肝性脑病发病机制新进展
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摘要
肝性脑病是急性肝功能衰竭和肝硬化患者常见的并发症,表现为从轻微认知障碍到昏迷等一系列神经症状。根据临床表现可分为轻微肝性脑病、明显肝性脑病和昏迷;依据基础肝病的类型,HE分为A、B、C 3型。10%～50%接受门体静脉分流术的患者1年内可发生明显的B型肝性脑病。肝性脑病是影响预后的不利因素,1年内病死率为54%～85%。肝性脑病的发病机制尚未明确,本文通过对肝性脑病发病机制的阐述,以期对临床诊断及治疗提供帮助。
Hepatic encephalopathy(HE) is a common complication of acute liver failure and liver cirrhosis. HE presents as a spectrum of neuropsychiatric symptoms ranging from subtle fluctuating cognitive impairment to coma. HE can be divided into minimal HE(MHE), overt HE(OHE) and coma. According to the type of basic liver diseases, HE is divided into A, B and C types. The 1-year incidence of patients with type B OHE who underwent transjugular intrahepatic portosystemic shunt(TIPS) is estimated to be 10%～50%. HE is a very poor prognostic factor with a 1-year mortality of 54%～85%. The pathogenesis of HE is not clear. This review explains the pathogenesis of HE, which is helpful for clinical diagnosis and treatment.
Hepatic encephalopathy(HE) is a common complication of acute liver failure and liver cirrhosis. HE presents as a spectrum of neuropsychiatric symptoms ranging from subtle fluctuating cognitive impairment to coma. HE can be divided into minimal HE(MHE), overt HE(OHE) and coma. According to the type of basic liver diseases, HE is divided into A, B and C types. The 1-year incidence of patients with type B OHE who underwent transjugular intrahepatic portosystemic shunt(TIPS) is estimated to be 10%～50%. HE is a very poor prognostic factor with a 1-year mortality of 54%～85%. The pathogenesis of HE is not clear. This review explains the pathogenesis of HE, which is helpful for clinical diagnosis and treatment.
引文
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[9]Liang C,Du T,Zhou J,et al.Ammonium increases Ca2+signalling and up-regulates expression of TRPC1 gene in astrocytes in primary cultures and in the in vivo brain[J].Neurochem Res,2014,39(11):2127-2135.
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[13]G?rg B,Karababa A,Shafigullina A,et al.Ammonia-induced senescence in cultured rat astrocytes and in human cerebral cortex in hepatic encephalopathy[J].Glia,2015,63(1):37-50.
[14]Oenarto J,Karababa A,Castoldi M,et al.Ammonia-induced miRNAexpression changes in cultured rat astrocytes[J].Sci Rep,2016,6:18493.
[15]Jayakumar AR,Tong XY,Curtis KM,et al.Decreased astrocytic thrombospondin-1 secretion after chronic ammonia treatment reduces the level of synaptic proteins:in vitro and in vivo studies[J].JNeurochem,2014,131(3):333-347.
[16]Bobermin LD,Arús BA,Leite MC,et al.Gap junction intercellular communication mediates ammonia-induced neurotoxicity[J].Neurotox Res,2016,29(2):314-324.
[17]Lemberg A,Fernández MA.Hepatic encephalopathy,ammonia,glutamate,glutamine and oxidative stress[J].Ann Hepatol,2009,8(2):95-102.
[18]Milewski K,Hilgier W,Albrecht J,et al.The dimethylarginine(ADMA)/nitric oxide pathway in the brain and periphery of rats with thioacetamide-induced acute liver failure:Modulation by histidine[J].Neurochem Int,2015,88:26-31.
[19]Ruszkiewicz J,Albrecht J.Changes of the thioredoxin system,glutathione peroxidase activity and total antioxidant capacity in rat brain cortex during acute liver failure:modulation by L-histidine[J].Neurochem Res,2015,40(2):293-300.
[20]Wu YB,Zhang L,Li WT,et al.Artesunate restores spatial learning of rats with hepatic encephalopathy by inhibiting ammonia-induced oxidative damage in neurons and dysfunction of glutamate signaling in astroglial cells[J].Biomed Pharmacother,2016,84:972-978.
[21]Mladenovi?D,Petronijevi?N,Stojkovi?T,et al.Finasteride has regionally different effects on brain oxidative stress and acetylcholinesterase activity in acute thioacetamide-induced hepatic encephalopathy in rats[J].PLoS One,2015,10(8):e0134434.
[22]Bosoi CR,Tremblay M,Rose CF.Induction of systemic oxidative stress leads to brain oedema in portacaval shunted rats[J].Liver Int,2014,34(9):1322-1329.
[23]Walsh TS,McLellan S,Mackenzie SJ,et al.Hyperlactatemia and pulmonary lactate production in patients with fulminant hepatic failure[J].Chest,1999,116(2):471-476.
[24]Rose C,Ytreb?LM,Davies NA,et al.Association of reduced extracellular brain ammonia,lactate,and intracranial pressure in pigs with acute liver failure[J].Hepatology,2007,46(6):1883-1892.
[25]Zwingmann C,Chatauret N,Leibfritz D,etal.Selective increase of brain lactate synthesis in experimental acute liver failure:results of a[H-C]nuclear magnetic resonance study[J].Hepatology,2003,37(2):420-428.
[26]Fitzpatrick SM,Hetherington HP,Behar KL,et al.Effects of acute hyperammonemia on cerebral amino acid metabolism and pHi in vivo,measured by 1H and 31P nuclear magnetic resonance[J].JNeurochem,1989,52(3):741-749.
[27]Dabos KJ,Parkinson JA,Sadler IH,et al.1H nuclear magnetic resonance spectroscopy-based metabonomic study in patients with cirrhosisand hepaticenc ephalop athy[J].Worl d JHepatol,2015,7(12):1701-1707.
[28]Hadjihambi A,De Chiara F,Hosford PS,et al.Ammonia mediates cortical hemichannel dysfunction in rodent models of chronic liver disease[J].Hepatology,2017,65(4):1306-1318.
[29]Magistretti PJ.Neuron-glia metabolic coupling and plasticity[J].J Exp Biol[J].2006,209(Pt 12):2304-2311.
[30]Zemtsova I,G?rg B,Keitel V,et al.Microglia activation in hepatic encephalopathy in rats and humans[J].Hepatology,2011,54(1):204-215.
[31]G?rg B,Bidmon HJ,H?ussinger D.Gene expression profiling in the cerebral cortex of patients with cirrhosis with and without hepatic encephalopathy[J].Hepatology,2013,57(6):2436-2447.
[32]McMillin M,Grant S,Frampton G,et al.Fractalkine suppression during hepatic encephalopathy promotes neuroinflammation in mice[J].J Neuroinflammation,2016,13(1):198.
[33]Hernández-Rabaza V,Cabrera-Pastor A,Taoro-González L,et al.Hyperammonemia induces glial activation,neuroinflammation and alters neurotransmitter receptors in hippocampus,impairing spatial learning:reversal by sulforaphane[J].J Neuroinflammation,2016,13:41.
[34]Agusti A,Hernández-Rabaza V,Balzano T,et al.Sildenafil reduces neuroinflammation in cerebellum,restores GABAergic tone,and improves motor in-coordination in rats with hepatic encephalopathy[J].CNS Neurosci Ther,2017,23(5):386-394.
[35]Hernandez-Rabaza V,Cabrera-Pastor A,Taoro-Gonzalez L,et al.Neuroinflammation increases GABAergic tone and impairs cognitive and motor function in hyperammonemia by increasing GAT-3membrane expression.Reversal by sulforaphane by promoting M2polarization of microglia[J].J Neuroinflammation,2016,13(1):83.
[36]Llansola M,Montoliu C,Agusti A,et al.Interplay between glutamatergic and GABAergic neurotransmission alterations in cognitive and motor impairment in minimal hepatic encephalopathy[J].Neurochem Int,2015,88:15-19.
[37]Palomero-Gallagher N,Zilles K.Neurotransmitter receptor alterations in hepatic encephalopathy:a review[J].Arch Biochem Biophys,2013,536(2):109-121.
[38]Butterworth RF.Neurosteroids in hepatic encephalopathy:Novel insights and new therapeutic opportunities[J].J Steroid Biochem Mol Biol,2016,160:94-97.
[39]Tsutsui K,Haraguchi S.Breakthrough in neuroendocrinology by discovering novel neuropeptides and neurosteroids:2.Discovery of neurosteroids and pineal neurosteroids[J].Gen Comp Endocrinol,2014,205:11-22.
[40]Mladenovi?D,Hrn?i?D,Petronijevi?N,et al.Finasteride improves motor,EEG,and cellular changes in rat brain in thioacetamideinduced hepatic encephalopathy[J].Am J Physiol Gastrointest Liver Physiol,2014,307(9):G931-G940.
[41]Johansson M,Agusti A,Llansola M,et al.GR3027 antagonizes GABAA receptor-potentiating neurosteroids and restores spatial learning and motor coordination in rats with chronic hyperammonemia and hepatic encephalopathy[J].Am J Physiol Gastrointest Liver Physiol,2015,309(5):G400-G409.
[42]Ding S,Liu L,Jing H,et al.Dopamine from cirrhotic liver contributes to the impaired learning and memory ability of hippocampus in minimal hepatic encephalopathy[J].Hepatol Int,2013,7(3):923-936.
[43]Ding S,Hu J,Yang J,et al.The inactivation of JAK2/STAT3 signaling and desensitization of M1 mAChR in minimal hepatic encephalopathy(MHE)and the protection of naringin against MHE[J].Cell Physiol Biochem,2014,34(6):1933-1950.
[44]Ding S,Wang W,Wang X,et al.Dopamine burden triggers neurodegeneration via production and release of TNF-αfrom astrocytes in minimal hepatic encephalopathy[J].Mol Neurobiol,2016,53(8):5324-5343.
[45]Bron B,Waldram R,Silk DB,et al.Serum,cerebrospinal fluid,and brain levels of bile acids in patients with fulminant hepatic failure[J].Gut,1977,18(9):692-696.
[46]McMillin M,Frampton G,Quinn M,et al.Bile Acid signaling is involved in the neurological decline in a murine model of acute liver failure[J].Am J Pathol,2016,186(2):312-323.
[47]Quinn M,McMillin M,Galindo C,et al.Bile acids permeabilize the blood brain barrier after bile duct ligation in rats via Rac1-dependent mechanisms[J].Dig Liver Dis,2014,46(6):527-534.
[48]Wright G,Swain M,Annane D,et al.Neuroinflammation in liver disease:sessional talks from ISHEN[J].Metab Brain Dis,2016,31(6):1339-1354.
[49]Dhanda S,Sandhir R.Blood-Brain Barrier Permeability Is Exacerbated in Experimental Model of Hepatic Encephalopathy via MMP-9 Activation and Downregulation of Tight Junction Proteins[J].Mol Neurobiol,2018,55(5):3642-3659.
[50]McMillin MA,Frampton GA,Seiwell AP,et al.TGFβ1 exacerbates blood-brain barrier permeability in a mouse model of hepatic encephalopathy via upregulation of MMP9 and downregulation of claudin-5[J].Lab Invest,2015,95(8):903-913.
[51]Shimojima N,Eckman CB,McKinney M,et al.Altered expression of zonula occludens-2 precedes increased blood-brain barrier permeability in a murine model of fulminant hepatic failure[J].J Invest Surg,2008,21(3):101-108.
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