Magdalena Salcedo

Influence of hepatic venous pressure gradient on the prediction of survival of patients with cirrhosis in the MELD era

Measurements of portal pressure, usually obtained via the hepatic venous pressure gradient (HVPG) may be a prognostic marker in cirrhosis. The aim of this study was to evaluate the impact of HVPG on survival in patients with cirrhosis in addition to the Model for End‐Stage Liver Disease (MELD) score. We also examined whether inclusion of HVPG in a model with MELD variables improves its prognostic ability. Retrospective analyses of all patients who had HVPG measurements between January 1998 and December 2002 were considered. Proportional hazards Cox models were developed. Prognostic calibrative and discriminative ability of the model was evaluated. In this period, 693 patients had a hepatic hemodynamic study, and 393 patients were included. Survival was significantly worse in those patients with greater HVPG value (univariate HR, 1.05; 95% CI, 1.02‐1.08; P = .001). HVPG remained as an independent variable in a model adjusted by MELD, ascites, encephalopathy, and age (multivariate HR, 1.03; 95% CI, 1.00‐1.06; P = .05) so that each 1‐mmHg increase in HVPG had a 3% increase in death risk. In addition, HVPG as well as MELD score variables and age, significantly contributes to the calibrative predictive capacity of the prognostic model; however, discriminative ability improved only slightly (overall C statistic [95% CI]; MELD score variables: 0.71 [0.62‐0.80], MELD score variables, age, and HVPG 0.76: [0.69‐0.83]). In conclusion, HVPG has an independent effect on survival in addition to the MELD score. Although inclusion of HVPG and age in a survival predicting model would improve the calibrative ability of MELD, its discriminative ability is not significantly improved. (HEPATOLOGY 2005;42:793–801.)

Antiviral therapy decreases hepatic venous pressure gradient in patients with chronic hepatitis C and advanced fibrosis.

BACKGROUNDS:Antiviral therapy (AVT) may improve liver histology in patients with advanced viral hepatitis but its effect on portal pressure remains unknown.AIM:This study was aimed to evaluate the influence of antiviral therapy (AVT) on hepatic venous pressure gradient (HVPG) in hepatitis C virus infected patients with portal hypertension.METHODS:Twenty compensated patients with chronic hepatitis C, fibrosis stage 3 or 4 and HVPG > 5 mmHg received PEG-IFN α2b plus ribavirin. Every patient underwent liver biopsy and portal pressure measurements before and immediately after AT. Biopsies were evaluated according to METAVIR score.RESULTS:HVPG significantly dropped in all but one treated patient, with a mean (SD) reduction of 28.2 (12)% [13.8 (5.6) Vs. 10.2 (3.8) mmHg, p = 0.005]. The percentage of HVPG decrease was significantly greater in patients who achieved a virological end of treatment response [26.2 (12.5)% Vs. 12.7 (8.5)%, p = 0.05] and in those with a decrease of at least 2 points in the grade of inflammation [35.7 (4.5)% Vs. 22.1 (9.5)%, p = 0.015]. Nine out of 11 patients with baseline HVPG ≥ 12 mmHg showed a decrease greater than 20% (3/11) or under the 12 mmHg threshold (6/11).CONCLUSIONS:AVT reduces HVPG in compensated patients with advanced hepatitis C (fibrosis stage 3 or 4) and portal hypertension.

Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation

There is currently no consensus on the most suitable treatment for the recurrence of hepatocellular carcinoma (HCC) after liver transplantation. This open, multicenter, retrospective, uncontrolled cohort study was designed to evaluate the safety and preliminary efficacy of the combined use of a mammalian target of rapamycin (mTOR) inhibitor and sorafenib in this setting. In 31 patients who suffered from HCC recurrence after liver transplantation, the immunosuppressive therapy was changed to mTOR inhibitors, and systemic treatment with sorafenib was initiated. This combination was maintained until symptomatic tumor progression, death, hepatic decompensation, or unacceptable toxicity occurred. Primary treatment efficacy was determined by overall survival and progression‐free survival, and secondary efficacy was determined by the overall response rate. Toxicity parameters associated with the use of sorafenib and mTOR inhibitors were also analyzed. The overall response rate according to the Response Evaluation Criteria in Solid Tumors was 3.8% (1/26), and there was sustained stabilization of the disease in 13 additional cases (50.0%). The median overall survival was 19.3 months [95% confidence interval (CI) = 13.4–25.1 months], and the median time to progression was 6.77 months (95% CI = 2.3–11.1 months). Only 2 grade 3/4 cases of hyperglycemia and 1 case of grade 3/4 mucositis were reported, and they were possibly related to mTOR inhibitors. The most common severe adverse event probably related to sorafenib was diarrhea (12.9%). In conclusion, the coadministration of sorafenib and an mTOR inhibitor could be effective despite notable toxicity in patients with post–liver transplant HCC recurrence not suitable for radical therapy. The toxicity and efficacy need to be further evaluated in randomized controlled studies for this combination to be considered a valid option. Liver Transpl 18:45–52, 2012.

Hepatic and systemic haemodynamic changes after MARS in patients with acute on chronic liver failure.

Abstract Hyperdynamic circulation and portal hypertension characterize acute on chronic liver failure (AoCLF), partially because of circulating mediators. Molecular Absorbents Recirculating System (MARS) may remove some of these substances. The objective of this study was to evaluate the effect of MARS on portal pressure, systemic haemodynamic and endogenous vasoactive systems. MARS treatment was performed in four patients with AoCLF (mean age 36.2 ± 3.1 years; Child–Pugh C 11 ± 1.8 points; three AAH and one NASH). Systemic and splanchnic haemodynamic measurements were performed before and after each session. Plasmatic renin activity (PRA) and NE were measured at baseline, at the end of the sessions and 10 days after MARS. All patients had severe portal hypertension (HVPG = 23 ± 7 mmHg) and pronounced hyperdynamic circulation (MAP 77.8 ± 11.7 mmHg; CO 11.2 ± 1.6 L/min; SVRI 478.5 ± 105 dyne s/cm5). HVPG decreased at the end of the first session in all patients (23 ± 7 mmHg vs 17.3 ± 9.9 mmHg; P = 0.05; mean decrease 32 ± 24%) because of a decrease in WHVP (40.7 ± 5.6 mmHg vs 34 ± 9.6 mmHg; P = 0.025; mean decrease 18 ± 19%). MARS significantly attenuated hyperdynamic circulation as shown by a decrease in CO (11.2 ± 1.6 L/min vs 9.4 ± 2.1 L/min; mean decrease 12.3%), with an increase in MAP (77.8 ± 11.7 mmHg vs 84.2 ± 8 mmHg; mean increase 9.2%) and in SVRI (478.5 ± 105 dyne s/cm5 vs 622 ± 198 dyne s/cm5; mean increase 41%). PRA and NE decreased significantly (14.2 ± 17.2 ng/mL/h vs 3.7 ± 3.4 ng/mL/h; 1319 ± 1002 pg/mL vs 617 ± 260 pg/mL, respectively). The NE decrease was correlated to HVPG decrease (r = 1, P = 0.01). MARS decreases portal hypertension and ameliorates hyperdynamic circulation in patients with AoCLF, probably mediated by clearance of vasoactive substances. Further studies are necessary to confirm these results.

Risk factors for developing de novo autoimmune hepatitis associated with anti-glutathione S-transferase T1 antibodies after liver transplantation.

De novo autoimmune hepatitis (de novo AIH) is a rare form of graft dysfunction that develops after liver transplantation (LT) in patients transplanted for conditions other than autoimmune disorders. Although characterized by biochemical, serological, and histological features of AIH, de novo AIH is sometimes associated with atypical serum autoantibodies, many of which are directed against glutathione S‐transferase T1 (anti‐GSTT1). GSTT1 donor/recipient genotype mismatch has been suggested as a necessary condition for the appearance of autoantibodies and de novo AIH. However, clinically evident disease is not observed in all patients with anti‐GSTT1 antibodies. We examined the incidence of de novo AIH and its conditioning (risk) factors in patients with anti‐GSTT1 antibodies. Anti‐GSTT1 autoantibodies were detected in 29 of 419 [6.9%; 95% confidence interval (CI), 4.9–9.8] consecutive adult LT recipients with donor/recipient GSTT1 mismatch. Twenty of 27 assessable patients (74%) developed de novo AIH after a median follow‐up of 26 months (95% CI, 19.2–32.8). The probability of de novo AIH was 11%, 44%, and 60% 12, 24, and 36 months after LT, respectively. No relationship emerged between de novo AIH and recipient gender, donor and recipient age, rejection episodes, immunosuppressive regime, allelic GSTT1 expression, human leukocyte antigen distribution, or cytomegalovirus infection. Multivariate analysis identified male donor [hazard ratio (HR), 3.3; 95% CI, 1.18–9.26; P = 0.018], nonalcoholic etiology (HR, 4.67; 95% CI, 1.64–13.3; P = 0.002), and high anti‐GSTT1 titer (HR, 2.98; 95% CI, 1.04–8.57; P = 0.035) as independent predictors of de novo AIH. Most patients with anti‐GSTT1 antibodies and donor/recipient GSTT1 mismatch developed clinically evident de novo AIH after LT. The risk of developing the disease was increased by male donor gender, nonalcoholic etiology of original liver disease, and a high anti‐GSTT1 titer. Liver Transpl 15:530–539, 2009.

Epidemiology and outcome of infections in human immunodeficiency virus/hepatitis C virus-coinfected liver transplant recipients: a FIPSE/GESIDA prospective cohort study.

Information about infections unrelated to acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus (HIV)–infected liver recipients is scarce. The aims of this study were to describe the prevalence, clinical characteristics, time of onset, and outcomes of bacterial, viral, and fungal infections in HIV/hepatitis C virus (HCV)–coinfected orthotopic liver transplant recipients and to identify risk factors for developing severe infections. We studied 84 consecutive HIV/HCV‐coinfected patients who underwent liver transplantation at 17 sites in Spain between 2002 and 2006 and were followed until December 2009. The median age was 42 years, and 76% were men. The median follow‐up was 2.6 years (interquartile range = 1.25‐3.53 years), and 54 recipients (64%) developed at least 1 infection. Thirty‐eight (45%) patients had bacterial infections, 21 (25%) had cytomegalovirus (CMV) infections (2 had CMV disease), 13 (15%) had herpes simplex virus infections, and 16 (19%) had fungal infections (7 cases were invasive). Nine patients (11%) developed 10 opportunistic infections with a 44% mortality rate. Forty‐three of 119 infectious episodes (36%) occurred in the first month after transplantation, and 53 (45%) occurred after the sixth month. Thirty‐six patients (43%) had severe infections. Overall, 36 patients (43%) died, and the deaths were related to severe infections in 7 cases (19%). Severe infections increased the mortality rate almost 3‐fold [hazard ratio (HR) = 2.9, 95% confidence interval (CI) = 1.5‐5.8]. Independent factors for severe infections included a pretransplant Model for End‐Stage Liver Disease (MELD) score >15 (HR = 3.5, 95% CI = 1.70‐7.1), a history of AIDS‐defining events before transplantation (HR = 4.0, 95% CI = 1.9‐8.6), and non–tacrolimus‐based immunosuppression (HR = 2.5, 95% CI = 1.3‐4.8). In conclusion, the rates of severe and opportunistic infections are high in HIV/HCV‐coinfected liver recipients and especially in those with a history of AIDS, a high MELD score, or non–tacrolimus‐based immunosuppression. Liver Transpl 18:70–82, 2012.

Early noninvasive measurement of the indocyanine green plasma disappearance rate accurately predicts early graft dysfunction and mortality after deceased donor liver transplantation

Early diagnosis of graft dysfunction in liver transplantation is essential for taking appropriate action. Indocyanine green clearance is closely related to liver function and can be measured noninvasively by spectrophotometry. The objectives of this study were to prospectively analyze the relationship between the indocyanine green plasma disappearance rate (ICGPDR) and early graft function after liver transplantation and to evaluate the role of ICGPDR in the prediction of severe graft dysfunction (SGD). One hundred seventy‐two liver transplants from deceased donors were analyzed. Ten patients had SGD: 6 were retransplanted, and 4 died while waiting for a new graft. The plasma disappearance rate was measured 1 hour (PDRr60) and within the first 24 hours (PDR1) after reperfusion, and it was significantly lower in the SGD group. PDRr60 and PDR1 were excellent predictors of SGD. A threshold PDRr60 value of 10.8%/minute and a PDR1 value of 10%/minute accurately predicted SGD with areas under the receiver operating curve of 0.94 (95% confidence interval, 0.89‐0.97) and 0.96 (95% confidence interval, 0.92‐0.98), respectively. In addition, survival was significantly lower in patients with PDRr60 values below 10.8%/minute (53%, 47%, and 47% versus 95%, 94%, and 90% at 3, 6, and 12 months, respectively) and with PDR1 values below 10%/minute (62%, 62%, and 62% versus 94%, 92%, and 88%). In conclusion, very early noninvasive measurement of ICGPDR can accurately predict early severe graft dysfunction and mortality after liver transplantation. Liver Transpl 15:1247–1253, 2009.

Randomized controlled trial of aspiration needle versus automated biopsy device for transjugular liver biopsy.

PURPOSE The efficacy and safety of transjugular liver biopsy used to obtain liver specimens in patients with coagulation disorders have been widely proven. However, histopathologic examination is not always possible because of fragmented samples provided by the aspiration technique. Recently, an automated device with a Tru-Cut-type needle was designed. In this randomized controlled trial, the use of this new device is compared with the traditional method in terms of efficacy and safety. METHOD Fifty-six patients were included in the study; 28 were randomized to undergo the aspiration technique and 28 were randomized to undergo the automated biopsy technique. RESULTS Correct positioning of the device was achieved in 93% of patients undergoing the aspiration technique and 96% of patients undergoing the automated biopsy technique (P = NS). Mean duration of the procedure and total number of passes were significantly higher in the aspiration needle group than in the automated device group (22.6 min +/- 12.6 vs 15.5 min +/- 9.4; P = .03, and 3.3 min +/- 1.9 vs 1.5 min +/- 0.63; P < .001, respectively). The number of portal tracts was significantly higher in the automated device group (4.7 +/- 2.5 vs. 2.7 +/- 3.4; P < .05). Adequate specimens for histopathologic evaluation were obtained in 26 patients in the automated device group and 24 patients in the aspiration needle group (92.8% vs 85.7%; P = NS), but a definite histopathologic diagnosis was more frequently obtained with the automated biopsy device (68% vs 43%; P = .05). No significant differences were observed in complication rates (7.14% vs. 10.7%; P = NS). CONCLUSION The automated biopsy device for transjugular liver biopsy is more effective than an aspiration needle in obtaining good samples for a definite histologic diagnosis.

Oral probiotic VSL#3 attenuates the circulatory disturbances of patients with cirrhosis and ascites

The modulation of gut flora constitutes a therapeutic tool in patients with liver disease, but some of its modalities require further investigation. Here, we evaluated the effects of probiotics on the hepatic and systemic haemodynamic alterations of advanced liver disease.

Granulocyte Colony-Stimulating Factor Improves Deficient In Vitro Neutrophil Transendothelial Migration in Patients with Advanced Liver Disease

ABSTRACT Bacterial infections are frequent complications in patients with liver cirrhosis. Cirrhotic patients present abnormalities in both innate and adaptive immune responses, including a deficient neutrophil recruitment to infected sites. The purpose of this study was to assess neutrophil-endothelium interactions in cirrhotic patients and evaluate the effects of G-CSF on this process. We studied neutrophil adhesion and transendothelial migration in 14 cirrhotic patients and 14 healthy controls. We also analyzed neutrophil expression of the adhesion molecules CD62L and CD11b in whole blood by flow cytometry. Cirrhotic patients expressed higher levels of CD11b than healthy controls, whereas CD62L expression was significantly lower, suggesting exposure of neutrophils to activating agents within the bloodstream. Neutrophils from cirrhotic patients showed increased adhesion to both resting and tumor necrosis factor alpha-stimulated microvascular endothelial cells and decreased transendothelial migration. Granulocyte colony-stimulating factor (G-CSF) (100 ng/ml) significantly enhanced neutrophil adhesion to microvascular endothelial cells in healthy controls but not in cirrhotic patients. G-CSF also significantly improved neutrophil transmigration in cirrhotic patients and healthy controls. In conclusion, cirrhotic patients exhibit increased neutrophil adhesion to microvascular endothelium and deficient transendothelial migration. G-CSF enhances neutrophil transendothelial migration in cirrhotic patients despite having no effect on neutrophil adhesion. Therefore, G-CSF may be able to increase neutrophil recruitment into infected sites in these patients.