|
1
|
Granados-Fuentes D, Cho K, Patti GJ, Costa R, Herzog ED, Montagnese S. Hyperammonaemia disrupts daily rhythms reversibly by elevating glutamate in the central circadian pacemaker. Liver Int 2023; 43:673-683. [PMID: 36367321 PMCID: PMC9974605 DOI: 10.1111/liv.15476] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/21/2022] [Accepted: 11/09/2022] [Indexed: 11/13/2022]
Abstract
Patients with cirrhosis exhibit features of circadian disruption. Hyperammonaemia has been suggested to impair both homeostatic and circadian sleep regulation. Here, we tested if hyperammonaemia directly disrupts circadian rhythm generation in the central pacemaker, the suprachiasmatic nuclei (SCN) of the hypothalamus. Wheel-running activity was recorded from mice fed with a hyperammonaemic or normal diet for ~35 days in a 12:12 light-dark (LD) cycle followed by ~15 days in constant darkness (DD). The expression of the clock protein PERIOD2 (PER2) was recorded from SCN explants before, during and after ammonia exposure, ±glutamate receptor antagonists. In LD, hyperammonaemic mice advanced their daily activity onset time by ~1 h (16.8 ± 0.3 vs. 18.1 ± 0.04 h, p = .009) and decreased their total activity, concentrating it during the first half of the night. In DD, hyperammonaemia reduced the amplitude of daily activity (551.5 ± 27.7 vs. 724.9 ± 59 counts, p = .007), with no changes in circadian period. Ammonia (≥0.01 mM) rapidly and significantly reduced PER2 amplitude, and slightly increased circadian period. The decrease in PER2 amplitude correlated with decreased synchrony among circadian cells in the SCN and increased extracellular glutamate, which was rescued by AMPA glutamate receptor antagonists. These data suggest that hyperammonaemia affects circadian regulation of rest-activity behaviour by increasing extracellular glutamate in the SCN.
Collapse
Affiliation(s)
| | - Kevin Cho
- Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, USA
| | - Gary J. Patti
- Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, USA
| | - Rodolfo Costa
- Department of Biology, University of Padova, Padova, Italy
- Institute of Neuroscience, National Research Council of Italy (CNR), Padova, Italy
- Chronobiology Section, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
| | - Erik D. Herzog
- Biology Department, Washington University in St. Louis, USA
| | - Sara Montagnese
- Chronobiology Section, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
- Department of Medicine, University of Padova, Italy
| |
Collapse
|
|
2
|
The effect of induced hyperammonaemia on sleep and melanopsin-mediated pupillary light response in patients with liver cirrhosis: A single-blinded randomized crossover trial. PLoS One 2022; 17:e0275067. [PMID: 36170326 PMCID: PMC9518847 DOI: 10.1371/journal.pone.0275067] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 09/06/2022] [Indexed: 11/25/2022] Open
Abstract
Background & aims Sleep disturbances are related to hepatic encephalopathy and hyperammonaemia in patients with cirrhosis. The circadian rhythm is regulated by light stimulation of the retina via melanopsin-containing ganglion cells. The study aimed to investigate whether induced hyperammonaemia affects the pupillary light response and sleep efficiency in patients with cirrhosis. Methods The study was a single-blinded crossover trial including nine patients with cirrhosis. Sleep was evaluated by Pittsburgh Sleep Quality Index (PSQI) and monitored for twelve nights with wrist accelerometers and sleep diaries. On two experimental days, separated by one week, patients were randomized to ingest either an oral amino acid challenge (AAC) or an isocaloric glucose solution (GS). We measured pupillary light response, capillary ammonia, the Karolinska Sleepiness Scale (KSS), and two neuropsychological tests on both experimental days. Results The patients had poor self-assessed sleep quality. The amino acid challenge led to a significant increase in capillary ammonia and KSS. The time spent in bed sleeping after AAC was longer and with a reduced movement index compared to baseline but not different from GS. We found no difference in the pupillary light response or neuropsychiatric tests when comparing the effect of AAC with GS. Conclusions Patients with cirrhosis had impaired sleep quality. Induced hyperammonaemia led to increased sleepiness but had no acute effect on pupillary light response or the neuropsychiatric tests. Trial registration Registration number: NCT04771104.
Collapse
|
|
3
|
Mallet M, Desplats V, Bouzbib C, Sultanik P, Alioua I, Marika Rudler MS, Weiss N, Thabut D. Blood ammonia in patients with chronic liver diseases: A better defined role in clinical practice. Anal Biochem 2022; 657:114873. [PMID: 36108794 DOI: 10.1016/j.ab.2022.114873] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 07/26/2022] [Accepted: 08/18/2022] [Indexed: 11/28/2022]
Abstract
Ammonia is one of the main players in the pathogenesis of hepatic encephalopathy (HE) in patients with chronic liver diseases. The usefulness of measuring ammonemia has been debated since many years. New data reveal that besides helping in the differential diagnosis of HE, ammonemia could be a prognostic marker not only in patients with HE, but also in patients without any neurological symptoms, suggesting a potential toxic role of ammonia beyond the brain. Finally, targeting ammonemia while monitoring therapeutic response could be a way to improve outcomes in patients with HE.
Collapse
Affiliation(s)
- Maxime Mallet
- Sorbonne Université, AP-HP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Service D'hépato-gastroentérologie, Unité de soins intensifs D'hépatologie, Paris, France & Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, Maladies Métaboliques, Biliaires et fibro-inflammatoire du Foie, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
| | - Victor Desplats
- Sorbonne Université, AP-HP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Service D'hépato-gastroentérologie, Unité de soins intensifs D'hépatologie, Paris, France & Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, Maladies Métaboliques, Biliaires et fibro-inflammatoire du Foie, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
| | - Charlotte Bouzbib
- Sorbonne Université, AP-HP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Service D'hépato-gastroentérologie, Unité de soins intensifs D'hépatologie, Paris, France & Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, Maladies Métaboliques, Biliaires et fibro-inflammatoire du Foie, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
| | - Philippe Sultanik
- Sorbonne Université, AP-HP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Service D'hépato-gastroentérologie, Unité de soins intensifs D'hépatologie, Paris, France & Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, Maladies Métaboliques, Biliaires et fibro-inflammatoire du Foie, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
| | - Imen Alioua
- Sorbonne Université, AP-HP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Service D'hépato-gastroentérologie, Unité de soins intensifs D'hépatologie, Paris, France & Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, Maladies Métaboliques, Biliaires et fibro-inflammatoire du Foie, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France; Université Paris-Saclay, CEA, INRAE, Département Médicaments et Technologies pour la Santé (MTS), MetaboHUB, F-91191, Gif sur Yvette, France
| | - M S Marika Rudler
- Sorbonne Université, AP-HP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Service D'hépato-gastroentérologie, Unité de soins intensifs D'hépatologie, Paris, France & Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, Maladies Métaboliques, Biliaires et fibro-inflammatoire du Foie, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
| | - Nicolas Weiss
- Sorbonne Université, AP-HP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Département de Neurologie, Unité de Médecine Intensive Réanimation à orientation Neurologique, Paris, France & Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, Maladies Métaboliques, Biliaires et fibro-inflammatoire du foie, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France & Groupe de Recherche Clinique en REanimation et Soins intensifs du Patient en Insuffisance Respiratoire aiguE (GRC-RESPIRE) Sorbonne Université, France
| | - Dominique Thabut
- Sorbonne Université, AP-HP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Service D'hépato-gastroentérologie, Unité de soins intensifs D'hépatologie, Paris, France & Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, INSERM UMR_S 938, Centre de Recherche Saint-Antoine, Maladies Métaboliques, Biliaires et fibro-inflammatoire du Foie, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
| |
Collapse
|
|
4
|
Kroupina K, Bémeur C, Rose CF. Amino acids, ammonia, and hepatic encephalopathy. Anal Biochem 2022; 649:114696. [PMID: 35500655 DOI: 10.1016/j.ab.2022.114696] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 03/30/2022] [Accepted: 04/21/2022] [Indexed: 11/30/2022]
|
|
5
|
Costa R, Montagnese S. The role of astrocytes in generating circadian rhythmicity in health and disease. J Neurochem 2021; 157:42-52. [PMID: 33539604 DOI: 10.1111/jnc.15312] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/25/2021] [Accepted: 01/28/2021] [Indexed: 01/26/2023]
Abstract
Evidence is accumulating that the mammalian circadian clock system is considerably more complex than previously believed, also in terms of the cell types that actually contribute to generating the oscillation within the master clock, in the suprachiasmatic nuclei of the hypothalamus. Here we review the evidence that has lead to the identification of a bona fide astrocytic circadian clock, and that of the potential contribution of such clock to the generation of circadian and seasonal rhythmicity in health and in neurodegenerative disorders. Finally, we speculate on the role of the astrocytic clock in determining some of the clinical features of hepatic encephalopathy, a reversible neuropsychiatric syndrome associated with advanced liver disease, which is characterized by transient, profound morphological and functional astrocytic abnormalities, in the absence of significant, structural neuronal changes.
Collapse
Affiliation(s)
- Rodolfo Costa
- Department of Biology, University of Padova, Padova, Italy
| | | |
Collapse
|
|
6
|
Variability and Lability of Ammonia Levels in Healthy Volunteers and Patients With Cirrhosis: Implications for Trial Design and Clinical Practice. Am J Gastroenterol 2020; 115:783-785. [PMID: 31449156 PMCID: PMC7192538 DOI: 10.14309/ajg.0000000000000384] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Ammonia levels are used to assess hepatic encephalopathy, but their levels are highly variable in clinical practice. METHODS We studied factors associated with variation in ammonia values in cirrhotic patients without previous hepatic encephalopathy and healthy volunteers (HVs). RESULTS Ammonia increased by 12% and 18% at 1 and 2 hour, respectively, after a protein meal in 64 cirrhotic patients (P < 0.001). In 237 HVs, ammonia levels varied significantly between sites (P < 0.0001). New site-specific ammonia upper limits based on HV levels using a strict analysis protocol differed from routinely used values. Correlation between paired fresh samples was high (r = 0.83) but modest between fresh and frozen samples (r = 0.62). DISCUSSION Sample handling, processing, and protein intake impact ammonia levels across sites.
Collapse
|
|
7
|
Senzolo M, Zarantonello L, Formentin C, Orlando C, Beltrame R, Vuerich A, Angeli P, Burra P, Montagnese S. Predictive value of induced hyperammonaemia and neuropsychiatric profiling in relation to the occurrence of post-TIPS hepatic encephalopathy. Metab Brain Dis 2019; 34:1803-1812. [PMID: 31506797 DOI: 10.1007/s11011-019-00490-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 09/03/2019] [Indexed: 01/16/2023]
Abstract
Hepatic encephalopathy (HE) occurs in 20-50% of patients after transjugular intrahepatic portosystemic shunt (TIPS) placement. Older age, HE history and severe liver failure have all been associated with post-TIPS HE but it remains difficult to identify patients at risk. The aim of the present pathophysiological, pilot study was to assess the role of induced hyperammonaemia and associated neuropsychological and neurophysiological changes as predictors of post-TIPS HE. Eighteen TIPS candidates with no overt HE history (56 ± 8 yrs., MELD 11 ± 3) underwent neurophysiological [Electroencephalography (EEG)], neuropsychological [Psychometric Hepatic Encephalopathy Score (PHES) and Scan tests], ammonia and sleepiness assessment at baseline and after the induction of hyperammonaemia by an oral amino acid challenge (AAC). Pre-AAC, 17% of patients had abnormal EEG, 5% abnormal PHES, and 33% abnormal Scan performance. Post-AAC, 17% had abnormal EEG, 0% abnormal PHES, and 17% abnormal Scan performance. Pre-AAC, ammonia concentrations were 201 ± 73 μg/dL and subjective sleepiness 2.5 ± 1.2 (1-9 scale). Post-AAC, patients exhibited the expected increase in ammonia/sleepiness. Six months post-TIPS, 3 patients developed an episode of HE requiring hospitalization; these showed significantly lower pre-AAC fasting ammonia concentrations compared to patients who did not develop HE (117 ± 63 vs. 227 ± 57 μg/dL p = 0.015). They also showed worse PHES/Scan performance pre-AAC, and worse Scan performance post-AAC. Findings at 12 months follow-up (n = 5 HE episodes) were comparable. In conclusion, baseline ammonia levels and both pre- and post-AAC neuropsychiatric indices hold promise in defining HE risk in TIPS candidates with no HE history.
Collapse
Affiliation(s)
- Marco Senzolo
- Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy
| | | | | | - Costanza Orlando
- Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Raffaello Beltrame
- Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Anna Vuerich
- Department of Medicine, University of Padova, Padova, Italy
| | - Paolo Angeli
- Department of Medicine, University of Padova, Padova, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit, Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Sara Montagnese
- Department of Medicine, University of Padova, Padova, Italy.
| |
Collapse
|
|
8
|
Marini S, Santangeli O, Saarelainen P, Middleton B, Chowdhury N, Skene DJ, Costa R, Porkka-Heiskanen T, Montagnese S. Abnormalities in the Polysomnographic, Adenosine and Metabolic Response to Sleep Deprivation in an Animal Model of Hyperammonemia. Front Physiol 2017; 8:636. [PMID: 28912724 PMCID: PMC5583967 DOI: 10.3389/fphys.2017.00636] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 08/14/2017] [Indexed: 12/17/2022] Open
Abstract
Patients with liver cirrhosis can develop hyperammonemia and hepatic encephalopathy (HE), accompanied by pronounced daytime sleepiness. Previous studies with healthy volunteers show that experimental increase in blood ammonium levels increases sleepiness and slows the waking electroencephalogram. As ammonium increases adenosine levels in vitro, and adenosine is a known regulator of sleep/wake homeostasis, we hypothesized that the sleepiness-inducing effect of ammonium is mediated by adenosine. Eight adult male Wistar rats were fed with an ammonium-enriched diet for 4 weeks; eight rats on standard diet served as controls. Each animal was implanted with electroencephalography/electromyography (EEG/EMG) electrodes and a microdialysis probe. Sleep EEG recording and cerebral microdialysis were carried out at baseline and after 6 h of sleep deprivation. Adenosine and metabolite levels were measured by high-performance liquid chromatography (HPLC) and targeted LC/MS metabolomics, respectively. Baseline adenosine and metabolite levels (12 of 16 amino acids, taurine, t4-hydroxy-proline, and acetylcarnitine) were lower in hyperammonemic animals, while putrescine was higher. After sleep deprivation, hyperammonemic animals exhibited a larger increase in adenosine levels, and a number of metabolites showed a different time-course in the two groups. In both groups the recovery period was characterized by a significant decrease in wakefulness/increase in NREM and REM sleep. However, while control animals exhibited a gradual compensatory effect, hyperammonemic animals showed a significantly shorter recovery phase. In conclusion, the adenosine/metabolite/EEG response to sleep deprivation was modulated by hyperammonemia, suggesting that ammonia affects homeostatic sleep regulation and its metabolic correlates.
Collapse
Affiliation(s)
- Selena Marini
- Department of Biology, University of PaduaPadua, Italy.,Department of Physiology, Institute of Biomedicine and Physiology, University of HelsinkiHelsinki, Finland
| | - Olena Santangeli
- Department of Physiology, Institute of Biomedicine and Physiology, University of HelsinkiHelsinki, Finland
| | - Pirjo Saarelainen
- Department of Physiology, Institute of Biomedicine and Physiology, University of HelsinkiHelsinki, Finland
| | - Benita Middleton
- Chronobiology, Faculty of Health and Medical Sciences, University of SurreyGuildford, United Kingdom
| | - Namrata Chowdhury
- Chronobiology, Faculty of Health and Medical Sciences, University of SurreyGuildford, United Kingdom
| | - Debra J Skene
- Chronobiology, Faculty of Health and Medical Sciences, University of SurreyGuildford, United Kingdom
| | - Rodolfo Costa
- Department of Biology, University of PaduaPadua, Italy
| | - Tarja Porkka-Heiskanen
- Department of Physiology, Institute of Biomedicine and Physiology, University of HelsinkiHelsinki, Finland
| | | |
Collapse
|
|
9
|
Campollo O, Sprengers D, Dam G, Vilstrup H, McIntyre N. Protein tolerance to standard and high protein meals in patients with liver cirrhosis. World J Hepatol 2017; 9:667-676. [PMID: 28588751 PMCID: PMC5437611 DOI: 10.4254/wjh.v9.i14.667] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 02/21/2017] [Accepted: 04/23/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the plasma amino acid response and tolerance to normal or high protein meals in patients with cirrhosis. METHODS The plasma amino acid response to a 20 g mixed protein meal was compared in 8 biopsy-proven compensated cirrhotic patients and 6 healthy subjects. In addition the response to a high protein meal (1 g/kg body weight) was studied in 6 decompensated biopsy-proven cirrhotics in order to evaluate their protein tolerance and the likelihood of developing hepatic encephalopathy (HE) following a porto-caval shunt procedure. To test for covert HE, the "number connection test" (NCT) was done on all patients, and an electroencephalogram was recorded in patients considered to be at Child-Pugh C stage. RESULTS The changes in plasma amino acids after a 20 g protein meal were similar in healthy subjects and in cirrhotics except for a significantly greater increase (P < 0.05) in isoleucine, leucine and tyrosine concentrations in the cirrhotics. The baseline branched chain amino acids/aromatic amino acids (BCAA/AAA) ratio was higher in the healthy persons and remained stable-but it decreased significantly after the meal in the cirrhotic group. After the high protein meal there was a marked increase in the levels of most amino acids, but only small changes occurred in the levels of taurine, citrulline, cysteine and histidine.The BCAA/AAA ratio was significantly higher 180 and 240 min after the meal. Slightly elevated basal plasma ammonia levels showed no particular pattern. Overt HE was not observed in any patients. CONCLUSION Patients with stable liver disease tolerate natural mixed meals with a standard protein content. The response to a high protein meal in decompensated cirrhotics suggests accumulation of some amino acids but it did not precipitate HE. These results support current nutritional guidelines that recommend a protein intake of 1.2-1.5 g/kg body weight/day for patients with cirrhosis.
Collapse
Affiliation(s)
- Octavio Campollo
- Octavio Campollo, Center of Studies on Alcohol and Addictions, Antigüo Hospital Civil de Guadalajara, Universidad de Guadalajara, Guadalajara, Jal CP 44280, Mexico
| | - Dirk Sprengers
- Octavio Campollo, Center of Studies on Alcohol and Addictions, Antigüo Hospital Civil de Guadalajara, Universidad de Guadalajara, Guadalajara, Jal CP 44280, Mexico
| | - Gitte Dam
- Octavio Campollo, Center of Studies on Alcohol and Addictions, Antigüo Hospital Civil de Guadalajara, Universidad de Guadalajara, Guadalajara, Jal CP 44280, Mexico
| | - Hendrik Vilstrup
- Octavio Campollo, Center of Studies on Alcohol and Addictions, Antigüo Hospital Civil de Guadalajara, Universidad de Guadalajara, Guadalajara, Jal CP 44280, Mexico
| | - Neil McIntyre
- Octavio Campollo, Center of Studies on Alcohol and Addictions, Antigüo Hospital Civil de Guadalajara, Universidad de Guadalajara, Guadalajara, Jal CP 44280, Mexico
| |
Collapse
|
|
10
|
Montagnese S, De Rui M, Angeli P, Amodio P. Neuropsychiatric performance in patients with cirrhosis: Who is "normal"? J Hepatol 2017; 66:825-835. [PMID: 27923694 DOI: 10.1016/j.jhep.2016.11.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 11/24/2016] [Accepted: 11/24/2016] [Indexed: 02/08/2023]
Abstract
In patients with cirrhosis a normal neuropsychiatric performance has been traditionally defined by the absence of any degree of hepatic encephalopathy and/or the absence of psychometric or neurophysiological abnormalities, compared with data from the healthy population. As the understanding and management of end-stage liver disease continues to change, it is our impression that the concept of normal neuropsychiatric performance also needs updating. This review explores novel and more pragmatic interpretations of neuropsychiatric "normality" compared with top personal performance, in terms of risk of overt hepatic encephalopathy or brain failure and in relation with events such as liver transplantation, decompensation, acute-on-chronic liver failure and transjugular intrahepatic portosystemic shunt placement.
Collapse
Affiliation(s)
| | - Michele De Rui
- Department of Medicine, University of Padua, Padua, Italy
| | - Paolo Angeli
- Department of Medicine, University of Padua, Padua, Italy
| | - Piero Amodio
- Department of Medicine, University of Padua, Padua, Italy
| |
Collapse
|
|
11
|
Garrido M, Skorucak J, Raduazzo D, Turco M, Spinelli G, Angeli P, Amodio P, Achermann P, Montagnese S. Vigilance and wake EEG architecture in simulated hyperammonaemia: a pilot study on the effects of L-Ornithine-L-Aspartate (LOLA) and caffeine. Metab Brain Dis 2016; 31:965-74. [PMID: 27193025 DOI: 10.1007/s11011-016-9835-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Accepted: 05/10/2016] [Indexed: 12/21/2022]
Abstract
UNLABELLED Hyperammonaemia/mild hepatic encephalopathy (HE) can be simulated by the oral administration of a so-called amino acid challenge (AAC). This study sought to assess the effects of the AAC alone and in combination with either ammonia-lowering [L-ornithine-L-aspartate (LOLA)] or vigilance-enhancing medication (caffeine). Six patients with cirrhosis (5 males; 61.3 ± 9.2 years; 5 Child A, 1 Child B) and six healthy volunteers (5 males; 49.8 ± 10.6 years) were studied between 08:00 and 19:00 on Monday of three consecutive weeks. The following indices were obtained: hourly capillary ammonia, hourly subjective sleepiness, paper & pencil/computerized psychometry and wake electroencephalography (EEG) at 12:00, i.e. at the time of the maximum expected effect of the AAC. RESULTS On average, patients had worse neuropsychological performance and slower EEG than healthy volunteers in all conditions but differences did not reach significance. In healthy volunteers, the post-AAC increase in capillary ammonia levels was contained by both the administration of LOLA and of caffeine (significant differences between 10:00 and 14:00 h). The administration of caffeine also resulted in a reduction in subjective sleepiness and in the amplitude of the EEG on several frontal/temporal-occipital sites (p < 0.05; paired t-test). Changes in ammonia levels, subjective sleepiness and the EEG in the three conditions were less obvious in patients. In conclusion, both LOLA and caffeine contained the AAC-induced increase in capillary ammonia, especially in healthy volunteers. Caffeine also counteracted the AAC effects on sleepiness/EEG amplitude. The association of ammonia-lowering and vigilance-enhancing medication in the management of HE is worthy of further study.
Collapse
Affiliation(s)
- Maria Garrido
- Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padova, Italy
| | - Jelena Skorucak
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland
- Center for Interdisciplinary Sleep Research, University of Zurich, Zurich, Switzerland
| | - Daniela Raduazzo
- Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padova, Italy
- USO Dipartimentale di Servizio Urgenza ed Emergenza Medica, ULSS 13, Dolo, Regione Veneto, Italy
| | - Matteo Turco
- Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padova, Italy
| | - Giuseppe Spinelli
- Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padova, Italy
- Department of Psychology, Sapienza University of Rome, Rome, Italy
| | - Paolo Angeli
- Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padova, Italy
| | - Piero Amodio
- Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padova, Italy
| | - Peter Achermann
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland
- Center for Interdisciplinary Sleep Research, University of Zurich, Zurich, Switzerland
- Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Sara Montagnese
- Department of Medicine, University of Padua, Via Giustiniani, 2, 35128, Padova, Italy.
| |
Collapse
|
|
12
|
Casula EP, Bisiacchi PS, Corrias M, Schiff S, Merkel C, Amodio P, Montagnese S. Acute hyperammonaemia induces a sustained decrease in vigilance, which is modulated by caffeine. Metab Brain Dis 2015; 30:143-9. [PMID: 25052067 DOI: 10.1007/s11011-014-9590-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2014] [Accepted: 07/07/2014] [Indexed: 01/29/2023]
Abstract
UNLABELLED Hyperammonaemia is observed after prolonged, intense exercise, or in patients with hepatic failure. In the latter, it is associated with a set of neurological and psychiatric abnormalities termed hepatic encephalopathy. THE AIMS OF OUR STUDY WERE 1. to measure vigilance in a condition of induced hyperammonaemia; 2. to assess whether caffeine modulates the effects of hyperammonaemia on vigilance, if any. Ten healthy volunteers (28.5 ± 5 years; 5 males) underwent three experimental sessions consisting of two-hourly measurements of capillary ammonia, subjective sleepiness (Karolinska Sleepiness Scale) and vigilance (Psychomotor Vigilance Task, PVT), in relation to the intake of breakfast (+/-coffee), an amino acid mixture which induces hyperammonaemia (amino acid challenge; AAC), and AAC+coffee (only for participants who had coffee with their standard breakfast). The AAC resulted in: 1. the expected increase in capillary ammonia levels, with highest values at approximately 4 h after the administration; 2. a significant increase in subjective sleepiness ratings; 3. a sustained increase in PVT-based reaction times. When caffeine was administered after the AAC, both subjective sleepiness and the slowing in RTs were significantly milder than in the AAC-only condition. In conclusion, acute hyperammonaemia induces an increase in subjective sleepiness and a sustained decrease in vigilance, which are attenuated by the administration of a single espresso coffee.
Collapse
Affiliation(s)
- E P Casula
- Department of Medicine, University of Padova, Via Giustiniani, 2, 35128, Padova, Italy
| | | | | | | | | | | | | |
Collapse
|
|
13
|
Wunsch E, Koziarska D, Kotarska K, Nowacki P, Milkiewicz P. Normalization of the psychometric hepatic encephalopathy score in Polish population. A prospective, quantified electroencephalography study. Liver Int 2013; 33:1332-40. [PMID: 23651263 DOI: 10.1111/liv.12194] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Accepted: 04/14/2013] [Indexed: 02/13/2023]
Abstract
BACKGROUND The psychometric hepatic encephalopathy score (PHES) is recommended as a gold standard in evaluation of minimal hepatic encephalopathy (HE). Normative databases have been collected in few countries, clearly showing differences among studied groups. Thus, the standardization of PHES for selected populations remains necessary. AIMS To standardize PHES in a large cohort of Polish healthy subjects and to evaluate the normograms in patients with cirrhosis with quantified electroencephalography (EEG). METHODS Three hundred and sixteen (142 males/174 females, aged 44.5 ± 12.1) normal individuals and 50 (31 males/19 females, aged 52.8 ± 12.4) patients with cirrhosis without overt HE were included. Key correction variables of psychometric tests were performed. The multivariate linear regression was used to calculate PHES normograms. RESULTS Age and education levels were identified as predictors of all tests, therefore age- and education-adjusted normograms were developed. A weighted time-errors regression model for line tracing test (LTT) scoring was used. The PHES ranged between +5 and -15 points and the cut-off between normal and pathological PHES was set on ≤-5 points. By this cut-off level, PHES had a sensitivity of 57% and specificity of 97% to diagnose minimal HE (AUC = 0.866 ± 0.028). In patients with cirrhosis, PHES correlated with severity of liver disease (MELD, r = -0.475, P < 0.001 and Child-Pugh classification, r = -0.452, P < 0.002) and EEG (r = 0.547, P < 0.002). In patients with impaired EEG, PHES was lower than in individuals with unaltered EEG (P < 0.02); however, agreement between these two modalities was limited. CONCLUSIONS Valid Polish PHES normograms, which incorporates w-LTT scoring system have been developed. Future multi-centre international studies are needed to validate widely applicable norms.
Collapse
Affiliation(s)
- Ewa Wunsch
- Liver Research Laboratories, Pomeranian Medical University, Szczecin, Poland
| | | | | | | | | |
Collapse
|
|
14
|
Abstract
Induction of hyperammonaemia with nitrogen challenge in man can be used to study the pathogenesis and treatment of hepatic encephalopathy complicating cirrhosis. Initially 20 g of glutamine was given orally as a flavored solution which resulted in doubling of blood ammonia concentration and this was associated with a deterioration in performance of the choice reaction time. The effect could have been due to a direct effect of glutamine rather than the ammonia generated so in subsequent experiments a glutamine free mixture of amino acids resembling the composition of haemoglobin was used (gastrointestinal bleeding is a known precipitant of hepatic encephalopathy). In Child grade B and C patients, 2-3 h after 54 g, slowing of the EEG was observed. The cerebral effects of induced hyperammonaemia were studied with diffusion weighted imaging and MR spectroscopy after giving 54 g of a mixture of threonine, serine and glycine when apparent diffusion coefficient increased. Also the change in ammonia levels correlated with the change in cerebral glutamine levels (r = 0.78, p = 0.002) suggesting intra cerebral formation of glutamine from ammonia and this may have accounted for the fall in cerebral myoinositol concentrations observed. Finally a colonic source for ammonia was confirmed by administering urea using colon coated capsules when ammonia concentrations slowly increased from 5 h after administration and rapidly after 10 h. In two patients the hyperammonaemia was ameliorated by pre treatment with Rifaximin 1200 mg per day for 1 week. Nitrogen challenge studies are thus a valuable model for studying new treatments for hepatic encephalopathy without the need to simultaneously treat precipitating factors.
Collapse
Affiliation(s)
- Hanan Mardini
- Institute of Cellular Medicine, The Medical School, Newcastle University, NE2 4HH Newcastle u Tyne, UK
| | | |
Collapse
|
|
15
|
Bersagliere A, Raduazzo I, Schiff S, Gatta A, Merkel C, Amodio P, Achermann P, Montagnese S. Ammonia-related changes in cerebral electrogenesis in healthy subjects and patients with cirrhosis. Clin Neurophysiol 2013; 124:492-6. [DOI: 10.1016/j.clinph.2012.08.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2012] [Revised: 08/16/2012] [Accepted: 08/18/2012] [Indexed: 12/20/2022]
|
|
16
|
Chavarria L, Oria M, Romero-Giménez J, Alonso J, Lope-Piedrafita S, Cordoba J. Brain magnetic resonance in experimental acute-on-chronic liver failure. Liver Int 2013; 33:294-300. [PMID: 23295057 DOI: 10.1111/liv.12032] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2012] [Accepted: 10/18/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIM Acute-on-chronic liver failure is the term that refers to sustained liver injury with acute decompensation, usually induced by a precipitating factor. A common link between ensuing failures of various organs is impairment of the vascular supply, which may also induce vasogenic oedema in the brain. The aim of this study was to perform magnetic resonance (MR) study of the brain in a rat model combining bile duct ligation (BDL) and lipopolysaccharide (LPS) administration to investigate brain oedema in liver failure. METHODS Bile duct-ligated rats underwent in vivo brain MR imaging at 4, 5 and 6 weeks, and after superimposed administration of LPS. The MR techniques applied enabled assessment of brain metabolites, and intra- or extracellular water distribution. Brain water content was assessed by gravimetry. RESULTS MR spectroscopy showed an increase in brain glutamine and a decrease in myo-inositol and choline in relation to progression of liver disease. BDL rats showed a slight, progressive increase in the amount of cortical brain water that was significant after LPS injection. These changes did not modify the apparent diffusion coefficient, supporting a mixed origin of brain oedema (vasogenic and cytotoxic). CONCLUSIONS The mechanisms leading to the development of brain oedema in an experimental liver disease model were related to the time course of liver failure and to pro-inflammatory stimuli. MR findings support the presence of cytotoxic and vasogenic mechanisms in induced brain oedema in BDL rats exposed to LPS.
Collapse
|
|
17
|
Kappus MR, Bajaj JS. Covert hepatic encephalopathy: not as minimal as you might think. Clin Gastroenterol Hepatol 2012; 10:1208-19. [PMID: 22728384 DOI: 10.1016/j.cgh.2012.05.026] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Revised: 05/30/2012] [Accepted: 05/31/2012] [Indexed: 02/07/2023]
Abstract
Hepatic encephalopathy (HE) is a serious neuropsychiatric and neurocognitive complication of acute and chronic liver disease. Symptoms are often overt (confusion, disorientation, ataxia, or coma) but can also be subtle (difficulty with cognitive abilities such as executive decision-making and psychomotor speed). There is consensus that HE is characterized as a spectrum of neuropsychiatric symptoms in the absence of brain disease, ranging from overt HE (OHE) to minimal HE (MHE). The West Haven Criteria are most often used to grade HE, with scores ranging from 0-4 (4 being coma). However, it is a challenge to diagnose patients with MHE or grade 1 HE; it might be practical to combine these entities and name them covert HE for clinical use. The severity of HE is associated with the stage of liver disease. Although the pathologic mechanisms of HE are not well understood, they are believed to involve increased levels of ammonia and inflammation, which lead to low-grade cerebral edema. A diagnosis of MHE requires dedicated psychometric tests and neurophysiological techniques rather than a simple clinical assessment. Although these tests can be difficult to perform in practice, they are cost effective and important; the disorder affects patients' quality of life, socioeconomic status, and driving ability and increases their risk for falls and the development of OHE. Patients with MHE are first managed by excluding other causes of neurocognitive dysfunction. Therapy with gut-specific agents might be effective. We review management strategies and important areas of research for MHE and covert HE.
Collapse
Affiliation(s)
- Matthew R Kappus
- Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, Virginia 23249, USA
| | | |
Collapse
|
|
18
|
Bersagliere A, Raduazzo ID, Nardi M, Schiff S, Gatta A, Amodio P, Achermann P, Montagnese S. Induced hyperammonemia may compromise the ability to generate restful sleep in patients with cirrhosis. Hepatology 2012; 55:869-78. [PMID: 21994139 DOI: 10.1002/hep.24741] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Accepted: 10/01/2011] [Indexed: 01/19/2023]
Abstract
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.
Collapse
Affiliation(s)
- Alessia Bersagliere
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
| | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Kappus MR, Bajaj JS. Assessment of minimal hepatic encephalopathy (with emphasis on computerized psychometric tests). Clin Liver Dis 2012; 16:43-55. [PMID: 22321464 PMCID: PMC3312030 DOI: 10.1016/j.cld.2011.12.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Minimal hepatic encephalopathy (MHE) is associated with a high risk of development of overt hepatic encephalopathy, impaired quality of life, and driving accidents. The detection of MHE requires specialized testing because it cannot, by definition, be diagnosed on standard clinical examination. Psychometric and neurophysiologic techniques are often used to test for MHE. Paper-pencil psychometric batteries and computerized tests have proved useful in diagnosing MHE and predicting its outcomes. Neurophysiologic tests also provide useful information. The diagnosis of MHE is an important issue for clinicians and patients alike. Testing strategies depend on the normative data available, patient comfort, and local expertise.
Collapse
Affiliation(s)
- Matthew R Kappus
- Division of Gastroenterology, Hepatology and Nutrition, McGuire VA Medical Center, Virginia Commonwealth University, 1201 Broad Rock Boulevard, Richmond, VA 23249, USA
| | | |
Collapse
|
|
20
|
Ditisheim S, Giostra E, Burkhard PR, Goossens N, Mentha G, Hadengue A, Spahr L. A capillary blood ammonia bedside test following glutamine load to improve the diagnosis of hepatic encephalopathy in cirrhosis. BMC Gastroenterol 2011; 11:134. [PMID: 22151412 PMCID: PMC3253684 DOI: 10.1186/1471-230x-11-134] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Accepted: 12/08/2011] [Indexed: 12/29/2022] Open
Abstract
Background Hepatic encephalopathy (HE) is a frequent and severe complication of cirrhosis. A single determination of ammonia in venous blood correlates poorly with neurological symptoms. Thus, a better biological marker is needed. Aim To make a diagnosis of HE, we explored the value of ammonia in capillary blood, an equivalent to arterial blood, measured at bedside following an oral glutamine challenge. Methods We included 57 patients (age 56 yrs; M/F: 37/20) with cirrhosis (alcoholic = 42; MELD score 13.8 [7-29], esophageal varices = 38) and previous episodes of HE (n = 19), but without neurological deficits at time of examination, and 13 healthy controls (age 54 yrs). After psychometric tests and capillary (ear lobe) blood ammonia measurements, 20 gr of glutamine was administered orally. Tests were repeated at 60 minutes (+ blood ammonia at 30'). Minimal HE was diagnosed if values were > 1.5 SD in at least 2 psychometric tests. Follow-up lasted 12 months. Results The test was well tolerated (nausea = 1; dizziness = 1). Patients showed higher values of capillary blood ammonia over time as compared to controls (0'-30'-60 minutes: 75, 117, 169 versus 52, 59, 78 umol/L, p < 0.05). At baseline, 25 patients (44%) had minimal HE, while 38 patients (67%) met the criteria for HE at 60 minutes (chi2: p < 0.01). For the diagnosis of minimal HE, using the ROC curve analysis, baseline capillary blood ammonia showed an AUC of 0.541 (CI: 0.38-0.7, p = 0.6), while at 60 minutes the AUC was 0.727 (CI: 0.58-0.87, p < 0.006). During follow-up, 18 patients (31%) developed clinical episodes of HE. At multivariate analysis, the MELD score (1.12 [1.018-1.236]), previous episodes of HE (3.2[1.069-9.58]), but not capillary blood ammonia, were independent predictors of event. Conclusions In patients with cirrhosis and normal neurological examination, bedside determination of ammonia in capillary blood following oral glutamine load is well tolerated and achieves a better diagnostic performance for minimal HE than basal capillary ammonia levels. However, capillary blood ammonia is a poor predictor of development of clinically overt HE.
Collapse
Affiliation(s)
- Saskia Ditisheim
- Gastroenterology and Hepatology, University Hospitals and Faculty of Medicine, 4, Rue Gabrielle Perret-Gentil, 1211 Geneva, Switzerland
| | | | | | | | | | | | | |
Collapse
|
|
21
|
Wilkinson DJ, Smeeton NJ, Castle PC, Watt PW. Absence of neuropsychological impairment in hyperammonaemia in healthy young adults; possible synergism in development of hepatic encephalopathy (HE) symptoms? Metab Brain Dis 2011; 26:203-12. [PMID: 21773808 DOI: 10.1007/s11011-011-9251-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2011] [Accepted: 07/04/2011] [Indexed: 12/16/2022]
Abstract
The aetiology of minimal hepatic encephalopathy (mHE) remains unclear. It is generally accepted that hyperammonaemia plays a major role, however there are a multitude of metabolic perturbations present. To determine the contribution of hyperammonaemia to mHE symptom development, ten healthy males (Age:25 ± 5 yrs, BM:76.3 ± 7.1 kg, Height:178.6 ± 4.5 cm, mean ± SD) received two 4 h intravenous infusions of either a 2% ammonium chloride solution (AMM) or a placebo (PLA;0.9% sodium chloride) using a double blind cross-over design. Sensations of fatigue were measured at baseline, 2 and 4 h using the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) questionnaire. Learning & memory, motor control and cognition were assessed using Rey's Auditory Verbal Learning Test (AVL), Continuous Compensatory Tracking (COMPTRACK) Task and Inhibitory Control Test (ICT) respectively. Arterialised venous blood samples were collected every hour, and analysed for ammonia concentration. There was a significantly higher plasma ammonia concentration in the AMM trial than the PLA trial at every time point during the infusion, peaking at 2 h (57 ± 4 μmol/L PLA, 225 ± 14 μmol/L AMM; p < 0.05). At 2 h there were significantly higher sensations of general fatigue (Z = -2.527, p = 0.008, 2 tailed) and physical fatigue (Z = -2.156, p = 0.027, 2 tailed), and lower sensations of vigour (Z = -2.456, p = 0.012, 2 tailed) for the AMM trial. There were no significant effects on the performance of the psychological tasks. These results demonstrate that hyperammonaemia in the absence of other complications induces significant sensations of fatigue but does not cause the typically observed performance impairment in individuals with mHE. Supporting the hypothesis for synergism between ammonia and other co-factors in mHE.
Collapse
Affiliation(s)
- Daniel J Wilkinson
- Department of Sport and Exercise Science, Chelsea School, University of Brighton, 30 Carlisle Road, Eastbourne BN20 7SN, UK.
| | | | | | | |
Collapse
|
|
22
|
Mardini H, Smith FE, Record CO, Blamire AM. Magnetic resonance quantification of water and metabolites in the brain of cirrhotics following induced hyperammonaemia. J Hepatol 2011; 54:1154-60. [PMID: 21145802 DOI: 10.1016/j.jhep.2010.09.030] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2010] [Revised: 09/07/2010] [Accepted: 09/15/2010] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Hepatic encephalopathy (HE) is now thought to be caused by cerebral oedema although the precise pathogenesis is uncertain. We hypothesised that if ammonia is a key factor, induced hyperammonaemia would lead to transient changes in brain water distribution and metabolite concentration, detectable by diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS). METHODS Thirteen cirrhotic patients being evaluated for liver transplantation were challenged with 54 g of equal parts of threonine, serine, and glycine. Conventional magnetic resonance imaging was performed to exclude structural lesions and localise regions of interest. DTI was used to generate white matter apparent diffusion coefficient (ADC) maps and proton MRS to measure brain metabolite concentrations before and after the challenge. RESULTS The challenge caused a mean (±SD) rise in blood ammonia of 58 (±41) μmol/L, which was accompanied by a significant 9% increase in ADC (p=0.004). Increased ADC significantly correlated with blood ammonia (r=0.58, p=0.04). The change in ammonia levels also correlated with the increase in glutamine levels (r=0.78, p=0.002). Myo-inositol concentration decreased significantly by 0.7 (±0.7)mMol/L between scans and this correlated with the mean difference in ADC (r=0.59, p<0.04). CONCLUSIONS These results show that ammonia can directly drive changes in brain water distribution as a mechanism for cerebral oedema development. Since cerebral astrocytes contain glutamine synthetase, our MRS data suggest intracerebral formation of glutamine from ammonia. The rapid decrease in myo-inositol indicates that this organic osmolyte plays a protective role in HE by release from astrocytes in order to maintain cell volume.
Collapse
Affiliation(s)
- Hanan Mardini
- Liver Unit and Institute of Cellular Medicine, Freeman Hospital and Newcastle University, Newcastle Upon Tyne, UK
| | | | | | | |
Collapse
|
|
23
|
Wilkinson DJ, Smeeton NJ, Watt PW. Ammonia metabolism, the brain and fatigue; revisiting the link. Prog Neurobiol 2010; 91:200-19. [PMID: 20138956 DOI: 10.1016/j.pneurobio.2010.01.012] [Citation(s) in RCA: 115] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2009] [Revised: 01/27/2010] [Accepted: 01/29/2010] [Indexed: 12/15/2022]
Abstract
This review addresses the ammonia fatigue theory in light of new evidence from exercise and disease studies and aims to provide a view of the role of ammonia during exercise. Hyperammonemia is a condition common to pathological liver disorders and intense or exhausting exercise. In pathology, hyperammonemia is linked to impairment of normal brain function and the onset of the neurological condition, hepatic encephalopathy. Elevated blood ammonia concentrations arise due to a diminished capacity for removal via the liver and lead to increased exposure of organs, such as the brain, to the toxic effects of ammonia. High levels of brain ammonia can lead to deleterious alterations in astrocyte morphology, cerebral energy metabolism and neurotransmission, which may in turn impact on the functioning of important signalling pathways within the neuron. Such changes are believed to contribute to the disturbances in neuropsychological function, in particular the learning, memory, and motor control deficits observed in animal models of liver disease and also patients with cirrhosis. Hyperammonemia in exercise occurs as a result of an increased production by contracting muscle, through adenosine monophosphate (AMP) deamination (the purine nucleotide cycle) and branched chain amino acid (BCAA) deamination prior to oxidation. Plasma concentrations of ammonia during exercise often achieve or exceed those measured in liver disease patients, resulting in increased cerebral uptake. In this article we propose that exercise-induced hyperammonemia may lead to concomitant disturbances in brain function, potentially through similar mechanisms underpinning pathology, which may impact on performance as fatigue or reduced function, especially during extreme exercise.
Collapse
Affiliation(s)
- Daniel J Wilkinson
- Department of Sport and Exercise Science, Chelsea School, University of Brighton, 30 Carlisle Road, Eastbourne, UK.
| | | | | |
Collapse
|
|
24
|
Guerit JM, Amantini A, Fischer C, Kaplan PW, Mecarelli O, Schnitzler A, Ubiali E, Amodio P. Neurophysiological investigations of hepatic encephalopathy: ISHEN practice guidelines. Liver Int 2009; 29:789-96. [PMID: 19638107 DOI: 10.1111/j.1478-3231.2009.02030.x] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
By studying neuronal activity through neuronal electrogenesis, neurophysiological investigations provide a functional assessment of the nervous system and, therefore, has been used for quantitative assessment and follow-up of hepatic encephalopathy (HE). The different clinical neurophysiological approaches can be classified depending on the function to explore and their sensitivity to HE. The reliable techniques are those that reflect cortical function, i.e., cognitive-evoked potentials (EPs) (P300 paradigm), electroencephalogram (EEG), visual EPs (latency>100 ms) and somatosensory EPs (SEPs) (latency between 25 and 100 ms). Short-latency EPs (brainstem acoustic EPs, SEPs of a latency<25 ms) are in principle insensitive to HE, but can disclose brainstem conduction deficits due to oedema. SEPs and motor EPs can disclose myelopathies. Because of its parallelism to the clinical examination, clinical neurophysiology can complement the neurological examination: (i) to provide evidence of HE in patients who have normal consciousness; (ii) to rule out, at least under some conditions, disturbances of consciousness due to other causes (e.g. drug-induced disturbances, non-convulsive status epilepticus) with the reservation that the mildest degrees of encephalopathy might be associated with an EEG pattern similar to that induced by drugs; and (iii) to demonstrate the worsening or, conversely improvement, of HE in the follow-up period.
Collapse
|
|
25
|
Liu F, Zhang CQ. Pathogenesis of hepatic encephalopathy and its prevention after transjugular intrahepatic portosystemic shunt. Shijie Huaren Xiaohua Zazhi 2009; 17:798-804. [DOI: 10.11569/wcjd.v17.i8.798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
With the increasing use of transjugular intrahepatic portosystemic shunt (TIPS), we have obtained a breakout progress in the therapy of acute esophageal and gastric-fundus variceal bleeding and refractory ascites. whereas the patency of stent and hepatic encephalopathy (or namely portal-systemic encephalopathy, PSE) after TIPS become two great problems for TIPS. The patency of stent has been improved greatly after the use of covered stent such as Viator stents or covered vascular stents. But the problem of hepatic encephalopathy has not been well solved. In this review, we try to explore the pathogenesis of hepatic encephalopathy and its prevention after TIPS.
Collapse
|
|
26
|
Mardini H, Saxby BK, Record CO. Computerized psychometric testing in minimal encephalopathy and modulation by nitrogen challenge and liver transplant. Gastroenterology 2008; 135:1582-90. [PMID: 18647604 DOI: 10.1053/j.gastro.2008.06.043] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2008] [Revised: 06/04/2008] [Accepted: 06/19/2008] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS A lack of standardized tests was cited by hepatologists for not testing for minimal hepatic encephalopathy. We therefore compared paper and pencil neuropsychologic tests with a comprehensive computerized assessment (Cognitive Drug Research [CDR], Goring-on-Thames, United Kingdom) of cognitive function. METHODS Eighty-nine cirrhotic patients were studied. Composite scores were calculated from the CDR subtests to reflect 5 cognitive domains, and results were validated by comparison with those from 6 standard paper and pencil tests. Level of impairment was defined using the sum of the standard deviations by which each CDR domain (CDR factor score [CDRS]) and each paper and pencil test score (PHES) differed from age-matched norms. CDRS and PHES were repeated in 21 patients after liver transplantation and CDRS in 24 patients after a 108-g amino acid challenge. RESULTS There was a high correlation between the 2 assessment methods (r = 0.748; P = .001). Using multiple regression, Model of End-Stage Liver Disease score (P = .011) correlated with PHES. In contrast, the CDR domains Continuity of Attention and Quality of Episodic Memory were significantly related to venous blood ammonia levels (adjusted R(2) = 0.200; F(6,76) = 4.41; P = .001). There were marked deteriorations in the CDR composite scores representing Accuracy of Working (P = .005) and Episodic Memory (P = .001) after amino acid challenge when blood ammonia increased from 63 +/- 36 to 126 +/- 62 micromol/L (P = .001). Both PHES and CDRS returned to the control range after liver transplantation (PHES: pretransplantation, -6; posttransplantation, 0; P < .001; CDRS: pretransplantation, -6; posttransplantation, -2; P = .003). CONCLUSIONS CDRS is valuable for the recognition of minimal hepatic encephalopathy.
Collapse
Affiliation(s)
- Hanan Mardini
- Centre for Liver Research, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom
| | | | | |
Collapse
|
|
27
|
Amodio P, Campagna F, Olianas S, Iannizzi P, Mapelli D, Penzo M, Angeli P, Gatta A. Detection of minimal hepatic encephalopathy: normalization and optimization of the Psychometric Hepatic Encephalopathy Score. A neuropsychological and quantified EEG study. J Hepatol 2008; 49:346-53. [PMID: 18602716 DOI: 10.1016/j.jhep.2008.04.022] [Citation(s) in RCA: 148] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2007] [Revised: 03/28/2008] [Accepted: 04/22/2008] [Indexed: 12/19/2022]
Abstract
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%, Cohen's 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.
Collapse
Affiliation(s)
- Piero Amodio
- Department of Clinical and Experimental Medicine, Cirmanmec, University of Padua, Via Giustiniani, 2, 35128 Padua, Italy.
| | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Abstract
This article has arisen from presentations made at the 4th International Hannover Conference on Hepatic Encephalopathy held in Dresden, 2006. Each author as listed describes their presentation given as part of a section entitled "Therapeutic Studies in Hepatic Encephalopathy." The first section deals with the justification for placebo-controlled trials in hepatic encephalopathy. The other two sections discuss, in detail, outcome parameters for therapeutic studies in the clinical and research setting, respectively.
Collapse
Affiliation(s)
- Kevin D Mullen
- Department of Gastroenterology/Hepatology, MetroHealth Medical Center, Cleveland, OH, USA
| | | | | |
Collapse
|
|
29
|
Shawcross DL, Wright G, Olde Damink SWM, Jalan R. Role of ammonia and inflammation in minimal hepatic encephalopathy. Metab Brain Dis 2007; 22:125-38. [PMID: 17260161 DOI: 10.1007/s11011-006-9042-1] [Citation(s) in RCA: 200] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Minimal hepatic encephalopathy (MHE) is common in cirrhosis but its pathophysiologic basis remains undefined. We evaluated whether the presence of MHE was associated with severity of liver disease, ammonia levels or the presence of inflammation and assessed factors determining neuropsychological deterioration accompanying induction of hyperammonemia. METHODS Eighty four cirrhotics were studied. A neuropsychological test battery was performed and blood taken for ammonia, WCC, CRP, nitrate/nitrite, IL-6 and amino acids, before and after, induction of hyperammonemia by administration of a solution mimicking the amino acid composition of haemoglobin (60) or placebo (24). RESULTS The presence and severity of MHE were independent of severity of liver disease and ammonia concentration but markers of inflammation were significantly higher in those with MHE compared with those without. Induction of hyperammonemia produced deterioration in one or more neuropsychological tests by > or =1 SD in 73.3%. This was independent of the magnitude of change in plasma ammonia and severity of liver disease but was significantly greater in those with more marked inflammation. CONCLUSION Our data show that inflammation is an important determinant of the presence and severity of MHE. The change in neuropsychological function following induced hyperammonemia is greater in those with more severe inflammation.
Collapse
Affiliation(s)
- D L Shawcross
- Liver Failure Group, The UCL Institute of Hepatology, Division of Medicine, University College London, 69-75 Chenies Mews, London, WC1E 6HX, UK.
| | | | | | | |
Collapse
|
|
30
|
Al Mardini H, Douglass A, Record C. Amino acid challenge in patients with cirrhosis and control subjects: ammonia, plasma amino acid and EEG changes. Metab Brain Dis 2006; 21:1-10. [PMID: 16773465 DOI: 10.1007/s11011-006-9006-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2004] [Accepted: 08/01/2005] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS The pathogenesis of hepatic encephalopathy (HE) is controversial. We have therefore studied the effect of induced hyperammonaemia in man. PATIENTS AND METHODS 108 g of an amino acid mixture was given orally to 18 cirrhotics and 11 control subjects and changes in blood ammonia, EEG and plasma amino acids were observed. RESULTS Basal (39+/-6 versus 14+/-2 micromol/l) and 120-min post amino acid (77+/-10 versus 27+/-4) blood ammonia concentrations in cirrhotics were significantly increased compared to healthy controls (p < 0.001). Associated with these changes there was a significant increase in the ratio of slow-to-fast wave activity indicating EEG slowing (+0.41+/-0.16; N=13 versus -0.05+/-0.08; N=8; p=0.036). As expected in cirrhotics, basal valine and leucine concentrations were decreased while phenylalanine, tyrosine and methionine were significantly increased. Although the basal molar ratio of branched chain amino acids to the aromatic amino acids phenylalanine and tyrosine was significantly decreased in cirrhotics (1.5+/-0.2 versus 3.2+/-0.2; p < 0.0001), after the challenge when EEG changes were apparent in cirrhotics, the ratio significantly increased (p < 0.005) in both groups to 2.7+/-0.3 versus 4.1+/-0.3 (p=0.002). In the combined groups, there were significant correlations between EEG ratio change and the 120-min blood ammonia concentration (r=0.498; p=0.022). CONCLUSION The alterations in plasma amino acid patterns do not support a specific role for any of the amino acid groups in the pathogenesis of hepatic encephalopathy. They are however more in keeping with the direct or indirect role of ammonia.
Collapse
Affiliation(s)
- Hanan Al Mardini
- Department of Medicine, University of Newcastle upon Tyne, Newcastle upon Tyne, NE1 7RU, UK
| | | | | |
Collapse
|
|
31
|
Abstract
The term minimal hepatic encephalopathy refers to the subtle changes in cognitive function, electrophysiological parameters, cerebral neurochemical/neurotransmitter homeostasis, cerebral blood flow, metabolism, and fluid homeostasis that can be observed in patients with cirrhosis who have no clinical evidence of hepatic encephalopathy. Use of this term emphasizes the fact that the entity of hepatic encephalopathy is a single syndrome with quantitatively distinct features relating to severity. The absence of clinical evidence of hepatic encephalopathy is key to the diagnosis and can only be determined by a detailed assessment of the patients' history and a comprehensive neurological assessment of consciousness, cognitive, and motor function. The neuropsychological features of minimal hepatic encephalopathy point to a disorder of executive functioning, particularly selective attention and psychomotor speed, but other abnormalities may be observed. Alterations in electrophysiological variables have been described; endogenous evoked potentials are, in principle, more likely to reflect the presence of minimal hepatic encephalopathy, since they reflect cognitive phenomena rather than mere stimulus conduction but the specificity of the changes observed is unclear at present. Changes have also been described in the execution of diadochokinetic movements and in the capacity to discriminate flickering light, both of which may have diagnostic potential. The changes observed in cerebral blood flow and metabolism in SPET, PET, and 1H and 31P MRS studies reflect the pathogenic process that underlies the condition rather than providing diagnostic information. Similarly, the morphological brain abnormalities identified in this population, including mild brain oedema, hyperintensity of the globus pallidus and other subcortical nuclei observed in cerebral MR studies, and the central and cortical atrophy observed in neural imaging studies, are unlikely to have diagnostic utility. The presence of minimal hepatic encephalopathy is not without clinical consequence; it has a detrimental effect on health-related quality of life, the ability to perform complex tasks such as driving, and on outcome.
Collapse
Affiliation(s)
- Piero Amodio
- Clinica Medica 5, CIRMANMEC, University of Padova, Italy.
| | | | | | | |
Collapse
|
|
32
|
Shawcross DL, Balata S, Olde Damink SWM, Hayes PC, Wardlaw J, Marshall I, Deutz NEP, Williams R, Jalan R. Low myo-inositol and high glutamine levels in brain are associated with neuropsychological deterioration after induced hyperammonemia. Am J Physiol Gastrointest Liver Physiol 2004; 287:G503-9. [PMID: 15130875 DOI: 10.1152/ajpgi.00104.2004] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The neuropsychological effect of hyperammonemia is variable. This study tests the hypothesis that the effect of ammonia on the neuropsychological function in patients with cirrhosis is determined by the ability of the brain to buffer ammonia-induced increase in glutamine within the astrocyte by losing osmolytes like myo-inositol (mI) and not by the magnitude of the induced hyperammonemia. Fourteen cirrhotic patients with no evidence of overt hepatic encephalopathy were given a 75-g amino acid (aa) solution mimicking the hemoglobin molecule to induce hyperammonemia. Measurement of a battery of neuropsychological function tests including immediate memory, ammonia, aa, and short-echo time proton magnetic resonance spectroscopy were performed before and 4 h after administration of the aa solution. Eight patients showed deterioration in the Immediate Memory Test at 4 h. Demographic factors, severity of liver disease, change in plasma ammonia, and aa profiles after the aa solution were similar in those that showed a deterioration compared with those who did not. In patients who showed deterioration in the memory test, the mI-to-creatine ratio (mI/Cr) was significantly lower at baseline than those that did not deteriorate. In contrast, the glutamate/glutamine-to-Cr ratio was significantly greater in the patients that deteriorated. The observation that deterioration in the memory test scores was greater in those with lower mI/Cr supports the hypothesis that the neuropsychological effects of induced hyperammonemia is determined by the capacity of the brain to handle ammonia-induced increase in glutamine.
Collapse
Affiliation(s)
- D L Shawcross
- Institute of Hepatology, University College London, London, WC1E 6HX United Kingdom
| | | | | | | | | | | | | | | | | |
Collapse
|
|
33
|
Shawcross DL, Davies NA, Williams R, Jalan R. Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 2004; 40:247-54. [PMID: 14739095 DOI: 10.1016/j.jhep.2003.10.016] [Citation(s) in RCA: 379] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND/AIMS Studies in acute liver failure show correlation between evidence of a systemic inflammatory response syndrome (SIRS) and progression of hepatic encephalopathy (HE). We tested the hypothesis that SIRS mediators, such as nitric oxide and proinflammatory cytokines, may exacerbate the neuropsychological effects of hyperammonemia in cirrhosis. METHODS Ten patients with cirrhosis were studied, 24-36 h after admission with clinical evidence of infection, and following its resolution. Hyperammonemia was induced by oral administration of an amino-acid (aa) solution mimicking hemoglobin composition. Inflammatory mediators, nitrate/nitrite, ammonia, aa profiles and a battery of neuropsychological tests were measured. RESULTS The hyperammonemia generated in response to the aa solution was similar prior to, and after resolution, of the inflammation (P=0.77). With treatment of the infection there were significant reductions in white blood cell count (WBC), C-reactive protein (CRP), nitrate/nitrite, interleukin-6, interleukin-1beta and tumour necrosis factor alpha. Induced hyperammonemia resulted in significant worsening of the neuropsychological scores when patients showed evidence of SIRS but not after its resolution. CONCLUSIONS The significant deterioration of neuropsychological test scores following induced hyperammonemia during the inflammatory state, but not after its resolution, suggests that the inflammation and its mediators may be important in modulating the cerebral effect of ammonia in liver disease.
Collapse
Affiliation(s)
- Debbie L Shawcross
- Liver Failure Group, Institute of Hepatology, University College London Medical School, 69-75, Chenies Mews, London WC1E 6HX, UK
| | | | | | | |
Collapse
|
|
34
|
Douglass A, Al Mardini H, Record CO. Oral tryptophan challenge studies in cirrhotic patients: no evidence of neuropsychiatric changes. Metab Brain Dis 2003; 18:179-86. [PMID: 14567468 DOI: 10.1023/a:1025577614928] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Hepatic encephalopathy is a frequent complication of cirrhosis. Abnormalities of 5-hydroxytryptamine (5-HT) and its metabolites are recognized and may contribute to its pathogenesis. We therefore studied the effect of an oral tryptophan load (6-18 g) upon psychometric test scores and analyzed EEG's in alcoholic cirrhotic patients. Eight patients had had previous encephalopathic episodes related to variceal bleeds and one patient was awaiting a liver transplant. Five out of the 10 patients had at least one abnormal baseline psychometric test. Following tryptophan challenge there were no changes in blood ammonia but plasma tryptophan levels were elevated approximately 10-fold (p < 0.01 x 10(-7)). Nevertheless, there were no statistically significant changes in psychometric testing or analyzed EEG frequency distribution. All patients reported nausea or vomiting while one patient developed a short-lived serotonin like syndrome. We conclude that in this group of patients, an oral tryptophan load does not induce or worsen subclinical hepatic encephalopathy. If the high blood levels of tryptophan seen in these studies are able to influence cerebral neurotransmitter synthesis, the results do not support a primary role for abnormalities of 5-HT neurotransmission in hepatic encephalopathy.
Collapse
Affiliation(s)
- Andrew Douglass
- Department of Medicine, University of Newcastle Upon Tyne, United Kingdom
| | | | | |
Collapse
|
|
35
|
Riggio O, Efrati C, Masini A, Angeloni S, Merli M. Is hyperammonemia really the true cause of altered neuropsychology, brain MR spectroscopy and magnetization transfer after an oral amino acid load in cirrhosis? Hepatology 2003; 38:777; author reply 778. [PMID: 12939607 DOI: 10.1053/jhep.2003.50388] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
|
|
36
|
Balata S, Olde Damink SWM, Ferguson K, Marshall I, Hayes PC, Deutz NEP, Williams R, Wardlaw J, Jalan R. Induced hyperammonemia alters neuropsychology, brain MR spectroscopy and magnetization transfer in cirrhosis. Hepatology 2003; 37:931-9. [PMID: 12668989 DOI: 10.1053/jhep.2003.50156] [Citation(s) in RCA: 80] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Hyperammonemia is a universal finding after gastrointestinal hemorrhage in cirrhosis. We administered an oral amino acid solution mimicking the hemoglobin molecule to examine neuropsychological changes, brain glutamine levels, and brain magnetization transfer ratio (MTR). Forty-eight metabolically stable patients with cirrhosis and no evidence of "overt" hepatic encephalopathy (HE) were randomized to receive 75 g of amino acid solution or placebo; measurements were performed before and 4 hours after administration. Neuropsychological tests included the Trails B Test, Digit Symbol Substitution Test, memory subtest of the Randt battery, and reaction time. Plasma was collected for ammonia and amino acid measurements, and brain metabolism was studied using proton magnetic resonance (MR) spectroscopy in the first 16 randomized patients. In 7 other patients, MTR was measured. A significant increase in ammonia levels was observed in the amino acid group (amino acid group, 76 +/- 7.3 to 121 +/- 6.4 micromol/L; placebo, 83 +/- 3.3 to 78 +/- 2.9 micromol/L; P <.001). Neuropsychological function improved significantly in the placebo group, but no significant change in neuropsychological function was observed in the amino acid group. Brain glutamate/glutamine (Glx)/creatine (Cr) ratio increased significantly in the amino acid group. MTR decreased significantly from 30 +/-2.9 to 23 +/- 4 (P <.01) after administration of the amino acid solution. In conclusion, an improvement in neuropsychological test results followed placebo, which was not observed in patients administered the amino acid solution. Induced hyperammonemia resulted in an increase in brain Glx/Cr ratio and a decrease in MTR, which may indicate an increase in brain water as the operative mechanism.
Collapse
Affiliation(s)
- Sherzad Balata
- Liver Unit, Royal Infirmary of Edinburgh, Edinburgh, Scotland
| | | | | | | | | | | | | | | | | |
Collapse
|