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Raduazzo, Iolanda Daniela (2014) L'IPERAMMONIEMIA INDOTTA: CORRELATI NEUROPSICHICI, CORRELATI ELETTROFISIOLOGICI E NUOVE STRATEGIE TERAPEUTICHE. [Ph.D. thesis]

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Abstract (english)

ABSTRACT

Introduction.
Hepatic encephalopathy (HE) is a neuropsychological syndrome which may accompany acute or chronic liver failure, being mainly due to the toxic effect of ammonia on the central nervous system [83]. HE encompasses a wide clinical spectrum, ranging from minimal forms, which are only detected by use of neuropsychological and/or electrophysiological techniques, to coma [7,8, 11, 144, 175, 190]. HE, even in its minimal form, impinges on quality of life and self-sufficiency [10, 76, 120, 164] and it carries negative prognostic value in terms of survival. Thus it is useful to identify patients with HE and reduced life expectancy, also for purposes of transplant selection procedures. The electrophysiological diagnosis of HE is based on the detection of slow wake-EEG frequencies [8]. However, some studies have shown that the regional distribution of the wake-EEG rhythms is also abnormal [126]. The detection of HE through psychometric and electrophysiological techniques is usually carried out in "standard" conditions. More recently, it has been proposed to artificially induce a condition of hyperammonaemia, thus simulating HE, by the oral administration of an amino-acid load (AAL). These amino-acids mimic the composition of hemoglobin, thus reproducing, at least to some extent, the HE which is observed after a gastrointestinal bleed [4, 65]. This allows doctors and researchers to measure more directly a patient's sensitivity to hyperammonaemia.
Disorders of the sleep-wake rhythm are common in patients with cirrhosis, heavily affecting their quality of life [129]. Sleep is regulated by the interaction of two processes: a homeostatic and a circadian process [31]. The former determines the propensity to fall asleep in connection to prior sleep-wake history (i.e. the need for sleep increases with prolonged wakefulness). The latter, which is reflected in the 24-hour rhythm of the hormone melatonin (high plasma levels at night and extremely low levels in the daytime), determines the alternation of periods of low/high sleep propensity in relation to environmental light/dark conditions. The interaction of such two processes results in a high likelihood of falling asleep after a prolonged period of wakefulness and when it gets dark, namely in the evening.
The alterations of the sleep-wake rhythm in patients with liver have traditionally been interpreted as being part of the HE syndrome [175]. More recent data suggest that this is the case for excessive daytime sleepiness, while insomnia probably has a different pathogenesis [128]. The causes of sleep-wake abnormalities in patients with cirrhosis are not completely clear. The documented changes in the circadian system (reduced sensitivity to light and altered rhythm/metabolism of melatonin) do not offer a complete explanation [128, 129]. Sleep can also be studied by polysomnography, which reflects homeostatic regulation. Information on homeostatic regulation in these patients is limited [179]. The exact neurochemical correlates of human sleep homeostasis remain unknown, although adenosinergic neurotransmission is likely to be implicated. In healthy subjects caffeine, an adenosine receptor antagonist, significantly affects both the wake EEG (reduction in theta activity, which increases with the increase of sleep pressure) and the sleep EEG, and attenuates the subjective sleepiness which is associated with prolonged wakefulness and sleep deprivation [106].

This set of studies was performed in order to evaluate:
- the effect of induced hyperammonaemia on neuropsychological performance and the wake EEG (Study 1);
- the relationship between daytime sleepiness, HE, and the sleep EEG (Study 2);
- the effects of ammonia-lowering drugs (L-ornithine-L-aspartate, LOLA) and caffeine on the wake and sleep EEG (Study3).

Materials and methods.
Well-characterized patients with compensated cirrhosis and with no history of HE and matched healthy volunteers were enrolled and underwent:
- Assessing and monitoring the quality and time of sleep with questionnaires and sleep diaries.
- Oral load of amino acids (AAL), mixture of 54 grams of amino acids mimicking the hemoglobin contained in 400 ml of blood, taken in the morning per os.
- Detection time of subjective sleepiness and capillary ammonia.
- Neuropsychological assessment, including psychometric paper and pencil (PHES battery), computerized psychometry and EEG recording of wakefulness.
- Polysomnographic recording. Patients were given the opportunity to sleep between 17:00 and 19:00 in favorable environmental conditions (dark and isolated room).
- Administration of LOLA 20g in 500cc of saline in 4-hour infusion (8-12) or 200mg caffeine per os(at 10 am) under inducedhyperammonemia (Study 3).

Results.
Study 1. Effects of hyperammonaemia on neuropsychological performance and waking EEG.
- The study population included 10 patients with liver cirrhosis (9 men, mean ± SD, age: 54 ± 14 years) and 10 healthy volunteers matched for age and sex (5 men, 49 ± 13 years). One patient (male 55 years) underwent EEG recording also after the insertion of a trans-jugular portal-systemic shunt (TIPS), a procedure which is associated with increased risk of HE.
- The subjects were studied with a neuropsychological evaluation and monitoring of capillary ammonia at baseline (4th or 8th day of the study) and after oral amino acids (AAL) (4th or 8th day of the study).
- At baseline, patients had higher ammonia levels than healthy volunteers [median (interquartile range): 30 (22-44) vs. 38 (34-47)mmol/L, p < 0.1]. The AAL has produced the expected increase in ammonia in both groups, the peak of ammonia was higher (ammonia 11:00, p < 0.03) and more prolonged in patients.
- The AAL has produced a significant slowing of EEG waking such as to define the presence of a minimal HE in 2 (20 %) patients. By contrast, the AAL no significant changes in the psychometric performance paper & pencil or computerized.
- At baseline, the dominant frequency EEG activity was slower in patients compared to healthy volunteers in most derivations(p < 0.05). The AAL did not alter the dominant frequency in healthy volunteers, while that of patients slowed further along the midline (p < 0.05).
- At baseline, the waking EEG spectral power had an occipital-temporal predominance in both groups. The patients had higher power in all derivations (p < 0.05). The AAL induced a significant increase of power in almost all derivations in healthy volunteers (p < 0.05), while it did not affect power in patients.
- In the patient studied on three occasions, the spectral power of dominant wake EEG progressively increased from baseline after AAL and after TIPS, while there was a decrease in the frequency of the wake EEG after insertion of TIPS.

Study 2. Effect of hyperammonaemia on sleepiness and sleep EEG.
- The study population (see Study 1) was subjected to neuropsychological assessment, detection time of sleepiness and ammonia and polysomnographic recording, in basal conditions (4th or 8th day of the study) and after AAL (4th or 8th day of the study).
The AAL has produced
- an increase in subjective sleepiness parallel to increased concentrations of ammonia both in patients and in healthy volunteers;in both groups, the peak of sleepiness (at 11 am), absent in basal condition, coincides with the peak concentration of ammonia (p <0.01);
- an increase in sleep duration in healthy volunteers compared with baseline (mean ± SD, 49.3 ± 26.6vs. 30.4 ± 15.6 min), although the differences are not statistically significant (p 0.08). No changes arebeen observedon the duration of sleep in patients;
- significant decrease in the relative power beta (fast activity)of the sleep EEG in healthy volunteers (p < 0.05);
- significant reduction in the relative power of delta (activity very slow)of thesleep EEG in patients (p < 0.05).

Study 3. Effects of L-ornithine-L-aspartate (LOLA, substance that reduce ammonia) and caffeine (adenosine receptor antagonist) on cognitive performance,wake and sleep EEG in conditions of induced hyperammonaemia.
- The study population consisted of 6 patients with liver cirrhosis (5 men, mean ± SD, age: 61 ± 9 years) and 5 healthy volunteers matched for age, sex and level of education (4 men, 49 ± 12 years).
- The subjects were studied with neuropsychological assessment, detection sleepiness and ammonia hourly and polysomnographic recording, after AAL, AAL+LOLA, AAL+caffeine) on the 4th, 11th and 18th day of the study.
- patients presented a paper and pencil and computerized psychometric performance significantly worse than the healthy volunteers (p < 0.05);
- patients had levels of ammonia above those of healthy volunteers in all conditions;
the AAL has produced the expected increase of ammonia in both groups, with a peak higher and more prolonged in patients.
- The LOLA has resulted in a reduction although not significant levels of plasmatic ammonia in both groups.
- Neither the LOLA nor caffeine resulted in significant changes of subjective sleepiness, on psychometric performance and the wake EEG.
- Sleep EEG data are being analyzed (at the Institute of Pharmacology and Toxicology, University of Zurich, Switzerland).

Conclusions.
- The waking EEG is extremely sensitive to hyperammonaemia.
- A moderate/chronic (patients in baseline) or acute (healthy volunteers after AAL) hyperammonaemia results in an increased power of the dominant EEG rhythm, especially over posterior and central areas of the scalp.
- An acute on chronic hyperammonaemia (patients after AAL) slows further the dominant EEG frequency.
- EEG parameters based on power can provide useful information to the neurophysiological definition of HE.
- Hyperammonaemia leads to a significant increase in subjective daytime sleepiness.
- Hyperammonaemia causes opposing changes in the sleep EEG of patients and controls, making the sleep of patients fragmented and more superficial, and that of healthy volunteers deeper and more stable.
- L-ornithine-L-aspartate leads to a reduction in the levels of ammonia.

Abstract (italian)

L'encefalopatia epatica (EE) è una sindrome neuropsichica che può accompagnare l'insufficienza epatica acuta o cronica ed è legata principalmente all'effetto tossico dell'ammonio sul sistema nervoso centrale [83]. Clinicamente, l'EE è caratterizzata da uno spettro di manifestazioni che va da forme minime, evidenziabili solo con tecniche psicometriche ed elettrofisiologiche, fino al coma, passando per quadri clinici di encefalopatia conclamata, caratterizzati da alterazioni neurologiche e psichiatriche più o meno invalidanti [7, 8, 11, 145, 176, 191]. L'EE, anche nelle sue forme minime, si ripercuote non solo sull'autonomia e sulla qualità di vita del paziente [10, 76, 121, 165], ma anche su quelle familiari e sulle strutture socio-sanitarie. Inoltre, contribuisce ad individuare pazienti con ridotta aspettativa di vita, per i quali può essere indicato l'inserimento in lista per trapianto di fegato. La diagnosi elettrofisiologica dell'EE si basa sulla rilevazione di un rallentamento delle frequenze dell'EEG [8]. Tuttavia, alcuni studi hanno dimostrato che anche la distribuzione regionale dei ritmi dell'EEG di veglia può essere anormale nei pazienti con cirrosi e soprattutto in quelli con EE [127]. Il rilievo di EE mediante tecniche psicometriche ed elettrofisiologiche viene di solito effettuato in condizioni basali. Più di recente, È stato proposto di indurre un’iperammoniemia e quindi di simulare una condizione di EE minima/conclamata lieve tramite la somministrazione orale di un carico di aminoacidi (COAA) mimanti l’emoglobina (simulazione di encefalopatia/iperammoniemia associate al sanguinamento digestivo) e di studiarne l’effetto su psicometria ed elettroencefalogramma [4, 65], misurando quindi più direttamente la sensibilità del singolo paziente all’iperammoniemia.
I disturbi del ritmo sonno-veglia sono comuni nei pazienti con cirrosi epatica e incidono pesantemente sulla loro qualità di vita [130]. Il sonno è regolato dall'interazione tra due processi: un processo omeostatico e uno circadiano [31]. Il primo determina la propensione ad addormentarsi in rapporto alla precedente storia di sonno/veglia, facendo sì che la necessità di dormire aumenti con il prolungarsi della veglia. Invece il processo circadiano, che si riflette nel ritmo 24-ore dell'ormone melatonina (livelli plasmatici elevati la notte e pressoché assenti di giorno), determina l'alternarsi di periodi di bassa/alta propensione all’addormentamento in relazione ai segnali ambientali di luce/buio. Il risultato dell’interazione fra questi due processi fa sì che la probabilità di addormentarsi sia alta quando sono passate numerose ore dal risveglio e quando si fa buio, vale a dire la sera.
Le alterazioni del ritmo sonno-veglia dei pazienti con cirrosi epatica sono state tradizionalmente interpretate come facenti parte del complesso sindromico dell’encefalopatia epatica [176]. Dati più recenti suggeriscono che l'eccessiva sonnolenza diurna sia effettivamente un tratto dell'EE, mentre l'insonnia abbia una patogenesi distinta [129]. Tuttavia le cause di questi disturbi restano dibattute. Le documentate alterazioni del sistema di regolazione circadiano (ridotta sensibilità alla luce e disturbato ritmo/metabolismo della melatonina) non offrono una spiegazione esauriente [129, 130]. Anche le informazioni disponibili in questi pazienti sulla regolazione omeostatica del sonno, che può essere studiata con la polisonnografia, sono scarse [180]. Le esatte correlazioni neurochimiche dell’omeostasi del sonno umano rimangono sconosciute, anche se sempre più numerose evidenze dimostrano un possibile importante ruolo nella trasmissione adenosinergica. Nei soggetti sani infatti la caffeina, un antagonista recettoriale dell'adenosina, influenza in modo significativo l’elettroencefalogramma di veglia (riduzione dell'attività theta, che aumenta con l’aumentare della pressione del sonno) e di sonno, e attenua la sonnolenza soggettiva associata alla veglia prolungata/deprivazione di sonno [107].

I miei studi di dottorato sono stati eseguiti allo scopo di valutare, in un gruppo di pazienti con la cirrosi epatica e in un gruppo di volontari sani, l’effetto dell’iperammonimia indotta:
- sulla prestazione neuropsichica e sull'EEG di veglia (Studio 1);
- sul rapporto tra sonnolenza diurna ed EE e sulle caratteristiche dell'EEG di sonno (Studio 2);
- sugli effetti di sostanze ipoammoniemizzanti (L-ornitina-L-aspartato, LOLA) e della caffeina (antagonista del recettore dell'adenosina) su EEG di veglia e su EEG di sonno (Studio 3).


Materiali e metodi.
Sono stati arruolati pazienti ben caratterizzati con cirrosi epatica compensata e con anamnesi negativa per EE minima o conclamata e volontari sani confrontabili per età , sesso e livello d'istruzione.
I soggetti sono stati sottoposti a:
- valutazione e monitoraggio della qualità e degli orari del sonno con questionari e diari del sonno;
- carico orale di aminoacidi (COAA), miscela di 54 gr di aminoacidi mimanti l’emoglobina contenuta in 400 ml di sangue, assunta al mattino per os;
- rilevazione oraria di sonnolenza soggettiva ed ammoniemia capillare;
- valutazione neuropsichica, comprendente psicometria carta e matita (batteria PHES), psicometria computerizzata e registrazione dell’EEG di veglia.
- registrazione polisonnografica. Ai pazienti veniva data la possibilità di dormire tra le 17:00 e le 19:00 in condizioni ambientali favorevoli (stanza buia ed isolata).
- somministrazione di LOLA 20gr in 500cc di soluzione fisiologica in infusione di 4 ore (8-12) o caffeina 200mg per os (ore 10) in corso di iperammoniemia dopo COAA (studio 3).

Risultati.
Studio 1. Effetti dell’iperammoniemia sulla prestazione neuropsichica e sull’EEG di veglia
• la popolazione di studio comprendeva 10 pazienti con cirrosi epatica (9 uomini; media ± SD; età : 54 ± 14 anni) e 10 volontari sani appaiati per età e sesso (5 uomini, 49 ± 13 anni). Un paziente (maschio di 55 anni) è stato sottoposto a registrazione EEG anche dopo l'inserimento di uno shunt porto-sistemico trans-giugulare (TIPS), procedura associata ad un aumentato rischio di sviluppo di EE.
• I soggetti sono stati studiati con una valutazione neuropsichica e monitoraggio dell’ammoniemia oraria in condizioni basali (4° o 8° giorno di studio) e dopo carico orale di aminoacidi (COAA) (4° o 8° giorno di studio).
• Al basale, i pazienti avevano livelli di ammoniaca superiori a quelli dei volontari sani [mediana (range interquartile): 30 (22-44) vs 38 (34-47) µmol/L, p < 0.1]. Il COAA ha prodotto l’atteso aumento dell’ammoniemia in entrambi i gruppi; il picco dell’ammoniemia è stato più alto (ammoniemia ore 11:00, p<0.03) e più prolungato nei pazienti.
• Il COAA ha prodotto un rallentamento significativo dell’EEG di veglia tale da definire la presenza di EE minima in 2 (20%) pazienti. Per contro, il COAA non ha prodotto cambiamenti significativi della prestazione psicometrica carta&matita o computerizzata.
• Al basale, la frequenza dominante dell'attività EEG era più lenta nei pazienti rispetto ai volontari sani in diverse derivazioni (p<0.05). Il COAA non ha alterato la frequenza dominante nei volontari sani, mentre ha rallentato ulteriormente quella dei pazienti lungo la linea mediana (p<0.05)
• In condizioni basali, la potenza spettrale dell’EEG di veglia aveva una predominanza occipito-temporale in entrambi i gruppi. I pazienti avevano potenza superiore in tutte le derivazioni (p<0.05). Il COAA ha indotto un aumento significativo di potenza in quasi tutte le derivazioni nei volontari sani (p<0.05), mentre nessuna modifica della potenza è stata osservata nei pazienti.
• Nel paziente studiato in tre occasioni, la potenza dell'attività dominante dell’EEG è aumentata progressivamente dal basale, dopo COAA, dopo TIPS, mentre si è osservato un calo della frequenza dominante dell’EEG dopo l’inserimento della TIPS.

Studio 2. Effetto dell’iperammoniemia su sonnolenza ed EEG di sonno
• la popolazione di studio (vedi studio 1) è stata sottoposta a valutazione neuropsichica, rilevazione oraria di sonnolenza ed ammoniemia oraria e registrazione polisonnografica, in condizioni basali (4° o 8° giorno di studio) e dopo COAA (4° o 8° giorno di studio).
Il COAA ha prodotto
• un aumento della sonnolenza soggettiva parallela all’aumento delle concentrazioni dell’ammoniaca sia nei pazienti che nei volontari sani; in entrambi i gruppi il picco di sonnolenza (ore 11), assente in condizione basale, coincide con il picco di concentrazione dell’ammoniaca (p<0.01)
• un aumento della durata del sonno nei volontari sani rispetto al basale (media ± SD, 49.3 ± 26.6 vs 30.4 ± 15.6 min), sebbene le differenze non siano statisticamente significative (p= 0.08). Nessuna modifica sulla durata del sonno nei pazienti.
• diminuzione significativa della potenza relativa beta (attività veloce) dell’EEG di sonno nei volontari sani (p<0.05);
• riduzione significativa della potenza relativa delta (attività molto lenta) del sonno in pazienti (p<0.05);

Studio 3. Effetti di L-ornitina-L-aspartato (LOLA, sostanza ipoammoniemizzante) e di caffeina (antagonista del recettore dell’adenosina) su prestazione cognitiva, EEG di veglia e sonno in condizioni di iperammoniemia indotta
• la popolazione di studio comprendeva 6 pazienti con cirrosi epatica (5 uomini; media ± SD; età : 61 ± 9 anni) e 5 volontari sani appaiati per età , sesso e livello d’istruzione (4 uomini, 49 ± 12 anni).
• I soggetti sono stati studiati con valutazione neuropsichica, rilevazione oraria di sonnolenza ed ammoniemia oraria e registrazione polisonnografica, dopo COAA COAA+LOLA- COAA + caffeina) il 4°, 11° e 18° giorno di studio.
• I pazienti rispetto ai volontari sani hanno presentato una prestazione psicometrica sia carta e matita che computerizzata significativamente peggiore rispetto ai volontari sani (p<0.05)
• i pazienti avevano livelli di ammoniaca superiori a quelli dei volontari sani in tutte le condizioni; il COAA ha prodotto l’atteso aumento dell’ammoniemia in entrambi i gruppi, con un picco più elevato e più prolungato nei pazienti.
• il LOLA ha determinato una riduzione seppur non significativa dei livelli plasmatici dell’ammonio in entrambi i gruppi
• né il LOLA né la caffeina hanno determinato cambiamenti significativi su la sonnolenza soggettiva, su prestazione psicometrica e su EEG di veglia
• i dati sull’EEG di sonno sono in corso di analisi (presso l’Istituto Farmacologia e Tossicologia dell’Università di Zurigo, Svizzera).

Conclusioni.
- l'EEG di veglia è estremamente sensibile all'iperammoniemia
- un’iperammoniemia moderata/cronica (pazienti in basale) o acuta (volontari sani dopo COAA) si traduce in una maggiore potenza del ritmo dominante di EEG, specialmente sulle zone posteriori dello scalpo.
- un’iperammoniemia acuta su cronica (pazienti dopo COAA) rallenta ulteriormente la frequenza dominante dell'EEG
- parametri EEG basati sulla potenza possono fornire informazioni utili alla definizione neurofisiologica dell'EE.
- l’iperammoniemia comporta un notevole aumento della sonnolenza diurna soggettiva
- l’iperammoniemia provoca cambiamenti opposti nell’EEG di sonno dei pazienti e dei controlli, rendendo il sonno dei pazienti più superficiale ed interrotto e quello dei volontari sani più profondo e stabile.
- l’EE può forse quindi essere inquadrata come un difetto di vigilanza, che rende simili l’EEG di sonno a quello di veglia, compromettendo quindi il raggiungimento di una veglia “piena” e la produzione di un sonno “ristoratore”.
- L-ornitina-L-aspartato determina una riduzione dei livelli di ammoniemia

Statistiche Download - Aggiungi a RefWorks
EPrint type:Ph.D. thesis
Tutor:Amodio, Piero and Montagnese, Sara
Ph.D. course:Ciclo 26 > Scuole 26 > SCIENZE MEDICHE, CLINICHE E SPERIMENTALI > EPATOLOGIA E CHIRURGIA EPATOBILIARE E TRAPIANTOLOGICA
Data di deposito della tesi:26 January 2014
Anno di Pubblicazione:26 January 2014
Key Words:encefalopatia epatica/ hepatic encephalopathy
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/09 Medicina interna
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina
Codice ID:6383
Depositato il:20 Sep 2016 14:32
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