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Vasoactive Substances and Inflammatory Factors in Progression of Liver Cirrhosis with Portal Hypertension

Written By

Hao Lu, Guoqiang Li, Ling Lu, Ye Fan, Xiaofeng Qian, Ke Wang and Feng Zhang

Submitted: 08 July 2012 Published: 13 February 2013

DOI: 10.5772/52663

Hepatic Surgery IntechOpen
Hepatic Surgery Edited by Hesham Abdeldayem

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Hepatic Surgery

Edited by Hesham Abdeldayem

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1. Introduction

Portal hypertension (PH), a detrimental complication of many diseases, is abnormalities in pre-, intra- or post-hepatic portal venous system. Intrahepatic PH is the most common type, which is mainly cause by liver cirrhosis [1], liver cancer, and sometimes intrahepatic vascular abnormalities [2].

Hepatic venous pressure gradient (HVPG) is the difference between wedged hepatic venous pressure and infra vena cava pressure. PH is defined as an HVPG higher than 5 mmHg [3]. According to absence or presence of complications (splenomegaly and hypersplenism, esophageal varices and ascites), PH can be classified into compensated or decompensated phase. Meanwhile, an HVPG higher than 10 mmHg has been considered as a direct predictor of decompensation and a 10-year-follow-up study showed the significant worse long-term survival when HVPG ＞ 10 mmHg [4-6].

In cirrhotic PH, increased intrahepatic vascular resistance (IHVR) is the primary factor [7, 8] and subsequently increased portal vein inflow (PVI) worsens the situation of PH patients. This review will focus on the physiopathological changes happened in PH.

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2. Correlation between vasoactive substances and IHVR/PVI

2.1. Nitric oxide

Nitric oxide (NO) is a potential vasodilator, produced by NO synthase (NOS). In a rat PH model induced by Thioacetamide, contraction of hepatic stellate cells, which resulting the increase of intrahepatic vascular tone, was inhibited by incubated with nitroflurbiprofen in vitro, a nitric oxide-releasing cyclooxygenase inhibitor in a dose-dependent manner. In wild-type BDL mice, expression of NOS, especially eNOS was down-regulated [9]. Moreover, the significantly elevated total intrahepatic resistance was reduced significantly in vivo by the drug, indicating a potential role of NO on portal pressure [10]. In another rat PH model induced by bile-duct-ligation, intrahepatic vascular resistance increased significantly. Besides, relative level of phos-NOS decreased compared with sham group, leading to an inhibition of intrahepatic NO, although the relative mRNA level was increased [11]. Intrahepatic NO production is largely mediated by endothelial NO synthase (eNOS) and impaired when cirrhosis and secondary endothelial dysfunction existed, leading to the increase of intrahepatic vascular resistance. But the inhibition of NO might be the result of up-regulation of caveolin-1, a down-regulator of eNOS [12].

Contrastingly, extrahepatic NO is increased in PH patients. A clinical trial has shown that serum nitrate level was positively correlated with clinical presentation, (e.g. pulse rate, jaundice, hepatic encephalopathy, lower limb edema) and esophageal varices [13]. It is well established that NO results in dilation of splanchnic and systemic circulation as a powerful vasodilator and blood level of NO is increased as PH progresses [14-16]. Administration of CCl4 to eNOS(-/-) mice also led to an elevated NO production, which is eNOS independent [17]. Another study suggested that iNOS might be involved [18].

2.2. Carbon monoxide

Carbon monoxide (CO), a vasodilator producing by heme oxygenases (HOs) from heme [19], changes as HO-1 expression altered in PH patients [20, 21], which shares the same characters with NO [12]. Expression of intrahepatic HO-1 and -2 decreased in cirrhotic rats than that in normal ones. In situ perfusion with CO-releasing molecule-2, which leads to relaxation of hepatic stellate cells, and HO-1 inducer hemin could attenuated increased IHVR. ZnPP caused a higher IHVR attributing to inhibition of intrahepatic HO-1 in cirrhotic liver[22].

But things are different in splanchnic and systemic circulation. Reportedly, portal vein pressure (PVP) was significantly higher in bile-duct-ligated rats than that in sham group. Meanwhile, mRNA and protein level of HO-1 was also elevated significantly in lung [23].A clinical study has shown an activated HO/CO system in cirrhotic patients while the HO-1 activity and plasma level of CO were related with the severity of PH [20]. Arterial blood gas analysis showed an increase of COHb in bile-duct-ligated rats which could be reversed by ZnPP [23]. HO-1 could promote expression of VEGF and thereafter lead to formation of collateral vessels and higher splanchnic circulation [24].

2.3. Endothelin

Endothelin-1 (ET-1) is the most powerful vasoconstrictor in ETs family [25], which is primarily synthesized and acts in liver mainly in a paracrine fashion via ET A receptor causing vessel constriction [26]. In liver cirrhotic rats induced by carbon tetrachloride, both plasma ET-1 level and PVP elevated dramatically while the mean hepatic tissue portal inflow reduced. And, perfusion with an antagonist of ET A receptor led to a reduction of plasma ET-1 level and PVP but did not improve the hepatic infusion suggesting that ET-1 was involved in development of PH [26]. It is consistent with a previous study which had demonstrated that liver blood inflow fluctuated in ET A and B receptors antagonist infusion groups and control group [27]. ET A and B receptors play different roles in CCl4-induced portal hypertensive rats. Antagonism of ET A or B receptor led to a reduced or increased of PVP and sinusoidal area in the cirrhotic rats respectively [28]. However, activation of ET B receptor leads to production of other vasoactive molecules, e.g. TXA2 [29]. Besides, antagonism of ET A receptor alone cannot improve splanchnic circulation indicating ET B receptor plays a role on regulation in PH [30].

2.4. RAAS

It is well established that renin -angiotensin II (Ang II) -aldosterone -system (RAAS) plays an important role on body circulation. Ang II promotes proliferation and contraction of HSC and formation of collagen, leading to liver fibrosis [31]. In hepatorenal syndrome, a severe complication of cirrhotic portal hypertension with hyperdynamic circulation, systemic resistance, circulatory renin activity and plasma aldosterone were significantly increased [32]. Besides, angiotensin converting enzyme (ACE) and Ang II elevated in liver cirrhosis [33, 34]. Role of RAAS on portal pressure provides a new therapeutic alternative [35]. Animal model studies and clinical trials have shown that blockade of Ang II type 1 receptor (AT1R) significantly reduced portal perfusion pressure and HVPG [36-39]. ACE inhibitor also effects to reduce portal pressure in cirrhotic patients [40]. Inhibition of RAAS by losartan could also lead to a reduction of eNOS and ROS level in BDL rats [41].

2.5. Catecholamines

Catecholamines (CA) cause general physiological changes including increases in heart rate, blood pressure, blood glucose levels, and a general reaction of the sympathetic nervous system. In BDL cirrhotic rats, noradrenaline correlated with perfusion pressure dose-dependently, and this constrictive effect might be normalized by phentolamine but not propranolol, indicating that noradrenaline influences PVP through α-receptor on portal-systemic collaterals [42]. In short-term PH induced by partial portal vein ligation (PVL), antagonism of phentolamine on α-receptor was reduced; meanwhile, release of noradrenaline was down-regulated as NO up-regulated, indicating a potential role of CA, together with NO, on hyperhemodynamics and increased PVI [43]. Besides, expressions of tyrosine hydroxylase and dopamine β-hydroxylase were down-regulated in superior mesenteric artery revealing genetic regulation of adrenergic neurotransmitter system participating in the splanchnic vasodilation in PH [44]. Nevertheless, protein level of α-receptor was higher in cirrhotic livers than in normal livers; activation of these α-receptors located on HSC induced calcium spikes and HSC constriction through MAPK, NK-κB and AP-1 pathways, resulting in increased intrahepatic resistance [45]. When response to β-blockers was defined as a reduction ＞ 10% in HVPG from baseline, the proportion of non-responsers decreased, the rate of first-bleeding among them increased and the diagnostic acuracy improved significantly contrasting with a 20% cut-off value.[46] Also, acute responsers to β-blockers have a better long-term outcome.[47]

2.6. Cannabinoid

Correlation between Cannabinoid and portal hypertension was paid attention in the last decades. Administration of anandamide, an endogenous cannabinoid, resulted in a drop of systemic circulation, mainly mean arterial pressure, although venous pressure changes verified, because of its effect on heart rate. Contrastingly, PVI and PVP increased in a dose-dependent fashion [48]. Treatment with antagonist of cannabinoid CB1 receptor in rats might lead to an elevation of blood pressure and a reduction of PVI and PVP, indicating cannabinoid is responsible for the dilation of systemic circulation [49]. It is in agreement with human. In cirrhotic patients, plasma level of cannabinoid was increased regardless of well-compensated or not [50]. But things are different in liver. Expression of CB1 receptor was dramatically down-regulated in both wild-type and eNOS knock-out group mice [9]. However, more researches are needed.

2.7. Cyclooxygenase, prostanoids and TXA2

Activation of COX-2/prostanoid pathway promotes production of TXA2 and PGE2 [51]. In BDL rats, TXB2, a stable metabolic of TXA2 in isolated liver perfusate and PVP were increased in a time-dependent manner. Both inhibition of Kuffer cells and COX attenuate these changes. Further results indicated that COX-2 interact with Kuffer cells-derived TXA2 was involved and its expression increased significantly [52]. Another group reported that COX-1 and PGI2 were responsible for decreased splanchnic resistance and increased PVI [53, 54]. However, elevated PVP of intrahepatic or pre-hepatic hypertension rats might be reduced by short- or long-term administration of COX inhibitor [18]. It is consistent with Graupera M et. al. [55]. In BDL portal hypertensive rats, elevated ET-1 interacted with Kuffer cells, increasing the responsiveness of p38MAPK through ET B receptor, activating cPLA2 and promoting production of TXA2, contributing to progression of portal hypertension [29].

2.8. Reactive oxygen species

Reactive oxygen species (ROS) is involved in many pathologic processes. In the case of PH, ROS level increases when circulatory NO decreases [56]. Administration of tempol, a type of superoxide dismutase, normalizes these changes with statistical significance in endothelial cells and cirrhotic liver, reduces intrahepatic vessel resistance and consequently increases PVI [57]. ROS also takes part in oxidative stress [58], lipid peroxidation, apoptosis and dysfunction of endothelial cells [41]. Reportedly, carvedilol, a β-blocker might ameliorate oxidative stress as well as inflammation and fibrosis in a CCl4-induced liver damage model, by reducing depletion of antioxidant enzyme, formation of collagen, and activation of NF-κB pathway, indicating a relationship between ROS and liver damage and fibrosis [59].

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3. Cytokines and liver fibrosis

Cytokine is a group of soluble protein or polypeptide, regulating immunologic response and hematopoiesis, participating inflammatory damage and repair. It consists of interleukins (IL), interferons (IFN), tumor necrosis factors (TNF), colony stimulating factors (CSF), chemokines, and growth factors. It has been reported that serum levels IL-6, TNF-α [60, 61], and IL-1β [62] were elevated in hepatoportal sclerosis, and plasma IL-6 level was correlated with the deterioration of liver function [63]. Although IL-6 was increased, expression of IL-6 receptor in cirrhotic liver was decreased, leading to a reduction of hepatocyte response to IL-6, accompanied by an increase of gp130, indicating gp130 might be the potential negative regulator of liver IL-6 signal pathway [64]. In chronic patients with hepatitis C and/or schistosomal, plasma IL-4 level, as well as ROS, was increased and correlated with portal vein diameter, suggesting IL-4 might plays a role on PVI [65]. A clinical trial has shown that administration of probiotic led to a trend to reduction of plasma endotoxin, a mild but significant increase of TNF-α and a significant reduction of aldosterone [66]. Besides, increased PVP induced a up-regulation of α-smooth muscle actin and collagen Ⅳ and ethanol exposure enhanced expression of TGF-β and production of extracellular matrix via ERK1/2-JNK and p38MAPK pathway respectively, leading to fibrosis of liver [67]. Reportedly, IL-18 gene knock-out mice fed with methionine-choline-deficient diet (MCDD) showed significant exacerbated inflammation, revealing IL-18 was a negative regulator of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Tnf mRNA, but not il-6 or il-1b levelm was higher in db/db (Asc-/-) group than db/db (wt) group, indicating TNF-α expression drove the progression of non-alcoholic steatohepatitis [68]. In another type of liver cirrhosis caused by chronic infection of schistosomiasis, inflammation and following tissue repair led to obstruction of intrahepatic vessels and increased intrahepatic resistance. These defenses in liver was mediated by IL-10. But surprisingly, blockade of IL-10R resulted in an elevation of PH and a reduction of parasitic antigen specific B cells, but worsened pulmonary accumulation of eggs without an increase of PVP [69]. Co-infection of bacteria led to production of IL-17 [70]. Consistently, knock-out of IL-10, IL-12p40, and IL-13Rα2 contributed to a progressive and lethal liver fibrosis, showing the anti-fibrosis effects of these Th2-derived interleukins in schistosomiasis mansoni treated mice [71]. As demonstrated by Pinter M et. Al. [72], responders to sorafenib showed a decreased HVPG and VEGF, PDGF, PIGF, RhoA kinase, and TNF-α expression, revealed a potential effect of these growth factors and TNF-α on HVPG. And level of soluble TNF-α receptor in portal vein and hepatic vein was correlated with model for end-stage liver disease score, in accordance with previous studies [73]. However, intrahepatic TNF-α, IL-1β, IL-4, and IL-10 were down-regulated while splanchnic levels were increased [74]. It is shown that IFN is involved in progression of hypertension, especially in viral infection- associated hepatitis [60, 75, 76]. Nowadays, IFN is usually used as antiviral treatment. Combination of 5-fluorouracil and IFN might reduce the portal hypertension related events [77]. Also, combination with IFN enhanced the viral clearance effect of ribavirin [78]. But IFN alone therapy only led to a temporary reduction of viral DNA load [79]. As documented, TGF-β promotes liver fibrosis in rats with biliary cirrhosis, cooperates with IFN-γ, IL-4, and TNF-α, etc [80]. More studies are needed to illustrate the detail effects of cytokines network on portal hypertension and liver fibrosis.

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4. Molecules in further physiopathological progression

4.1. Splenomegaly and hypersplenism

Volume of spleen or splenomegaly in cirrhotic hypertension patients is primarily attributed to increased splanchnic circulation and congestion, in which vasoactive substances play important roles. And the main pathologic changes are lower counts of red blood cells, white blood cells, and platelets. Compared to normal spleen, lymphocytes in PH spleen were relatively reduced with a similar distribution; but total number of lymphocytes was increased due to the increase of spleen weight, with an elevated proliferation [81, 82]. MicroRNAome analysis showed that microRNA, expecially miR-615-3p was up-regulated in PH spleen significantly [83, 84]. It targeted on ligand-dependent nuclear receptor corepressor (LCoR), promoted the phagocytic capacity of macrophages through PPARγ pathway [84]. On the other hand, phagocytic capacity of macrophages might be inhibit by Phosphatidylinositol 3-kinase regulatory subunit 1 (PI3KR1) knock-down, accompanied by down-regulation of IL-1β and TNF-α [85]. Similarly, expressions of IL-1β and NALP3, a potential NF-κB activator participating in inflammation and immunologic response were up-regulated significantly in CCl4-induced cirrhotic PH group compared to control group, together with typical splenomegaly histopathological changes [86]. In cirrhotic spleen, different from extrahepatic portal vein obstruction, thromopoietin (TPO) was reduced and this reduction is positively correlated with exacerbation of liver function, leading to a decrease of platelet counts [87].

4.2. Esophageal varices

Cirrhotic hypertension is characterized by hyperdynamic circulation and increased intrahepatic resistance as discussed before in this review. Splanchnic vasodilation results in increasing in HVPG. When HVPG is higher than 12 mmHg, risk of esophageal varices dramatically increased [88, 89]. Generally speaking, esophageal varices, as well as development of other collateral vessels, occur after HVPG and is followed by variceal bleeding [90]. Angiogenesis is associated with esophageal varices and portal hypertension, and expressions of VEGF are up-regulated, alone or together with TNF-α or PEGF[91-93]. Inhibition of VEGF/VEGF receptor pathway led to a decrease in hyperdynamic splanchnic circulation and collateral vessels [94]. Besides, metabolic disturbances occurred in cirrhotic PH lead to an elevation of glucagon [95]. The ratio of glycated albumin (GA) to glycated hemoglobin (HbA1c) was associated positively with the progression of liver cirrhosis, and patients with elevated GA/HbA1c ratio have severer esophageal variceal and higher risk of bleeding in HCV-related cirrhotic patients. This parameter might become a potential biomarker to predict the prognosis of these patients [96].

4.3. Ascites

Portal hypertension in cirrhotic liver diseases is a main cause of ascites. As discussed before, vasoactive substances lead to an elevation of intrahepatic vessels resistance and a relative decrease of blood back-flow to liver. Besides, mechanisms below are involved: 1) hyperdynamic circulation. Hyperdynamic circulation is associated with disturbance of vasoactive substances. It is characterized by increased cardiac index and plasma volume and decreased systemic and splanchnic resistance [90]. 2) hypoalbuminemia following damage of liver function. One of the hyperalbuminemia occurred in cirrhotic PH is dysfunction of hepatocytes. In is shown that hypertension is a negative regulator to the number and structure of hepatocytes [97]. Poor blood supply induced by liver fibrosis and disturbance of hemodynamics results in intrahepatic hypoxia and damage of hepatocytes. Besides, primary liver diseases also cause inflammation and damage in liver. 3) renal function changes. This part will be discussed below.

4.4. Hepatorenal syndrome

It is well established that main cause of hepatorenal syndrome (HRS) is constriction of vessels in kidney induced by reduction of effective circulating blood volume (ECBV). As discussed previously, ECBV is reduced by systemic and splanchnic vasodilation induced by changes of NO, ET, PGs and TXA2. Besides, some localized physiopathologic should be paid attention on. Expression of HO-1 in kidney was significantly reduced in BDL-induced cirrhotic rats [98]. Cyctatin C was increased in decompensated liver cirrhosis and HRS, thus it could be used as a predictor of HRS [99, 100]. Additionally, plasma level of ADAMTS13 was decreased and supplemental therapy might improve prognosis of patients with severe liver cirrhosis and HRS [101, 102].

4.5. Hepatic encephalopathy

Hepatic encephalopathy (HE) in portal hypertension is defined as C type HE. In PVL-induced PH rats, chemokine changes in splanchnic system, liver, and central nervous system (CNS) are different [103]. As reported, in CNS, CX3CL1/CX3CR1 and SDF1-α/CXCR4 were increased. The former one promotes inflammation in CNS while the latter one modulates neuron activity through inhibitory neurotransmitters, e.g. gamma-amino butyric acid (GABA) [104]. ROS also participates in pre-hepatic portal hypertension [105, 106]. GABA level is also negatively regulated by dehydroepiandrosterone sulfate (DHEAS), which reduced in cirrhotic HE [107]. Besides, IL-6 has synergistic effect with ammonia in cirrotic HE patients [108]. Ammonia impairs brain eNOS activity, leading to significant abnormality of NO regulation and disturbance of blood supply [109]. Due to liver dysfunction in HE patients, elevated plasma manganese also indicates a bad prognosis [110].

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5. Conclusion

Portal hypertension concerns a great number of molecules and complicated physiopathologic mechanisms. It can be classified into pre-, intra-, and post-hepatic PH according to the primary disease, with similar but not same involvement of molecules and mechanisms. However, we can still conclude that: 1) vasoactive substances play an important in systemic, splanchnic, hepatic, and even neurologic circulations which are closely related to blood supply, affecting the development, progression, and outcome of PH; 2) imbalance of pro-/anti-inflammatory cytokines lead to a systemic and/or localized regulation of signal pathways and modulate gene expression and silencing, cell proliferation and apoptosis, tissue damage and repair, and eventually life and death; 3) accumulating research advancements provide us new targets for treatment of PH, but it has a long way to go from bench to bedside.

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Acknowledgments

This study was supported by the International Collaboration Foundation of Jiangsu Province (BZ2011041, BK2009439, ZX05 200904, WS2011106), Development of Innovative Research Team in the First Affiliated Hospital of NJMU and the National Nature Science Foundation of China (81210108017, 81100270, 81070380). First Innovation Team Foundation of Jiangsu province Hospital (for Sun BC).

References

  1. 1. Bari K,Garcia-Tsao G. Treatment of portal hypertension. World J Gastroenterol 2012;18:1166-1175. PMID: 22468079
  2. 2. Arya A, Kakani N, Hussain N, Chandok N. Massive avascular malformations causing life threatening portal hypertension. Ann Hepatol 2012;11:552-553. PMID: 22700638
  3. 3. Bosch J. Vascular deterioration in cirrhosis: the big picture. J Clin Gastroenterol 2007;41 Suppl 3:S247-253. PMID: 17975472
  4. 4. Bruix J, Castells A, Bosch J, Feu F, Fuster J, Garcia-Pagan JC, et al. Surgical resection of hepatocellular carcinoma in cirrhotic patients: prognostic value of preoperative portal pressure. Gastroenterology 1996;111:1018-1022. PMID: 8831597
  5. 5. Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999;30:1434-1440. PMID: 10573522
  6. 6. Zipprich A, Garcia-Tsao G, Rogowski S, Fleig WE, Seufferlein T, Dollinger MM. Prognostic indicators of survival in patients with compensated and decompensated cirrhosis. Liver Int 2012. PMID: 22679906
  7. 7. Bosch J,Garcia-Pagan JC. Complications of cirrhosis. I. Portal hypertension. J Hepatol 2000;32:141-156. PMID: 10728801
  8. 8. Rodriguez-Vilarrupla A, Fernandez M, Bosch J, Garcia-Pagan JC. Current concepts on the pathophysiology of portal hypertension. Ann Hepatol 2007;6:28-36. PMID: 17297426
  9. 9. Biecker E, Sagesser H, Reichen J. Vasodilator mRNA levels are increased in the livers of portal hypertensive NO-synthase 3-deficient mice. Eur J Clin Invest 2004;34:283-289. PMID: 15086360
  10. 10. Laleman W, Van Landeghem L, Van der Elst I, Zeegers M, Fevery J, Nevens F. Nitroflurbiprofen, a nitric oxide-releasing cyclooxygenase inhibitor, improves cirrhotic portal hypertension in rats. Gastroenterology 2007;132:709-719. PMID: 17258737
  11. 11. Luo W, Meng Y, Ji HL, Pan CQ, Huang S, Yu CH, et al. Spironolactone Lowers Portal Hypertension by Inhibiting Liver Fibrosis, ROCK-2 Activity and Activating NO/PKG Pathway in the Bile-Duct-Ligated Rat. PLoS One 2012;7:e34230. PMID: 22479572
  12. 12. Goh BJ, Tan BT, Hon WM, Lee KH, Khoo HE. Nitric oxide synthase and heme oxygenase expressions in human liver cirrhosis. World J Gastroenterol 2006;12:588-594. PMID: 16489673
  13. 13. El-Sherif AM, Abou-Shady MA, Al-Bahrawy AM, Bakr RM, Hosny AM. Nitric oxide levels in chronic liver disease patients with and without oesophageal varices. Hepatol Int 2008;2:341-345. PMID: 19669263
  14. 14. Bories PN, Campillo B, Azaou L, Scherman E. Long-lasting NO overproduction in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 1997;25:1328-1333. PMID: 9185747
  15. 15. Arkenau HT, Stichtenoth DO, Frolich JC, Manns MP, Boker KH. Elevated nitric oxide levels in patients with chronic liver disease and cirrhosis correlate with disease stage and parameters of hyperdynamic circulation. Z Gastroenterol 2002;40:907-913. PMID: 12436367
  16. 16. Moriyama A, Masumoto A, Nanri H, Tabaru A, Unoki H, Imoto I, et al. High plasma concentrations of nitrite/nitrate in patients with hepatocellular carcinoma. Am J Gastroenterol 1997;92:1520-1523. PMID: 9317076
  17. 17. Theodorakis NG, Wang YN, Wu JM, Maluccio MA, Sitzmann JV, Skill NJ. Role of endothelial nitric oxide synthase in the development of portal hypertension in the carbon tetrachloride-induced liver fibrosis model. Am J Physiol Gastrointest Liver Physiol 2009;297:G792-799. PMID: 19628654
  18. 18. Xu J, Cao H, Liu H, Wu ZY. Role of nitric oxide synthase and cyclooxygenase in hyperdynamic splanchnic circulation of portal hypertension. Hepatobiliary Pancreat Dis Int 2008;7:503-508. PMID: 18842497
  19. 19. Pannen BH, Kohler N, Hole B, Bauer M, Clemens MG, Geiger KK. Protective role of endogenous carbon monoxide in hepatic microcirculatory dysfunction after hemorrhagic shock in rats. J Clin Invest 1998;102:1220-1228. PMID: 9739056
  20. 20. Tarquini R, Masini E, La Villa G, Barletta G, Novelli M, Mastroianni R, et al. Increased plasma carbon monoxide in patients with viral cirrhosis and hyperdynamic circulation. Am J Gastroenterol 2009;104:891-897. PMID: 19277027
  21. 21. Makino N, Suematsu M, Sugiura Y, Morikawa H, Shiomi S, Goda N, et al. Altered expression of heme oxygenase-1 in the livers of patients with portal hypertensive diseases. Hepatology 2001;33:32-42. PMID: 11124818
  22. 22. Van Landeghem L, Laleman W, Vander Elst I, Zeegers M, van Pelt J, Cassiman D, et al. Carbon monoxide produced by intrasinusoidally located haem-oxygenase-1 regulates the vascular tone in cirrhotic rat liver. Liver Int 2009;29:650-660. PMID: 18795901
  23. 23. Guo SB, Duan ZJ, Li Q, Sun XY. Effects of heme oxygenase-1 on pulmonary function and structure in rats with liver cirrhosis. Chin Med J (Engl) 2011;124:918-922. PMID: 21518603
  24. 24. Angermayr B, Mejias M, Gracia-Sancho J, Garcia-Pagan JC, Bosch J, Fernandez M. Heme oxygenase attenuates oxidative stress and inflammation, and increases VEGF expression in portal hypertensive rats. J Hepatol 2006;44:1033-1039. PMID: 16458992
  25. 25. Giaid A. Nitric oxide and endothelin-1 in pulmonary hypertension. Chest 1998;114:208S-212S. PMID: 9741571
  26. 26. Takashimizu S, Kojima S, Nishizaki Y, Kagawa T, Shiraishi K, Mine T, et al. Effect of endothelin A receptor antagonist on hepatic hemodynamics in cirrhotic rats. Implications for endothelin-1 in portal hypertension. Tokai J Exp Clin Med 2011;36:37-43. PMID: 21769771
  27. 27. Watanabe N, Takashimizu S, Nishizaki Y, Kojima S, Kagawa T, Matsuzaki S. An endothelin A receptor antagonist induces dilatation of sinusoidal endothelial fenestrae: implications for endothelin-1 in hepatic microcirculation. J Gastroenterol 2007;42:775-782. PMID: 17876548
  28. 28. Feng HQ, Weymouth ND, Rockey DC. Endothelin antagonism in portal hypertensive mice: implications for endothelin receptor-specific signaling in liver disease. Am J Physiol Gastrointest Liver Physiol 2009;297:G27-33. PMID: 19299580
  29. 29. Miller AM,Zhang JX. Altered endothelin-1 signaling in production of thromboxane A2 in kupffer cells from bile duct ligated rats. Cell Mol Immunol 2009;6:441-452. PMID: 20003820
  30. 30. Andersson A, Fenhammar J, Weitzberg E, Sollevi A, Hjelmqvist H, Frithiof R. Endothelin-mediated gut microcirculatory dysfunction during porcine endotoxaemia. Br J Anaesth 2010;105:640-647. PMID: 20710019
  31. 31. Liu J, Gong H, Zhang ZT, Wang Y. Effect of angiotensin II and angiotensin II type 1 receptor antagonist on the proliferation, contraction and collagen synthesis in rat hepatic stellate cells. Chin Med J (Engl) 2008;121:161-165. PMID: 18272044
  32. 32. Umgelter A, Wagner KS, Reindl W, Luppa PB, Geisler F, Huber W, et al. Renal and circulatory effects of large volume plasma expansion in patients with hepatorenal syndrome type 1. Ann Hepatol 2012;11:232-239. PMID: 22345341
  33. 33. Lotfy M, El-Kenawy Ael M, Abdel-Aziz MM, El-Kady I, Talaat A. Elevated renin levels in patients with liver cirrhosis and hepatocellular carcinoma. Asian Pac J Cancer Prev 2010;11:1263-1266. PMID: 21198274
  34. 34. Beyazit Y, Ibis M, Purnak T, Turhan T, Kekilli M, Kurt M, et al. Elevated levels of circulating angiotensin converting enzyme in patients with hepatoportal sclerosis. Dig Dis Sci 2011;56:2160-2165. PMID: 21290180
  35. 35. Hidaka H, Kokubu S, Nakazawa T, Okuwaki Y, Ono K, Watanabe M, et al. New angiotensin II type 1 receptor blocker olmesartan improves portal hypertension in patients with cirrhosis. Hepatol Res 2007;37:1011-1017. PMID: 17608670
  36. 36. Huang HC, Chang CC, Wang SS, Lee FY, Teng TH, Lee JY, et al. The roles of angiotensin II receptors in the portosystemic collaterals of portal hypertensive and cirrhotic rats. J Vasc Res 2012;49:160-168. PMID: 22285953
  37. 37. Loiola RA, Fernandes L, Eichler R, Passaglia Rde C, Fortes ZB, de Carvalho MH. Vascular mechanisms involved in angiotensin II-induced venoconstriction in hypertensive rats. Peptides 2011;32:2116-2121. PMID: 21945423
  38. 38. Hidaka H, Nakazawa T, Shibuya A, Minamino T, Takada J, Tanaka Y, et al. Effects of 1-year administration of olmesartan on portal pressure and TGF-beta1 in selected patients with cirrhosis: a randomized controlled trial. J Gastroenterol 2011;46:1316-1323. PMID: 21850387
  39. 39. Debernardi-Venon W, Martini S, Biasi F, Vizio B, Termine A, Poli G, et al. AT1 receptor antagonist Candesartan in selected cirrhotic patients: effect on portal pressure and liver fibrosis markers. J Hepatol 2007;46:1026-1033. PMID: 17336417
  40. 40. Tandon P, Abraldes JG, Berzigotti A, Garcia-Pagan JC, Bosch J. Renin-angiotensin-aldosterone inhibitors in the reduction of portal pressure: a systematic review and meta-analysis. J Hepatol 2010;53:273-282. PMID: 20570385
  41. 41. Dal-Ros S, Oswald-Mammosser M, Pestrikova T, Schott C, Boehm N, Bronner C, et al. Losartan prevents portal hypertension-induced, redox-mediated endothelial dysfunction in the mesenteric artery in rats. Gastroenterology 2010;138:1574-1584. PMID: 19879274
  42. 42. Chan CC, Chang CC, Huang HC, Wang SS, Lee FY, Chang FY, et al. Effects of norepinephrine and acetylcholine on portal-systemic collaterals of common bile duct-ligated cirrhotic rat. J Gastroenterol Hepatol 2005;20:1867-1872. PMID: 16336446
  43. 43. Sastre E, Balfagon G, Revuelta-Lopez E, Aller MA, Nava MP, Arias J, et al. Effect of short- and long-term portal hypertension on adrenergic, nitrergic and sensory functioning in rat mesenteric artery. Clin Sci (Lond) 2012;122:337-348. PMID: 21999248
  44. 44. Coll M, Genesca J, Raurell I, Rodriguez-Vilarrupla A, Mejias M, Otero T, et al. Down-regulation of genes related to the adrenergic system may contribute to splanchnic vasodilation in rat portal hypertension. J Hepatol 2008;49:43-51. PMID: 18457899
  45. 45. Sancho-Bru P, Bataller R, Colmenero J, Gasull X, Moreno M, Arroyo V, et al. Norepinephrine induces calcium spikes and proinflammatory actions in human hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 2006;291:G877-884. PMID: 16782692
  46. 46. Villanueva C, Aracil C, Colomo A, Hernandez-Gea V, Lopez-Balaguer JM, Alvarez-Urturi C, et al. Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary prophylaxis of variceal bleeding. Gastroenterology 2009;137:119-128. PMID: 19344721
  47. 47. La Mura V, Abraldes JG, Raffa S, Retto O, Berzigotti A, Garcia-Pagan JC, et al. Prognostic value of acute hemodynamic response to i.v. propranolol in patients with cirrhosis and portal hypertension. J Hepatol 2009;51:279-287. PMID: 19501930
  48. 48. Garcia N, Jr., Jarai Z, Mirshahi F, Kunos G, Sanyal AJ. Systemic and portal hemodynamic effects of anandamide. Am J Physiol Gastrointest Liver Physiol 2001;280:G14-20. PMID: 11123193
  49. 49. Shah V. Portal hypertension and the hyperdynamic circulation: nitric oxide in a haze of cannabinoid smoke. Hepatology 2001;34:1060-1061. PMID: 11679979
  50. 50. Fernandez-Rodriguez CM, Romero J, Petros TJ, Bradshaw H, Gasalla JM, Gutierrez ML, et al. Circulating endogenous cannabinoid anandamide and portal, systemic and renal hemodynamics in cirrhosis. Liver Int 2004;24:477-483. PMID: 15482346
  51. 51. Piston D, Wang S, Feng Y, Ye YJ, Zhou J, Jiang KW, et al. The role of cyclooxygenase-2/prostanoid pathway in visceral pain induced liver stress response in rats. Chin Med J (Engl) 2007;120:1813-1819. PMID: 18028778
  52. 52. Yokoyama Y, Xu H, Kresge N, Keller S, Sarmadi AH, Baveja R, et al. Role of thromboxane A2 in early BDL-induced portal hypertension. Am J Physiol Gastrointest Liver Physiol 2003;284:G453-460. PMID: 12431905
  53. 53. Cao H, Xu J, Liu H, Meng FB, Qiu JF, Wu ZY. Influence of nitric oxide synthase and cyclooxygenase blockade on expression of cyclooxygenase and hemodynamics in rats with portal hypertension. Hepatobiliary Pancreat Dis Int 2006;5:564-569. PMID: 17085343
  54. 54. Cao H, Xu J, Hua R, Meng FB, Qiu JF, Wu ZY. Expression of cyclooxygenase in hyperdynamic portal hypertensive rats. Hepatobiliary Pancreat Dis Int 2006;5:252-256. PMID: 16698586
  55. 55. Graupera M, Garcia-Pagan JC, Abraldes JG, Peralta C, Bragulat M, Corominola H, et al. Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers. Hepatology 2003;37:172-181. PMID: 12500202
  56. 56. Vujanac A, Jakovljevic V, Djordjevic D, Zivkovic V, Stojkovic M, Celikovic D, et al. Nitroglycerine effects on portal vein mechanics and oxidative stress in portal hypertension. World J Gastroenterol 2012;18:331-339. PMID: 22294839
  57. 57. Garcia-Caldero H, Rodriguez-Vilarrupla A, Gracia-Sancho J, Divi M, Lavina B, Bosch J, et al. Tempol administration, a superoxide dismutase mimetic, reduces hepatic vascular resistance and portal pressure in cirrhotic rats. J Hepatol 2011;54:660-665. PMID: 21159403
  58. 58. Huang YT, Hsu YC, Chen CJ, Liu CT, Wei YH. Oxidative-stress-related changes in the livers of bile-duct-ligated rats. J Biomed Sci 2003;10:170-178. PMID: 12595753
  59. 59. Hamdy N,El-Demerdash E. New therapeutic aspect for carvedilol: Antifibrotic effects of carvedilol in chronic carbon tetrachloride-induced liver damage. Toxicol Appl Pharmacol 2012. PMID: 22543095
  60. 60. Koksal AS, Koklu S, Ibis M, Balci M, Cicek B, Sasmaz N, et al. Clinical features, serum interleukin-6, and interferon-gamma levels of 34 turkish patients with hepatoportal sclerosis. Dig Dis Sci 2007;52:3493-3498. PMID: 17404864
  61. 61. Cariello R, Federico A, Sapone A, Tuccillo C, Scialdone VR, Tiso A, et al. Intestinal permeability in patients with chronic liver diseases: Its relationship with the aetiology and the entity of liver damage. Dig Liver Dis 2010;42:200-204. PMID: 19502117
  62. 62. Tan G, Pan S, Li J, Dong X, Kang K, Zhao M, et al. Hydrogen sulfide attenuates carbon tetrachloride-induced hepatotoxicity, liver cirrhosis and portal hypertension in rats. PLoS One 2011;6:e25943. PMID: 22022478
  63. 63. [The role of interleukin-6 and nitric oxide in pathogenesis of portal hypertension and decompensation of liver cirrhosis]. Klin Med (Mosk) 2012;90:47-49. PMID: 22567940
  64. 64. Lemmers A, Gustot T, Durnez A, Evrard S, Moreno C, Quertinmont E, et al. An inhibitor of interleukin-6 trans-signalling, sgp130, contributes to impaired acute phase response in human chronic liver disease. Clin Exp Immunol 2009;156:518-527. PMID: 19438606
  65. 65. Elsammak MY, Al-Sharkaweey RM, Ragab MS, Amin GA, Kandil MH. IL-4 and reactive oxygen species are elevated in Egyptian patients affected with schistosomal liver disease. Parasite Immunol 2008;30:603-609. PMID: 19067841
  66. 66. Tandon P, Moncrief K, Madsen K, Arrieta MC, Owen RJ, Bain VG, et al. Effects of probiotic therapy on portal pressure in patients with cirrhosis: a pilot study. Liver Int 2009;29:1110-1115. PMID: 19490420
  67. 67. Okada Y, Tsuzuki Y, Hokari R, Miyazaki J, Matsuzaki K, Mataki N, et al. Pressure loading and ethanol exposure differentially modulate rat hepatic stellate cell activation. J Cell Physiol 2008;215:472-480. PMID: 18064666
  68. 68. Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 2012;482:179-185. PMID: 22297845
  69. 69. Fairfax KC, Amiel E, King IL, Freitas TC, Mohrs M, Pearce EJ. IL-10R blockade during chronic schistosomiasis mansoni results in the loss of B cells from the liver and the development of severe pulmonary disease. PLoS Pathog 2012;8:e1002490. PMID: 22291593
  70. 70. Perona-Wright G, Lundie RJ, Jenkins SJ, Webb LM, Grencis RK, MacDonald AS. Concurrent bacterial stimulation alters the function of helminth-activated dendritic cells, resulting in IL-17 induction. J Immunol 2012;188:2350-2358. PMID: 22287718
  71. 71. Mentink-Kane MM, Cheever AW, Wilson MS, Madala SK, Beers LM, Ramalingam TR, et al. Accelerated and progressive and lethal liver fibrosis in mice that lack interleukin (IL)-10, IL-12p40, and IL-13Ralpha2. Gastroenterology 2011;141:2200-2209. PMID: 21864478
  72. 72. Pinter M, Sieghart W, Reiberger T, Rohr-Udilova N, Ferlitsch A, Peck-Radosavljevic M. The effects of sorafenib on the portal hypertensive syndrome in patients with liver cirrhosis and hepatocellular carcinoma--a pilot study. Aliment Pharmacol Ther 2012;35:83-91. PMID: 22032637
  73. 73. Trebicka J, Krag A, Gansweid S, Appenrodt B, Schiedermaier P, Sauerbruch T, et al. Endotoxin and tumor necrosis factor-receptor levels in portal and hepatic vein of patients with alcoholic liver cirrhosis receiving elective transjugular intrahepatic portosystemic shunt. Eur J Gastroenterol Hepatol 2011;23:1218-1225. PMID: 21971377
  74. 74. Garcia-Dominguez J, Aller MA, Garcia C, de Vicente F, Corcuera MT, Gomez-Aguado F, et al. Splanchnic Th(2) and Th(1) cytokine redistribution in microsurgical cholestatic rats. J Surg Res 2010;162:203-212. PMID: 20031157
  75. 75. Dragoteanu M, Balea IA, Dina LA, Piglesan CD, Grigorescu I, Tamas S, et al. Staging of portal hypertension and portosystemic shunts using dynamic nuclear medicine investigations. World J Gastroenterol 2008;14:3841-3848. PMID: 18609707
  76. 76. Di Marco V, Almasio PL, Ferraro D, Calvaruso V, Alaimo G, Peralta S, et al. Peg-interferon alone or combined with ribavirin in HCV cirrhosis with portal hypertension: a randomized controlled trial. J Hepatol 2007;47:484-491. PMID: 17692985
  77. 77. Katamura Y, Aikata H, Takaki S, Azakami T, Kawaoka T, Waki K, et al. Intra-arterial 5-fluorouracil/interferon combination therapy for advanced hepatocellular carcinoma with or without three-dimensional conformal radiotherapy for portal vein tumor thrombosis. J Gastroenterol 2009;44:492-502. PMID: 19330281
  78. 78. Iacobellis A, Ippolito A, Andriulli A. Antiviral therapy in hepatitis C virus cirrhotic patients in compensated and decompensated condition. World J Gastroenterol 2008;14:6467-6472. PMID: 19030197
  79. 79. Pozzi M, Pizzala DP, Maldini FF, Doretti A, Ratti L. Portal pressure reduction after entecavir treatment in compensated HBV cirrhosis. Hepatogastroenterology 2009;56:231-235. PMID: 19453064
  80. 80. Albillos A, Nieto M, Ubeda M, Munoz L, Fraile B, Reyes E, et al. The biological response modifier AM3 attenuates the inflammatory cell response and hepatic fibrosis in rats with biliary cirrhosis. Gut 2010;59:943-952. PMID: 20442198
  81. 81. Li ZF, Zhang S, Huang Y, Xia XM, Li AM, Pan D, et al. Morphological changes of blood spleen barrier in portal hypertensive spleen. Chin Med J (Engl) 2008;121:561-565. PMID: 18364147
  82. 82. Li ZF, Zhang S, Lv GB, Huang Y, Zhang W, Ren S, et al. Changes in count and function of splenic lymphocytes from patients with portal hypertension. World J Gastroenterol 2008;14:2377-2382. PMID: 18416465
  83. 83. Li Z, Zhang S, Huang C, Zhang W, Hu Y, Wei B. MicroRNAome of splenic macrophages in hypersplenism due to portal hypertension in hepatitis B virus-related cirrhosis. Exp Biol Med (Maywood) 2008;233:1454-1461. PMID: 18791127
  84. 84. Jiang A, Zhang S, Li Z, Liang R, Ren S, Li J, et al. miR-615-3p promotes the phagocytic capacity of splenic macrophages by targeting ligand-dependent nuclear receptor corepressor in cirrhosis-related portal hypertension. Exp Biol Med (Maywood) 2011;236:672-680. PMID: 21565892
  85. 85. Zhang W, Zhang S, Li ZF, Huang C, Ren S, Zhou R, et al. Knockdown of PIK3R1 by shRNA inhibits the activity of the splenic macrophages associated with hypersplenism due to portal hypertension. Pathol Res Pract 2010;206:760-767. PMID: 20846792
  86. 86. Xia Z, Wang G, Wan C, Liu T, Wang S, Wang B, et al. Expression of NALP3 in the spleen of mice with portal hypertension. J Huazhong Univ Sci Technolog Med Sci 2010;30:170-172. PMID: 20407867
  87. 87. El-Sayed R, El-Ela MA, El-Raziky MS, Helmy H, El-Ghaffar AA, El-Karaksy H. Relation of serum levels of thrombopoietin to thrombocytopenia in extrahepatic portal vein obstruction versus cirrhotic children. J Pediatr Hematol Oncol 2011;33:e267-270. PMID: 21941130
  88. 88. Boleslawski E, Petrovai G, Truant S, Dharancy S, Duhamel A, Salleron J, et al. Hepatic venous pressure gradient in the assessment of portal hypertension before liver resection in patients with cirrhosis. Br J Surg 2012;99:855-863. PMID: 22508371
  89. 89. Garcia-Tsao G, Groszmann RJ, Fisher RL, Conn HO, Atterbury CE, Glickman M. Portal pressure, presence of gastroesophageal varices and variceal bleeding. Hepatology 1985;5:419-424. PMID: 3873388
  90. 90. Maruyama H,Yokosuka O. Pathophysiology of portal hypertension and esophageal varices. Int J Hepatol 2012;2012:895787. PMID: 22666604
  91. 91. Yin ZH, Liu XY, Huang RL, Ren SP. Expression of TNF-alpha and VEGF in the esophagus of portal hypertensive rats. World J Gastroenterol 2005;11:1232-1236. PMID: 15754412
  92. 92. Huang HC, Haq O, Utsumi T, Sethasine S, Abraldes JG, Groszmann RJ, et al. Intestinal and plasma VEGF levels in cirrhosis: the role of portal pressure. J Cell Mol Med 2012;16:1125-1133. PMID: 21801303
  93. 93. Pan WD, Liu Y, Lin N, Xu R. The expression of PEDF and VEGF in the gastric wall of prehepatic portal hypertensive rats. Hepatogastroenterology 2011;58:2152-2155. PMID: 22024088
  94. 94. Fernandez M, Mejias M, Angermayr B, Garcia-Pagan JC, Rodes J, Bosch J. Inhibition of VEGF receptor-2 decreases the development of hyperdynamic splanchnic circulation and portal-systemic collateral vessels in portal hypertensive rats. J Hepatol 2005;43:98-103. PMID: 15893841
  95. 95. Tsui CP, Sung JJ, Leung FW. Role of acute elevation of portal venous pressure by exogenous glucagon on gastric mucosal injury in rats with portal hypertension. Life Sci 2003;73:1115-1129. PMID: 12818720
  96. 96. Sakai Y, Enomoto H, Aizawa N, Iwata Y, Tanaka H, Ikeda N, et al. Relationship between Elevation of Glycated Albumin to Glycated Hemoglobin Ratio in Patients with a High Bleeding Risk of Esophageal Varices. Hepatogastroenterology 2012;59. PMID: 22440250
  97. 97. Dursun H, Albayrak F, Uyanik A, Keles NO, Beyzagul P, Bayram E, et al. Effects of hypertension and ovariectomy on rat hepatocytes. Are amlodipine and lacidipine protective? (A stereological and histological study). Turk J Gastroenterol 2010;21:387-395. PMID: 21331992
  98. 98. Guo SB, Duan ZJ, Li Q, Sun XY. Effect of heme oxygenase-1 on renal function in rats with liver cirrhosis. World J Gastroenterol 2011;17:322-328. PMID: 21253390
  99. 99. Sharawey MA, Shawky EM, Ali LH, Mohammed AA, Hassan HA, Fouad YM. Cystatin C: a predictor of hepatorenal syndrome in patients with liver cirrhosis. Hepatol Int 2011. PMID: 21484118
  100. 100. Barakat M,Khalil M. Serum cystatin C in advanced liver cirrhosis and different stages of the hepatorenal syndrome. Arab J Gastroenterol 2011;12:131-135. PMID: 22055590
  101. 101. Uemura M, Fujimura Y, Ko S, Matsumoto M, Nakajima Y, Fukui H. Determination of ADAMTS13 and Its Clinical Significance for ADAMTS13 Supplementation Therapy to Improve the Survival of Patients with Decompensated Liver Cirrhosis. Int J Hepatol 2011;2011:759047. PMID: 21994870
  102. 102. Takaya H, Uemura M, Fujimura Y, Matsumoto M, Matsuyama T, Kato S, et al. ADAMTS13 activity may predict the cumulative survival of patients with liver cirrhosis in comparison with the Child-Turcotte-Pugh score and the Model for End-Stage Liver Disease score. Hepatol Res 2012;42:459-472. PMID: 22292786
  103. 103. Merino J, Aller MA, Rubio S, Arias N, Nava MP, Loscertales M, et al. Gut-brain chemokine changes in portal hypertensive rats. Dig Dis Sci 2011;56:2309-2317. PMID: 21347560
  104. 104. Guyon A,Nahon JL. Multiple actions of the chemokine stromal cell-derived factor-1alpha on neuronal activity. J Mol Endocrinol 2007;38:365-376. PMID: 17339399
  105. 105. Rosello DM, Balestrasse K, Coll C, Coll S, Tallis S, Gurni A, et al. Oxidative stress and hippocampus in a low-grade hepatic encephalopathy model: protective effects of curcumin. Hepatol Res 2008;38:1148-1153. PMID: 19000058
  106. 106. Nikonenko AG, Radenovic L, Andjus PR, Skibo GG. Structural features of ischemic damage in the hippocampus. Anat Rec (Hoboken) 2009;292:1914-1921. PMID: 19943345
  107. 107. Ahboucha S, Talani G, Fanutza T, Sanna E, Biggio G, Gamrani H, et al. Reduced brain levels of DHEAS in hepatic coma patients: Significance for increased GABAergic tone in hepatic encephalopathy. Neurochem Int 2012;61:48-53. PMID: 22490610
  108. 108. Luo M, Li L, Yang EN, Cao WK. Relationship between interleukin-6 and ammonia in patients with minimal hepatic encephalopathy due to liver cirrhosis. Hepatol Res 2012. PMID: 22646055
  109. 109. Balasubramaniyan V, Wright G, Sharma V, Davies NA, Sharifi Y, Habtesion A, et al. Ammonia reduction with ornithine phenylacetate restores brain eNOS activity via the DDAH-ADMA pathway in bile duct-ligated cirrhotic rats. Am J Physiol Gastrointest Liver Physiol 2012;302:G145-152. PMID: 21903766
  110. 110. Zeron HM, Rodriguez MR, Montes S, Castaneda CR. Blood manganese levels in patients with hepatic encephalopathy. J Trace Elem Med Biol 2011;25:225-229. PMID: 21975221

Written By

Hao Lu, Guoqiang Li, Ling Lu, Ye Fan, Xiaofeng Qian, Ke Wang and Feng Zhang

Submitted: 08 July 2012 Published: 13 February 2013

© 2013 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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