Diego Rincón

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.)

A New Scoring System for Prognostic Stratification of Patients With Alcoholic Hepatitis

OBJECTIVES: Prognostic stratification of patients with alcoholic hepatitis (AH) may improve the clinical management and facilitate clinical trials. We aimed at developing a scoring system capable of providing prognostic stratification of patients with AH.METHODS: Patients with biopsy-proven AH were prospectively included between 2000 and 2006. The biochemical, clinical, portal hemodynamic and histological parameters were evaluated. A Cox regression model was used for univariate and multivariate analyses. A predictive score was built using variables obtained at admission identified in the multivariate analysis. The resulting score was validated in an independent prospective cohort.RESULTS: In total, 103 patients with biopsy-proven AH were included in the study cohort. Age, serum bilirubin, serum creatinine, and international normalized ratio (INR) independently predicted 90-day mortality. We generated the Age, serum Bilirubin, INR, and serum Creatinine (ABIC) score: (age × 0.1) + (serum bilirubin × 0.08) + (serum creatinine × 0.3) + (INR × 0.8). The area under the curve (AUC) was 0.82. Using the Kaplan-Meier analysis with the cutoff values of 6.71 and 9.0, we identified patients with low, intermediate, and high risk of death at 90 days (100%, 70%, and 25% of survival rate, respectively). Using the same cutoff values, the ABIC score also stratified patients according to their risk of death at 1 yr. These results were validated by a confirmatory cohort (N = 80).CONCLUSIONS: The ABIC score is a new tool that allows the stratification of risk of death in patients with AH at 90 days and 1 yr. This score can help improve the management of these patients and also help to perform clinical trials.

A Histologic Scoring System for Prognosis of Patients With Alcoholic Hepatitis

BACKGROUND & AIMS There is no histologic classification system to determine prognoses of patients with alcoholic hepatitis (AH). We identified histologic features associated with disease severity and created a histologic scoring system to predict short-term (90-day) mortality. METHODS We analyzed data from 121 patients admitted to the Liver Unit (Hospital Clinic, Barcelona, Spain) from January 2000 to January 2008 with features of AH and developed a histologic scoring system to determine the risk of death using logistic regression. The system was tested and updated in a test set of 96 patients from 5 academic centers in the United States and Europe, and a semiquantitative scoring system called the Alcoholic Hepatitis Histologic Score (AHHS) was developed. The system was validated in an independent set of 109 patients. Interobserver agreement was evaluated by weighted κ statistical analysis. RESULTS The degree of fibrosis, degree of neutrophil infiltration, type of bilirubinostasis, and presence of megamitochondria were independently associated with 90-day mortality. We used these 4 parameters to develop the AHHS to identify patients with a low (0-3 points), moderate (4-5 points), or high (6-9 points) risk of death within 90 days (3%, 19%, and 51%, respectively; P < .0001). The AHHS estimated 90-day mortality in the training and test sets with an area under the receiver operating characteristic value of 0.77 (95% confidence interval, 0.71-0.83). Interrater agreement values were 0.65 for fibrosis, 0.86 for bilirubinostasis, 0.60 for neutrophil infiltration, and 0.46 for megamitochondria. Interestingly, the type of bilirubinostasis predicted the development of bacterial infections. CONCLUSIONS We identified histologic features associated with the severity of AH and developed a patient classification system that might be used in clinical decision making.

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.

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.

Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial

BACKGROUND The once-daily, ribavirin-free, pangenotypic, direct-acting antiviral regimen, glecaprevir coformulated with pibrentasvir, has shown high rates of sustained virological response in phase 2 and 3 studies. We aimed to assess the efficacy and safety of 12 weeks of coformulated glecaprevir and pibrentasvir in patients with hepatitis C virus (HCV) infection and compensated cirrhosis. METHODS We did this single-arm, open-label, multicentre phase 3 study at 40 sites in Belgium, Canada, Germany, South Africa, Spain, and the USA. We enrolled patients aged 18 years or older with HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. Patients were either HCV treatment-naive or had not responded to treatment with interferon or pegylated interferon with or without ribavirin, or sofosbuvir plus ribavirin with or without pegylated interferon. Oral glecaprevir (300 mg) coformulated with pibrentasvir (120 mg) was administered once daily for 12 weeks. The primary efficacy endpoint was sustained virological response at post-treatment week 12 (HCV RNA <15 IU/mL). We assessed efficacy and safety in all patients who received at least one dose of study drug (intention-to-treat population). This study is registered with ClinicalTrials.gov, number NCT02642432. FINDINGS Between Dec 7, 2015, and May 4, 2016, we enrolled 146 patients with compensated cirrhosis, of whom 48 (33%) had genotype 1a HCV infection, 39 (27%) had genotype 1b infection, 34 (23%) had genotype 2 infection, 16 (11%) had genotype 4 infection, two (1%) had genotype 5 infection, and seven (5%) had genotype 6 infection. 12 weeks after treatment, 145 patients (99%, 95% CI 98-100) achieved sustained virological response, with one (1%) relapse at post-treatment week 8. We recorded 101 (69%) adverse events, of which 65 (64%) were mild. The most common adverse events were fatigue (n=28 [19%]) and headache (n=20 [14%]). 11 (8%) patients had serious adverse events, none of which were deemed related to study drugs. No patients had elevations in alanine aminotransferase and no patients prematurely discontinued treatment because of adverse events. INTERPRETATION Our results show that 99% of patients treated with once-daily glecaprevir plus pibrentasvir achieved a sustained virological response at 12 weeks. Furthermore, this drug regimen had a favourable safety profile in previously treated or untreated patients with chronic HCV genotype 1, 2, 4, 5, or 6 infection and compensated cirrhosis. These findings could help simplify treatment algorithms and reduce treatment burden. FUNDING AbbVie.

Prognostic value of hepatic venous pressure gradient for in-hospital mortality of patients with severe acute alcoholic hepatitis

Hepatic venous pressure gradient (HVPG) has prognostic value in complications and survival of patients with liver cirrhosis. However, the relationship between HVPG and the outcome of acute alcoholic hepatitis (AAH), as well as the specific features of portal hypertension syndrome in this setting, have not been defined.

Peginterferon Plus Ribavirin and Sustained Virological Response in HCV-Related Cirrhosis: Outcomes and Factors Predicting Response

OBJECTIVES Patients with hepatitis C virus (HCV) cirrhosis are difficult to treat and have a high risk of liver decompensation or hepatocellular carcinoma. We sought to identify factors that could predict treatment response. METHODS Collaborating centers (n=26) provided data for patients (n=568) with HCV cirrhosis undergoing treatment with peginterferon-α plus ribavirin (RBV). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. RESULTS Sustained viral response (SVR) in naive patients was 30.7%, with no significant differences between centers. Median follow-up was 35 months (range: 1-81). Factors predicting SVR were: non-genotype 1 (odds ratio (OR)=4.183; 95% confidence interval (CI): 2.353-7.438) overall dose and ≥80% of the scheduled time of treatment (OR=3.177; 95% CI: 1.752-5.760); serum γ-glutamyl transpeptidase (GGT) <76 IU per ml (OR=4.092; 95% CI: 2.418-6.927); baseline viral load <6 × 10(5) (OR=2.597; 95% CI: 1.583-4.262); absence of ultrasound signs of portal hypertension (OR=2.067; 95% CI: 1.26-3.39). No patient with a HCV-RNA decline <1 log(10) at week 4 achieved SVR. Event-free survival at 5 years was 91% in patients with SVR vs. 59% in non-responders (P<0.001). Overall survival in patients with SVR was 98% vs. 86% in non-responders (P=0.005). Independent factors predicting events were absence of SVR (hazard ratio (HR)=2.66; 95% CI: 1.32-5.54), baseline serum albumin <3.9 g per 100 ml (HR=3.06; 95% CI: 1.81-5.15), presence of esophageal varices on endoscopy (HR=2.489; 95% CI: 1.546-4). Improved outcome was more evident in responders with less advanced disease at baseline. CONCLUSIONS SVR can be achieved in approximately one-third of patients with HCV-related cirrhosis. SVR independently reduces the likelihood of clinical decompensation and improves survival.OBJECTIVES:Patients with hepatitis C virus (HCV) cirrhosis are difficult to treat and have a high risk of liver decompensation or hepatocellular carcinoma. We sought to identify factors that could predict treatment response.METHODS:Collaborating centers (n=26) provided data for patients (n=568) with HCV cirrhosis undergoing treatment with peginterferon-α plus ribavirin (RBV). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes.RESULTS:Sustained viral response (SVR) in naive patients was 30.7%, with no significant differences between centers. Median follow-up was 35 months (range: 1–81). Factors predicting SVR were: non-genotype 1 (odds ratio (OR)=4.183; 95% confidence interval (CI): 2.353–7.438) overall dose and ≥80% of the scheduled time of treatment (OR=3.177; 95% CI: 1.752–5.760); serum γ-glutamyl transpeptidase (GGT) <76 IU per ml (OR=4.092; 95% CI: 2.418–6.927); baseline viral load <6 × 105 (OR=2.597; 95% CI: 1.583–4.262); absence of ultrasound signs of portal hypertension (OR=2.067; 95% CI: 1.26–3.39). No patient with a HCV-RNA decline <1 log10 at week 4 achieved SVR. Event-free survival at 5 years was 91% in patients with SVR vs. 59% in non-responders (P<0.001). Overall survival in patients with SVR was 98% vs. 86% in non-responders (P=0.005). Independent factors predicting events were absence of SVR (hazard ratio (HR)=2.66; 95% CI: 1.32–5.54), baseline serum albumin <3.9 g per 100 ml (HR=3.06; 95% CI: 1.81–5.15), presence of esophageal varices on endoscopy (HR=2.489; 95% CI: 1.546–4). Improved outcome was more evident in responders with less advanced disease at baseline.CONCLUSIONS:SVR can be achieved in approximately one-third of patients with HCV-related cirrhosis. SVR independently reduces the likelihood of clinical decompensation and improves survival.

Cardiac dysfunction during liver transplantation: incidence and preoperative predictors.

Background. The aim was to investigate the cardiac response during liver transplantation (LT) and analyze its relationship with clinical factors, echocardiographic, and hemodynamic findings. Methods. All patients undergoing LT for cirrhosis from 1998 to 2004 were included. Clinical data, comprehensive echocardiography, hepatic, and right heart hemodynamic measurements were analyzed. During LT patients underwent continuous right-heart pressure monitorization. Measurements 10 min after reperfusion were compared with baseline values. Abnormal cardiac response was defined as a decrease in left ventricular stroke work index despite a rise in pulmonary wedge capillary pressure. Predictors of abnormal cardiac response were investigated using logistic regression. Results. Data were available from 209 patients (mean age 52 (9) yrs; Child A 27; B 93; C 89) with a mean model for end-stage liver disease score 16.3 (4.7). Abnormal cardiac response was observed in 47 (22.5%) patients after reperfusion. Patients who developed this response had hyponatremia, lower central venous pressure, lower pulmonary artery pressure, and lower pulmonary wedged capillary pressure. Abnormal cardiac response was related to a longer postoperative intubation time. Conclusion. Abnormal cardiac response is observed during LT and may be a manifestation of occult cirrhotic cardiomyopathy. This finding is underestimated with usual diagnostic tools and could be related to indirect signs of circulatory dysfunction of advanced liver disease.

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.