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• W2083469788 abstract "Jaime BoschView Large Image Figure ViewerDownload Hi-res image Download (PPT)Andres BleiView Large Image Figure ViewerDownload Hi-res image Download (PPT)Vincente ArroyoView Large Image Figure ViewerDownload Hi-res image Download (PPT) Portal hypertension is a clinical syndrome defined by a portal venous pressure gradient exceeding 5 mm Hg.1Garcia-Pagan J.C. Groszmann R. Bosch J. Portal hypertension.in: Weinstein W.M. Hawkey C.J. Bosch J. Portal hypertension. 1st ed. Elsevier Mosby, Philadelphia2005: 707-716Google Scholar Cirrhosis is the most common cause of portal hypertension in the Western world.1Garcia-Pagan J.C. Groszmann R. Bosch J. Portal hypertension.in: Weinstein W.M. Hawkey C.J. Bosch J. Portal hypertension. 1st ed. Elsevier Mosby, Philadelphia2005: 707-716Google Scholar The goal of this review is to provide an overview of the current understanding of the pathophysiology and treatment of portal hypertension. The hallmark of portal hypertension is a pathologic increase in the pressure gradient between the portal vein and the inferior vena cava, which is measured by the hepatic venous pressure gradient (HVPG).2Garcia-Pagan J.C. Groszmann R. Bosch J. Measurement of portal pressure.in: Weinstein W.M. Hawkey C.J. Bosch J. Clinical gastroenterology and hepatology. Elsevier Mosby, Philadelphia2005: 981-986Google Scholar Briefly, the wedged hepatic vein pressure (WHVP), a marker of sinusoidal pressure, and the free hepatic vein pressure (FHVP) are measured with radiologic assistance. HVPG is calculated by the following formula2Garcia-Pagan J.C. Groszmann R. Bosch J. Measurement of portal pressure.in: Weinstein W.M. Hawkey C.J. Bosch J. Clinical gastroenterology and hepatology. Elsevier Mosby, Philadelphia2005: 981-986Google Scholar, 3Groszmann R.J. Glickman M. Blei A.T. et al.Wedged and free hepatic venous pressure measured with a balloon catheter.Gastroenterology. 1979; 76: 253-258PubMed Google Scholar, 4Wongcharatrawee S. Groszmann R.J. Diagnosing portal hypertension.Baillieres Best Pract Res Clin Gastroenterol. 2000; 14: 881-894Abstract Full Text PDF PubMed Scopus (15) Google Scholar:HVPG⁢=WHVP⁢−FHVP(1) The FHVP is subtracted from the WHVP to correct for intra-abdominal pressure to provide an accurate measure of the portal vein pressure. As in any other vessel, the pressure within the portal vein is determined by the product of blood flow and resistance to its egress, as defined by Ohm's law (Figure 1):P⁢(pressure)=Q⁢(blood⁢flow)×R⁢(resistance)(2) Portal hypertension is initiated by increased outflow resistance; this can occur at a presinusoidal (intra- or extrahepatic), sinusoidal, or postsinusoidal level. As the condition progresses, there is a rise in portal blood flow, a combination that maintains and worsens the portal hypertension.5Vorobioff J. Bredfeldt J.E. Groszmann R.J. Increased blood flow through the portal system in cirrhotic rats.Gastroenterology. 1984; 87: 1120-1126Abstract Full Text PDF PubMed Google Scholar In cirrhosis, the principal site of increased resistance to outflow of portal venous blood is within the liver itself. This results from 2 factors: (1) mechanical obstruction to flow because of fibrotic disruption of architecture and (2) a dynamic component produced by active contraction of vascular smooth muscle cells and activated stellate cells.1Garcia-Pagan J.C. Groszmann R. Bosch J. Portal hypertension.in: Weinstein W.M. Hawkey C.J. Bosch J. Portal hypertension. 1st ed. Elsevier Mosby, Philadelphia2005: 707-716Google Scholar, 6Wanless I.R. Wong F. Blendis L.M. et al.Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension.Hepatology. 1995; 21: 1238-1247PubMed Google Scholar, 7Bataller R. Gines P. Nicolas J.M. et al.Angiotensin II induces contraction and proliferation of human hepatic stellate cells.Gastroenterology. 2000; 118: 1149-1156Abstract Full Text Full Text PDF PubMed Google Scholar, 8Bataller R. Sancho-Bru P. Gines P. et al.Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II.Gastroenterology. 2003; 125: 117-125Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar Although the former is not acutely modifiable, disease stabilization and improvement, eg, after successful treatment of hepatitis C or abstinence from alcohol, can improve fibrosis and the mechanical component.9Rincon D. Ripoll C. Lo I.O. et al.Antiviral therapy decreases hepatic venous pressure gradient in patients with chronic hepatitis C and advanced fibrosis.Am J Gastroenterol. 2006; 101: 2269-2274Crossref PubMed Scopus (61) Google Scholar The dynamic component accounts for approximately 30% of the intrahepatic resistance in cirrhosis and is an important target for future therapy.10Bhathal P.S. Grossman H.J. Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators.J Hepatol. 1985; 1: 325-337Abstract Full Text PDF PubMed Google Scholar Cirrhosis is associated with evidence of endothelial dysfunction, both in the systemic circulation and within the liver.11Atucha N.M. Shah V. Garcia-Cardena G. et al.Role of endothelium in the abnormal response of mesenteric vessels in rats with portal hypertension and liver cirrhosis.Gastroenterology. 1996; 111: 1627-1632Abstract Full Text PDF PubMed Google Scholar, 12Gupta T.K. Toruner M. Chung M.K. et al.Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats.Hepatology. 1998; 28: 926-931Crossref PubMed Scopus (210) Google Scholar The net effect in the liver is intrahepatic vasoconstriction. This is mediated by decreased endothelial nitric oxide synthetase (eNOS) activity and NO production.12Gupta T.K. Toruner M. Chung M.K. et al.Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats.Hepatology. 1998; 28: 926-931Crossref PubMed Scopus (210) Google Scholar, 13Shah V. Garcia-Cardena G. Sessa W.C. et al.The hepatic circulation in health and disease: report of a single-topic symposium.Hepatology. 1998; 27: 279-288Crossref PubMed Scopus (41) Google Scholar, 14Gupta T.K. Toruner M. Groszmann R.J. Intrahepatic modulation of portal pressure and its role in portal hypertension Role of nitric oxide.Digestion. 1998; 59: 413-415Crossref PubMed Scopus (20) Google Scholar Hepatic eNOS activity is decreased because of impaired Akt-mediated eNOS phosphorylation (which is partially reversible by statins) and increased caveolin expression (particularly if folate deficiency exists).15Morales-Ruiz M. Cejudo-Martn P. Fernandez-Varo G. et al.Transduction of the liver with activated Akt normalizes portal pressure in cirrhotic rats.Gastroenterology. 2003; 125: 522-531Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 16Shah V. Toruner M. Haddad F. et al.Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental cirrhosis in the rat.Gastroenterology. 1999; 117: 1222-1228Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 17Matei V. Rodriguez-Vilarrupla A. Deulofeu R. et al.The eNOS cofactor tetrahydrobiopterin improves endothelial dysfunction in livers of rats with CCl4 cirrhosis.Hepatology. 2006; 44: 44-52Crossref PubMed Scopus (36) Google Scholar Other factors that contribute to intrahepatic vasoconstriction include decreased NO availability because of its utilization for nitrosylation reactions secondary to oxidative stress18Loureiro-Silva M.R. Iwakiri Y. Abraldes J.G. et al.Increased phosphodiesterase-5 expression is involved in the decreased vasodilator response to nitric oxide in cirrhotic rat livers.J Hepatol. 2006; 44: 886-893Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar and vasoconstriction mediated by endothelin, angiotensinogen, and eicosanoids.18Loureiro-Silva M.R. Iwakiri Y. Abraldes J.G. et al.Increased phosphodiesterase-5 expression is involved in the decreased vasodilator response to nitric oxide in cirrhotic rat livers.J Hepatol. 2006; 44: 886-893Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar, 19Moore K. Endothelin and vascular function in liver disease.Gut. 2004; 53: 159-161Crossref PubMed Scopus (19) Google Scholar The role of several other vasoactive mediators such as carbon monoxide, adrenergic tone, endotoxemia, and inflammatory cytokines are currently under investigation. Mesenteric arterial vasodilation is a hallmark of cirrhosis and contributes to both increased portal venous inflow and a systemic hyperdynamic circulatory state (low systemic vascular resistance and mean arterial pressure with high cardiac output).5Vorobioff J. Bredfeldt J.E. Groszmann R.J. Increased blood flow through the portal system in cirrhotic rats.Gastroenterology. 1984; 87: 1120-1126Abstract Full Text PDF PubMed Google Scholar, 20Iwakiri Y. Groszmann R.J. The hyperdynamic circulation of chronic liver disease: from the patient to the molecule.Hepatology. 2006; 43: S121-S131Crossref PubMed Scopus (157) Google Scholar Increased NO production because of increased eNOS activity in the systemic circulation is a major driver of arterial vasodilation.21Pizcueta M.P. Pique J.M. Bosch J. et al.Effects of inhibiting nitric oxide biosynthesis on the systemic and splanchnic circulation of rats with portal hypertension.Br J Pharmacol. 1992; 105: 184-190Crossref PubMed Google Scholar Shear stress, increased vascular endothelial growth factor (VEGF), and tumor necrosis factor-α are causes of increased splanchnic NO production in cirrhosis.22Abraldes J.G. Iwakiri Y. Loureiro-Silva M. et al.Mild increases in portal pressure upregulate vascular endothelial growth factor and endothelial nitric oxide synthase in the intestinal microcirculatory bed, leading to a hyperdynamic state.Am J Physiol Gastrointest Liver Physiol. 2006; 290: G980-G987Crossref PubMed Scopus (54) Google Scholar, 23Wang J.J. Gao G.W. Gao R.Z. et al.Effects of tumor necrosis factor, endothelin and nitric oxide on hyperdynamic circulation of rats with acute and chronic portal hypertension.World J Gastroenterol. 2004; 10: 689-693PubMed Google Scholar, 24Fernandez-Martinez E. Perez-Alvarez V. Tsutsumi V. et al.Chronic bile duct obstruction induces changes in plasma and hepatic levels of cytokines and nitric oxide in the rat.Exp Toxicol Pathol. 2006; 58: 49-58Crossref PubMed Scopus (23) Google Scholar Increased heme oxygenase activity and CO production may also contribute to the hemodynamic disturbances.25Fernandez M. Bonkovsky H.L. Increased heme oxygenase-1 gene expression in liver cells and splanchnic organs from portal hypertensive rats.Hepatology. 1999; 29: 1672-1679Crossref PubMed Scopus (77) Google Scholar Bacteremia can increase vasodilation by stimulating tumor necrosis factor-α production and activation of endocannabinoids, which are potent vasodilators.26Batkai S. Jarai Z. Wagner J.A. et al.Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis.Nat Med. 2001; 7: 827-832Crossref PubMed Scopus (218) Google Scholar Blockade of VEGF signaling attenuates the increase in portal venous inflow seen in cirrhosis.27Fernandez M. Vizzutti F. Garcia-Pagan J.C. et al.Anti-VEGF receptor-2 monoclonal antibody prevents portal-systemic collateral vessel formation in portal hypertensive mice.Gastroenterology. 2004; 126: 886-894Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar Nature decompresses the hypertensive portal vein by diverting up to 90% of the portal flow through porta-systemic collaterals back to the heart, resulting in flow-mediated remodeling and enlargement of these vessels. VEGF, NO-driven VEGF type II receptor expression, and platelet-derived growth factor drive this process.21Pizcueta M.P. Pique J.M. Bosch J. et al.Effects of inhibiting nitric oxide biosynthesis on the systemic and splanchnic circulation of rats with portal hypertension.Br J Pharmacol. 1992; 105: 184-190Crossref PubMed Google Scholar, 28Fernandez M. Mejias M. Angermayr B. et al.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: 98-103Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar A common location for such vessels is at the gastroesophageal junction at which they lie immediately subjacent to the mucosa and present as gastric and esophageal varices. Varices do not form until the HVPG exceeds 10 mm Hg and usually do not bleed unless the HVPG exceeds 12 mm Hg.29Groszmann R.J. Garcia-Tsao G. Bosch J. et al.Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.N Engl J Med. 2005; 353: 2254-2261Crossref PubMed Scopus (256) Google Scholar, 30Garcia-Tsao G. Groszmann R.J. Fisher R.L. et al.Portal pressure, presence of gastroesophageal varices and variceal bleeding.Hepatology. 1985; 5: 419-424Crossref PubMed Scopus (344) Google Scholar Variceal rupture occurs when the wall tension exceeds the elastic limits of the variceal wall (Figure 1). The wall tension is defined by Frank's modification of Laplace's law31Rigau J. Bosch J. Bordas J.M. et al.Endoscopic measurement of variceal pressure in cirrhosis: correlation with portal pressure and variceal hemorrhage.Gastroenterology. 1989; 96: 873-880Abstract Full Text PDF PubMed Google Scholar:T=(Pvarices−Pesophageal⁢lumen)×(radius⁢of⁢varix)/wall⁢thickness(3) The variceal pressure is dependent on variceal flow and resistance to outflow (see equation 2 above). Variceal flow is driven by the severity of portal hypertension. Thus, a high portal pressure and the variceal diameter are major determinants of variceal hemorrhage; an HVPG > 20 mm Hg has been associated with continued bleeding and failure of medical therapy in acute variceal hemorrhage.32Moitinho E. Escorsell A. Bandi J.C. et al.Prognostic value of early measurements of portal pressure in acute variceal bleeding.Gastroenterology. 1999; 117: 626-631Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar In addition, varices are most superficial at the gastroesophageal junction and thus have the thinnest wall in that region: consequently, esophageal variceal hemorrhage invariably occurs in this region.33Vianna A. Hayes P.C. Moscoso G. et al.Normal venous circulation of the gastroesophageal junction A route to understanding varices.Gastroenterology. 1987; 93: 876-889Abstract PubMed Google Scholar Ascites is a common complication of cirrhosis.34D'amico G. Garcia-Tsao G. Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.J Hepatol. 2006; 44: 217-231Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar Increased hepatic sinusoidal pressure is an essential prerequisite for the development of ascites. Three interrelated pathophysiologic processes contribute to the development of ascites. These include systemic arteriolar vasodilation, activation of Na and H2O retention, and sinusoidal portal hypertension. Cirrhosis is associated with systemic arteriolar dilatation35Schrier R.W. Arroyo V. Bernardi M. et al.Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.Hepatology. 1988; 8: 1151-1157Crossref PubMed Google Scholar (Figure 2). Systemic arteriolar dilatation increases the fraction of the total capillary bed in the body open for perfusion resulting in decreased filling of the available vascular space. This is known as effective hypovolemia. Another consequence of systemic arteriolar vasodilation is a decrease in mean arterial pressure. Increased heart rate and cardiac output tends to compensate for the decreased systemic vascular resistance and maintains mean arterial pressure, especially early in the course of the disease.20Iwakiri Y. Groszmann R.J. The hyperdynamic circulation of chronic liver disease: from the patient to the molecule.Hepatology. 2006; 43: S121-S131Crossref PubMed Scopus (157) Google Scholar As arteriolar vasodilation worsens with disease progression, cardiac output fails to rise further.36Ruiz-Del-Arbol L. Monescillo A. Arocena C. et al.Circulatory function and hepatorenal syndrome in cirrhosis.Hepatology. 2005; 42: 439-447Crossref PubMed Scopus (175) Google Scholar In fact, the inotropic and chronotropic functions are impaired, and the cardiac output, although high in absolute terms, is disproportionately low for the degree of vasodilation.36Ruiz-Del-Arbol L. Monescillo A. Arocena C. et al.Circulatory function and hepatorenal syndrome in cirrhosis.Hepatology. 2005; 42: 439-447Crossref PubMed Scopus (175) Google Scholar This is accompanied by intense activation of endogenous vasoconstrictive mechanisms such as the renin-angiotensin, sympathetic nervous system, and the antidiuretic hormone (ADH).37Arroyo V. Bosch J. Mauri M. et al.Effect of angiotensin-II blockade on systemic and hepatic haemodynamics and on the renin-angiotensin-aldosterone system in cirrhosis with ascites.Eur J Clin Invest. 1981; 11: 221-229Crossref PubMed Google Scholar Although unable to reverse the mesenteric arteriolar vasodilation, they produce severe vasoconstriction in other vascular beds, eg, the kidneys, brain, muscle, and skin.38Sieber C.C. Lopez-Talavera J.C. Groszmann R.J. Role of nitric oxide in the in vitro splanchnic vascular hyporeactivity in ascitic cirrhotic rats.Gastroenterology. 1993; 104: 1750-1754Abstract PubMed Google Scholar, 39Maroto A. Gines P. Arroyo V. et al.Brachial and femoral artery blood flow in cirrhosis: relationship to kidney dysfunction.Hepatology. 1993; 17: 788-793PubMed Google Scholar The renal arteries are very sensitive to the vasoconstrictive effects of angiotensin II, norepinephrine, and ADH. This explains the low glomerular filtration rate and renal perfusion pressure with progression of cirrhosis; when the glomerular filtration rate is decreased enough to cause overt renal failure, hepatorenal syndrome (HRS) is considered to be present.40Arroyo V. Planas R. Gaya J. et al.Sympathetic nervous activity, renin-angiotensin system and renal excretion of prostaglandin E2 in cirrhosis Relationship to functional renal failure and sodium and water excretion.Eur J Clin Invest. 1983; 13: 271-278Crossref PubMed Google Scholar Effective hypovolemia activates the renin-angiotensin-aldosterone pathway and sympathetic nerve activity. Both cause renal Na and water retention (Figure 2). These pathways are activated late in the course of ascites,41Bosch J. Arroyo V. Betriu A. et al.Hepatic hemodynamics and the renin-angiotensin-aldosterone system in cirrhosis.Gastroenterology. 1980; 78: 92-99PubMed Google Scholar, 42Salo J. Gines A. Anibarro L. et al.Effect of upright posture and physical exercise on endogenous neurohormonal systems in cirrhotic patients with sodium retention and normal supine plasma renin, aldosterone, and norepinephrine levels.Hepatology. 1995; 22: 479-487PubMed Google Scholar suggesting that there are yet other undiscovered mechanisms that are operative early in the course of cirrhosis. ADH secretion increases with more profound vasodilatation, resulting in water retention and hyponatremia.43Arroyo V. Claria J. Salo J. et al.Antidiuretic hormone and the pathogenesis of water retention in cirrhosis with ascites.Semin Liver Dis. 1994; 14: 44-58Crossref PubMed Google Scholar Hyponatremia is a marker for advanced disease and is an independent predictor of outcome.44Heuman D.M. Abou-Assi S.G. Habib A. et al.Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death.Hepatology. 2004; 40: 802-810Crossref PubMed Google Scholar Increased sinusoidal hydrostatic pressure leads to increased fluid movement from the sinusoids to the space of Disse, thereby increasing hepatic and thoracic duct lymph flow, which can be as much as 24-fold elevated vs normal.45Witte C.L. Witte M.H. Dumont A.M. Progress in liver disease: physiological factors involved in the causation of cirrhotic ascites.Gastroenterology. 1971; 61: 742-750PubMed Google Scholar Both increased outflow resistance and portal venous inflow contribute to sinusoidal hypertension and the formation of splanchnic lymph. When lymph production exceeds the capacity of the lymphatics to return it to circulation, the excess lymph spills into the peritoneal cavity. This is initially reabsorbed via microscopic stoma on the peritoneal surface of the diaphragm that communicates with supradiaphragmatic lymphatics.46Leak L.W. Rahil K. Permeability of the diaphrgmatic mesothelium: the ultrastructural basis for “stomata.”.Am J Anat. 1978; 151: 557-594Crossref PubMed Google Scholar When ascites formation exceeds its reabsorption, clinically evident ascites occurs. Cirrhosis is also associated with a closing of the normal fenestrae and the deposition of a basement membrane below the sinusoidal endothelium.47Huet P.M. Goresky C.A. Villeneuve J.P. et al.Assessment of liver microcirculation in human cirrhosis.J Clin Invest. 1982; 70: 1234-1244Crossref PubMed Google Scholar This decreases sinusoidal endothelial permeability. Thus, for a given elevation of sinusoidal hydrostatic pressure, the ascites that is formed has a low protein and albumin concentration. A serum to ascites albumin gradient >1.1 suggests the presence of portal hypertension with cirrhosis.48Hoefs J.C. Serum protein concentration and portal pressure determine the ascitic fluid protein concentration in patients with chronic liver disease.J Lab Clin Med. 1983; 102: 260-273PubMed Google Scholar Low levels of ascites proteins and opsonins increase the risk of spontaneous bacterial peritonitis (SBP).49Llach J. Rimola A. Navasa M. et al.Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: relevance of ascitic fluid protein concentration.Hepatology. 1992; 16: 724-727Crossref PubMed Google Scholar, 50Runyon B.A. Antillon M.R. McHutchison J.G. Diuresis increases ascitic fluid opsonic activity in patients who survive spontaneous bacterial peritonitis.J Hepatol. 1992; 14: 249-252Abstract Full Text PDF PubMed Google Scholar Initially, ascites is manageable with Na restriction and diuretic therapy. However, over time, some patients cease to respond even to maximal diuretic therapy and are considered to have refractory ascites.51Arroyo V. Gines P. Gerbes A.L. et al.Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis International Ascites Club.Hepatology. 1996; 23: 164-176Crossref PubMed Google Scholar This is associated with further exaggeration of the pathophysiologic mechanisms outlined above and decreased glomerular filtration rate, which may manifest as overt renal failure52Salerno F. Gerbes A. Gines P. et al.Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (0) Google Scholar (Table 1).Table 1Definition of Refractory Ascites and Hepatorenal SyndromeRefractory ascites Diuretic resistant ascites: Ascites that is difficult to mobilize, as defined by a failure to lose at least 1.5 kg/week of fluid weight, despite maximal diuretic therapy with spironolactone (400 mg/day) and furosemide (160 mg/day) or an equivalent dose of a distal-acting and loop-acting diuretic, respectively Diuretic intractable ascites: Ascites that is difficult to mobilize, as defined above, because of the inability to provide effective doses of diuretics because of diuretic-induced adverse effects, eg, azotemia, hyponatremia, and othersHepatorenal syndrome Presence of cirrhosis with ascites Presence of renal failure (creatinine level >1.5 mg/dL or 133 mol/L) Lack of improvement in serum creatinine after 48 hours of diuretic withdrawal and volume expansion with intravenous albumin administration (1 g/kg/day up to 100 g/day) Absence of shock Use of nephrotoxic drugs, eg, aminoglycosides Parenchymal renal disease (urine protein >500 mg/day, granular or red cell casts, hematuria, urinary obstruction by sonography)NOTE. Based on International Ascites Club Criteria.51Arroyo V. Gines P. Gerbes A.L. et al.Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis International Ascites Club.Hepatology. 1996; 23: 164-176Crossref PubMed Google Scholar, 52Salerno F. Gerbes A. Gines P. et al.Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (0) Google Scholar Open table in a new tab NOTE. Based on International Ascites Club Criteria.51Arroyo V. Gines P. Gerbes A.L. et al.Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis International Ascites Club.Hepatology. 1996; 23: 164-176Crossref PubMed Google Scholar, 52Salerno F. Gerbes A. Gines P. et al.Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (0) Google Scholar HRS is functional renal failure that occurs because of marked mesenteric arterial vasodilation, impaired cardiac response to the vasodilation, and increased renal vasoconstriction.52Salerno F. Gerbes A. Gines P. et al.Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (0) Google Scholar Increased angiotensin, sympathetic nerve activity, and ADH all contribute to renal vasoconstriction. Initially, these are compensated for by intrarenal vasodilatory mechanisms (prostaglandins, NO, and others).40Arroyo V. Planas R. Gaya J. et al.Sympathetic nervous activity, renin-angiotensin system and renal excretion of prostaglandin E2 in cirrhosis Relationship to functional renal failure and sodium and water excretion.Eur J Clin Invest. 1983; 13: 271-278Crossref PubMed Google Scholar As the renal balance between vasodilation and vasoconstriction tilts toward vasoconstriction, renal perfusion and glomerular filtration rate decrease. This process occurs in the transition from diuretic-responsive ascites to refractory ascites to HRS, and these states often form a clinical continuum rather than distinct clinical-pathophysiologic entities. The progression to and rate of development of renal failure is often accelerated by intermittent bouts of infection, particularly SBP, which are associated with increasing vasodilatation and impaired cardiac response to the vasodilatation.53Ruiz-Del-Arbol L. Urman J. Fernandez J. et al.Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis.Hepatology. 2003; 38: 1210-1218Crossref PubMed Scopus (202) Google Scholar These, in turn, further activate vasconstrictive pathways, causing renal vasoconstriction. Depending on the rate of development of renal failure, HRS is classified as type 1 (rapidly progressive) or type 2 (slowly progressive).52Salerno F. Gerbes A. Gines P. et al.Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (0) Google Scholar Type 2 HRS is usually seen in the context of refractory ascites. Type 1 HRS is associated with worsening hepatic function. The latter is believed to be due to decreased hepatic blood flow from increased sinusoidal resistance secondary to angiotensin-II, norepinephrine, and ADH-mediated stellate cell contraction.36Ruiz-Del-Arbol L. Monescillo A. Arocena C. et al.Circulatory function and hepatorenal syndrome in cirrhosis.Hepatology. 2005; 42: 439-447Crossref PubMed Scopus (175) Google Scholar, 53Ruiz-Del-Arbol L. Urman J. Fernandez J. et al.Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis.Hepatology. 2003; 38: 1210-1218Crossref PubMed Scopus (202) Google Scholar Hepatic encephalopathy (HE) is a broad entity that encompasses mental status changes in subjects with acute and chronic liver failure. Variable degrees of hepatocellular failure and portal-systemic shunting are the anatomic substrate of HE, although either one can produce HE. Several mechanisms have been implicated in the genesis of HE and are reviewed below. Ammonia is a key factor in the pathogenesis of HE.54Felipo V. Butterworth R.F. Neurobiology of ammonia.Prog Neurobiol. 2002; 67: 259-279Crossref PubMed Scopus (273) Google Scholar In cirrhosis, decreased hepatic uptake of ammonia occurs as a result of intrahepatic portal-systemic shunts and/or reduced urea and glutamine synthesis. A substantial portion of gut-derived ammonia originates in the small bowel from the deamination of glutamine by glutaminase, which is activated in cirrhosis.55Romero-Gomez M. Ramos-Guerrero R. Grande L. et al.Intestinal glutaminase activity is increased in liver cirrhosis and correlates with minimal hepatic encephalopathy.J Hepatol. 2004; 41: 49-54Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar The potential importance of this enzyme is exemplified by its sensitivity to neomycin, which is used to treat HE.56Hawkins R.A. Jessy J. Mans A.M. et al.Neomycin reduces the intestinal production of ammonia from glutamine.Adv Exp Med Biol. 1994; 368: 125-134Crossr" @default.
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• W2083469788 title "Portal Hypertension and Its Complications" @default.
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