Acute-on-chronic Liver Failure: Pathogenesis, Prognostic Factors And .

Blasco-Algora S et al . Acute-on-chronic liver failure: Pathogenesis, prognostic factors, and managementTable 1 Chronic liver failure-sequential organ failure assessment scoreOrgan failureLiver (Tbil, mg/L)Kidney (cr, mg/dl)Cerebral (HE grade)Coagulation (INR)Circulation (MAP, mmHg)Lung PaO2/FiO2Or SpO2/FiO201234 1.2 1.2 1.2 to 2.0 2.0 to 6.0 6.0 to 12 12.0 1.2 to 2.0 2.0 to 3.5 6.0 to 12Or use of renal replacement therapy 5.0No HE 1.1 70ⅠⅡⅢⅣ 1.1 to 1.25 1.25 to 1.5 1.5 to 2.5 2.5 or PLT 20 10 /L 70 400 512 300 to 400 357 to 512DA 5 or DOB orTerlipressin 200 to 300 214 to 3579DA 5 or E 0.1 or NE 0.1 DA 15 or E 0.1 or NE 0.1 100 to 200 89 to 214 100 89This score is used to categorize patients into grades of ACLF. ACLF: Acute-on-chronic liver failure; CLIF: Chronic liver failure; SOFA: Sequential organfailure assessment; Tbil: Total bilirubin; cr: Serum creatinine; HE: Encephalopathy; INR: International normalized ratio; PLT: Plateletes; DA: Dopamine;DOB: Dobutamine; E: Epinephrine; NE: Norepinephrine; PaO2: Partial pressure of arterial oxygen; FiO2: Fraction of inspired oxygen; SpO2: Pulse oximetrysaturation. Data from Moreau et al[12].Table 2 Grades of acute-on-chronic liver failure according tothe number of organ failure and the type of organNo. ACLFACLF grade 1ACLF grade 2ACLF grade 3Single- organ failure (coagulation, liver, circulation,lungs) in patients with sCr 1.5-1.9 mg/dL and/orgrades 1-2 HE or braine failure with sCr range from1.5-1.9 mg/dLTwo organ failuresThree or more organ failuresData from the CANONIC study[12]. ACLF: Acute-on-chronic liver failure;OF: Organ failure.of facts in this entity.PredispositionAlmost any kind of CLD can be a main predisposingfactor on its own. In the Western countries, alcoholiccirrhosis is the cause of 50%-70% of all predisposingliver diseases of ACLF, comparing to the 10%-30%caused by chronic viral infection. In the Easterncountries hepatitis B virus (HBV) accounts for 70%,[6,10]and only 15% is related to alcohol. Nevertheless,some widespread infections like simple steatosisare not included as an underlying factor, whereasnon-alcoholic steatohepatitis is. Also, metabolicand cholestatic liver diseases constitute part ofsusceptibility of the ACLF. This status of chronic liverimpairment predisposes not only to an altered proinflammatory situation based on elevated serumcytokines, but also to a dysfunction in cellular immunesystem, reticulo-endothelial, and impairment in the[25]bacterial translocation defense system .InsultSimilarly to sepsis syndrome, infection may playa major role in triggering the whole inflammatoryresponse. In the Asian continent HBV reactivation isone of the principal causes of ACLF. Other hepatotropicviruses like virus C reactivation might also provoke this[26]failure . In India, superimposed hepatitis E has been[27,28]described as a major precipitant of ACLF.WJG www.wjgnet.comBacterial, fungal or viral primary infection can leadto systemic inflammatory response syndrome (SIRS)that has the potential to cause acute liver failure. Inthe CANONIC study, the principal infections related toACLF were spontaneous bacterial peritonitis (SBP) and[12]pneumonia .Among the non-infective precipitating events,[12]alcoholic hepatitis is one of the most common causes .In the CANONIC study, one of the main predisposingevents of ACLF was active alcoholism during theprevious 3 mo (about 25%). Other situations describedas precipitating events were less frequent (about 8%),and included acute toxic hepatitis, major surgery, orTIPS insertion. Paracentesis without adequate albumin[12,25]replacement, has been reported as well. However,in 40% of cases an obvious precipitating event could[12]not be identified .Host responseHost response is probably the leading factor indetermining the severity of the ACLF and its prognosticoutcome. The extension and range of inflammatoryactivation may result in the development of SIRS,characterized by a strong pro-inflammatory status(despite of an impairment of immune response) thatcan lead to ALF, and dysfunction in other organs.Role of inflamatory response: The host immuneresponse and the inflammatory cascade takeespecially high importance in this syndrome. Thesimilarity between the SIRS produced by sepsis,and ACLF suggests that both entities share commonpathogenic mechanisms. In SIRS there is an activationof the immune system relating leukocytes, endothelialcells, monocyte/macrophages, cytokines, enzymes,chemotactic mediators, and adhesion moleculesoverproduction. In this state, hepatocytes are believedto result in sensitized tumor necrosis factor (TNF)[29]induced apoptosis .Comparing septic patients to ACLF patients, Wasmuth[30]et al formulated the concept of “sepsis- like immuneparalysis” based on a profoundly decreased production12127November 14, 2015 Volume 21 Issue 42

Blasco-Algora S et al . Acute-on-chronic liver failure: Pathogenesis, prognostic factors, and management79.1ACLF-376.752.3ACLF-23240.7ACLF-190-d mortality rates28-d mortality rates22.114No ACLF4.7020406080Figure 1 Mortality rates according to the grade of acute-on-chronic liver failure at 28 d and 90 d according to the grade of acute-on-chronic liver failure.Data from the CANONIC study[12]. Mortality increases with the grade of ACLF, directly related to the type and number of organ failure. ACLF: Acute-on-chronic liverfailure.of TNF-α and low monocyte HLA-DR expression inboth groups. He postulated that this cellular immuneimpairment could contribute to increased mortality.Endotoxins have also been proposed to play a rolein mediating the full activation of neutrophils, whichparadoxically would render them unable to act againstthe insult. An enhanced pro inflammatory cytokineenvironment was proved present in ACLF, as comparedwith cirrhosis alone. As ACLF is a pro-inflammatorystate, it could result in chronically primed neutrophils,but in a deleterious form that might cause functionalfailure in phagocytosis due to a continuous energydepletion, which would prevent them from fighting[31]against further infections .The role that cytokines play in ACLF remains akey point in the pathogenesis of the inflammatoryresponse. Elevated serum levels of many cytokinesincluding TNF-α, sTNF-αR1, sTNF-αR2, interleukin(IL)-2, IL-2R, IL-4, IL-6, IL-8, IL-10, and interferon-αhas been described. In particular IL-6 and TNF-αhad been proposed to have a dual action, producinghepatocyte death and also enhancing hepatocyteproliferation through a complex interplay with Kupffer[10,32]cells (KCs) and hepatocytes.The mechanism in the rise of cytokines can berelated to necrotic liver cells, decreased hepaticclearance or, probably the most important, activationof toll-like receptors (TLRs). These receptors[33,34]activate KCs. Causing KCs to change into M1[35]pro-inflammatory macrophages . TLRs have thecapacity to interact with many different agents,recognizing multiple molecular patterns in pathogen[36]or damage- associated pathways . KCs play a keyrole in liver injury, as they internalize ligands andactivate the signaling cascades, transcription of proinflammatorycytokines, and superoxide agents. Thispromotes oxidative stress and releases proteolyticenzymes, vasoactive substances such as endothelin-1(ET-1), thromboxane A2, nitric oxide (NO), and pro WJG www.wjgnet.comstaglandins, thereby contributing to microcirculatory[37]dysfunction .This entire cascade eventually leads to hepatocytedeath and liver dysfunction. Hepatocyte apoptosisrather than necrosis seems to be the predominantmode of cell death in ACLF, as high levels of theapoptosis marker cytokeratin M30 occurs in ACLF[38]patients . Nevertheless, both paths are not mutuallyexclusive and the concept of “necroapoptosis” is onlyas of late been proposed. Also, the same patient can[38]present both forms of cell damage dynamically .role of bacterial infectionThough the precise mechanisms involved in ACLFhave yet to be clarified, the immune system seems tobe play a predominant role in the setting of cirrhosis,which paradoxically is one of the most common forms[39,40]of immunodeficiency.The homeostatic role of the liver in the systemic[41-43]immune response is well known. This role isdefines as “cirrhosis-associated immune dysfunction”which includes the main syndromic abnormalities ofimmune function, immunodeficiency, and systemic[44]inflammation . This is a dynamic condition which leadsto oscillation from predominantly pro-inflammatory to[44,45]predominantly immunodeficient situations.Immune dysfunction in cirrhosis is multifactorialand reflects a complex interaction between manysystems, predisposing these patients to infections.It is thought that this susceptibility is not due to asole responsible factor, but rather to the concomitantpresence of various facilitating mechanisms such as:portal hypertension with porto-systemic shunting (thusimpairing detoxification and reticuloendothelial systemphagocytic activity), increased gut permeability andbacterial overgrowth (all of them increases the riskof bacteremia and the occurrence of endotoxemia),albumin and lipoprotein dysfunction, or aberrant toll[33,46-49]like receptor expression in KCs.12128November 14, 2015 Volume 21 Issue 42

Blasco-Algora S et al . Acute-on-chronic liver failure: Pathogenesis, prognostic factors, and managementThe presence of innate immune dysfunction in ACLFcan be inferred from susceptibility to infections: 30% to50% of cirrhotic patients presented bacterial infections[50-53]upon their admission or during hospitalization.The most common bacterial infections are SBP (25%),urinary tract infections (20%), pneumonia (15%)[54]and spontaneous bacteremia (12%) . Clinical andbiochemical parameters in bacterial infection weregenerally correlated with the severity of liver disease.Child-Pugh score (CPs) showed a predominance ofclass C in infected cirrhotic patients compared to non[55]infected ones .PATHOPHYSIOLOGY OF ORGANSFAILUREHepato-adrenal axis failureAdrenal dysfunction is frequently reported in patientswith CLD (compensated or decompensated), andsevere sepsis (51%-68%), especially in patients withhigh CPs, model of end stage liver disease (MELD)scores, and hemodynamic instability, thereby reflecting[56-58]a more advanced liver disease. Some hypothesesto explain adrenal dysfunction pathophysiology havebeen proposed, such as: decreased cholesterol levels,overstimulation of the hypothalamus-pituitary-adrenal[56,59]axis by cytokines, and endotoxemia. However, themechanism leading to adrenal insufficiency remains[60]unclear .This dysfunction called “hepato-adrenal syndrome”,is associated with renal failure, hemodynamicinstability, and increased mortality. Hydrocortisoneadministration can have initial favourable effectson hemodynamic parameters, but it has not been[57,61]confirmed to improve the outcome.Test to assess adrenal function and its interpretationin cirrhosis and ACLF is difficult due to the absence ofconsensus, and normal values of this test, therefore[62]recommendations cannot be made .Pulmonary failureRespiratory failure can be classified in two types ofcomplications. First, complications typically relatedto cirrhosis, like hepatic hydrothorax (that canbecome infected), portopulmonary hypertension,hepatopulmonary syndrome, and transfusion-related[63,64]acute lung injury (among others). Secondly,infectious complications (which are the most common),like aspiration pneumonia. Bacterial respiratory tractinfections in cirrhotic patients represent 14% to 48%[65]of all bacterial infections . These patients are atincreased risk of pneumonia due to unprotected airwayfrom altered consciousness, increased intra-abdominalpressure from ascites, endoscopic procedures forgastrointestinal bleeding and increased risk of bacterialtranslocation because of excessive use of proton pump[66-68]inhibitors.The relevance of this OF, and its impact on mortalityWJG www.wjgnet.comin ACLF, can be emphasized by its incorporation intothe CLIF-SOFA score. Respiratory failure is definedin CLIF-SOFA by gasometric parameters, as a partialpressure of arterial oxygen (PaO2)/fraction of inspiredoxygen (FiO2) ratio of 200 or less, or a pulse oximetry[12,69]saturation/FiO2 ratio of 200 or less.Haematological failureFailure in the coagulation system is defined in CLIFSOFA as an international normalized ratio (INR) of 2.5[12]or more, or a platelet count 20000/μL .Patients with liver disease are in a state of“rebalanced haemostasis” which results in an increase[70,71]of both pro-thrombotic and anti-thrombotic factors.As explained above, in ACLF the inflammatory processmay trigger the “unstable balance” to any of these twostates and may be manifested by either bleeding orthrombotic complications. Anti-thrombotic alterationsare thrombocytopenia, abnormal platelet functions,deficiency in the coagulation factors (except forFactor Ⅷ), and increased fibrinolysis. On the otherside of the balance, the pro-thrombotic state, whichis manifested by a decrease of anti-coagulation andplasminogen, associated with an increase in theplasminogen activator inhibitor (PAI), Von Willebrand[72-76]factor and in factor Ⅷ. Summarizing, the mostsignificant haematological abnormalities describedin ACLF are defective platelet function and increased[77,78]fibrinolysis.Coagulopathy is worsened in sepsis by the presenceof endogenous low-molecular weight heparinoids whichdisappear with resolution of infection. In addition,there is an increased risk of bleeding complicationsdue to further increased portal pressure secondaryto infections and may explain the beneficial role ofantibiotics administration in reducing early variceal[79-81]rebleeding. Standard laboratory values, such asthe determination of the INR or the activated partialthromboplastin time, poorly reflect the pathophysiologicalchanges in ACLF, therefore a deeper comprehension ofunderlying mechanisms is needed to guide correction[71,82]of coagulation abnormalities on these patients.Neurological failureHE is a common manifestation of ACLF. Neurologicalfailure is defined by CLIF-SOFA by the development of[83]encephalopathy grade Ⅲ or Ⅳ . Local and systemicdisturbances have been implicated in the developmentof this syndrome. Patients with HE show a functionalderangement in the blood brain barrier leadingto increased transport of neutral amino acids and[84]reduced transport of basic amino acids . Elevatedbrain ammonia level and cerebral hemodynamicdysfunction are known to be the major etiologicalfactors. Recent data suggest that in light of functionalimmunoparesis of patients with liver dysfunction, apoorly understood relationship between ammonia,inflammation and oxidative stress may underlie[85-87]the HE pathogenesis. These alterations include12129November 14, 2015 Volume 21 Issue 42

Blasco-Algora S et al . Acute-on-chronic liver failure: Pathogenesis, prognostic factors, and managementabnormalities in neurotransmission [i.e., disturbancesin aminobutyric acid (GABA) ergic systems], energyimpairment (i.e., decrease in cerebral blood flow,inhibition of cerebral energy metabolism by ammonia),brain oedema (i.e., elevated ammonia levels, hypo natremia) and neuro-inflammation (generation on[88,89]nitric oxide, prostanoids, astrocytic swelling).EH in the setting of ACLF have a different course[90]from cirrhotic patients with AD but without ACLF .Isolated EH usually develops in the context oflong-term diuretic use, and is not associated to animpairment of liver function. The absence of significantinflammatory reaction and the low prevalence oforgan’s failure relatively preserve good prognosis. Bycontrast, patients with HE associated with ACLF hasan extremely poor survival rate, as a consequence ofa generalized inflammatory reaction that may play arole in brain and other organs dysfunction. In additionto liver dysfunction, HE in the setting of ACLF isfrequently associated with bacterial infections, active[91,92]alcoholism or dilutional hyponatremia.Circulatory failureAccording to the CLIF-SOFA, patients requiringinotropic drugs are considered to present circulatory[6,12]failure.Mechanisms underlying haemodynamic and cardiacdysfunction in ACLF resembles closely to those insevere sepsis, as TNF and NO are increased and[57,58]cortisol is decreased. This circulatory dysfunctionis typically characterised by an intense hyperdynamicstate with the inability to obtain adequate perfusionpressure despite volume expansion and requirementof large doses of inotropic agents, with subsequent[93-95]development of lactic acidosis. The increasedinfections risk is often coupled to cardiac dysfunction.This situation may be aggravated by sepsis related toincreased susceptibility to infections, by impairmentin cardiac systolic and/or diastolic function or by the[96,97]presence of hepatoadrenal syndrome. It hasbeen speculated that any acute inflammatory insult inpatients with underlying cirrhotic cardiomyopathy may[97]precipitate cardiovascular collapse . In ACLF there isoften incapacity to appropriately increase the cardiac[98]output in response to the insult . This finding is incontrast to decompensated cirrhosis, where cardiacoutput remains elevated, until advanced stages ofliver disease, secondary to splanchnic vasodilatation.This cardiovascular abnormality is associated with anincreased risk of death, particularly in those patients[99]who present with renal dysfunction . Inotropicsupport is often needed, however the best therapeutic[100]approach remains unclear .Kidney dysfunctionRenal failure is defined by the CLIF-SOFA as acreatinine 2 mg/d and the use of renal replacement[12]therapy . In the CANONIC study kidney failurewas the most frequent OF for ACLF grades (55.8%),WJG www.wjgnet.comfollowed by liver, cerebral, and coagulation failures[12] .(43.6%, 27.7% and 24.1%, respectively) . Asshown, acute kidney injury (AKI) is a frequent and animportant component of ACLF, as it is associated with[101-105]poor prognosis. Mortality is associated to thetype and number of organs failure, and was higherin the subgroup of patients with single kidney failurethan in those with involvement of other organs. Astudy including 562 hospitalised patients with cirrhosis,suggested that the most frequent causes of renalfailure were related to bacterial infections (46%),hypovolaemia (32%), hepato-renal syndrome (HRS)[106](13%) and intrinsic renal failure (9%). Other[107-109]studies support these results. Renal failure maybe categorized into four types: HRS, parenchymaldisease, hypovolemia-induced and drug-induced[106,107,110]renal failure. Attributing the renal failure to asingle mechanism in patients with multiorgan failureis usually difficult. There are many aetiologies of renal[111,112]failure in patients with ACLF. Prerenal factors aregenerally associated with renal hypoperfusion, whichmay be associated with intravascular volume depletion(haemorrhage, renal and gastro-intestinal fluid loss) ormarked deterioration of effective arterial blood volume,[99]leading to HRS . Most intrarenal causes are relatedto ischemic acute tubular necrosis, also due to renal[109,113]hypoperfusion.Undoubtedly, systemic haemodynamics and cardiacdysfunction play an important role in the developmentof renal failure. Thus, in some patients the circulatorychanges may predominate, whilst in other patientsthere may be increased synthesis of pro-inflammatorymediators (or both). SIRS has also been suggested tobe involved, accompanying and aggravating the above[114-116]mentioned mechanisms. The benefit of the antiinflammatory or immunomodulatory agents such ascorticosteroids or pentoxifylline in the prevention ofrenal failure in patients with acute alcoholic hepatitis[106,109,117,118]might support this observation.Liver failureLiver failure is defined by the CLIF-SOFA as a totalbilirubin 12 mg/dL. The hallmark of the livermanifestation of ACLF is hyperbilirubinemia and[12]coagulopathy .Some lines of evidence suggest that the histo pathological characteristics of the liver during ACLFwill

In recent years, a new clinical form of liver failure has been recognised. Traditionally there were two types of liver failure: Acute liver failure (ALF), a rapid deterioration of the liver function in the absence of pre-existing liver disease, in the setting of an acute hepatic insult and chronic liver failure (CLF), a progressive