Non invasive blood flow measurement in cerebellum detects minimal hepatic encephalopathy earlier than psychometric tests

AIM: To assess whether non invasive blood flow measurement by arterial spin labeling in several brain regions detects minimal hepatic encephalopathy.METHODS: Blood flow (BF) was analyzed by arterial spin labeling (ASL) in different brain areas of 14 controls, 24 cirrhotic patients without and 16 cirrhotic patients with minimal hepatic encephalopathy (MHE). Images were collected using a 3 Tesla MR scanner (Achieva 3T-TX, Philips, Netherlands). Pulsed ASL was performed. Patients showing MHE were detected using the battery Psychometric Hepatic Encephalopathy Score (PHES) consisting of five tests. Different cognitive and motor functions were also assessed: alterations in selective attention were evaluated using the Stroop test. Patients and controls also performed visuo-motor and bimanual coordination tests. Several biochemical parameters were measured: serum pro-inflammatory interleukins (IL-6 and IL-18), 3-nitrotyrosine, cGMP and nitrates+nitrites in plasma, and blood ammonia. Bivariate correlations were evaluated.RESULTS: In patients with MHE, BF was increased in cerebellar hemisphere (P = 0.03) and vermis (P = 0.012) and reduced in occipital lobe (P = 0.017). BF in cerebellar hemisphere was also increased in patients without MHE (P = 0.02). Bimanual coordination was impaired in patients without MHE (P = 0.05) and much more in patients with MHE (P < 0.0001). Visuo-motor coordination was impaired only in patients with MHE (P < 0.0001). Attention was slightly affected in patients without MHE and more strongly in patients with MHE (P < 0.0001). BF in cerebellar hemisphere and vermis correlated with performance in most tests of PHES [(number connection tests A (NCT-A), B (NCT-B)and line tracing test] and in the congruent task of Stroop test. BF in frontal lobe correlated with NCT-A. Performance in bimanual and visuomotor coordination tests correlated only with BF in cerebellar hemisphere. BF in occipital lobe correlates with performance in the PHES battery and with CFF. BF in cerebellar hemisphere correlates with plasma cGMP and nitric oxide (NO) metabolites. BF in vermis cerebellar also correlates with NO metabolites and with 3-nitrotyrosine. IL-18 in plasma correlates with BF in thalamus and occipital lobe.CONCLUSION: Non invasive BF determination in cerebellum using ASL may detect MHE earlier than the PHES. Altered NO-cGMP pathway seems to be associated to altered BF in cerebellum

Learning and Memory Impairments in Patients with Minimal Hepatic Encephalopathy are Associated with Structural and Functional Connectivity Alterations in Hippocampus

Patients with minimal hepatic encephalopathy (MHE) show mild cognitive impairment associated with alterations in attentional and executive networks. There are no studies evaluating the relationship between memory in MHE and structural and functional connectivity (FC) changes in the hippocampal system. This study aimed to evaluate verbal learning and long-term memory in cirrhotic patients with (C-MHE) and without MHE (C-NMHE) and healthy controls. We assessed the relationship between alterations in memory and the structural integrity and FC of the hippocampal system. C-MHE patients showed impairments in learning, long-term memory, and recognition, compared to C-NMHE patients and controls. Cirrhotic patients showed reduced fimbria volume compared to controls. Larger volumes in hippocampus subfields were related to better memory performance in C-NMHE patients and controls. C-MHE patients presented lower FC between the L-presubiculum and L-precuneus than C-NMHE patients. Compared to controls, C-MHE patients had reduced FC between L-presubiculum and subiculum seeds and bilateral precuneus, which correlated with cognitive impairment and memory performance. Alterations in the FC of the hippocampal system could contribute to learning and long-term memory impairments in C-MHE patients. This study demonstrates the association between alterations in learning and long-term memory and structural and FC disturbances in hippocampal structures in cirrhotic patients

Costes de hospitalización asociados a la hepatitis crónica C en la Comunidad Valenciana en 2013

ABSTRACT Background: Hospital costs associated with Hepatitis C (HCC) arise in the final stages of the disease. Its quantification is very helpful in order to estimate and check the burden of the disease and to make financial decisions for new antivirals. The highest costs are due to the decompensation of cirrosis. Methods: Cross-sectional observational study of hospital costs of HCC diagnoses in the Valencian Community in 2013 (n= 4.486 hospital discharges). Information source: Minimum basic set of data/Basic Minimum Data Set. The costs were considered according to the rates established for the DRG associated with the episodes with diagnosis of hepatitis C. The average survival of patients since the onset of the decompensation of their cirrhosis was estimated by a Markov model, according to the probabilities of evolution of the disease existing in Literatura. Results: There were 4.486 hospital episodes, 1,108 due to complications of HCC, which generated 6,713 stays, readmission rate of 28.2% and mortality of 10.2%. The hospital cost amounted to 8,788.593EUR: 3,306.333EUR corresponded to Cirrhosis (5,273EUR/patient); 1,060,521EUR to Carcinoma (6,350EUR/patient) and 2,962,873EUR to transplantation (70.544EUR/paciente. Comorbidity was 1,458,866EUR. These costs are maintained for an average of 4 years once the cirrhosis decompensation begins. Conclusions: Cirrhosis due to HCC generates a very high hospitalization’s costs. The methodology used in the estimation of these costs from the DRG can be very useful to evaluate the trend and economic impact of this disease.RESUMEN Fundamentos: Los costes hospitalarios asociados a la Hepatitis Crónica C (HCC) surgen en los estadíos finales de la enfermedad. Su cuantificación es de gran utilidad para estimar la carga de la enfermedad y establecer decisiones de financiación de los nuevos antivirales. Los costes más elevados son motivados por la descompensación de la cirrosis. Métodos: Estudio observacional de corte transversal de los costes hospitalarios de episodios con diagnóstico de HCC en la Comunidad Valenciana en 2013. Fuente de información: Conjunto mínimo básico de datos. Se estimaron los costes según las tarifas establecidas para los GRD (Grupos relacionados por el diagnóstico) asociados a los episodios con diagnóstico de hepatitis C. La supervivencia media de los pacientes desde que se inició la descompensación de su cirrosis se estimó mediante un modelo de Markov, según las probabilidades de evolución de la enfermedad existentes en la literatura. Resultados: Se registraron 4.486 episodios de hospitalización con diagnóstico de HCC, 1.108 fueron debidos a complicaciones de la HCC que generaron 6.713 estancias, tasa de reingresos del 28,2 % y mortalidad del 10,2%. El coste hospitalario ascendió a 8.788.593EUR: 3.306.333EUR correspondieron a Cirrosis (5.273EUR/paciente); 1.060.521EUR a Carcinoma (6.350EUR/paciente) y 2.962.873EUR a trasplante (70.544EUR/paciente). La comorbilidad por Hepatitis C supuso 1.458.866EUR. Estos costes se mantienen durante una media de 4 años una vez comienza la descompensación de la cirrosis. Conclusiones: La cirrosis por HCC genera un coste muy elevado por hospitalización, la metodología utilizada en la estimación de estos costes a partir de los GRD puede ser de gran utilidad para evaluar la tendencia e impacto económico de esta enfermedad

The PHES battery does not detect all cirrhotic patients with early neurological deficits, which are different in different patients.

BACKGROUND AND AIMS:The psychometric hepatic encephalopathy score (PHES) is the "gold standard" for minimal hepatic encephalopathy (MHE) diagnosis. Some reports suggest that some cirrhotic patients "without" MHE according to PHES show neurological deficits and other reports that neurological alterations are not homogeneous in all cirrhotic patients. This work aimed to assess whether: 1) a relevant proportion of cirrhotic patients show neurological deficits not detected by PHES; 2) cirrhotic patients with mild neurological deficits are a homogeneous population or may be classified in sub-groups according to specific deficits. METHODS:Cirrhotic patients "without" (n = 56) or "with" MHE (n = 41) according to PHES and controls (n = 52) performed psychometric tests assessing attention, concentration, mental processing speed, working memory and bimanual and visuomotor coordination. Heterogeneity of neurological alterations was analysed using Hierarchical Clustering Analysis. RESULTS:PHES classified as "with" MHE 42% of patients. Around 40% of patients "without" MHE according to PHES fail two psychometric tests. Oral SDMT, d2, bimanual and visuo-motor coordination tests are failed by 54, 51, 51 and 43% of patients, respectively. The earliest neurological alterations are different for different patients. Hierarchical clustering analysis shows that patients "without" MHE according to PHES may be classified in clusters according to the tests failed. In some patients coordination impairment appear before cognitive impairment while in others concentration and attention deficits appear before. CONCLUSIONS:PHES is not sensitive enough to detect early neurological alterations in a relevant proportion of cirrhotic patients. Oral SDMT, d2 and bimanual and visuo-motor coordination tests are more sensitive. The earliest neurological alterations are different in different cirrhotic patients. These data also have relevant clinical implications. Patients classified as "without MHE" by PHES belonging to clusters 3 and 4 in our study have a high risk of suffering clinical complications, including overt HE and must be diagnosed and clinically followed

Reduced resting state connectivity and gray matter volume correlate with cognitive impairment in minimal hepatic encephalopathy.

Minimal hepatic encephalopathy (MHE) is associated with cognitive alterations and changes in connectivity. We assessed the relationship of the abnormalities of resting-state functional connectivity (rs-FC) and gray matter (GM) volume with different cognitive alterations and biochemical parameters associated to MHE.Thirty-nine cirrhotic patients (26 without and 13 with MHE) and 24 controls were widely cognitive assessed with a battery of psychometric tests. Atrophy was determined using Voxel-Based Morphometry and rs-FC was assessed by independent component analysis. Receiver operating characteristic (ROC) curves was performed to assess the diagnostic utility of rs-FC and GM reduction for the discrimination of patients with and without MHE. Blood ammonia, cGMP, and levels of pro-inflammatory interleukins were measured.MHE patients showed significant decrease of GM volume and lesser degree of rs-FC in different networks related to attention and executive functions as compared to controls and patients without MHE. There is a progressive reduction in rs-FC in the default mode network with the progression of cognitive impairment. MHE patients showed GM reduction in the right frontal lobe, right insula and right cerebellum compared to patients without MHE. Alterations in GM volume and rs-FC correlated with the scores of different cognitive tests.Decreased cognitive performance is associated by reduced rs-FC and GM atrophy in MHE patients. These changes could have predictive value for detecting MHE

Dendrogram showing the clustering of all individuals in main groups and sub-groups.

<p>All subjects included in the study have been arranged according to the similarity-dissimilarity of their performance in the combination of tests indicated using hierarchical clustering analysis. This analysis provides clusters including subjects more closely related between them than subjects assigned to a different cluster. These clusters are visualized in the dendrogram shown. The first column shows the number identifying each subject, which have been coloured according to their classification by the PHES: control (black), without MHE (red) or with MHE (green). These colours are repeated in the second column to facilitate its identification. The tests failed by each individual are indicated by blue colour in the corresponding box. The following tests have been included: PHES, critical flicker frequency (CFF), the congruent, neutral and incongruent tasks of the Stroop test, Bimanual and visuo-motor coordination, d2 test, TOT: total correctly processed and d2-CON: concentration, measured with the d2 test; Oral SDMT test, Digit Span and Letter-number test.</p

Performance in psychometric tests.

<p>Performance in psychometric tests.</p

Composition of the different groups and etiology of liver disease.

<p>Composition of the different groups and etiology of liver disease.</p

Patients “without” MHE according to PHES show impaired performance in some psychometric tests.

<p>The tests were performed by patients classified as “without” or “with” MHE according to PHES and by controls. (A) Percentage of individuals of each group that fail the indicated number of tests or more. (B) Percentage of tests failed by each group (mean±SD). (C) Each bar represents the percentage of tests failed by each individual subject. (D) Percentage of total cirrhotic patients (“without” or “with” MHE according to PHES) failing the indicated tests: Oral SDMT test, total items; d2 test, TOT: total correctly processed; bimanual coordination; concentration, measured with the d2 test and in visuo-motor coordination.</p