Pathogenesis and management of hepatorenal syndrome in patients with cirrhosis
Authors: Paolo Angeli, Carlo Merkel
Journal: Journal of Hepatology (2008)

Hepatorenal syndrome is a severe complication of advanced liver cirrhosis, in patients with ascites and marked circulatory dysfunction. It is clearly established that it has a functional nature, and that it is related to intense renal vasoconstriction. Despite its functional origin, the prognosis is very poor. In the present review, the most recent advances in diagnosis, pathophysiology, and treatment are discussed. Recent developments in pathophysiology are the basis of the new therapeutic strategies, which are currently under evaluation in randomised clinical trials. Hepatorenal syndrome is a severe complication of advanced liver cirrhosis, in patients with ascites and marked circulatory dysfunction. It is clearly established that it has a functional nature, and that it is related to intense renal vasoconstriction. Despite its functional origin, the prognosis is very poor. In the present review, the most recent advances in diagnosis, pathophysiology, and treatment are discussed. Recent developments in pathophysiology are the basis of the new therapeutic strategies, which are currently under evaluation in randomised clinical trials. 1. IntroductionThe occurrence of liver failure in patients with cirrhosis was first described during the 19th century, but the term hepatorenal syndrome (HRS) was first introduced in 1932 by Helvig and Schutz [[1]Helvig F.C. Schutz C.B. A liver and kidney syndrome: clinical, pathological, and experimental studies.Surg Gynecol Obstet. 1932; 55: 570-582Google Scholar] to describe a condition of acute renal failure occurring after biliary tract surgery in patients who showed a pathological pattern of acute tubular necrosis or tubular interstitial nephritis. Later on, this term reached a very wide diffusion, and was generally used to describe any kind of simultaneous severe impairment of liver and renal function. When, in the middle of the century it became progressively understood that pathophysiology of acute renal failure is grossly divided into an organic and a functional form of disease, it was clearly shown that renal involvement in advanced liver disease was generally a functional form of renal failure [[2]Hecker R. Sherlock S. Electrolyte and circulatory changes in terminal liver failure.Lancet. 1956; 2: 1121-1129Abstract Scopus (135) Google Scholar].Further studies showed that functional renal failure in advanced cirrhosis may be further divided into two forms, a more frequent, easily reversible and less severe condition of pre-renal failure due to vascular underfilling (bleeding, diarrhoea, excessive use of diuretics, heart failure), and a more severe condition, which is characterized by intense renal vasoconstriction and is similar in pathophysiological characteristics to conventional pre-renal failure, but does not improve after correction of vascular underfilling. The term HRS was thus restricted to this form of unexplained pre-renal failure in the course of advanced liver disease [[3]Papper S. The hepato-renal syndrome.Clin Nephrol. 1975; 4: 41-54PubMed Google Scholar]. Around the same time, it was observed that kidneys of patients dying of HRS could be successfully transplanted to patients with organic renal failure [[4]Koppel M.H. Coburn J.W. Mims M.M. Goldstein H. Boyle J.D. Rubini M.E. Transplantation of cadaveric kidneys from patients with hepato-renal syndrome: evidence for the functional nature of renal failure in advanced liver disease.N Engl J Med. 1969; 280: 1367-1371Crossref PubMed Scopus (223) Google Scholar], and it was shown that the intense renal vasoconstriction, which is usually observed at renal arteriography in patients with HRS (Fig. 1), disappeared at post-mortem vascular injection [[5]Epstein M. Berk D.P. Hollenberg N.K. Adams D.F. Chalmers T.C. Abrams H.L. et al.Renal failure in the patient with cirrhosis. The role of active vasoconstriction.Am J Med. 1970; 49: 175-185Abstract Full Text PDF PubMed Scopus (381) Google Scholar], emphasizing the functional nature of such renal insufficiency.In the last few years, there has been an extensive debate on the optimal criteria to define HRS and the first consensus definition was agreed upon at the 1994 meeting of the International Ascites Club [[6]Arroyo V. Gines P. Gerbes A.L. Dudley F.J. Gentilini P. Laffi G. et al.Definition and diagnostic criteria of refractory ascites and hepato-renal syndrome in cirrhosis.Hepatology. 1996; 23: 164-176Crossref PubMed Google Scholar] (Table 1). With the extensive application of these diagnostic criteria, it soon became apparent that there were some ambiguities and pitfalls in the definition of HRS, and that new and more precise diagnostic criteria were required. These new criteria were developed by the International Ascites Club at a focused study group held in San Francisco in 2006, and reported in 2007 [[7]Salerno F. Gerbes A. Gines P. Wong F. Arroyo V. Diagnosis, prevention and treatment of the hepato-renal syndrome in cirrhosis.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (75) Google Scholar] (Table 2). It is evident that this new definition is more precise (clear definition of the procedures requested to exclude a prerenal failure), but is less strict than the previous one, since patients with recent or present infections, in particularly spontaneous bacterial peritonitis (SBP), are not excluded from a diagnosis of HRS.Table 1International Ascites Club's diagnostic criteria of hepatorenal syndrome (1996; Ref. [6]Arroyo V. Gines P. Gerbes A.L. Dudley F.J. Gentilini P. Laffi G. et al.Definition and diagnostic criteria of refractory ascites and hepato-renal syndrome in cirrhosis.Hepatology. 1996; 23: 164-176Crossref PubMed Google Scholar)Major criteria:-Chronic or acute liver disease with advanced hepatic failure and portal hypertension-Low glomerular filtration rate (s-creatinine >1.5 mg/dL or creatinine clearance <40 mL/min)-Absence of shock, ongoing bacterial infection, and current or recent treatment with nephrotoxic drugs. Absence of gastrointestinal fluid losses (repeated vomiting or intense diarrhoea) or renal fluid losses (weight loss >500 g/day in patients with ascites without peripheral edema or 1000 g/day in patients with peripheral edema)-No sustained improvement in renal function (decrease in s-creatinine to 1.5 mg/dL or less, or increase in creatinine clearance to 40/mL/min or more) following diuretic withdrawal and expansion of plasma volume with 1.5 L of isotonic saline-Proteinuria <500 mg/day nad no ultrasonographic evidence of obstructive uropathy or parenchymal renal diseaseAdditional criteria (not necessary for the diagnosis):-Urine volume <500 mL/day-Urine sodium <10 mEq/L-Urine osmolality greater than plasma osmolality-Urine red blood cells <50/HPF-Serum sodium concentration <130 mEq/L Open table in a new tab Table 2New International Ascites Club's diagnostic criteria of hepatorenal syndrome (2007; Ref. [7]Salerno F. Gerbes A. Gines P. Wong F. Arroyo V. Diagnosis, prevention and treatment of the hepato-renal syndrome in cirrhosis.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (75) Google Scholar)-Cirrhosis with ascites-Serum creatinine > 1.5 mg/dL-No improvement in serum creatinine (decrease to a level of <1.5 mg/dL) after at least 2 days with diuretic withdrawal and volume expansion with albumin. The recommended dose of albumin is 1 g/kg of body weight per day up to a maximum of 100 g/day-Absence of shock-No current or recent treatment with nephrotoxic drugs-Absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, microhematuria (<50 RBC/high power field) and/or abnormal renal ultrasonography Open table in a new tab Such changes should be taken into consideration when comparing treatment results of new studies with those obtained in the previous years, because changes in definitions may lead to a sort of stage migration, a phenomenon that is well known to bio-statisticians [[8]Feinstein A.R. Sosin D.M. Wells C.K. The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer.N Engl J Med. 1985; 312: 1604-1608Crossref PubMed Scopus (1278) Google Scholar], and is characterized by an improvement in outcome in both stages involved (Fig. 2). Indeed, if patients with infections unresponsive to a 2-day infusion of albumin have a mortality rate intermediate between classical HRS and pre-renal azotemia (with the values suggested in the figure), the migration of these patients towards the group of patients with HRS would decrease mortality in HRS from 80% to 65%, and that of pre-renal azotemia from 27.5% to 20%.Fig. 2Expected changes in mortality rate of HRS and of pre-renal failure according to the old (1996 – Ref. [[6]Arroyo V. Gines P. Gerbes A.L. Dudley F.J. Gentilini P. Laffi G. et al.Definition and diagnostic criteria of refractory ascites and hepato-renal syndrome in cirrhosis.Hepatology. 1996; 23: 164-176Crossref PubMed Google Scholar]) and new (2007- Ref. [[7]Salerno F. Gerbes A. Gines P. Wong F. Arroyo V. Diagnosis, prevention and treatment of the hepato-renal syndrome in cirrhosis.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (75) Google Scholar]) definitions of HRS because of the stage-migration effect of patients with infections not responding to a 2-day course of albumin. Frequencies and mortality rates are approximate and only used for exemplifying purpose.View Large Image Figure ViewerDownload Hi-res image Download (PPT)2. Natural historyHRS is a potentially reversible form of renal failure that occurs in patients with cirrhosis and ascites as well as in patients with acute liver failure. In cirrhotic patients with ascites, pre-renal failure (42%) and acute tubular necrosis (ATN) (38%) represent the most common forms of acute renal failure while HRS [[9]Moreau R. Lebrec D. Acute renal failure in patients with cirrhosis: perspectives in the age of MELD.Hepatology. 2003; 37: 233-243Crossref PubMed Scopus (198) Google Scholar] is somewhat less frequent (20%) (Table 3). The incidence of HRS in patients with cirrhosis and ascites is equal to 18% after 1 year, and reaches 39% after 5 years [[10]Gines A. Escorsell A. Gines P. Salo J. Jimenez W. Inglada L. et al.Incidence, predictive factors and prognosis of the hepato-renal syndrome in cirrhosis with ascites.Gastroenterology. 1993; 105: 229-236Abstract PubMed Google Scholar]. In almost half the cases of HRS, one or more precipitating factors may be identified, including bacterial infections (57%), gastrointestinal hemorrhage (36%), and large volume paracentesis (7%) [[10]Gines A. Escorsell A. Gines P. Salo J. Jimenez W. Inglada L. et al.Incidence, predictive factors and prognosis of the hepato-renal syndrome in cirrhosis with ascites.Gastroenterology. 1993; 105: 229-236Abstract PubMed Google Scholar].Table 3Acute renal failure in patients with cirrhosis and ascites (Ref. [9]Moreau R. Lebrec D. Acute renal failure in patients with cirrhosis: perspectives in the age of MELD.Hepatology. 2003; 37: 233-243Crossref PubMed Scopus (198) Google Scholar)1.Acute tubular necrosis (41.7%)2.Pre-renal failure (38%)3.Hepatorenal syndrome (20%)4.Post-renal failure (0.3%) Open table in a new tab HRS is characterized by (a) marked renal vasoconstriction with a consequent reduction in renal plasma flow and glomerular filtration rate, (b) the absence of pathological changes in the renal tissue, and (c) preserved renal tubular function. HRS usually arises when the chronic liver disease is associated with a marked circulatory dysfunction with low values of arterial pressure despite an overactivity of the sympathetic nervous and renin–angiotensin systems, which, according to the "arterial vasodilation hypothesis" occurs as a consequence of a marked arterial vasodilation, mainly located in the splanchnic circulation [[11]Schrier R.W. Arroyo V. Bernardi M. Epstein M. Henriksen J.H. Rodes J. Peripheral arteriolar vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.Hepatology. 1988; 8: 1151-1157Crossref PubMed Scopus (1376) Google Scholar]. Until a few years ago, the prognosis of cirrhotic patients developing HRS was very poor with mortality reaching 100% in some series, and a median survival time of two weeks from diagnosis [[10]Gines A. Escorsell A. Gines P. Salo J. Jimenez W. Inglada L. et al.Incidence, predictive factors and prognosis of the hepato-renal syndrome in cirrhosis with ascites.Gastroenterology. 1993; 105: 229-236Abstract PubMed Google Scholar]. Thereafter, some new promising treatments of HRS have been proposed, and improvement in survival has been observed in some studies.3. Diagnosis of HRSThe diagnostic criteria for a diagnosis of HRS have been reported above in the introduction (Table 1, Table 2). Within the diagnostic category of HRS, two different types of HRS can be distinguished (Table 4). Type-1 HRS is characterized by a rapid progression of renal failure; therefore the main clinical presentation is overt acute renal failure. By contrast, in patients with Type 2 HRS the degree of the impairment of renal failure is less severe and more stable over time. As a consequence, the main clinical problem in these patients is refractory ascites (Table 4). The two types of HRS substantially differ in prognosis, since median survival of type-1 HRS averages 2 weeks, whilst that of type 2 is generally around 4–6 months [[12]Gines P. Guevara M. Arroyo V. Rodes J. Hepato-renal syndrome.Lancet. 2003; 362: 1819-1827Abstract Full Text Full Text PDF PubMed Scopus (492) Google Scholar]. Besides the obvious differences in the severity of renal function impairment, further pathophysiological differences between type-1 and type-2 HRS are not fully elucidated, and it is not clearly defined if the two types share all the same pathophysiological mechanisms; nevertheless, it may be observed that Type-1 HRS is often induced by a precipitating event (Table 5), in particular spontaneous bacterial peritonitis [13Follo A. Llovet J.M. Navasa M. Planas R. Forns X. Francitorra A. et al.Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis.Hepatology. 1994; 20: 1495-1501Crossref PubMed Scopus (460) Google Scholar, 14Angeli P. Guarda S. Fasolato S. Miola E. Craighero R. Piccolo F. et al.Switch therapy with ciprofloxacin versus intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in patients with cirrhosis:similar efficacy at lower cost.Alimentary Pharmacol Ther. 2006; 23: 75-84Crossref PubMed Scopus (68) Google Scholar]. Almost one third of patients with spontaneous bacterial peritonitis develop a progressive form of renal failure [13Follo A. Llovet J.M. Navasa M. Planas R. Forns X. Francitorra A. et al.Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis.Hepatology. 1994; 20: 1495-1501Crossref PubMed Scopus (460) Google Scholar, 14Angeli P. Guarda S. Fasolato S. Miola E. Craighero R. Piccolo F. et al.Switch therapy with ciprofloxacin versus intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in patients with cirrhosis:similar efficacy at lower cost.Alimentary Pharmacol Ther. 2006; 23: 75-84Crossref PubMed Scopus (68) Google Scholar] which in most cases fulfils the most recent diagnostic criteria of type 1 HRS [[14]Angeli P. Guarda S. Fasolato S. Miola E. Craighero R. Piccolo F. et al.Switch therapy with ciprofloxacin versus intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in patients with cirrhosis:similar efficacy at lower cost.Alimentary Pharmacol Ther. 2006; 23: 75-84Crossref PubMed Scopus (68) Google Scholar]. More recently it has been observed that renal failure can be precipitated in cirrhotic patients with ascites by all types of bacterial infections. In most cases renal failure is transient and recovers after the resolution of the infection. However, in some cases an acute renal failure with the hallmarks of type 1 HRS can also be precipitated by urinary, biliary, or intestinal infections [[15]Fasolato S. Angeli P. Dallagnese L. Maresio G. Zola E. Mazza E. et al.Renal failure and bacterial infections in patients with cirrhosis: epidemiology and clinical features.Hepatology. 2007; 45: 223-229Crossref PubMed Scopus (238) Google Scholar]. The risk factors for the development of renal failure after bacterial infections are (a) the severity of infection, (b) the MELD score at the diagnosis of infection and (c) the persistence of infection despite antibiotic treatment [15Fasolato S. Angeli P. Dallagnese L. Maresio G. Zola E. Mazza E. et al.Renal failure and bacterial infections in patients with cirrhosis: epidemiology and clinical features.Hepatology. 2007; 45: 223-229Crossref PubMed Scopus (238) Google Scholar, 16Terra C. Guevara M. Torre A. Gilabert R. Fernandez J. Martin-Llahi M. et al.Renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis: value of MELD score.Gastroenterology. 2005; 129: 1944-1953Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar]. In addition, the risk of developing type-1 HRS following a bacterial infection is higher in patients with cirrhosis who already present a type-2 HRS [13Follo A. Llovet J.M. Navasa M. Planas R. Forns X. Francitorra A. et al.Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis.Hepatology. 1994; 20: 1495-1501Crossref PubMed Scopus (460) Google Scholar, 14Angeli P. Guarda S. Fasolato S. Miola E. Craighero R. Piccolo F. et al.Switch therapy with ciprofloxacin versus intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in patients with cirrhosis:similar efficacy at lower cost.Alimentary Pharmacol Ther. 2006; 23: 75-84Crossref PubMed Scopus (68) Google Scholar]. There are some observations suggesting that type-1 HRS in this clinical situation may occur as a consequence of an abrupt and severe additional deterioration in circulatory dysfunction characterized by a further enhancement in splanchnic arterial vasodilation and a decrease in cardiac output.Table 4Clinical types of hepatorenal syndrome (Ref. [7]Salerno F. Gerbes A. Gines P. Wong F. Arroyo V. Diagnosis, prevention and treatment of the hepato-renal syndrome in cirrhosis.Gut. 2007; 56: 1310-1318Crossref PubMed Scopus (75) Google Scholar)-Type-1 hepatorenal syndrome: rapidly progressive reduction of renal function as defined by doubling of the initial s-creatinine to a level >2.5 mg/dL (226 μM/L) in less than two weeksClinical pattern: acute renal failure-Type-2 hepatorenal syndrome: moderate renal failure (s-creatinine ranging from 1.25 to 2.5 mg/dL or 113–226 μM/L) with a steady or slowly progressive courseClinical pattern: refractory ascites Open table in a new tab Table 5Precipitating events of hepatorenal syndrome-Spontaneous bacterial peritonitis-Paracentesis without plasma expansion-Gastrointestinal hemorrhage-Alcoholic hepatitis Open table in a new tab 4. Pathophysiology of HRSThe causes of the intense renal vasoconstriction underlying the occurrence of HRS are not fully understood. Compared to control subjects or cirrhotic patients with ascites but without HRS, patients with HRS consistently show lower splanchnic vascular resistance. Renal vasoconstriction, which is the pathophysiological basis of HRS, therefore develops in a context of a marked reduction of effective circulating volume related to peripheral arterial vasodilation [6Arroyo V. Gines P. Gerbes A.L. Dudley F.J. Gentilini P. Laffi G. et al.Definition and diagnostic criteria of refractory ascites and hepato-renal syndrome in cirrhosis.Hepatology. 1996; 23: 164-176Crossref PubMed Google Scholar, 13Follo A. Llovet J.M. Navasa M. Planas R. Forns X. Francitorra A. et al.Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis.Hepatology. 1994; 20: 1495-1501Crossref PubMed Scopus (460) Google Scholar]. The involvement of endogenous vasoconstrictor systems induced by the reduction of effective circulating volume in the development of HRS is clearly shown in clinical [17Arroyo V. Planas R. Gaya J. Deulofeu J. Rimola A. Perez-Ayuso R.M. 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 Scopus (199) Google Scholar, 18Henriksen J.H. Ring-Larsen H. Hepato-renal disorders: role of the sympathetic nervous system.Sem Liver Dis. 1994; 14: 35-43Crossref PubMed Scopus (76) Google Scholar, 19Gentilini P. Romanelli R.G. La Villa G. Maggiore Q. Pesciullesi E. Cappelli G. et al.Effects of low-dose captopril on renal hemodynamics and function in patients with cirrhosis of the liver.Gastroenterology. 1993; 104: 588-594Abstract PubMed Google Scholar] and experimental studies [[20]Solis-Herruzo J.A. Duran A. Favela V. Castellano G. Madrid J.L. Munoz-Yague M.T. et al.Effects of lumbar sympathetic block on kidney function in cirrhotic patients with hepato-renal syndrome.J Hepatol. 1987; 5: 167-173Abstract Full Text PDF PubMed Scopus (83) Google Scholar]. The most recent advances in our understanding of the pathogenesis of HRS have focused on mainly two new aspects. The first one is that the peripheral arterial vasodilation occurs mainly in the splanchnic arterial vascular bed and the second is that in patients with cirrhosis and HRS, the modulation of cardiac output is relatively unable to prevent the severe reduction of effective circulating volume due to the splanchnic arterial vasodilation.The first of these concepts has been formulated on the basis of the results of some clinical studies in which Doppler ultrasonography was used to evaluate regional blood flow in cirrhotic patients. These studies consistently demonstrated that arterial vasodilation occurs in the splanchnic circulation in patients with cirrhosis, while arterial vasoconstriction occurs in other vascular beds, including renal, brachial, femoral, and cerebral beds [21Piscaglia F. Zironi G. Gaiani S. Ferlito M. Rapezzi C. Siringo S. et al.Relationship between splanchnic, peripheral and cardiac haemodynamics in liver cirrhosis of different degrees of severity.Eur J Gastroenterol Hepatol. 1997; 9: 799-804Crossref PubMed Scopus (24) Google Scholar, 22Fernandez-Seara J. Prieto J. Quiroga J. Zozaia J.M. Cobos M.A. Rodriguez-Eire J.L. et al.Systemic and regional hemodynamics in patients with liver cirrhosis and ascites with and without functional renal failure.Gastroenterology. 1989; 97: 1304-13012PubMed Google Scholar, 23Maroto A. Gines P. Arroyo V. Gines A. Salò J. 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Bataller R. et al.Increased cerebrovascular resistance in cirrhotic patients with ascites.Hepatology. 1998; 28: 39-44Crossref PubMed Scopus (134) Google Scholar, 28Sugano S. Yamamoto K. Atobe T. Watanabe M. Vakui N. Iwasaki N. et al.Postprandial middle cerebral arterial vasoconstriction in cirrhotic patients. A placebo controlled evaluation.J Hepatol. 2001; 34: 373-377Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar]. At the same time, clinical studies directed to assess tissue-related blood flows, such as cutaneous and muscular blood flows, gave contrasting results, ranging from low to normal or even increased values [[29]Moller S. Henriksen J. The systemic circulation in cirrhosis.in: Gines P. Arroyo V. Rodes J. Schrier R.W. Ascites and renal dysfunction in liver disease. II ed. Blackwell Publ., 2005: 139-155Google Scholar]. These discrepancies were also dependent on the methods used to estimate blood flow, which included color Doppler ultrasonography [21Piscaglia F. Zironi G. Gaiani S. Ferlito M. Rapezzi C. Siringo S. et al.Relationship between splanchnic, peripheral and cardiac haemodynamics in liver cirrhosis of different degrees of severity.Eur J Gastroenterol Hepatol. 1997; 9: 799-804Crossref PubMed Scopus (24) Google Scholar, 30Luca A. Garcia-Pagan J.C. Feu F. Lopez-Talavera J.C. Fernandez M. Bru C. et al.Noninvasive measurement of femoral blood flow and portal pressure response to propranolol in patients with cirrhosis.Hepatology. 1995; 21: 83-88PubMed Google Scholar], nuclear medicine techniques [[31]Carella M. Hunter J.O. Fazio S. Dela Piano C. Bartoli G.C. Capillary blood flow in the skin of forearm in cirrhosis.Angiology. 1992; 43: 969-974Crossref PubMed Scopus (15) Google Scholar], and plethysmography [[32]Newby D.E. Jalan R. Masumori S. Hayes P.C. Boon N.A. Webb D.J. Peripheral vascular tone in patients with cirrhosis: role of the rennin–angiotensin and sympathetic nervous systems.Cardiovasc Res. 1998; 38: 223-228Google Scholar]. The main clinical problem related to abnormalities of muscle blood flow is the occurrence of muscle cramps, which may be improved by a chronic expansion of effective plasma volume by means of albumin administration [[33]Angeli P. Albino G. Carraro P. Dalla Pria M. Merkel C. Caregaro L. et al.Cirrhosis and muscle cramps: evidence of a causal relationship.Hepatology. 1996; 23: 264-273Crossref PubMed Google Scholar], a procedure which probably contributes to correct the abnormalities of muscle blood flow.Splanchnic arterial vasodilatation is thought to be the consequence of an increased release of endogenous vasodilators due to portal hypertension and/or hepatic failure. Among the endogenous vasodilators, nitric oxide [[34]Wiest R. Groszmann R.J. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough.Hepatology. 2002; 35: 478-491Crossref PubMed Scopus (370) Google Scholar], carbon monoxide [[35]Bolognesi M. Sacerdoti D. Piva A. Di Pascoli M. Zampieri F. Quarta S. et al.Carbon monoxide-mediated activation of large conductance calcium-activated potassium channels contributes to mesenteric vasodilation in cirrhotic rats.J Pharmacol Exp Ther. 2007; 321: 187-194Crossref PubMed Scopus (55) Google Scholar], glucagon [[36]Sieber C.C. Mosca P.G. Groszmann R.J. Effect of somatostatin on mesenteric vascular resistance in normal and portal hypertensive rats.Am J Physiol. 1992; 262: G274-G277PubMed Google Scholar], prostacyclin [[37]Fernandez M. Garcia-Pagan J.C. Casadevall M. Acute and chronic cyclooxygenase blockade in portal-hypertensive rats: influence on nitric oxide biosynthesis.Gastroenterology. 1998; 110: 1529-1535Abstract Full Text Full Text PDF Scopus (95) Google Scholar], adrenomedullin [[38]Guevara M. Gines P. Jimenez W. Sort P. Fernandez-Esparrach G. Escorsell A. et al.Increased adrenomedullin levels in cirrhosis: relationship with hemodynamic abnormalities and vasoconstrictor systems.Gastroenterology. 1998; 114: 336-343Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar] and endogenous opiates [[39]Ros J. Claria J. To-Figueras J. Planagumà A. Cejudo-Martı`n P. Fernandez-Varo G. et al.Endogenous cannabinoids: a new system involved in the homeostasis of arterial pressure in experimental cirrhosis in the rat.Gastroenterology. 2002; 122: 85-93Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar] seem to be the most clearly involved. A detailed analysis of all possible vasodilators involved in the pathogenesis of splanchnic arterial vasodilations goes beyond the purposes of this paper; however it is apparent that several endogenous vasodilators can contribute to splanchnic arterial vasodilation in every stage of progression of cirrhosis, and that the relative role of each of them can vary in the different stages of the liver disease [[40]Angeli P. Fernandez-Varo G. Dalla Libera V. Fasolato S. Galioto A. Arroyo V. et al.The role of nitric oxide in the pathogenesis of systemic and splanchnic vasodilation in cirrhotic rats before and after the onset of ascites.Liver. 2005; 29: 429-437Google Scholar]. Indeed, early in the course of the disease, the decrease in the systemic vascular resistance due to the arterial splanchnic vasodilation is compensated by the increase in heart rate and in cardiac output (the so-called "hyperdynamic circulation"). However, as the liver disease progresses leading to a further impairment in portal hypertension and hepatic failure, the hyperdynamic circulation is no longer adequate to compensate the severity of the reduction of the effective blood volume due to the splanchnic arterial vasodilation. This leads to a further activation of the systemic endogenous vasoconstrictor systems (the sympathetic nervous system, the renin–angiotensin system, a