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•Liver stiffness improves after antiviral therapy in most patients.•Hepatocellular carcinoma can still occur after antiviral therapy in patients with cACLD.•Non-invasive tests at ...follow-up can stratify the risk of hepatocellular carcinoma.•Portal hypertension-related decompensation is rare after treatment in patients with cACLD.
It is important to know which patients with hepatitis C are likely to develop liver-related complications after achieving a sustained virological response (SVR) to direct-acting antiviral (DAA) therapy. We aimed to describe the incidence of liver-related events in a population of patients with HCV-associated compensated advanced chronic liver disease (cACLD) who achieved SVR and to identify non-invasive parameters that predict the occurrence of liver-related events.
This 2-center prospective study included 572 patients with cACLD who had been treated with DAAs and had achieved SVR. Patients had liver stiffness measurement (LSM) ≥10 kPa at baseline and had never decompensated (Child-Pugh class A). Laboratory work-up and LSM were performed at baseline and at 1 year of follow-up.
The median follow-up was 2.8 years during which 32 patients (5.6%) presented with a liver-related event. The incidence rate (IR) of portal hypertension-related decompensation was 0.34/100 patient-years. These patients all had baseline LSM >20 kPa, and LSM did not improve during follow-up in 4 out of 5 of them. Hepatocellular carcinoma (HCC) occurred in 25 patients (IR 1.5/100 patient-years). Albumin levels at follow-up (hazard ratio HR 0.08; 95% CI 0.02–0.25) and LSM <10 kPa at follow-up (HR 0.33; 95% CI 0.11–0.96) were independently associated with the risk of HCC. Combining both predictors identified 2 groups with differing risk of HCC occurrence: those with LSM ≥20 kPa at follow-up or those with LSM between 10–20 kPa and albumin levels <4.4 g/dl were at the highest risk (IR ≥1.9/100 patient-years). Visual nomograms predicting HCC risk based on LSM and albumin at 1 year of follow-up were constructed.
In patients with HCV-related cACLD who have achieved SVR with DAAs, HCC is the most frequent liver-related event. Both albumin levels and LSM are useful for stratifying patients based on their risk of developing HCC during follow-up.
New oral antivirals can cure chronic hepatitis C infection, however patients with advanced chronic liver disease are still at risk of presenting with liver-related complications. The most frequent complication after oral antiviral therapy in asymptomatic patients with advanced chronic liver disease was liver cancer. The use of simple parameters such liver stiffness and albumin levels after treatment can help to identify patients at higher or lower risk of liver cancer.
Malnutrition is a frequent complication in patients with cirrhosis and liver transplant (LT) candidates. It is highly related to sarcopenia, and their implications in morbidity and mortality go ...beyond the waiting list period throughout the post-LT. However, there are no specific interventions defined by guidelines regarding the kind or the timing of the nutritional intervention to improve LT outcomes. Results from studies developed in the LT setting and evaluating their impact on the LT candidates or recipients are discussed in this review, and new research lines are presented.
Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in hepatocyte injury, inflammation, and fibrosis in non-alcoholic steatohepatitis (NASH). We evaluated the safety and antifibrotic effect ...of selonsertib, a selective inhibitor of ASK1, in patients with advanced fibrosis due to NASH.
We conducted 2 randomized, double-blind, placebo-controlled, phase III trials of selonsertib in patients with NASH and bridging fibrosis (F3, STELLAR-3) or compensated cirrhosis (F4, STELLAR-4). Patients were randomized 2:2:1 to receive selonsertib 18 mg, selonsertib 6 mg, or placebo once daily for 48 weeks. Liver biopsies were performed at screening and week 48 and non-invasive tests of fibrosis (NITs) were evaluated. The primary efficacy endpoint was the proportion of patients with ≥1-stage improvement in fibrosis without worsening of NASH at week 48. Additional endpoints included changes in NITs, progression to cirrhosis (in STELLAR-3), and liver-related clinical events.
Neither trial met the primary efficacy endpoint. In STELLAR-3, fibrosis improvement without worsening of NASH was observed in 10% (31/322, p = 0.49 vs. placebo), 12% (39/321, p = 0.93 vs. placebo), and 13% (21/159) of patients in the selonsertib 18 mg, selonsertib 6 mg, and placebo groups, respectively. In STELLAR-4, the primary endpoint was achieved in 14% (51/354; p = 0.56), 13% (45/351; p = 0.93), and 13% (22/172) of patients, respectively. Although selonsertib led to dose-dependent reductions in hepatic phospho-p38 expression indicative of pharmacodynamic activity, it had no significant effect on liver biochemistry, NITs, progression to cirrhosis, or adjudicated clinical events. The rates and types of adverse events were similar among selonsertib and placebo groups.
Forty-eight weeks of selonsertib monotherapy had no antifibrotic effect in patients with bridging fibrosis or compensated cirrhosis due to NASH.
Patients with non-alcoholic steatohepatitis (NASH) can develop scarring of the liver (fibrosis), including cirrhosis, which increases the risks of liver failure and liver cancer. We tested whether 48 weeks of treatment with selonsertib reduced fibrosis in patients with NASH and advanced liver scarring. We did not find that selonsertib reduced fibrosis in these patients.
Clinicaltrials.gov numbers NCT03053050 and NCT03053063.
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•Selonsertib was safe and inhibited its target (ASK1) but did not lead to fibrosis regression or reduce disease progression in NASH.•Improvement in liver fibrosis on biopsy was associated with improvement only in other histologic features.•Improvements in ELF score and liver stiffness by transient elastography correlated with a variety of clinical parameters.
Clinical decompensation of cirrhosis is associated with poor prognosis. Clinically significant portal hypertension (CSPH), defined by a hepatic venous pressure gradient (HVPG) ≥10 mm Hg, is the ...strongest predictor of decompensation. This study aimed at assessing whether lowering HVPG with β blockers could decrease the risk of decompensation or death in compensated cirrhosis with CSPH.
This study on β blockers to prevent decompensation of cirrhosis with portal hypertension (PREDESCI) was an investigator-initiated, double-blind, randomised controlled trial done in eight hospitals in Spain. We enrolled patients with compensated cirrhosis and CSPH without high-risk varices. All participants had HVPG measurements with assessment of acute HVPG-response to intravenous propranolol. Responders (HVPG-decrease ≥10%) were randomly assigned to propranolol (up to 160 mg twice a day) versus placebo and non-responders to carvedilol (≤25 mg/day) versus placebo. Doses were individually determined during an open-label titration period after which randomisation was done with 1:1 allocation by a centralised web-based system. The primary endpoint was incidence of cirrhosis decompensation (defined as development of ascites, bleeding, or overt encephalopathy) or death. Since death in compensated cirrhosis is usually unrelated to the liver, an intention-to-treat analysis considering deaths unrelated to the liver as competing events was done. This study is registered with ClinicalTrials.gov, number NCT01059396. The trial is now completed.
Between Jan 18, 2010, and July 31, 2013, 631 patients were evaluated and 201 were randomly assigned. 101 patients received placebo and 100 received active treatment (67 propranolol and 33 carvedilol). The primary endpoint occurred in 16 (16%) of 100 patients in the β blockers group versus 27 (27%) of 101 in the placebo group (hazard ratio HR 0·51, 95% CI 0·26–0·97, p=0·041). The difference was due to a reduced incidence of ascites (HR 0·42, 95% CI 0·19–0·92, p=0·03). The overall incidence of adverse events was similar in both groups. Six patients (four in the β blockers group) had severe adverse events.
Long-term treatment with β blockers could increase decompensation-free survival in patients with compensated cirrhosis and CSPH, mainly by reducing the incidence of ascites.
Spanish Ministries of Health and Economy.
Background & Aims Detecting portal hypertension (PH) before the development of varices is important for prognosis and for designing interventional studies. None of the available strategies is used in ...practice. We evaluated a sequential screening-diagnostic strategy based on clinical data and transient elastography (TE) to detect PH in asymptomatic outpatients with liver disease. Methods Consecutive patients with chronic liver disease and no previous diagnosis of PH were screened by TE. Patients with liver stiffness (LS) ⩾13.6 kPa were further evaluated by endoscopy and hepatic venous pressure gradient (HVPG). For analysis, patients were classified in 3 groups: group A, platelets ⩾150,000/mm3 , normal abdominal ultrasound; group B, platelets <150,000/mm3 , normal ultrasound; group C, platelets <150,000/mm3 , abnormal ultrasound (splenomegaly, nodular liver surface). Results 250 patients were evaluated (69% group A, 20% group B, 11% group C). In 9% elastography was non-valid. LS ⩾13.6 was found in 54 patients (8% A, 43% B, and 81% C, p <0.001). Endoscopy was performed in 49 of these: 20% had small varices, 0% high-risk varices. No patients from group A had varices, and 90% with varices belonged to group C. HVPG was obtained in 40 patients: 93% had PH (HVPG >5 mmHg) and 65% clinically significant PH (CSPH, HVPG ⩾10). Only 3 patients, all from group A, had HVPG <5. All patients from groups B and C with LS ⩾13.6 had PH. The LS 25 cut-off was excellent at ruling-in CSPH. Conclusions A simple strategy based on routine clinical data and TE could be useful to detect early PH among asymptomatic patients with chronic liver disease.
Background & Aims Patients with cirrhosis with acute variceal bleeding (AVB) have high mortality rates (15%–20%). Previously described models are seldom used to determine prognoses of these patients, ...partially because they have not been validated externally and because they include subjective variables, such as bleeding during endoscopy and Child–Pugh score, which are evaluated inconsistently. We aimed to improve determination of risk for patients with AVB. Methods We analyzed data collected from 178 patients with cirrhosis (Child–Pugh scores of A, B, and C: 15%, 57%, and 28%, respectively) and esophageal AVB who received standard therapy from 2007 through 2010. We tested the performance (discrimination and calibration) of previously described models, including the model for end-stage liver disease (MELD), and developed a new MELD calibration to predict the mortality of patients within 6 weeks of presentation with AVB. MELD-based predictions were validated in cohorts of patients from Canada (n = 240) and Spain (n = 221). Results Among study subjects, the 6-week mortality rate was 16%. MELD was the best model in terms of discrimination; it was recalibrated to predict the 6-week mortality rate with logistic regression (logit, -5.312 + 0.207 • MELD; bootstrapped R2 , 0.3295). MELD values of 19 or greater predicted 20% or greater mortality, whereas MELD scores less than 11 predicted less than 5% mortality. The model performed well for patients from Canada at all risk levels. In the Spanish validation set, in which all patients were treated with banding ligation, MELD predictions were accurate up to the 20% risk threshold. Conclusions We developed a MELD-based model that accurately predicts mortality among patients with AVB, based on objective variables available at admission. This model could be useful to evaluate the efficacy of new therapies and stratify patients in randomized trials.
Cirrhosis, highly prevalent worldwide, develops after years of hepatic inflammation triggering progressive fibrosis. Currently, the main etiologies of cirrhosis are non‐alcoholic fatty liver disease ...and alcohol‐related liver disease, although chronic hepatitis B and C infections are still major etiological factors in some areas of the world. Recent studies have shown that liver fibrosis can be assessed with relatively high accuracy noninvasively by serological tests, transient elastography, and radiological methods. These modalities may be utilized for screening for liver fibrosis in at‐risk populations. Thus far, a limited number of population‐based studies using noninvasive tests in different areas of the world indicate that a significant percentage of subjects without known liver disease (around 5% in general populations and a higher rate −18% to 27%‐in populations with risk factors for liver disease) have significant undetected liver fibrosis or established cirrhosis. Larger international studies are required to show the harms and benefits before concluding that screening for liver fibrosis should be applied to populations at risk for chronic liver diseases. Screening for liver fibrosis has the potential for changing the current approach from diagnosing chronic liver diseases late when patients have already developed complications of cirrhosis to diagnosing liver fibrosis in asymptomatic subjects providing the opportunity of preventing disease progression.
Patients with compensated cirrhosis with clinically significant portal hypertension (CSPH: HVPG > 10 mm Hg) have a high risk of decompensation. HVPG is, however, an invasive procedure not available ...in all centers. The present study aims to assess whether metabolomics can improve the capacity of clinical models in predicting clinical outcomes in these compensated patients.
This is a nested study from the PREDESCI cohort (an RCT of nonselective beta-blockers vs. placebo in 201 patients with compensated cirrhosis and CSPH), including 167 patients for whom a blood sample was collected. A targeted metabolomic serum analysis, using ultra-high-performance liquid chromatography-mass spectrometry, was performed. Metabolites underwent univariate time-to-event cox regression analysis. Top-ranked metabolites were selected using Log-Rank p -value to generate a stepwise cox model. Comparison between models was done using DeLong test. Eighty-two patients with CSPH were randomized to nonselective beta-blockers and 85 to placebo. Thirty-three patients developed the main endpoint (decompensation/liver-related death). The model, including HVPG, Child-Pugh, and treatment received ( HVPG/Clinical model ), had a C-index of 0.748 (CI95% 0.664-0.827). The addition of 2 metabolites, ceramide (d18:1/22:0) and methionine (HVPG/Clinical/Metabolite model), significantly improved the model's performance C-index of 0.808 (CI95% 0.735-0.882); p =0.032. The combination of these 2 metabolites together with Child-Pugh and the type of treatment received (Clinical/Metabolite model) had a C-index of 0.785 (CI95% 0.710-0.860), not significantly different from the HVPG-based models including or not metabolites.
In patients with compensated cirrhosis and CSPH, metabolomics improves the capacity of clinical models and achieves similar predictive capacity than models including HVPG.
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