Transgender Males on Gender-Affirming Hormone Therapy and Hepatobiliary Neoplasms: A Systematic Review.

OBJECTIVE: Behavioral therapy, gender-affirming hormone therapy (GAHT), and surgery are all components of a successful gender transition, but due to a historical lack of access, there is paucity of long-term data in this population. We sought to better characterize the risk of hepatobiliary neoplasms in transgender males undergoing GAHT with testosterone. METHODS: In addition to the 2 case reports, a systematic literature review of hepatobiliary neoplasms in the setting of testosterone administration or endogenous overproduction across indications was conducted. The medical librarian created search strategies using keywords and controlled vocabulary in Ovid Medline, Embase.com, Scopus, Cochrane Database of Systematic Reviews, and clinicaltrials.gov. A total of 1273 unique citations were included in the project library. All unique abstracts were reviewed, and abstracts were selected for complete review. Inclusion criteria were articles reporting cases of hepatobiliary neoplasm development in patients with exogenous testosterone administration or endogenous overproduction. Non-English language articles were excluded. Cases were collated into tables based on indication. RESULTS: Forty-nine papers had cases of hepatocellular adenoma, hepatocellular carcinoma, cholangiocarcinoma, or other biliary neoplasm in the setting of testosterone administration or endogenous overproduction. These 49 papers yielded 62 unique cases. CONCLUSION: Results of this review are not sufficient to conclude that there is an association between GAHT and hepatobiliary neoplasms. This supports current evaluation and screening guidelines for initiation and continuation of GAHT in transgender men. The heterogeneity of testosterone formulations limits the translation of risks of hepatobiliary neoplasms in other indications to GAHT.

Increased Risk of Advanced Colonic Adenomas and Timing of Surveillance Colonoscopy Following Solid Organ Transplantation.

BACKGROUND: Detection and removal of colonic adenomatous polyps (CAP) decreases colorectal cancer (CRC) development, particularly with more or larger polyps or polyps with advanced villous/dysplastic histology. Immunosuppression following solid organ transplantation (SOT) may accelerate CAP development and progression compared to average-risk population but the benefit of earlier colonoscopic surveillance is unclear. AIMS: Study the impact of maintenance immunosuppression post-SOT on developmental timing, multiplicity and pathological features of CAP, by measuring incidence of advanced CAP (villous histology, size ≥ 10 mm, ≥ 3 polyps, presence of dysplasia) post-SOT and the incidence of newly diagnosed CRC compared to average-risk age-matched population. METHODS: Single-center retrospective cohort study of SOT recipients. RESULTS: 295 SOT recipients were included and were compared with 291 age-matched average-risk controls. The mean interval between screening and surveillance colonoscopies between SOT and control groups was 6.3 years vs 5.9 years (p = 0.13). Post-SOT maintenance immunosuppression mean duration averaged 59.9 months at surveillance colonoscopy. On surveillance examinations, SOT recipients exhibited more advanced (≥ 10 mm) adenomas compared to matched controls (9.2% vs. 3.8%, p = 0.034; adjusted OR 2.38; 95% CI 1.07-5.30). CONCLUSION: SOT recipients appear at higher risk for developing advanced CAP, suggesting that earlier surveillance should be considered.

Liver transplantation for hepatitis C patients in the era of direct-acting antiviral treatment: A retrospective cohort study.

INTRODUCTION: Direct-acting antivirals (DAA's) have revolutionized hepatitis-C virus (HCV) treatment, however controversy remains regarding timing of treatment in relation to liver-transplant (LT). METHODS: Single-center retrospective study assessing outcomes of listed HCV positive patients in the DAA-era (2014-2017). Patients treated with DAA's before LT (DAA pre-LT) were compared to those who were not treated before LT (No DAA pre-LT) RESULTS: 156 HCV positive patients were listed during study-period; 104 (67%) underwent LT while 52 (33%) were de-listed. Of transplanted patients, 48 (46%) received DAA pre-LT while 56 (54%) were treated post-LT. Both groups were comparable in age, gender, MELD, patient and graft survival and cure-rates (98% in DAA pre-LTvs.95% in No DAA pre-LT; p > 0.05). DAA pre-LT group required higher number of treatments-per-patient to clear virus (1.46vs.1.06; p = 0.0006), spent more time on waitlist (331d.vs150d; p = 0.0040) and were less likely to receive livers from HCV positive donors (6%vs.25%; p = 0.0148). Twenty-nine (56%) of the 52 delisted received DAA. They had lower listing-MELD (12vs.18; p = 0.0033), and were more likely to be delisted for "condition improved" (34%vs.4%; p = 0.0143) compared to the 23 (44%) delisted patients who did not receive DAA's. CONCLUSIONS: DAA's were equally effective in clearing HCV in listed patients irrespective of timing. DAA pre-LT can disadvantage some patients through increase number of treatments needed and longer waitlist times, but treatment in some listed patients with low-MELD can improve condition and alleviate need for LT.

Serum alpha-fetoprotein level per total tumor volume as a predictor of recurrence of hepatocellular carcinoma after resection.

BACKGROUND: Alpha-fetoprotein has been used as a predictor of recurrence for hepatocellular carcinoma and disease-free survival post-resection. Studies in East Asia have shown that serum alpha-fetoprotein per total tumor volume ratio is a better prognostic indicator than alpha-fetoprotein alone. Similar studies in the United States evaluating serum alpha-fetoprotein to total tumor volume ratio have not been conducted. Its relevance is incompletely understood. METHODS: Consecutive patients undergoing resection for hepatocellular carcinoma at a single tertiary center between 2000 and 2013 were identified for inclusion in this retrospective cohort study. Patient demographics, associated liver disease, Child-Pugh and Model for End-Stage Liver Disease scores, preoperative imaging, surgical pathology, alpha-fetoprotein at diagnosis, last alpha-fetoprotein before surgery, and peak alpha-fetoprotein levels were recorded. Actual tumor volume by imaging volumetrics was used when available (n = 70). For the remaining cases, total tumor volume was calculated using the sum of the volumes of all the tumors ((4/3)πr3) where "r" is the mean radius of each lesion. Peak serum alpha-fetoprotein was used to calculate the alpha-fetoprotein to total tumor volume ratio. RESULTS: A total of 124 patients resected for hepatocellular carcinoma between 2000 and 2013 were identified. Overall 1-, 3-, and 5-year survival post resection was 76%, 53%, and 35%, respectively. On multivariate analysis, peak alpha-fetoprotein to total tumor volume ratio > 20 (P < .001, HR = 3.72, 95% CI [1.82-7.58]) and lymphovascular space invasion (P = .002, HR = 3.30, 95% CI [1.57-6.94]) were found to affect hepatocellular carcinoma recurrence-free survival. CONCLUSION: A variety of prognostic values predict the recurrence of hepatocellular carcinoma postresection. Peak preoperative alpha-fetoprotein to total tumor volume > 20 and lymphovascular space invasion has been shown to predict recurrence of hepatocellular carcinoma. Our study confirms findings from East Asian studies. But larger series are needed to establish this correlation in patients with hepatocellular carcinoma not treated by resection.

Outcomes in Adults With Acute Liver Failure Between 1998 and 2013: An Observational Cohort Study.

BACKGROUND: Acute liver failure (ALF) is a rare syndrome of severe, rapid-onset hepatic dysfunction-without prior advanced liver disease-that is associated with high morbidity and mortality. Intensive care and liver transplantation provide support and rescue, respectively. OBJECTIVE: To determine whether changes in causes, disease severity, treatment, or 21-day outcomes have occurred in recent years among adult patients with ALF referred to U.S. tertiary care centers. DESIGN: Prospective observational cohort study. (ClinicalTrials .gov: NCT00518440). SETTING: 31 liver disease and transplant centers in the United States. PATIENTS: Consecutively enrolled patients-without prior advanced liver disease-with ALF (n = 2070). MEASUREMENTS: Clinical features, treatment, and 21-day outcomes were compared over time annually for trends and were also stratified into two 8-year periods (1998 to 2005 and 2006 to 2013). RESULTS: Overall clinical characteristics, disease severity, and distribution of causes remained similar throughout the study period. The 21-day survival rates increased between the two 8-year periods (overall, 67.1% vs. 75.3%; transplant-free survival [TFS], 45.1% vs. 56.2%; posttransplantation survival, 88.3% vs. 96.3% [P < 0.010 for each]). Reductions in red blood cell infusions (44.3% vs. 27.6%), plasma infusions (65.2% vs. 47.1%), mechanical ventilation (65.7% vs. 56.1%), and vasopressors (34.9% vs. 27.8%) were observed, as well as increased use of N-acetylcysteine (48.9% vs. 69.3% overall; 15.8% vs. 49.4% [P < 0.001] in patients with ALF not due to acetaminophen toxicity). When examined longitudinally, overall survival and TFS increased throughout the 16-year period. LIMITATIONS: The duration of enrollment, the number of patients enrolled, and possibly the approaches to care varied among participating sites. The results may not be generalizable beyond such specialized centers. CONCLUSION: Although characteristics and severity of ALF changed little over 16 years, overall survival and TFS improved significantly. The effects of specific changes in intensive care practice on survival warrant further study. PRIMARY FUNDING SOURCE: National Institutes of Health.

Indwelling Tunneled Pleural Catheters for the Management of Hepatic Hydrothorax. A Pilot Study.

RATIONALE: Hepatic hydrothorax is a complication of cirrhosis in which hydrostatic imbalances result in fluid accumulation within the pleural space. Although uncommon, this may cause significant morbidity, resulting in dyspnea requiring repeated pleural drainage procedures. Liver transplantation is curative, but it is rarely immediately available to qualified patients, presenting the clinical challenge of managing recurrent pleural effusions. Indwelling tunneled pleural catheters (ITPCs) have been used successfully to palliate dyspnea associated with recurrent malignant pleural effusions. OBJECTIVES: This study was performed to evaluate the feasibility of using ITPCs for the management of hepatic hydrothorax. METHODS: A single-center prospective feasibility study was performed to evaluate the use of ITPCs for the management of recurrent hepatic hydrothorax in patients who were eligible for liver transplant evaluation. MEASUREMENTS AND MAIN RESULTS: Twenty-five ITPCs were placed in 24 patients. The mean number of pleural drainage procedures before ITPC placement was 1.9, with no further pleural drainages required in any patient after ITPC placement. Spontaneous pleurodesis occurred in 8 of 24 patients (33%). All eight catheters were successfully removed without pleural fluid reaccumulation. Mean time to pleurodesis was 131.8 days. Pleural fluid infection occurred in 4 of 24 patients (16.7%), requiring catheter removal in 3 of the 4 patients. CONCLUSIONS: ITPCs may be successfully and safely used to control symptoms associated with hepatic hydrothorax. The rate of spontaneous pleurodesis that occurs is similar to that observed with ITPCs placed for malignant pleural effusion, although the infection rate may be higher. Clinical trial registered with www.clinicaltrials.gov (NCT02595567).

Liver transplantation for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is an increasing problem in the USA and worldwide. Current treatments for HCC include chemoembolization, radioembolization, liver resection, and liver transplantation in the setting of selected cirrhotic patients. Liver transplantation for HCC was controversial initially, but is now widely accepted as a curative approach. Cirrhotic patients who meet standards for transplantation and have a tumor burden within Milan criteria are eligible for transplantation and receive Model for End-Stage Liver Disease (MELD) exception points once listed. Given the decline in availability of donor organs, rewarding MELD exception points and performing liver transplants in these patients remain controversial. Despite this, various guidelines propose expanding eligibility criteria for cirrhotics with HCC, due to post-transplant outcomes comparable to patients transplanted without HCC. Following the transplant, issues include optimizing the type and amount of immunosuppression and screening for and treating recurrence of HCC.

Aortic balloon valvuloplasty prior to orthotopic liver transplantation: a novel approach to aortic stenosis and end-stage liver disease.

The combination of severe aortic stenosis and end-stage liver disease increases the morbidity and mortality of surgical aortic valve replacement or orthotopic liver transplantation resulting in a prohibitive operative risk. We propose a staged approach of balloon aortic valvuloplasty prior to orthotopic liver transplantation as a bridge to definitive aortic valve replacement. Between 2010 and 2012, four patients with severe aortic stenosis and end-stage liver disease underwent staged balloon aortic valvuloplasty followed by orthotopic liver transplantation. All patients had been deemed to be inappropriate candidates for liver transplantation or aortic valve surgery due to their comorbidity. One patient died of complications from a perivalvular abscess. Three patients went on to successful graft implantation and function and surgical recovery. Two of the three patients proceeded to definitive surgical aortic valve replacement with the remainder currently undergoing evaluation. In this case series, we present a novel approach of balloon aortic valvuloplasty prior to liver transplantation as a potential bridge to definitive treatment of severe aortic stenosis in the end-stage liver patient.

Assessment of hepatitis C risk factors and infection prevalence in a jail population.

OBJECTIVES: We sought to validate previous reports of HCV prevalence in jails, identify HCV risk factors prevalence, and identify risk factors associated with HCV infection in this population. METHODS: Inmates at the Buzz Westfall Justice Center (BWJC) in St. Louis, Missouri, were offered risk factor screening for HCV and anti-HCV antibody testing from December 2012 through May 2013. Demographic and risk factor information were assessed for significant associations with positive HCV antibody results. Risk factors that were significantly associated in univariate analysis were assessed using binary logistic regression to model the relationship between positive HCV results and the risk factors and demographics. RESULTS: Fifty of 304 inmates were positive for HCV, with a prevalence of 16.4%. The risk factors significantly associated with increased risk for positive HCV antibody were age (odds ratio [OR] = 1.09; 95% confidence interval [CI] = 1.04, 1.15 for each year), injection drug use (OR = 53.87; 95% CI = 17.78, 163.21), sex with HCV-positive partner (OR = 7.35; 95% CI = 1.41, 38.20), and tattoos by a nonlicensed provider (OR = 2.62; 95% CI = 1.09, 6.33). Prevalence for women was 3 times that of men (38% vs 12%). CONCLUSIONS: Prevalence of HCV at BWJC was similar to previous jail studies, which is lower than reported prison rates and higher than the general population.

Liver volume in the cirrhotic patient: does size matter?

BACKGROUND: While it is established that cirrhosis results in a decrease in liver volume (LV), whether LV itself predicts patient survival is unknown. We hypothesize that estimated LV is an important prognostic indicator in patients with cirrhosis. METHODS: Data was gathered retrospectively from consecutive patients evaluated for a liver transplant from January 2001 to June 2006. Of 500 patients identified, 323 patients met both inclusion and exclusion criteria. LV per ideal body weight (IBW) was used to correct for body size, and LV/IBW was stratified by median split for survival analyses. Patients were classified into one of three clinical groups: hepatocellular disease (n = 229), cholestatic disease (n = 56), and miscellaneous (n = 38). One of three possible clinical outcomes (survival, liver transplantation, or death) was recorded during the 5-year follow-up, the latter two grouped together as "transplant/death." RESULTS: Transplant/death occurred in 283 (88 %) subjects. Overall, there was a significant increase in transplant/death in those with lower LV/IBW (χ(2) = 5.27, p = 0.022). When considering the subset with hepatocellular disease, lower LV/IBW was a robust predictor of transplant/death (χ(2) = 9.62, p = 0.002). In multivariate analyses, the LV/IBW trended toward predicting transplant/death (ExpB = 0.943, p = 0.053) independent of Model for End stage Liver Disease (MELD) (ExpB = 1.13, p = 0.001). DISCUSSION: LV has important predictive value in patients with cirrhosis from hepatocellular disease. This observation appears to be independent of MELD, suggesting LV may impart important prognostic information that is not captured by the MELD score alone. Thus, LV may serve as an important adjunct to the MELD score in patients with hepatocellular disease.

Hepatitis C virus-induced changes in microRNA 107 (miRNA-107) and miRNA-449a modulate CCL2 by targeting the interleukin-6 receptor complex in hepatitis.

UNLABELLED: Hepatitis C virus (HCV)-mediated liver diseases are one of the major health issues in the United States and worldwide. HCV infection has been reported to modulate microRNAs (miRNAs) that control various cell surface receptors and gene-regulatory complexes involved in hepatic inflammation and liver diseases. We report here that specific downregulation of miRNA-107 and miRNA-449a following HCV infection in patients with HCV-mediated liver diseases modulates expression of CCL2, an inflammatory chemokine upregulated in patients with chronic liver diseases, by targeting components of the interleukin-6 receptor (IL-6R) complex. Computational analysis for DNA-bound transcription factors in the CCL2 promoter identified adjacent binding sites for CCAAT/CEBPα, spleen focus-forming virus, proviral integration oncogene (SPI1/PU.1), and STAT3. We demonstrate that CEBPα, PU.1, and STAT3 interacted with each other physically to cooperatively bind to the promoter and activate CCL2 expression. Analysis of IL-6R and JAK1 expression in HCV patients by quantitative PCR showed significant upregulation when there was impaired miRNA-107 and miRNA-449a expression, along with upregulation of PU.1 and STAT3, but not CEBPα. miRNA-449a and miRNA-107 target expression of IL-6R and JAK1, respectively, in vitro and also inhibit IL-6 signaling and impair STAT3 activation in human hepatocytes. Taken together, our results demonstrate a novel gene-regulatory mechanism in which HCV-induced changes in miRNAs (miRNA-449a and miRNA-107) regulate CCL2 expression by activation of the IL-6-mediated signaling cascade, which we propose will result in HCV-mediated induction of inflammatory responses and fibrosis. IMPORTANCE: Hepatitis C virus (HCV)-induced hepatitis is a major health concern worldwide. HCV infection results in modulation of noncoding microRNAs affecting major cellular pathways, including inflammatory responses. In this study, we have identified a microRNA-regulated pathway for the chemokine CCL2 in HCV-induced hepatitis. Understanding microRNA-mediated transcriptional-regulatory pathways will result in development of noninvasive biomarkers for better disease prediction and development of effective therapeutics.

Perioperative blood transfusion affects hepatitis C virus (HCV)-specific immune responses and outcome following liver transplantation in HCV-infected patients.

OBJECTIVES: Perioperative factors can affect outcomes of liver transplantation (LT) in recipients with hepatitis C virus (HCV) infection. This study was conducted to investigate whether the immunomodulatory effects of packed red blood cells (PRBC) and platelets administered in the perioperative period might affect immune responses to HCV and thus outcomes in LT recipients. METHODS: Data for a total of 257 HCV LT recipients were analysed. Data on clinical demographics including perioperative transfusion (during and within the first 24 h), serum cytokine concentration, HCV-specific interferon-γ (IFN-γ) and interleukin-17 (IL-17) producing cells, and outcomes including graft and patient survival were analysed. RESULTS: Patient survival was higher in HCV LT recipients who did not receive transfusions (Group 1, n = 65) than in those who did (Group 2, n = 192). One-year patient survival was 95% in Group 1 and 88% in Group 2 (P = 0.02); 5-year survival was 77% in Group 1 and 66% in Group 2 (P = 0.05). Group 2 had an increased post-transplant viral load (P = 0.032) and increased incidence of advanced fibrosis at 1 year (P = 0.04). After LT, Group 2 showed increased IL-10, IL-17, IL-1ß and IL-6, and decreased IFN-γ, and a significantly increased rate of IL-17 production against HCV antigen. Increasing donor age (P = 0.02), PRBC transfusion (P < 0.01) and platelets administration were associated with worse survival. CONCLUSIONS: Transfusion had a negative impact on LT recipients with HCV. The associated early increase in pro-HCV IL-17 and IL-6, with decreased IFN-γ, suggests that transfusion may be associated with the modulation of HCV-specific responses, increased fibrosis and poor transplant outcomes.

Hepatitis C virus induced miR200c down modulates FAP-1, a negative regulator of Src signaling and promotes hepatic fibrosis.

Hepatitis C virus (HCV) induced liver disease is the leading indication for liver transplantation (LTx). Reinfection and accelerated development of fibrosis is a universal phenomenon following LTx. The molecular events that lead to fibrosis following HCV infection still remains poorly defined. In this study, we determined microRNA (miRNA) and mRNA expression profiles in livers from chronic HCV patients and normals using microarrays. Using Genego software and pathway finder we performed an interactive analysis to identify target genes that are modulated by miRNAs. 22 miRNAs were up regulated (>2 fold) and 35 miRNAs were down regulated (>2fold) compared to controls. Liver from HCV patients demonstrated increased expression of 306 genes (>3 fold) and reduced expression of 133 genes (>3 fold). Combinatorial analysis of the networks modulated by the miRNAs identified regulation of the phospholipase C pathway (miR200c, miR20b, and miR31through cellular proto-oncogene tyrosine-protein kinase Src (cSrc)), response to growth factors and hormones (miR141, miR107 and miR200c through peroxisome proliferator-activated receptor alpha and extracellular-signal-regulated kinases, and regulation of cellular proliferation (miR20b, miR10b, and miR141 through cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1 p21). Real time PCR (RT-PCR) validation of the miRNA in HCV infected livers demonstrated a 3.3 ±0.9 fold increase in miR200c. In vitro transfection of fibroblasts with miR200c resulted in a 2.2 fold reduction in expression of tyrosine-protein phosphatase non-receptor type 13 or FAS associated phosphatase 1 (FAP-1) and 2.3 fold increase in expression of cSrc. miR200c transfection resulted in significant increases in expression of collagen and fibroblast growth factor (2.8 and 3.4 fold, p<0.05). Therefore, we propose that HCV induced increased expression of miR200c can down modulate the expression of FAP1, a critical regulator of Src and MAP kinase pathway that play an important role in the production of fibrogenic growth factors and development of fibrosis.

Successful orthotopic liver transplantation in an adult patient with sickle cell disease and review of the literature.

Sickle cell disease can lead to hepatic complications ranging from acute hepatic crises to chronic liver disease including intrahepatic cholestasis, and iron overload. Although uncommon, intrahepatic cholestasis may be severe and medical treatment of this complication is often ineffective. We report a case of a 37 year-old male patient with sickle cell anemia, who developed liver failure and underwent successful orthotopic liver transplantation. Both pre and post-operatively, he was maintained on red cell transfusions. He remains stable with improved liver function 42 months post transplant. The role for orthotopic liver transplantation is not well defined in patients with sickle cell disease, and the experience remains limited. Although considerable challenges of post-transplant graft complications remain, orthotopic liver transplantation should be considered as a treatment option for sickle cell disease patients with end-stage liver disease who have progressed despite conventional medical therapy. An extended period of red cell transfusion support may lessen the post-operative complications.

Once weekly fluconazole for antifungal prophylaxis post-liver transplantation.

BACKGROUND: Invasive fungal infections (IFI) remain a significant cause of morbidity and mortality in orthotopic liver transplantation (OLT) recipients. In this retrospective study, the outcomes of a protocol using once weekly fluconazole for 3 months after OLT in low- and high-risk patients were reviewed. METHODS: In total, 221 OLTs were evaluated in the 3-year period after institution of the new protocol to determine the incidence of IFI within 6 months post-OLT. RESULTS: In this cohort, 11 IFIs developed during the 6-month post-transplant period, with the majority being non-albicans Candida. High-risk patients had a greater rate of IFI (16.7% versus 3.4%, P = 0.038) and a significantly longer intensive unit care (ICU) and hospital lengths of stay compared with low-risk patients. Patient and graft survival were similar between the groups. Our patient population appeared to be at low risk for IFI, with 92% of the entire cohort considered low risk. DISCUSSION: Given the low incidence of IFI in the low-risk group and the possibility of such protocol selecting out for fluconazole-resistant fungi, the use of weekly fluconazole for 3 months may not be justifiable in low-risk OLT recipients. Given the increased resource utilization observed with IFI, further examination of a more intensive prophylactic strategy in high-risk patients may be warranted.

Parenchymal alterations in cirrhotic livers in patients with hepatopulmonary syndrome or portopulmonary hypertension.

Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH) are distinct pulmonary vascular complications of cirrhosis. Little is known about possible associated hepatic histopathological features. Explanted livers from patients clinically diagnosed with HPS (n = 8) or PPH (n = 7) and cirrhotic explants from controls (n = 30) without HPS or PPH were evaluated with trichrome histochemistry, anti-glutamine synthetase (anti-GS), and anti-CD34 immunohistochemistry (IHC). Trichrome stains were characterized by cirrhotic nodules (CNs) of various sizes, including incomplete septal cirrhosis (ISC). ISC was overrepresented in the HPS (4/8 or 50%) and PPH livers (3/7 or 43%); in addition, neither group had micronodular cirrhosis. The control explants showed the entire spectrum of nodules: micronodular, macronodular, mixed CNs, and ISC (P = 0.04). The variability of cirrhosis severity was shown with the Laennec grading system (0-6). The cirrhosis of the majority of the HPS (6/8) and PPH livers (6/7) was scored as mild, whereas the control explants were more evenly distributed across the mild (14/30) and moderate/severe grades (16/30). GS positivity was retained in a perivenular location as the dominant pattern in each explant group. CD34 staining detected capillarized sinusoids of CNs as well as vascular channels within septa, but no significant differences were found between the groups. None of the observed light microscopy or histochemistry and IHC patterns showed a correlation with the underlying liver disease. Although our results demonstrate variable architectural and vascular remodeling within and between explant livers regardless of the presence or types of pulmonary complications, there were differences in explants with HPS or PPH versus controls that correlated with less severe cirrhosis.

Hepatitis C virus mediated changes in miRNA-449a modulates inflammatory biomarker YKL40 through components of the NOTCH signaling pathway.

Liver disease due to hepatitis C virus (HCV) infection is an important health problem worldwide. HCV induced changes in microRNAs (miRNA) are shown to mediate inflammation leading to liver fibrosis. Gene expression analyses identified dysregulation of miRNA-449a in HCV patients but not in alcoholic and non-alcoholic liver diseases. By sequence analysis of the promoter for YKL40, an inflammatory marker upregulated in patients with chronic liver diseases with fibrosis, adjacent binding sites for nuclear factor of Kappa B/P65 and CCAAT/enhancer-binding protein alpha (CEBPα) were identified. P65 interacted with CEBPα to co-operatively activate YKL40 expression through sequence specific DNA binding. In vitro analysis demonstrated that tumor necrosis factor alpha (TNFα) mediated YKL40 expression is regulated by miRNA-449a and its target NOTCH1 in human hepatocytes.NOTCH1 facilitated nuclear localization of P65 in response to TNFα. Further, HCV patients demonstrated upregulation of NOTCH1 along with downregulation of miRNA-449a. Taken together it is demonstrated that miRNA-449a plays an important role in modulating expression of YKL40 through targeting the components of the NOTCH signaling pathway following HCV infection. Therefore, defining transcriptional regulatory mechanisms which control inflammatory responses and fibrosis will be important towards developing strategies to prevent hepatic fibrosis especially following HCV recurrence in liver transplant recipients.

Modulation of immune responses following solid organ transplantation by microRNA.

Organ transplantation, an accepted treatment for end stage organ failure, is often complicated by allograft rejection and disease recurrence. In this review we will discuss the potential role of microRNAs in allograft immunity especially leading to rejection of the transplanted organ. microRNAs (miRNAs), originally identified in C. elegans, are short non-coding 21-24 nucleotide sequences that bind to its complementary sequences in functional messenger RNAs and inhibits post-translational processes through RNA duplex formation resulting in gene silencing (Lau et al., 2001). Gene specific translational silencing by miRNAs regulates pathways for immune responses such as development of innate immunity, inflammation, T-cell and B-cell differentiation and signaling that are implicated in various stages of allograft rejection. miRNAs also play a role in development of post-transplant complicacies like fibrosis, cirrhosis, carcinogenesis often leading to graft loss and poor patient outcome. Recent advancements in the methods for detecting and quantifying miRNA in tissue biopsies, as well as in serum and urine samples, has led to identification of specific miRNA signatures in patients with allograft rejection and have been utilized to predict allograft status and survival. Therefore, miRNAs play a significant role in post-transplant events including allograft rejection, disease recurrence and tumor development impacting patient outcome.