Introduction: An early detection of low-grade hepatic encephalopathy (HE) is of high importance. The aim of the study was to compare a neuropsychological with a psychophysical test on the basis of the psychometric hepatic encephalopathy score (PHES) regarding effectiveness in diagnosing minimal HE (MHE). Methods: In our prospective controlled observational study, we examined a total of 103 patients with liver cirrhosis for HE. The PHES, CFF, and EncephalApp were performed in all patients. Graduation was based on the result of the PHES. Patients without evidence for HE 1&2 according to the mental state (West-Haven criteria) with a PHES <- 4 value points and no clinical symptoms were defined as having MHE. Patients were considered as HE0 when in the PHES none of the psychometric subtest results was abnormal or with a PHES >=- 4 value points. Patients with clinical symptoms were considered HE 1&2 patients. Different cut-off values were determined, and their specificity and sensitivity were calculated. Results: Ninety-six of the involved patients had liver cirrhosis and 25 acted as a healthy control group. The ROC analysis for the classification resulted in an AUC of 0.806, with the highest Youden index for the cut-off time > 224 s, for which the sensitivity was 82% and the specificity 75%. Cases of withdrawals were seen in 10.74% of all tested patients. Conclusion: The EncephalApp distinguishes well between HE0 and MHE but has its limitations in grading higher forms of HE. Diagnosis using only the EncephalApp is not sufficient. (c) 2024 S. Karger AG, Basel

Hepatic encephalopathy is a neuropsychiatric syndrome that occurs in patients with liver disease. This Primer discusses the epidemiology, pathophysiology, diagnosis and treatment of hepatic encephalopathy, and discusses how this disorder affects the quality of life of patients. Hepatic encephalopathy (HE) is a prognostically relevant neuropsychiatric syndrome that occurs in the course of acute or chronic liver disease. Besides ascites and variceal bleeding, it is the most serious complication of decompensated liver cirrhosis. Ammonia and inflammation are major triggers for the appearance of HE, which in patients with liver cirrhosis involves pathophysiologically low-grade cerebral oedema with oxidative/nitrosative stress, inflammation and disturbances of oscillatory networks in the brain. Severity classification and diagnostic approaches regarding mild forms of HE are still a matter of debate. Current medical treatment predominantly involves lactulose and rifaximin following rigorous treatment of so-called known HE precipitating factors. New treatments based on an improved pathophysiological understanding are emerging.

Hepatic encephalopathy (HE) is a prognostically relevant neuropsychiatric syndrome that occurs in the course of acute or chronic liver disease. Besides ascites and variceal bleeding, it is the most serious complication of decompensated liver cirrhosis. Ammonia and inflammation are major triggers for the appearance of HE, which in patients with liver cirrhosis involves pathophysiologically low-grade cerebral oedema with oxidative/nitrosative stress, inflammation and disturbances of oscillatory networks in the brain. Severity classification and diagnostic approaches regarding mild forms of HE are still a matter of debate. Current medical treatment predominantly involves lactulose and rifaximin following rigorous treatment of so-called known HE precipitating factors. New treatments based on an improved pathophysiological understanding are emerging.

BACKGROUND AND AIMS:Patients with hepatic encephalopathy (HE) show low quality of life, recurrent hospitalizations and an increased mortality. We aimed to assess the natural course of patients after a recent episode of overt HE and to identify risk factors for HE recurrence in Germany. METHODS:Fifteen sites took part in a prospective, observational study including patients with liver cirrhosis who had been hospitalized for HE within 3 months before recruitment. Clinical data, psychometric hepatic encephalopathy score (PHES) and critical flicker frequency were assessed quarterly for 1 year. Primary endpoint was HE recurrence requiring hospitalization, all-cause-mortality was treated as a competing risk factor. RESULTS:From January 2014 to March 2016, a total of 115 patients were recruited. Overall 14 premature deaths were documented. For 78 subjects follow-up data were available in accordance with the protocol. After a median of 118 days, more than half of the per-protocol cohort was readmitted to hospital due to HE (N = 34) or died (N = 11). The risk for hospitalization was significantly increased in patients who had been recruited by liver transplant centers (P = 0.003), had had frequent HE relapses prior to recruitment (P = <0.0001) or an abnormal PHES result of <-4 (P = 0.044). Abnormal PHES results barely missed level of significance as an independent risk factor for re-hospitalization in a multivariable competing risk model (P = 0.093). CONCLUSION:Patients with a history of HE are at high risk for the development of recurrent overt HE demanding hospitalization. The PHES test may aid in detection, monitoring and risk stratification of recurrent HE.

OBJECTIVE:Hepatic encephalopathy (HE) is a potentially reversible brain dysfunction caused by liver failure. Altered synaptic plasticity is supposed to play a major role in the pathophysiology of HE. Here, we used paired associative stimulation with an inter-stimulus interval of 25 ms (PAS25), a transcranial magnetic stimulation (TMS) protocol, to test synaptic plasticity of the motor cortex in patients with manifest HE.METHODS:23 HE-patients and 23 healthy controls were enrolled in the study. Motor evoked potential (MEP) amplitudes were assessed as measure for cortical excitability. Time courses of MEP amplitude changes after the PAS25 intervention were compared between both groups.RESULTS:MEP-amplitudes increased after PAS25 in the control group, indicating PAS25-induced synaptic plasticity in healthy controls, as expected. In contrast, MEP-amplitudes within the HE group did not change and were lower than in the control group, indicating no induction of plasticity.CONCLUSIONS:Our study revealed reduced synaptic plasticity of the primary motor cortex in HE.SIGNIFICANCE:Reduced synaptic plasticity in HE provides a link between pathological changes on the molecular level and early clinical symptoms of the disease. This decrease may be caused by disturbances in the glutamatergic neurotransmission due to the known hyperammonemia in HE patients.

Introduction Hepatic encephalopathy (HE) represents a frequent complication of liver cirrhosis with negative effects on patients' lives. The prevalence of clinical HE is estimated to be between 30-45 %. Regardless of its clinical and prognostic relevance HE is considered to be underdiagnosed. Methods Beyond a systematic analysis of mortality of HE, we investigated the economic impact and reimbursement situation for HE in patients with liver cirrhosis in Germany. For the retrospective analysis, anonymized data (2011-2015) concerning expenses and diagnoses (</n> 21-4 KHEntgG) were obtained from 74 participating hospitals of the Diagnosis Related Groups (DRG) Project of the German Gastroenterological Association (DGVS). Furthermore, results were compared with case data from all German hospitals provided by the German Federal Authority on Statistics (Statistische Bundesamt (Destatis), Wiesbaden). Results In participating hospitals 59 093 cases with liver cirrhosis were identified of which 14.6 % were coded as having HE. Hospital mortality was threefold increased compared to cirrhosis-patients without HE (20.9 versus 7.5 %). Cases with cirrhosis as well as the proportion with HE increased over time. Compared to all patients with cirrhosis, reimbursement for HE patients produced a deficit (of up to 634 euro for HE grade 4). Discussion Mortality is threefold increased in patients with cirrhosis when an additional HE is diagnosed. Hospitals participating in the DGVS-DRG-project coded 2 % more HE cases among their cirrhosis cases than the rest of hospitals either because of a selection bias for greater disease severity or because of better coding quality. At present, reimbursement for HE patients on the basis of F-DRG-system produced a deficit.

Die Hepatische Enzephalopathie (HE) ist in ihrer Ausprägungsform sehr vielfältig und ein Prädiktor für eine erhöhte Mortalität. In der täglichen klinischen Praxis wird der Nachweis der covert/overt HE selten durchgeführt, ist jedoch dringlich erforderlich.

BACKGROUND: In daily clinical practice, the detection of HE is still less represented but strongly required. Therefore, we assessed the EncephalApp (Stroop-Test) in a German population by standard diagnostic procedures such as the Critical Flicker Frequency (CFF) and the PHES-Test (Psychometric Hepatic Encephalopathy Score). One of the purposes of the trial was finding a Cut-Off value for the EncephalApp in the German population. METHODS: 81 patients with liver cirrhosis underwent the testing of the CFF, the PHES-Test and the EncephalApp. A control group of 25 healthy subjects were examined in the same manner. The CFF was considered pathological with <39 Hz and the PHES-Test with < - 4 value points. The On-plus-Off Time of the EncephalApp was compared to the results of the CFF and the PHES-Test. Different Cut-Offs of the On-plus-Off Time were analyzed. Within these HE groups, the mean values of the PHES-Test, the CFF and the On-plus-Off Time of the EncephalApp were compared and the ROC Analysis (receiver operating characteristic) was conducted. Laboratory parameters, clinical data, and further imaging techniques were also included and compared. RESULTS: The study group (n = 81) included 52 men and 29 women (62.8 years ± 12.5). For the evaluation of the EncephalApp, different Cut-Off values were determined and their specificity and sensitivity were calculated. The comparative parameter was the result of the PHES-Test. Through the creation of a ROC curve, the AUC (area under the curve) showed that the Cut-Off time of >224 sec with 0.803 is the most efficient with better sensitivity (79%) and specificity (82%). Other Cut-Off values showed lower sensitivities and higher false negative values. CONCLUSIONS: After evaluating the specificity, sensitivity and AUC the most efficient Cut-Off value for the On-plus-Off Time in the EncephalApp is >224 sec. In comparison with the CFF and the PHES testing, most of the patient withdrawals (especially in higher grade HE) within the study were registered by the EncephalApp. The EncephalApp is a valid and quick method to diagnose minimal HE but has its limitations in the grading between HE grade 1 and 2.

L-Ornithine L-aspartate (LOLA), a stable salt of L-ornithine and L-aspartate, readily dissociates into its constituent amino acids that are readily absorbed by active transport, distributed, and metabolized. L-ornithine serves as an intermediary in the urea cycle in periportal hepatocytes in the liver and as an activator of carbamoyl phosphate synthetase, and, like L-aspartate, by transamination to glutamate via glutamine synthetase in perivenous hepatocytes as well as by skeletal muscle and brain. By way of these metabolic pathways, both amino acids participate in reactions whereby the ammonia molecule is incorporated into urea and glutamine and it is the nature, cellular, and biological location of these pathways that underpins the application of LOLA as an effective ammonia-lowering strategy widely used for the management and treatment of hepatic encephalopathy. These metabolic pathways were elucidated based upon studies in experimental animals and were confirmed by studies in patients with severe liver diseases. More recent studies suggest that LOLA may have additional direct hepatoprotective properties. Moreover, its use may result in improvements in skeletal muscle function in cirrhosis.

Zusammenfassung Einleitung Die hepatische Enzephalopathie (HE) ist eine häufige Komplikation der Leberzirrhose, die für betroffene Patienten mit vielfältigen negativen Auswirkungen im Alltag verbunden ist. Die Prävalenz klinisch manifester Stadien wird auf 30–45 % geschätzt. Ungeachtet ihrer klinischen und prognostischen Bedeutung gilt die HE als unterdiagnostiziert. Methoden Ziele der Studie waren neben der systematischen Analyse der Krankenhausletalität der HE erstmals eine Untersuchung der ökonomischen Auswirkungen und der Vergütungssituation einer HE bei Leberzirrhose in Deutschland. Für die retrospektive Studie standen die anonymisierten Fall- und Kostendaten (§ 21 Abs. 4 KHEntgG) von 74 Krankenhäusern des DRG-Projekts der Deutschen Gesellschaft für Gastroenterologie, Verdauungs- und Stoffwechselkrankheiten (DGVS) aus den Jahren 2011 bis 2015 zur Verfügung. Außerdem wurden diese Ergebnisse mit denen aller deutschen Krankenhäuser auf der Basis der Falldaten des Statistischen Bundesamtes (Destatis, Wiesbaden) verglichen. Ergebnisse In den Häusern des DRG-Projekts der DGVS wurden 59 093 Behandlungsfälle mit Leberzirrhose erfasst, bei denen in 14,6 % eine HE kodiert war. Die Krankenhausletalität von Zirrhose-Patienten mit HE war gegenüber derjenigen von Patienten ohne HE nahezu dreifach erhöht (20,9 versus 7,7 %). Die Zahl der Behandlungsfälle mit Leberzirrhose ebenso wie der Anteil von Patienten mit HE stieg kontinuierlich über den Erfassungszeitraum an. Im Gegensatz zu Patienten mit Zirrhose allgemein ist die Behandlung von Patienten mit HE nicht kostendeckend (Unterdeckung bis zu 634 € bei HE Grad 4). Diskussion Die Letalität war bei Patienten mit Zirrhose dreifach erhöht, wenn gleichzeitig eine HE diagnostiziert wurde. In den am DGVS-DRG-Projekt teilnehmenden Häusern wurde die HE um 2 % häufiger erfasst als im Rest der Kalkulationshäuser, was entweder in einer höheren Fallschwere oder in einer besseren Kodierqualität begründet ist. Gegenwärtig ist die Behandlung der HE bei Zirrhose nicht kostendeckend im DRG-System.

Background/objectives: L-Ornithine L-Aspartate (LOLA) is a mixture of two endogenous amino acids with the capacity to fix ammonia in the form of urea and/or glutamine. Its' efficacy for the treatment of Hepatic Encephalopathy (HE), a known hyperammonemic disorder, remains the subject of debate. This study quantitatively analyzed the efficacy of LOLA in patients with cirrhosis and HE. Methods: Efficacy was defined as the extent of lowering of blood ammonia and improvement of mental state assessed in clinically overt HE (OHE) by Westhaven criteria or psychometric testing for assessment of Minimal HE (MHE). Appropriate keywords were used for electronic and/or manual searches of databases to identify RCTs for inclusion. Study quality and risk of bias were assessed using the Jadad Composite Scale together with The Cochrane Scoring Tool. Random Effects Models were used to express pooled Risk Ratio (RR) or Mean Difference (MD) with associated 95% Confidence Intervals (CI). Results: 10 RCTs (884 patients) were included. Regression analysis showed no evidence of publication bias or other small study effects. Eight RCTs had low risk of bias by Jadad/Cochrane criteria. Comparison with placebo/no intervention controls revealed that LOLA was significantly more effective for improvement of mental state in all types of HE (RR 1.36 (95% CI 1.10-1.69), p = 0.005), OHE(RR: 1.19, 95% CI of 1.01-1.39, test for overall effect: Z = 2.14, p = 0.03), MHE(RR: 2.15 (1.48-3.14), p < 0.0001) and for lowering of blood ammonia (MD: -17.50 mu mol/l (-27.73 to (-7.26)), p = 0.0008). Improvement of mental state was greater in trials with low risk of bias. Heterogeneity was reduced in trials from Europe or with >100 participants. Oral LOLA appeared particularly effective for the treatment of MHE. Conclusion: LOLA appears to improve mental state and lower ammonia in patients with HE or MHE. Further studies are required in some subgroups of HE and in the era of HE reclassification.

Hepatic encephalopathy (HE) is triggered by liver cirrhosis and is associated with an increased ammonia level within the brain tissue. The goal of this study was to investigate effects of ammonia on in vitro amide proton transfer (APT)-weighted chemical exchange saturation transfer (CEST) imaging in order to develop an ammonia-sensitive brain imaging method. APT-weighted CEST imaging was performed on phantom solutions including pure ammonia, bovine serum albumin (BSA), and tissue homogenate samples doped with various ammonia concentrations. All CEST data were assessed by magnetization transfer ratio asymmetry. In addition, optical methods were used to determine possible structural changes of the proteins in the BSA phantom. In vivo feasibility measurements were acquired in one healthy participant and two patients suffering from HE, a disease associated with increased brain ammonia levels. The CEST effect of pure ammonia showed a base-catalyzed behavior. At pH values greater than 5.6 no CEST effect was observed. The APT-weighted signal was significantly reduced for ammonia concentrations of 5mM or more at fixed pH values within the different protein phantom solutions. The optical methods revealed no protein aggregation or denaturation for ammonia concentrations less than 5mM. The in vivo measurements showed tissue specific and global reduction of the observed CEST signal in patients with HE, possibly linked to pathologically increased ammonia levels. APT-weighted CEST imaging is sensitive to changes in ammonia concentrations. Thus, it seems useful for the investigation of pathologies with altered tissue ammonia concentrations such as HE. However, the underlying mechanism needs to be explored in more detail in future in vitro and in vivo investigations.

Die hepatische Enzephalopathie (HE) ist eine häufige Komplikation der Leberzirrhose und hat wesentlichen Einfluss auf die Lebensqualität. Zudem steigt mit jeder manifesten HE-Episode das Risiko, kurzfristig eine weitere Episode zu erleiden oder zu versterben. Entsprechende Daten sind jedoch überwiegend älteren Datums und nicht unter den aktuellen Behandlungsmöglichkeiten erhoben.

Recent studies have proposed a connection between the individual alpha band peak frequency and the temporal resolution of visual perception in healthy human participants. This connection rests on animal studies describing oscillations in the alpha band as a mode of phasic thalamocortical information transfer for low-level visual stimuli, which critically relies on GABAergic interneurons. Here, we investigated the interplay of these parameters by measuring occipital alpha band peak frequency by means of magnetoencephalography, visual temporal resolution by means of behavioral testing, and occipital GABA levels by means of magnetic resonance spectroscopy. Importantly, we investigated a sample of healthy participants and patients with varying grades of hepatic encephalopathy, which are known to exhibit decreases in the investigated parameters, thus providing an increased parameter space. We found that occipital alpha band peak frequency and visual temporal resolution were positively correlated, i.e., higher occipital alpha band peak frequencies were on average related to a higher temporal resolution. Likewise, occipital alpha band peak frequency correlated positively with occipital GABA levels. However, correlations were significant only when both healthy participants and patients were included in the analysis, thereby indicating a connection of the measures on group level (instead of the individual level). These findings provide new insights into neurophysiological and neurochemical underpinnings of visual perception.

The devastating consequences of hepatic failure include hepatic encephalopathy, a severe, life threatening impairment of neuronal function. Hepatic encephalopathy is caused by impaired hepatic clearance of NH4 +. Cellular NH4 + uptake is accomplished mainly by the Na+,K+,2Cl− cotransporter. Here we show that hepatic clearance of NH4 + is impaired in TNFα deficient as well as TNFR1&TNFR2 double knockout mice, which both develop hyperammonemia. Despite impaired hepatic clearance of NH4 +, TNFα deficient mice and TNFR1 deficient mice were protected against acute ammonia intoxication. While 54% of the wild-type mice and 60% of TNFR2 deficient mice survived an NH4 + load, virtually all TNFα deficient mice and TNFR1 deficient mice survived the treatment. Conversely, TNFα treatment of wild type mice sensitized the animals to the toxic effects of an NH4 + load. The protection of TNFα-deficient mice against an NH4 + load was paralleled by decreased cerebral expression of NKCC1. According to the present observations, inhibition of TNFα formation and/or NKCC1 may be strategies to favorably influence the clinical course of hepatic encephalopathy.

The liver is intensely involved in glucose metabolism and is thereby closely related to diabetes pathophysiology. Adult patients with type 1 diabetes mellitus (DM) are at an increased risk for non-alcoholic fatty liver disease (NAFLD). Here, we studied the prevalence of NAFLD in a cohort of children and adolescents with type 1 DM in a tertiary care paediatric diabetes centre in Germany. We screened 93 children and adolescents with type 1 DM using ultrasound, laboratory investigations, and liver stiffness measurements (Fibroscan® [FS] and acoustic radiation force imaging [ARFI]). Of these, 82 (88.1%) had completely normal results in all examined aspects. Only one patient (1.1%) fulfilled the criteria as potential NAFLD with ALT > twice the upper limit of normal. Ten of the 93 patients (10.8%) showed any mild abnormality in at least one examined category including ALT, conventional ultrasounds and liver stiffness measurements. However, none of these ten fulfilled the NAFLD case definition criteria. Therefore, these slightly abnormal results were judged to be unspecific or at least of unknown significance in terms of NAFLD indication.

Die hepatische Enzephalopathie (HE) ist eine Störung des Zentralnervensystems, die als Komplikation akuter oder chronischer Lebererkrankungen und/oder portosystemischer Kollateralkreisläufe auftreten kann, und umfasst ein breites Spektrum kognitiver, psychischer und motorischer Veränderungen.

Minimal hepatic encephalopathy is the term applied to the neuropsychiatric status of patients with cirrhosis who are unimpaired on clinical examination but show alterations in neuropsychological tests exploring psychomotor speed/executive function and/or in neurophysiological variables. There is no gold standard for the diagnosis of this syndrome. As these patients have, by definition, no recognizable clinical features of brain dysfunction, the primary prerequisite for the diagnosis is careful exclusion of clinical symptoms and signs. A large number of psychometric tests/test systems have been evaluated in this patient group. Of these the best known and validated is the Portal Systemic Hepatic Encephalopathy Score (PHES) derived from a test battery of five paper and pencil tests; normative reference data are available in several countries. The electroencephalogram (EEG) has been used to diagnose hepatic encephalopathy since the 1950s but, once popular, the technology is not as accessible now as it once was. The performance characteristics of the EEG are critically dependent on the type of analysis undertaken; spectral analysis has better performance characteristics than visual analysis; evolving analytical techniques may provide better diagnostic information while the advent of portable wireless headsets may facilitate more widespread use. A large number of other diagnostic tools have been validated for the diagnosis of minimal hepatic encephalopathy including Critical Flicker Frequency, the Inhibitory Control Test, the Stroop test, the Scan package and the Continuous Reaction Time; each has its pros and cons; strengths and weaknesses; protagonists and detractors. Recent AASLD/EASL Practice Guidelines suggest that the diagnosis of minimal hepatic encephalopathy should be based on the PHES test together with one of the validated alternative techniques or the EEG. Minimal hepatic encephalopathy has a detrimental effect on the well-being of patients and their care-givers. It responds well to treatment with resolution of test abnormalities and the associated detrimental effects on quality of life, liver-related mortality and morbidity. Patients will only benefit in this way if they can be effectively diagnosed. Corporate efforts and consensus agreements are needed to develop effective diagnostic algorithms.

In cirrhotic patients with portosystemic encephalopathy, OA has confirmed its efficacy both in uncontrolled clinical trials and more recently in placebo-controlled double-blind studies in patients with manifest hepatic encephalopathy and hyperammonemia. OA improved performance in Psyhometric Tests as well as mental state gradation. The therapy had little side effects, increasing with higher intravenously administered dosages, and was well tolerated after oral and parenteral administration.

Introduction Hepatic encephalopathy is defined as brain dysfunction caused by liver insufficiency and/or portosystemic shunting. Symptoms include nonspecific cognitive impairment, personality changes and changes in consciousness. Overt (symptomatic) hepatic encephalopathy is a common complication of cirrhosis that is associated with a poor prognosis. Patients with hepatic encephalopathy may present to healthcare providers who do not have primary responsibility for management of patients with cirrhosis. Therefore, we developed a series of ‘consensus points’ to provide some guidance on management. Methods Using a modified ‘Delphi’ process, consensus statements were developed that summarize our recommendations for the diagnosis and management of patients with hepatic encephalopathy. Points on which full consensus could not be reached are also discussed. Results Our recommendations emphasize the role of all healthcare providers in the identification of cognitive impairment in patients with cirrhosis and provide guidance on steps that might be considered to make a diagnosis of overt hepatic encephalopathy. In addition, treatment recommendations are summarized. Minimal hepatic encephalopathy can have a significant impact on patients; however, in most circumstances identification and management of minimal hepatic encephalopathy remains the responsibility of specialists in liver diseases. Conclusion Our opinion statements aim to define the roles and responsibilities of all healthcare providers who at times care for patients with cirrhosis and hepatic encephalopathy. We suggest that these recommendations be considered further by colleagues in other disciplines and hope that future guidelines consider the management of patients with cirrhosis and with a ‘suspicion’ of cognitive impairment through to a formal diagnosis of hepatic encephalopathy.