Acute kidney injury in patients with cirrhosis: Acute Disease Quality Initiative (ADQI) and International Club of Ascites (ICA) joint multidisciplinary consensus meeting.

Patients with cirrhosis are prone to developing acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along with a risk of progression to chronic kidney disease. Whereas patients with cirrhosis are at increased risk of developing any phenotype of AKI, hepatorenal syndrome (HRS), a specific form of AKI (HRS-AKI) in patients with advanced cirrhosis and ascites, carries an especially high mortality risk. Early recognition of HRS-AKI is crucial since administration of splanchnic vasoconstrictors may reverse the AKI and serve as a bridge to liver transplantation, the only curative option. In 2023, a joint meeting of the International Club of Ascites (ICA) and the Acute Disease Quality Initiative (ADQI) was convened to develop new diagnostic criteria for HRS-AKI, to provide graded recommendations for the work-up, management and post-discharge follow-up of patients with cirrhosis and AKI, and to highlight priorities for further research.

Serum aryl hydrocarbon receptor activity is associated with survival in patients with alcohol-associated hepatitis.

BACKGROUND AND AIMS: Patients with alcohol-associated hepatitis (AH) have an altered fecal metabolome, including reduced microbiota-derived tryptophan metabolites, which function as ligands for aryl hydrocarbon receptor (AhR). The aim of this study was to assess serum AhR ligand activity in patients with AH. APPROACH AND RESULTS: The study included 74 controls without AUD, 97 patients with AUD, and 330 patients with AH from 2 different multicenter cohorts (InTeam: 134, AlcHepNet: 196). Serum AhR activity was evaluated using an AhR reporter assay with HepG2-Lucia cells incubated with serum for 24 hours. Serum AhR activity was significantly higher in patients with AH compared with both controls (1.59 vs. 0.96-fold change, p < 0.001) and patients with AUD (1.59 vs. 0.93, p < 0.001). In both AH cohorts, patients with AhR activity ≥ 2.09 had significantly lower cumulative survival rates at 30, 60, 90, and 180 days compared to those with AhR activity < 2.09. When serum AhR activity was used to further stratify patients with severe AH, the cumulative 30, 60, 90, and 180-day survival rates for patients with severe AH and the AhR activity ≥ 2.09 group were all significantly lower than those with an AhR activity < 2.09 group. CONCLUSIONS: Serum AhR activity was significantly higher in patients with AH compared with controls and individuals with AUD, and this increased activity was associated with higher mortality. Consequently, serum AhR activity holds potential as a prognostic marker.

The effect of endoscopic gastric plication on portosystemic pressure gradient in patients with nonalcoholic fatty liver disease and compensated advanced chronic liver disease.

BACKGROUND: The goals of therapy for patients with nonalcoholic fatty liver disease and compensated advanced chronic liver disease include weight loss and reduction of the portosystemic pressure gradient (PPG) to decrease the risk of hepatic decompensation. Endoscopic gastric plication (EGP) is an effective endoscopic weight loss procedure. This study aimed to assess the effect of EGP on PPG. METHODS: In this prospective pilot study, patients with nonalcoholic fatty liver disease and compensated advanced chronic liver disease underwent endoscopic ultrasound-guided PPG measurement prior to and at 6 months following EGP. Primary outcomes were the change in PPG and proportion of patients experiencing ≥ 20 % reduction in PPG at 6 months. Secondary outcomes included percent total weight loss (TWL) and changes in noninvasive tests of fibrosis. RESULTS: 20 patients were included. Baseline median body mass index and liver stiffness measurement were 40.2 kg/m2 (range 30.1-56.7) and 14.7 kPa (range 8.2-36), respectively. At 6 months, median PPG decreased from 5.4 mmHg (range 0.7-19.6) to 1.8 mmHg (range 0.4-17.6) (P = 0.002), with 79 % (11/14) experiencing ≥ 20 % reduction. Patients experienced 12.5 % (6.5 %-26.1 %) TWL (P < 0.001) at 6 months, with 89 % (17/19) achieving ≥ 7 % and 68 % (13/19) achieving ≥ 10 % TWL. There were significant improvements in noninvasive tests of fibrosis. CONCLUSION: EGP appeared to be effective at reducing PPG in patients with nonalcoholic fatty liver disease and compensated advanced chronic liver disease.

AGA Clinical Practice Update on the Use of Vasoactive Drugs and Intravenous Albumin in Cirrhosis: Expert Review.

DESCRIPTION: Cirrhosis is a major cause of morbidity and mortality in the United States and worldwide. It consists of compensated, decompensated, and further decompensated stages; median survival is more than 15 years, 2 years, and 9 months for each stage, respectively. With each stage, there is progressive worsening of portal hypertension and the vasodilatory-hyperdynamic circulatory state, resulting in a progressive decrease in effective arterial blood volume and renal perfusion. Vasoconstrictors reduce portal pressure via splanchnic vasoconstriction and are used in the management of variceal hemorrhage. Intravenous (IV) albumin increases effective arterial blood volume and is used in the prevention of acute kidney injury (AKI) and death after large-volume paracentesis and in patients with spontaneous bacterial peritonitis (SBP). The combination of vasoconstrictors and albumin is used in the reversal of hepatorenal syndrome (HRS-AKI), the most lethal complication of cirrhosis. Because a potent vasoconstrictor, terlipressin, was recently approved by the US Food and Drug Administration, and because recent trials have explored use of IV albumin in other settings, it was considered that a best practice update would be relevant regarding the use of vasoactive drugs and IV albumin in the following 3 specific scenarios: variceal hemorrhage, ascites and SBP, and HRS. METHODS: This expert review was commissioned and approved by the American Gastroenterological Association (AGA) Institute Clinical Practice Updates Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership. It underwent internal peer review through standard procedures of Gastroenterology. These Best Practice Advice statements were drawn from a review of the published literature and from expert opinion. Some of the statements are unchanged from published guidelines because of lack of new evidence in the literature. Because systematic reviews were not performed, these Best Practice Advice statements do not carry formal ratings regarding the quality and evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Vasoactive drugs should be initiated as soon as the diagnosis of variceal hemorrhage is suspected or confirmed, preferably before diagnostic and/or therapeutic endoscopy. BEST PRACTICE ADVICE 2: After initial endoscopic hemostasis, vasoactive drugs should be continued for 2-5 days to prevent early rebleeding. BEST PRACTICE ADVICE 3: Octreotide is the vasoactive drug of choice in the management of variceal hemorrhage based on its safety profile. BEST PRACTICE ADVICE 4: IV albumin should be administered at the time of large-volume (>5 L) paracentesis. BEST PRACTICE ADVICE 5: IV albumin may be considered in patients with SBP. BEST PRACTICE ADVICE 6: Albumin should not be used in patients (hospitalized or not) with cirrhosis and uncomplicated ascites. BEST PRACTICE ADVICE 7: Vasoconstrictors should not be used in the management of uncomplicated ascites, after large-volume paracentesis or in patients with SBP. BEST PRACTICE ADVICE 8: IV albumin is the volume expander of choice in hospitalized patients with cirrhosis and ascites presenting with AKI. BEST PRACTICE ADVICE 9: Vasoactive drugs (eg, terlipressin, norepinephrine, and combination of octreotide and midodrine) should be used in the treatment of HRS-AKI, but not in other forms of AKI in cirrhosis. BEST PRACTICE ADVICE 10: Terlipressin is the vasoactive drug of choice in the treatment of HRS-AKI and use of concurrent albumin can be considered when accounting for patient's volume status. BEST PRACTICE ADVICE 11: Terlipressin treatment does not require intensive care unit monitoring and can be administered intravenously through a peripheral line. BEST PRACTICE ADVICE 12: Terlipressin use is contraindicated in patients with hypoxemia and in patients with ongoing coronary, peripheral, or mesenteric ischemia, and should be used with caution in patients with acute-on-chronic liver failure grade 3. The benefits may not outweigh the risks in patients with serum creatinine >5 mg/dL and in patients listed for transplantation with a Model for End-stage Liver Disease ≥35.

Further decompensation in cirrhosis: Results of a large multicenter cohort study supporting Baveno VII statements.

BACKGROUND AND AIMS: The prognostic weight of further decompensation in cirrhosis is still unclear. We investigated the incidence of further decompensation and its effect on mortality in patients with cirrhosis. APPROACH AND RESULTS: Multicenter cohort study. The cumulative incidence of further decompensation (development of a second event or complication of a decompensating event) was assessed using competing risks analysis in 2028 patients. A 4-state model was built: first decompensation, further decompensation, liver transplant, and death. A cause-specific Cox model was used to assess the adjusted effect of further decompensation on mortality. Sensitivity analyses were performed for patients included before or after 1999. In a mean follow-up of 43 months, 1192 patients developed further decompensation and 649 died. Corresponding 5-year cumulative incidences were 52% and 35%, respectively. The cumulative incidences of death and liver transplant after further decompensation were 55% and 9.7%, respectively. The most common further decompensating event was ascites/complications of ascites. Five-year probabilities of state occupation were 24% alive with first decompensation, 21% alive with further decompensation, 7% alive with a liver transplant, 16% dead after first decompensation without further decompensation, 31% dead after further decompensation, and <1% dead after liver transplant. The HR for death after further decompensation, adjusted for known prognostic indicators, was 1.46 (95% CI: 1.23-1.71) ( p <0.001). The significant impact of further decompensation on survival was confirmed in patients included before or after 1999. CONCLUSIONS: In cirrhosis, further decompensation occurs in ~60% of patients, significantly increases mortality, and should be considered a more advanced stage of decompensated cirrhosis.

Controversies regarding albumin therapy in cirrhosis.

Albumin is the most abundant protein in the human body and is synthetized exclusively by the liver. Therefore, serum albumin levels are reduced in acute and/or chronic liver disease. In cirrhosis, low levels of albumin predict the outcome. In advanced cirrhosis, the quality of albumin is decreased due to high oxidative stress and a proinflammatory state. Therefore, the administration of i.v. albumin would seem to be of pathophysiological relevance and benefit. Yet, the questions that remain are who, when, how much, and how often. While albumin infusion is recommended after large-volume paracentesis, at diagnosis of spontaneous bacterial peritonitis, in acute kidney injury, and in hepatorenal syndrome, the amount and schedule of albumin to be administered require refinement, particularly given complications related to volume overload that have become increasingly apparent. Other indications for albumin such as infections other than spontaneous bacterial peritonitis, hyponatremia, HE, prevention of poor outcomes in hospitalized, and in outpatients with cirrhosis are still debated. The results of studies in these settings are either negative, controversial, or inconclusive. This sheds some doubts regarding the use of albumin as a "one size fits all" strategy. The indication and patient selection are crucial and not always intuitive. The amount and frequency also seem to play a role in the success or failure of albumin. This review will critically discuss the evidence and underline areas where there are indications for albumin use and others where evidence is still insufficient and will have to await the development/results of randomized controlled trials.

Emerging concepts in the care of patients with cirrhosis and septic shock.

Septic shock impacts approximately 6% of hospitalized patients with cirrhosis and is associated with high rates of morbidity and mortality. Although a number of landmark clinical trials have paved the way for incremental improvements in the diagnosis and management of septic shock in the general population, patients with cirrhosis have largely been excluded from these studies and critical knowledge gaps continue to impact the care of these individuals. In this review, we discuss nuances in the care of patients with cirrhosis and septic shock using a pathophysiology-based approach. We illustrate that septic shock may be challenging to diagnose in this population in the context of factors such as chronic hypotension, impaired lactate metabolism, and concomitant hepatic encephalopathy. Furthermore, we demonstrate that the application of routine interventions such as intravenous fluids, vasopressors, antibiotics, and steroids should be carefully considered among those with decompensated cirrhosis in light of hemodynamic, metabolic, hormonal, and immunologic disturbances. We propose that future research should include and characterize patients with cirrhosis in a systematic manner, and clinical practice guidelines may need to be refined accordingly.

Medications for alcohol use disorder improve survival in patients with hazardous drinking and alcohol-associated cirrhosis.

BACKGROUND: Medications for alcohol use disorder (MAUD) are highly effective in achieving and maintaining abstinence in patients with alcohol use disorder (AUD). Our aim was to evaluate the effect of MAUD on all-cause mortality in patients with alcohol-associated cirrhosis and active alcohol use. METHODS: This was a retrospective cohort study of patients with alcohol-associated cirrhosis and high-risk alcohol use disorder in the Veterans Outcomes and Costs Associated with Liver Disease (VOCAL) database. Propensity score matching for exposure to MAUD (acamprosate or naltrexone) within a year after cirrhosis diagnosis was performed to account for potential confounders, and the association between MAUD and all-cause mortality was subsequently evaluated using Cox regression analysis. RESULTS: A total of 9131 patients were included, of whom 886 (9.7%) were exposed to MAUD (naltrexone: 520, acamprosate: 307, both medications: 59). The duration of MAUD exposure was >3 months in 345 patients (39%). The strongest positive predictor of MAUD prescription was an inpatient diagnosis code for AUD, followed by a concurrent diagnosis of depression; the strongest negative predictor was a history of cirrhosis decompensation. After propensity score matching (866 patients in each group) with excellent covariate balance (absolute standardized mean differences <0.1), MAUD exposure was associated with improved survival, with an HR of 0.80 relative to no MAUD exposure (95% CI: 0.67-0.97, p = 0.024). CONCLUSION: MAUD are underutilized in patients with alcohol-associated cirrhosis with high-risk alcohol use behavior but are associated with improved survival after adjustment for confounders such as the severity of liver disease, age, and engagement in the healthcare system.

Update in the Treatment of the Complications of Cirrhosis.

Cirrhosis consists of 2 main stages: compensated and decompensated, the latter defined by the development/presence of ascites, variceal hemorrhage, and hepatic encephalopathy. The survival rate is entirely different, depending on the stage. Treatment with nonselective ß-blockers prevents decompensation in patients with clinically significant portal hypertension, changing the previous paradigm based on the presence of varices. In patients with acute variceal hemorrhage at high risk of failure with standard treatment (defined as those with a Child-Pugh score of 10-13 or those with a Child-Pugh score of 8-9 with active bleeding at endoscopy), a pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) improves the mortality rate and has become the standard of care in many centers. In patients with bleeding from gastrofundal varices, retrograde transvenous obliteration (in those with a gastrorenal shunt) and/or variceal cyanoacrylate injection have emerged as alternatives to TIPS. In patients with ascites, emerging evidence suggests that TIPS might be used earlier, before strict criteria for refractory ascites are met. Long-term albumin use is under assessment for improving the prognosis of patients with uncomplicated ascites and confirmatory studies are ongoing. Hepatorenal syndrome is the least common cause of acute kidney injury in cirrhosis, and first-line treatment is the combination of terlipressin and albumin. Hepatic encephalopathy has a profound impact on the quality of life of patients with cirrhosis. Lactulose and rifaximin are first- and second-line treatments for hepatic encephalopathy, respectively. Newer therapies such as L-ornithine L-aspartate and albumin require further assessment.

Machine learning liver histology scores correlate with portal hypertension assessments in nonalcoholic steatohepatitis cirrhosis.

BACKGROUND AND AIMS: In cirrhotic nonalcoholic steatohepatitis (NASH) clinical trials, primary efficacy endpoints have been hepatic venous pressure gradient (HVPG), liver histology and clinical liver outcomes. Important histologic features, such as septa thickness, nodules features and fibrosis area have not been included in the histologic assessment and may have important clinical relevance. We assessed these features with a machine learning (ML) model. METHODS: NASH patients with compensated cirrhosis and HVPG ≥6 mm Hg (n = 143) from the Belapectin phase 2b trial were studied. Liver biopsies, HVPG measurements and upper endoscopies were performed at baseline and at end of treatment (EOT). A second harmonic generation/two-photon excitation fluorescence provided an automated quantitative assessment of septa, nodules and fibrosis (SNOF). We created ML scores and tested their association with HVPG, clinically significant HVPG (≥10 mm Hg) and the presence of varices (SNOF-V). RESULTS: We derived 448 histologic variables (243 related to septa, 21 related to nodules and 184 related to fibrosis). The SNOF score (≥11.78) reliably distinguished CSPH at baseline and in the validation cohort (baseline + EOT) [AUC = 0.85 and 0.74, respectively]. The SNOF-V score (≥0.57) distinguished the presence of varices at baseline and in the same validation cohort [AUC = 0.86 and 0.73, respectively]. Finally, the SNOF-C score differentiated those who had >20% change in HVPG against those who did not, with an AUROC of 0.89. CONCLUSION: The ML algorithm accurately predicted HVPG, CSPH, the development of varices and HVPG changes in patients with NASH cirrhosis. The use of ML histology model in NASH cirrhosis trials may improve the assessment of key outcome changes.

Endovascular Assessment of Liver Hemodynamics in Patients with Cirrhosis Complicated by Portal Hypertension.

The hepatic venous pressure gradient (HVPG) is currently considered the gold standard to assess portal hypertension (PH) in patients with cirrhosis. A meticulous technique is important to achieve accurate and reproducible results, and values obtained during measurement are applied in risk stratification of patients with PH, allocating treatment options, monitoring follow-up, and deciding management options in surgical patients. The use of portosystemic pressure gradients in patients undergoing placement of transjugular intrahepatic portosystemic shunts has been studied extensively and has great influence on decisions on shunt diameter. The purpose of this study was to describe the recommended technique to measure HVPG and portosystemic pressure gradient and to review the existing literature describing the importance of these hemodynamic measurements in clinical practice.

Role of Oral Health, Frailty, and Minimal Hepatic Encephalopathy in the Risk of Hospitalization: A Prospective Multi-Center Cohort of Outpatients With Cirrhosis.

BACKGROUND & AIMS: Hospitalizations are a sentinel event in cirrhosis; however, the changing demographics in patients with cirrhosis require updated hospitalization prediction models. Periodontitis is a risk factor for liver disease and potentially progression. The aim of this study was to determine factors, including poor oral health, associated with 3-month hospitalizations in a multi-center cohort of outpatients with cirrhosis. METHODS: North American Consortium for Study of End-stage Liver Disease (NACSELD-3), a new study cohort, recruits outpatients with cirrhosis. Cirrhosis details, demographics, minimal hepatic encephalopathy (MHE), frailty, and comorbid conditions including oral health were collected. All patients were followed for 3 months for nonelective hospitalizations. Multi-variable models were created for this outcome using demographics, cirrhosis details, oral health, MHE, frailty, and comorbid conditions with K-fold internal validation using 25%/75% split. RESULTS: A total of 442 outpatients (70% men; 37% compensated; Model for End-stage Liver Disease-Sodium, 12; 42% ascites; and 33% prior HE) were included. MHE was found in 70%, frailty in 10%; and both in 8%. In terms of oral health, 15% were edentulous and 10% had prior periodontitis. Regarding 3-month hospitalizations, 14% were admitted for mostly liver-related reasons. These patients were more likely to be decompensated with higher cirrhosis complications, MHE, frailty and periodontitis history. Multi-variable analysis showed prior periodontitis (P = .026), composite MHE + frailty score (P = .0016), ascites (P = .004), prior HE (P = .008), and hydrothorax (P = .004) were associated with admissions using the training and validation subsets. CONCLUSIONS: In a contemporaneous, prospective, multi-center cohort study in outpatients with cirrhosis, poor oral health is significantly associated with 3-month hospitalizations independent of portal hypertensive complications, MHE, and frailty. Potential strategies to reduce hospitalizations should consider oral evaluation in addition to MHE and frailty assessment in practice pathways.

Admission Serum Metabolites and Thyroxine Predict Advanced Hepatic Encephalopathy in a Multicenter Inpatient Cirrhosis Cohort.

BACKGROUND & AIMS: Grades 3 to 4 hepatic encephalopathy (advanced HE), also termed brain failure, is an organ failure that defines acute-on-chronic liver failure. It is associated with poor outcomes in cirrhosis but cannot be predicted accurately. We aimed to determine the admission metabolomic biomarkers able to predict the development of advanced HE with subsequent validation. METHODS: Prospective inpatient cirrhosis cohorts (multicenter and 2-center validation) without brain failure underwent admission serum collection and inpatient follow-up evaluation. Serum metabolomics were analyzed to predict brain failure on random forest analysis and logistic regression. A separate validation cohort also was recruited. RESULTS: The multicenter cohort included 602 patients, of whom 144 developed brain failure (105 only brain failure) 3 days after admission. Unadjusted random forest analysis showed that higher admission microbially derived metabolites and lower isoleucine, thyroxine, and lysophospholipids were associated with brain failure development (area under the curve, 0.87 all; 0.90 brain failure only). Logistic regression area under the curve with only clinical variables significantly improved with metabolites (95% CI 0.65-0.75; P = .005). Four metabolites that significantly added to brain failure prediction were low thyroxine and maltose and high methyl-4-hydroxybenzoate sulfate and 3-4 dihydroxy butyrate. Thyroxine alone also significantly added to the model (P = .05). The validation cohort including 81 prospectively enrolled patients, of whom 11 developed brain failure. Admission hospital laboratory thyroxine levels predicted brain failure development despite controlling for clinical variables with high specificity. CONCLUSIONS: In a multicenter inpatient cohort, admission serum metabolites, including thyroxine, predicted advanced HE development independent of clinical factors. Admission low local laboratory thyroxine levels were validated as a predictor of advanced HE development in a separate cohort.

Thromboelastography-Guided Therapy Enhances Patient Blood Management in Cirrhotic Patients: A Meta-analysis Based on Randomized Controlled Trials.

Patients with cirrhosis often have abnormal hemostasis, with increased risk of hemorrhage and thrombosis. Thromboelastography provides a rapid assessment of the coagulation status and can guide product transfusions in adult patients with cirrhosis. This study aimed to determine whether the use of thromboelastography in adult patients with cirrhosis decreases blood product use and impacts adverse events or mortality compared with standard practice. A registered (PROSPERO CRD42020192458) systematic review and meta-analysis was conducted for randomized controlled trials (RCTs) comparing thromboelastography-guided hemostatic management versus standard practice (control). Co-primary outcomes were the number of transfused platelet units and fresh frozen plasma (FFP) units. Secondary outcomes were mortality, adverse events, utilization of individual blood products, blood loss or excessive bleeding events, hospital/intensive care unit stay, and liver transplant/intervention outcomes. The search identified 260 articles, with five RCTs included in the meta-analysis. Platelet use was five times lower with thromboelastography versus the control, with a relative risk of 0.17 (95% confidence interval [CI]: [0.03-0.90]; p = 0.04), but FFP use did not differ significantly. Thromboelastography was associated with less blood product (p < 0.001), FFP + platelets (p < 0.001), and cryoprecipitate (p < 0.001) use. No differences were reported in bleeding rates or longer term mortality between groups, with the thromboelastography group having lower mortality at 7 days versus the control (relative risk [95% CI] = 0.52 [0.30-0.91]; p = 0.02). Thromboelastography-guided therapy in patients with cirrhosis enhances patient blood management by reducing use of blood products without increasing complications.