Prior Overt Hepatic Encephalopathy Research Articles

Medically Tailored Meals for Patients With Cirrhosis and Hepatic Encephalopathy: The BRAINFOOD Proof-of-concept Trial

Background and AimsGuidelines recommend that patients with Hepatic Encephalopathy (HE) receive a high-protein diet (roughly 1 g/kg actual body weight). Concommitant sodium restriction, low health literacy, and food insecurity limit patients’ ability to meet this goal. We aimed to determine the feasibility of home-delivered high protein medically tailored meals (MTM) for patients with a recent episode of overt HE. MethodWe enrolled patients with prior overt HE on active HE therapy in a 6 month trial of MTM. All received 12 weeks of 21 home-delivered meals/week with protein snacks (mid-day and bedtime). Patients completed follow-up at week 24. The primary outcome was feasibility. Additional outcomes included change in protein and micronutrient intake (measured using 24-hour dietary recalls performed by dieticians), cognitive function (animal naming test, ANT; encephalapp stroop), physical function (liver frailty index, LFI), and quality of life (SF-8). Healthcare utilization was also assessed. Results10 patients competed the study with >90% of MTM consumed. Protein intake rose from 74.6+25.1g at baseline to 93.8+24.3g on MTM (p=0.04). Branched-chain amino acids also increased – valine 3.73+1.26g to 5.17+1.28, isoleucine 3.32+1.18 to 4.69+1.55, leucine 5.83+2.00 to 7.49+2.07, all p<0.001. LFI improved from 4.42±0.32 to 3.96±0.82 by the end of the MTM phase (p=0.03). SF-8 quality of life scores improved from 55.5±15.5 at baseline to 64.7±18.3 after the MTM phase, to 64.4±19.1 at the end of the study (p=0.1). EncephalApp-Stroop time improved from 227±94 to 194±58s by the end of the MTM phase (p=0.08). ANT scores were similarly non-significantly improved. ConclusionHome delivered MTM are feasible, increase protein consumption, and may improve patient well-being. A randomized trial is needed.

From the Editor’s Desk...

From the Editor’s Desk...

Liver-Unrelated Comorbid Conditions Do Not Affect Cognitive Performance or Hepatic Encephalopathy Progression in Cirrhosis.

We aimed to determine the effect of comorbidities on covert hepatic encephalopathy (CHE) diagnosis and overt hepatic encephalopathy (OHE) development. Cirrhotic outpatients underwent CHE testing and 2-year follow-up. Cox regression was performed for time to OHE. In total, 700 patients (60 years, 84% men, model for end-stage liver disease 11) and 33% prior OHE underwent testing and follow-up. Major comorbidities were hypertension (54%), diabetes (35%), and depression (29%). Common medications were proton pump inhibitor (49%), beta-blockers (32%), and opioids (21%). Approximately 90 (40%) prior-OHE patients developed recurrence 93 (30,206) days post-testing predicted only by liverrelated variables. Demographics, cirrhosis characteristics, and opioid use, but not other comorbid conditions, were associated with CHE diagnosis and OHE progression.

Usefulness of the Stroop Test in Diagnosing Minimal Hepatic Encephalopathy and Predicting Overt Hepatic Encephalopathy.

Minimal hepatic encephalopathy (MHE) adversely affects the clinical outcomes of patients with liver cirrhosis. This prospective study aimed to evaluate the utility of the Stroop test in the diagnosis of MHE and prediction of overt hepatic encephalopathy (OHE) in Japanese patients with cirrhosis. We enrolled 152 patients who underwent the Stroop test between November 2018 and February 2020. MHE was diagnosed using a combination of neuropsychological tests as the gold standard. The enrolled patients were followed up prospectively until the occurrence of OHE or August 2020. The optimal cutoff value of the Stroop test measurements was determined by receiver operating characteristic (ROC) curve analysis, and its predictive ability was assessed using the area under the ROC curve (AUC). Among the 139 eligible patients, 50 (36%) were diagnosed with MHE. The OffTime+OnTime cutoff value of 218.3 seconds had the best discriminative ability for MHE diagnosis, with an AUC of 0.77, a sensitivity of 74%, and a specificity of 75%. During a median follow‐up of 10.8 months, 6 (4%) patients developed OHE. The OffTime+OnTime cutoff value of 305.6 seconds had the highest predictive ability for OHE, with an AUC of 0.79, a sensitivity of 67%, and a specificity of 92%. This value predicted OHE occurrence independent of liver functional reserve and prior OHE (hazard ratio, 19.8; P = 0.003). These two cutoff values remained statistically significant even when patients with prior OHE were excluded from the analysis. Conclusion: The Stroop test was useful for diagnosing patients with MHE and predicting OHE in Japanese patients with cirrhosis.

Bowel Movement Frequency Is Not Linked With Cognitive Function in Cirrhosis

The spectrum of hepatic encephalopathy (HE) ranges from overt HE (OHE) to cognitive impairment (ie, covert) HE (CHE).1 The first-line therapy is lactulose, which is titrated to achieve ~2-3 soft/loose daily bowel movements (BM). This metric is considered dogma for practitioners despite erratic results, GI adverse events, and poor tolerance in Western countries.1 There are logistic barriers for the widespread uptake of rifaximin, the second-line therapy. Moreover, although BM frequency-directed dose titration of lactulose is the usual practice, its impact on objective cognitive performance is unclear. Our aim is to determine the impact of BM frequency on cognition in patients with/without prior OHE.

Raised serum Interleukin-6 identifies patients with liver cirrhosis at high risk for overt hepatic encephalopathy.

Systemic inflammation is a driving force for the development of hepatic encephalopathy and recent studies demonstrated that elevated Interleukin-6 (IL-6) serum levels are associated with the presence of minimal hepatic encephalopathy in patients with liver cirrhosis. To test the hypothesis that IL-6 is a suitable marker to identify patients with liver cirrhosis at high risk for the development of overt hepatic encephalopathy. 201 patients were included into this prospective cohort study and were followed for a mean time of 322days. Covert hepatic encephalopathy was diagnosed according to the West-Haven criteria (hepatic encephalopathy grade 1) and with the portosystemic encephalopathy (PSE) test. The cumulative incidence of overt hepatic encephalopathy was higher in patients with IL-6 levels above the median of 9pg/mL than in patients with IL-6 levels at or below the median (35.6% vs 1.9%, P<.001). After adjustment for covert hepatic encephalopathy, history of overt hepatic encephalopathy, C-reactive protein (CRP) and model for end-stage liver disease (MELD), IL-6 levels above the median remained independently associated with the development of overt hepatic encephalopathy. The predictive performance of IL-6 regarding the development of overt hepatic encephalopathy during the next 180days (AUROC, 0.931) was numerically higher than that of MELD (AUROC, 0.841) or CRP (AUROC, 0.835). In patients without prior overt hepatic encephalopathy, the predictive performance of IL-6 (AUROC, 0.966) was even significantly higher than that of MELD (AUROC 0.843) or CRP (AUROC 0.850). The ideal cut-off for IL-6 in this setting was 23.5pg/mL with a sensitivity and specificity of 89.3% and 89.5% respectively. IL-6 serum levels are closely linked to the development of overt hepatic encephalopathy in patients with liver cirrhosis.

Diagnosis of covert hepatic encephalopathy: a multi-center study testing the utility of single versus combined testing.

Covert hepatic encephalopathy (CHE) affects cognition in a multidimensional fashion. Current guidelines recommend performing Psychometric Hepatic Encephalopathy Score (PHES) and a second test to diagnose CHE for multi-center trials. We aimed to determine if a two-test combination strategy improved CHE diagnosis agreement, and accuracy to predict overt hepatic encephalopathy (OHE), compared to single testing. Cirrhotic outpatients without baseline OHE performed PHES, Inhibitory Control Test (ICT), and Stroop EncephAlapp (StE) at three centers. Patients were followed for OHE development. Areas under the receiver operation characteristic curve (AUROC) were calculated. We included 437 patients (399 with follow-up data). CHE prevalence varied with testing strategy: PHES+ICT 18%, ICT + StE 25%, PHES+StE 29%, ICT 35%, PHES 37%, and StE 54%. Combination with best test agreement was PHES+StE (k = 0.34). Sixty patients (15%) developed OHE. Although CHE by StE showed the highest sensitivity to predict OHE, PHES and PHES+StE were more accurate at the expense of a lower sensitivity (55%, AUROC: 0.587; 36%, AUROC: 0.629; and 29%, AUROC: 0.623; respectively). PHES+ICT was the most specific (85%) but all strategies including ICT showed sensitivities in the 33-45% range. CHE diagnosis by PHES (HR = 1.79, p= 0.04), StE (HR = 1.69, p= 0.04), and PHES+StE (HR = 1.72, p= 0.04), were significant OHE predictors even when adjusted for prior OHE and MELD. Our results demonstrate that combined testing decreases CHE prevalence without improving the accuracy of OHE prediction. Testing with PHES or StE alone, or a PHES+StE combination, is equivalent to diagnose CHE and predict OHE development in a multi-center setting.

Aberrant topological organization of the functional brain network associated with prior overt hepatic encephalopathy in cirrhotic patients.

A higher risk of cognitive impairments has been found after an overt hepatic encephalopathy (OHE) episode in cirrhotic patients. We investigated the effect of prior OHE episodes on the topological organization of the functional brain network and its association with the relevant cognitive impairments. Resting-state functional MRI data were acquired from 41 cirrhotic patients (19 with prior OHE (Prior-OHE) and 22 without (Non-Prior-OHE)) and 21 healthy controls (HC). A Psychometric Hepatic Encephalopathy Score (PHES) assessed cognition. The whole-brain functional network was constructed by thresholding functional correlation matrices of 90 brain regions (derived from the Automated Anatomic Labeling atlas). The topological properties of the brain network, including small-worldness, network efficiency, and nodal efficiency, were examined using graph theory-based analysis. Globally, the Prior-OHE group had a significantly decreased clustering coefficient and local efficiency, compared with the controls. Locally, the nodal efficiency in the bilateral medial superior frontal gyrus and the right postcentral gyrus decreased in the Prior-OHE group, while the nodal efficiency in the bilateral anterior cingulate/paracingulate gyri and right superior parietal gyrus increased in the Prior-OHE group. The alterations of global and regional network parameters progressed from Non-Prior-OHE to Prior-OHE and the clustering coefficient and local efficiency values were significantly correlated with PHES results. In conclusion, cirrhosis leads to the reduction of brain functional network efficiency, which could be aggravated by a prior OHE episode. Aberrant topological organization of the functional brain network may contribute to a higher risk of cognitive impairments in Prior-OHE patients.

Overt hepatic encephalopathy impairs learning on the EncephalApp stroop which is reversible after liver transplantation.

After an initial exposure, patients can develop test-taking/learning strategies called the "test sophistication effect." Patients with cirrhosis with prior overt hepatic encephalopathy (OHE) could have persistent learning impairments. The aim was to define learning/test sophistication on EncephalApp (downloadable application) in OHE patients compared with patients without prior overt hepatic encephalopathy (no-OHE) patients and controls cross-sectionally and longitudinally. The EncephalApp Stroop App consists of 2 sections: the easier "Off" run assesses psychomotor speed while the difficult "On" run assesses cognitive flexibility. For the cross-sectional analysis, outpatients with cirrhosis with/without controlled OHE and healthy controls underwent EncephalApp testing, which requires 5 Off and 5 On runs. We studied the difference in time required between completing trial 1 compared with trial 5 (delta 1-5) in both the On and Off runs in controls, all patients with cirrhosis, and between prior OHE/no-OHE patients with cirrhosis. For the longitudinal analyses, 2 groups of patients with cirrhosis were studied; 1 was administered the EncephalApp ≥ 2 weeks apart, and the second was administered before and 6 months after liver transplantation. The study included 89 controls and 230 patients with cirrhosis (85 prior OHE; Model for End-Stage Liver Disease, 11) with similar age (64 versus 61 years; P = 0.92). Patients with cirrhosis had impaired EncephalApp total times and impaired learning on the On runs compared with controls. OHE patients had worse EncephalApp times and learning with the On runs compared with no-OHE patients, which persisted in the longitudinal cohort. No differences in learning were seen in the Off runs. After transplant, there was restoration of learning capability with the On runs in the OHE patients. In conclusion, cognitive flexibility tested by the EncephalApp On runs improves over time in healthy controls and no-OHE but not prior OHE. Psychomotor speed remains similar over time. The learning impairment manifested by patients with cirrhosis with OHE is restored after transplant. Liver Transplantation 23 1396-1403 2017 AASLD.

Disrupted topological organization of brain structural network associated with prior overt hepatic encephalopathy in cirrhotic patients.

To investigate structural brain connectome alterations in cirrhotic patients with prior overt hepatic encephalopathy (OHE). Seventeen cirrhotic patients with prior OHE (prior-OHE), 18 cirrhotic patients without prior OHE (non-prior-OHE) and 18 healthy controls (HC) underwent diffusion tensor imaging. Neurocognitive functioning was assessed with Psychometric Hepatic Encephalopathy Score (PHES). Using a probabilistic fibre tracking approach, we depicted the whole-brain structural network as a connectivity matrix of 90 regions (derived from the Automated Anatomic Labeling atlas). Graph theory-based analyses were performed to analyse topological properties of the brain network. The analysis of variance showed significant group effects on several topological properties, including network strength, global efficiency and local efficiency. A progressive decrease trend for these metrics was found from non-prior-OHE to prior-OHE, compared with HC. Among the three groups, the regions with altered nodal efficiency were mainly distributed in the frontal and occipital cortices, paralimbic system and subcortical regions. The topological metrics, such as network strength and global efficiency, were correlated with PHES among cirrhotic patients. The cirrhotic patients developed structural brain connectome alterations; this is aggravated by prior OHE episode. Disrupted topological organization of the brain structural network may account for cognitive impairments related to prior OHE. • Altered structural brain connectome is found in cirrhotic patients. • Structural brain connectome alterations could be aggravated by prior-OHE episode. • Altered structural brain connectome may account for cognitive impairments associated with prior OHE.

A Meta-analysis on the Role of Probiotics in the Prevention of Overt Hepatic Encephalopathy

Overt hepatic encephalopathy (OHE) is a strong predictor of subsequent episodes of OHE, hospitalizations and mortality. Latest practice guidelines have yet to recommend any treatment for the primary prophylaxis of OHE. Lactulose has been the mainstay of treatment only for secondary prophylaxis, but its use suffers from side effects. Probiotics in recent trials have been found to be effective in preventing the occurrence of OHE without the side effects associated with lactulose. Comprehensive literature search of PubMed, Cochrane Central Register of Controlled Trials, EMBASE and reference lists was done. Studies on adults with liver cirrhosis, without OHE at the time of enrollment, with at least 1 month follow-up period, were included. The authors independently reviewed each included trial. Quality of included studies was assessed using the Cochrane Collaboration’s tool for evaluating risk of bias. Seven studies were included in the meta-analysis. Probiotics significantly reduced the development of OHE (RR (CI 95%): 0.49[0.37,0.65], P<0.00001), regardless of history of prior OHE. As primary prophylaxis and secondary prophylaxis, probiotics significantly reduced the development of OHE (Primary: RR (CI 95%): 0.52[0.28,0.95], P=0.03; Secondary: RR (95% CI): 0.64[0.48,0.85], P=0.002). Probiotics did not provide any mortality benefit, whether given as primary or secondary prophylaxis (Overall: RR (CI 95%): 0.79[0.53,1.19], P=0.26; Primary: RR (CI 95%): 0.80[0.30,2.14], P=0.67; Secondary: RR (CI 95%): 0.77[0.49,1.23], P=0.68). Probiotics, whether as primary or secondary prophylaxis, are effective in preventing OHE in patients with liver cirrhosis. Role of probiotics in reducing mortality is still uncertain. Studies with larger sample sizes and longer duration are recommended.

Cost-effectiveness analysis of rifaximin-α administration for the reduction of episodes of overt hepatic encephalopathy in recurrence compared with standard treatment in France.

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome that occurs most often in a context of acute or chronic liver disease. Despite the seriousness of the pathology, only a few treatments have been developed for improving its management. Rifaximin-α is the first treatment that has been clinically developed for overt HE (OHE) episodes. Recent results of clinical studies demonstrated its significant improvement in the health-related quality of life. The objective of the current study was to estimate the long-term cost-effectiveness of rifaximin-α used in combination with lactulose compared with lactulose monotherapy in cirrhotic patients, who have experienced at least two prior OHE events. A Markov model was used to estimate rifaximin-α cost-effectiveness, evaluating it from the perspective of all contributors as recommended by French health technology assessment guidelines. Costs were based on current French treatment practices. The transition between health states was based on the reanalysis of the rifaximin-α pivotal clinical trials RFHE3001 and RFHE3002. The main outcome of the model was cost per quality adjusted life year (QALY). The results indicate that rifaximin-α is a cost-effective treatment option with an incremental cost per QALY gained of €19,187 and €18,517 over two different time horizons (2 and 5 years). The robustness of the model was studied using probabilistic sensitivity analysis. For the societal willingness to pay threshold of €27,000 per QALY gained, rifaximin-α in combination with lactulose is a cost-effective and affordable treatment for patients who have experienced at least two prior overt HE episodes.

Diagnosis of Minimal Hepatic Encephalopathy Using Stroop EncephalApp: A Multicenter US-Based, Norm-Based Study.

Diagnosing minimal hepatic encephalopathy (MHE) is challenging, and point-of-care tests are needed. Stroop EncephalApp has been validated for MHE diagnosis in single-center studies. The objective of the study was to validate EncephalApp for MHE diagnosis in a multicenter study. Outpatient cirrhotics (with/without prior overt hepatic encephalopathy (OHE)) and controls from three sites (Virginia (VA), Ohio (OH), and Arkansas (AR)) underwent EncephalApp and two gold standards, psychometric hepatic encephalopathy score (PHES) and inhibitory control test (ICT). Age-/gender-/education-adjusted values for EncephalApp based on direct norms, and based on ICT and PHES, were defined. Patients were followed, and EncephalApp cutoff points were used to determine OHE prediction. These cutoff points were then used in a separate VA-based validation cohort. A total of 437 cirrhotics (230 VA, 107 OH, 100 AR, 36% OHE, model for end-stage liver disease (MELD) score 11) and 308 controls (103 VA, 100 OH, 105 AR) were included. Using adjusted variables, MHE was present using EncephalApp based on norms in 51%, EncephalApp based on PHES in 37% (sensitivity 80%), and EncephalApp based on ICT in 54% of patients (sensitivity 70%). There was modest/good agreement between sites on EncephalApp MHE diagnosis using the three methods. OHE developed in 13% of patients, which was predicted by EncephalApp independent of the MELD score. In the validation cohort of 121 VA cirrhotics, EncephalApp directly and based on gold standards remained consistent for MHE diagnosis with >70% sensitivity. In this multicenter study, EncephalApp, using adjusted population norms or in the context of existing gold standard tests, had good sensitivity for MHE diagnosis and predictive capability for OHE development.

Cognitive impairment and electroencephalographic alterations before and after liver transplantation: what is reversible?

The influence of liver transplantation (LT) on mental performance is debated, as is the role of pretransplant overt hepatic encephalopathy (OHE). The aim of this study was to evaluate the time course of the neuropsychological and electroencephalogram (EEG) features of patients with cirrhosis before and after LT with respect to prior OHE. The study population included 65 patients with cirrhosis on the transplant waiting list; 23 had a history of OHE. Each patient underwent an extensive psychometric assessment (10 tests, including paper and pencil tests and a computerized test) and an EEG before and 9 to 12 months after LT. For a subgroup of 11 patients, the assessment was also performed 3 and 6 months after LT. EEGs were analyzed spectrally, and the mean dominant frequencies were obtained. Both psychometric tests and EEGs improved 9 to 12 months after LT. Patients with a history of OHE before LT had worse cognitive performances (P < 0.001) and EEG performances in comparison with their counterparts with a negative history. They also showed greater cognitive improvement after LT (P < 0.01); however, their global cognitive performance remained slightly impaired (P < 0.01). After LT, EEGs normalized for 98% of the patients (P < 0.01), regardless of any history of OHE. In the subgroup of patients evaluated every 3 months, psychometric and EEG findings showed deterioration at 3 months and subsequently steady improvements from 6 months onward. In conclusion, both neuropsychological and EEG performances had significantly improved 1 year after LT. Patients with a history of OHE showed greater improvements after LT than patients with a negative history, but their global cognitive function remained slightly worse; in contrast, EEGs normalized in both groups.

Mo1022 Effect of Body Mass Index (BMI) on Functional Status of Patients With Cirrhosis Based on the Six-Minute Walk Test (6mwt)

Background & Aims: Hepatic encephalopathy (HE) represents a spectrum of neurocognitive impairment seen in cirrhotic patients and is considered to be fully reversible with treatment, however recent evidence suggests otherwise. This longitudinal study was carried out to evaluate the persistence of cognitive impairment in cirrhotics with prior overt HE (OHE) episode despite treatment. Methods: Of 213 patients screened, 107 patients who met the eligibility criteria were enrolled and 102 patients completed the study (52 patients without prior OHE episode and 50 patients with prior OHE). Among 102 patients included in the study, 86 were men and 16 were women; 67 (65.7%) patients had alcoholic etiology and 35 (34.3%) had non-alcoholic etiology (hepatitis B virus 6 patients, hepatitis C virus 4 patients, cryptogenic 14 patients, miscellaneous 11 patients). All patients underwent psychometric hepatic encephalopathy score (PHES) evaluation at 3 separate visits (Day 1, Day 3 and between 30 and 60 days, median 34). PHES ≤5 was considered abnormal and diagnostic of minimal HE (MHE). One point improvement in PHES between first and second evaluation was considered as a measure of learning. Results: Thirty-four (33.3%) of patients with cirrhosis of liver had MHE; 20 (40%) with prior episode and 14 (26.9%) without prior episode of OHE had MHE. Patients with previous OHE episode showed learning impairment in PHES on repetition on 3rd day [Day 1, mean -3.70 (95% confidence intervals -4.71 -2.68) versus Day 3, -4.02 (-5.06-2.97); P = 0.084] as compared to patients without prior OHE episode [Day 1, -2.26 (-3.13 -1.40) versus Day 3, -0.44 (-1.24 0.35); P <0.0001] irrespective of having MHE or not. In this study, 57 patients were learners, i.e., 1point improvement in PHES (55.8%) and 45 patients were non-learners (44.2%). Univariate analysis demonstrated that Child-Turcotte-Pugh score, lactulose and/or rifaximin therapy, presence of MHE and previous OHE episode were associated with learning impairment. Multivariate analysis demonstrated that only presence of previous episode of OHE (adjusted odds ratio [95%, confidence interval; 38.398, 9.192 160.4]; p <0.0001) significantly affected learning. Conclusions: This study conclusively demonstrated learning impairment in cirrhotic patients with previous episode of OHEdespite normalmental status. Improvement in PHES on repetition can be used as a measure of learning in future studies.

Hepatic encephalopathy

Hepatic encephalopathy causes significant cognitive impairment and morbidity in patients with cirrhosis; however, hepatic encephalopathy is considered a reversible syndrome once recognized clinically. Although hepatic encephalopathy is not a single clinical entity, the pathophysiology resulting in brain dysfunction is not fully understood, although it is believed that ammonia production is an important contributing factor. The purpose of this review is to highlight studies used to test for hepatic encephalopathy and those utilizing specific new treatments. A 'STROOP' smartphone app has been developed to allow clinicians to test for covert hepatic encephalopathy (CHE). Lactulose therapy was effective for cirrhotic patients as primary prophylaxis to prevent overt hepatic encephalopathy (OHE) episodes. In patients without prior OHE, probiotics can be useful in preventing OHE. Lactulose, probiotics, L-ornithine-L-aspartate, and potassium-iron-phosphate-citrate have been studied in the treatment of CHE. Rifaximin was found to be safe and well tolerated in long-term maintenance of remission from OHE; however, compared to lactulose therapy in CHE, it is not cost-effective. Refinement in clinical management strategies for patients with cirrhosis and hepatic encephalopathy appears to continue to contribute to improved patient outcomes.

Persistence of cognitive impairment after resolution of overt hepatic encephalopathy.

Hepatic encephalopathy (HE) represents a spectrum of neurocognitive impairment seen in cirrhotic patients and is considered to be fully reversible with treatment; however, recent evidence suggests otherwise. This longitudinal study was carried out to evaluate the persistence of cognitive impairment in cirrhotics with prior overt HE (OHE) episode despite treatment. Of the 213 patients screened, 107 patients who met the eligibility criteria were enrolled and 102 patients completed the study (52 patients without prior OHE episode and 50 patients with prior OHE). All patients underwent psychometric hepatic encephalopathy score (PHES) evaluation at three separate visits (day 1, day 3, and between 30 and 60 days). A one-point improvement in PHES between the first and second evaluation was considered as a measure of learning. Patients with a previous OHE episode showed learning impairment in PHES on repetition on day 3 (P=0.084), whereas patients without a previous OHE episode demonstrated learning effect (P<0.0001) irrespective of whether they had minimal HE (MHE) or not. Univariate analysis demonstrated that Child-Turcotte-Pugh score, lactulose and/or rifaximin therapy, the presence of MHE, and a previous OHE episode were associated with learning impairment. Multivariate analysis demonstrated that only the presence of a previous episode of OHE (adjusted odds ratio 38.398; 95% confidence interval 9.192-160.4; P<0.0001) significantly affected learning. This study conclusively demonstrated learning impairment in cirrhotic patients with a previous episode of OHE despite normal mental status. Improvement in PHES on repetition may be a measure of learning.

Persistence of Cognitive Impairment After Resolution of Overt Hepatic Encephalopathy

Background and Objectives: Hepatic encephalopathy (HE) represents a spectrum of neurocognitive impairment seen in cirrhotic patients and is considered to be fully reversible with treatment, however recent evidence suggests otherwise. This longitudinal study was carried out to evaluate the persistence of cognitive impairment in cirrhotics with prior overt HE (OHE) episode despite treatment.

Cognitive Dysfunction Is Associated With Poor Socioeconomic Status in Patients With Cirrhosis: An International Multicenter Study

In patients with cirrhosis, cognitive dysfunction most often results from covert hepatic encephalopathy (HE). These patients are not tested routinely for cognitive dysfunction despite single-center evidence that it could be associated with poor socioeconomic status (SES). We investigated the association between SES and cognition in a multicenter study of cirrhosis. In a cross-sectional study, 236 cirrhotic patients from 3 centers (84 subjects from Virginia, 102from Ohio, and 50 from Rome, Italy; age 57.7 ± 8.6 y; 14% with prior overt HE) were given recommended cognitive tests and a validated SES questionnaire that included questions about employment, personal and family income, and overall financial security. Comparisons were made among centers and between subjects who were employed or not. Regression analysis was performed using employment and personal income as outcomes. Only 37% of subjects had been employed in the past year. Subjects had substantial financial insecurity-their yearly personal income ranged from $16,000 to $24,999, and their family income ranged from $25,000 to $49,999. They would be able to maintain a residence for only 3 to 6 months if their income stopped, and their current liquid assets were $500 to $4999 (<$500 if debt was subtracted). Cognition and SES were worst in Ohio and best in Virginia. Cognition correlated with personal and family income, within and between centers. On regression analysis, cognitive performance (digit symbol, lures, and line tracing) was associated with personal yearly income, after controlling for demographics, country, employment, and overt HE. Unemployed subjects had a higher rate of overt HE, worse cognition, and lower personal income than employed subjects. On regression analysis, performance on digit symbol, line tracing, inhibitory control test lures, and serial dotting tests remained associated with employment, similar to income. In an international multicenter study of patients with cirrhosis, socioeconomic condition, based on employment and personal income, was associated strongly with cognitive performance, independent of age, education, and country.

Persistence of Cognitive Impairment After Resolution of Overt Hepatic Encephalopathy

In patients with cirrhosis, hepatic encephalopathy (HE) has acute but reversible as well as chronic components. We investigated the extent of residual cognitive impairment following clinical resolution of overt HE (OHE). Cognitive function of cirrhotic patients was evaluated using psychometric tests (digit symbol, block design, and number connection [NCT-A and B]) and the inhibitory control test (ICT). Improvement (reduction) in ICT lures and first minus second halves (DeltaL(1-2)) were used to determine learning of response inhibition. Two cross-sectional studies (A and B) compared data from stable cirrhotic patients with or without prior OHE. We then prospectively assessed cognitive performance, before and after the first episode of OHE. In study A (226 cirrhotic patients), 54 had experienced OHE, 120 had minimal HE, and 52 with no minimal HE. Despite normal mental status on lactulose after OHE, cirrhotic patients were cognitively impaired, based on results from all tests. Learning of response inhibition (DeltaL(1-2) > or =1) was evident in patients with minimal HE and no minimal HE but was lost after OHE. In study B (50 additional patients who developed > or =1 documented OHE episode during follow-up), the number of OHE hospitalizations correlated with severity of residual impairment, indicated by ICT lures (r = 0.5, P = .0001), digit symbol test (r = -0.39, P = .002), and number connection test-B (r = 0.33, P = .04). In the prospective study (59 cirrhotic patients without OHE), 15 developed OHE; ICT lure response worsened significantly after OHE (12 before vs 18 after, P = .0003), and learning of response inhibition was lost. The 44 patients who did not experience OHE did not have deteriorations in cognitive function in serial testing. In cirrhosis, episodes of OHE are associated with persistent and cumulative deficits in working memory, response inhibition, and learning.