Cognitive and neurophysiological assessment of patients with minimal hepatic encephalopathy in Brazil.

Minimal hepatic encephalopathy is a syndrome caused by cirrhosis, with a broad spectrum of clinical manifestations. Its diagnosis is based on abnormal results of cognitive and neurophysiological tests, but there are no universally available criteria, especially in Brazil, where local testing standards are required. The objective of the present study was to compare the performance of the mini-mental state examination (MMSE), Rey's auditory-verbal learning test (RAVLT), psychometric score of hepatic encephalopathy (PHES), topographic mapping of brain electrical activity (TMBEA) and long-latency auditory evoked potential (P300) in the detection of minimal hepatic encephalopathy in Brazil. From 224 patients with cirrhosis included in the global sample, 82.5% were excluded due to secondary causes responsible for cognitive or neurophysiological dysfunction. The final sample consisted of 29 cirrhotics, with predominance of A5 Child-Pugh classification, and 29 controls paired in critical variables such as age, educational level, gender, professional category, scores suggestive of mild depression, association with compensated type 2 diabetes mellitus and sociodemographic characteristics. Overall, performance on cognitive tests and TMBEA did not show a statistically significant difference. There was a marked difference in P300 latency adjusted for age, with patients with cirrhosis showing a mean of 385 ± 78 ms (median of 366.6 ms) and healthy volunteers exhibiting a mean of 346.2 ± 42.8 ms (median of 348.2 ms) (p < 0.01). These findings suggest that, in the earliest stages of cirrhosis, age-adjusted P300 latency was superior to cognitive assessment and TMBEA for detection of minimal hepatic encephalopathy.

Delineation of microhemorrhage in acute hepatic encephalopathy using susceptibility-weighted imaging.

INTRODUCTION: Microhemorrhages (MH's) in patients with acute hepatic encephalopathy (AHE) have scarcely been described. This study set out to assess if MH's occur in characteristic locations and frequency in patients with AHE superimposed on chronic liver failure, and to determine if such findings correlate with the clinical and MRI severity. MATERIALS AND METHODS: Over a 4.5-year period, AHE patients with SWI MRI were included. The maximum plasma ammonia level (PAL), number and location of "frank" hemorrhages (>5mm size) or MH's (<5mm) on SWI, and severity of DWI and FLAIR were recorded. Susceptibility foci in the basal ganglia were disregarded, as those changes might represent common mineralization. The presence of MH's was correlated with the MRI and clinical severity. RESULTS: Punctate MH foci were found in 18/38 (47.4%) patients. The most common locations were periventricular white matter (6/38 patients, 15.8%) and cerebral cortex (5/38, 13.2%). Of 47 MH's, only a tiny minority (8.5%) occurred in regions of abnormality on FLAIR or DWI. Both the MRI severity on FLAIR (r=0.420, p=0.013) and DWI (r=0.320, p=0.045) mildly correlated with clinical outcome, but the correlation was not significant after Bonferroni correction. No significant correlation was found between the number of MH's and the clinical score, clinical outcome, FLAIR severity, or DWI severity (range r=-0.083-0.152, p=0.363-0.618). The number of MH's was not significantly different among various vasculopathies. Foci on SWI improved in two patients following liver transplantation. CONCLUSION: SWI-positive foci outside of the basal ganglia (presumed MH's) are present in nearly half of AHE patients, but do not portend outcome. Regions with the most observed MH's were the periventricular white matter, cortical gray matter, and subcortical white matter.

Prospective Multicenter Observational Study of Overt Hepatic Encephalopathy.

BACKGROUND: Overt hepatic encephalopathy (OHE) is a frequent complication of decompensated cirrhosis. AIMS: A multicenter prospective observational study was performed to assess the most commonly recorded presenting manifestations of OHE and its associated health-care burden. METHODS: Qualifying patients must have experienced ≥1 OHE episode within 30 days of enrollment (qualifying OHE) and were followed for recurrence (on-study OHE). RESULTS: Two hundred and sixty-five patients were enrolled at 30 sites and followed for up to 9 months (mean 72 days). Seventy-two patients experienced 122 on-study episodes; with 72, 23, and 13 having ≥1, ≥2, or ≥3 on-study episodes with median days to occurrence of the 1st, 2nd, and 3rd episode of 34, 19, and 11, respectively. The most frequently recorded OHE manifestations included confusion (78 %), change in mental status (57 %), disorientation (48 %), lethargy (46 %), and asterixis (45 %). West Haven grade was used inconsistently and recorded for only 28 % of episodes. Most qualifying and on-study episodes occurred on rifaximin (60 and 82 %, respectively) and were associated with hospitalization (68 and 85 %, respectively). Twenty-three patients experienced ≥2 on-study episodes within 2 months of enrollment on average (median 45 days) and accounted for 60 % of on-study episodes. CONCLUSIONS: In this prospective study, OHE's most commonly recorded presenting manifestations included confusion, altered mental status, disorientation, lethargy, and asterixis. As reflected by frequent recurrence and hospitalizations, OHE, particularly the approximately 10 % of "high-resource-utilizing" patients with frequent recurrence, continues to pose a major unmet medical need and health-care burden despite the use of rifaximin.

The role of fecal calprotectin in assessment of hepatic encephalopathy in patients with liver cirrhosis.

INTRODUCTION: Calprotectin is a cytoplasmatic protein of neutrophilic granulocytes and it is an established marker for the assessment of localized intestinal inflammation. AIM: To explore correlation between values of fecal calprotectin and degree of liver cirrhosis and hepatic encephalopathy. METHODS: We included 60 patients with liver cirrhosis and 37 healthy patients as controls. Patients revealing other causes of abnormal calprotectin results (gastrointestinal bleeding or inflammatory bowel disease) were excluded. The degree of liver insufficiency was assessed according to the Child-Pugh classification and Model of End Stage Liver Disease (MELD), and degree of hepatic enceph- alopathy by West-Haven criteria, serum concentration of ammonium ion and the number connection test. RESULTS: The mean value of fecal calprotectin in patients with liver cirrhosis was 189.1 ± 168.0 µg/g, and 35.0 ± 26.0 µg/g in the control group, respectively. We have confirmed significantly higher fecal calprotectin in patients with cirrhosis (p < 0.001). There were no significant differences in values of fecal calprotectin between the patients with different stages of liver cirrhosis according to Child-Pugh classification and MELD score (p > 0.05). We observed statistically significant difference comparing fecal calprotectin by West-Haven criteria of hepatic encephalopathy (p < 0.001), while there were no correlation with the number connection test and serum concentration of ammonium ion (p > 0.05). CONCLUSION: We confirmed significantly higher values of fecal calprotectin in patients with liver cirrhosis, especially in hepatic encephalopathy according to West-Haven criteria.

Serial evaluation of children with ALF with advanced MRI, serum proinflammatory cytokines, thiamine, and cognition assessment.

OBJECTIVES: This prospective, sequential study was done to understand changes in cerebral edema (CE) on magnetic resonance imaging and magnetic resonance spectroscopy, liver functions, and neurocognitive testing (NCT) in children with acute liver failure (ALF). METHODS: A total of 11 ALF and 8 healthy controls were evaluated with advanced magnetic resonance (MR) imaging, blood proinflammatory cytokines (PCs), thiamine levels, liver functions, and NCT. Reevaluation was done at 43.5 ±â€Š26.9 days (first follow-up, n = 8) and 157.3 ±â€Š52.3 days (second follow-up, n = 6) after discharge. RESULTS: At diagnosis, patients with ALF had vasogenic and cytotoxic CE, raised brain glutamine (23.2 ±â€Š3.4 vs. 15.3 ±â€Š2.7), and serum PCs (tumor necrosis factor [TNF]-α 40.1 ±â€Š8.9 vs. 7.2 ±â€Š2.7  pg/mL, interleukin [IL]-6 29.2 ±â€Š14.4 vs. 4.7 ±â€Š1.2  pg/mL). The mammillary bodies (MBs) were smaller, and brain choline (1.9 ±â€Š0.36 vs. 2.6 ±â€Š0.6) and blood thiamine (55.2 ±â€Š6.7 vs. 81.8 ±â€Š10.2  nmol/L) were lower than controls. At first follow-up, the brain glutamine and CE recovered. Brain choline and MBs volume showed improvement and thiamine levels normalized. Significant reduction in TNF-α and IL-6 was seen. The patients performed poorly on NCT, which normalized at second follow-up. Liver biochemistry and thiamine levels were normal and TNF-α and IL-6 showed further reduction at second follow-up. CONCLUSIONS: Patients with ALF have CE contributed by raised brain glutamine and PCs. MBs are small because of thiamine deficiency and show recovery in follow-up. CE and brain glutamine recover earlier than normalization of NCT and liver functions. Persistence of raised cytokines up to 6 months after insult suggests possible contribution from liver regeneration.

Risk assessment of development of hepatic decompensation in histologically proven hepatitis B viral cirrhosis using liver stiffness measurement.

BACKGROUND/AIMS: There are few studies regarding the predictive value of liver stiffness measurement (LSM) for development of hepatic decompensation. We assessed the risk of hepatic decompensations in B-viral compensated cirrhosis, using an LSM and LSM-based model (LSM-spleen diameter to platelet ratio score, LSPS = LSM × spleen diameter/platelet count) in a prospective, longitudinal study. METHODS: We analyzed 217 patients with histologically proven B-viral cirrhosis, well-preserved liver function, and no history of decompensation. The Kaplan-Meier and Cox regression method were used to examine the major endpoint, time to the first decompensation event, defined as development of ascites, hepatic encephalopathy, variceal hemorrhage, and deterioration of liver function to Child-Pugh class B/C. RESULTS: During follow-up, 26 patients experienced hepatic decompensation, ascites (n = 22), hepatic encephalopathy (n = 11), variceal hemorrhage (n = 9), and deterioration of liver function (n = 20). For risk stratification, patients were grouped as LSM <13, 13-18, and ≥18 kPa, and from multivariate analysis, patients with LSM 13-18 kPa [hazard ratio (HR) 4.547/ p = 0.044] and ≥18 kPa (HR 12.446/p < 0.001) retained independently higher risks than patients with LSM <13 kPa. Similarly, when patients were grouped as LSPS <1.1, 1.1-2.5, and ≥2.5, those with LSPS 1.1-2.5 (HR 5.796/p = 0.004) and ≥2.5 (HR 13.618/p < 0.001) retained independently higher risks than those with LSPS <1.1. CONCLUSION: LSM and LSPS are useful in risk assessment of hepatic decompensation among complication-naive B-viral cirrhotic patients.

Assessment and usefulness of clinical scales for semiquantification of overt hepatic encephalopathy.

Hepatic encephalopathy (HE) represents the effects of liver dysfunction on the brain. When HE is clinically obvious (eg, confusion, poor judgment, personality change), it is termed overt HE. The severity of HE is measured by different methods. Assessing the severity of HE is important for determining patient prognosis and effectiveness of therapy. This article discusses the different methods for grading HE, including clinical rating scales, neuropsychological tests, and neurophysiologic measures.

Validation of model for end-stage liver disease score to serum sodium ratio index as a prognostic predictor in patients with cirrhosis.

AIM: To evaluate the prognostic ability of model for end-stage liver disease (MELD) to serum sodium (SNa) ratio (MESO) index and to compare the predictive accuracy of the MESO index with the MELD score and the modified Child-Turcotte-Pugh (CTP) score for short-term survival in cirrhotic patients. METHODS: A total of 256 patients with cirrhosis were retrospectively evaluated. The predictive accuracy of the MESO index, MELD score and modified CTP score were compared by the area under the receiver-operator characteristic curve (AUC). RESULTS: Using 1-month and 3-month mortality as the end-point, overall, MESO and MELD were significantly better than the CTP score in predicting the risk of mortality at 1 month (AUC, 0.866,0.819 vs 0.722, P < 0.01) and 3 months (AUC, 0.875,0.820 vs 0.721, P < 0.01). In the low MELD group, the AUC of MESO index (0.758, 0.759) and CTP score (0.754, 0.732) were higher than that of the MELD score (0.608, 0.611) at 1 month and 3 months, respectively (P < 0.01). However, in the high MELD group, the AUC of MESO index (0.762, 0.779) and MELD (0.737, 0.773) were higher than that of the CTP score (0.710, 0.752) at 1 month and 3 months, respectively, although there were no significant differences (P > 0.05). With appropriate cut-offs for the MESO index, the mortality rate of patients in high MESO was higher (57.1% at 1 month and 69.2% at 3 months) than that of the low MESO (5.5% at 1 month and 7.9% at 3 months) (P < 0.01). CONCLUSIONS: The MESO index, which adds SNa to MELD, is a useful prognostic marker and is found to be superior to the MELD score and modified CTP score for short-term prognostication of patients with cirrhosis.

Causes of death in fulminant hepatic failure and relationship to quantitative histological assessment of parenchymal damage.

The clinical course and causes of death in 132 consecutive patients with fulminant hepatic failure and grade III or IV encephalopathy have been reviewed. 105 patients died and in 96 of these an autopsy examination was performed. In 36 patients there was cerebral oedema and the mean age of this group was significantly younger than the other fatal cases. In 28 patients death was attributed to major haemorrhage which originated in the gastrointestinal tract in 25. The prothrombin time ratio was not significantly greater in patients with major bleeding than in those without but they did have a significantly lower platelet count. Sepsis contributed to death in 12 patients. In 25 patients massive hepatic necrosis only was found at autopsy and death was considered to be due solely to hepatic failure. The degree of hepatocyte loss was assessed in 80 fatal cases by a histological morphometric technique on a needle specimen of liver taken immediately post-mortem. The proportion of the liver volume occupied by hepatocytes (hepatocyte volume fraction, HVF) was greatly reduced in all patients (normal 85+/-SD 5 percent) but the mean value was significantly higher in the patients dying with sepsis, cerebral oedema or haemorrhage than in the group in whom death was attributed solely to hepatic failure. There were ten patients in whom liver function was improving at the time of death which was due to cerebral (9) or haemorrhage (1). These observations suggest that many patients presently dying from fulminant hepatic failure may be expected to survive, once more effective therapy is available for the complications of the illness.