinoma from secondary adenocarcinoma of colorectal origin.