Abstract
Hepatic encephalopathy is a common complication of hepatic cirrhosis. The clinical diagnosis is based on two concurrent types of symptoms: impaired mental status and impaired neuromotor function. Impaired mental status is characterized by deterioration in mental status with psychomotor dysfunction, impaired memory, and increased reaction time, sensory abnormalities, poor concentration, disorientation and coma. Impaired neuromotor function include hyperreflexia, rigidity, myoclonus and asterixis. The pathogenesis of hepatic encephalopathy has not been clearly defined. The general consensus is that elevated levels of ammonia and an inflammatory response work in synergy to cause astrocyte to swell and fluid to accumulate in the brain which is thought to explain the symptoms of hepatic encephalopathy. Acetyl-L-carnitine, the short-chain ester of carnitine is endogenously produced within mitochondria and peroxisomes and is involved in the transport of acetyl-moieties across the membranes of these organelles. Acetyl-L-carnitine administration has shown the recovery of neuropsychological activities related to attention/concentration, visual scanning and tracking, psychomotor speed and mental flexibility, language short-term memory, attention, and computing ability. In fact, Acetyl-L-carnitine induces ureagenesis leading to decreased blood and brain ammonia levels. Acetyl-L-carnitine treatment decreases the severity of mental and physical fatigue, depression cognitive impairment and improves health-related quality of life. The aim of this review was to provide an explanation on the possible toxic effects of ammonia in HE and evaluate the potential clinical benefits of ALC.
References
Aureli T, Di Cocco ME, Puccetti C, Ricciolini R, Scalibastri M, Miccheli A, Manetti C, Conti F (1998) Acetyl-Lcarnitine modulates glucose metabolism and stimulates glycogen synthesis in rat brain. Brain Res 796(1–2):75–81. doi:10.1016/S0006-8993(98)00319-9
Cauli O, Rodrigo R, Llansola M, Montoliu C, Monfort P, Piedrafita B, El Mlili N, Boix J, Agustí A, Felipo V (2009) Glutamatergic and gabaergic neurotransmission and neuronal circuits in hepatic encephalopathy. Metab Brain Dis 24(1):69–80. doi:10.1007/s11011-008-9115-4
Di Cesare Mannelli L, Ghelardini C, Toscano A, Pacini A, Bartolini A (2010) The neuropathy-protective agent acetylL-carnitine activates protein kinase C-gamma and MAPKs in a rat model of neuropathic pain. Neuroscience 165(4):1345–1352. doi:10.1016/j.neuroscience.2009.11.021
Fiskum G, Rosenthal RE, Vereczki V, Martin E, Hoffman GE, Chinopoulos C, Kowaltowski A (2004) Protection against ischemic brain injury by inhibition of mitochondrial oxidative stress. J Bioenerg Biomembr 36(4):347–352. doi:10.1023/B:JOBB.0000041766.71376.81
Flanagan JL, Simmons PA, Vehige J, Willcox MD, Garrett Q (2010) Role of carnitine in disease. Nutr Metab (Lond) 7:30. doi:10.1186/1743-7075-7-30
Jones EA, Mullen KD (2012) Theories of the pathogenesis of hepatic encephalopathy. Clin Liver Dis 16(1):7–26. doi:10.1016/j.cld.2011.12.010
Limketkai BN, Zucker SD (2008) Hyperammonemic encephalopathy caused by carnitine deficiency. J Gen Intern Med 23:210–213. doi:10.1007/s11606-007-0473-0
Llansola M, Erceg S, Hernández-Viadel M, Felipo V (2002) Prevention of ammonia and glutamate neurotoxicity by carnitine: molecular mechanisms. Metab Brain Dis 17(4):389–397. doi:10.1023/A:1021922305036
Malaguarnera M, Pistone G, Astuto M, Vecchio I, Raffaele R, Lo Giudice E, Rampello L (2006) Effects of Lacetylcarnitine on cirrhotic patients with hepatic coma: randomized double-blind, placebo-controlled trial. Dig Dis Sci 51(12):2242–2247. doi:10.1007/s10620-006-9187-0
Malaguarnera M, Gargante MP, Cristaldi E, Vacante M, Risino C, Cammalleri L, Pennisi G, Rampello L (2008) Acetyl-L-carnitine treatment in minimal hepatic encephalopathy. Dig Dis Sci 53(11):3018–3025. doi:10.1007/s10620-008-0238-6
Malaguarnera M, Risino C, Cammalleri L, Malaguarnera L, Astuto M, Vecchio I, Rampello L (2009) Branched chain amino acids supplemented with L-acetyl carniti ne versus BCAA treatment in hepatic coma: a randomized and controlled double blind study. Eur J Gastroenterol Hepatol 21(7):762–770. doi:10.1097/MEG.0b013e328309c791
Malaguarnera M, Bella R, Vacante M, Giordano M, Malaguarnera G, Gargante MP, Motta M, Mistretta A, Rampello L, Pennisi G (2011a) Acetyl-L-carnitine reduces depression and improves quality of life in patients with minimal hepatic encephalopathy. Scand J Gastroenterol 46(6):750–759. doi:10.3109/00365521.2011.565067
Malaguarnera M, Vacante M, Giordano M, Pennisi G, Bella R, Rampello L, Malaguarnera M, Li Volti G, Galvano F (2011b) Oral acetyl-L-carnitine therapy reduces fatigue in overt hepatic encephalopathy: a randomized, double-blind, placebo-controlled study. Am J Clin Nutr 93(4):799–808. doi:10.3945/ajcn.110.007393
Malaguarnera M, Vacante M, Motta M, Giordano M, Malaguarnera G, Bella R, Nunnari G, Rampello L, Pennisi G (2011c) Acetyl-L-carniti ne improves cognitive functions in severe hepatic encephal opathy: a randomized and controlled clinical trial. Metab Brain Dis 26(4):281–289. doi:10.1007/s11011-011-9260-z
Malaguarnera M, Vacante M, Giordano M, Motta M, Bertino G, Pennisi M, Neri S, Malaguarnera M, Li Volti G, Galvano F (2011d) L-carnitine supplementation improves hematological pattern in patients affected by HCV treated with Peg interferon-a 2b plus ribavirin. World J Gastroenterol 17(39):4414–4420. doi:10.3748/wjg.v17.i39.4414
Matsuda I, Ohtani Y (1986) Carnitine status in Reye and Reye-like syndromes. Pediatr Neurol 2(2):90–94
McPhail MJ, Bajaj JS, Thomas HC, Taylor-Robinson SD (2010) Pathogenesis and diagnosis of hepatic encephalopathy. Expert Rev Gastroenterol Hepatol 4(3):365–378. doi:10.1586/egh.10.32
Miñana MD, Hermenegildo C, Llsansola M, Montoliu C, Grisolía S, Felipo V (1996) Carnitine and choline derivatives containing a trimethylamine group prevent ammonia toxicity in mice and glutamate toxicity in primary cultures of neurons. J Pharmacol Exp Ther 279(1):194–199
Norenberg MD, Jayakumar AR, Rama Rao KV (2004) Oxidative stress in the pathogenesis of hepatic encephalopathy. Metab Brain Dis 19(3–4):313–329. doi:10.1023/B:MEBR.0000043978.91675.79
Peluso G, Barbarisi A, Savica V, Reda E, Nicolai R, Benatti P, Calvani M (2000) Carnitine: an osmolyte that plays a metabolic role. J Cell Biochem 80(1):1–10. doi:10.1002/1097-4644(20010101)
Rama Rao KV, Norenberg MD (2012) Brain energy metabolism and mitochondrial dysfunction in acute and chronic hepatic encephalopathy. Neurochem Int 60(7):697–706. doi:10.1016/j.neuint.2011.09.007
Rama Rao KV, Jayakumar AR, Norenberg MD (2012) Glutamine in the pathogenesis of acute hepatic encephalopathy. Neurochem Int. doi:10.1016/j.neuint.2012.01.012
Ratnakumari L, Qureshi IA, Butterworth RF (1993) Effect of L-carnitine on cerebral and hepatic energy metabolites in congenitally hyperammonemic sparse-fur mice and its role during benzoate therapy. Metabolism 42(8):1039–1046. doi:10.1016/0026-0495(93)90020-O
Rebouche CJ (1992) Carnitine function and requirements during the life cycle. FASEB J 6(15):3379–3386
Rodrigo R, Cauli O, Boix J, ElMlili N, Agusti A, Felipo V (2009) Role of NMDA receptors in acute liver failure and ammonia toxicity: therapeutical implications. Neurochem Int 55(1–3):113–118. doi:10.1016/j.neuint.2009.01.007
Rose C, Felipo V (2005) Limited capacity for ammonia removal by brain in chronic liver failure: potential role of nitric oxide. Metab Brain Dis 20(4):275–283. doi:10.1007/s11011-005-7906-4
Scafidi S, Fiskum G, Lindauer SL, Bamford P, Shi D, Hopkins I, McKenna MC (2010) Metabolism of acetyl-Lcarnitine for energy and neurotransmitter synthesis in the immature rat brain. J Neurochem 114(3):820–831. doi:10.1111/j.1471-4159.2010.06807.x
Therrien G, Rose C, Butterworth J, Butterworth RF (1997) Protective effect of L-carnitine in ammonia-precipitated encephalopathy in the portacaval shunted rat. Hepatology 25(3):551–556. doi:10.1002/hep.510250310
Acknowledgments
Michele Malaguarnera was supported by the International PhD program in Neuropharmacology of the University of Catania.
Competing interests
The author declares that he has no competing interests
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Malaguarnera, M. Acetyl-L-carnitine in hepatic encephalopathy. Metab Brain Dis 28, 193–199 (2013). https://doi.org/10.1007/s11011-013-9376-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-013-9376-4