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ABSTRACT: The discovery of the IL28B single-nucleotide polymorphisms (SNPs) has opened an important new area of research in liver transplantation (LT) for hepatitis C (HCV). Both recipient and donor derived IL28B genotypes affect post-LT treatment response, with sustained virological response (SVR) rates oscillating between >50% in homozygotes for the favorable allele (up to 90% when this is present in both recipient and donor), to <15% SVR in homozygotes for the unfavorable allele, and 30-50% in the heterozygotes. Other key posttransplant outcomes affected by IL28B genotype are time to histological recurrence, HCV RNA and ALT levels, histological variables including the rate of fibrosis progression, and hepatocarcinoma. Interactions between donor and recipient IL28B genotype are complex and may affect outcomes not directly related to HCV infection, such as acute cellular rejection and metabolic diseases. A preferential allocation system, in which livers from donors who are homozygous for the favorable allele are given to HCV patients, might be postulated to improve SVR and post-LT outcomes in recipients with HCV infection (25% increase in SVR and 8% decrease in mortality at 5 years). Although difficult to predict, negative effects from this could include an accelerated progression of fibrosis in patients with failed HCV eradication, and an increase in acute cellular rejection in non-HCV patients. The precise role of IL28B genotypes in the course of post-LT HCV is evolving, but existing knowledge suggests the possibility of exploring strategies that use IL28B genotyping to reduce the impact of post-LT adverse outcomes. Liver Transpl, 2012. © 2012 AASLD.
Liver Transplantation 09/2012; · 3.39 Impact Factor
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ABSTRACT: Liver disease and portal hypertension can be associated with pulmonary vascular complications, including portopulmonary hypertension (POPH), characterised by an elevated mean pulmonary artery pressure secondary to an increased pulmonary vascular resistance, and hepatopulmonary syndrome (HPS), characterised by hypoxaemia due to pulmonary vasodilatation and shunting. Although clear diagnostic guidelines exist for both conditions on the basis of echocardiography, right heart catheterisation and arterial blood gases, there is considerable variation between centres regarding diagnosis and management of these conditions. Awareness of evaluation and management algorithms for POPH and HPS are critical for optimisation of outcomes in patients with these conditions. Key aspects of management of POPH and HPS include identification of patients likely to benefit from liver transplantation (LTx) and management before and after LTx. Although both disorders may improve after LTx, severe forms of POPH represent a contraindication to LTx. Novel approaches to the treatment of POPH and HPS offer new management options that may expand the pool of transplantable patients and improve overall outcomes.
European Respiratory Review 09/2012; 21(125):223-33.
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ABSTRACT: The IL28B genotype has been linked to sustained virological response (SVR) in hepatitis C virus (HCV). Its role on disease biology and progression is less clear. We characterized the effects of IL28B genotype on HCV recurrence, allograft histology, rate of SVR, and survival after liver transplantation (LT) in HCV.
Consecutive patients who underwent LT with HCV were studied. The rs12979860 genotype from both the donor was and recipient was determined. Measured endpoints included histologic HCV recurrence (inflammatory grade and fibrosis stage), acute cellular rejection, SVR, retransplantation, and death.
The study cohort comprised 272 consecutive LT in 255 patients. C-allele frequency was 56% in recipients and 70% in donors (P<0.001). Recipient IL28B CC genotype was associated with lower alanine aminotransferase levels and viral load at recurrence and a lower frequency of F≥2 on liver biopsy at 1 year after LT, when compared with the non-CC genotype (P=0.012). The opposite was observed in LT with donor CC genotype (P=0.003). Both recipient and donor CC genotype favored SVR, and when the two of them occurred together, the SVR rate reached 90%. Survival analysis after 5.5 years of follow-up showed a higher rate of progression to cirrhosis (hazard ratio, 5.96; 95% confidence interval, 1.29-27.6), liver-related death, or retransplantation among liver transplant recipients with a CC genotype donor.
The IL28B genotype is predictive not only of SVR but also of the histologic diagnosis of posttransplant hepatitis C, with donor CC genotype favoring inflammation and fibrosis, and adverse outcomes during long-term follow-up. A favorable effect of donor CC genotype is manifest only after antiviral therapy.
Transplantation 06/2012; 94(2):197-203. · 4.00 Impact Factor
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ABSTRACT: By analyzing 26,414 patients [12,589 with hepatitis C virus (HCV)] in the Scientific Registry of Transplant Recipients Database, we sought to determine comparative risk factors (including primary immunosuppression) predictive of death and graft loss among patients with HCV and patients without HCV. Immunosuppression was examined at the baseline and as a time-dependent variable, and the results were stratified by the transplant center and were adjusted for variables well known to affect patient and graft survival. A multivariate analysis of patient mortality demonstrated that recipient age, donor age, hepatocellular carcinoma, diabetes, and creatinine were significantly associated with increased 3-year mortality for both groups. Tacrolimus-based immunosuppression was associated with superior survival in both groups. In contrast, the use of sirolimus was strongly associated with increased mortality in the HCV group, and cyclosporine was associated with increased mortality in the non-HCV group. Adjusting for known and unknown factors predictive of posttransplant outcomes, a propensity analysis confirmed the association of sirolimus use with an increased risk of death in HCV patients as well as the association of tacrolimus use with a decreased risk of death in all patients. In conclusion, this study suggests a novel association between sirolimus use and an increased risk of death and graft loss after liver transplantation in HCV patients that is not seen in patients without HCV. This study confirms the association of tacrolimus with superior outcomes. Sirolimus should be used sparingly in recipients with HCV infections.
Liver Transplantation 05/2012; 18(9):1029-36. · 3.39 Impact Factor
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Stepan Sembera,
Craig Lammert,
Jayant A Talwalkar,
Schuyler O Sanderson,
John J Poterucha,
J Eileen Hay,
Russell H Wiesner,
Gregory J Gores,
Charles B Rosen,
Julie K Heimbach, Michael R Charlton
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ABSTRACT: Drug-induced liver injury (DILI) is increasingly being recognized as a common cause of acute hepatitis. The clinical impact of DILI after liver transplantation (LT) is not known. The aim of this study was to describe the frequency, clinical presentation, and outcomes of DILI in LT recipients. LT recipients with possible DILI were identified with electronic pathology records and clinical note database retrieval tools. Diagnostic criteria were applied to identify cases of DILI. Twenty-nine of 1689 LT recipients (1.7%) were identified with DILI. The mean age was 52 years, and 52% were women. The major indications for LT were primary sclerosing cholangitis (28%), cholangiocarcinoma (14%), and hepatocellular carcinoma (14%). The severity of DILI was mild or moderate in 92% of the cases. Nausea or diarrhea (31%), jaundice (24%), and pruritus (10%) were the most common symptoms at the time of diagnosis. The mean biochemistry values were as follows: alanine aminotransferase, 204 ± 263 U/L; aspartate aminotransferase, 108 ± 237 U/L; alkaline phosphatase, 469 ± 689 U/L; and total bilirubin, 1.9 ± 10.3 mg/dL. The median duration of medication use until the diagnosis of DILI was 57 days, and the major agent classes were antibiotics (48%), immunosuppressive agents (14%), and antihyperlipidemic drugs (7%). Trimethoprim-sulfamethoxazole was the most common implicated agent (n = 11). Serum liver enzymes improved within a median time of 34 days (range = 5-246 days) after drug withdrawal. Hepatic retransplantation or death did not occur. Among the 50 cases with possible DILI explained by other causes, 13 individuals (26%) had no alternative diagnosis despite histological findings compatible with DILI. In conclusion, DILI is a rare yet underrecognized event among LT recipients. The majority of cases are not clinically severe, and they resolve after drug cessation without hepatic retransplantation or death.
Liver Transplantation 03/2012; 18(7):803-10. · 3.39 Impact Factor
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ABSTRACT: Ultrasound-based transient elastography (TE) is a promising noninvasive alternative to liver biopsy for the detection of hepatic fibrosis due to recurrent hepatitis C virus (HCV) after liver transplantation (LT). However, its overall test performance in various settings remains unknown. The aim of this study was to perform a systematic review and diagnostic accuracy meta-analysis of studies comparing ultrasound-based TE to liver biopsy for the detection of hepatic fibrosis due to a recurrent HCV infection after LT. Electronic and manual bibliographic searches (including scientific abstracts) were performed to identify potential studies. A meta-analysis was conducted to generate pooled estimates of the sensitivity values, specificity values, likelihood ratios, and diagnostic odds ratios of individual studies. The extent of the heterogeneity and the reasons for it were assessed. Six fully published studies were identified for analysis. Five studies that evaluated significant fibrosis were identified. Among these studies, the pooled estimates were 83% for sensitivity [95% confidence interval (CI) = 77%-88%], 83% for specificity (95% CI = 77%-88%), 4.95 for the positive likelihood ratio (95% CI = 3.4-7.2), 0.17 for the negative likelihood ratio (95% CI = 0.09-0.35), and 30.5 for the diagnostic odds ratio (95% CI = 12.8-72.4). For the 5 studies that assessed cirrhosis, the pooled estimates were 98% for sensitivity (95% CI = 90%-100%), 84% for specificity (95% CI = 80%-88%), 7 for the positive likelihood ratio (95% CI = 2.8-17.3), 0.06 for the negative likelihood ratio (95% CI = 0.02-0.19), and 130 for the diagnostic odds ratio (95% CI = 36.5-462.1). A diagnostic threshold (or cutoff value) bias was identified as an important cause of heterogeneity for the pooled results of both patient groups. In conclusion, ultrasound-based TE has excellent diagnostic accuracy for identifying cirrhosis due to a recurrent HCV infection after LT. The detection of significant fibrosis is more accurate for these patients versus patients whose native liver is chronically infected with HCV.
Liver Transplantation 12/2011; 18(3):323-31. · 3.39 Impact Factor
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Göran B Klintmalm,
Gary L Davis,
Lewis Teperman,
George J Netto,
Kenneth Washburn,
Stephen M Rudich,
Elizabeth A Pomfret,
Hugo E Vargas,
Robert Brown,
Devin Eckhoff, [......],
John M Ham,
David D Douglas,
Linda Sher,
Prabhakar K Baliga,
Milan Kinkhabwala,
Baburao Koneru,
Michael Abecassis,
Michael Millis,
Linda W Jennings,
Carlos G Fasola
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ABSTRACT: This randomized, prospective, multicenter trial compared the safety and efficacy of steroid-free immunosuppression (IS) to the safety and efficacy of 2 standard IS regimens in patients undergoing transplantation for hepatitis C virus (HCV) infection. The outcome measures were acute cellular rejection (ACR), severe HCV recurrence, and survival. The patients were randomized (1:1:2) to tacrolimus (TAC) and corticosteroids (arm 1; n = 77), mycophenolate mofetil (MMF), TAC, and corticosteroids (arm 2; n = 72), or MMF, TAC, and daclizumab induction with no corticosteroids (arm 3; n = 146). In all, 295 HCV RNA-positive subjects were enrolled. At 2 years, there were no differences in ACR, HCV recurrence (biochemical evidence), patient survival, or graft survival rates. The side effects of IS did not differ, although there was a trend toward less diabetes in the steroid-free group. Liver biopsy samples revealed no significant differences in the proportions of patients in arms 1, 2, and 3 with advanced HCV recurrence (ie, an inflammation grade ≥ 3 and/or a fibrosis stage ≥ 2) in years 1 (48.2%, 50.4%, and 43.0%, respectively) and 2 (69.5%, 75.9%, and 68.1%, respectively). Although we have found that steroid-free IS is safe and effective for liver transplant recipients with chronic HCV, steroid sparing has no clear advantage in comparison with traditional IS.
Liver Transplantation 08/2011; 17(12):1394-403. · 3.39 Impact Factor
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ABSTRACT: The relative frequency of nonalcoholic steatohepatitis (NASH) as an indication for liver transplantation and comparative outcomes following transplantation are poorly understood.
We analyzed the Scientific Registry of Transplant Recipients for primary adult liver transplant recipients from 2001 to 2009.
From 2001 to 2009, 35,781 patients underwent a primary liver transplant, including 1959 for who NASH was the primary or secondary indication. The percentage of patients undergoing a liver transplant for NASH increased from 1.2% in 2001 to 9.7% in 2009. NASH is now the third most common indication for liver transplantation in the United States. No other indication for liver transplantation increased in frequency during the study period. Compared with other indications for liver transplantation, recipients with NASH are older (58.5±8.0 vs 53.0±8.9 years; P<.001), have a larger body mass index (>30 kg/m2) (63% vs 32%; P<.001), are more likely to be female (47% vs 29%; P<.001), and have a lower frequency of hepatocellular carcinoma (12% vs 19%; P<.001). Survival at 1 and 3 years after liver transplantation for NASH was 84% and 78%, respectively, compared with 87% and 78% for other indications (P=.67). Patient and graft survival for liver recipients with NASH were similar to values for other indications after adjusting for level of creatinine, sex, age, and body mass index.
NASH is the third most common indication for liver transplantation in the United States and is on a trajectory to become the most common. Outcomes for patients undergoing a liver transplant for NASH are similar to those for other indications.
Gastroenterology 07/2011; 141(4):1249-53. · 11.68 Impact Factor
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ABSTRACT: Saturated free fatty acids (FFA) induce hepatocyte lipoapoptosis, a key mediator of liver injury in nonalcoholic fatty liver disease (NAFLD). Lipoapoptosis involves the upregulation of the BH3-only protein PUMA, a potent pro-apoptotic protein. Given that dysregulation of hepatic microRNA expression has been observed in NAFLD, we examined the role of miRNA in regulating PUMA expression during lipotoxicity. By in silico analysis, we identified two putative binding sites for miR-296-5p within the 3' untranslated region (UTR) of PUMA mRNA. Enforced miR-296-5p levels efficiently reduced PUMA protein expression in Huh-7 cells, while antagonism of miR-296-5p function increased PUMA cellular levels. Reporter gene assays identified PUMA 3'UTR as a direct target of miR-296-5p. The saturated FFA, palmitate, repressed miR-296-5p expression; and Huh-7 cells were sensitized to palmitate-induced lipotoxicity by antagonism of miR-296-5p function using a targeted locked nucleic acid (LNA). Finally, miR-296-5p was reduced in liver samples from nonalcoholic steatohepatitis (NASH) patients compared with patients with simple steatosis (SS) or controls. Also miR-296-5p levels inversely varied with PUMA mRNA levels in human liver specimens. Our results implicate miR-296-5p in the regulation of PUMA expression during hepatic lipoapoptosis. We speculate that enhancement of miR-296-5p expression may represent a novel approach to minimize apoptotic damage in human fatty liver diseases.
The Journal of Lipid Research 06/2011; 52(8):1517-25. · 5.56 Impact Factor
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ABSTRACT: The efficacy, tolerability, and safety of the prophylactic treatment of hepatitis C virus (HCV) after liver transplantation (LT) with peginterferon alfa-2a and ribavirin are not known. LT recipients with HCV were randomized to peginterferon alfa-2a/ribavirin treatment or observation 10 to 26 weeks post-LT. Prophylaxis patients received peginterferon alfa-2a (135 μg/week for 4 weeks and then 180 μg/week for 44 weeks) plus ribavirin (the initial dose of 400 mg/day was escalated to 1200 mg/day). Observation patients received the same regimen only upon significant HCV recurrence (histological activity index ≥ 3 and/or fibrosis score ≥ 2). The primary endpoint was the proportion of patients with histological evidence of significant HCV recurrence 120 weeks after randomization. In all, 115 patients were randomized (prophylaxis arm, n = 55; observation arm, n = 60). Sustained virological response was achieved by 12 of 54 prophylaxis patients (22.2%) and by 3 of 14 observation patients who switched to treatment (21.4%). On an intent-to-treat basis, significant HCV recurrence at 120 weeks was similar in the prophylaxis (61.8%) and observation arms (65.0%, P = 0.725). The patient and graft survival rates and the rates of biopsy-proven acute cellular rejection were similar in the 2 study arms. Approximately 70% of the treated patients in both arms had at least one dose reduction for safety reasons. The most common adverse event leading to treatment withdrawal was anemia. Because of the safety profile of peginterferon alfa-2a/ribavirin and the lack of a clear benefit in terms of HCV recurrence and patient or graft survival, this study does not support the routine use of prophylactic antiviral therapy.
Liver Transplantation 05/2011; 17(5):528-38. · 3.39 Impact Factor
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ABSTRACT: Polymorphism in the interleukin-28B (IL28B) gene region, encoding interferon (IFN)-λ3, is strongly predictive of response to antiviral treatment in the nontransplant setting. We sought to determine the prevalence and impact on clinical outcomes of donor and recipient IL28B genotypes among liver transplant recipients. The cohort study included 189 consecutive patients infected with hepatitis C virus (HCV) who underwent liver transplantation between January 1, 1995, and January 1, 2005, at the Mayo Clinic, Rochester, MN. Genotyping of the polymorphism rs12979860 was performed on DNA collected from all donors and recipients in the cohort. Sixty-five patients received IFN-based antiviral therapy. The CC IL28B variant was less common in the chronic HCV-infected recipients than in non-HCV donor livers (33% versus 47%, P = 0.03). IL28B recipient genotype was significantly predictive of fibrosis stage, with TT genotype being associated with more rapid fibrosis (Pearson chi-square P = 0.024 for the comparison G versus A). Donor and recipient IL28B genotype were independently associated with sustained virologic response (P < 0.005). The presence of IL28B CC variant in either the recipient (R) or donor (D) liver was associated with increased rate of sustained virologic response (D-non-CC/R-non-CC = 3/19 [16%] versus D-CC/R-non-CC = 11/22 [50%] versus D-non-CC/R-CC = 5/12 [42%] versus R-CC/D-CC = 6/7 [86%], P = 0.0095). IL28B genotype was not significantly associated with survival (overall/liver-related). CONCLUSION: Recipient IL28B TT genotype is associated with more severe histological recurrence of HCV. Recipient and donor liver IL28B genotype are strongly and independently associated with IFN-based treatment response in patients after orthotopic liver transplantation. The data suggest that CC donor livers might be preferentially allocated to patients with HCV infection.
Hepatology 01/2011; 53(1):317-24. · 11.66 Impact Factor
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ABSTRACT: Cardiovascular complications are major causes of morbidity and mortality after liver transplantation. Identifying candidates at highest risk of postoperative complications is a cornerstone of optimizing outcomes and utility. Using traditional cardiac risk factors in addition to C-reactive protein (CRP) levels, troponin levels, and echocardiographic parameters before transplantation, we sought to define cardiac risk so that we could predict cardiovascular events after transplantation. From December 1998 to December 2001, 230 adult patients who underwent liver transplantation with a median follow-up of 8.2 years were studied. The risk factors for cardiac disease were as follows: male gender with a mean age of approximately 50 years (57%), smoking history (60%), diabetes (23%), hypertension (19%), elevated troponin (25%), elevated CRP (25%), and preexisting cardiac disease (16%). Fifty-nine cardiac events occurred over 8.2 years. Risk factors (univariate analysis) for first cardiac events included age in decades [hazard ratio (HR) = 1.31, P = 0.047], diabetes (HR = 2.20, P = 0.004), prior cardiovascular disease (HR = 4.77, P < 0.0001), a troponin I level > 0.07 ng/mL (HR = 2.00, P = 0.023), left ventricular hypertrophy (HR = 2.06, P = 0.047), stress wall abnormalities (HR = 2.25, P = 0.018), and ischemia on stress imaging (HR = 2.89, P = 0.015). Multivariate analysis confirmed age, diabetes, a troponin I level > 0.07, and prior cardiac disease as independent risk factors for posttransplant cardiac events. In conclusion, pretransplant elevated troponin levels, diabetes, and a history of cardiovascular disease, alone or in combination, are strongly associated with the occurrence of posttransplant cardiovascular events.
Liver Transplantation 01/2011; 17(1):23-31. · 3.39 Impact Factor
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ABSTRACT: Interferon-induced depression affects 20% to 40% of patients treated for chronic hepatitis C virus (HCV). The aim of our study was to examine the influence of antidepressant treatment and whether this improves the likelihood of completing therapy.
One hundred randomly selected patients with chronic HCV undergoing antiviral therapy at a single center were identified. Patients were categorized as Group 1 (no depressive symptoms during treatment), Group 2 (depressive symptoms without antidepressant therapy), Group 3 (preexisting or prophylactic antidepressants before therapy), and Group 4 (on-demand antidepressant therapy for depressive symptoms).
Mean age was 49 years with 72% men. Genotype 1 infection was noted in 65% of patients, and the mean pretreatment HCV RNA level was 1,419,919 IU. Patients without earlier depression receiving on-demand therapy (Group 4) had a significantly higher rate of antiviral treatment completion compared with Group 3 (92% vs. 52%; P=0.01). Patients in groups 1 and 4 with no baseline history of depression had similar treatment completion rates. No significant relationship between the use of antidepressant therapy, SVR or premature cessation of therapy was observed.
Preexisting depression was associated with lower antiviral treatment completion rates despite the use of prophylactic antidepressant therapy. In patients without preexisting depression, however, on-demand antidepressant therapy for depressive symptoms was strongly associated with the highest treatment completion rates in the cohort. Antidepressant therapy for new or worsening depressive symptoms independent of baseline depression status did not affect the probability of achieving SVR or stopping treatment prematurely.
Journal of clinical gastroenterology 09/2010; 44(8):e178-85. · 2.21 Impact Factor
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ABSTRACT: Optimizing the utility of liver transplantation requires the identification of factors that confer increased risk of posttransplant mortality. Elevated serum troponin (TN) levels are strongly predictive of posttransplant mortality after kidney transplantation. We sought to determine whether pretransplant TN levels were predictive of mortality and graft loss after liver transplantation in 236 liver transplant recipients from 1998 to 2001 with 8.2 years of follow-up. Elevated TN levels [hazard ratio (HR) = 2.19, P = 0.004] and a pretransplant history of cardiovascular disease (CVD; HR = 1.90, P = 0.031) were predictive of patient mortality. Elevated TN levels (HR = 2.44, P < 0.001), a history of CVD (HR = 1.83, P = 0.031), and a combination of elevated TN levels and CVD (HR = 2.75, P = 0.027) were associated with increased graft loss. Multivariate analysis confirmed TN and CVD as independent predictors of mortality and graft loss. CVD (HR = 2.39, P = 0.032) and a combination of elevated TN levels and a history of CVD (HR = 6.67, P < 0.001) were predictive of graft loss within 1 year. Age, smoking, diabetes, hypertension, obesity, creatinine levels, and Model for End-Stage Liver Disease scores were not predictive of posttransplant mortality or graft loss. In summary, elevated pretransplant serum TN levels are strongly predictive of mortality and graft loss after liver transplantation and may be helpful in risk stratification of potential liver transplant recipients.
Liver Transplantation 08/2010; 16(8):990-8. · 3.39 Impact Factor
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ABSTRACT: Metabolic syndrome is common among liver transplant recipients before and after transplantation. The components of metabolic syndrome are often exacerbated in the post-transplant period by transplant specific factors, such as immunosuppression, and are strong predictors of patient morbidity and mortality. Many aspects of the metabolic syndrome are modifiable. Early recognition, prevention and treatment of post-transplant hypertension, obesity, dyslipidemia and diabetes may impact long-term post-transplant survival. Further study into the prevention and management of these issues in the transplant patient are needed.
Journal of Hepatology 07/2010; 53(1):199-206. · 9.26 Impact Factor
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ABSTRACT: Increasing evidence suggests that hepatic fibrosis and pathological angiogenesis are interdependent processes that occur in parallel. Endothelial cell invasion is requisite for angiogenesis, and thus studies of the mechanisms governing liver endothelial cell (LEC) invasion during cirrhosis are of great importance. Emerging research implicates amoeboid-type motility and membrane blebbing as features that may facilitate invasion through matrix-rich microenvironments. Aquaporins (AQPs) are integral membrane water channels, recognized for their importance in epithelial secretion and absorption. However, recent studies also suggest links between water transport and cell motility or invasion. Therefore, the purpose of this study was to test the hypothesis that AQP-1 is involved in amoeboid motility and angiogenic invasion during cirrhosis. AQP-1 expression and localization was examined in normal and cirrhotic liver tissues derived from human and mouse. AQP-1 levels were modulated in LEC using retroviral overexpression or small interfering RNA (siRNA) knockdown and functional effects on invasion, membrane blebbing dynamics, and osmotic water permeability were assayed. Results demonstrate that AQP-1 is up-regulated in the small, angiogenic, neovasculature within the fibrotic septa of cirrhotic liver. AQP-1 overexpression promotes fibroblast growth factor (FGF)-induced dynamic membrane blebbing in LEC, which is sufficient to augment invasion through extracellular matrix. Additionally, AQP-1 localizes to plasma membrane blebs, where it increases osmotic water permeability and locally facilitates the rapid, trans-membrane flux of water. CONCLUSION: AQP-1 enhances osmotic water permeability and FGF-induced dynamic membrane blebbing in LEC and thereby drives invasion and pathological angiogenesis during cirrhosis.
Hepatology 07/2010; 52(1):238-48. · 11.66 Impact Factor
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ABSTRACT: Saturated free fatty acids induce hepatocyte lipoapoptosis. This lipotoxicity involves an endoplasmic reticulum stress response, activation of JNK, and altered expression and function of Bcl-2 proteins. The mono-unsaturated free fatty acid palmitoleate is an adipose-derived lipokine which suppresses free fatty acid-mediated lipotoxicity by unclear mechanisms. Herein we examined the mechanisms responsible for cytoprotection.
We employed isolated human and mouse primary hepatocytes, and the Huh-7 and Hep 3B cell lines for these studies. Cells were incubated in presence and absence of palmitate (16:0), stearate (18:0), and or palmitoleate (16:1, n-7).
Palmitoleate significantly reduced lipoapoptosis by palmitate or stearate in both primary cells and cell lines. Palmitoleate accentuated palmitate-induced steatosis in Huh-7 cells excluding inhibition of steatosis as a mechanism for reduced apoptosis. Palmitoleate inhibited palmitate induction of the endoplasmic reticulum stress response as demonstrated by reductions in CHOP expression, eIF2-alpha phosphorylation, XBP-1 splicing, and JNK activation. Palmitate increased expression of the BH3-only proteins PUMA and Bim, which was attenuated by palmitoleate. Consistent with its inhibition of PUMA and Bim induction, palmitoleate prevented activation of the downstream death mediator Bax.
These data suggest palmitoleate inhibits lipoapoptosis by blocking endoplasmic reticulum stress-associated increases of the BH3-only proteins Bim and PUMA.
Journal of Hepatology 02/2010; 52(4):586-93. · 9.26 Impact Factor
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Michael R Charlton,
William J Wall,
Akinlolu O Ojo,
Pere Ginès,
Stephen Textor,
Fuad S Shihab,
Paul Marotta,
Marcelo Cantarovich,
James D Eason,
Russell H Wiesner,
Michael A Ramsay,
Juan C Garcia-Valdecasas,
James M Neuberger,
Sandy Feng,
Connie L Davis,
Thomas A Gonwa
Liver Transplantation 11/2009; 15(11):S1-34. · 3.39 Impact Factor
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Eugenia Raichlin,
Richard C Daly,
Charles B Rosen,
Christopher G McGregor, Michael R Charlton,
Robert P Frantz,
Alfredo L Clavell,
Richard J Rodeheffer,
Naveen L Pereira,
Walter K Kremers,
Sudhir S Kushwaha,
Brooks S Edwards
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ABSTRACT: Simultaneous combined orthotopic heart and liver transplantation (CHLTx) remains a lifesaving procedure for the patients suffering from coincident end-stage heart and liver disease and several metabolic disorders. We analyze the long-term outcome of the patients undergoing CHLTx.
Between January 1992 and May 2007, 15 CHLTx were attempted at the Mayo Clinic including two combined heart, liver, and kidney transplantations and one combined heart, lung, and liver transplantations. Pretransplant cardiac diagnoses were familial amyloidosis (11), hemochromatosis (1), restrictive cardiomyopathy and cardiac cirrhosis (1), previously operated congenital heart disease and cardiac cirrhosis (1), and primary pulmonary hypertension with primary biliary cirrhosis (1).
Heart and liver transplantation were performed as a single combined procedure in 13 (93%) hemodynamically stable patients, and there was no perioperative mortality. Survival rates for the CHLTx recipients at 1 year, 5 years, and 10 years were 100%, 75%, and 60%, respectively, and did not differ from survival after isolated heart transplantation (93%, 83%, and 65%, respectively, P=0.39). Freedom from cardiac allograft rejection (ISHLT > or =grade 2) for CHLTx was 83% at 1 month, did not change with time, and was lower than after isolated heart transplantation (P=0.02). At the mean follow-up of 61.6+/-53.6 months, normal left ventricular ejection fraction and good liver allograft function were demonstrated. Three patients developed end-stage renal failure secondary to calcineurin nephrotoxicity.
Simultaneous heart and liver transplantation is feasible and achieved excellent results for selected patients.
Transplantation 08/2009; 88(2):219-25. · 4.00 Impact Factor
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Sophie C Cazanave,
Justin L Mott,
Nafisa A Elmi,
Steven F Bronk,
Nathan W Werneburg,
Yuko Akazawa,
Alisan Kahraman,
Sean P Garrison,
Gerard P Zambetti, Michael R Charlton,
Gregory J Gores
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ABSTRACT: Free fatty acids (FFA) induce hepatocyte lipoapoptosis by a c-Jun N-terminal kinase (JNK)-dependent mechanism. However, the cellular processes by which JNK engages the core apoptotic machinery during lipotoxicity, especially activation of BH3-only proteins, remain incompletely understood. Thus, our aim was to determine whether JNK mediates induction of BH3-only proteins during hepatocyte lipoapoptosis. The saturated FFA palmitate, but not the monounsaturated FFA oleate, induces an increase in PUMA mRNA and protein levels. Palmitate induction of PUMA was JNK1-dependent in primary murine hepatocytes. Palmitate-mediated PUMA expression was inhibited by a dominant negative c-Jun, and direct binding of a phosphorylated c-Jun containing the activator protein 1 complex to the PUMA promoter was identified by electrophoretic mobility shift assay and a chromatin immunoprecipitation assay. Short hairpin RNA-targeted knockdown of PUMA attenuated Bax activation, caspase 3/7 activity, and cell death. Similarly, the genetic deficiency of Puma rendered murine hepatocytes resistant to lipoapoptosis. PUMA expression was also increased in liver biopsy specimens from patients with non-alcoholic steatohepatitis as compared with patients with simple steatosis or controls. Collectively, the data implicate JNK1-dependent PUMA expression as a mechanism contributing to hepatocyte lipoapoptosis.
Journal of Biological Chemistry 08/2009; 284(39):26591-602. · 4.77 Impact Factor
