Patients with manifest hepatic encephalopathy can reveal impaired thermal perception.

OBJECTIVES: Previous evoked potential studies indicated central impairments of somatosensory function in patients suffering from hepatic encephalopathy (HE). The aim of this study was to quantify the somatosensory perception in patients with minimal and overt HE. MATERIALS AND METHODS: Forty-two patients with liver cirrhosis and HE up to grade 2 and 12 age-matched healthy controls underwent a comprehensive graduation of HE including the West Haven criteria, the critical flicker frequency (CFF), and neuropsychometric testing. Quantitative sensory testing, standardized by the German Research Network on Neuropathic Pain, was performed on both hands. RESULTS: Pain and mechanical detection thresholds were unchanged in HE. Tests of thermal processing revealed that patients with HE of grade 2 perceive cold at lower temperatures (cold detection threshold) and need a higher temperature difference to distinguish between warm and cold (thermal sensory limen). These impairments correlated with the CFF. A correction for attention deficits by performing partial correlations using neuropsychometric test results canceled these correlations. CONCLUSIONS: The present findings demonstrate an impairment of temperature perception in HE. The extent of this impairment correlates with HE severity as quantified by the CFF. The attenuation of the correlations after correction for attention deficits suggests a strong role of attention deficits for the impaired thermal perception. Thus, it provides initial evidence for a central impairment of thermal processing in HE due to alterations in high-level processes rather than due to peripheral neuropathic processes, which are a frequent complication in patients with liver cirrhosis.

Evaluation of Acoustic Radiation Force Impulse Imaging (ARFI) for the Determination of Liver Stiffness Using Transient Elastography as a Reference in Children.

PURPOSE: Transient elastography (Fibroscan(©); (FS)) and acoustic radiation force impulse imaging (ARFI) represent noninvasive, user-friendly and quick methods providing an objective and reproducible measure of liver stiffness. The aim of the study was to evaluate cut-off values and performance of ARFI measurements in children using transient elastography as a reference. METHODS/PATIENTS: A total of 198 children were enrolled in this study. All patients underwent liver stiffness measurements with FS (FS-LS) as well as ARFI (with shear wave velocity quantification; ARFI-SWV) and the performance of ARFI in comparison to FS was studied. RESULTS: Significantly higher rates of successful measurements were found for ARFI compared to FS (198/198 (100%) vs. 160/198 (80.8%); p<0.001). ARFI-SWV correlated significantly with FS-LS (r=0.751, p=0.001). ARFI-SWV increased significantly with the stage of fibrosis (1.19+0.15 m/s for patients with FS-LS<7.6 kPa); 1.34+0.22 m/s for patients with 7.613.0 kPa). ARFI-SWV cut-off values were identified for no significant fibrosis (1.31 m/s; sensitivity 61.8% and specificity 79.5%) and for liver cirrhosis (1.63 m/s; sensitivity 70.0% and specificity 97.4%). The median values of liver stiffness measured by FS were age-dependent in 90 children without liver diseases with 4.8, 5.6, and 5.7 kPa in children 0-5, 6-11, and 12-18 years, respectively.

Cortical activation associated with asterixis in manifest hepatic encephalopathy.

OBJECTIVES: Severe hepatic encephalopathy gives rise to asterixis, a striking motor symptom also called flapping tremor, which is characterized by a sudden ceasing of muscle tone in all muscles of a limb. In this study, we aimed at scrutinizing the cortical activation associated with asterixis and unraveling the underlying pathophysiological mechanisms. MATERIAL AND METHODS: We recorded simultaneously neural activity with magnetoencephalography (MEG) and muscle activity with surface EMG in nine patients with manifest hepatic encephalopathy showing asterixis. Asterixis events were detected semiautomatically and served as triggers for averaging MEG signals. Evoked responses averaged time-locked to asterixis events were subjected to equivalent current dipole (ECD) modeling. Additionally, we localized the strongest cortico-muscular coherence in the frequency of the co-occurring tremulousness. RESULTS: Evoked fields averaged time-locked to asterixis events were best explained by a single dipolar source in the contralateral primary motor cortex (M1, Talairach coordinates of mean localization: -40, -20, and 64; Brodmann area 4). This dipole showed a twofold field reversal, that is biphasic wave, with frontal dipole orientation at 49 ms before flap onset and 99 ms after flap onset. Conversely, two maxima with occipital dipole orientation were observed 2 ms and 160 ms after flap onset. Cortico-muscular coherence for the tremulousness was likewise localized in the contralateral M1 confirming earlier findings in the present patient cohort. CONCLUSIONS: Our results reveal an involvement of M1 in the generation of asterixis. As also tremulousness, also called mini-asterixis, was shown to originate in M1, asterixis and mini-asterixis may share common pathophysiological mechanisms.

Cholestatic liver diseases from child to adult: the diversity of MDR3 disease.

The phospholipidfloppase MDR3 (gene symbol: ABCB4) is expressed in the canalicular membrane of hepatocytes and mediates the biliary excretion of phosphatidylcholine, which is required for the formation of mixed micelles in bile. Several mutations of ABCB4 have been identified, which cause cholestatic liver diseases of varying severity including progressive familial intrahepatic cholestasis type 3 (PFIC-3), intrahepatic cholestasis of pregnancy (ICP) and the low phospholipid associated cholelithiasis syndrome (LPAC). Here, we report on four new (S1076N; L 23Hfs16X; c.286 + 1G > A; Q 1181E) and one known (S27G) MDR3 mutations in eight patients of three families. The patients presented with a wide spectrum of liver diseases. The clinical presentation and decisive laboratory findings or the association to a trend-setting family history led to the identification of the genetic background in these patients. Even the same mutation may be associated with varying disease progression.

Motor impairment in liver cirrhosis without and with minimal hepatic encephalopathy.

AIM: Manifest hepatic encephalopathy (HE) goes along with motor symptoms such as ataxia, mini-asterixis, and asterixis. The relevance of motor impairments in cirrhotics without and with minimal HE (mHE) is still a matter of debate. PATIENTS AND METHODS: We tested three different groups of patients with liver cirrhosis: no signs of HE (HE 0), mHE, and manifest HE grade 1 according to the West Haven criteria (HE 1). All patients (n = 24) and 11 healthy control subjects were neuropsychometrically tested including critical flicker frequency (CFF), a reliable measure for HE. Motor abilities were assessed using Fahn Tremor Scale and International Ataxia Rating Scale. Fastest alternating index finger movements were analyzed for frequency and amplitude. RESULTS: Statistical analyses showed an effect of HE grade on tremor and ataxia (P < 0.01). Additionally, both ratings yielded strong negative correlation with CFF (P < 0.01, R = -0.5). Analysis of finger movements revealed an effect of HE grade on movement frequency (P < 0.03). Moreover, decreasing movement frequency and increasing movement amplitude parallel decreasing CFF (P < 0.01, R = 0.6). CONCLUSION: Our results indicate that ataxia, tremor, and slowing of finger movements are early markers for cerebral dysfunction in HE patients even prior to neuropsychometric alterations becoming detectable.

Quantitative cerebral water content mapping in hepatic encephalopathy.

There is increasing evidence that the pathophysiology of hepatic encephalopathy is tightly associated with low-grade cerebral oedema; however, no method has yet specifically and unambiguously confirmed this hypothesis in vivo. The current study describes the quantitative measurement of localised water content using MRI in a cohort of 38 patients suffering from hepatic encephalopathy. A significant global increase in cerebral water content was observed in white matter whereas water content in grey matter was globally unaffected. However, significant spatial variations in the water content distribution, especially in grey matter, were observed and were correlated with disease grade and critical flicker frequency. In addition, regions-of-interest were defined and a significant change in water content with disease grade was found in the frontal and occipital white matter, the globus pallidus, the anterior limb of the internal capsule and the putamen. No association of water content and HE grade was established for the occipital visual and frontal cortices, the thalamus, the posterior limb of the internal capsule, the caudate nucleus and the coronal white matter. In conclusion, the measurements presented here are the first direct and quantitative demonstration of the presence of low-grade cerebral oedema in patients with hepatic encephalopathy. Further, absolute changes in tissue water content were quantified for various brain regions.

Impaired cerebral oscillatory processing in hepatic encephalopathy.

OBJECTIVE: Hepatic encephalopathy (HE) is characterized by neuropsychological and motor deficits. The present study tested the hypothesis that worsening of motor and sensory symptoms of HE results from a common basic deficit in the cerebral oscillatory processing within the human motor and visual system. METHODS: We investigated in 32 patients with liver cirrhosis and HE grades 0-2 critical flicker frequency (CFF) and cortico-muscular (M1-EMG) coherence as a measure of coupling between the surface EMGs of hand muscles and primary motor cortex (M1) activity recorded non-invasively with magnetoencephalography (MEG) during forearm elevation. RESULTS: Patients with HE-grade 2 developed excessive M1-EMG coherence at low frequencies. In contrast, maximum M1-EMG coherence in patients with no HE showed frequency and amplitude in the physiological range. CFF was continuously reduced with worsening grades of HE. Correlation analysis revealed significant correlation between the frequency of M1-EMG coherence and CFF. CONCLUSIONS: Taken together, we demonstrate that increased grades of HE lead to a pathological M1-EMG drive which is reduced in frequency. These effects are correlated with an impaired perception of oscillatory visual stimuli. SIGNIFICANCE: The results suggest that pathological oscillatory neural processing in different human cerebral systems may represent a basic mechanism for the clinical manifestation of HE.

The treatment of hepatic encephalopathy.

Current recommendations for the treatment of hepatic encephalopathy are based, to a large extent, on open or uncontrolled trials, undertaken in very small numbers of patients. In consequence, there is ongoing discussion as to whether the classical approach to the treatment of this condition, which aims at reducing ammonia production and absorption using either non-absorbable disaccharides and/or antibiotics, should be revisited, modified or even abandoned. Pros and cons of present therapeutic strategies and possible future developments were discussed at the fourth International Hannover Conference on Hepatic Encephalopathy held in Dresden in June 2006. The content of this discussion is summarized.

1H-MR spectroscopy, magnetization transfer, and diffusion-weighted imaging in alcoholic and nonalcoholic patients with cirrhosis with hepatic encephalopathy.

PURPOSE: Mild swelling of astrocytes is proposed as a key event in the pathogenesis of hepatic encephalopathy. Proton MR spectroscopy ((1)H-MR spectroscopy), diffusion-weighted imaging (DWI), and magnetization transfer imaging were performed in patients with alcoholic and nonalcoholic liver cirrhosis and correlated with different clinical stages of hepatic encephalopathy to assess alterations in cerebral water metabolism in different subgroups of patients with cirrhosis. MATERIAL AND METHODS: Forty-five patients (26 alcoholics, 19 nonalcoholics [due to hepatitis C (n = 9), hemochromatosis (n = 2), primary chronic cholangitis (n = 2), hepatitis B (n = 1), Wilson disease (n = 1), cryptogenic cirrhosis (n = 4)]) and 18 controls underwent (1)H-MR spectroscopy, magnetization transfer imaging, and DWI of the basal ganglia and normally appearing occipital white matter (NAWM). N-acetylaspartate (NAA), choline (Cho), myo-inositol (mIns), and glutamine/glutamate (Glx) relative to creatine (Cr), the apparent diffusion coefficients (ADC), and the magnetization transfer ratios (MTR) were correlated to the neuropsychologic status, which was assessed by computerized psychometry and mental state grading, according to the West Haven criteria. RESULTS: Compared with controls, nonalcoholic subjects exhibited a gradual increase of Glx/Cr in the basal ganglia and NAWM; a decrease in mIns/Cr; a significant decrease of MTR in the thalamus, the putamen, the pallidum, and NAWM; and an increase in the ADC of the NAWM with increasing hepatic encephalopathy severity. In alcoholics, mIns/Cr of the basal ganglia and the NAWM, Cho/Cr of the basal ganglia, and MTR of all assessed regions were decreased. Glx/Cr of the basal ganglia and of the NAWM was increased, compared with that of controls; but no correlation to the clinical hepatic encephalopathy grading was found. ADC did not change significantly between the groups. CONCLUSIONS: Apart from a typical pattern of (1)H-MR spectroscopy alterations in hepatic encephalopathy, a gradual decrease in MTR and an increase of ADC was found correlating to clinical grading of hepatic encephalopathy in nonalcoholic patients with cirrhosis. In alcoholic patients with hepatic encephalopathy, there was no such correlation. Abnormalities detected by MR imaging may hint at different pathways of brain damage in alcohol-induced liver disease.

Deficits in cortico-striatal synaptic plasticity and behavioral habituation in rats with portacaval anastomosis.

Hepatic encephalopathy is characterized by disturbances of motor and cognitive functions involving the basal ganglia. So far no standards for assessment of neuropsychiatric abnormalities (disorders of sleep, mood, anxiety and personality) in subclinical hepatic encephalopathy have been defined. Using an animal model of mild (subclinical) hepatic encephalopathy we investigated now striatum-related behaviors and cortico-striatal synaptic plasticity in rats 2 months after introduction of a portacaval shunt and sham-operated matched controls. In a novel open field portacaval shunt rats displayed less locomotor activity; unlike controls they also showed no habituation to the field and no recall of the field environment after 24 h, indicative of cognitive deficit. The elevated-plus maze test indicated no differences in fear/anxiety in the portacaval shunt animals. Tetanic stimulation of cortical afferents in magnesium-free solution evoked an N-methyl-D-aspartate-dependent long-term potentiation in sham-operated animals. In portacaval shunt animals long-term potentiation was significantly impaired. Histamine, a potent modulator of cortico-striatal transmission, induced a larger long-term depression of field potentials in control compared with portacaval shunt rats. In conclusion, a combination of electrophysiological and behavioral approaches has revealed functional changes in cortico-striatal transmission. These data are relevant for understanding the mechanisms of motor and cognitive dysfunctions in hepatic encephalopathy patients and for the development of precise psychometric tests, evaluating cognitive deficits in subclinical hepatic encephalopathy.

Pathological oscillatory coupling within the human motor system in different tremor syndromes as revealed by magnetoencephalography.

Whole-head MEG-systems and modern spatial-filter-based analysis tools recently provided new possibilities to analyze non-invasively cerebral networks of human tremor syndromes. We compared tremor syndromes in Parkinsonian patients with a typical resting tremor as well as in patients with hepatic encephalopathy (HE) with a postural tremor called "mini-asterixis". In 6 patients with idiopathic Parkinson's disease (PD) we found strong coherence between the electromyography (EMG) of forearm muscles and activity in the contralateral primary motor cortex (M1) at tremor frequency but also at double tremor frequency. Furthermore, significant coherences were observed between M1 and medial wall areas (CMA/SMA), lateral premotor cortex, diencephalon, SII cortex, posterior parietal cortex and the contralateral cerebellum at tremor and, stronger, at double tremor frequency. In contrast, in 6 patients with "mini-asterixis" and HE due to chronic liver cirrhosis excessive corticomuscular coherence occurred at the individual tremor frequency between EMG and M1 activity. Interestingly, thalamus-M1 coupling was significantly altered towards lower frequencies matching the individual frequency of the mini-asterixis. Cerebro-muscular or cerebro-cerebral coupling at double tremor frequency was not observed. Therefore, "mini-asterixis" reflects most likely a pathologically decelerated and augmented synchronized rhythmical motor cortical output. This could be due to functional alterations in the M1-basal-ganglia-thalamo-cortical loops in severe HE. In summary, tremor syndromes in PD as well as in patients with HE and "mini-asterixis" are characterized by pathological oscillatory activity within cerebral networks of motor areas. However, the present study shows different mechanisms of tremor generation in PD and HE patients.

Mini-asterixis in hepatic encephalopathy induced by pathologic thalamo-motor-cortical coupling.

Recently, it was shown that a slowed motor cortical drive in hepatic encephalopathy (HE) results in mini-asterixis (MA). During forearm elevation, the authors have now investigated the coupling between motor cortex and thalamic activity using magnetoencephalography in six cirrhotic patients with HE and MA and in six control subjects. HE patients showed thalamo-motor-cortical coupling at a significantly lower frequency than the coupling in control subjects. The pathologic motor cortical drive in HE probably results from altered thalamocortical oscillatory coupling.

[Hepatic encephalopathy]. / Hepatische Enzephalopathie.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome which develops during chronic or acute liver disease. It is functional in nature and potentially reversible and symptoms range from subtle personality changes to deep coma. Diagnosis of manifest HE is made on a clinical basis, whereas psychometric tests are required to diagnose subclinical HE (SHE). Paper-pencil tests are frequently used for diagnosing SHE, but they may be inferior to measurements of critical flicker frequency, which pick minimal and low grade manifest HE as a continuum. Pathogenetically, HE is seen as clinical manifestation of low grade chronic cerebral edema, which is accompanied by alterations in glioneuronal communication. Different factors such as ammonia, inflammatory cytokines, benzodiazepines and electrolyte imbalances may precipitate or aggravate glia edema, thereby explaining precipitation of HE episodes by a variety of unrelated factors. Recognition and rigorous treatment of these precipitating factors is the most important measure in HE therapy, which may be augmented by dietary and medical approaches.

Cortical origin of mini-asterixis in hepatic encephalopathy.

The authors investigated 12 patients with cirrhosis who had hepatic encephalopathy (HE): six with continuous mini-asterixis and six with subclinical HE without asterixis. They studied the coupling between hand-muscle electromyography (EMG) recordings and brain activity recorded by magnetoencephalography. On forearm elevation, patients with tremor developed excessive coupling between activity in the motor cortex (M1) and contralateral hand-muscle EMG recordings at the frequency of mini-asterixis, which was not found in controls. The corticomuscular coupling demonstrates the involvement of M1 in asterixis and may reflect a pathologically slowed and synchronized motor cortical drive.

Clinical efficacy of L-ornithine-L-aspartate in the management of hepatic encephalopathy.

The clinical efficacy of both oral and parenteral L-ornithine-L-aspartate (OA) was confirmed by randomized, placebo-controlled, double-blind studies in patients with manifest hepatic encephalopathy and hyperammonemia. The drug was able to reduce high blood ammonia levels induced either by ammonium chloride or protein ingestion or existing as a clinical complication of cirrhosis per se. Furthermore, OA improved performance in Number Connection Test-A as well as mental state gradation. In contrast to the positive effects observed in patients with more advanced hepatic encephalopathy, oral OA does not seem to affect minimal hepatic encephalopathy. In a recent trial, OA decreased protein breakdown and stimulated protein synthesis in muscle. The therapy had little side effects, increasing with higher intravenously administered dosages, and was well tolerated after oral and parenteral administration.

L-ornithine-L-aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain edema in rats with acute liver failure.

Brain edema sufficient to cause intracranial hypertension and brain herniation remains a major cause of mortality in acute liver failure (ALF). Studies in experimental animal models of ALF suggest a role for ammonia in the pathogenesis of both encephalopathy and brain edema in this condition. As part of a series of studies to evaluate the therapeutic efficacy of ammonia-lowering agents, groups of rats with ALF caused by hepatic devascularization were treated with L-ornithine-L-aspartate (OA), an agent shown previously to be effective in reducing blood ammonia concentrations in both experimental and human chronic liver failure. Treatment of rats in ALF with infusions of OA (0.33 g/kg/h, intravenously) resulted in normalization of plasma ammonia concentrations and in a significant delay in onset of severe encephalopathy. More importantly, brain water content was significantly reduced in OA-treated rats with ALF. These protective effects of OA were accompanied by increased plasma concentrations of several amino acids including glutamate, gamma-aminobutyric acid (GABA), taurine, and alanine, as well as the branched-chain amino acids, leucine, isoleucine, and valine. Increased availability of glutamate following OA treatment provides the substrate for the major ammonia-removal mechanism (glutamine synthetase). Plasma (but not cerebrospinal fluid) glutamine concentrations were increased 2-fold (P <.02) in OA-treated rats, consistent with increased muscle glutamine synthesis. Direct measurement of glutamine synthetase activities revealed a 2-fold increase following OA treatment. These findings demonstrate a significant ammonia-lowering effect of OA together with a protective effect on the development of encephalopathy and brain edema in this model of ALF.