Francesca Campagna

Detection of minimal hepatic encephalopathy: Normalization and optimization of the Psychometric Hepatic Encephalopathy Score. A neuropsychological and quantified EEG study ☆

BACKGROUND/AIMS Psychometric Hepatic Encephalopathy Score (PHES) and EEG are used to detect minimal hepatic encephalopathy (MHE). We aimed at standardizing PHES in Italy and comparing Italian, German and Spanish norms in EEG characterized cirrhotic patients. METHODS PHES was standardized on 228 normal individuals. Repeatability was studied in 128 individuals. One hundred patients with liver cirrhosis underwent EEG and PHES which was computed on the Spanish, German and the Italian norms. RESULTS Age and education levels were predictors of psychometric tests; therefore, adjusted Z scores were calculated. Practice effect (p<0.01) was detected. In the patients, the Italian norms were closer to the Spanish norms (difference -0.14+/-1.32, p=0.29) than to the Germans ones (difference 1.97+/-2.07, p<0.001). The PHES calculated on the Italian norms was correlated with the EEG mean dominant frequency more closely than the ones calculated on the German and Spanish norms (r=0.38, r=0.31, r=0.33, respectively -p<0.01). The detection of MHE on the basis of PHES and EEG showed limited agreement (73%, Cohens K=0.32). CONCLUSIONS (i) Valid norms for PHES were produced, (ii) clues for the use of common norms in Latin Countries were found, (iii) different findings between PHES and EEG possibly reflect various features of MHE.

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. Liver Transpl 20:977‐986, 2014.

The animal naming test: An easy tool for the assessment of hepatic encephalopathy

Screening for hepatic encephalopathy (HE) that does not cause obvious disorientation or asterixis (minimal HE [MHE]/grade 1 HE) is important. We examined if the animal naming test (ANT1) (maximum number of animals listed in 1 minute) is useful in this context. In total, 208 healthy controls, 40 controls with inflammatory bowel disease, and 327 consecutive patients with cirrhosis underwent the ANT1. Patients were tested for MHE by the psychometric HE score, and 146 were assessed by electroencephalography; 202 patients were followed up regarding the occurrence of overt HE and death. In the healthy controls, ANT1 was influenced by limited education (<8 years) and advanced age (>80 years, P < 0.001). Using an age and education adjusting procedure, the simplified ANT1 (S‐ANT1) was obtained. An S‐ANT1 of <10 animals was abnormal. Of the patients, 169 were considered unimpaired, 32 as having HE ≥grade 2, and 126 as having MHE/grade 1 HE. This group had lower S‐ANT1 than unimpaired patients (12 ± 0.4 versus 16 ± 0.7, P < 0.001) and higher S‐ANT1 than those with HE ≥grade 2 (4 ± 0.9). In grade 1 HE the S‐ANT1 was lower than in MHE. Following receiver operating characteristic analysis (Youdens index), 15 animals produced the best discrimination between unimpaired and MHE/grade 1 HE patients. Thus, a three‐level score (0 for S‐ANT1 ≥15, 1 for 10 ≤ S‐ANT1 < 15, 2 for S‐ANT1 <10) was obtained. This score was correlated both to the psychometric HE score (P < 0.0001) and to electroencephalography (P = 0.007). By sample random split validation, both S‐ANT1 and its three‐level score showed prognostic value regarding the 1‐year risk of overt HE and death. No inflammatory bowel disease control had S‐ANT <15. Conclusion: The S‐ANT1 is an easily obtainable measure useful for the assessment of HE. (Hepatology 2017;66:198–208).

Confounders in the detection of minimal hepatic encephalopathy: a neuropsychological and quantified EEG study

Chronic alcohol misuse, HCV infection and cirrhosis may cause cognitive alterations. The aim of the present study was to assess the influence of alcohol misuse, HCV infection and cirrhosis per se on the neuropsychological and electroencephalogram (EEG) profile and to evaluate the role of alcohol misuse and HCV infections as potential confounding factors in the detection of minimal hepatic encephalopathy.

Increased Th1 immune response in SERPINB3 transgenic mice during acute liver failure.

Acute liver failure (ALF) is characterized by severe neurological complications, known as acute hepatic encephalopathy, where brain ammonia and inflammatory processes play a dominant role. In experimental models of acute liver failure SERPINB3 was found significantly increased in microglia, the intrinsic immune cells of the central nervous system. The aim of the present study was to investigate the extent of brain tissue damage and the inflammatory milieu in experimental acute liver failure using a SERPINB3-transgenic mouse model. C57BL/6J wild-type and transgenic mice were inoculated with acetaminophen or phosphate-buffered saline and sacrificed 20 h postinjection. Proliferation and apoptotic activity were analyzed in brain tissue by immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling technique. The expression of cytokines was analysed in brain and liver tissue by real time polymerase chain reaction and in the corresponding serum samples using a Bio-Plex system. Acetaminophen induced a significantly lower body temperature and shorter survival in transgenic than in wild-type mice, despite liver function was similar in both groups. The brain of transgenic mice, expressing SERPINB3 positivity in microglia, showed increased glial cell number, associated to significant lower apoptotic death events, compared with wild-type mice. In mice injected with acetaminophen, remarkably higher values of cytokines mRNA were observed in the liver of both groups, with a trend toward higher values in transgenic animals. In brain tissue similar increase of tumor necrosis factor-αwas detected in transgenic and wild-type mice, while IL-10 mRNA increased only in the wild-type group. A remarkable increase of circulating Th1 cytokines was detected in serum of transgenic mice, while in the wild-type group they remained rather unchanged. These figures were associated with lower levels of granulocyte macropage colony-stimulating factor, despite similar increase of IL-10 values in both groups. In conclusion, in acute liver failure SERPINB3 determines an enhanced inflammatory background, mainly mediated by higher levels of Th1 proinflammatory cytokines.

461 INCOMPLETE REVERSAL OF COGNITIVE DYSFUNCTION AFTER LIVER TRANSPLANTATION IN INDIVIDUALS WHO HAD HAD OVERT HEPATIC ENCEPHALOPATHY BEFORE LIVER TRANSPLANTATION

Results: The MTHFR C677T homozygote mutation (TT) was found in 28 (21%) patients, while the remaining 107 (79%) were wild types or heterozygotes (C/*). TT as compared to C/* patients had significantly higher DMELD-score (0.329±0.093 vs 0.146±0.096 means±SE, respectively; p < 0.01) before LT. At multivariate analysis, TT genotype was independently associated with MELD-score worsening during the waiting list (OR 5.21, lower 95% C.L 1.33, upper 95% C.L 20.31, p = 0.018), after adjustment for patient age, PL-MELD score, sex, portal vein thrombosis and cirrhosis aetiology. Post-transplant patient survival was significantly (Log-Rank test p = 0.007) lower in TT (median follow-up 27 months; range 0.1–85 months) than in C/* (median follow-up 33 months; range 0.1– 102 months) recipients. At Cox regression analysis, recipient TT genotype was independently associated with post-transplant patient survival (OR 2.44, lower 95% C.L 1.22, upper 95% C.L 4.84, p = 0.011), after adjustment for recipient age, LT-MELD score, sex, HCV status, and donor risk index. Conclusions: Cirrhotic patients with the MTHFR C677T homozygous mutation have faster disease progression before LT and worse survival after LT.