UNIVERSITÀ DEGLI STUDI DI CATANIA Dipartimento di Scienze della Senescenza, Urologiche e Neurourologiche
LA L-ACETILCARNITINA NELLA ENCEFALOPATIA EPATICA Prof. Mariano Malaguarnera Direttore Scuola di Specializzazione in Gerontologia e Geriatria
Milano 24-26 Febbraio 2011
L-Carnitine/Acetyl-L-Carnitine •Transports long-chain fatty acids into mitochondria •Removes short- and medium-chain fatty acids that accumulate
•Mediates the ratio of acetyl-CoA/CoA •Decreases with age in plasma and in brain
Metabolismo della L-carnitina
Carenza di Carnitina L'organismo umano può sintetizzare la carnitina a partire dagli amminoacidi lisina e metionina.
Alcune disfunzioni possono condurre ad una significativa carenza di carnitina. Questi deficit sono messi in correlazione con varie patologie, tra cui la sindrome da affaticamento cronico
Gli effetti della carenza di carnitina sono stati descritti per la prima volta nel 1973, associati ad una miopatia grave con accumulo di acidi grassi non ossidati nel muscolo scheletrico: tale sindrome è nota come deficit primario di carnitina, carnitina la cui causa è una mutazione genetica a carico dell‘ Na+dependent organic cation transporter (OCTN2).
Deficit primario di carnitina In tale quadro, la concentrazione ematica di carnitina è inferiore a 10 nmol/l, contro i valori di riferimento di 40-80.
Tale deficit si presenta sin dai primi anni di vita, ed è letale se non si interviene con dosaggi soprafisiologici di L-carnitina.
Soggetti con livelli di carnitina molto bassi, come coloro che hanno una mutazione genetica nell'espressione di OCTN2, possono presentare i sintomi tipici della sindrome di Reye, Reye in cui il metabolismo degli acidi grassi è alterato.
Reye's syndrome Stage I •Persistent, heavy vomiting that is not relieved by eating •Generalized lethargy •General mental symptoms, e.g. confusion •Nightmares
Reye's syndrome Stage II • Stupor caused by minor brain inflammation • Hyperventilation • Fatty liver (found by biopsy) • Hyperactive reflexes
Reye's syndrome Stage III •Continuation of Stage I and II symptoms •Possible coma •Possible cerebral edema •Rarely, respiratory arrest
Reye's syndrome Stage IV • Deepening coma • Large pupils with minimal response to light • Minimal but still present hepatic dysfunction
Reye's syndrome Stage V • Very rapid onset following stage IV • Deep coma • Seizures • Respiratory failure • Flaccidity • Extremely high blood ammonia (above 300mg per 100mL of blood) • Death
Disturbi metabolici ereditari i cui sintomi possono essere sovrapponibili a quelli della sindrome di Reye 1.Disordini dell'ossidazione mitocondriale degli acidi grassi a. Difetti della beta-ciclo-ossigenasi a. Deficit dell'acetil-CoA deidrogenasi a catena intermedia b. Deficit dell'acetil-CoA deidrogenasi a catena molto lunga c. Deficit dell'acetil-CoA deidrogenasi a catena lunga b. Difetti nella fase di trasferimento degli elettroni a. Deficit moderato o grave dell'acetil CoA - deidrogenasi multipla b. Deficit dell'acetil CoA - deidrogenasi multipla sensibile alla riboflavina
c. Difetti nel ciclo della carnitina a. Deficit di carnitina - palmitoil trasferasi di tipo 1 e 11 b. Deficit della traslocazione della carnitina all'acetilcarnitina c. Deficit del carrier della carnitina (deficienza primaria di carnitina)
Disturbi metabolici ereditari i cui sintomi possono essere sovrapponibili a quelli della sindrome di Reye 2. Difetti nel metabolismo di amino-acidi a catena ramificata (valina, leucina, isoleucina e relative acidemie organiche) 1. Disordine delle urine a sciroppo d'acero 2. Acidemia multipla da deficienza isovalerica della carbossilasi 3. Acidemia propionica 4. Acidemia metil-malonica 5. Deficienza della 3-idrossi-3 metil glutaril CoA liasi 6. Aciduria 3-metil glutaconica
Disturbi metabolici ereditari i cui sintomi possono essere sovrapponibili a quelli della sindrome di Reye 3. Difetti nel metabolismo dei carboidrati • Intolleranza ereditaria al fruttosio • Disordini della gluconeogenesi • Deficienza della fruttosio-1,6-difosfatasi • Disturbi nel deposito di glicogeno • GSD di tipo 1 • Disordini del metabolismo del glicerolo • Deficienza della glicerolo-chinasi
Disturbi metabolici ereditari i cui sintomi possono essere sovrapponibili a quelli della sindrome di Reye 4. Disordini nella detossificazione dell'ammoniaca - difetti del ciclo dell'urea • Deficit di ornitina transcarbamilasi (OTC) • Deficit di carbamilfosfato sintetasi 1 (CPS) • Aciduria arginino-succinica • Citrullinemia • Sindrome HHH (iperammonemia, iperornitinemia, omocitrullinemia 5. Disordini del trasporto degli amino-acidi • Intolleranza alle proteine lisinuriche (lisina, arginina ed ornitina)
The Urea Cycle
Aspartate Transaminase(AST)
Alanine Transaminase (ALT)
Stages of Hepatic Encephalopathy Stage
Symptoms
I
Mild Confusion, agitation, irritability, sleep disturbance, decreased attention
II
Lethargy, disorientation, inappropriate behavior, drowsiness
III
Somnolent but arousable, slurred speech, confused, aggressive
IV
Coma
Minimal hepatic encephalopathy
MHE is an important disorder that impairs patients daily functioning and health-related quality of life (HRQL).
In fact patients with MHE had a significant impairment in daily functioning, such as social interaction, alertness, emotional behaviour, sleep, work, home management and recreation and pastimes
Diagnosis of MHE Neuropsychological
- Older tests include the "numbers connecting test" A and B (measuring the speed at which one could connect randomly dispersed numbers 1–20), the "block design test" and the "digit-symbol test".
Disorders in patients with Severe Hepatic Encephalopathy (grade 3 of the West Haven grading scale) Consciousness
somnolence confusion semistupor
Intellectual function
disorientation in space amnesia for recent and past events inability to perform calculations
Personality and behaviour
strange behaviour paranoia or anger rage asterixis
Neuromuscular abnormalities
hyperactive reflexes nistagmus Babinski myoclonus
Pathogenesis Theories
Endogenous Neurotoxins – – – –
Ammonia Mercaptans Phenols Short-medium fatty acids
Increased Permeability of Blood-Brain Barrier
Change in Neurotransmitters and Receptors – GABA – Altered BCAA/AAA ratio
Other – Zinc defficiency – Manganese deposits
Neurotoxic Action of Ammonia
Readily crosses blood-brain barrier
Increased NH3 = increased glutamate – α-ketoglutarate+NH3+NADH→glutamate+NAD – glutamate+NH3+ATP→glutamine+ADP+Pi
As a-ketoglutarate is depleted TCA cycle activity halted
Increased glutamine formation depletes glutamate stores which are needed by neural tissue – Irrepairable cell damage and neural cell death ensue. – In liver disease, conversion of ammonia to urea and glutamine can be reduced up to 80%
Pathogenesis Theories: False Neurotransmitter Hypothesis
AAA are precursors to neurotransmitters and elevated levels result in shunting to secondary pathways
Pathogenesis Theories: Change In Neurotransmitters and Receptors
Gamma-Aminobutyric Acid (GABA)
Pathogenesis Theories: Change In Neurotransmitters and Receptors
BCAA-Ammonia Connection
Inter-organ trafficking of ammonia both in healthy individuals and in patients with cirrhosis
Diagnostic Criteria
Asterixis (“flapping tremor”)
Hx liver disease
Impaired performance on neuropsychological tests – Visual, sensory, brainstem auditory evoked potentials
Sleep disturbances
Diagnostic Criteria
Fetor Hepaticus
Slowing of brain waves on EEG
PET scan – Changes of neurotransmission, astrocyte function
Elevated serum NH3 – Stored blood contains ~30ug/L ammonia – Elevated levels seen in 90% pts with HE – Not needed for diagnosis
Branched Chain Amino Acids (BCAA) Valine Leucine Isoleucine •Important fuel sources for skeletal muscle during periods of metabolic stress •Metabolized in muscle & brain, not liver -promote protein synthesis -suppress protein catabolism -substrates for gluconeogenesis •Catabolized to L-alanine and Lglutamine in skeletal muscle
L-Carnitine in the treatment of mild or moderate hepatic encephalopathy Dig Dis. 2003;21:271-5 The authors have shown a protective effect of LC in ammoniaprecipitated encephalopathy in cirrhotic patients. Either in subjects with HE 1 or 2 the authors observed a significant reduction at day 30 and more markedly at day 60 of treatment
Effects of L-carnitine in patients with hepatic encephalopathy World J Gastroenterol 2005;11:7197:202 A significant decrease in NH4 fasting serum levels was found in patients with hepatic encephalopathy after the treatment with levocarnitine.
Effects of L-Acetylcarnitine on Cirrhotic patients with hepatic coma: randomized double-blind, placebocontrolled trial Dig Dis Sci 2006;51:2242-2247 The study demonstrates that LAC administration improved neurological and biohumoral symptoms in selective cirrhotic patients with hepatic coma. Seven patients went from grade 4 down to grade 3, and one from grade 4 down to grade 1.
Acetyl-L-carnitine treatment in minimal hepatic encephalopathy Dig Dis Sci 2008;53:3018-25 After 90 days in group A treated with ALC, the authors observed a . significant decrease in prothrombin time, bilirubin serum levels , AST, fasting NH4 serum levels, Trail Making Test-A and Trail Making Test-B (P<0,01)
Serum carnitine levels in chronic hepatitis C patients before and after lymphoblastoid interferon-alpha treatment. BioDrugs. 1999;12:65-9.
L-carnitine decreases severity and type of fatigue induced by interferon-alpha in the treatment of patients with hepatitis C. Neuropsychobiology. 2003;47:94-7.
Levocarnitine administration in elderly subjects with rapid muscle fatigue: effect on body composition, lipid profile and fatigue. Drugs Aging. 2003;20:761-7.
L-Carnitine treatment reduces steatosis in patients with chronic hepatitis C treated with α-Interferon and Ribavirin Dig Dis Sci 2008;53:1114-1121
Branched chain amino acids supplemented with Lacetylcarnitine versus BCAA treatment in hepatic coma: arandomized and controlled double blind study Eur J Gastroenterol Hepatol 2009;21:762-70
Oral acetyl-L-carnitine therapy reduces fatigue in overt hepatic encephalopathy: a randomized, double bind, placebo-controlled study Am J Clin Nutr 2011;93:1-10
Acetyl L-carnitine (ALC) treatment in elderly patients with fatigue Arch Gerontol Geriatr. 2008;46:181-90
