Abstract
To assess the contribution of hyperammonemia and inflammation to induction of mild cognitive impairment (or MHE). We analyzed the presence of mild cognitive impairment (CI) by using the PHES battery of psychometric tests and measured the levels of ammonia and of the inflammatory cytokines IL-6 and IL-18 in blood of patients with different types of liver or dermatological diseases resulting in different grades of hyperammonemia and/or inflammation. The study included patients with 1) liver cirrhosis, showing hyperammonemia and inflammation; 2) non-alcoholic fatty liver disease (NAFLD) showing inflammation but not hyperammonemia; 3) non-alcoholic steatohepatitis (NASH) showing inflammation and very mild hyperammonemia; 4) psoriasis, showing inflammation but not hyperammonemia; 5) keloids, showing both inflammation and hyperammonemia and 6) controls without inflammation or hyperammonemia. The data reported show that in patients with liver diseases, cognitive impairment may appear before progression to cirrhosis if hyperammonemia and inflammation are high enough. Five out of 11 patients with NASH, without liver cirrhosis, showed cognitive impairment associated with hyperammonemia and inflammation. Patients with keloids showed cognitive impairment associated with hyperammonemia and inflammation, in the absence of liver disease. Hyperammonemia or inflammation alone did not induce CI but the combination of certain levels of hyperammonemia and inflammation is enough to induce CI, even without liver disease.
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References
Amodio P, Montagnese S, Gatta A, Morgan MY (2004) Characteristics of minimal hepatic encephalopathy. Metab Brain Dis 19:253–267. doi:10.1023/B:MEBR.0000043975.01841.de
Cauli O, Rodrigo R, Piedrafita B, Boix J, Felipo V (2007) Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with porto-caval shunts. Hepatology 46:514–519. doi:10.1002/hep.21734
Cauli O, Rodrigo R, Piedrafita B, Llansola M, Mansouri MT, Felipo V (2009) Neuroinflammation contributes to hypokinesia in rats with hepatic encephalopathy. Ibuprofen restores its motor activity. J Neurosci Res 87:1369–1374. doi:10.1002/jnr.21947
Das A, Dhiman RK, Saraswat VA, Verma M, Naik SR (2001) Prevalence and natural history of subclinical hepatic encephalopathy in cirrhosis. J Gastroenterol Hepatol 16:531–535. doi:10.1046/j.1440-1746.2001.02487.x
Felipo V (2008) Hyperammonemia. In: Handbook of Neurochemistry and Molecular Neurobiology, 3rd Edition. Kluwer Academic/Plenum Publishers. USA, vol. 24: 1–27
Felipo V, Butterworth RF (2002) Neurobiology of Ammonia. Prog Neurobiol 67:259–279. doi:10.1016/S0301-0082(02)00019-9
Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT (2002) Hepatic encephalopahy-Definition, Nomenclature, Diagnosis and Quantification: Final report of the working party at the 11 World Congress of Gastroenterology, Viena 1998. Hepatology 35:716–721. doi:10.1053/jhep.2002.31250
Ghazizadeh M, Tosa M, Shimizu H, Hyakusoku H, Kawanami O (2007) Functional implications of the IL-6 signaling pathway in keloid pathogenesis. J Invest Dermatol 127:98–105. doi:10.1038/sj.jid.5700564
Groeneweg M, Quero JC, De Bruijn I, Hartmann IJC, Essink-bot ML, Hop WCJ, Schalm SW (1998) Subclinical hepatic encephalopathy impairs daily functioning. Hepatology 28:45–49. doi:10.1002/hep.510280108
Häussinger D (2006) Low grade cerebral edema and the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology 43:1187–1190. doi:10.1002/hep.21235
Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ (2005) Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41:1313–1321. doi:10.1002/hep.20701
Maccioni RB, Rojo LE, Fernández JA, Kuljis RO (2009) The role of neuroimmunomodulation in Alzheimer’s disease. Ann N Y Acad Sci 1153:240–246. doi:10.1111/j.1749-6632.2008.03972.x
Marini JC, Broussard SR (2006) Hyperammonemia increases sensitivity to LPS. Mol Genet Metab 88:131–137. doi:10.1016/j.ymgme.2005.12.013
McPhail MJ, Bajaj JS, Thomas HC, Taylor-Robinson SD (2010) Pathogenesis and diagnosis of hepatic encephalopathy. Expert Rev Gastroenterol Hepatol 4:365–378. doi:10.1586/egh.10.32
Montoliu C, Piedrafita B, Serra MA, Del Olmo JA, Ferrandez A, Rodrigo JM, Felipo V (2007) Activation of soluble guanylate cyclase by nitric oxide in lymphocytes correlates with minimal hepatic encephalopathy in cirrhotic patients. J Mol Med 85:233–241. doi:10.1007/s00109-006-0149-y
Montoliu C, Piedrafita B, Serra MA, Del Olmo JA, Urios A, Rodrigo JM, Felipo V (2009) IL-6 and IL-18 in blood may discriminate cirrhotic patients with and without minimal hepatic encephalopathy. J Clin Gastroenterol 43:272–279. doi:10.1097/MCG.0b013e31815e7f58
Norenberg MD, Jayakumar AR, Rama Rao KV (2004) Oxidative stress in the pathogenesis of hepatic encephalopathy. Metab Brain Dis 19:313–329. doi:10.1023/B:MEBR.0000043978.91675.79
Romero-Gómez M, Boza F, García-Valdecasas MS, García E, Aguilar-Reina J (2001) Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy. Am J Gastroenterol 96:2718–2723. doi:10.1016/S0002-9270(01)02692-2 and 10.1111/j.1572-0241.2001.04130.x
Shawcross DL, Davies NA, Williams R, Jalan R (2004) Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol 40:247–254. doi:10.1016/j.jhep.2003.10.016
Shawcross DL, Wright G, Olde Damink SW, Jalan R (2007) Role of ammonia and inflammation in minimal hepatic encephalopathy. Metab Brain Dis 22:125–138. doi:10.1007/s11011-006-9042-1
Seiler N (1993) Is ammonia a pathogenetic factor in Alzheimer’s disease? Neurochem Res 18:235–245. doi:10.1007/BF00969079
Seiler N (2002) Ammonia and Alzheimer’s disease. Neurochem Int 41:189–207. doi:10.1016/S0197-0186(02)00041-4
Szekely CA, Thorne JE, Zandia PP, Eka M, Messiasa E, Breitnerc JCS, Goodman SN (2004) Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer’s disease: a systematic review. Neuroepidemiology 23:159–169. doi:10.1159/000078501
Teunissen CE, van Boxtel MP, Bosma H, Bosmans E, Delanghe J, De Bruijn C, Wauters A, Maes M, Jolles J, Steinbusch HWM, de Vente J (2003) Inflammation markers in relation to cognition in a healthy aging population. J Neuroimmunol 134:142–150. doi:10.1016/S0165-5728(02)00398-3
Weaver JD, Huang MH, Albert M, Harris T, Rowe JW, Seeman TE (2002) Interleukin-6 and risk of cognitive decline: MacArthur studies of successful aging. Neurology 59:371–378
Wein C, Koch H, Popp B, Oehler G, Schauder P (2004) Minimal hepatic encephalopathy impairs fitness to drive. Hepatology 39:739–745. doi:10.1002/hep.20095
Weissenborn K, Ennen JC, Schomerus H, Rückert N, Hecker H (2001) Neuropsychological characterization of hepatic encephalopathy. J Hepatol 34:768–773. doi:10.1016/S0168-8278(01)00026-5
World Medical Organization (1996) Declaration of Helsinki. BMJ 313:1448–1449
Wright G, Jalan R (2007) Ammonia and inflammation in the pathogenesis of hepatic encephalopathy: Pandora’s box? Hepatology 46:291–294. doi:10.1002/hep.21843
Xue H, McCauley RL, Zhang W (2000) Elevated interleukin-6 expression in keloid fibroblasts. J Surg Res 89:74–77. doi:10.1006/jsre.1999.5805
Yaffe K, Lindquist K, Penninx BW, Simonsick EM, Pahor M, Kritchevsky S, Launer L, Kuller L, Rubin S, Harris T (2003) Inflammatory markers and cognition in well-functioning African-American and white elders. Neurology 61:76–80
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Supported by grants from Ministerio de Ciencia e Innovacion (SAF2008-00062, CSD2008-00005 to VF and FIS 06/0065 and PS09/00806 to CM) and from Consellería de Educación (ACOMP/2009/191; ACOMP-2009-025; PROMETEO/2009/027) and AP-079/08, AP-092/09, AP-028/10 and AP-087/11 from Conselleria de Sanitat, Generalitat Valenciana and from Fundacion Investigacion Medica Mutua Madrileña (CM) and Fundacion MAPFRE (CM).
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Felipo, V., Urios, A., Montesinos, E. et al. Contribution of hyperammonemia and inflammatory factors to cognitive impairment in minimal hepatic encephalopathy. Metab Brain Dis 27, 51–58 (2012). https://doi.org/10.1007/s11011-011-9269-3
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DOI: https://doi.org/10.1007/s11011-011-9269-3