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Current Status of Liver Transplantation for Cholangiocarcinoma.

Fri, 10/13/2017 - 12:45

Current Status of Liver Transplantation for Cholangiocarcinoma.

Liver Transpl. 2017 Oct 11;:

Authors: Goldaracena N, Gorgen A, Sapisochin G

Abstract
Cholangiocarcinoma (CCA) is the second most common liver cancer and it is associated with a poor prognosis. CCA can be divided into intrahepatic, hilar and distal. Despite the subtype, the median survival is 12-24 months without treatment. Liver transplantation (LT) is worldwide recognized as a curative option for hepatocellular carcinoma. On the other hand, the initial results for LT for CCA were very poor mainly due to a lack of adequate patient selection. In the last two decades, improvement has been made in the management of unresectable hilar CCA, and the results of LT after neoadjuvant chemoradiation have been shown to be promising. This has prompted to consider hilar CCA as an indication for LT in some centers. Furthermore, some recent research has shown promising results after LT for patients with early stages of intrahepatic CCA. Better understanding of the best tools to prognosticate the outcomes of LT for CCA are still needed. Here, we aimed to review the role of LT for the treatment of patients with perihilar and intrahepatic CCA. Also, we will discuss the most recent advances in the field and the future direction of the management of this disease in an era of transplantation oncology. This article is protected by copyright. All rights reserved.

PMID: 29024405 [PubMed - as supplied by publisher]

Healthcare utilization after liver transplantation is highly variable both among centers and recipients.

Fri, 10/13/2017 - 12:45

Healthcare utilization after liver transplantation is highly variable both among centers and recipients.

Am J Transplant. 2017 Oct 11;:

Authors: Bittermann T, Hubbard RA, Serper M, Lewis JD, Hohmann SF, VanWagner LB, Goldberg DS

Abstract
The relationship between healthcare utilization before and after liver transplantation (LT) and its association with center characteristics is incompletely understood. This was a retrospective cohort study of 34,402 adult LTs between 2002-2013 using Vizient inpatient claims data linked to the United Network for Organ Sharing database. Multivariable mixed-effects linear regression models evaluated the association between hospitalization 90 days pre-LT and the number of days alive and out of the hospital (DAOH) 1 year post-LT. Of those alive at LT discharge, 24.7% spent ≥30 days hospitalized during the first year. Hospitalization in the 90 days pre-LT was inversely associated with DAOH (β=-3.4 DAOH/week hospitalized pre-LT; p=0.002). Centers with >30% of their LT recipients hospitalized ≥30 days in the first LT year were typically smaller volume and/or transplanting higher risk recipients (Model for End-Stage Liver Disease [MELD] score ≥35, inpatient or ventilated pre-LT). In conclusion, pre-LT hospitalization predicts 1-year post-LT hospitalization independent of MELD score at the patient-level, while center-specific post-LT healthcare utilization is associated with certain center behaviors and selection practices. This article is protected by copyright. All rights reserved.

PMID: 29024364 [PubMed - as supplied by publisher]

Exercise and physical activity for patients with ESLD: Improving functional status and sarcopenia while on the transplant waitlist.

Fri, 10/13/2017 - 12:45

Exercise and physical activity for patients with ESLD: Improving functional status and sarcopenia while on the transplant waitlist.

Liver Transpl. 2017 Oct 11;:

Authors: Duarte-Rojo A, Ruiz-Margáin A, Montaño-Loza AJ, Macías-Rodríguez R, Ferrando A, Kim WR

Abstract
Sarcopenia and physical deconditioning are frequent complications in patients with cirrhosis and end-stage liver disease (ESLD). They are the end result of impaired dietary intake, chronic inflammation, altered macro- and micronutrient metabolism, and low physical activity. Frailty is the end result of prolonged sarcopenia and physical deconditioning. It severely affects a patient's functional status, and presents in about 1 in 5 patients on the liver transplant (LT) waitlist. Sarcopenia, poor physical fitness/cardiopulmonary endurance, and frailty are all associated with increased mortality in ESLD. Clinical trials addressing the usefulness of exercise in patients with cirrhosis have shown that it improves the metabolic syndrome, sarcopenia, cardiopulmonary endurance, health-related quality of life, and hepatic venous pressure gradient. Although evidence on the benefits of exercise on clinical outcomes derived from large clinical trials is still missing, based on existing literature from multiple medical subspecialties, we believe that an exercise program coupled to a tailored nutritional intervention benefits both cardiopulmonary and musculoskeletal functions, ultimately translating into improved functional status, sense of well-being, and possibly less complications from portal hypertension.
CONCLUSION: Although supervised exercise training is the prevailing approach to manage ESLD patients, such intervention is not sustainable or feasible for most patients. Innovative home-based physical activity interventions may be able to effectively reach a larger number of patients. This article is protected by copyright. All rights reserved.

PMID: 29024353 [PubMed - as supplied by publisher]

Long-term outcome of rendezvous technique for hepaticojejunal anastomotic obstruction after pediatric living donor liver transplantation.

Fri, 10/13/2017 - 12:45

Long-term outcome of rendezvous technique for hepaticojejunal anastomotic obstruction after pediatric living donor liver transplantation.

Liver Transpl. 2017 Oct 12;:

Authors: Sanada Y, Yano T, Urahashi T, Ihara Y, Okada N, Yamada N, Hirata Y, Katano T, Yamamoto H, Mizuta K

PMID: 29024347 [PubMed - as supplied by publisher]

De novo hepatocellular carcinoma post-multivisceral transplantation in a child.

Fri, 10/13/2017 - 12:45

De novo hepatocellular carcinoma post-multivisceral transplantation in a child.

Pediatr Transplant. 2017 Nov;21(7):

Authors: Tran P, Zhou S, Wang L, Finegold M, Mascarenas L, Alexopolous S, Genyk Y, Kerkar N

Abstract
De novo hepatocellular carcinoma (HCC) post-transplantation in patients without viral hepatitis is extremely rare, with only three reported adult cases in the English literature. Here, we present a case of de novo HCC that developed in a 7-year-old female, who at 8 months of age received a liver, small bowel, spleen, and pancreas transplantation 6.5 years ago for gastroschisis and total parenteral nutrition (TPN)-related cirrhosis. The post-transplant course was complicated by Epstein-Barr virus (EBV) infection, post-transplant lymphoproliferative disease, and subsequent development of multifocal EBV-associated post-transplant smooth muscle tumors (EBV-PTSMT) in the small bowel 1 year and 10 months after transplantation, respectively. This was managed by reducing immunosuppression with rituximab and EBV-specific cytotoxic T-cell therapy. She was noted to have a new lesion in her transplanted liver graft 6.5 years post-transplantation that was diagnosed as HCC. The HCC was resected, and the patient remained clinically stable for 7 months. At that time, recurrence of the HCC was discovered on MRI. She passed away 6 months after. To the best of our knowledge, this is the first reported occurrence of de novo HCC post-transplantation in the pediatric population that is unrelated to viral hepatitis in either recipient or donor.

PMID: 29024228 [PubMed - in process]

The impact of adult-to-adult living donor liver transplantation on transplant center outcomes reporting.

Fri, 10/13/2017 - 12:45

The impact of adult-to-adult living donor liver transplantation on transplant center outcomes reporting.

Clin Transplant. 2017 Oct 12;:

Authors: Renz JF, Diaz GC

Abstract
BACKGROUND: The Scientific Registry of Transplant Recipients (SRTR) has released a 5-tier performance ranking system based upon results of deceased-donor and living-donor liver transplantation.
MATERIALS AND METHODS: An analysis of Spring 2017 SRTR Program Specific Reports for outcomes of adult living-donor and deceased-donor liver transplantation.
RESULTS: Utilizing the current SRTR performance algorithm, living-donor liver transplant results may disproportionately affect transplant center performance ranking.
CONCLUSION: Improvements in SRTR performance ranking including transparency in outcomes calculation, a calculating tool for transplant centers, and the potential reporting of living-donor outcomes as a separate report are necessary.

PMID: 29024048 [PubMed - as supplied by publisher]

Hepatobiliary and Pancreatic: Fulminant liver failure from diffuse leukemoid hepatic infiltration of melanoma.

Fri, 10/13/2017 - 12:45

Hepatobiliary and Pancreatic: Fulminant liver failure from diffuse leukemoid hepatic infiltration of melanoma.

J Gastroenterol Hepatol. 2017 Nov;32(11):1795

Authors: Schlevogt B, Rehkämper J, Hild B, Schmidt HH

PMID: 29024015 [PubMed - in process]

Myeloid Notch1 Deficiency Activates RhoA/ROCK Pathway and Aggravates Hepatocellular Damage In Mouse Ischemic Livers.

Fri, 10/13/2017 - 12:45

Myeloid Notch1 Deficiency Activates RhoA/ROCK Pathway and Aggravates Hepatocellular Damage In Mouse Ischemic Livers.

Hepatology. 2017 Oct 12;:

Authors: Lu L, Yue S, Jiang L, Li C, Zhu Q, Ke M, Lu H, Wang X, Busuttil RW, Ying QL, Kupiec-Weglinski JW, Ke B

Abstract
Notch signaling plays an emerging role in the regulation of immune cell development and function during inflammatory response. Activation of the ras homolog gene family, member A (RhoA)/Rho-associated protein kinase (ROCK) pathway promotes leukocyte accumulation in tissue injury. However, it remains unknown whether Notch signaling regulates RhoA/ROCK-mediated immune responses in liver ischemia and reperfusion injury (IRI). This study investigated intracellular signaling pathways regulated by Notch receptors in the IR-stressed liver and in vitro. In a mouse model of IR-induced liver inflammatory injury, we found that mice with myeloid specific Notch1 knockout (Notch1(M-KO) ) showed aggravated hepatocellular damage, with increased serum ALT levels, hepatocellular apoptosis, macrophage/neutrophil trafficking, and pro-inflammatory mediators compared to the Notch1-proficient (Notch1(FL/FL) ) controls. Unlike in the Notch1(FL/FL) controls, myeloid Notch1 ablation diminished hairy and enhancer of split-1 (Hes1) and augmented c-Jun N-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1), JNK, ROCK1, and PTEN activation in ischemic livers. Disruption of JSAP1 in Notch1(M-KO) livers improved hepatocellular function and reduced JNK, ROCK1, PTEN, and TLR4 activation. Moreover, ROCK1 knockdown inhibited PTEN and promoted Akt, leading to depressed TLR4. In parallel in vitro studies, transfection of lentivirus-expressing Notch1 intracellular domain (NICD) promoted Hes1 and inhibited JSAP1 in LPS-stimulated bone marrow-derived macrophages (BMMs). Hes1 deletion enhanced JSAP1/JNK activation whereas CRISPR/Cas9-mediated JSAP1 knockout diminished ROCK1/PTEN and TLR4 signaling.
CONCLUSIONS: Myeloid Notch1 deficiency activates the RhoA/ROCK pathway and exacerbates hepatocellular injury by inhibiting transcriptional repressor Hes1 and inducing scaffold protein JSAP1 in IR-triggered liver inflammation. Our findings underscore the crucial role of the Notch-Hes1 axis as a novel regulator of innate immunity-mediated inflammation and imply the therapeutic potential for the management of organ IRI in transplant recipients. This article is protected by copyright. All rights reserved.

PMID: 29024000 [PubMed - as supplied by publisher]

Pembrolizumab for Metastatic Hepatocellular Carcinoma Following Live Donor Liver Transplantation: The Silver Bullet?

Fri, 10/13/2017 - 12:45

Pembrolizumab for Metastatic Hepatocellular Carcinoma Following Live Donor Liver Transplantation: The Silver Bullet?

Hepatology. 2017 Oct 10;:

Authors: Rammohan A, Reddy MS, Farouk M, Vargese J, Rela M

Abstract
Therapeutic options for extrahepatic metastases following Liver Transplantation(LT) for Hepatocellular carcinoma(HCC) are limited, and the prognosis remains poor. Innovative blockade of immune checkpoints, such as monoclonal antibodies against programmed death receptor 1 have shown promise in the treatment of solid organ malignancies. Here, we report a case of metastatic HCC after LT, where Pembrolizumab was started following a poor response with Sorafenib. There was a complete radiological response to the drug with no liver graft rejection or dysfunction. This article is protected by copyright. All rights reserved.

PMID: 29023959 [PubMed - as supplied by publisher]

Radioembolization for hepatocellular carcinoma - the time has come.

Fri, 10/13/2017 - 12:45

Radioembolization for hepatocellular carcinoma - the time has come.

Hepatology. 2017 Oct 12;:

Authors: Toskich B, Patel T

PMID: 29023925 [PubMed - as supplied by publisher]

The Rise of the Opioid Epidemic and Hepatitis C Positive Organs: A New Era in Liver Transplantation.

Fri, 10/13/2017 - 12:45

The Rise of the Opioid Epidemic and Hepatitis C Positive Organs: A New Era in Liver Transplantation.

Hepatology. 2017 Oct 10;:

Authors: Gonzalez SA, Trotter JF

Abstract
The use of hepatitis C virus (HCV) positive organs in liver transplantation has increased in the era of direct-acting antiviral therapy. A rising demand for organs, the ability to effectively treat HCV infection in the transplant setting, and an unprecedented increase in HCV positive donors have all contributed to this trend. A recent abrupt rise in opioid use in the US has resulted in a surge of injection drug use, transmission of HCV, and opioid-related overdose deaths. Geographic areas most affected by the opioid epidemic have experienced a rapid increase in recovery and utilization of HCV positive donor organs, in which the proportion of deceased donor liver transplants in the US from donors who are HCV positive has increased nearly two-fold within the last three years. The prospect of expanding the organ donor pool with HCV positive donors and achieving acceptable post-transplant outcomes has generated much interest in the areas of liver, kidney, and thoracic transplantation, including the potential for transplanting organs from HCV positive donors into HCV negative recipients. Developing strategies to ensure appropriate selection of potential recipients of HCV positive organs, initiating timely antiviral therapy, and defining associated risks will be critical in achieving optimal post-transplant outcomes in this setting. This article is protected by copyright. All rights reserved.

PMID: 29023920 [PubMed - as supplied by publisher]

Visceral adiposity increases risk for hepatocellular carcinoma in male patients with cirrhosis and recurrence after liver transplant.

Fri, 10/13/2017 - 12:45

Visceral adiposity increases risk for hepatocellular carcinoma in male patients with cirrhosis and recurrence after liver transplant.

Hepatology. 2017 Oct 10;:

Authors: Montano-Loza AJ, Mazurak VC, Ebadi M, Meza-Junco J, Sawyer MB, Baracos VE, Kneteman N

Abstract
Visceral adipose tissue (VAT) is a metabolically active organ, associated with higher risk of malignancies. We aimed to evaluate if VAT is associated with the risk of hepatocellular carcinoma (HCC) in patients presenting with cirrhosis as well as HCC recurrence after liver transplantation (LT). Cirrhotic patients (n=678; 457 males) who were assessed for LT (289 with HCC) were evaluated for body composition analysis. Patients who underwent LT (n=247, 168 males) were subsequently evaluated for body composition, and 96 of these patients (78 males) had HCC. VAT, subcutaneous (SAT) and total adipose tissues (TAT) were quantified by computed tomography at the level of the 3(rd) lumbar vertebra and reported as indexes (cross-sectional area normalized for height [cm(2) /m(2) ]). At the time of LT assessment, VAT index (VATI) was higher in male patients with HCC compared to non-HCC patients (75±3 vs. 60±3 cm(2) /m(2) , P=0.001). VATI, and SAT and TAT indexes were higher in male patients with HCC compared to non-HCC patients. By multivariate analysis, male patients with VATI ≥65 cm(2) /m(2) had a higher risk of HCC (HR 1.90, 95% CI 1.31-2.76, P=0.001). In male patients with HCC who underwent LT, a VATI ≥65 cm(2) /m(2) adjusted for Milan criteria was independently associated with higher risk of HCC recurrence (HR 5.34, 95% CI 1.19-23.97, P=0.03).
CONCLUSIONS: High VATI is a novel and independent risk factor for HCC in male patients with cirrhosis, and for recurrence of HCC after LT. This article is protected by copyright. All rights reserved.

PMID: 29023899 [PubMed - as supplied by publisher]

Impact of Surveillance for Hepatocellular Carcinoma on Survival in Patients with Compensated Cirrhosis.

Fri, 10/13/2017 - 12:45

Impact of Surveillance for Hepatocellular Carcinoma on Survival in Patients with Compensated Cirrhosis.

Hepatology. 2017 Oct 12;:

Authors: Yang JD, Mannalithara A, Piscitello AJ, Kisiel JB, Gores GJ, Roberts LR, Kim WR

Abstract
Surveillance for hepatocellular carcinoma (HCC) has been recommended in patients with cirrhosis. In this work, we examine the extent to which the competing risk of hepatic decompensation influences the benefit of HCC surveillance, by investigating the impact of availability of liver transplantation (LTx) and rate of progression of hepatic decompensation on survival gain from HCC surveillance. A multistate Markov model was constructed simulating a cohort of 50-year old patients with compensated cirrhosis. The primary outcome of interest was all-cause and HCC-specific mortality. The main input data included incidence of HCC, sensitivity of screening test, and mortality from hepatic decompensation. Treatment modalities modeled included LTx, resection, and radiofrequency ablation. In the base case scenario, LTx would be available to rescue a proportion of patient from deaths. In the absence of surveillance, 68.2% of the cohort members died by 15 years, which was from HCC in 25.1% and from hepatic decompensation in 43.6% of decedents. With surveillance, the median survival improved from 10.4 years to 11.2 years. The number needed to be under surveillance to reduce one all- cause and HCC-specific death over 15 years was 28 and 18, respectively. In sensitivity analyses, incidence of HCC and progression of cirrhosis had the strongest effect on the benefit of surveillance, whereas LTx availability had negligible impact.
CONCLUSIONS: HCC surveillance decreases all-cause and tumor-specific mortality in patients with compensated cirrhosis regardless of LTx availability. In addition, incidence of HCC and sensitivity of surveillance test also had a substantial impact on the benefits of surveillance. This article is protected by copyright. All rights reserved.

PMID: 29023828 [PubMed - as supplied by publisher]

Polycystic liver disease: Hepatic venous outflow obstruction lesions of the non-cystic parenchyma have major consequences.

Fri, 10/13/2017 - 12:45

Polycystic liver disease: Hepatic venous outflow obstruction lesions of the non-cystic parenchyma have major consequences.

Hepatology. 2017 Oct 10;:

Authors: Barbier L, Ronot M, Aussilhou B, Cauchy F, Francoz C, Vilgrain PV, Soubrane O, Paradis V, Belghiti J

Abstract
BACKGROUND: In patients with polycystic liver disease, development of cysts induces hepatic venous outflow obstruction (HVOO) and parenchymal modifications, challenging the paradigm of a normal non-cystic liver parenchyma. The aims were to reappraise the pathology of the non-cystic parenchyma, by focusing on HVOO lesions; and to investigate the association with outflow obstruction at imaging and perioperative course after liver resection.
METHODS: This is a retrospective study conducted in one tertiary center between 1993 and 2014. Polycystic liver disease patients (n=125) who underwent resection (n=90) or transplantation (n=35) were included. HVOO parenchymal lesions were assessed for all patients and a liver congestion score was built. Imaging was analysed for 45 patients with CT-scan and perioperative course was assessed in resected patients.
RESULTS: At pathology, 92% of the patients had HVOO lesions, sinusoidal dilatation being the most common feature. HVOO was more severe in patients who underwent transplantation compared to liver resection, as assessed by the congestion score. At imaging, all patients had HVOO with at least two hepatic veins involved. Mosaic enhancement pattern of the parenchyma was associated with the severity of hepatic vein obstruction (p=0.045) and the compression of the inferior vena cava (p=0.014). In case of liver resection, intraoperative course was characterized by haemorrhage, related to HVOO at imaging. Ascites (44%) and liver failure (9%) in the postoperative period were associated with blood losses and transfusions.
CONCLUSIONS: Hepatic venous outflow obstruction, including development of venous collaterality and parenchymal changes, is frequent in polycystic liver disease and has major consequences on intraoperative bleeding and postoperative ascites and liver failure. Hepatic venous outflow obstruction should be taken into account to choose surgical treatment the most suited. This article is protected by copyright. All rights reserved.

PMID: 29023812 [PubMed - as supplied by publisher]

HBeAg levels at week 24 predict response to 8 years of tenofovir in HBeAg-positive chronic hepatitis B patients.

Fri, 10/13/2017 - 12:45

HBeAg levels at week 24 predict response to 8 years of tenofovir in HBeAg-positive chronic hepatitis B patients.

Aliment Pharmacol Ther. 2017 Oct 11;:

Authors: Wong D, Littlejohn M, Yuen L, Jackson K, Mason H, Bayliss J, Rosenberg G, Gaggar A, Kitrinos K, Subramanian M, Marcellin P, Buti M, Janssen HLA, Gane E, Locarnini S, Thompson A, Revill PA

Abstract
BACKGROUND: Hepatitis B e antigen (HBeAg) seroconversion is a treatment endpoint for HBeAg-positive CHB, and a necessary precursor to HBsAg loss. Biomarkers that predict serological outcomes would be useful.
AIM: To evaluate the utility of measuring HBeAg levels for predicting HBeAg seroconversion and HBsAg loss under long-term tenofovir (TDF) therapy.
METHODS: A total of 266 patients were enrolled into a phase III study of TDF vs adefovir (ADV) for 48 weeks in HBeAg-positive patients, followed by open-label TDF up to 384 weeks. Serum HBeAg levels were measured for subjects with samples available at both baseline and week 24 of treatment (n = 200). Analysis compared subjects who achieved HBeAg seroconversion by week 384 vs no HBeAg seroconversion.
RESULTS: HBeAg seroconversion rate was 52% by week 384. Time to HBeAg seroconversion was 80 weeks (IQR: 36-162). HBeAg decline at week 24 was associated with HBeAg seroconversion (1.63 vs 0.90 log10 PEIU/mL, P = .002). The optimal threshold for identifying HBeAg seroconversion was HBeAg decline ≥2.2 log10 PEIU/mL at week 24, with HBeAg seroconversion achieved by 76% of patients, compared to 44% if HBeAg decline <2.2 log10 (P < .0001). HBeAg decline ≥2.2 log10 PEIU/mL at week 24 was associated with HBsAg loss in genotype A or D patients (38% vs 15%, P = .03). Precore/basal core promotor variants were associated with lower baseline HBeAg levels, but not HBeAg seroconversion.
CONCLUSION: Decline in HBeAg levels by week 24 was associated with HBeAg seroconversion and HBsAg loss in HBeAg-positive chronic hepatitis B patients treated with long-term TDF.

PMID: 29023803 [PubMed - as supplied by publisher]

Liver diseases in Adult Life after Childhood Cancer in Scandinavia (ALiCCS): A population-based cohort study of 32,839 one-year survivors.

Fri, 10/13/2017 - 12:45

Liver diseases in Adult Life after Childhood Cancer in Scandinavia (ALiCCS): A population-based cohort study of 32,839 one-year survivors.

Int J Cancer. 2017 Oct 11;:

Authors: Bonnesen TG, Winther JF, Andersen KK, Asdahl PH, de Fine Licht S, Gudmundsdottir T, Holmqvist AS, Madanat-Harjuoja LM, Tryggvadottir L, Wesenberg F, Heilmann C, Olsen JH, Hasle H, ALiCCS study group.

Abstract
Information on late onset liver complications after childhood cancer is scarce. To ensure an appropriate follow-up of childhood cancer survivors and reducing late liver complications, the need for comprehensive and accurate information is presented. We evaluate the risk of liver diseases in a large childhood cancer survivor cohort. We included all one-year survivors of childhood cancer treated in the five Nordic countries. A Cox proportional hazards model was used to estimate hospitalisation rate (hazard) ratios (HRs) for each liver outcome according to type of cancer. We used the risk among survivors of central nervous system tumour as internal reference. With a median follow-up time of 10 years, 659 (2%) survivors had been hospitalised at least once for a liver disease. The risk for hospitalisation for any liver disease was high after hepatic tumour (HR=6.9) and leukaemia (HR=1.7). The Danish sub-cohort of leukaemia treated with haematopoietic stem cell transplantation had a substantially higher risk for hospitalisation for all liver diseases combined (HR=3.8). Viral hepatitis accounted for 286 of 659 hospitalisations corresponding to 43% of all survivors hospitalised for liver disease. The 20-year cumulative risk of viral hepatitis was 1.8% for survivors diagnosed with cancer before 1990 but only 0.3% for those diagnosed after 1990. The risk of liver disease was low but significantly increased among survivors of hepatic tumours and leukaemia. Further studies with focus on the different treatment modalities are needed to further strengthen the prevention of treatment-induced late liver complications. This article is protected by copyright. All rights reserved.

PMID: 29023764 [PubMed - as supplied by publisher]

Acute autoimmune hemolytic anemia due to anti-En(a) autoantibody successfully treated with rituximab.

Fri, 10/13/2017 - 12:45

Acute autoimmune hemolytic anemia due to anti-En(a) autoantibody successfully treated with rituximab.

Transfusion. 2017 Oct 11;:

Authors: Nedelcu E, Desai M, Green J, Bensing KM, Turner A, Head D, Young PP

Abstract
BACKGROUND: Autoimmune hemolytic anemia (AIHA) due to anti-En(a) has been previously reported in association with massive intravascular hemolysis, disseminated intravascular coagulation, and fatal outcomes. Here we report a case of successfully treated AIHA due to anti-En(a) .
CASE REPORT: A 69-year-old male with a past medical history of cirrhosis due to nonalcoholic steatohepatitis status post-orthotopic liver transplant presented with 1-month history of progressive anemia. At presentation, his hemoglobin (Hb) was 5.6 g/dL, hematocrit (Hct) 16%, reticulocytes 0.3%, direct bilirubin (bili) 4 g/dL, lactate dehydrogenase 533 units/L (reference, 125-220 units/L), and haptoglobin 254 mg/dL (reference, 40-273 mg/dL). Blood bank testing revealed an autoantibody present in his plasma and a direct antiglobulin test positive for immunoglobulin G (IgC) but negative for complement. He received 1 unit of an incompatible blood group O phenotypically matched red blood cell unit.
RESULTS: Over the course of the next 5 days, the Hb and Hct decreased to 4.1 g/dL and 12%, respectively, direct bili increased to 12.3 mg/day, reticulocytes slightly increased to 0.9%, and haptoglobin decreased to less than 8 mg/dL. Marrow study showed a hypercellular marrow with erythroid hyperplasia. Additional workup performed at a reference laboratory identified an anti-En(a) autoantibody. He received prednisone and weekly rituximab infusions and was monitored weekly. At the 2-month visit, Hb and Hct were 10 g/dL and 32%, respectively.
CONCLUSION: Unlike two of the previously reported fatal cases of AIHA with anti-En(a) specificity, this 69-year-old male treated with weekly rituximab infusion underwent clinical recovery and significant anemia improvement.

PMID: 29023757 [PubMed - as supplied by publisher]

Honokiol Increases CD4+ T Cell Activation and Decreases TNF but Fails to Improve Survival Following Sepsis.

Fri, 10/13/2017 - 12:45

Honokiol Increases CD4+ T Cell Activation and Decreases TNF but Fails to Improve Survival Following Sepsis.

Shock. 2017 Oct 11;:

Authors: Klingensmith NJ, Chen CW, Liang Z, Burd EM, Farris AB, Arbiser JL, Ford ML, Coopersmith CM

Abstract
Honokiol is a biphenolic isolate extracted from the bark of the magnolia tree that has been used in traditional Chinese and Japanese medicine, and has more recently been investigated for its anti-inflammatory and anti-bacterial properties. Honokiol has previously been demonstrated to improve survival in sepsis models that have rapid 100% lethality. The purpose of this study was to determine the impact of Honokiol on the host response in a model of sepsis that more closely approximates human disease. Male and female C57BL/6 mice underwent cecal ligation and puncture (CLP) to induce polymicrobial intraabdominal sepsis. Mice were then randomized to receive an injection of either Honokiol (120 mg/kg/day) or vehicle and were sacrificed after 24 hours for functional studies or followed 7 days for survival. Honokiol treatment after sepsis increased the frequency of CD4 T cells and increased activation of CD4 T cells as measured by the activation marker CD69. Honokiol also increased splenic dendritic cells. Honokiol simultaneously decreased frequency and number of CD8 T cells. Honokiol decreased systemic TNF without impacting other systemic cytokines. Honokiol did not have a detectable effect on kidney function, lung physiology, liver function or intestinal integrity. In contrast to prior studies of Honokiol in a lethal model of sepsis, Honokiol did not alter survival at seven days (70% mortality for Honokiol vs. 60% mortality for vehicle). Honokiol is thus effective in modulating the host immune response and inflammation following a clinically relevant model of sepsis but is not sufficient to alter survival.

PMID: 29023360 [PubMed - as supplied by publisher]

Renal dysfunction and cirrhosis.

Fri, 10/13/2017 - 12:45

Renal dysfunction and cirrhosis.

Curr Opin Crit Care. 2017 Oct 11;:

Authors: Durand F, Olson JC, Nadim MK

Abstract
PURPOSE OF REVIEW: Hepatorenal syndrome (HRS) does not represent the predominant phenotype of acute kidney injury (AKI) in cirrhosis. Early recognition of HRS helps initiate appropriate therapy. The aims of this review are to present redefinition of AKI, to list new biomarkers, to report recent data on vasopressors in HRS and to propose criteria for simultaneous liver and kidney transplantation (SLKT).
RECENT FINDINGS: Urine output, which was not part of the definition of AKI might be reconsidered as it has an independent prognostic value. Biomarkers (NGAL and IL-18) could help identify ATN. However, cut-off values have to be clarified. Vasopressors with albumin represent first option in HRS. Continuous infusion of terlipressin has a better safety profile than intravenous boluses. SLKT should be considered whenever native kidney recovery is unlikely [i.e. prolonged renal replacement therapy (RRT) and/or GFR less than 25 ml/min for 6 weeks prior to transplantation].
SUMMARY: New definitions and recent biomarkers may help differentiate HRS from ATN at an earlier stage. Urine output should be reconsidered in the definitions. Even in patients who are not candidates for transplantation, a short trial of RRT is justified whenever needed. SLKT should be considered whenever posttransplant renal recovery is unlikely.

PMID: 29023314 [PubMed - as supplied by publisher]

The level of caveolin-1 expression determines response to TGF-β as a tumour suppressor in hepatocellular carcinoma cells.

Fri, 10/13/2017 - 12:45

The level of caveolin-1 expression determines response to TGF-β as a tumour suppressor in hepatocellular carcinoma cells.

Cell Death Dis. 2017 Oct 12;8(10):e3098

Authors: Moreno-Càceres J, Caballero-Díaz D, Chike Nwosu Z, Meyer C, López-Luque J, Malfettone A, Lastra R, Serrano T, Ramos E, Dooley S, Fabregat I

Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous tumour associated with poor prognostic outcome. Caveolin-1 (CAV1), a membrane protein involved in the formation of caveolae, is frequently overexpressed in HCC. Transforming growth factor-beta (TGF-β) is a pleiotropic cytokine having a dual role in hepatocarcinogenesis: inducer of apoptosis at early phases, but pro-tumourigenic once cells acquire mechanisms to overcome its suppressor effects. Apoptosis induced by TGF-β is mediated by upregulation of the NADPH oxidase NOX4, but counteracted by transactivation of the epidermal growth factor receptor (EGFR) pathway. Previous data suggested that CAV1 is required for the anti-apoptotic signals triggered by TGF-β in hepatocytes. Whether this mechanism is relevant in hepatocarcinogenesis has not been explored yet. Here we analysed the TGF-β response in HCC cell lines that express different levels of CAV1. Accordingly, stable CAV1 knockdown or overexpressing cell lines were generated. We demonstrate that CAV1 is protecting HCC cells from TGF-β-induced apoptosis, which attenuates its suppressive effect on clonogenic growth and increases its effects on cell migration. Downregulation of CAV1 in HLE cells promotes TGF-β-mediated induction of the pro-apoptotic BMF, which correlates with upregulation of NOX4, whereas CAV1 overexpression in Huh7 cells shows the opposite effect. CAV1 silenced HLE cells show attenuation in TGF-β-induced EGFR transactivation and activation of the PI3K/AKT pathway. On the contrary, Huh7 cells, which do not respond to TGF-β activating the EGFR pathway, acquire the capacity to do so when CAV1 is overexpressed. Analyses in samples from HCC patients revealed that tumour tissues presented higher expression levels of CAV1 compared with surrounding non-tumoural areas. Furthermore, a significant positive correlation among the expression of CAV1 and TGFB1 was observed. We conclude that CAV1 has an essential role in switching the response to TGF-β from cytostatic to tumourigenic, which could have clinical meaning in patient stratification.

PMID: 29022911 [PubMed - in process]

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