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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 (ANT 1 ) (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 ANT 1 . 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, ANT 1 was influenced by limited education (<8 years) and advanced age (>80 years, P < 0.001). Using an age and education adjusting procedure, the simplified ANT 1 (S-ANT 1 ) was obtained. An S-ANT 1 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-ANT 1 than unimpaired patients (12 ± 0.4 versus 16 ± 0.7, P < 0.001) and higher S-ANT 1 than those with HE ≥grade 2 (4 ± 0.9). In grade 1 HE the S-ANT 1 was lower than in MHE. Following receiver operating characteristic analysis (Youden's index), 15 animals produced the best discrimination between unimpaired and MHE/grade 1 HE patients. Thus, a three-level score (0 for S-ANT 1 ≥15, 1 for 10 ≤ S-ANT 1 < 15, 2 for S-ANT 1 <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-ANT 1 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-ANT 1 is an easily obtainable measure useful for the assessment of HE. (Hepatology 2017;66:198-208)., (© 2017 by the American Association for the Study of Liver Diseases.)

Unlabelled: Electroencephalography (EEG) is useful to objectively diagnose/grade hepatic encephalopathy (HE) across its spectrum of severity. However, it requires expensive equipment, and hepatogastroenterologists are generally unfamiliar with its acquisition/interpretation. Recent technological advances have led to the development of low-cost, user-friendly EEG systems, allowing EEG acquisition also in settings with limited neurophysiological experience. The aim of this study was to assess the relationship between EEG parameters obtained from a standard-EEG system and from a commercial, low-cost wireless headset (light-EEG) in patients with cirrhosis and varying degrees of HE. Seventy-two patients (58 males, 61 ± 9 years) underwent clinical evaluation, the Psychometric Hepatic Encephalopathy Score (PHES), and EEG recording with both systems. Automated EEG parameters were calculated on two derivations. Strong correlations were observed between automated parameters obtained from the two EEG systems. Bland and Altman analysis indicated that the two systems provided comparable automated parameters, and agreement between classifications (normal versus abnormal EEG) based on standard-EEG and light-EEG was good (0.6 < κ < 0.8). Automated parameters such as the mean dominant frequency obtained from the light-EEG correlated significantly with the Model for End-Stage Liver Disease score (r = -0.39, P < 0.05), fasting venous ammonia levels (r = -0.41, P < 0.01), and PHES (r = -0.49, P < 0.001). Finally, significant differences in light-EEG parameters were observed in patients with varying degrees of HE., Conclusion: Reliable EEG parameters for HE diagnosing/grading can be obtained from a cheap, commercial, wireless headset; this may lead to more widespread use of this patient-independent tool both in routine liver practice and in the research setting. (, (© 2016 by the American Association for the Study of Liver Diseases.)

A considerable proportion of patients with cirrhosis exhibit insomnia, delayed sleep habits, and excessive daytime sleepiness. These have been variously attributed to hepatic encephalopathy and impaired hepatic melatonin metabolism, but the understanding of their pathophysiology remains limited and their treatment problematic. Sleep is regulated by the interaction of a homeostatic and a circadian process. The homeostatic process determines sleep propensity in relation to sleep-wake history, thus the need to sleep increases with the duration of the waking period. The circadian process, which is marked by the 24-hour rhythm of the hormone melatonin, is responsible for the alternation of high/low sleep propensity in relation to dark/light cues. Circadian sleep regulation has been studied in some depth in patients with cirrhosis, who show delays in the 24-hour melatonin rhythm, most likely in relation to reduced sensitivity to light cues. However, while melatonin abnormalities are associated with delayed sleep habits, they do not seem to offer a comprehensive explanation to the insomnia exhibited by these patients. Fewer data are available on homeostatic sleep control: it has been recently hypothesized that patients with cirrhosis and hepatic encephalopathy might be unable, due to excessive daytime sleepiness, to accumulate the need/ability to produce restorative sleep. This review will describe in some detail the features of sleep-wake disturbances in patients with cirrhosis, their mutual relationships, and those, if any, with hepatic failure/hepatic encephalopathy. A separate section will cover the available information on their pathophysiology. Finally, etiological treatment will be briefly discussed., (© 2013 by the American Association for the Study of Liver Diseases.)

Unlabelled: Nitrogen metabolism plays a major role in the development of hepatic encephalopathy (HE) in patients with cirrhosis. Modulation of this relationship is key to the management of HE, but is not the only nutritional issue that needs to be addressed. The assessment of nutritional status in patients with cirrhosis is problematic. In addition, there are significant sex-related differences in body composition and in the characteristics of tissue loss, which limit the usefulness of techniques based on measures of muscle mass and function in women. Techniques that combine subjective and objective variables provide reasonably accurate information and are recommended. Energy and nitrogen requirements in patients with HE are unlikely to differ substantially from those recommended in patients with cirrhosis per se viz. 35-45 kcal/g and 1.2-1.5g/kg protein daily. Small meals evenly distributed throughout the day and a late-night snack of complex carbohydrates will help minimize protein utilization. Compliance is, however, likely to be a problem. Diets rich in vegetables and dairy protein may be beneficial and are therefore recommended, but tolerance varies considerably in relation to the nature of the staple diet. Branched chain amino acid supplements may be of value in the occasional patient intolerant of dietary protein. Increasing dietary fiber may be of value, but the utility of probiotics is, as yet, unclear. Short-term multivitamin supplementation should be considered in patients admitted with decompensated cirrhosis. Hyponatremia may worsen HE; it should be prevented as far as possible and should always be corrected slowly., Conclusion: Effective management of these patients requires an integrated multidimensional approach. However, further research is needed to fill the gaps in the current evidence base to optimize the nutritional management of patients with cirrhosis and HE., (Copyright © 2013 American Association for the Study of Liver Diseases.)

Unlabelled: In patients with cirrhosis, hyperammonemia and hepatic encephalopathy are common after gastrointestinal bleeding and can be simulated by an amino acid challenge (AAC), or the administration of a mixture of amino acids mimicking the composition of hemoglobin. The aim of this study was to investigate the clinical, psychometric, and wake-/sleep-electroencephalogram (EEG) correlates of induced hyperammonemia. Ten patients with cirrhosis and 10 matched healthy volunteers underwent: (1) 8-day sleep quality/timing monitoring; (2) neuropsychiatric assessment at baseline/after AAC; (3) hourly ammonia/subjective sleepiness assessment for 8 hours after AAC; (4) sleep EEG recordings (nap opportunity: 17:00-19:00) at baseline/after AAC. Neuropsychiatric performance was scored according to age-/education-adjusted Italian norms. Sleep stages were scored visually for 20-second epochs; power density spectra were calculated for consecutive 20-second epochs and average spectra determined for consolidated episodes of non-rapid eye movement (non-REM) sleep of minimal common length. The AAC resulted in: (i) an increase in ammonia concentrations/subjective sleepiness in both patients and healthy volunteers; (ii) a worsening of neuropsychiatric performance (wake EEG slowing) in two (20%) patients and none of the healthy volunteers; (iii) an increase in the length of non-REM sleep in healthy volunteers [49.3 (26.6) versus 30.4 (15.6) min; P = 0.08]; (iv) a decrease in the sleep EEG beta power (fast activity) in the healthy volunteers; (v) a decrease in the sleep EEG delta power in patients., Conclusion: AAC led to a significant increase in daytime subjective sleepiness and changes in the EEG architecture of a subsequent sleep episode in patients with cirrhosis, pointing to a reduced ability to produce restorative sleep., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Unlabelled: The diagnosis of hepatic encephalopathy (HE) relies on clinical, neurophysiological, psychometric and laboratory variables. The relationships between such tests remain debated. The aim of this study was to determine the laboratory correlates/prognostic value of neurophysiological/psychometric abnormalities in patients with cirrhosis. Seventy-two patients and 14 healthy volunteers underwent EEG and paper-and-pencil psychometry (PHES). Blood was obtained for C reactive protein (CRP), interleukin 6 (IL6), tumor necrosis factor (TNF)α, ammonia and indole/oxindole. Patients were followed prospectively for a median of 22 months in relation to the occurrence of death, transplantation and HE-related hospitalizations. Thirty-three patients had normal PHES and EEG, 6 had abnormal PHES, 18 abnormal EEG and 13 abnormal PHES and EEG. Patients with abnormal PHES had higher CRP (17 ± 22 vs 7 ± 6, P < 0.01), IL6 (32 ± 54 vs 12 ± 13, P < 0.05) and TNFα (17 ± 8 vs 11 ± 7, P < 0.001) levels than those with normal PHES. Patients with abnormal EEG had higher indole (430 ± 270 vs 258 ± 255, P < 0.01) and ammonia (66 ± 35 vs 45 ± 27, P < 0.05) levels than those with normal EEG. Psychometric test scores showed significant correlations with CRP, TNFα and IL6; EEG indices with ammonia and IL6. CRP and TNFα concentrations were independent predictors of abnormal PHES, ammonia and indole of abnormal EEG on multivariate analysis. Seven patients were lost to follow-up; of the remaining 65, 20 died and 14 underwent transplantation; 15 developed HE requiring hospitalization. PHES and EEG performance were independent predictors of HE and death (P < 0.05)., Conclusion: PHES and EEG abnormalities in patients with cirrhosis have partially different biochemical correlates and independently predict outcome., (Copyright © 2010 American Association for the Study of Liver Diseases.)

It is clearly established that beta-blockers decrease the risk of a first variceal bleeding in cirrhosis. We have recently shown that the addition of isosorbide mononitrate to nadolol decreases the rate of variceal bleeding in patients with cirrhosis and varices, compared with nadolol alone, after a median follow-up of 30 months. It is not established if the long-term treatment with the combination continues to be beneficial. Therefore, we assessed the long-term effect of this combination on first variceal bleeding, complications, and death. One hundred forty-six cirrhotic patients with esophageal varices included in a previously published multicenter, randomized study comparing nadolol (40-160 mg/d) with the combination nadolol plus isosorbide mononitrate (10-20 mg 3 times per day) were followed up for up to 7 years (median follow-up, 55 months). The primary end-point was variceal bleeding of any severity. Twenty-four patients (16 in the nadolol group, and 8 in the combination group) experienced variceal bleeding (log rank test, P =.02). Cumulative risk of bleeding was 29% and 12%, respectively (95% CI for the difference, 1%-23%). Two and 4 patients, respectively, had bleeding from portal hypertensive gastropathy (log rank test, P =.20). Thirty and 25 patients, respectively, died during follow-up (log rank test, P =.13). Twelve and 10 patients, respectively, had de novo occurrence of ascites during follow-up (log rank test, P =.29). In conclusion, nadolol plus isosorbide mononitrate is significantly more effective than nadolol alone in the long-term use. Side effects are few, and no deleterious effects on ascites occurrence or on survival occur after long-term use of this combination.

The prevalence and the clinical implications of subclinical cognitive alterations in cirrhotic patients have not been well defined as yet. Therefore, we performed a study to assess the clinical features and the survival of cirrhotic patients with cognitive alterations detected by the number connection test (NCT) and a set of computerized psychometric tests (Scan, Choice1, and Choice2) measuring the reaction times and the percentage of errors in performing specific tasks. Ninety-four cirrhotic patients (aged 58 +/- 9 years) without overt hepatic encephalopathy and 80 controls (aged 53 +/- 15 years) were consecutively enrolled. The median follow-up in cirrhotic patients was 426 days (lower quartile = 213 days; upper quartile = 718 days). Results of the NCT, Scan test, and Choice2 test were significantly worse in cirrhotic patients, whereas Choice1 did not differ significantly from the controls. In cirrhotic patients, the prevalence of altered psychometric tests was 21% (CI95% = 14%-31%) by NCT, 23% (CI95% =15%-33%) by Scan test, and 20% (CI95% =16%-30%) by Choice2 test. The alterations of NCT, Scan, and Choice2 were found to be related to the severity of liver disease, independently of its etiology. Increased risk of death was found to be associated with altered Scan test (hazard ratio = 2.4; CI95% =1. 1-5.3), or altered Choice2 test (hazard ratio = 2.8; CI95% = 1.2-6. 3). Multivariate regression showed that Scan and Choice2 tests had prognostic value on survival, in addition to Child-Pugh classes in the first year of follow-up.

The aim of the study was to verify the effects of the administration of an inhibitor of the release of endogenous vasodilators together with a vasoconstrictor agent in patients with hepatorenal syndrome (HRS). This new medical perspective was compared with a traditional medical approach for HRS, such as the infusion of nonpressor doses of dopamine to produce renal vasodilation. Thirteen patients with type 1 HRS were enrolled in the study. Five of them were treated with the oral administration of midodrine and the parenteral administration of octreotide. In addition, the patients received 50 to 100 mL of 20% human albumin solution daily for 20 days. Midodrine and octreotide were dosed to obtain a stable increase of at least 15 mm Hg of mean arterial pressure. Eight patients were treated with the intravenous administration of nonpressor doses of dopamine (2-4 micrograms/kg/min) and the same daily amount of albumin. After 20 days of treatment with midodrine and octreotide, an impressive improvement in renal plasma flow (RPF), glomerular filtration rate, and urinary sodium excretion was observed in patients. This was accompanied by a significant reduction in plasma renin activity, plasma vasopressin, and plasma glucagon. No side effects were observed. Three patients were discharged from the hospital. One of them successfully underwent liver transplantation. One of the two remaining patients is still alive after 472 days with a preserved renal function, and the other died from terminal liver failure after 76 days. One of the two patients who were not discharged from the hospital successfully underwent liver transplantation, and the other died from pneumonia after 29 days. Seven out of eight patients who were treated with dopamine experienced a progressive deterioration in renal function and died during the first 12 days. Only one patient recovered renal function and underwent liver transplantation. In conclusion, the long-term administration of midodrine and octreotide seems to be an effective and safe treatment of type 1 HRS in patients with cirrhosis.

Attentional dysfunction, which influences overall cognitive productivity, is not well characterized in cirrhotic patients. The aim of this study was to clarify the features of covert visual attention orienting in cirrhotics without overt hepatic encephalopathy. One hundred consecutive cirrhotic patients and 40 controls were enrolled. Visual covert attention orienting was assessed by the Posner test, which evaluates the effect of a cue on visual reaction times. Patients were characterized by the number connection test (NCT) and electroencephalographic (EEG) spectral analysis. The severity of liver disease was graded using standard laboratory parameters and the Child-Pugh's classification. Fifty-five psychometric and EEG evaluations were performed in the follow-up of 17 patients to assess the relationship between the variations of psychometric and neurophysiological findings. NCT and quantified-EEG parameters (altered in 19% and 40% of cirrhotic patients, respectively) were linked to each other and to the severity of liver disease. The Posner test showed a delay of visual reaction times in class B-C cirrhotic patients. Reaction times were correlated with ammonia and EEG parameters. The effect of the cue was higher in cirrhotic patients than in controls, particularly in the invalid position. This study suggests that cirrhotic patients have a reduced activity rate and reduced capacity to disengage attention previously focused on a cue. Such alterations are linked to NCT and EEG findings.

The association beta-blockers plus nitrates has been reported to impair renal function and renal sodium handling, leading to increased risk of development of ascites, or worsening of a preexisting ascites, or increase in the requirements of diuretic agents. In 81 patients with cirrhosis and esophageal varices, participating in a multicenter controlled clinical trial of prophylaxis of variceal bleeding comparing nadolol (NAD) plus isosorbide-5-mononitrate (I5M) with NAD alone, renal function, presence of ascites, and diuretic requirements were assessed at inclusion and after 6 months of follow-up. No significant variation in s-urea or s-creatinine was observed in either group, Three patients in the nadolol group and two in the NAD plus I5M developed ascites at 6 months (P = .70), and a need to increase diuretic regimen was observed in four and three patients, respectively (P = .76). Decrease in heart rate and in mean arterial pressure was similar in the two groups. There was a significant correlation between increases in s-creatinine and decrease in mean arterial pressure in the whole series (P = .015). Only in patients treated with the association was there a significant larger proportion of patients ascitic who became anascitic, than of patients anascitic who became ascitic (P = .03). In patients treated with the association, there was a significantly larger decrease in hepatic venous pressure gradient (P = .05). It is concluded that patients treated with the association NAD plus I5M are not at increased risk of developing renal dysfunction or worsening of ascites compared with patients treated with NAD alone.(ABSTRACT TRUNCATED AT 250 WORDS)

The reticuloendothelial system plays an important role in the prevention of bacterial infection in patients with cirrhosis. Few data are available, however, on its activity in such patients. The aim of this study was to evaluate the maximum removal capacity of hepatic reticuloendothelial system in patients with cirrhosis on the basis of study of the removal kinetics of increasing amounts of 99mTc millimicrospheres and to verify its value as a prognostic factor for death and development of spontaneous bacterial peritonitis. Common clinical and biochemical parameters, Pugh score, maximum removal capacity, aminopyrine metabolic capacity and galactose elimination capacity were measured in 43 patients with cirrhosis (33 with alcoholic cirrhosis, 8 with posthepatitic cirrhosis and 2 with cryptogenic cirrhosis). Hepatic plasma flow and indocyanine green plasma clearance were also measured in 16 of these patients. Reference range of maximum removal capacity was determined in seven normal subjects. Maximal removal capacity below the normal range was found in 24 patients (56%). In the whole series maximum removal capacity averaged 16 +/- 12 micrograms/kg body wt/min (mean +/- S.D.). Maximal removal capacity was significantly correlated with serum albumin, prothrombin index, Pugh score, aminopyrine breath test, galactose elimination capacity and indocyanine green plasma clearance but not with hepatic plasma flow. During follow-up of up to 48 mo, spontaneous bacterial peritonitis developed in six patients, all with impaired maximum uptake capacity, and 11 patients died. Survival was significantly shorter in patients with impaired maximum removal capacity than in those with normal maximum removal capacity (log-rank test: p = 0.024).(ABSTRACT TRUNCATED AT 250 WORDS)