Advertisement

Human serum albumin, systemic inflammation, and cirrhosis

Open AccessPublished:April 18, 2014DOI:https://doi.org/10.1016/j.jhep.2014.04.012

      Summary

      Human serum albumin (HSA) is one of the most frequent treatments in patients with decompensated cirrhosis. Prevention of paracentesis-induced circulatory dysfunction, prevention of type-1 HRS associated with bacterial infections, and treatment of type-1 hepatorenal syndrome are the main indications. In these indications treatment with HSA is associated with improvement in survival. Albumin is a stable and very flexible molecule with a heart shape, 585 residues, and three domains of similar size, each one containing two sub-domains. Many of the physiological functions of HSA rely on its ability to bind an extremely wide range of endogenous and exogenous ligands, to increase their solubility in plasma, to transport them to specific tissues and organs, or to dispose of them when they are toxic. The chemical structure of albumin can be altered by some specific processes (oxidation, glycation) leading to rapid clearance and catabolism. An outstanding feature of HSA is its capacity to bind lipopolysaccharide and other bacterial products (lipoteichoic acid and peptidoglycan), reactive oxygen species, nitric oxide and other nitrogen reactive species, and prostaglandins. Binding to NO and prostaglandins are reversible, so they can be transferred to other molecules at different sites from their synthesis. Through these functions, HSA modulates the inflammatory reaction. Decompensated cirrhosis is a disease associated systemic inflammation, which plays an important role in the pathogenesis of organ or system dysfunction/failure. Although, the beneficial effects of HAS have been traditionally attributed to plasma volume expansion, they could also relate to its effects modulating systemic and organ inflammation.

      Abbreviations:

      HSA (human serum albumin), HRS (hepatorenal), PICD (paracentesis-induced circulatory dysfunction), SBP (spontaneous bacterial peritonitis), RCT (randomized controlled trial), LPS (lipopolisaccharide), TLR4 (Toll-like receptor 4), PAMPs (pathogen-associated molecular paterns), DAMPs (damaged-associated molecular paterns), ROS (reactive oxygen species), RNS (reactive nitrogen species), HMA (human-mercapto-albumin), NMA (non-mercapto-albumin), NO (nitric oxide), CRP (c-reactive protein), RAS (renin-angiotensin system), SNS (sympathetic nervous system), ADH (antidiuretic hormone), PGs (prostaglandins), BDK (bradikinin), ACLF (acute-on-chronic liver failure), TNFα (tumor necrosis factor α)

      Keywords

      Human serum albumin (HSA) and the management of decompensated cirrhosis: Background and current indications

      History

      Diuretics, antibiotics, and HSA are the most frequently used treatments for the management of patients with cirrhosis. According to the CANONIC study database [
      • Moreau R.
      • Jalan R.
      • Ginès P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ], a prospective European investigation in 1348 patients with decompensated cirrhosis, HSA was indicated in 60% of the patients during hospital admission (Table 1).
      Table 1Use of albumin in patients with acute decompensation of cirrhosis in Europe. Results from the CANONIC study database.
      The CANONIC study was made in 1348 patients. The table only includes patients with hospitalization follow-up. There were patients with more than one complication requiring albumin administration.
      The history of HSA started in 1940, when a long-term stable substitute of blood was required by the US military authorities to treat shock on the battlefield during the World War II [
      • Peters Jr., T.
      All about albumin. Biochemistry and medical applications.
      ]. It was used for first time in December 1941 in seven severely burned sailors after the attack on Pearl Harbor. At that period, the association of portal hypertension, hypoalbuminemia, and ascites was already known. Not surprisingly, ascites was one of the first indications of HSA. Three studies published between 1946 and 1949 assessing the effect of short- and long-term i.v. infusion of HSA in cirrhotic patients with ascites defined the first indications of HSA in cirrhosis [
      • Thorn G.W.
      • Armstrong Jr., S.H.
      • Davenport V.D.
      Chemical, clinical, and immunological studies on the products of human plasma fractionation. XXXI. The use of salt-poor concentrated human serum albumin solution in the treatment of hepatic cirrhosis.
      ,
      • Kunkel H.G.
      • Labby D.H.
      • Ahrens E.H.
      • Shank R.E.
      • Hoagland C.L.
      The use of concentrated human serum albumin in the treatment of cirrhosis of the liver.
      ,
      • Faloon W.W.
      • Eckhardt R.D.
      • Lynch Murphy T.
      • Cooper A.M.
      • Davidson C.S.
      An evaluation of human serum albumin in the treatment of cirrhosis of the liver.
      ]. Serum albumin concentration and urine volume increased in most patients. Peripheral edema also improved. However, only some patients showed improvement of ascites. First indication of HSA was, therefore, hypoalbuminemia in patients treated by frequent paracentesis. The introduction of spironolactone and furosemide in the early 1960’s and the article by Hecker and Sherlock [
      • Hecker R.
      • Sherlock S.
      Electrolyte and circulatory changes in terminal liver failure.
      ] first describing hepatorenal syndrome (HRS) lead to great changes in the management of ascites. The concept that paracentesis could be followed by rapid reformation of ascites and renal failure extended rapidly through the medical community and therapeutic paracentesis was formally proscribed. Only in 10% of patients not responding to diuretics (refractory ascites) was HSA prescribed to increase the plasma volume and diuretic effect [
      • Traverso H.
      • Vesin P.
      • Combrisson A.
      • Besson P.
      • Cattan R.
      Intravenous albumin loading in ascitic cirrhosis. Biological study.
      ]. In the 1970’s LeVeen designed the first peritoneo-venous shunt [
      • Wapnick S.
      • Grosberg S.
      • Kinney M.
      • Azzara V.
      • LeVeen H.H.
      Renal failure in ascites secondary to hepatic, renal, and pancreatic disease. Treatment with a LeVeen peritoneovenous shunt.
      ]. It consisted in a multi-perforated intra-peritoneal tube connected to a unidirectional valve and to a second tube that subcutaneously reached the superior vena cava through the internal jugular vein. The positive abdominal pressure and the negative intra-thoracic pressure facilitated the opening of the valve and the continuous passage of ascites into the circulation. LeVeen shunt was widely used in the management of refractory ascites for more than a decade. Following the introduction of LeVeen shunt, HSA disappeared from the therapeutic armamentarium of cirrhosis for more than a decade.

      Current indications of albumin

      Management of ascites

      In 1988 a Spaniard inter-hospital group [
      • Ginès P.
      • Arroyo V.
      • Quintero E.
      • Planas R.
      • Bory F.
      • Cabrera J.
      • et al.
      Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites. Results of a randomized study.
      ] demonstrated that paracentesis, if performed in association to HSA, was an effective and safe therapy of ascites. They compared repeated large volume paracentesis (4 liters/day) associated with HSA (8 g per liter of ascitic fluid removed) vs. diuretics. The incidence of renal impairment, hyponatremia and encephalopathy was significantly lower in the paracentesis group. No significant change in plasma renin activity was observed indicating no impairment in effective blood volume. Survival probability was similar in both groups. In a second investigation, total paracentesis (complete removal of ascites in only one tap) associated with HSA was also found to be safe [
      • Titó L.
      • Ginès P.
      • Arroyo V.
      • Planas R.
      • Panés J.
      • Rimola A.
      • et al.
      Total paracentesis associated with intravenous albumin management of patients with cirrhosis and ascites.
      ]. Treatment of ascites was therefore considerably simplified. Instead of requiring 2–4 weeks in hospital to compensate a tense ascites with diuretics, patients could be managed by paracentesis in a single day hospitalization regime [
      • Arroyo V.
      • Ginès A.
      • Saló J.
      A European survey on the treatment of ascites in cirrhosis.
      ]. Paracentesis associated with HSA was subsequently compared to peritoneo-venous shunting in patients with refractory ascites [
      • Ginès P.
      • Arroyo V.
      • Vargas V.
      • Planas R.
      • Casafont F.
      • Panés J.
      • et al.
      Paracentesis with intravenous infusion of albumin as compared with peritoneovenous shunting in cirrhosis with refractory ascites.
      ]. Peritoneo-venous shunting was superior to paracentesis in the long-term control of ascites. However, due to the high rate of complications associated with the prosthesis, the total time in hospital and the probability of survival was similar with both treatments. Based on these data, paracentesis plus HSA was considered the treatment of choice for tense ascites.
      When paracentesis is performed without HSA or if HSA is substituted by synthetic plasma expanders, a high proportion of patients develop marked activation of the renin-angiotensin system, a feature known as paracentesis-induced circulatory dysfunction (PICD) [
      • Ginès P.
      • Titó L.
      • Arroyo V.
      • Planas R.
      • Panés J.
      • Viver J.
      • et al.
      Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis.
      ,
      • Planas R.
      • Ginès P.
      • Arroyo V.
      • Llach J.
      • Panés J.
      • Vargas V.
      • et al.
      Dextran-70 vs. albumin as plasma expanders in cirrhotic patients with tense ascites treated with total paracentesis. Results of a randomized study.
      ,
      • Ginès A.
      • Fernández-Esparrach G.
      • Monescillo A.
      • Vila C.
      • Domènech E.
      • Abecasis R.
      • et al.
      Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis.
      ]. The prevalence of PICD in patients not receiving volume expansion is 70%. In patients receiving dextran or polygeline it is also high (37.8%). PICD is due to an accentuation of the arterial vasodilation already present in cirrhosis and a lack of appropriated cardiac response [
      • Saló J.
      • Ginès A.
      • Ginès P.
      • Piera C.
      • Jiménez W.
      • Guevara M.
      • et al.
      Effect of therapeutic paracentesis on plasma volume and transvascular escape rate of albumin in patients with cirrhosis.
      ,
      • Ruiz-del-Arbol L.
      • Monescillo A.
      • Jimenéz W.
      • Garcia-Plaza A.
      • Arroyo V.
      • Rodés J.
      Paracentesis-induced circulatory dysfunction: mechanism and effect on hepatic hemodynamics in cirrhosis.
      ,
      • Vila M.C.
      • Solà R.
      • Molina L.
      • Andreu M.
      • Coll S.
      • Gana J.
      • et al.
      Hemodynamic changes in patients developing effective hypovolemia after total paracentesis.
      ] (Fig. 1). PICD, although asymptomatic, is a serious complication. It is not spontaneously reversible and is associated with shorter time to hospital readmission, higher incidence of renal failure, and shorter probability of survival [
      • Ginès A.
      • Fernández-Esparrach G.
      • Monescillo A.
      • Vila C.
      • Domènech E.
      • Abecasis R.
      • et al.
      Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis.
      ]. A recent meta-analysis (17 trials, 1,225 patients) comparing HSA vs. alternative treatments (no volume expansion, synthetic plasma expanders or vasoconstrictors) has shown that HSA significantly reduces the incidence of PICD and mortality [
      • Bernardi M.
      • Caraceni P.
      • Navickis R.J.
      • Wilkes M.M.
      Albumin infusion in patients undergoing large-volume paracentesis: a meta-analysis of randomized trials.
      ].
      Figure thumbnail gr1
      Fig. 1Paracentesis-induced circulatory dysfunction in patients not receiving HSA. Relationship to changes in systemic vascular resistance. (A) Plasma renin activity before and after therapeutic paracentesis in cirrhotic patients with ascites not receiving HSA. Plasma renin activity increased in most patients indicating the development of paracentesis-induced circulatory dysfunction
      [
      • Ginès P.
      • Titó L.
      • Arroyo V.
      • Planas R.
      • Panés J.
      • Viver J.
      • et al.
      Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis.
      ]
      . (B) Relationship between changes in systemic vascular resistance and of plasma renin activity. An inverse relationship was observed indicating that circulatory dysfunction is related to arterial vasodilation
      [
      • Ruiz-del-Arbol L.
      • Monescillo A.
      • Jimenéz W.
      • Garcia-Plaza A.
      • Arroyo V.
      • Rodés J.
      Paracentesis-induced circulatory dysfunction: mechanism and effect on hepatic hemodynamics in cirrhosis.
      ]
      .

      Prevention of type-1 HRS associated with spontaneous bacterial peritonitis (SBP)

      Despite infection resolution, 20–40% of patients with SBP develop type-1 HRS in relation to arterial vasodilation, acute impairment in cardiac function, and compensatory activation of the renin-angiotensin and sympathetic nervous systems [
      • Follo 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.
      ,
      • Ruiz-del-Arbol L.
      • Urman J.
      • Fernández J.
      • González M.
      • Navasa M.
      • Monescillo A.
      • et al.
      Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis.
      ,
      • 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.
      ,
      • Navasa M.
      • Follo A.
      • Filella X.
      • Jiménez W.
      • Francitorra A.
      • Planas R.
      • et al.
      Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality.
      ] (Table 2). Type 1 HRS also develops in cirrhotic patients with other type of bacterial infections although the prevalence is lower [
      • Terra C.
      • Guevara M.
      • Torre A.
      • Gilabert R.
      • Fernández J.
      • Martín-Llahí M.
      • et al.
      Renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis: value of MELD score.
      ,
      • Pereira G.
      • Guevara M.
      • Fagundes C.
      • Solá E.
      • Rodríguez E.
      • Fernández J.
      • et al.
      Renal failure and hyponatremia in patients with cirrhosis and skin and soft tissue infection. A retrospective study.
      ,
      • Byl B.
      • Roucloux I.
      • Crusiaux A.
      • Dupont E.
      • Devière J.
      Tumor necrosis factor alpha and interleukin 6 plasma levels in infected cirrhotic patients.
      ]. The reason why SBP is such a frequent precipitating event of type-1 HRS is multifactorial. First, an exaggerated inflammatory response to sepsis occurs in patients with cirrhosis and ascites with an increase in plasma levels of cytokines 20-fold greater than in individuals without cirrhosis [
      • Byl B.
      • Roucloux I.
      • Crusiaux A.
      • Dupont E.
      • Devière J.
      Tumor necrosis factor alpha and interleukin 6 plasma levels in infected cirrhotic patients.
      ]. This feature has also been observed in experimental animals in which doses of bacterial endotoxin that do not produce any change in systemic hemodynamics in healthy rats, induce arterial hypotension and increase the plasma levels of cytokines by 100-fold in rats with cirrhosis and ascites [
      • Ramírez M.J.
      • Ibáñez A.
      • Navasa M.
      • Casals E.
      • Morales-Ruiz M.
      • Jiménez W.
      • et al.
      High-density lipoproteins reduce the effect of endotoxin on cytokine production and systemic hemodynamics in cirrhotic rats with ascites.
      ]. Second, the inflammatory response to bacterial infection persists for a longer duration in cirrhosis. Finally, patients with cirrhosis and ascites already have severe impairment in cardio-circulatory and renal function, which predispose these patients to further deterioration in organ function [
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodés J.
      Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      ]. In support to this contention, patients with SBP who have increased serum creatinine concentration or dilutional hyponatremia prior to infection, and those with intense inflammatory response (high concentration of polymorphonuclear leukocytes, tumor-necrosis-factor alpha and interleukin-6 in plasma, and ascitic fluid) are at high risk of developing type-1 HRS [
      • Navasa M.
      • Follo A.
      • Filella X.
      • Jiménez W.
      • Francitorra A.
      • Planas R.
      • et al.
      Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality.
      ,
      • Ginès A.
      • Escorsell A.
      • Ginès P.
      • Saló J.
      • Jiménez W.
      • Inglada L.
      • et al.
      Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites.
      ,
      • Fernández J.
      • Navasa M.
      • Planas R.
      • Montoliu S.
      • Monfort D.
      • Soriano G.
      • et al.
      Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis.
      ]. If untreated, type-1 HRS in patients with SBP is associated with a mortality rate approaching 100% [
      • Sort P.
      • Navasa M.
      • Arroyo V.
      • Aldeguer X.
      • Planas R.
      • Ruiz-del-Arbol L.
      • et al.
      Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.
      ].
      Table 2Effect of treatment with vasoconstrictors (ornipressin and terlipressin) and i.v. albumin in type-1 HRS (n = 15).
      Data obtained from
      • Guevara M.
      • Ginès P.
      • Fernández-Esparrach G.
      • Sort P.
      • Salmerón J.M.
      • Jiménez W.
      • et al.
      Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion.
      ,
      • Uriz J.
      • Ginès P.
      • Cárdenas A.
      • Sort P.
      • Jiménez W.
      • Salmerón J.M.
      • et al.
      Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome.
      .
      MAP, mean arterial pressure; PRA, plasma renin activity; NE, plasma norepinephrine concentration.
      In 1999 we reported the use of HSA (1.5 g/kg b.wt. at infection diagnosis and 1 g/kg b.wt. at the third day) in SBP [
      • Sort P.
      • Navasa M.
      • Arroyo V.
      • Aldeguer X.
      • Planas R.
      • Ruiz-del-Arbol L.
      • et al.
      Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.
      ]. HSA prevented cardiovascular dysfunction and this was associated with a dramatic decrease in the prevalence of type 1 HRS and hospital mortality (10% in the HSA group and 30% in the control group). A recent meta-analysis has confirmed these findings [
      • Salerno F.
      • Navickis R.J.
      • Wilkes M.M.
      Albumin infusion improves outcomes of patients with spontaneous bacterial peritonitis: a meta-analysis of randomized trials.
      ].

      Treatment of type-1 HR

      The use of vasopressin analogs and HSA for the treatment of type-1 HRS was based on two features. First, arterial vasodilation in cirrhosis occurs in the splanchnic circulation and vasopressin analogs act preferentially in this area [
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodés J.
      Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      ]. Second, studies using head-out water immersion, a procedure that expands the central blood volume, and vasoconstrictors showed that improvement in renal function in cirrhosis only occurs when both procedures are applied simultaneously [
      • Shapiro M.D.
      • Nicholls K.M.
      • Groves B.M.
      • Kluge R.
      • Chung H.M.
      • Bichet D.G.
      • et al.
      Interrelationship between cardiac output and vascular resistance as determinants of effective arterial blood volume in cirrhotic patients.
      ]. In our first study we used ornipressin and HSA [1 g/kg b.wt. on the first day followed by 20 to 40 g/day] [
      • Guevara M.
      • Ginès P.
      • Fernández-Esparrach G.
      • Sort P.
      • Salmerón J.M.
      • Jiménez W.
      • et al.
      Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion.
      ]. A remarkably improvement in circulatory function was observed with rapid suppression of the renin-angiotensin and sympathetic nervous systems, progressive normalization in serum creatinine and increase in renal perfusion and GFR (Table 3). Because treatment was associated with ischemic events in some patients, the study was repeated using i.v. terlipressin (1–2 mg/4–6 h) with identical results but no ischemic complications [
      • Uriz J.
      • Ginès P.
      • Cárdenas A.
      • Sort P.
      • Jiménez W.
      • Salmerón J.M.
      • et al.
      Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome.
      ].
      Table 3Cardiovascular hemodynamics in 8 patients developing HRS after spontaneous bacterial peritonitis.
      Obtained from
      • Ruiz-del-Arbol L.
      • Urman J.
      • Fernández J.
      • González M.
      • Navasa M.
      • Monescillo A.
      • et al.
      Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis.
      .
      Mean time elapsed between measurement was 6 days.
      BUN, blood urea nitrogen; MAP, mean arterial pressure; PRA, plasma renin activity; NE, plasma norepinephrine concentration; SVR, systemic vascular resistance; CO, cardiac output; RAP, right atrial pressure; PCWP, pulmonary capillary wedged pressure; HR, heart rate.
      Many studies have been subsequently published on the use of terlipressin and albumin for HRS and their main conclusions are the following: (1) Terlipressin plus HSA reverses type-1 HRS (serum creatinine <1.5 mg/dl) in 40–65% of patients [
      • Ginès P.
      • Cárdenas A.
      • Arroyo V.
      • Rodés J.
      Management of cirrhosis and ascites.
      ,
      • Garcia-Tsao G.
      • Lim J.K.
      Members of Veterans Affairs Hepatitis C Resource Center Program. Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program.
      ,
      • Ginès P.
      • Angeli P.
      • Lenz K.
      • Møller S.
      • Moore K.
      • Moreau R.
      • et al.
      EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis.
      ]. In less than 20% of responders type-1 HRS recurs after discontinuation of treatment but it may reverse again following retreatment. (2) The rate of response may increase if terlipressin is given by continuous infusion [
      • Angeli P.
      • Fasolato S.
      • Cavallin M.
      • Trotta E.
      • Maresio G.
      • Callegaro A.
      • et al.
      Terlipressin given as continuous intravenous infusion vs. terlipressin given as intravenous boluses in the treatment of type 1 hepatorenal syndrome (HRS) in patients with cirrhosis.
      ]. (3) Predictors of response include low baseline serum creatinine (<5 mg/dl) and bilirubin (<10 mg/dl), and increase in mean arterial pressure (>5 mm/Hg) within the first 3 days of treatment [
      • Boyer T.D.
      • Sanyal A.J.
      • Garcia-Tsao G.
      • Blei A.
      • Carl D.
      • Bexon A.S.
      • et al.
      Predictors of response to terlipressin plus albumin in hepatorenal syndrome (HRS) type 1: relationship of serum creatinine to hemodynamics.
      ,
      • Velez J.C.
      • Nietert P.J.
      Therapeutic response to vasoconstrictors in hepatorenal syndrome parallels increase in mean arterial pressure: a pooled analysis of clinical trials.
      ,
      • Nazar A.
      • Pereira G.H.
      • Guevara M.
      • Martín-Llahi M.
      • Pepin M.N.
      • Marinelli M.
      • et al.
      Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type 1 hepatorenal syndrome.
      ]. (4) Reversal of HRS is associated with improvement in survival [
      • Moreau R.
      • Durand F.
      • Poynard T.
      • Duhamel C.
      • Cervoni J.P.
      • Ichaï P.
      • et al.
      Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study.
      ,
      • Arroyo V.
      • Fernández J.
      Management of hepatorenal syndrome in patients with cirrhosis.
      ]. (5) Noradrenaline is as effective as terlipressin [
      • Alessandria C.
      • Ottobrelli A.
      • Debernardi-Venon W.
      • Todros L.
      • Cerenzia M.T.
      • Martini S.
      • et al.
      Noradrenalin vs. terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study.
      ,
      • Sharma P.
      • Kumar A.
      • Shrama B.C.
      • Sarin S.K.
      An open label, pilot, randomized controlled trial of noradrenaline vs. terlipressin in the treatment of type 1 hepatorenal syndrome and predictors of response.
      ,
      • Singh V.
      • Ghosh S.
      • Singh B.
      • Kumar P.
      • Sharma N.
      • Bhalla A.
      • et al.
      Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: a randomized study.
      ]. (6) Reversal of type 1 HRS is significantly lower if terlipressin is given without HSA [
      • Ortega R.
      • Ginès P.
      • Uriz J.
      • Cárdenas A.
      • Calahorra B.
      • De Las Heras D.
      • et al.
      Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study.
      ]. (7) Type-1 HRS may reverse with HSA alone [
      • Martín-Llahí M.
      • Pépin M.N.
      • Guevara M.
      • Díaz F.
      • Torre A.
      • Monescillo A.
      • et al.
      Terlipressin and albumin vs. albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study.
      ,
      • Sanyal A.J.
      • Boyer T.
      • Garcia-Tsao G.
      • Regenstein F.
      • Rossaro L.
      • Appenrodt B.
      • et al.
      A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome.
      ,
      • Péron J.M.
      • Bureau C.
      • Gonzalez L.
      • Garcia-Ricard F.
      • de Soyres O.
      • Dupuis E.
      • et al.
      Treatment of hepatorenal syndrome as defined by the international ascites club by albumin and furosemide infusion according to the central venous pressure: a prospective pilot study.
      ]. (8) Patients with ongoing bacterial infections should be treated as soon as type-1 HRS is diagnosed [
      • Rodríguez E.
      • Elia C.
      • Solà E.
      • Barreto R.
      • Graupera I.
      • Andrealli A.
      • et al.
      Terlipressin and albumin for type-1 hepatorenal syndrome associated with sepsis.
      ]. (9) Treatment is not indicated in type-2 HRS because HRS recurrence is the rule [
      • Alessandria C.
      • Venon W.D.
      • Marzano A.
      • Barletti C.
      • Fadda M.
      • Rizzetto M.
      Renal failure in cirrhotic patients: role of terlipressin in clinical approach to hepatorenal syndrome type 2.
      ].

      Other potential indications for albumin in cirrhosis

      There are four studies assessing long-term administration of HSA in cirrhosis with ascites. The rationale behind these investigations is that long-term improvement of circulatory function may prevent acute complications of cirrhosis, including recurrence of ascites, HRS, encephalopathy, and bacterial infections. The first investigation was a comparative study in 17 patients, 9 receiving between 184 to 558 g of HSA within 6 months [
      • Tarao K.
      • Iwamura K.
      Influence of long-term administration of serum albumin on the prognosis of liver cirrhosis in man.
      ]. All patients in the HSA group survived for more than 2 years. In the control group mortality rate was 30%. The second study was a randomized controlled trial (RCT) in 126 patients hospitalized for ascites [
      • Gentilini P.
      • Casini-Raggi V.
      • Di Fiore G.
      • Romanelli R.G.
      • Buzzelli G.
      • Pinzani M.
      • et al.
      Albumin improves the response to diuretics in patients with cirrhosis and ascites: results of a randomized, controlled trial.
      ]. Half of the patients received diuretics and half diuretics plus HSA [12.5 g/day during hospitalization, 25 g/week during the first year and 25 g/2 weeks during the second and third year]. Cumulative incidence of acute complications and hospital admission was significantly lower in patients receiving albumin. There were no significant differences in survival. Two other studies are still ongoing. The MUCH study (ClinicalTrials.gov, Identifier: NTC00839358) is a RCT comparing standard therapy vs. standard therapy, HSA (40 g every 2 weeks) and midodrine (an oral α-adrenergic agonist) in 190 patients with ascites. The main end-points of the study are incidence of complications and survival. The ANSWER study (ClinicalTrials.gov, Identifier: NTC01288794) is a RCT in 400 patients with ascites comparing standard therapy vs. standard therapy plus HSA (40 g twice weekly in the first two weeks and once weekly for one year). The main end points are mortality and incidence of refractory ascites.
      Figure thumbnail fx4

      Chemistry and physiology of HSA

      Molecular structure and chemical properties

      HSA is a multi-domain protein stabilized by 17 disulfide bonds that confer a remarkable stability to its structure [
      • He X.M.
      • Carter D.C.
      Atomic structure and chemistry of human serum albumin.
      ]. In addition to the 34 cysteine residues involved in disulfide bonds HSA also possesses a free cysteine (Cys-34) that is relatively solvent-exposed (Fig. 2) and plays an important role in its antioxidant activity [
      • Oettl K.
      • Birner-Gruenberger R.
      • Spindelboeck W.
      • Stueger H.P.
      • Dorn L.
      • Stadlbauer V.
      Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity, liver dysfunction and survival.
      ,
      • Anraku M.
      • Chuang V.T.G.
      • Maruyama T.
      • Otagiri M.
      Redox properties of serum albumin.
      ]. The structure of HSA at low resolution (6 Å) was first solved in 1989 [
      • Carter D.C.
      • He X.M.
      • Munson S.H.
      • Twigg P.D.
      • Gernert K.M.
      • Broom M.B.
      • et al.
      Three-dimensional structure of human serum albumin.
      ] and a high resolution atomic structure (2.8 Å) was reported in 1992 [
      • He X.M.
      • Carter D.C.
      Atomic structure and chemistry of human serum albumin.
      ]. These revealed this protein to be composed of three domains of similar size (residues 1–197, 198–381, and 381–585) arranged in a heart shape and formed by eight α-helices. Owing to their structural similarity the domains can be divided in sub-domains (IA, IB, IIA, IIB, IIIA, and IIIB) that have functional relevance as they define the binding sites of many HSA ligands (Fig. 2) [
      • Bhattacharya A.A.
      • Grüne T.
      • Curry S.
      Crystallographic analysis reveals common modes of binding of medium and long-chain fatty acids to HSA.
      ].
      Figure thumbnail gr2
      Fig. 2Molecular structure of human serum albumin. Crystal structure (pdb code 1e7i) of HSA with an indication of the its subdomains (IA, IB, IIA, IIB, IIIA an IIIB), of the N and C termini, of Sudlow’s sites I and II and of the seven LCFA binding sites (FA1 to FA7). The heavy atoms of the side chain of residue Cys-34 are shown as purple spheres. LCFA binding sites also bind prostaglandins. Cys-34 binds ROS and RNS, including NO
      [
      • Bhattacharya A.A.
      • Grüne T.
      • Curry S.
      Crystallographic analysis reveals common modes of binding of medium and long-chain fatty acids to HSA.
      ]
      .
      Due to the presence of a substantial number of intra-domain disulfide bonds the domains of HSA have significant stability. Domains I and III are particularly stable and a construct containing domains I and II [1–381] as well as a construct containing domains II and III [198–585] fold autonomously by adopting the same structure that they have in the full-length protein [
      • Mao H.
      • Gunasekera A.H.
      • Fesik S.W.
      Expression, refolding, and isotopic labeling of human serum albumin domains for NMR spectroscopy.
      ,
      • Milojevic J.
      • Melacini G.
      Stoichiometry and affinity of the human serum albumin-Alzheimer’s Aβ peptide interactions.
      ]. In spite of its large size and owing to its remarkable stability and its relatively simple structure, where residues that are connected by disulfides or in contact are not particularly distant in sequence, HSA can be refolded from the fully reduced state unassisted by molecular chaperones [
      • Burton S.J.
      • Quirk A.V.
      • Wood P.C.
      Refolding human serum albumin at relatively high protein concentration.
      ,
      • Chen Z.
      • He Y.
      • Shi B.
      • Yang D.
      Human serum albumin from recombinant DNA technology: challenges and strategies.
      ]. This greatly facilitates its synthesis in the laboratory and the study of its structural and biophysical properties [
      • Mao H.
      • Gunasekera A.H.
      • Fesik S.W.
      Expression, refolding, and isotopic labeling of human serum albumin domains for NMR spectroscopy.
      ].
      Again owing to its relatively simple structure and modular nature HSA appears to be a very flexible protein. According to various experimental approaches the heart shape that the protein adopts in the crystal is likely to be only one in the range of inter-domain orientations that HSA samples show in solution. Experiments monitoring the rate of exchange between exchangeable hydrogens and water have shown these to be particularly labile, indicating that in addition to inter-domain motions HSA undergoes local unfolding events where the hydrogen bonds that stabilize its secondary structure are transiently disrupted [
      • Hvidt A.
      • Wallevik K.
      Conformational changes in human serum albumin as revealed by hydrogen-deuterium exchange studies.
      ].
      Many of the physiological functions of HSA rely on its ability to reversibly bind to an extremely wide range of ligands to increase their solubility in plasma, to transport them to specific tissues or organs or to dispose of them when they are toxic. The structures of HSA bound to various of these substrates have been determined by X-ray crystallography, revealing that on many occasions the protein must experience substantial structural changes to accommodate the ligand and therefore strongly suggesting a functional role for its high flexibility. Although many binding sites for ligands have been reported in HSA the most important sites are commonly known as Sudlow’s sites I and II (Fig. 2) which are found in subdomains IIA and IIIA, respectively.
      Long chain fatty acids (LCFAs) are intermediates in lipid metabolism that circulate in plasma both in soluble form as well as associated with HSA. According to crystallographic studies they can bind up to seven sites in HSA (FA1 to FA7) including both Sudlow’s sites, with site I corresponding to FA7 and site II corresponding to FA3 and FA4 [
      • Bhattacharya A.A.
      • Grüne T.
      • Curry S.
      Crystallographic analysis reveals common modes of binding of medium and long-chain fatty acids to human serum albumin.
      ]. It is however likely that many of these sites are secondary and therefore do not play an important role in LCFA binding in physiological conditions, where it is thought that up to two LCFA molecules, bound to Sudlow’s site I, are bound to HSA at a given time.
      Drugs such as warfarin, indomethacin, ibuprofen, diazepam are another heavily studied class of HSA ligands. Similarly to what is the case for LCFAs these molecules can bind to various sites in HSA and, although they tend to mainly interact with Sudlow’s sites I and II, this can vary depending on the relative concentration of competing ligands and on the allosteric effects discussed below [
      • Ghuman J.
      • Zunszain P.A.
      • Petitpas I.
      • Bhattacharya A.A.
      • Otagiri M.
      • Curry S.
      Structural basis of the drug-binding specificity of human serum albumin.
      ]. That these and other drugs can compete for HSA binding sites for their transport in plasma emphasizes the importance of understanding the physicochemical basis of their interaction with HSA [
      • Yamasaki K.
      • Chuang V.T.G.
      • Maruyama T.
      • Otagiri M.
      Albumin-drug interaction and its clinical implication.
      ].
      Given that HSA is a flexible protein that can bind to various substrates in different sites there have been suggestions that it is an allosteric protein, i.e., that its affinity for specific ligands can depend on whether a second ligand is occupying a different binding site. Specific examples of such a behavior, among others, include an allosteric coupling between the binding sites of heme that binds to FA1 in sub-domain IB, and the drug warfarin, that binds to Sudlow’s site I [
      • Fanali G.
      • Pariani G.
      • Ascenzi P.
      • Fasano M.
      Allosteric and binding properties of Asp1-Glu382 truncated recombinant human serum albumin – an optical and NMR spectroscopic investigation.
      ]. The structural, dynamical, and thermodynamic coupling between domains occurring in HSA is highly suggestive of this possibility as these are sufficient conditions to give rise to allosteric binding [
      • Hilser V.J.
      • Thompson E.B.
      Structural dynamics, intrinsic disorder, and allostery in nuclear receptors as transcription factors.
      ].
      Given its high stability HSA has a long half-life in plasma, of about 19 days [
      • Peters Jr., T.
      All about albumin. Biochemistry and medical applications.
      ]. During this relatively long time its chemical structure can be altered by oxidation as well as by non-enzymatic glycosylation, among other irreversible modifications. The accumulation of chemically altered HSA has been linked to specific pathologies such as cirrhosis [
      • Jalan R.
      • Schnurr K.
      • Mookerjee R.P.
      • Sen S.
      • Cheshire L.
      • Hodges S.
      • et al.
      Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality.
      ] and diabetes [
      • Furusyo N.
      • Hayashi J.
      Glycated albumin and diabetes mellitus.
      ]. The highly flexible nature of this protein and the growing body of evidence, suggesting that the various binding sites that contribute to HSA function are strongly coupled, suggests that such chemical alterations can have functional consequences. In this scenario the oxidation or glycosylation of specific positions in the surface of HSA would cause structural changes that could propagate to different regions of structure either by concerted conformational changes or through local changes in the stability known to give rise to long range effects in simpler systems.
      Figure thumbnail fx5

      Physiology

      Synthesis and metabolism

      Albumin is synthesized by the liver and rapidly released to the intravascular compartment [
      • Peters Jr., T.
      All about albumin. Biochemistry and medical applications.
      ]. The total amount of albumin in humans is approximately 360 g, 120 being in the intravascular and 240 in the extravascular compartment. Intravascular albumin is constantly being exchanged (4–5%/h) through the endothelium with the extravascular pool. In organs having sinusoids or capillaries with fenestrated endothelium albumin can pass through the large capillary gaps. In the remaining capillaries with continuous endothelium, albumin is transported by an active transcytotic mechanism mediated by the gp60 receptor (albondin) [
      • Schnitzer J.E.
      • Oh P.
      Albondin-mediated capillary permeability to albumin. Differential role of receptors in endothelial transcytosis and endocytosis of native and modified albumins.
      ,
      • Minshall R.D.
      • Tiruppathi Ch.
      • Vogel S.M.
      • Malik A.B.
      Vesicle formation and trafficking in endothelial cells and regulation of endothelial barrier function.
      ,
      • Malik A.B.
      Targeting endothelial cell surface receptors: novel mechanisms of microvascular endothelial barrier transport.
      ,
      • Sleep D.
      • Cameron J.
      • Evans L.R.
      Albumin as a versatile platform for drug half-life extension.
      ]. There is a second group of receptors (gp18 and gp30) expressed in many tissues that governs degradation of albumin [
      • Sleep D.
      • Cameron J.
      • Evans L.R.
      Albumin as a versatile platform for drug half-life extension.
      ,
      • Ghinea N.
      • Fixman A.
      • Alexandru D.
      • Popov D.
      • Hasu M.
      • Ghitescu L.
      Identification of albumin-binding proteins in capillary endothelial cells.
      ,
      • Schnitzer J.E.
      • Sung A.
      • Horvat R.
      • Bravo J.
      Preferential interaction of albumin-binding proteins, gp30 and gp18, with conformationally modified albumins. Presence in many cells and tissues with a possible role in catabolism.
      ,
      • Schnitzer J.E.
      • Bravo J.
      High affinity binding, endocytosis, and degradation of conformationally modified albumins. Potential role of gp30 and gp18 as novel scavenger receptors.
      ]. These surface cell receptors shows 1000-fold higher affinity for chemically modified albumin (i.e., oxidized albumin). Once internalized, this modified albumin is degraded. Finally, a third type of albumin receptor (FcRn) that rescues albumin from lysosomal degradation contributes to extend the albumin half life [
      • Sleep D.
      • Cameron J.
      • Evans L.R.
      Albumin as a versatile platform for drug half-life extension.
      ,
      • Andersen J.T.
      • Daba M.B.
      • Berntzen G.
      • Michaelsen T.E.
      • Sandlie I.
      Cross-species binding analyses of mouse and human neonatal Fc receptor show dramatic differences in immunoglobulin G and albumin binding.
      ,
      • Andersen J.T.
      • Pehrson R.
      • Tolmachev V.
      • Daba M.B.
      • Abrahmsén L.
      • Ekblad C.
      Extending half-life by indirect targeting of the neonatal Fc receptor (FcRn) using a minimal albumin binding domain.
      ,
      • Smith B.J.
      • Popplewell A.
      • Athwal D.
      • Chapman A.P.
      • Heywood S.
      • Shauna M.
      • et al.
      Prolonged in vivo residence times of antibody fragments associated with albumin.
      ].

      Physiology

      The effects of HSA rely in the following features: an appropriated molecular mass and negative charge generate high oncotic pressure; a high solubility in water and density of binding sites make the protein an ideal vehicle to transport water-insoluble substances; the effects of active exogenous and endogenous substances are modulated following binding to HSA; the high extracellular concentration of HSA magnified its biological actions.
      Among the substances transported, fatty acids stand up. HSA is the main fatty acid binding protein in the extracellular space. It carries fatty acids from the intestines to the liver and from the liver to muscle and to and from adipose tissues [
      • Fujiwara S.
      • Amisaki T.
      Fatty acid binding to serum albumin: molecular simulation approaches.
      ,
      • Van der Vusse G.J.
      Albumin as fatty acid transporter.
      ]. Transportation of unconjugated bilirubin from the spleen or bone marrow to the liver is the best example of albumin transportation of a water insoluble endogenous metabolite to its elimination site [
      • Petersen C.E.
      • Ha C.E.
      • Harohalli K.
      • Feix J.B.
      • Bhagavan N.V.
      A dynamic model for bilirubin binding to human serum albumin.
      ]. Other endogenous substances that bind to albumin are the eicosanoids, bile acids, steroids, hematin, tiroxin, vitamin D, and folate [
      • Peters Jr., T.
      All about albumin. Biochemistry and medical applications.
      ,
      • Ha C.E.
      • Bhagavan N.V.
      Novel insights into the pleiotropic effects of human serum albumin in health and disease.
      ]. Among the exogenous molecules transported by albumin there is a wide variety of drugs [
      • Peters Jr., T.
      All about albumin. Biochemistry and medical applications.
      ,
      • Yamasaki K.
      • Chuang V.T.G.
      • Maruyama T.
      • Otagiri M.
      Albumin-drug interaction and its clinical implication.
      ,
      • Wang Z.M.
      • Ho J.X.
      • Ruble J.R.
      • Rose J.
      • Rüker F.
      • Ellenburg M.
      • et al.
      Structural studies of several clinically important oncology drugs in complex with human serum albumin.
      ]. In addition to drug solubility, albumin binding decreases toxicity and increases drug half-life [
      • Yamasaki K.
      • Chuang V.T.G.
      • Maruyama T.
      • Otagiri M.
      Albumin-drug interaction and its clinical implication.
      ]. Drug binding to HSA can be affected by other drugs that compete with specific sites in the molecule. As a consequence, an increase in the free fraction may lead to changes in pharmacokinetics and pharmacodynamics. Drug-albumin binding may be also altered in diseased states, including liver and renal diseases [
      • Oettl K.
      • Birner-Gruenberger R.
      • Spindelboeck W.
      • Stueger H.P.
      • Dorn L.
      • Stadlbauer V.
      Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity, liver dysfunction and survival.
      ,
      • Klammt S.
      • Wojak H.J.
      • Mitzner A.
      • Koball S.
      • Rychly J.
      • Reisinger E.C.
      • et al.
      Albumin-binding capacity (ABiC) is reduced in patients with chronic kidney disease along with an accumulation of protein-bound uraemic toxins.
      ,
      • Klammt S.
      • Mitzner S.
      • Stange J.
      • Brinkmann B.
      • Drewelow B.
      • Emmrich J.
      • et al.
      Albumin-binding function is reduced in patients with decompensated cirrhosis and correlates inversely with severity of liver disease assessed by model for end-stage liver disease.
      ], due to the increase in endogenous substances that compete for binding sites, but pharmacokinetic consequences of this does rarely cause important effects [
      • Fanali G.
      • di Massi A.
      • Trezza V.
      • Marino M.
      • Fasano M.
      • Ascenzi P.
      Human serum albumin: from bench to bedside.
      ,
      • Smith D.A.
      • Di L.
      • Kerns E.H.
      The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery.
      ].
      An outstanding feature of HSA is its capacity to bind pro-inflammatory substances and mediators of inflammation. Lipopolysaccharide (LPS), lipoteichoic acid, and peptidoglycan are surface components of gram-negative and gram-positive bacteria that activate the innate immune system through Toll-like receptor 4 (TLR4) and induce inflammation. HSA binds these molecules by electrostatic and hydrofobic forces [
      • Jurgens G.
      • Muller M.
      • Garidel P.
      • Koch M.H.
      • Nakakubo H.
      • Blume A.
      • et al.
      Investigation into the interaction of recombinant human serum albumin with Re-lipopolysaccharide and lipid A.
      ,
      • Fukui H.
      Relation of endotoxin, endotoxin binding proteins and macrophages to severe alcoholic liver injury and multiple organ failure.
      ,
      • Dziarski R.
      Cell-bound albumin is the 70-kDa peptidoglycan-, lipopolysaccharide-, and lipoteichoic acid-binding protein on lymphocytes and macrophages.
      ,
      • David S.A.
      • Balaram P.
      • Mathan V.I.
      Characterization of the interaction of lipid A and lipopolysaccharide with human serum albumin: implications for an endotoxin carrier function for albumin.
      ]. Cell activation by LPS requires an ordered interaction with several host proteins including LPS-binding protein, CD14 and co-receptor MD-2. Recent studies showed that albumin may also participate in LPS presentation to TLR4 facilitating disaggregation of LPS-Lipid A polymers and donation of monomers to CD14 [
      • Gioannini T.L.
      • Zhang D.
      • Teghanemt A.
      • Weiss J.P.
      An essential role for albumin in the interaction of endotoxin with lipopolysaccharide-binding protein and sCD14 and resultant cell activation.
      ,
      • Blomkalns A.L.
      • Stoll L.L.
      • Shaheen W.
      • Romig-Martin S.A.
      • Dickson E.W.
      • Weintraub N.L.
      • et al.
      Low level bacterial endotoxin activates two distinct signaling pathways in human peripheral blood mononuclear cells.
      ,
      • Esparza G.A.
      • Teghanemt A.
      • Zhang D.
      • Gioannini T.L.
      • Weiss J.P.
      Endotoxin{middle dot}albumin complexes transfer endotoxin monomers to MD-2 resulting in activation of TLR4.
      ]. This suggests that albumin promotes the inflammatory response. In contrast, LPS-albumin complexes are much less effective in immune activation than endotoxin-CD14 complexes [
      • Esparza G.A.
      • Teghanemt A.
      • Zhang D.
      • Gioannini T.L.
      • Weiss J.P.
      Endotoxin{middle dot}albumin complexes transfer endotoxin monomers to MD-2 resulting in activation of TLR4.
      ]. Giving the abundance of albumin and the lower relative cell activation capacity of the LPS-albumin complex, albumin could play a role in moderating the inflammatory response to bacterial infections. Therefore, albumin could play a dual role either stimulating or moderating immune cells activation depending on pathophysiological conditions [
      • Gioannini T.L.
      • Zhang D.
      • Teghanemt A.
      • Weiss J.P.
      An essential role for albumin in the interaction of endotoxin with lipopolysaccharide-binding protein and sCD14 and resultant cell activation.
      ,
      • Esparza G.A.
      • Teghanemt A.
      • Zhang D.
      • Gioannini T.L.
      • Weiss J.P.
      Endotoxin{middle dot}albumin complexes transfer endotoxin monomers to MD-2 resulting in activation of TLR4.
      ].
      Systemic inflammatory response can be triggered by antigens derived from bacteria (Pathogens-Associated Molecular Patterns, PAMPs) or by intrinsic factors released into the circulation as a result of trauma or cell injury (Damaged Associated Molecular Patterns, DAMPs). Specialized receptors of the innate immune system recognized these factors and release inflammatory mediators among which cytokines, and reactive oxygen (ROS) and nitrogen species (RNS) are the most important [
      • Takeuchi O.
      • Akira S.
      Pattern recognition receptors and inflammation.
      ,
      • Chan J.K.
      • Roth J.
      • Oppenheim J.J.
      • Tracey K.J.
      • Vogl T.
      • Feldmann M.
      • et al.
      Alarmins: awaiting a clinical response.
      ]. Generation of ROS and RNS (superoxide, nitric oxide, hydrogen peroxide, hydroxyl radical, peroxynitrite, hypochlorous acid, nitrogen dioxide radical, hydroperoxide radical, and peroxyl radical) by neutrophils, macrophages, and endothelial cells, which represent the innate immune system, is the first line of defense against sepsis [
      • Singer M.
      The role of mitochondrial dysfunction in sepsis-induced multi-organ failure.
      ,
      • Galley H.F.
      Oxidative stress and mitochondrial dysfunction in sepsis.
      ,
      • Galley H.F.
      Bench-to-bedside review: targeting antioxidants to mitochondria in sepsis.
      ]. The aim of the modification of the redox state in plasma and extracellular fluid is to destroy the bacteria by energy depletion and oxidative damage of lipids, proteins, and DNA. This extracellular oxidative “burst” however may be transferred into mitochondria leading to cell dysfunction and organ failure [
      • Singer M.
      The role of mitochondrial dysfunction in sepsis-induced multi-organ failure.
      ]. Extracellular fluid and the mitochondria dispose of antioxidant systems to prevent excessive oxidative damage [
      • Singer M.
      The role of mitochondrial dysfunction in sepsis-induced multi-organ failure.
      ,
      • Galley H.F.
      Oxidative stress and mitochondrial dysfunction in sepsis.
      ,
      • Galley H.F.
      Bench-to-bedside review: targeting antioxidants to mitochondria in sepsis.
      ]. HSA is the main extracellular defense against oxidative stress. It provides 80% of extracellular thiols, which are potent scavengers of ROS and RNS [
      • Carter D.C.
      • He X.M.
      • Munson S.H.
      • Twigg P.D.
      • Gernert K.M.
      • Broom M.B.
      • et al.
      Three-dimensional structure of human serum albumin.
      ,
      • Taverna M.
      • Marie A.L.
      • Mira J.P.
      • Guidet B.
      Specific antioxidant properties of human serum albumin.
      ,
      • Bruschi M.
      • Candiano G.
      • Santucci L.
      • Ghiggeri G.M.
      Oxidized albumin. The long way of a protein of uncertain function.
      ]. The glutathione system is the most abundant mitochondrial antioxidant. Intracellular albumin catabolism represents a source of sulfur-containing amino acids for the synthesis of glutathione. Albumin therefore modulates the intracellular levels of this antioxidant system [
      • Cantin A.M.
      • Paquette B.
      • Richter M.
      • Larivée P.
      Albumin-mediated regulation of cellular glutathione and nuclear factor kappa B activation.
      ].
      Two mechanisms account for the antioxidant effect of HSA. The first is related to its capacity to bind and inactivate free metals such as cooper and iron, which catalyse the formation of aggressive ROS [
      • Bal W.
      • Sokołowska M.
      • Kurowska E.
      • Faller P.
      Binding of transition metal ions to albumin: sites, affinities and rates.
      ,
      • Stohs S.J.
      • Bagchi D.
      Oxidative mechanisms in the toxicity of metal ions.
      ]. HSA-bound bilirubin inhibits lipid peroxidation and represents an indirect antioxidant effect [
      • Neuzil J.
      • Stocker R.
      Free and albumin-bound bilirubin are efficient co-antioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation.
      ]. The second and most important mechanism is related to the capacity of HSA to trap free radicals. Two-thirds of the HSA molecules exist in a reduced form with a free thiol group in the Cys-34 residue. Working as a free radical scavenger, the Cys-34 residue is able to trap multiple ROS and RNS [
      • Carter D.C.
      • He X.M.
      • Munson S.H.
      • Twigg P.D.
      • Gernert K.M.
      • Broom M.B.
      • et al.
      Three-dimensional structure of human serum albumin.
      ,
      • Bruschi M.
      • Candiano G.
      • Santucci L.
      • Ghiggeri G.M.
      Oxidized albumin. The long way of a protein of uncertain function.
      ]. As indicated, in physiological conditions the Cys-34 residue exists in two different forms, namely human-mercapto-albumin (HMA; reduced) in which the thiol group is in the free state and human non-mercapto albumin (NMA; oxidized) [
      • Carter D.C.
      • He X.M.
      • Munson S.H.
      • Twigg P.D.
      • Gernert K.M.
      • Broom M.B.
      • et al.
      Three-dimensional structure of human serum albumin.
      ,
      • Bruschi M.
      • Candiano G.
      • Santucci L.
      • Ghiggeri G.M.
      Oxidized albumin. The long way of a protein of uncertain function.
      ,
      • Bourdon E.
      • Loreau N.
      • Lagrost L.
      • Blache D.
      Differential effects of cysteine and methionine residues in the antioxidant activity of human serum albumin.
      ]. In this later form the thiol group may be present as a disulfide that is formed reversibly with Cys or glutathione or as sulfinic or sulfonic acid that is formed irreversibly. Irreversible albumin oxidation is associated with a loss of function and rapid degradation. Cys-34 is a good indicator for evaluating oxidative stress in the systemic circulation [
      • Carter D.C.
      • He X.M.
      • Munson S.H.
      • Twigg P.D.
      • Gernert K.M.
      • Broom M.B.
      • et al.
      Three-dimensional structure of human serum albumin.
      ,
      • Bruschi M.
      • Candiano G.
      • Santucci L.
      • Ghiggeri G.M.
      Oxidized albumin. The long way of a protein of uncertain function.
      ]. HSA contains six methionine residues which can also be oxidized [
      • Bourdon E.
      • Loreau N.
      • Lagrost L.
      • Blache D.
      Differential effects of cysteine and methionine residues in the antioxidant activity of human serum albumin.
      ,
      • Berlett B.S.
      • Stadtman E.R.
      Protein oxidation in aging, disease, and oxidative stress.
      ].
      Under nitrosative stress by nitric oxide (NO) or other nitrosylating agents, mercaptalbumin can be converted in nitroso-HSA. This is a reversible reaction, so that NO can be transferred to other molecules [
      • Oettl K.
      • Marsche G.
      Redox state of human serum albumin in terms of cysteine-34 in health and disease.
      ,
      • Rafikova O.
      • Rafikov R.
      • Nudler E.
      Catalysis of S-nitrosothiols formation by serum albumin: the mechanism and implication in vascular control.
      ]. HSA also binds arachidonic acid, prostaglandins, thomboxanes, and leukotrienes [
      • Fitzpatrick F.A.
      • Liggett W.F.
      • Wynalda M.A.
      Albumin-eicosanoid interactions. A model system to determine their attributes and inhibition.
      ,
      • Kragh-Hansen U.
      Molecular and practical aspects of the enzymatic properties of human serum albumin and of albumin-ligand complexes.
      ,
      • Yang J.
      • Petersen C.E.
      • Ha C.E.
      • Bhagavan N.V.
      Structural insights into human serum albumin-mediated prostaglandin catalysis.
      ,
      • Wynalda M.A.
      • Fitzpatrick F.A.
      Albumins stabilize prostaglandin I2.
      ,
      • Folco G.
      • Granström E.
      • Kindahl H.
      Albumin stabilizes thromboxane A2.
      ]. HSA has two-sided effects on eicosanoids. In some cases the protein, which has intrinsic enzymatic activity, catalyzes their synthesis or degradation. In others (i.e., PGI2, thromboxanes, and leukotrienes) it stabilizes the molecule by delaying hydrolysis. HSA, therefore, functions as storage, carrier, and supplier of NO and eicosanoids to target sites to initiate physiological actions (vasodilation and inhibition of platelet aggregation) and as protector agents to diminish harmful biological effects if produced in too large amounts. By these mechanisms HSA modulates endothelial function and inflammation.

      Decompensated cirrhosis is associated with systemic inflammation

      Three major features characterize decompensated cirrhosis. The first is multi-organ dysfunction. The second is a systemic inflammatory reaction with increased plasma and ascitic fluid concentration of cytokines and C-reactive protein (CRP) [
      • Le Moine O.
      • Soupison T.
      • Sogni P.
      • Marchant A.
      • Moreau R.
      • Hadengue A.
      • et al.
      Plasma endotoxin and tumor necrosis factor-alpha in the hyperkinetic state of cirrhosis.
      ,
      • Bac D.J.
      • Pruimboom W.M.
      • Mulder P.G.
      • Zijlstra F.J.
      • Wilson J.H.
      High interleukin-6 production within the peritoneal cavity in decompensated cirrhosis and malignancy-related ascites.
      ,
      • Odeh M.
      • Sabo E.
      • Srugo I.
      • Oliven A.
      Serum levels of tumor necrosis factor-alpha correlate with severity of hepatic encephalopathy due to chronic liver failure.
      ,
      • Lee F.Y.
      • Lu R.H.
      • Tsai Y.T.
      • Lin H.C.
      • Hou M.C.
      • Li C.P.
      • et al.
      Plasma interleukin-6 levels in patients with cirrhosis. Relationship to endotoxemia, tumor necrosis factor-alpha, and hyperdynamic circulation.
      ,
      • Li C.P.
      • Lee F.Y.
      • Tsai Y.T.
      • Lin H.C.
      • Lu R.H.
      • Hou M.C.
      • et al.
      Plasma interleukin-8 levels in patients with post-hepatitic cirrhosis: relationship to severity of liver disease, portal hypertension and hyperdynamic circulation.
      ,
      • Tilg H.
      • Wilmer A.
      • Vogel W.
      • Herold M.
      • Nölchen B.
      • Judmaier G.
      • et al.
      Serum levels of cytokines in chronic liver diseases.
      ,
      • Genesca J.
      • Gonzalez A.
      • Segura R.
      • Catalan R.
      • Marti R.
      • Varela E.
      • et al.
      Interleukin-6, nitric oxide, and the clinical and hemodynamic alterations of patients with liver cirrhosis.
      ,
      • Jain L.
      • Sharma B.C.
      • Sharma P.
      • Srivastava S.
      • Agrawal A.
      • Sarin S.K.
      Serum endotoxin and inflammatory mediators in patients with cirrhosis and hepatic encephalopathy.
      ,
      • Montoliu C.
      • Piedrafita B.
      • Serra M.A.
      • del Olmo J.A.
      • Urios A.
      • Rodrigo J.M.
      • et al.
      IL-6 and IL-18 in blood may discriminate cirrhotic patients with and without minimal hepatic encephalopathy.
      ]. Finally, the third is an increased systemic oxidative stress with a high levels of oxidized HSA and of other markers of oxidative stress [
      • Oettl K.
      • Birner-Gruenberger R.
      • Spindelboeck W.
      • Stueger H.P.
      • Dorn L.
      • Stadlbauer V.
      Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity, liver dysfunction and survival.
      ,
      • Jalan R.
      • Schnurr K.
      • Mookerjee R.P.
      • Sen S.
      • Cheshire L.
      • Hodges S.
      • et al.
      Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality.
      ]. Systemic inflammation, oxidative stress, and organ dysfunction are moderate in patients with decompensated cirrhosis and severe in patients with acute-on-chronic liver failure (ACLF) [
      • Moreau R.
      • Jalan R.
      • Ginès P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ,
      • Albillos A.
      • de la Hera A.
      • González M.
      • Moya J.L.
      • Calleja J.L.
      • Monserrat J.
      • et al.
      Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement.
      ] (Fig. 3). Translocation of bacterial products (i.e., lipopolysaccharide, bacterial DNA) or of viable organisms from the intestinal lumen to the circulation due to quantitative and qualitative changes in gut microbiota, impairment in intestinal mucosal barrier, increased epithelial permeability, and impaired intestinal immunity, are important mechanisms of systemic inflammation in cirrhosis [
      • Moreau R.
      • Jalan R.
      • Ginès P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ,
      • Navasa M.
      • Follo A.
      • Filella X.
      • Jiménez W.
      • Francitorra A.
      • Planas R.
      • et al.
      Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality.
      ,
      • Byl B.
      • Roucloux I.
      • Crusiaux A.
      • Dupont E.
      • Devière J.
      Tumor necrosis factor alpha and interleukin 6 plasma levels in infected cirrhotic patients.
      ,
      • Albillos A.
      • de la Hera A.
      • González M.
      • Moya J.L.
      • Calleja J.L.
      • Monserrat J.
      • et al.
      Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement.
      ,
      • Wiest R.
      • Lawson M.
      • Geuking M.
      Pathological bacterial translocation in liver cirrhosis.
      ]. However, systemic inflammation may also occur in response to acute liver injury (i.e., acute alcoholic hepatitis) or other mechanisms [
      • Moreau R.
      • Jalan R.
      • Ginès P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ].
      Figure thumbnail gr3
      Fig. 3Role of inflammation in the pathogenesis of decompensated cirrhosis and ACLF. Hypothesis on the role of inflammation in decompensated cirrhosis (left panel). The initial event is inflammation of the intestinal submucosa and arterial vasodilation related to bacterial translocation. As the disease progresses effective arterial hypovolemia develops leading to stimulation of the RAS, SNS and antidiuretic hormone (ADH). The SNS reduces intestinal motility, increases bacterial overgrowth and inhibits the intestinal immune system, worsening bacterial translocation and closing the first vicious circle that perpetuates circulatory dysfunction. The second vicious circle includes the extension of local inflammation to the systemic circulation and the organs. The final effects are the complications associated with decompensated cirrhosis. The red boxes point out the steps that may be influenced by HSA. Hypothesis on the role of inflammation in ACLF (right panel). ACLF is the result of a severe acute systemic inflammation secondary to PAMPs or DAMPs. Two types of processes then develop. The first is a rapid and severe impairment in systemic vascular resistance and left ventricular function leading to organ hypoperfusion. The second is the extension of systemic inflammation and oxidative stress to the organs leading to abnormal distribution in blood flow within the microcirculation and cell dysfunction. Both features lead to organ failure(s) and ACLF. The red boxes point out the steps that may be influenced by HSA.
      Closed interactions exist between bacterial translocation, local inflammation, and cardiovascular dysfunction in decompensated cirrhosis (Fig. 3). Activation of the intestinal immune system by bacterial translocation causes local release of NO and other vasodilators leading to the characteristic hyperdynamic circulation of cirrhosis and in more advanced stages, effective hypovolemia, activation of the renin-angiotensin system (RAS), sympathetic nervous systems (SNS) and antidiuretic hormone (ADH), and ascites formation [
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodés J.
      Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      ,
      • Albillos A.
      • de la Hera A.
      • González M.
      • Moya J.L.
      • Calleja J.L.
      • Monserrat J.
      • et al.
      Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement.
      ,
      • Wiest R.
      • Lawson M.
      • Geuking M.
      Pathological bacterial translocation in liver cirrhosis.
      ,
      • Wiest R.
      Role of sympathetic nervous activity for bacterial translocation in advanced experimental liver cirrhosis.
      ,
      • Wiest R.
      • Das S.
      • Cadelina G.
      • Garcia-Tsao G.
      • Milstien S.
      • Groszmann R.J.
      Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility.
      ,
      • Iwakiri Y.
      • Groszmann R.J.
      The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule.
      ]. On the other hand, the activated sympathetic nervous system induces changes in the gut microbiota and impairs intestinal immunity, thus producing a vicious circle promoting the progression cardiovascular dysfunction [
      • Wiest R.
      • Lawson M.
      • Geuking M.
      Pathological bacterial translocation in liver cirrhosis.
      ]. A slow but progressive impairment of left ventricular function and cardiac output also develops in decompensated cirrhosis and contributes to circulatory dysfunction [
      • Ruiz-del-Arbol L.
      • Monescillo A.
      • Arocena C.
      • Valer P.
      • Ginès P.
      • Moreira V.
      • et al.
      Circulatory function and hepatorenal syndrome in cirrhosis.
      ,
      • Krag A.
      • Bendtsen F.
      • Henriksen J.H.
      S Møller2. Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
      ]. Recent data suggest that impairment in cardiac function in experimental cirrhosis is related to inflammation, tumor-necrosis factor α (TNFα)-related activation of inducible NO-synthase and oxidative stress in the cardiac tissue [
      • Bortoluzzi A.
      • Ceolotto G.
      • Gola E.
      • Sticca A.
      • Bova S.
      • Morando F.
      • et al.
      Positive cardiac inotropic effect of albumin infusion in rodents with cirrhosis and ascites: molecular mechanisms.
      ].
      ACLF is characterized by acute development of organ failure(s) (liver, renal, brain, coagulation, circulation, respiration) in patients with compensated or decompensated cirrhosis [
      • Moreau R.
      • Jalan R.
      • Ginès P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ]. ACLF develops in the setting of severe systemic inflammatory reaction due to bacterial infection, acute alcoholic hepatitis or other precipitating events [
      • Moreau R.
      • Jalan R.
      • Ginès P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ,
      • Navasa M.
      • Follo A.
      • Filella X.
      • Jiménez W.
      • Francitorra A.
      • Planas R.
      • et al.
      Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality.
      ]. The number of organ failures correlates directly with the degree of systemic inflammation (Fig. 4) [
      • Moreau R.
      • Jalan R.
      • Ginès P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ]. Therefore, whereas systemic inflammation is chronic and moderate in decompensated cirrhosis, it is acute and severe in ACLF (Fig. 4). The mechanism of organ failure in ACLF is complex (Fig. 3). Acute impairment in cardiovascular function leading to intense organ hypoperfusion is a major feature [
      • Ruiz-del-Arbol L.
      • Urman J.
      • Fernández J.
      • González M.
      • Navasa M.
      • Monescillo A.
      • et al.
      Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis.
      ]. However recent studies in sepsis suggest that extension of systemic inflammation to organs leading to abnormal distribution of blood flow within the microcirculation and cell dysfunction related to mitochondrial oxidative stress are also important mechanisms [
      • Gomez H.
      • Ince C.
      • De Backer D.
      • Pickkers P.
      • Payen D.
      • Hotchkiss J.
      • et al.
      A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury.
      ,
      • Merx M.W.
      • Weber C.
      Sepsis and the heart.
      ].
      Figure thumbnail gr4
      Fig. 4Relationship between systemic inflammation and ACLF grade. Leukocyte count and C-reactive protein in patients with decompensated cirrhosis (no ACLF) and in patients with ACLF-1 (renal failure or single non renal organ failure associated with renal dysfunction or moderate hepatic encephalopathy; for further explanation see reference
      [
      • Moreau R.
      • Jalan R.
      • Ginès P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ]
      , ACLF-2
      [
      • Peters Jr., T.
      All about albumin. Biochemistry and medical applications.
      ]
      organ failures) and ACLF-3
      [
      • Thorn G.W.
      • Armstrong Jr., S.H.
      • Davenport V.D.
      Chemical, clinical, and immunological studies on the products of human plasma fractionation. XXXI. The use of salt-poor concentrated human serum albumin solution in the treatment of hepatic cirrhosis.
      ]
      or more organ failures. Normal values of C-reactive protein are below 5 mg/L. p <0.05; ∗∗p <0.001 with respect to no ACLF. Results obtained from the CANONIC data-base
      [
      • Moreau R.
      • Jalan R.
      • Ginès P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ]
      .
      Figure thumbnail fx6

      HSA may have therapeutic effects unrelated to volume expansion

      Considering the potential role of systemic inflammation in cirrhosis and the effect of HSA modulating the innate immune response and oxidative stress, it is rational to suggest that some effects of HSA (i.e., prevention and treatment of type-1 HRS) might be related to these features. Indeed, there are many steps in the process of acute decompensation of cirrhosis and ACLF that could be influenced by HSA (Fig. 3). There are three studies supporting this contention.
      Two studies compared the systemic hemodynamic changes in uncomplicated patients with SBP treated with albumin or hydroxyethyl starch [
      • Fernández J.
      • Navasa M.
      • Garcia-Pagan J.C.
      • G-Abraldes J.
      • Jiménez W.
      • Bosch J.
      • et al.
      Effect of intravenous albumin on systemic and hepatic hemodynamics and vasoactive neurohormonal systems in patients with cirrhosis and spontaneous bacterial peritonitis.
      ,
      • Fernández J.
      • Monteagudo J.
      • Bargallo X.
      • Jiménez W.
      • Bosch J.
      • Arroyo V.
      • et al.
      A randomized unblinded pilot study comparing albúmina vs. hydroxyethyl starch in spontaneous bacterial peritonitis.
      ]. Circulatory function only improved in patients receiving albumin. An increase in left ventricular function, cardiac output, and peripheral vascular resistance was observed, indicating a simultaneous effect of HSA in the heart and in the peripheral circulation. An effect of HSA modulating the cardiac and endothelial effect NO was proposed to explain the different circulatory response on the basis of distinct changes in the plasma levels of NO metabolites and von Willebrand Factor between groups [
      • Ferlitsch M.
      • Reiberger T.
      • Hoke M.
      • Salzl P.
      • Schwengerer B.
      • Ulbrich G.
      • et al.
      Von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis.
      ,
      • Albornoz L.
      • Alvarez D.
      • Otaso J.C.
      • Gadano A.
      • Salviú J.
      • Gerona S.
      • et al.
      Von Willebrand factor could be an index of endothelial dysfunction in patients with cirrhosis: relationship to degree of liver failure and nitric oxide levels.
      ,
      • Ferro D.
      • Quintarelli C.
      • Lattuada A.
      • Leo R.
      • Alessandroni M.
      • Mannucci P.M.
      • et al.
      High plasma levels of von Willebrand factor as a marker of endothelial perturbation in cirrhosis: relationship to endotoxemia.
      ].
      The third investigation was performed in cirrhotic rats with ascites [
      • Ruiz-del-Arbol L.
      • Monescillo A.
      • Arocena C.
      • Valer P.
      • Ginès P.
      • Moreira V.
      • et al.
      Circulatory function and hepatorenal syndrome in cirrhosis.
      ]. Plasma volume expansion with HSA but not with hydroxyethyl starch improved left ventricular function ex vivo. This effect was related to a normalization of activated protein expression of TNFα and inducible NO synthase, MAD(P)H-oxidase activity and nuclear translocation of NF-κB in cardiac tissue, indicating a decrease of heart inflammation and oxidative stress.

      Conflict of interest

      VA has a grant from Grifols. RG and XS declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. The EASL Chronic Liver Failure Consortium has an unrestricted grant from Grifols.

      Acknowledgements

      We are grateful to the Esther Koplowitz Foundation for its support.

      References

        • Moreau R.
        • Jalan R.
        • Ginès P.
        • Pavesi M.
        • Angeli P.
        • Cordoba J.
        • et al.
        Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
        Gastroenterology. 2013; 144: 1426-1437
        • Peters Jr., T.
        All about albumin. Biochemistry and medical applications.
        Academic Press, Inc San Diego1966
        • Thorn G.W.
        • Armstrong Jr., S.H.
        • Davenport V.D.
        Chemical, clinical, and immunological studies on the products of human plasma fractionation. XXXI. The use of salt-poor concentrated human serum albumin solution in the treatment of hepatic cirrhosis.
        J Clin Invest. 1946; 25: 304-323
        • Kunkel H.G.
        • Labby D.H.
        • Ahrens E.H.
        • Shank R.E.
        • Hoagland C.L.
        The use of concentrated human serum albumin in the treatment of cirrhosis of the liver.
        J Clin Invest. 1948; 27: 305-319
        • Faloon W.W.
        • Eckhardt R.D.
        • Lynch Murphy T.
        • Cooper A.M.
        • Davidson C.S.
        An evaluation of human serum albumin in the treatment of cirrhosis of the liver.
        J Clin Invest. 1949; 28: 583-594
        • Hecker R.
        • Sherlock S.
        Electrolyte and circulatory changes in terminal liver failure.
        Lancet. 1956; 271: 1121-1125
        • Traverso H.
        • Vesin P.
        • Combrisson A.
        • Besson P.
        • Cattan R.
        Intravenous albumin loading in ascitic cirrhosis. Biological study.
        Sem Hop. 1964; 40: 17-20
        • Wapnick S.
        • Grosberg S.
        • Kinney M.
        • Azzara V.
        • LeVeen H.H.
        Renal failure in ascites secondary to hepatic, renal, and pancreatic disease. Treatment with a LeVeen peritoneovenous shunt.
        Arch Surg. 1978; 113: 581-585
        • Ginès P.
        • Arroyo V.
        • Quintero E.
        • Planas R.
        • Bory F.
        • Cabrera J.
        • et al.
        Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites. Results of a randomized study.
        Gastroenterology. 1987; 93: 234-241
        • Titó L.
        • Ginès P.
        • Arroyo V.
        • Planas R.
        • Panés J.
        • Rimola A.
        • et al.
        Total paracentesis associated with intravenous albumin management of patients with cirrhosis and ascites.
        Gastroenterology. 1990; 98: 146-151
        • Arroyo V.
        • Ginès A.
        • Saló J.
        A European survey on the treatment of ascites in cirrhosis.
        J Hepatol. 1994; 21: 667-672
        • Ginès P.
        • Arroyo V.
        • Vargas V.
        • Planas R.
        • Casafont F.
        • Panés J.
        • et al.
        Paracentesis with intravenous infusion of albumin as compared with peritoneovenous shunting in cirrhosis with refractory ascites.
        N Engl J Med. 1991; 325: 829-835
        • Ginès P.
        • Titó L.
        • Arroyo V.
        • Planas R.
        • Panés J.
        • Viver J.
        • et al.
        Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis.
        Gastroenterology. 1988; 94: 1493-1502
        • Planas R.
        • Ginès P.
        • Arroyo V.
        • Llach J.
        • Panés J.
        • Vargas V.
        • et al.
        Dextran-70 vs. albumin as plasma expanders in cirrhotic patients with tense ascites treated with total paracentesis. Results of a randomized study.
        Gastroenterology. 1990; 99: 1736-1744
        • Ginès A.
        • Fernández-Esparrach G.
        • Monescillo A.
        • Vila C.
        • Domènech E.
        • Abecasis R.
        • et al.
        Randomized trial comparing albumin, dextran 70, and polygeline in cirrhotic patients with ascites treated by paracentesis.
        Gastroenterology. 1996; 111: 1002-1010
        • Saló J.
        • Ginès A.
        • Ginès P.
        • Piera C.
        • Jiménez W.
        • Guevara M.
        • et al.
        Effect of therapeutic paracentesis on plasma volume and transvascular escape rate of albumin in patients with cirrhosis.
        J Hepatol. 1997; 27: 645-653
        • Ruiz-del-Arbol L.
        • Monescillo A.
        • Jimenéz W.
        • Garcia-Plaza A.
        • Arroyo V.
        • Rodés J.
        Paracentesis-induced circulatory dysfunction: mechanism and effect on hepatic hemodynamics in cirrhosis.
        Gastroenterology. 1997; 113: 579-586
        • Vila M.C.
        • Solà R.
        • Molina L.
        • Andreu M.
        • Coll S.
        • Gana J.
        • et al.
        Hemodynamic changes in patients developing effective hypovolemia after total paracentesis.
        J Hepatol. 1998; 28: 639-645
        • Bernardi M.
        • Caraceni P.
        • Navickis R.J.
        • Wilkes M.M.
        Albumin infusion in patients undergoing large-volume paracentesis: a meta-analysis of randomized trials.
        Hepatology. 2012; 55: 1172-1181
        • Follo 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: 1495-1501
        • Ruiz-del-Arbol L.
        • Urman J.
        • Fernández J.
        • González M.
        • Navasa M.
        • Monescillo A.
        • et al.
        Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis.
        Hepatology. 2003; 38: 1210-1218
        • 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: 223-229
        • Navasa M.
        • Follo A.
        • Filella X.
        • Jiménez W.
        • Francitorra A.
        • Planas R.
        • et al.
        Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: relationship with the development of renal impairment and mortality.
        Hepatology. 1998; 27: 1227-1232
        • Terra C.
        • Guevara M.
        • Torre A.
        • Gilabert R.
        • Fernández J.
        • Martín-Llahí M.
        • et al.
        Renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis: value of MELD score.
        Gastroenterology. 2005; 129: 1944-1953
        • Pereira G.
        • Guevara M.
        • Fagundes C.
        • Solá E.
        • Rodríguez E.
        • Fernández J.
        • et al.
        Renal failure and hyponatremia in patients with cirrhosis and skin and soft tissue infection. A retrospective study.
        J Hepatol. 2012; 56: 1040-1046
        • Byl B.
        • Roucloux I.
        • Crusiaux A.
        • Dupont E.
        • Devière J.
        Tumor necrosis factor alpha and interleukin 6 plasma levels in infected cirrhotic patients.
        Gastroenterology. 1993; 104: 1492-1497
        • Ramírez M.J.
        • Ibáñez A.
        • Navasa M.
        • Casals E.
        • Morales-Ruiz M.
        • Jiménez W.
        • et al.
        High-density lipoproteins reduce the effect of endotoxin on cytokine production and systemic hemodynamics in cirrhotic rats with ascites.
        J Hepatol. 2004; 40: 424-430
        • Schrier R.W.
        • Arroyo V.
        • Bernardi M.
        • Epstein M.
        • Henriksen J.H.
        • Rodés J.
        Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
        Hepatology. 1988; 8: 1151-1157
        • Ginès A.
        • Escorsell A.
        • Ginès P.
        • Saló J.
        • Jiménez W.
        • Inglada L.
        • et al.
        Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites.
        Gastroenterology. 1993; 105: 229-236
        • Fernández J.
        • Navasa M.
        • Planas R.
        • Montoliu S.
        • Monfort D.
        • Soriano G.
        • et al.
        Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis.
        Gastroenterology. 2007; 133: 818-824
        • Sort P.
        • Navasa M.
        • Arroyo V.
        • Aldeguer X.
        • Planas R.
        • Ruiz-del-Arbol L.
        • et al.
        Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.
        N Engl J Med. 1999; 341: 403-409
        • Salerno F.
        • Navickis R.J.
        • Wilkes M.M.
        Albumin infusion improves outcomes of patients with spontaneous bacterial peritonitis: a meta-analysis of randomized trials.
        Clin Gastroenterol Hepatol. 2013; 11: 123-130
        • Shapiro M.D.
        • Nicholls K.M.
        • Groves B.M.
        • Kluge R.
        • Chung H.M.
        • Bichet D.G.
        • et al.
        Interrelationship between cardiac output and vascular resistance as determinants of effective arterial blood volume in cirrhotic patients.
        Kidney Int. 1985; 28: 206-211
        • Guevara M.
        • Ginès P.
        • Fernández-Esparrach G.
        • Sort P.
        • Salmerón J.M.
        • Jiménez W.
        • et al.
        Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion.
        Hepatology. 1998; 27: 35-41
        • Uriz J.
        • Ginès P.
        • Cárdenas A.
        • Sort P.
        • Jiménez W.
        • Salmerón J.M.
        • et al.
        Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome.
        J Hepatol. 2000; 33: 43-48
        • Ginès P.
        • Cárdenas A.
        • Arroyo V.
        • Rodés J.
        Management of cirrhosis and ascites.
        N Engl J Med. 2004; 350: 1646-1654
        • Garcia-Tsao G.
        • Lim J.K.
        Members of Veterans Affairs Hepatitis C Resource Center Program. Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program.
        Am J Gastroenterol. 2009; 104: 1802-1829
        • Ginès P.
        • Angeli P.
        • Lenz K.
        • Møller S.
        • Moore K.
        • Moreau R.
        • et al.
        EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis.
        J Hepatol. 2010; 53: 397-417
        • Angeli P.
        • Fasolato S.
        • Cavallin M.
        • Trotta E.
        • Maresio G.
        • Callegaro A.
        • et al.
        Terlipressin given as continuous intravenous infusion vs. terlipressin given as intravenous boluses in the treatment of type 1 hepatorenal syndrome (HRS) in patients with cirrhosis.
        J Hepatol. 2009; 50: S73
        • Boyer T.D.
        • Sanyal A.J.
        • Garcia-Tsao G.
        • Blei A.
        • Carl D.
        • Bexon A.S.
        • et al.
        Predictors of response to terlipressin plus albumin in hepatorenal syndrome (HRS) type 1: relationship of serum creatinine to hemodynamics.
        J Hepatol. 2011; 55: 315-321
        • Velez J.C.
        • Nietert P.J.
        Therapeutic response to vasoconstrictors in hepatorenal syndrome parallels increase in mean arterial pressure: a pooled analysis of clinical trials.
        Am J Kidney Dis. 2011; 58: 928-938
        • Nazar A.
        • Pereira G.H.
        • Guevara M.
        • Martín-Llahi M.
        • Pepin M.N.
        • Marinelli M.
        • et al.
        Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type 1 hepatorenal syndrome.
        Hepatology. 2010; 51: 219-226
        • Moreau R.
        • Durand F.
        • Poynard T.
        • Duhamel C.
        • Cervoni J.P.
        • Ichaï P.
        • et al.
        Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study.
        Gastroenterology. 2002; 122: 923-930
        • Arroyo V.
        • Fernández J.
        Management of hepatorenal syndrome in patients with cirrhosis.
        Nat Rev Nephrol. 2011; 7: 517-526
        • Alessandria C.
        • Ottobrelli A.
        • Debernardi-Venon W.
        • Todros L.
        • Cerenzia M.T.
        • Martini S.
        • et al.
        Noradrenalin vs. terlipressin in patients with hepatorenal syndrome: a prospective, randomized, unblinded, pilot study.
        J Hepatol. 2007; 47: 499-505
        • Sharma P.
        • Kumar A.
        • Shrama B.C.
        • Sarin S.K.
        An open label, pilot, randomized controlled trial of noradrenaline vs. terlipressin in the treatment of type 1 hepatorenal syndrome and predictors of response.
        Am J Gastroenterol. 2008; 103: 1689-1697
        • Singh V.
        • Ghosh S.
        • Singh B.
        • Kumar P.
        • Sharma N.
        • Bhalla A.
        • et al.
        Noradrenaline vs. terlipressin in the treatment of hepatorenal syndrome: a randomized study.
        J Hepatol. 2012; 56: 1293-1298
        • Ortega R.
        • Ginès P.
        • Uriz J.
        • Cárdenas A.
        • Calahorra B.
        • De Las Heras D.
        • et al.
        Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study.
        Hepatology. 2002; 36: 941-948
        • Martín-Llahí M.
        • Pépin M.N.
        • Guevara M.
        • Díaz F.
        • Torre A.
        • Monescillo A.
        • et al.
        Terlipressin and albumin vs. albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study.
        Gastroenterology. 2008; 134: 1352-1359
        • Sanyal A.J.
        • Boyer T.
        • Garcia-Tsao G.
        • Regenstein F.
        • Rossaro L.
        • Appenrodt B.
        • et al.
        A randomized, prospective, double-blind, placebo-controlled trial of terlipressin for type 1 hepatorenal syndrome.
        Gastroenterology. 2008; 134: 1360-1368
        • Péron J.M.
        • Bureau C.
        • Gonzalez L.
        • Garcia-Ricard F.
        • de Soyres O.
        • Dupuis E.
        • et al.
        Treatment of hepatorenal syndrome as defined by the international ascites club by albumin and furosemide infusion according to the central venous pressure: a prospective pilot study.
        Am J Gastroenterol. 2005; 100: 2702-2707
        • Rodríguez E.
        • Elia C.
        • Solà E.
        • Barreto R.
        • Graupera I.
        • Andrealli A.
        • et al.
        Terlipressin and albumin for type-1 hepatorenal syndrome associated with sepsis.
        J Hepatol. 2014; 60 ([pii: S0168-8278[14]00055-5, Epub ahead of print]): 955-961
        • Alessandria C.
        • Venon W.D.
        • Marzano A.
        • Barletti C.
        • Fadda M.
        • Rizzetto M.
        Renal failure in cirrhotic patients: role of terlipressin in clinical approach to hepatorenal syndrome type 2.
        Eur J Gastroenterol Hepatol. 2002; 14: 1363-1368
        • Tarao K.
        • Iwamura K.
        Influence of long-term administration of serum albumin on the prognosis of liver cirrhosis in man.
        Tokai J Exp Clin Med. 1983; 8: 71-78
        • Gentilini P.
        • Casini-Raggi V.
        • Di Fiore G.
        • Romanelli R.G.
        • Buzzelli G.
        • Pinzani M.
        • et al.
        Albumin improves the response to diuretics in patients with cirrhosis and ascites: results of a randomized, controlled trial.
        J Hepatol. 1999; 30: 639-645
        • Guevara M.
        • Terra C.
        • Nazar A.
        • Solà E.
        • Fernández J.
        • Pavesi M.
        • et al.
        Albumin for bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. A randomized, controlled study.
        J Hepatol. 2012; 57: 759-765
        • He X.M.
        • Carter D.C.
        Atomic structure and chemistry of human serum albumin.
        Nature. 1992; 358: 209-215
        • Oettl K.
        • Birner-Gruenberger R.
        • Spindelboeck W.
        • Stueger H.P.
        • Dorn L.
        • Stadlbauer V.
        Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity, liver dysfunction and survival.
        J Hepatol. 2013; 59: 978-983
        • Anraku M.
        • Chuang V.T.G.
        • Maruyama T.
        • Otagiri M.
        Redox properties of serum albumin.
        Biochim Biophys Acta. 2013; 1830: 5465-5472
        • Carter D.C.
        • He X.M.
        • Munson S.H.
        • Twigg P.D.
        • Gernert K.M.
        • Broom M.B.
        • et al.
        Three-dimensional structure of human serum albumin.
        Science. 1989; 244: 1195-1198
        • Bhattacharya A.A.
        • Grüne T.
        • Curry S.
        Crystallographic analysis reveals common modes of binding of medium and long-chain fatty acids to HSA.
        J Mol Biol. 2000; 303: 721-732
        • Mao H.
        • Gunasekera A.H.
        • Fesik S.W.
        Expression, refolding, and isotopic labeling of human serum albumin domains for NMR spectroscopy.
        Protein Expr Purif. 2000; 20: 492-499
        • Milojevic J.
        • Melacini G.
        Stoichiometry and affinity of the human serum albumin-Alzheimer’s Aβ peptide interactions.
        Biophys J. 2011; 100: 183-192
        • Burton S.J.
        • Quirk A.V.
        • Wood P.C.
        Refolding human serum albumin at relatively high protein concentration.
        Eur J Biochem. 1989; 179: 379-387
        • Chen Z.
        • He Y.
        • Shi B.
        • Yang D.
        Human serum albumin from recombinant DNA technology: challenges and strategies.
        Biochim Biophys Acta. 2013; 1830: 5515-5525
        • Hvidt A.
        • Wallevik K.
        Conformational changes in human serum albumin as revealed by hydrogen-deuterium exchange studies.
        J Biol Chem. 1972; 247: 1530-1535
        • Bhattacharya A.A.
        • Grüne T.
        • Curry S.
        Crystallographic analysis reveals common modes of binding of medium and long-chain fatty acids to human serum albumin.
        J Mol Biol. 2000; 303: 721-732
        • Ghuman J.
        • Zunszain P.A.
        • Petitpas I.
        • Bhattacharya A.A.
        • Otagiri M.
        • Curry S.
        Structural basis of the drug-binding specificity of human serum albumin.
        J Mol Biol. 2005; 353: 38-52
        • Yamasaki K.
        • Chuang V.T.G.
        • Maruyama T.
        • Otagiri M.
        Albumin-drug interaction and its clinical implication.
        Biochim Biophys Acta. 2013; 1830: 5435-5443
        • Fanali G.
        • Pariani G.
        • Ascenzi P.
        • Fasano M.
        Allosteric and binding properties of Asp1-Glu382 truncated recombinant human serum albumin – an optical and NMR spectroscopic investigation.
        FEBS J. 2009; 276: 2241-2250
        • Hilser V.J.
        • Thompson E.B.
        Structural dynamics, intrinsic disorder, and allostery in nuclear receptors as transcription factors.
        J Biol Chem. 2011; 286: 39675-39682
        • Jalan R.
        • Schnurr K.
        • Mookerjee R.P.
        • Sen S.
        • Cheshire L.
        • Hodges S.
        • et al.
        Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality.
        Hepatology. 2009; 50: 555-564
        • Furusyo N.
        • Hayashi J.
        Glycated albumin and diabetes mellitus.
        Biochim Biophys Acta. 2013; 1830: 5509-5514
        • Kawakami A.
        • Kubota K.
        • Yamada N.
        • Tagami U.
        • Takehana K.
        • Sonaka I.
        • et al.
        Identification and characterization of oxidized human serum albumin. A slight structural change impairs its ligand-binding and antioxidant functions.
        FEBS J. 2006; 273: 3346-3357
        • Schnitzer J.E.
        • Oh P.
        Albondin-mediated capillary permeability to albumin. Differential role of receptors in endothelial transcytosis and endocytosis of native and modified albumins.
        J Biol Chem. 1994; 269: 6072-6082
        • Minshall R.D.
        • Tiruppathi Ch.
        • Vogel S.M.
        • Malik A.B.
        Vesicle formation and trafficking in endothelial cells and regulation of endothelial barrier function.
        Histochem Cell Biol. 2002; 117: 105-112
        • Malik A.B.
        Targeting endothelial cell surface receptors: novel mechanisms of microvascular endothelial barrier transport.
        J Med Sci. 2009; 2: 13-17
        • Sleep D.
        • Cameron J.
        • Evans L.R.
        Albumin as a versatile platform for drug half-life extension.
        Biochim Biophys Acta. 2013; 1830: 5526-5534
        • Ghinea N.
        • Fixman A.
        • Alexandru D.
        • Popov D.
        • Hasu M.
        • Ghitescu L.
        Identification of albumin-binding proteins in capillary endothelial cells.
        J Cell Biol. 1988; 107: 231-239
        • Schnitzer J.E.
        • Sung A.
        • Horvat R.
        • Bravo J.
        Preferential interaction of albumin-binding proteins, gp30 and gp18, with conformationally modified albumins. Presence in many cells and tissues with a possible role in catabolism.
        J Biol Chem. 1992; 267: 24544-24553
        • Schnitzer J.E.
        • Bravo J.
        High affinity binding, endocytosis, and degradation of conformationally modified albumins. Potential role of gp30 and gp18 as novel scavenger receptors.
        J Biol Chem. 1993; 268: 7562-7570
        • Andersen J.T.
        • Daba M.B.
        • Berntzen G.
        • Michaelsen T.E.
        • Sandlie I.
        Cross-species binding analyses of mouse and human neonatal Fc receptor show dramatic differences in immunoglobulin G and albumin binding.
        J Biol Chem. 2010; 285: 4826-4836
        • Andersen J.T.
        • Pehrson R.
        • Tolmachev V.
        • Daba M.B.
        • Abrahmsén L.
        • Ekblad C.
        Extending half-life by indirect targeting of the neonatal Fc receptor (FcRn) using a minimal albumin binding domain.
        J Biol Chem. 2011; 286: 5234-5241
        • Smith B.J.
        • Popplewell A.
        • Athwal D.
        • Chapman A.P.
        • Heywood S.
        • Shauna M.
        • et al.
        Prolonged in vivo residence times of antibody fragments associated with albumin.
        Bioconjug Chem. 2001; 12: 750-756
        • Fujiwara S.
        • Amisaki T.
        Fatty acid binding to serum albumin: molecular simulation approaches.
        Biochim Biophys Acta. 2013; 1830: 5427-5434
        • Van der Vusse G.J.
        Albumin as fatty acid transporter.
        Drug Metab Pharmacokinet. 2009; 24: 300-307
        • Petersen C.E.
        • Ha C.E.
        • Harohalli K.
        • Feix J.B.
        • Bhagavan N.V.
        A dynamic model for bilirubin binding to human serum albumin.
        J Biol Chem. 2000; 275: 20985-20995
        • Ha C.E.
        • Bhagavan N.V.
        Novel insights into the pleiotropic effects of human serum albumin in health and disease.
        Biochim Biophys Acta. 2013; 1830: 5486-5493
        • Wang Z.M.
        • Ho J.X.
        • Ruble J.R.
        • Rose J.
        • Rüker F.
        • Ellenburg M.
        • et al.
        Structural studies of several clinically important oncology drugs in complex with human serum albumin.
        Biochim Biophys Acta. 2013; 1830: 5356-5374
        • Klammt S.
        • Wojak H.J.
        • Mitzner A.
        • Koball S.
        • Rychly J.
        • Reisinger E.C.
        • et al.
        Albumin-binding capacity (ABiC) is reduced in patients with chronic kidney disease along with an accumulation of protein-bound uraemic toxins.
        Nephrol Dial Transplant. 2012; 27: 2377-2383
        • Klammt S.
        • Mitzner S.
        • Stange J.
        • Brinkmann B.
        • Drewelow B.
        • Emmrich J.
        • et al.
        Albumin-binding function is reduced in patients with decompensated cirrhosis and correlates inversely with severity of liver disease assessed by model for end-stage liver disease.
        Eur J Gastroenterol Hepatol. 2007; 19: 257-263
        • Fanali G.
        • di Massi A.
        • Trezza V.
        • Marino M.
        • Fasano M.
        • Ascenzi P.
        Human serum albumin: from bench to bedside.
        Mol Aspects Med. 2012; 33: 209-290
        • Smith D.A.
        • Di L.
        • Kerns E.H.
        The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery.
        Nat Rev Drug Discov. 2010; 9: 929-939
        • Jurgens G.
        • Muller M.
        • Garidel P.
        • Koch M.H.
        • Nakakubo H.
        • Blume A.
        • et al.
        Investigation into the interaction of recombinant human serum albumin with Re-lipopolysaccharide and lipid A.
        J Endotoxin Res. 2002; 8: 115-126
        • Fukui H.
        Relation of endotoxin, endotoxin binding proteins and macrophages to severe alcoholic liver injury and multiple organ failure.
        Alcohol Clin Exp Res. 2005; 29: 172S-179S
        • Dziarski R.
        Cell-bound albumin is the 70-kDa peptidoglycan-, lipopolysaccharide-, and lipoteichoic acid-binding protein on lymphocytes and macrophages.
        J Biol Chem. 1994; 269: 20431-20436
        • David S.A.
        • Balaram P.
        • Mathan V.I.
        Characterization of the interaction of lipid A and lipopolysaccharide with human serum albumin: implications for an endotoxin carrier function for albumin.
        J Endotoxin Res. 1995; 2: 99-106
        • Gioannini T.L.
        • Zhang D.
        • Teghanemt A.
        • Weiss J.P.
        An essential role for albumin in the interaction of endotoxin with lipopolysaccharide-binding protein and sCD14 and resultant cell activation.
        J Biol Chem. 2002; 277: 47818-47825
        • Blomkalns A.L.
        • Stoll L.L.
        • Shaheen W.
        • Romig-Martin S.A.
        • Dickson E.W.
        • Weintraub N.L.
        • et al.
        Low level bacterial endotoxin activates two distinct signaling pathways in human peripheral blood mononuclear cells.
        J Inflamm (Lond). 2011; 8: 4
        • Esparza G.A.
        • Teghanemt A.
        • Zhang D.
        • Gioannini T.L.
        • Weiss J.P.
        Endotoxin{middle dot}albumin complexes transfer endotoxin monomers to MD-2 resulting in activation of TLR4.
        Innate Immun. 2012; 18: 478-491
        • Takeuchi O.
        • Akira S.
        Pattern recognition receptors and inflammation.
        Cell. 2010; 140: 805-820
        • Chan J.K.
        • Roth J.
        • Oppenheim J.J.
        • Tracey K.J.
        • Vogl T.
        • Feldmann M.
        • et al.
        Alarmins: awaiting a clinical response.
        J Clin Invest. 2012; 122: 2711-2719
        • Singer M.
        The role of mitochondrial dysfunction in sepsis-induced multi-organ failure.
        Virulence. 2014; 5: 66-72
        • Galley H.F.
        Oxidative stress and mitochondrial dysfunction in sepsis.
        Br J Anaesth. 2011; 107: 57-64
        • Galley H.F.
        Bench-to-bedside review: targeting antioxidants to mitochondria in sepsis.
        Crit Care. 2010; 14: 230
        • Taverna M.
        • Marie A.L.
        • Mira J.P.
        • Guidet B.
        Specific antioxidant properties of human serum albumin.
        Anaesth Intensive Care. 2013; 3: 4
        • Bruschi M.
        • Candiano G.
        • Santucci L.
        • Ghiggeri G.M.
        Oxidized albumin. The long way of a protein of uncertain function.
        Biochim Biophys Acta. 2013; 1830: 5473-5479
        • Cantin A.M.
        • Paquette B.
        • Richter M.
        • Larivée P.
        Albumin-mediated regulation of cellular glutathione and nuclear factor kappa B activation.
        Am J Respir Crit Care Med. 2000; 162: 1539-1546
        • Bal W.
        • Sokołowska M.
        • Kurowska E.
        • Faller P.
        Binding of transition metal ions to albumin: sites, affinities and rates.
        Biochim Biophys Acta. 2013; 1830: 5444-5455
        • Stohs S.J.
        • Bagchi D.
        Oxidative mechanisms in the toxicity of metal ions.
        Free Radic Biol Med. 1995; 18: 321-336
        • Neuzil J.
        • Stocker R.
        Free and albumin-bound bilirubin are efficient co-antioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation.
        J Biol Chem. 1994; 269: 16712-16719
        • Bourdon E.
        • Loreau N.
        • Lagrost L.
        • Blache D.
        Differential effects of cysteine and methionine residues in the antioxidant activity of human serum albumin.
        Free Radic Res. 2005; 39: 15-20
        • Berlett B.S.
        • Stadtman E.R.
        Protein oxidation in aging, disease, and oxidative stress.
        J Biol Chem. 1997; 272: 20313-20316
        • Oettl K.
        • Marsche G.
        Redox state of human serum albumin in terms of cysteine-34 in health and disease.
        Methods Enzymol. 2010; 474: 181-195
        • Rafikova O.
        • Rafikov R.
        • Nudler E.
        Catalysis of S-nitrosothiols formation by serum albumin: the mechanism and implication in vascular control.
        Proc Natl Acad Sci U S A. 2002; 99: 5913-5918
        • Fitzpatrick F.A.
        • Liggett W.F.
        • Wynalda M.A.
        Albumin-eicosanoid interactions. A model system to determine their attributes and inhibition.
        J Biol Chem. 1984; 259: 2722-2777
        • Kragh-Hansen U.
        Molecular and practical aspects of the enzymatic properties of human serum albumin and of albumin-ligand complexes.
        Biochim Biophys Acta. 2013; 1830: 5535-5544
        • Yang J.
        • Petersen C.E.
        • Ha C.E.
        • Bhagavan N.V.
        Structural insights into human serum albumin-mediated prostaglandin catalysis.
        Protein Sci. 2002; 11: 538-545
        • Wynalda M.A.
        • Fitzpatrick F.A.
        Albumins stabilize prostaglandin I2.
        Prostaglandins. 1980; 20: 853-861
        • Folco G.
        • Granström E.
        • Kindahl H.
        Albumin stabilizes thromboxane A2.
        FEBS Lett. 1977; 82: 321-324
        • Le Moine O.
        • Soupison T.
        • Sogni P.
        • Marchant A.
        • Moreau R.
        • Hadengue A.
        • et al.
        Plasma endotoxin and tumor necrosis factor-alpha in the hyperkinetic state of cirrhosis.
        J Hepatol. 1995; 23: 391-395
        • Bac D.J.
        • Pruimboom W.M.
        • Mulder P.G.
        • Zijlstra F.J.
        • Wilson J.H.
        High interleukin-6 production within the peritoneal cavity in decompensated cirrhosis and malignancy-related ascites.
        Liver. 1995; 15: 265-270
        • Odeh M.
        • Sabo E.
        • Srugo I.
        • Oliven A.
        Serum levels of tumor necrosis factor-alpha correlate with severity of hepatic encephalopathy due to chronic liver failure.
        Liver Int. 2004; 24: 110-116
        • Lee F.Y.
        • Lu R.H.
        • Tsai Y.T.
        • Lin H.C.
        • Hou M.C.
        • Li C.P.
        • et al.
        Plasma interleukin-6 levels in patients with cirrhosis. Relationship to endotoxemia, tumor necrosis factor-alpha, and hyperdynamic circulation.
        Scand J Gastroenterol. 1996; 31: 500-505
        • Li C.P.
        • Lee F.Y.
        • Tsai Y.T.
        • Lin H.C.
        • Lu R.H.
        • Hou M.C.
        • et al.
        Plasma interleukin-8 levels in patients with post-hepatitic cirrhosis: relationship to severity of liver disease, portal hypertension and hyperdynamic circulation.
        J Gastroenterol Hepatol. 1996; 11: 635-640
        • Tilg H.
        • Wilmer A.
        • Vogel W.
        • Herold M.
        • Nölchen B.
        • Judmaier G.
        • et al.
        Serum levels of cytokines in chronic liver diseases.
        Gastroenterology. 1992; 103: 264-274
        • Genesca J.
        • Gonzalez A.
        • Segura R.
        • Catalan R.
        • Marti R.
        • Varela E.
        • et al.
        Interleukin-6, nitric oxide, and the clinical and hemodynamic alterations of patients with liver cirrhosis.
        Am J Gastroenterol. 1999; 94: 169-177
        • Jain L.
        • Sharma B.C.
        • Sharma P.
        • Srivastava S.
        • Agrawal A.
        • Sarin S.K.
        Serum endotoxin and inflammatory mediators in patients with cirrhosis and hepatic encephalopathy.
        Dig Liver Dis. 2012; 44: 1027-1031
        • Montoliu C.
        • Piedrafita B.
        • Serra M.A.
        • del Olmo J.A.
        • Urios A.
        • Rodrigo J.M.
        • et al.
        IL-6 and IL-18 in blood may discriminate cirrhotic patients with and without minimal hepatic encephalopathy.
        J Clin Gastroenterol. 2009; 43: 272-279
        • Albillos A.
        • de la Hera A.
        • González M.
        • Moya J.L.
        • Calleja J.L.
        • Monserrat J.
        • et al.
        Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement.
        Hepatology. 2003; 37: 208-217
        • Wiest R.
        • Lawson M.
        • Geuking M.
        Pathological bacterial translocation in liver cirrhosis.
        J Hepatol. 2014; 60: 197-209
        • Wiest R.
        Role of sympathetic nervous activity for bacterial translocation in advanced experimental liver cirrhosis.
        Gastroenterol Hepatol. 2011; 34: 102-105
        • Wiest R.
        • Das S.
        • Cadelina G.
        • Garcia-Tsao G.
        • Milstien S.
        • Groszmann R.J.
        Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility.
        J Clin Invest. 1999; 104: 1223-1233
        • Iwakiri Y.
        • Groszmann R.J.
        The hyperdynamic circulation of chronic liver diseases: from the patient to the molecule.
        Hepatology. 2006; 43: S121-S131
        • Ruiz-del-Arbol L.
        • Monescillo A.
        • Arocena C.
        • Valer P.
        • Ginès P.
        • Moreira V.
        • et al.
        Circulatory function and hepatorenal syndrome in cirrhosis.
        Hepatology. 2005; 42: 439-447
        • Krag A.
        • Bendtsen F.
        • Henriksen J.H.
        S Møller2. Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites.
        Gut. 2010; 59: 105-110
        • Bortoluzzi A.
        • Ceolotto G.
        • Gola E.
        • Sticca A.
        • Bova S.
        • Morando F.
        • et al.
        Positive cardiac inotropic effect of albumin infusion in rodents with cirrhosis and ascites: molecular mechanisms.
        Hepatology. 2013; 57: 266-276
        • Gomez H.
        • Ince C.
        • De Backer D.
        • Pickkers P.
        • Payen D.
        • Hotchkiss J.
        • et al.
        A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury.
        Shock. 2014; 41: 3-11
        • Merx M.W.
        • Weber C.
        Sepsis and the heart.
        Circulation. 2007; 116: 793-802
        • Coltart I.
        • Tranah T.H.
        • Shawcross D.L.
        Inflammation and hepatic encephalopathy.
        Arch Biochem Biophys. 2013; 536: 189-196
        • Tranah T.H.
        • Vijay G.K.
        • Ryan J.M.
        • Shawcross D.L.
        Systemic inflammation and ammonia in hepatic encephalopathy.
        Metab Brain Dis. 2013; 28: 1-5
        • Seyan A.S.
        • Hughes R.D.
        • Shawcross D.L.
        Changing face of hepatic encephalopathy: role of inflammation and oxidative stress.
        World J Gastroenterol. 2010; 16: 3347-3357
        • Berg R.M.
        • Møller K.
        • Bailey D.M.
        Neuro-oxidative-nitrosative stress in sepsis.
        J Cereb Blood Flow Metab. 2011; 31: 1532-1544
        • Garcia-Martinez R.
        • Cordoba J.
        Liver-induced inflammation hurts the brain.
        J Hepatol. 2012; 56: 515-517
        • Guevara M.
        • Bru C.
        • Ginès P.
        • Fernández-Esparrach G.
        • Sort P.
        • Bataller R.
        • et al.
        Increased cerebrovascular resistance in cirrhotic patients with ascites.
        Hepatology. 1998; 28: 39-44
        • Wright G.
        • Davies N.A.
        • Shawcross D.L.
        • Hodges S.J.
        • Zwingmann C.
        • Brooks H.F.
        • et al.
        Endotoxemia produces coma and brain swelling in bile duct ligated rats.
        Hepatology. 2007; 45: 1517-1526
        • Shawcross D.L.
        • Davies N.A.
        • Williams R.
        • Jalan R.
        Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis.
        J Hepatol. 2004; 40: 247-254
        • Shawcross D.L.
        • Sharifi Y.
        • Canavan J.B.
        • Yeoman A.D.
        • Abeles R.D.
        • Taylor N.J.
        • et al.
        Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis.
        J Hepatol. 2011; 54: 640-649
        • Cordoba J.
        • Ventura-Cots M.
        • Simón-Talero M.
        • Amorós A.
        • Pavesi M.
        • Vilstrup H.
        • et al.
        Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF).
        J Hepatol. 2014; 60: 275-281
        • Fernández J.
        • Navasa M.
        • Garcia-Pagan J.C.
        • G-Abraldes J.
        • Jiménez W.
        • Bosch J.
        • et al.
        Effect of intravenous albumin on systemic and hepatic hemodynamics and vasoactive neurohormonal systems in patients with cirrhosis and spontaneous bacterial peritonitis.
        J Hepatol. 2004; 41: 384-390
        • Fernández J.
        • Monteagudo J.
        • Bargallo X.
        • Jiménez W.
        • Bosch J.
        • Arroyo V.
        • et al.
        A randomized unblinded pilot study comparing albúmina vs. hydroxyethyl starch in spontaneous bacterial peritonitis.
        Hepatology. 2005; 42: 627-634
        • Ferlitsch M.
        • Reiberger T.
        • Hoke M.
        • Salzl P.
        • Schwengerer B.
        • Ulbrich G.
        • et al.
        Von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis.
        Hepatology. 2012; 56: 1439-1447
        • Albornoz L.
        • Alvarez D.
        • Otaso J.C.
        • Gadano A.
        • Salviú J.
        • Gerona S.
        • et al.
        Von Willebrand factor could be an index of endothelial dysfunction in patients with cirrhosis: relationship to degree of liver failure and nitric oxide levels.
        J Hepatol. 1999; 30: 451-455
        • Ferro D.
        • Quintarelli C.
        • Lattuada A.
        • Leo R.
        • Alessandroni M.
        • Mannucci P.M.
        • et al.
        High plasma levels of von Willebrand factor as a marker of endothelial perturbation in cirrhosis: relationship to endotoxemia.
        Hepatology. 1996; 23: 1377-1383