Comparison of 6 tests for diagnosing minimal hepatic encephalopathy and predicting clinical outcome: A prospective, observational study.

BACKGROUND AND AIMS: Current guidelines recommend the assessment for minimal HE in patients with liver cirrhosis. Various efforts were made to find tools that simplify the diagnosis. Here, we compare the 6 most frequently used tests for their validity and their predictive value for overt hepatic encephalopathy (oHE), rehospitalization, and death. APPROACH AND RESULTS: One hundred thirty-two patients with cirrhosis underwent the Portosystemic Encephalopathy-Syndrome-Test yielding the psychometric hepatic encephalopathy score (PHES), Animal Naming Test (ANT), Critical Flicker Frequency (CFF), Inhibitory Control Test (ICT), EncephalApp (Stroop), and Continuous Reaction Time Test (CRT). Patients were monitored for 365 days regarding oHE development, rehospitalization, and death. Twenty-three patients showed clinical signs of HE grade 1-2 at baseline. Of the remaining 109 neurologically unimpaired patients, 35.8% had abnormal PHES and 44% abnormal CRT. Percentage of abnormal Stroop (79.8% vs. 52.3%), ANT (19.3% vs. 51.4%), ICT (28.4% vs. 36.7%), and CFF results (18.3% vs. 25.7%) changed significantly when adjusted norms were used for evaluation instead of fixed cutoffs. All test results correlated significantly with each other ( p <0.05), except for CFF. During follow-up, 24 patients developed oHE, 58 were readmitted to the hospital, and 20 died. Abnormal PHES results were linked to oHE development in the multivariable model. No other adjusted test demonstrated predictive value for any of the investigated endpoints. CONCLUSIONS: Where applicable, the diagnosis of minimal HE should be made based on adjusted norm values for the tests, exclusively. The minimal HE tests cannot be equated with one another and have an overall limited value in predicting clinical outcomes.

Metabolic disorder and functional disturbance in the central executive network in minimal hepatic encephalopathy.

The aim of this paper is to investigate dynamical functional disturbance in central executive network in minimal hepatic encephalopathy and determine its association with metabolic disorder and cognitive impairment. Data of magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging were obtained from 27 cirrhotic patients without minimal hepatic encephalopathy, 20 minimal hepatic encephalopathy patients, and 24 healthy controls. Central executive network was identified utilizing seed-based correlation approach. Dynamic functional connectivity across central executive network was calculated using sliding-window approach. Functional states were estimated by K-means clustering. Right dorsolateral prefrontal cortex metabolite ratios (i.e. glutamate and glutamine complex/total creatine, myo-inositol / total creatine, and choline / total creatine) were determined. Neurocognitive performance was determined by psychometric hepatic encephalopathy scores. Minimal hepatic encephalopathy patients had decreased myo-inositol / total creatine and choline / total creatine and increased glutamate and glutamine complex / total creatine in right dorsolateral prefrontal cortex (all P ≤ 0.020); decreased static functional connectivity between bilateral dorsolateral prefrontal cortex and between right dorsolateral prefrontal cortex and lateral-inferior temporal cortex (P ≤ 0.001); increased frequency and mean dwell time in state-1 (P ≤ 0.001), which exhibited weakest functional connectivity. Central executive network dynamic functional indices were significantly correlated with right dorsolateral prefrontal cortex metabolic indices and psychometric hepatic encephalopathy scores. Right dorsolateral prefrontal cortex myo-inositol / total creatine and mean dwell time in state-1 yielded best potential for diagnosing minimal hepatic encephalopathy. Dynamic functional disturbance in central executive network may contribute to neurocognitive impairment and could be correlated with metabolic disorder.

A neural mass model for disturbance of alpha rhythm in the minimal hepatic encephalopathy.

One of the early markers of minimal hepatic encephalopathy (MHE) is the disruption of alpha rhythm observed in electroencephalogram (EEG) signals. However, the underlying mechanisms responsible for this occurrence remain poorly understood. To address this gap, we develop a novel biophysical model MHE-AWD-NCM, encompassing the communication dynamics between a cortical neuron population (CNP) and an astrocyte population (AP), aimed at investigating the relationship between alpha wave disturbance (AWD) and mechanistical principles, specifically concerning astrocyte-neuronal communication in the context of MHE. In addition, we introduce the concepts of peak power density and peak frequency within the alpha band as quantitative measures of AWD. Our model faithfully reproduces the characteristic EEG phenomenology during MHE and shows how impairments of communication between CNP and AP could promote AWD. The results suggest that the disruptions in feedback neurotransmission from AP to CNP, along with the inhibition of GABA uptake by AP from the extracellular space, contribute to the observed AWD. Moreover, we found that the variation of external excitatory stimuli on CNP may play a key role in AWD in MHE. Finally, the sensitivity analysis is also performed to assess the relative significance of above factors in influencing AWD. Our findings align with the physiological observations and provide a more comprehensive understanding of the complex interplay of astrocyte-neuronal communication that underlies the AWD observed in MHE, which potentially may help to explore the targeted therapeutic interventions for the early stage of hepatic encephalopathy.

Episodic overt hepatic encephalopathy after transjugular intrahepatic portosystemic shunt does not increase mortality in patients with cirrhosis.

BACKGROUND & AIMS: Overt hepatic encephalopathy (OHE) is a major complication of transjugular intrahepatic portosystemic shunt (TIPS) placement, given its high incidence and possibility of refractoriness to medical treatment. Nevertheless, the impact of post-TIPS OHE on mortality has not been investigated in a large population. METHODS: We designed a multicenter, non-inferiority, observational study to evaluate the mortality rate at 30 months in patients with and without OHE after TIPS. We analyzed a database of 614 patients who underwent TIPS in three Italian centers and estimated the cumulative incidence of OHE and mortality with competitive risk analyses, setting the non-inferiority limit at 0.12. RESULTS: During a median follow-up of 30 months (IQR 12-30), 293 patients developed at least one episode of OHE. Twenty-seven (9.2%) of them experienced recurrent/persistent OHE. Patients with OHE were older (64 [57-71] vs. 59 [50-67] years, p <0.001), had lower albumin (3.1 [2.8-3.5] vs. 3.25 [2.9-3.6] g/dl, p = 0.023), and had a higher prevalence of pre-TIPS OHE (15.4% vs. 9.0%, p = 0.023). Child-Pugh and MELD scores were similar. The 30-month difference in mortality between patients with and without post-TIPS OHE was 0.03 (95% CI -0.042 to 0.102). Multivariable analysis showed that age (subdistribution hazard ratio 1.04, 95% CI 1.02-1.05, p <0.001) and MELD score (subdistribution hazard ratio 1.09, 95% CI 1.05-1.13, p <0.001), but not post-TIPS OHE, were associated with a higher mortality rate. Similar results were obtained when patients undergoing TIPS for variceal re-bleeding prophylaxis (n = 356) or refractory ascites (n = 258) were analyzed separately. The proportion of patients with persistent OHE after TIPS was significantly higher in the group of patients who died. The robustness of these results was increased following propensity score matching. CONCLUSION: Episodic OHE after TIPS is not associated with mortality in patients undergoing TIPS, regardless of the indication. IMPACT AND IMPLICATIONS: Overt hepatic encephalopathy (OHE) is a common complication in patients with advanced liver disease and it is particularly frequent following transjugular intrahepatic portosystemic shunt (TIPS) placement. In patients with cirrhosis outside the setting of TIPS, the development of OHE negatively impacts survival, regardless of the severity of cirrhosis or the presence of acute-on-chronic liver failure. In this multicenter, non-inferiority, observational study we demonstrated that post-TIPS OHE does not increase the risk of mortality in patients undergoing TIPS, irrespective of the indication. This finding alleviates concerns regarding the weight of this complication after TIPS. Intensive research to improve patient selection and risk stratification remains crucial to enhance the quality of life of patients and caregivers and to avoid undermining the positive effects of TIPS on survival.

QuickStroop Predicts Time to Development of Overt Hepatic Encephalopathy and Related Hospitalizations in Patients With Cirrhosis.

Cirrhosis-related neurocognitive impairment caused by covert or minimal hepatic encephalopathy (CHE) affects psychosocial function, increases risk of overt hepatic encephalopathy (OHE) development, and worsens survival.1,2 However, detection in clinical practice is challenging.2 One modality used for screening and prediction of outcomes related to cirrhosis is the EncephalApp Stroop, but it can require up to 10 minutes. Furthermore, the assessment comprises of distinct stages of difficulty, with an easier "Off" stage and a more challenging "On" stage.3 To alleviate these concerns, QuickStroop, which takes <1 minute, was developed. This uses only the first 2 runs of the Off stage of the EncephalApp Stroop, where number signs presented in red, green, or blue need to be matched quickly to their respective colors.4 A prior study showed these versions were comparable cross-sectionally to diagnose CHE.4 However, the utility of QuickStroop to predict cirrhosis-related outcomes is unclear.5-7 Our aim was to determine the ability of QuickStroop to determine time to development of OHE and OHE-related hospitalizations, all-cause hospitalizations, and death in outpatients with cirrhosis.

Prevalence and Characteristics of Covert/Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis: A Systematic Review and Meta-Analysis.

INTRODUCTION: Covert/minimal hepatic encephalopathy (C/MHE) is the mildest form of hepatic encephalopathy (HE), but it is closely related to the quality of life and prognosis of patients with cirrhosis. Currently, the epidemiological data of C/MHE have not been well described. METHODS: We searched the PubMed, Embase, and Cochrane Library databases for relevant articles. We performed a random-effects meta-analysis of proportions to estimate the pooled prevalence of C/MHE in patients with cirrhosis. We also examined potential risk factors for C/MHE by comparing characteristics of patients with and without C/MHE. RESULTS: Finally, a total of 101 studies were included. The prevalence of C/MHE was 40.9% (95% confidence interval, 38.3%-43.5%) among patients with cirrhosis worldwide. The pooled C/MHE prevalence was 39.9% (95% confidence interval 36.7%-43.1%) based on studies using the psychometric HE score as a diagnostic tool. Meta-regression models showed that geographic region, sample size, mean age, sex ratio, and Child-Pugh classification were influencing factors for the heterogeneity of C/MHE prevalence. The presence of C/MHE was found to be associated with various factors including age, level of education, alcoholic etiology, Child-Pugh classification, MELD score, history of overt HE, presence of other complications, and laboratory tests related to impaired liver function. DISCUSSION: This study reports detailed data on the prevalence of C/MHE as well as clinical features associated with C/MHE, suggesting that C/MHE is one of the most common complications of liver cirrhosis.

Diagnostic Performance of the ICD-10 Code K76.82 for Hepatic Encephalopathy in Patients With Cirrhosis.

INTRODUCTION: Hepatic encephalopathy (HE) is prevalent and is associated with increased morbidity and mortality among patients with cirrhosis. On October 1, 2022, a new, specific International Classification of Diseases-10 code for HE, K76.82, was introduced. We aimed to analyze the diagnostic accuracy of K76.82. METHODS: Diagnostic performance of K76.82 for HE (sensitivity, specificity, positive predictive ratio, and negative predictive ratio) was evaluated in 2 large health systems compared with lactulose, rifaximin, and K72.90. RESULTS: A total of 2,483 patients were analyzed. The combination term "lactulose or rifaximin" showed the highest sensitivity of >98% while K76.82 demonstrated a specificity of >87% in all cohorts. DISCUSSION: Although K76.82 is promising, the combination term "lactulose or rifaximin" identified patients with HE more accurately.

Thirty-Day Readmissions Are Largely Not Preventable in Patients With Cirrhosis.

INTRODUCTION: Hospital readmissions are common in patients with cirrhosis, but there are few studies describing readmission preventability. We aimed to describe the incidence, causes, and risk factors for preventable readmission in this population. METHODS: We performed a prospective cohort study of patients with cirrhosis hospitalized at a single center between June 2014 and March 2020 and followed up for 30 days postdischarge. Demographic, clinical, and socioeconomic data, functional status, and quality of life were collected. Readmission preventability was independently and systematically adjudicated by 3 reviewers. Multinomial logistic regression was used to compare those with (i) preventable readmission, (ii) nonpreventable readmission/death, and (iii) no readmission. RESULTS: Of 654 patients, 246 (38%) were readmitted, and 29 (12%) were preventable readmissions. Reviewers agreed on preventability for 70% of readmissions. Twenty-two (including 2 with preventable readmission) died. The most common reasons for readmission were hepatic encephalopathy (22%), gastrointestinal bleeding (13%), acute kidney injury (13%), and ascites (6%), and these reasons were similar between preventable and nonpreventable readmissions. Preventable readmission was often related to paracentesis timeliness, diuretic adjustment monitoring, and hepatic encephalopathy treatment. Compared with nonreadmitted patients, preventable readmission was independently associated with racial and ethnic minoritized individuals (odds ratio [OR] 5.80; 95% CI, 1.96-17.13), nonmarried marital status (OR 2.88; 95% CI, 1.18-7.05), and admission in the prior 30 days (OR 3.45; 95% CI, 1.48-8.04). DISCUSSION: For patients with cirrhosis, readmission is common, but most are not preventable. Preventable readmissions are often related to ascites and hepatic encephalopathy and are associated with racial and ethnic minorities, nonmarried status, and prior admissions.

Artificial Intelligence Evaluation of Stool Quality Guides Management of Hepatic Encephalopathy Using a Smartphone App.

Lactulose-based hepatic encephalopathy treatment requires bowel movements/day titration, which is improved with Bristol stool scale (BSS) incorporation. Dieta app evaluates artificial intelligence (AI)-based BSS (AI-BSS) with stool images. Initially, controls (N = 13) and cirrhosis patients on lactulose/not on lactulose (n = 33) were trained on the app. They entered self-reported BSS (self-BSS) with AI-BSS communicated. Lactulose dose changes were tracked. A subset (n = 12) was retested with AI communication blocked. Most subjects were comfortable with the app. Self/AI-BSS and lactulose dose/AI-BSS correlation increased with app use. AI-BSS communications improved insight into self-BSS over time. Dieta app to gauge stool AI characteristics was acceptable and increased insight into lactulose dose and BSS in cirrhosis.

Artificial Intelligence-Enabled Stool Analysis for Lactulose Titration Assistance in Hepatic Encephalopathy Through a Smartphone Application.

INTRODUCTION: Management of hepatic encephalopathy relies on self-titration of lactulose. In this feasibility trial, we assess an artificial intelligence-enabled tool to guide lactulose use through a smartphone application. METHODS: Subjects with hepatic encephalopathy on lactulose captured bowel movement pictures during lead-in and intervention phases. During the intervention phase, daily feedback on lactulose titration was delivered through the application. Goals were determined according to number of bowel movement and Bristol Stool Scale reports. RESULTS: Subjects completed the study with more than 80% satisfaction. In the lead-in phase, less compliant subjects achieved Bristol Stool Scale goal on 62/111 (56%) of days compared with 107/136 (79%) in the intervention phase ( P = 0.041), while the most compliant subjects showed no difference. Severe/recurrent hepatic encephalopathy group achieved Bristol Stool Scale goal on 80/104 (77%) days in the lead-in phase and 90/110 (82%) days in the intervention phase ( P = NS), compared with 89/143 (62%) days and 86/127 (68%) days in the stable group. DISCUSSION: Dieta application is a promising tool for objective Bowel Movement/Bristol Stool Scale tracking for hepatic encephalopathy and may potentially be used to assist with lactulose titration.

Deficiency of leucine-rich repeat kinase 2 aggravates thioacetamide-induced acute liver failure and hepatic encephalopathy in mice.

BACKGROUND: Hepatic encephalopathy (HE) is closely associated with inflammatory responses. However, as a crucial regulator of the immune and inflammatory responses, the role of leucine-rich repeat kinase 2 (LRRK2) in the pathogenesis of HE remains unraveled. Herein, we investigated this issue in thioacetamide (TAA)-induced HE following acute liver failure (ALF). METHODS: TAA-induced HE mouse models of LRRK2 wild type (WT), LRRK2 G2019S mutation (Lrrk2G2019S) and LRRK2 knockout (Lrrk2-/-) were established. A battery of neurobehavioral experiments was conducted. The biochemical indexes and pro-inflammatory cytokines were detected. The prefrontal cortex (PFC), striatum (STR), hippocampus (HIP), and liver were examined by pathology and electron microscopy. The changes of autophagy-lysosomal pathway and activity of critical Rab GTPases were analyzed. RESULTS: The Lrrk2-/--HE model reported a significantly lower survival rate than the other two models (24% vs. 48%, respectively, p < 0.05), with no difference found between the WT-HE and Lrrk2G2019S-HE groups. Compared with the other groups, after the TAA injection, the Lrrk2-/- group displayed a significant increase in ammonium and pro-inflammatory cytokines, aggravated hepatic inflammation/necrosis, decreased autophagy, and abnormal phosphorylation of lysosomal Rab10. All three models reported microglial activation, neuronal loss, disordered vesicle transmission, and damaged myelin structure. The Lrrk2-/--HE mice presented no severer neuronal injury than the other genotypes. CONCLUSIONS: LRRK2 deficiency may exacerbate TAA-induced ALF and HE in mice, in which inflammatory response is evident in the brain and aggravated in the liver. These novel findings indicate a need of sufficient clinical awareness of the adverse effects of LRRK2 inhibitors on the liver.

Minimal hepatic encephalopathy is associated with a higher risk of overt hepatic encephalopathy and poorer survival.

BACKGROUND AND AIMS: Minimal hepatic encephalopathy (MHE) is a frequent complication in patients with liver cirrhosis. Its impact on predicting the development of overt hepatic encephalopathy (OHE) and survival has not been studied in large multicenter studies. METHODS: Data from patients recruited at eight centers across Europe and the United States were analyzed. MHE was detected using the psychometric hepatic encephalopathy score (PHES). A subset was also tested with the simplified animal naming test (S-ANT1). Patients were followed for OHE development and death/liver transplantation (LTx). RESULTS: A total of 1462 patients with a median model of end-stage liver disease of 11 were included (Child-Pugh (CP) stages: A 47%/B 41%/C 12%). Median follow-up time was 19 months, during which 336 (23%) patients developed an OHE episode and 464 (32%) reached the composite end point of death/LTx (369 deaths, 95 LTx). In multivariable analyses, MHE (defined by PHES) was associated with the development of OHE (subdistribution hazard ratio 1.74, p < 0.001) and poorer LTx-free survival (hazard ratio 1.53, p < 0.001) in the total cohort as well as in the subgroup of patients without a history of OHE. In subgroup analyses, MHE (defined by PHES) was associated with OHE development in patients with CP B, whereas there was no association in patients with CP A or C. In the subgroup of patients with available S-ANT1, MHE (defined by S-ANT1) was independently associated with OHE development. Combined testing (PHES+S-ANT1) was superior to single testing for predicting OHE and poorer LTx-free survival. CONCLUSIONS: This large multicenter study demonstrates that screening for MHE is a useful tool for predicting OHE and poorer survival.

Excessive intragastric alcohol administration exacerbates hepatic encephalopathy and provokes neuronal cell death in male rats with chronic liver disease.

Hepatic encephalopathy (HE) is defined as decline in neurological function during chronic liver disease (CLD). Alcohol is a major etiological factor in the pathogenesis of fibrosis/cirrhosis and has also been documented to directly impact the brain. However, the role of alcohol in the development of HE in CLD remains unclear. Here, we investigated the impact of excessive alcohol administration on neurological deterioration in rats with CLD. Starting day 7 post-BDL surgery, rats were administered alcohol twice daily (51% v/v ethanol, 3 g/kg, via gavage) for 4 weeks. Motor coordination was assessed weekly using rotarod and anxiety-like behavior was evaluated with open field and elevated plus maze at 5 weeks. Upon sacrifice, brains were collected for western blot and immunohistochemical analyses to investigate neuronal integrity and oxidative stress status. Alcohol worsened motor coordination performance and increased anxiety-like behavior in BDL rats. Impairments were associated with decreased neuronal markers of NeuN and SMI311, increased apoptotic markers of cleaved/pro-caspase-3 and Bax/Bcl2, increased necroptosis markers of pRIP3 and pMLKL, decreased total antioxidant capacity (TAC), and increased 4-hydroxynonenal (4-HNE)modified proteins in the cerebellum of BDL-alcohol rats when compared to respective controls. Immunofluorescence confirmed the colocalization of cleaved caspase-3 and pMLKL in the granular neurons of the cerebellum of BDL-alcohol rats. Excessive alcohol consumption exacerbates HE which leads to associated apoptotic and necroptotic neuronal loss in the cerebellum of BDL-alcohol rats. Additionally, higher levels of 4-HNE and decreased TAC in the cerebellum of BDL-alcohol rats suggest oxidative stress is the triggering factor of apoptotic and necroptotic neuronal loss/injury.

Improved cognition after rifaximin treatment is associated with changes in intra- and inter-brain network functional connectivity.

BACKGROUND: Rifaximin is a non-reabsorbable antibiotic which acts at gut level, and improves cognition and inflammatory parameters in minimal hepatic encephalopathy (MHE) patients, but not all patients show the same level of response. This study aims to assess brain activity, both within and between brain networks, following rifaximin treatment, considering the differences between response groups as well. METHODS: Twenty-two healthy controls and 53 patients with cirrhosis (22 without and 31 with MHE, diagnosed by Psychometric Hepatic Encephalopathy Score, PHES) performed psychometric, attention and coordination tests, and blood inflammatory parameters were measured. Resting-state functional magnetic resonance imaging (fMRI) acquisitions were performed on controls and MHE patients. Eighteen MHE patients underwent a rifaximin treatment for 6 months, after which all measures were repeated. fMRI images were analysed and changes after treatment were assessed. RESULTS: After rifaximin treatment, 13 patients improved their PHES score (Responder patients) while 5 did not (Non-responder patients). No significant decrease in blood ammonia was observed after rifaximin treatment, but there was a decrease in plasma inflammatory cytokines in responder patients. A global effect of rifaximin was detected on the sensorimotor and fronto-parietal networks. Responder patients showed a relative increase of thalamic network connectivity in comparison to non-responder patients. Before treatment, responder and non-responder patients showed connectivity differences in basal ganglia network. The connection of the sensorimotor and thalamic networks between them and with other networks suffered changes after treatment. These connections between networks mostly decreased after treatment. All changes and differences showed a significant level of correlation with the performance of psychometric tests and the blood levels of inflammatory biomarkers. CONCLUSIONS: There was an improvement of the communication between executive, motor and attention-related brain areas, and their functional independence following rifaximin treatment. Patients who respond also show a less deteriorated connection involved in these functions before treatment. Results suggest that the improved inflammatory state of MHE patients, following rifaximin treatment would favour the observed changes in brain function and enhanced cognitive performance.

Lactulose therapy for patients with cirrhosis, portal hypertension, and poor patient-reported outcomes: The Mi-Kristal trial.

BACKGROUND AND AIMS: Poor patient-reported outcomes (PROs) are common in cirrhosis, including poor sleep and health-related quality of life (HRQOL). HE is a major driver of poor PROs. Many clinicians initiate lactulose therapy to address poor PROs. PRO-triggered therapy, however, has not been studied till date. METHODS: We conducted a 28-day randomized trial of crystalline lactulose therapy (20 g BID) compared with no HE-directed therapy in 52 patients with cirrhosis, portal hypertension, no prior HE, and high Work Productivity and Activity Impairment scores (0-10) attributed to cirrhosis. The primary outcome was change in global HRQOL measured with Short Form-8 Health Survey. Secondary outcomes included change in Animal Naming Test score, Work Productivity and Activity Impairment, and sleep quality (scored "very bad" to "very good"). APPROACH AND RESULTS: Overall, 52 patients underwent randomization; 3 subjects withdrew from the crystalline lactulose arm (1 before medication initiation, 1 due to an unrelated condition, and 1 due to high baseline bowel movements). The average age was 60 years, the average Model for Endstage Liver Disease-Sodium score was 10.5, and 56% of the patients had ascites. Baseline bowel movements were 2.3/day, with 35% of the patients having Bristol Stool Scale >4. At 28 days, there was no improvement in HRQOL: patients receiving crystalline lactulose had an 8.1-point (95% CI: 3.7-12.4) increase compared with 6.6 (95% CI: 2.3-10.8) in the control group ( p = 0.6). Lactulose was associated with a significantly ( p = 0.002) increased Animal Naming Test score (3.7, 95% CI: 2.1-5.4) versus the control group (0.2, 95% CI: -1.7, 1.4). Lactulose users reported more good sleep (92% vs. 52%, p = 0.001) and lower activity impairment (3.0 vs. 4.8, p = 0.02). CONCLUSIONS: Lactulose improves sleep and activity impairment in patients with poor PROs. We did not observe any improvement in global HRQOL after 28 days using the Short Form-8 Health Survey instrument.

Quantifying days at home in patients with cirrhosis: A national cohort study.

BACKGROUND AND AIMS: Days at home (DAH) is a patient-centric metric developed by the Medicare Payment Advisory Commission, capturing annual health care use, including and beyond hospitalizations and mortality. We quantified DAH and assessed factors associated with DAH differences among patients with cirrhosis. APPROACH AND RESULTS: Using a national claims database (Optum) between 2014 and 2018, we calculated DAH (365 minus mortality, inpatient, observation, postacute, and emergency department days). Among 20,776,597 patients, 63,477 had cirrhosis (median age, 66, 52% males, and 63% non-Hispanic White). Age-adjusted mean DAH for cirrhosis was 335.1 days (95% CI: 335.0 to 335.2) vs 360.1 (95% CI: 360.1 to 360.1) without cirrhosis. In mixed-effects linear regression, adjusted for demographic and clinical characteristics, patients with decompensated cirrhosis spent 15.2 days (95% CI: 14.4 to 15.8) in postacute, emergency, and observation settings and 13.8 days (95% CI: 13.5 to 14.0) hospitalized. Hepatic encephalopathy (-29.2 d, 95% CI: -30.4 to -28.0), ascites (-34.6 d, 95% CI: -35.3 to -33.9), and combined ascites and hepatic encephalopathy (-63.8 d, 95% CI: -65.0 to -62.6) were associated with decreased DAH. Variceal bleeding was not associated with a change in DAH (-0.2 d, 95% CI: -1.6 to +1.1). Among hospitalized patients, during the 365 days after index hospitalization, patients with cirrhosis had fewer age-adjusted DAH (272.8 d, 95% CI: 271.5 to 274.1) than congestive heart failure (288.0 d, 95% CI: 287.7 to 288.3) and chronic obstructive pulmonary disease (296.6 d, 95% CI: 296.3 to 297.0). CONCLUSIONS: In this national study, we found that patients with cirrhosis spend as many, if not more, cumulative days receiving postacute, emergency, and observational care, as hospitalized care. Ultimately, up to 2 months of DAH are lost annually with the onset of liver decompensation. DAH may be a useful metric for patients and health systems alike.

The role of transjugular intrahepatic portosystemic shunt in patients with cirrhosis and ascites: Recent evolution and open questions.

In selected patients with cirrhosis and ascites, transjugular intrahepatic portosystemic shunt (TIPS) placement improves control of ascites and may reduce mortality. In this review, we summarize the current knowledge concerning the use of TIPS for the treatment of ascites in patients with cirrhosis, from pathophysiology of ascites formation to hemodynamic consequences, patient selection, and technical issues of TIPS insertion. The combination of these factors is important to guide clinical decision-making and identify the best strategy for each individual patient. There is still a need to identify the best timing for TIPS placement in the natural history of ascites (recurrent vs. refractory) as well as which type and level of renal dysfunction is acceptable when TIPS is proposed for the treatment of ascites in cirrhosis. Future studies are needed to define the optimal stent diameter according to patient characteristics and individual risk of shunt-related side effects, particularly hepatic encephalopathy and insufficient cardiac response to hemodynamic consequences of TIPS insertion.

Predictors of clinical trajectories of patients with acutely decompensated cirrhosis. An external validation of the PREDICT study.

BACKGROUND AND AIMS: The PREDICT study recently showed that acutely decompensated (AD) patients with cirrhosis can present three different clinical phenotypes in the 90 days after admission: (1) pre-ACLF, developing acute-on-chronic liver failure (ACLF); (2) unstable decompensated cirrhosis (UDC), being re-admitted for AD without ACLF and (3) stable decompensated cirrhosis (SDC), not presenting readmission or ACLF. This study aimed to externally validate the existence of these three distinct trajectories and to identify predictors for the occurrence of each trajectory. METHODS: Baseline data, 3-month ACLF and readmission incidence and 1-year survival were analysed in a prospective cohort of patients admitted for AD. A multinomial multivariable model was used to evaluate the association between baseline features and clinical trajectories. RESULTS: Of the 311 patients enrolled, 55% met the criteria for SDC, 18% for UDC and 27% for pre-ACLF, presenting a significantly different 1-year mortality: pre-ACLF 65%, UDC 46%, SDC 21% (p < .001). The presence of hepatic encephalopathy (HE) was associated with UDC (p = .043), while the absence of ascites to SDC (p = .017). Among laboratory parameters, an increase in MELD-Na (p = .001) and C-reactive protein (p = .009) and a decrease in haemoglobin (p = .004) and albumin (p = .008) levels were associated with pre-ACLF. CONCLUSION: The present study confirms that AD patients have three different clinical trajectories with different mortality rates. Besides the severity of cirrhosis, the association with C-reactive protein supports the predominant role of systemic inflammation in ACLF pathophysiology. Finally, HE is associated with the UDC phenotype highlighting the need for better management of this complication after discharge.

Severe hepatic encephalopathy with mechanical ventilation may inform waitlist priority in acute liver failure: A UNOS database analysis.

BACKGROUND & AIMS: Patients with acute liver failure (ALF) awaiting liver transplantation (LT) may develop multiorgan failure, but organ failure does not impact waitlist prioritization. The aim of this study was to examine the impact of organ failure on waitlist mortality risk and post LT outcomes in patients with ALF. METHODS: We studied adults waitlisted for ALF in the United Network for Organ Sharing (UNOS) database (2002-2019). Organ failures were defined using a previously described Chronic Liver Failure modified sequential organ failure score assessment adapted to UNOS data. Regression analyses of the primary endpoints, 30-day waitlist mortality (Competing risk), and post-LT mortality (Cox-proportional hazards), were performed. Latent class analysis (LCA) was used to determine the organ failures most closely associated with 30-day waitlist mortality. RESULTS: About 3212 adults with ALF were waitlisted, for hepatotoxicity (41%), viral (12%) and unspecified (36%) etiologies. The median number of organ failures was three (interquartile range 1-3). Having ≥3 organ failures (vs. ≤2) was associated with a sub hazard ratio (HR) of 2.7 (95%CI 2.2-3.4)) and a HR of 1.5 (95%CI 1.1-2.5)) for waitlist and post-LT mortality, respectively. LCA identified neurologic and respiratory failure as most impactful on 30-day waitlist mortality. The odds ratios for both organ failures (vs. neither) were higher for mortality 4.5 (95% CI 3.4-5.9) and lower for delisting for spontaneous survival .5 (95%CI .4-.7) and LT .6 (95%CI .5-.7). CONCLUSION: Cumulative organ failure, especially neurologic and respiratory failure, significantly impacts waitlist and post-LT mortality in patients with ALF and may inform risk-prioritized allocation of organs.

Combined Spontaneous Portosystemic Shunt Embolization and Transjugular Intrahepatic Portosystemic Shunt Creation for Treatment of Hepatic Encephalopathy.

This retrospective case series assessed the early effectiveness of combined spontaneous portosystemic shunt (SPSS) embolization and preemptive transjugular intrahepatic portosystemic shunt (TIPS) creation for alleviation of medically refractory hepatic encephalopathy (HE) and prevention of portal hypertension complications in patients with liver cirrhosis. Eight patients with liver cirrhosis (5 men and 3 women; mean age, 61 years [SD ± 10]) and HE (overt [West-Haven Grade 2-4], n = 7; covert [West-Haven Grade 1], n = 1) refractory to lactulose and rifaximin therapy who underwent concurrent or staged SPSS embolization and TIPS creation between 2018 and 2022 were included in this study. The primary outcomes were 3-month improvement in HE and postprocedural HE-related hospitalizations. HE improvement was achieved in 7 (87.5%) of 8 cases. Among all patients, there was 1 HE-related hospitalization within 90 days that responded to repeat embolization with no further admissions. No patients developed new ascites, variceal hemorrhage, or other portal hypertension complications within 3 months.