Acute-on-chronic Liver Failure

Curr Gastroenterol Rep (2016) 18:61 DOI 10.1007/s11894-016-0535-8

LIVER (S COTLER AND E KALLWITZ, SECTION EDITORS)

Acute-on-chronic Liver Failure Shiv Kumar Sarin 1 & Ashok Choudhury 1

# Springer Science+Business Media New York 2016

Abstract Acute-on-chronic liver failure (ACLF) is a distinct entity that differs from acute liver failure and decompensated cirrhosis in timing, presence of treatable acute precipitant, and course of disease, with a potential for self-recovery. The core concept is acute deterioration of existing liver function in a patient of chronic liver disease with or without cirrhosis in response to an acute insult. The insult should be a hepatic one and presentation in the form of liver failure (jaundice, encephalopathy, coagulopathy, ascites) with or without extrahepatic organ failure in a defined time frame. ACLF is characterized by a state of deregulated inflammation. Initial cytokine burst presenting as SIRS, progression to CARS and associated immunoparalysis leads to sepsis and multi-organ failure. Early identification of the acute insult and mitigation of the same, use of nucleoside analogue in HBV-ACLF, steroid in severe alcoholic hepatitis, steroid in severe autoimmune hepatitis and/or bridging therapy lead to recovery, with a 90day transplant-free survival rate of up to 50 %. First-week presentation is crucial concerning SIRS/sepsis, development, multiorgan failure and consideration of transplant. A protocolbased multi-disciplinary approach including critical care hepatology, early liver transplant before multi-organ involvement, or priority for organ allocation may improve the outcome. Presentation with extrahepatic organ involvement or inclusion of sepsis as an acute insult in definition restricts the therapy, i.e., liver transplant or bridging therapy, and needs serious consideration. Augmentation of regeneration, cellThis article is part of the Topical Collection on Liver * Shiv Kumar Sarin [email protected] 1

Department of Hepatology and Liver Transplant, Institute of Liver and Biliary Sciences, D-1, VasantKunj, New Delhi 110070, India

based therapy, immunotherapy, and gut microbiota modulation are the emerging areas and need further research. Keywords ACLF . Organ failure (OF) . Inflammation . SIRS

Abbreviations AARC APASL ACLF Research Consortium ACLF Acute-on-chronic liver failure AD Acute Decompensation CARS Compensated anti-inflammatory response syndrome DAMP Damage-associated molecular pattern ESLD End-stage liver disease PAMP Pathogen-associated molecular pattern SAH Severe alcoholic hepatitis SIRS Systemic inflammatory response syndrome

Introduction Liver failure is an entity associated with poor outcomes and is often considered a medical emergency. It can present as acute liver failure (ALF) in a background of healthy and normal liver or as acute-on-chronic liver failure (ACLF) in a background of underlying chronic liver disease [1••]. Another entity is acute deterioration in liver failure leading to multiple organ failure in a known case of decompensated cirrhosis. While ALF and decompensated cirrhosis are wellestablished clinical entities with various prognostic models and established management plans [2], ACLF is still in need of a universal definition. The two most widely accepted definitions are from the Asian Pacific Association for the Study of Liver (APASL) [1••] and the European Association for the Study of Liver (EASL) Chronic Liver Failure (EASL-CLIF)

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consortium [3••]. Index presentation as acute hepatic decompensation in response to an acute insult in a stipulated time frame with a potential for recovery upon mitigation of insult is the core of the concept. The morbidity and 4-week mortality in ACLF reaches up to 50 % and hence early transplantation is the need [1••, 3••]. Lack of donor, expertise and resource further opens the door for new research to understand the mechanisms of progressive liver failure and newer therapeutic interventions to suppress the injury and for other alternatives to transplant. Bridging therapies like plasmapheresis, liver dialysis and bio-artificial liver are emerging. Augmentation of liver regeneration and various cellular therapies, i.e. stem cell and hepatocyte transplantation, are still nascent. The present review addresses the concept and need of a unified definition, mechanism of injury, prediction model preferably a dynamic one for early transplantation, for guiding therapies beyond transplant and prevention of ACLF.

The Concept of ACLF A healthy person with a normal liver in response to an acute insult leads to a fulminant presentation called ALF. In ALF, the acute insult is clearly known and is hepatic, the time frame is defined, the presentation is liver failure, i.e. jaundice, coagulopathy and encephalopathy, and follows a rapid course with either spontaneous recovery or high short-term mortality [2]. Decompensated cirrhosis is a spectrum, i.e. progressive liver failure with features of portal hypertension and its complications. Persistent decompensation is a state where the patient remains decompensated, and is referred to as end-stage liver disease (ESLD), in which the recovery is dismal and has a protracted course leading to death without LT [4]. In the same continuum, ACLF (Fig. 1) can be defined as an acute deterioration of a pre-existing liver disease, either unknown or known but compensated, in a patient who will develop liver failure, i.e. jaundice, encephalopathy and coagulopathy, suggestive of acute insult and ascites due to persistent injury or severe injury in a defined time period, like ALF [1••]. Progression of this liver failure leads to involvement of other extrahepatic organs like kidney, circulatory and respiratory and often complicated by sepsis [5•]. Occurrence of sepsis as in ALF noted after the onset of liver failure and leads to multi-organ involvement and poor survival [25•]. This understanding can create a spectrum from ALF to ACLF to decompensated cirrhosis without confusion. Acute decompensation (AD) is liver failure with or without the involvement of other organs often in response to a precipitant and the course is faster than decompensated cirrhotics but slower than ACLF [3••, 6]. These can be, for example, an acute development of large ascites, hepatic encephalopathy, gastrointestinal hemorrhage or bacterial infections,

Acute insult

CLD-Cirrhosis

Compensated

CLD-No Cirrhosis

Normal liver

ACLF

ALF

Prior Decompensation

Acute Decompensation

Persistent Decompensation

*Progressive Decompensation(ESLD) X = Needs validation The dotted line indicates the controversy in ACLF

Fig. 1 Acute insult across the spectrum of liver disease. The acute hepatic insult and its consequences depend upon the hepatic reserve and the liver disease status. In a normal healthy person, it leads to acute deterioration of liver function causing acute liver failure (ALF). The presence of chronic liver disease without cirrhosis or cirrhosis in the absence of prior hepatic decompensation in response to acute insult develops liver failure, i.e. jaundice, coagulopathy, hepatic encephalopathy and ascites (features of PHT as well as liver dysfunction). Those with prior decompensation but compensated at present develop acute decompensation in the form ascites, variceal bleed, HE, jaundice or sepsis. They behave in a rapid course leading to poor outcomes with a poor chance of spontaneous recovery. Those having persistent decompensation in response to acute insult showed a rapid deterioration like acute decompensation and no recovery in absence of transplant

hepatorenal syndrome or any combination of these [3••, 6]. However, a proper definition and time frame is lacking at present. However, the data extrapolated from the CANONIC study, i.e. patients with AD and not amounting to ACLF and having a mortality of 12.6 % in a 3-month period, can be considered as AD [6]. ACLF is an entity where two injuries operate, with first one being the acute injury in the form of an acute hepatic insult and the second one being a chronic liver disease with or without cirrhosis [1••]. The contribution of different etiologies for acute insult and chronic liver disease leading to ACLF needs to be discussed (see acute insult and chronic injury section). Irrespective of whether the acute insult is ethanol or viral hepatitis or drug-induced, the final common pathway is the hepatic injury and subsequent rapid deterioration leading to liver failure with or without extra-hepatic organ involvement [1••, 5•]. The Critical Mass and Hepatic Reserve Concept The differences in presentation and outcome in ALF, decompensated cirrhosis and ACLF depend upon the hepatic reserve (Fig. 2). An acute severe hepatic insult in a healthy liver could lead to acute liver failure (ALF), where, with aggressive critical care, the non-transplant survival up to 60 % can be achieved as the liver is in good condition [2]. In the presence of chronic liver disease (CLD), an acute insult leads to rapid and progressive liver failure, with a high short-term mortality

100%


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ALF

Golden Window

Hepatic reserve

Injury ACLF

Spontaneous Recovery

Decompensated Cirrhosis

Liver failure & Liver Transplant

0%

Multi Organ Failure Death Day 0

D7

Time in weeks

Fig. 2 The concept of hepatic reserve and liver failure. The hepatic reserve is normal, hence the patient in response to acute insult develops acute liver failure (ALF); if the acute insult can be mitigated or with aggressive critical care hepatology, the transplant-free survival is up to 60 %. Those recovered had a hepatic reserve back to normal. In ACLF with acute insult/injury had a rapid deterioration and the first week of injury constitutes the therapeutic Golden window. Both ALF and ACLF

had a recovery or eligible transplant before the onset of sepsis or multiorgan failure. D-Cirr showed a progressive downhill course with little recovery and early transplant is needed. The LT should be done prior to onset of MOFALF Acute liver failure, FLF fulminant liver failure, D-Cirr decompensated cirrhosis, LT liver transplant, MOF multi-organ failure. Modified from [5•] with permission of Nature Publishing Group

as the hepatic reserve is limited [1••]. ACLF has a potential of reversibility upon mitigation of the acute insult (specific therapy directed at the acute insult), in the crucial ‘window period’ (a time before the development of sepsis and multi-organ failure) and by supporting hepatic regeneration [7].

failure which is the dominant presentation in ACLF. Further, the time frame is 3 months after acute decompensation to be manifest, while in ACLF, the time course is 4 weeks. The progression can be sudden and insidious. The event can be hepatic and extra-hepatic and the trigger can also be hepatic or extra-hepatic. ACLF is not acute decompensation and is distinct (Fig. 1). The confusion in the definition between east and west is because, in the latter case, all varieties of hepatic and extra-hepatic insults and liver failures have been lumped together, such as acute worsening of decompensated cirrhosis, non-cirrhotic ACLF, hepatic and extra-hepatic ACLF, sepsis and ACLF, and acute decompensation of cirrhosis. Therefore, decompensation either in the past or the present should be separate from ALF or ACLF for the sake of homogeneity and therapeutic implications (Fig. 1, marked with dotted line with crosses). The definition from the east provides a homogenous group of patients with hepatic insults. The diagnosis and differentiation between ACLF and AD is needed for guiding therapy and prognostication. A large prospective multicenter study is needed to address this issue.

Differentiation of ACLF from Acute Decompensation The distinction of these two separate entities is still controversial mainly due to lack of consensus between east and west in defining ACLF. The current acute decompensation in previously decompensated cirrhosis which was earlier stable or those with ongoing decompensation (i.e. ascites, jaundice, coagulopathy, recurrent HE or HRS) with a recent worsening behave in a different manner. In ACLF, the initial good hepatic reserve prior to acute insult and its recovery with mitigation of acute insult is the main reason for transplant-free survival in nearly 50 % of cases [1••]. But in those with a prior decompensation, the hepatic reserve is poor and the recovery upon mitigation of acute insult is not like ACLF or ALF, rather they show a progressive deterioration of liver function in most cases leading to inevitable consideration of liver transplant (Fig. 2). As far as current knowledge is concerned, acute decompensation in cirrhosis may have 4 or 5 well-defined syndromes as outcomes, such as variceal bleed, hepatic encephalopathy, ascites, coagulopathy and liver failure. It is liver

Definition of ACLF At the outset, it is agreed that ACLF is a distinct entity, but there are still a dozen definitions adding to the controversies and confusion. However, the bottom line is the acute decompensation in an established chronic liver disease on

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exposure to an acute insult in a defined time frame. Two most widely used definitions were by APASL and EASL/CLIFSOFA. As per the APASL consensus, ACLF is an acute hepatic insult manifesting as jaundice (serum bilirubin ≥5 mg/dl (≥85 μmol/l) and coagulopathy (INR ≥1.5 or prothrombin activity 60 % cases of DILI in the west [23]. The baseline MELD score (survivors vs. nonsurvivor, 25.5 vs. 33, p < 0.001) and a rising INR or lactate by the fourth day of presentation predicts poor outcome, i.e. only 38 % survival at 90 days and prioritization for LT [22]. Acute Variceal Bleed (AVB): AVB was considered a precipitating event in 13.8 % of cases in the CANONIC study [3••] and 28 % cases in another study [23]. AVB may be considered as a precipitant if the occurrence of hepatic ischemia leads to jaundice and fulfills the criteria of liver failure [1••]. Sepsis and ACLF: Consideration of sepsis as an acute insult is still dubious and confusing. Sepsis is a consequence rather than the cause of ACLF. The APASL definition did not take sepsis into consideration, but in the western definition in fact it is the most common precipitant. The inclusion of sepsis in the definition associated with multi-organ involvement, poor prognosis did not guide toward any definitive therapy, i.e. liver transplant. Bacterial infections are commoner in cirrhosis than in the general population [24]. Cirrhosis Associated Immune Deficiency Syndrome [25••] reduced monocyte HLA-DR expression and an inability to produce TNF-α [26], reduced both pDCs and mDCs in addition to increased IFN-ϒ-producing CD8+T cells [27•] and included a genetic predisposition with the TLR2 GT microsatellite polymorphism and with NOD2 [28] increases the risk of infection. SIRS is


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Chronic Injury

the inflammatory response of the host. Hence, it could be a result of occult infection or sterile inflammation [29•]. In fact, in 60 % of patients fulfilling the SIRS criteria, infection could not be detected [7]. This highlights the limitations of the current techniques available to detect infections or it may be because of the use of prophylactic antibiotic. Various organ failures, i.e. renal, cerebral and coagulation, were significantly higher in the presence of SIRS with or without sepsis. The frequency of organ failure did not differ in patients with SIRS; whether or not sepsis was present [7]. This fact highlights the importance of SIRS and supports the fact that, irrespective of infection, SIRS is the major determinant of MOF and mortality seen in patients of ACLF, as was also reported in AH patients by Michelena et al. [30]. Prevention of the development of SIRS or its progression from SIRS to sepsis by immune modulation in the ‘Golden Window’ period could decrease the incidence of organ failure and improve survival (Figs. 2 and 3) [7, 31••]. But this needs further study and large amounts of data.

Like acute insult, the etiology of chronic liver disease and cirrhosis varies in different parts of the world. The common etiologies include alcohol and hepatitis B and C and NASH [1••]. A study from the west [21] and AARC from Asian region [1••, 11] reveal nearly half being ethanol-related and associated with poor outcome [12]. Chronic liver disease encompasses varying degrees of fibrosis or cirrhosis. While the APASL definition includes both cirrhotic and non-cirrhotic ACLF, the EASL/AASLD definition of ACLF has now been revised to include both, grouped as Type-A (non-cirrhotic ACLF) and Type-B (cirrhotic ACLF) [8]. Diagnosis of previously undetected CLD in the setting of ACLF is difficult unless overt signs of portal hypertension, such as enlarged spleen, along with laboratory parameters and endoscopic or radiologic evidence, are present. Often, liver biopsy through the transjugular route can establish the diagnosis. The AARC data using liver biopsy studies have corroborated that a proportion of patients presenting with ACLF have advanced fibrosis but not cirrhosis [1••].

Hepatic Environment

Gut

Hepatic Microcirculatory dysfunction

Systematic Circulation

Portal Hypertension

Hepatocytes

HSC activation ET-1,TxA2,PG

ROS

Leaky Gut and Dysbiosis LPS/Endotoxin

Neutrophil s

MERTK

CxCR3

TLR 4 C3 R Activated Kupffer Cells

NKT cells

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Dendritic cells pDC mDC

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Th-17

Necrosis & Apoptosis

NO

IL-10, TGF-B, IL-17

Pro-inflammatory TNF- ,IL-6, IL1 ,IL-17

Th-17 Monocytes T-regs T-regs

Fig. 3 The mechanism for immune mediated injury in ACLF. Increased gut permeability leads to migration of immune cells, endotoxin and LPS to the liver. The acute hepatic insult like viruses or alcohol activates the intrahepatic immune milieu. Kuppfer cells are the first line of defense, and with the help of TLR-4, complement receptors (C3R, C5R) and DAMPs, become activated. Release of inflammatory mediators TNF-α, sTNFαR1, sTNF-αR2, IL-2, IL-2R, IL-6, IL-17, CXCL-8, and IFN-α, along with regulatory cytokines IL-4, IL-10, TGF-β and free oxygen radicals, eicosanoids, and lysosomal and proteolytic enzymes occur at the local site. This leads to activated myofibroblasts from quiescent stellate cells and the release of endothelin-1 (ET-1), thromboxane A2, nitric oxide (NO), and prostaglandins. This causes hepatic microcirculatory

Anti-inflammatory IL-4,IL-10, TGF-

Liver failure, MODS, Shock

Resolution SIRS, CARS Clinical Recovery

dysfunction and raised portal pressure. NO release causes inflammatory cell death via necrosis or apoptosis of hepatocytes, which also damages its neighboring cells. The increase in pDCs dendritic cell infiltration along with a decrease in mDCs, and neutrophil infiltration by IL-8 CXCL1 and IL-1 occur. The cytokines burst and release of ROS perpetuate the inflammatory injury and ongoing hepatic apoptosis and necrosis. Tregs also exhibit significant inhibition in IFN-γ production. TGF-β and IL-6 secreted from monocytes help in generating IL-17A-secreting CD4+ T cells. MERTK expression further increases susceptibility to infection. This cytokine burst and inflammatory cascade leads to hepatocyte loss, persistent SIRS, CARS, immunoparalysis, MODS and to organ failure. (* Acute hepatic insult)

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Mechanism of ACLF and Development of Organ Failure Liver failure in ACLF is multifactorial and self-perpetuating mainly due to an inappropriate and widespread activation of the inflammatory pathways [32]. Immunomediated Injury in ACLF Immunological injury in ACLF relates to the relative inefficiency of the innate and adaptive immune system [32, 33] (Fig. 3). The Kupffer cells, the resident macrophages in the liver, are amongst the first line of defense and are of two types; M1 and M2 [34]. The activation of the M1 phenotype [34] occurs through TLRs and DAMPs in response to LPS. TNF-α and IL-6 have dual actions of inducing hepatocyte death as well as stimulating hepatocyte proliferation [35]. Simultaneously, M2 Kupffer cells are activated in response to IL-4 and IL-10 released from Th2 cells [34]. The M2 phenotype causes antiinflammatory effects through cytokines such as transforming growth factor-beta (TGF-β) and favors progression to CARS [36•]. Kupffer cells modulate stellate cell function and contribute to hepatic microcirculatory dysfunction [37, 38]. Neutrophils are increased, but mostly dysfunctional, with increased resting burst and reduced phagocytic function [36•, 39]. Monocytes and DCs are mediators which present antigens in their MHC class II molecules to T cells for T-cell activation and proliferation. ACLF patients show ‘early’ reduction in HLA-DR expression on monocytes with reduced ability to produce TNF-α. The persistent or long-term HLADR suppression is associated with poor outcome, and rebound increase in expression correlates with clinical recovery [40]. MER receptor tyrosine kinase (MERTK), a transmembrane protein expressed on monocytes/macrophages, DCs, and epithelial cells is a negative regulator of the immune system. MERTK expression is increased in ACLF patients, which correlates with SIRS components, inflammatory cytokines and subsequent increased infections [41, 42]. Regulatory T cells (Tregs) increase or cause inhibition of IFN-γ production leading to the deactivation of monocytes and macrophages. TGF-β and IL-6 secreted by the monocytes help in the production of IL-17A-secreting CD4+ T cells known as Th17 cells. The ratio of Th-17 to Tregs is inversely associated with survival in ACLF patients [43]. In brief, there is a loss of immunological balance between the pro-inflammatory and anti-inflammatory responses to stressors. The activated immune cells appear to be dysfunctional, paralyzed, and energy-depleted resulting in an exaggerated SIRS followed by CARS and a further increase in susceptibility to infections. Even in the absence of overt infection, ACLF display sepsis-like characteristics [36•].

Evolution of Organ Failure in ACLF In ACLF, the inflammatory mediators are released in liver [5•, 44]. The gut dysbiosis, leaky gut, and increased bacterial translocation lead to perpetuation of the inflammatory cascade [5•, 44]. This is in accordance with the concept of the inducer– sensor–mediator–effector cascade of inflammation and can best explain our observations in patients with ACLF who had acute hepatic decompensation in response to injury [29•]. Development of extra-hepatic organ failure, especially renal failure, follows liver failure with the development or persistence of SIRS (Fig. 4). These data support the concept of compartmentalization of the inflammatory response in noninfectious or infectious insults [43]. As expected, in sepsis and SIRS, the responses vary from one organ to another. This could be due to spill-over of inflammatory cytokines from the liver to the blood compartment and cross-talk between the liver and other organs, especially kidney. This was supported by AARC data on 561 patients where the presence of liver failure is an independent predictor for the development of SIRS [7]. This is supported by the study of Thabut et al. [45] and Maiwall et al. [46] who have shown higher incidence of AKI and mortality with SIRS. SIRS is the clinical, but often a surrogate, marker for biochemical and immunological response to inflammation. In ACLF patients, a new onset of SIRS or sepsis from no SIRS occurs in a median period of 7 days which can be considered as the window period [4]. This leads to organ dysfunction in up to 40 % of ACLF patients even in the absence of any overt infection [9]. SIRS is associated with more severe encephalopathy, an increased incidence of bacterial infections, renal failure and poor survival. In a large study, the persistence of SIRS up to 7 days, or new onset SIRS within the first week, correlated with progressive liver failure and high mortality (82 % with SIRS vs. 48.7 % without SIRS, p < 0.05) [7].

Management The management of ACLF is often a multidisciplinary approach that includes hepatology, transplant hepatology, nutritionists, infection control and critical care expertise for a better outcome. Disease Prognostication The various severity scores, i.e. SOFA and APACHE-II (commonly used in critical care settings) in addition to MELD, have been studied in patients with ACLF [9]. Currently, the CLIFSOFA score endorsed by EASL-CLIF is used for assessment of disease severity and prognostication [3••, 6]. Though it is


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Fig. 4 Evolution of organ failures in ACLF. Organ failure is a late phase of response by the host following acute hepatic insult in ACLF. The predisposition in genetic susceptibility (NOD2, etc), dysbiosis and leaky gut with increased bacterial translocation enable the persistence of the inflammation. This leads to SIRS, subsequent CARS and subsequent

immunoparalysis. This leads to extra-hepatic organ failure, which is proportionate to the persistence of SIRS, mostly associated with sepsis. The window period is from the time of onset to the development of SIRS or sepsis and the onset of multi-organ failure

useful, it is cumbersome in general practice. A recent study [47••] showed that a simple score considering only the number of organ failures is easier to recall and superior to the CLIFF SOFA score in predicting mortality in ACLF patients. All these scores have been validated at baselines but not in a dynamic manner for prognostication in ACLF patients.

A recently suggested AARC score from 1402 patients of ACLF considering bilirubin, creatinine, PT-INR, lactate and hepatic encephalopathy is dynamic and superior to the existing model in predicting the outcome with AUROC 0.78, a specificity of 76 %, and 70 % positive and negative predictive values [11]. Role of Liver Biopsy in Prediction of Outcome in ACLF

Need for a Dynamic Model The severity of ACLF, its rapid progression, the development of sepsis and subsequent MOF, and poor outcome with liver transplantation at the onset of MOF needs a balance with too early LT in a potential recoverable group. Recent studies support for developing a dynamic model that could predict the outcome and appropriate time for LT. Chan et al. [48] in 149 patients showed that APACHE-II scores ≥12 and MELD scores ≥28 after the first week of treatment were independent predictors of mortality. Mathurin et al. [49] showed that, in the absence of a response to corticosteroids for AH as assessed by a Lille score on day 7 and consideration of early LT lead to a significant cumulative 6-month survival rate (77 ± 8 vs. 8 %, p < 0.001). In large UK and US cohorts of severe autoimmune hepatitis, it is not the baseline MELD/UKELD score but the lack of improvement in MELD/UKELD scores within 7 days of initiation of corticosteroid which lead to a poor outcome and have been suggested for early consideration of alternative strategies including liver transplant [50, 51].

Liver biopsy in the presence of coagulopathy and ascites in ACLF patients is challenging and should be individualized by a transjugular approach. Rastogi et al. [52••] have shown that pattern I, showing marked ductular proliferation, coarse inspissated ductular bile plugs, eosinophilic degeneration of hepatocytes, foci of confluent/bridging necrosis, higher apoptosis, pericellular fibrosis, Mallory's hyaline, and higher stage of fibrosis (Fig. 5) is associated with poor prognosis [53]. Similarly, sub-massive hepatic necrosis (SMHN), characterized by extensive and confluent necrosis, cholestasis, ductular bilirubinostasis, fibrosis stage, polymorphonuclear infiltration, type of bilirubinostasis, and the presence of megamitochondria in SAH predict a poor outcome [53], while bilirubinostasis correlates with the development of bacterial infections (OR 1.57 95 % CI: 1.00–2.47; p = 0.04) and advanced fibrosis predicts poor regeneration [53]. So a dynamic disease severity score, considering the demographic profile, the etiology of acute insult and histologic changes could guide prognosis.

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Fig. 5 Histological pattern in ACLF. The histological pattern in patients with ACLF is shown; poor prognosis is indicated by ductular billirubinostasis (a), extensive necrosis (b), eosinophilic degeneration (c), advanced fibrosis with nodule formation (d) whereas favorable outcome is indicated by the presence of ballooning degeneration (e), confluent necrosis (f), acinar disarray with hepatocellular and canalicular bile (g) and thin septa and mild fibrosis (h). Reprinted from [5•] with permission of Nature Publishing Group

Pattern I: Poor Prognosis A

B

C

D

Pattern II: Good Prognosis E

F

Treatment of ACLF The treatment of ACLF includes general measures (nutrition, ICU care), specific therapies, bridging therapies, definitive therapies and emerging therapies. Nutrition Nutritional supplement and enteral tube feeding with a target of 1.5 g of protein/kg and 39 calories/kg/day may be considered in cases of poor oral intake [54]. In a recent study, a carbohydrate-predominant late evening snack has been shown to be beneficial in adults with ACLF [55]. Optimal nutritional support in ACLF has not been well defined. ICU Care These patients are relatively sick and need frequent monitoring for SIRS, sepsis and hypotension. Prophylactic antibiotics are often recommended with the onset of SIRS as it is difficult to differentiate SIRS from early sepsis [1••]. The choice of antibacterial therapy should be based on the type, severity, and origin of infection (community acquired or nosocomial), and on the local epidemiologic data about antibiotic resistance [1••]. Hepatic Encephalopathy (HE) In the recent AARC data, HE was seen in 40 % of the patients at admission and associated with higher mortality, especially in those with grades 3–4 HE. Ammonia-lowering therapies like lactulose and rifaximin remain the main therapy [1••]. Acute Kidney Injury (AKI) This is multifactorial and can often be due to hepatorenal syndrome, drugs, diuretics, bile pigment nephropathy, acute tubular necrosis [56] and sepsis. AKI is seen in 25 % at admission, associated with a high 7-day

G

H

mortality (38 vs. 7 %, p < 0.05) [57]. Only 45 % of ACLF patients with AKI respond to terlipressin and albumin with a survival advantage [57]. Nonresponders may need renal replacement therapy and should be preferred for continuous forms of renal support therapy like continuous venovenous hemodialysis (CVVHD) over conventional hemodialysis or slow low-efficiency dialysis (SLED) [58].

Specific Therapies A. Antiviral strategies in ACLF HBV reactivation: Reduction in HBV DNA of >2 logs from baseline after 2 weeks of tenofovir has been shown to improve transplant-free survival from 17 to 57 % in a randomized trial [59•]. Other potent antiviral agents such as entecavir or telbivudine can also be used. B. Alcoholic hepatitis: Nutrition, psychosocial rehabilitation, anti-craving agents like baclofen and corticosteroids remain the mainstay. Corticosteroid response is seen in approximately 60 % of patients [49] with better shortterm survival, but the 6-month mortality still remains ~30–40 %. Infection is commonly seen in around 25 % of patients with severe ASH at admission, and another quarter finally become infected while receiving corticosteroids during admission [60]. Sensitivity to corticosteroids improves by theophylline (enhanced recruitment of histone deacetylases), histone acetylation pathway (decreasing acetate levels via inhibition of acetyl-coA synthetase) or the IL-2 receptor [anti-CD25]) [61]. Pentoxifylline, N-Acetyl cysteine, S-adenosyl methionine and various anti-TNF agents have not yet been used


in routine practice. Newer approaches considering molecules targeting inflammation such as TLR4 antagonists or IL-1 receptor antagonists (anakinra), or those targeting bacterial translocation, apoptosis (emricasan) and/or liver regeneration, as well as antibiotics and synbiotics for gut flora modulation and or fecal microbiota transplants, have been under consideration [62]. C. Autoimmune Hepatitis About 20 % of patients with AIH have an acute presentation with jaundice, encephalopathy, and coagulopathy with or without ascites as autoimmune flares resembling acute liver failure or ACLF [50]. Some studies have argued against the use of corticosteroids but it is supported by the US-ALF group that defined this entity as AIH-ALF [51]. The corticosteroid responders and nonresponders did not differ in MELD/ UKELD scores, and incidence of sepsis, so the UK study group suggested that the use of corticosteroids and the failure to improvement in prognostic scores within 7 days should be considered for early alternative therapeutic strategies including liver transplant [50, 51]. The second-line immunosuppression with tacrolimus or mycophenolate has been shown in small studies but a definite conclusion can be drawn for routine use. So, to conclude, in the presence of ascites, jaundice and/or encephalopathy, the role of steroids may be limited warranting early referral for liver transplantation.

Definitive Therapy- Liver Transplantation ACLF is characterized by rapid progression and the need for multiple organ support with a high short- and medium-term mortality of 34–51 % [1••, 3••]. With improved critical care, transplant-free survival has improved to 60 % in patients with ALF. ACLF patients have one component of chronic liver disease, another being the acute precipitant. The mitigation of acute insult may lead to spontaneous recovery [1••]. Although many prediction models of early transplantation listing exist, none reliably predicts the chances of reversibility of ACLF. While early transplant in carefully selected patients with alcohol-related ACLF improves outcome, an ethical dilemma remains if the patient has been drinking until recently (Table 1). The decision to proceed with early liver transplant should be balanced against the possibility of spontaneous recovery [70]. Timing of liver transplant is crucial in this group of relatively sick patients and should be considered before the development of sepsis or multi-organ failure. A recent study showed that ACLF patients develop SIRS and sepsis within 7 days of hospitalization [7]. Pamecha et al. [70] proposed the serial assessment of this group of patients in the first week of hospitalization for prioritization for liver transplantation. The timing for LT in patients of ACLF due

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to severe alcoholic hepatitis is a major issue. Abstinence for 36 months, high short-term mortality, the scarcity of donors and the risk of recidivism require to be balanced. Mathurin et al. [71] showed that, in the absence of a response to corticosteroids for AH as assessed by the Lille score on day 7 and consideration of early LT leads to a significant cumulative 6month survival rate (77 ± 8 vs. 23 ± 8 %, p < 0.001) and this benefit was maintained through 2 years of follow-up (hazard ratio, 6.08; p = 0.004). Studies have shown that a MELD score >30 associated with high mortality and the number of extrahepatic organ failures determines the outcome of LT [64]. But when sick, often critically ill and admitted to ICUs, the rapid progression of liver failure and onset of multiorgan failure, means that transplantation is only feasible in ~25 % of patients. In the presence of ≥4 organ failures at admission and the persistence of same at 3–7 days leads to 100 % mortality by 28 days in the absence of liver transplantation [72••]. Results of liver transplant in ACLF in various studies have shown encouraging results with 1-year and 5 year survival close to 90 % (Table 1). Recently, Gustot et al. showed that early liver transplantation upon diagnosis of ACLF, that is, within a median of 11 (1–28) day’s led to a 75 % 1-year survival [72••]. A recently presented 1021 ACLF patient evaluation for LT in an APASL ACLF cohort [12] showed that despite 56 % needing LT at presentation upon diagnosis of ACLF, only onethird were eligible; however, by the end of 1 week, maximum recovery from sepsis and organ failure enabled LT possible in 625 cases, and beyond this the mortality showed a sharp increase. So the first week of presentation with ACLF is crucial for prognostication and consideration for LT.

Bridging therapy with Artificial Liver Support Systems (ALSS) In ACLF, there is an accumulation of various toxins and inflammatory cytokines. Removal of toxins improves the capacity of the liver to regenerate or else a liver support system can be a bridge to liver transplantation until a suitable organ is available [73•]. Artificial liver support systems are of two broad categories: artificial liver support systems and bioartificial liver support systems. Artificial Liver Support System (ALSS) Molecular Adsorbent Recirculating Systems (MARS) and fractionated plasma separation and adsorption (FPSA; the Prometheus device) have been the commonly used ones for patients with ALF and ACLF. The use of Prometheus in patients of ACLF (n = 145) showed a significant reduction in serum bilirubin levels without any survival benefit. However, a predetermined post hoc analysis in patients with type I hepatorenal syndrome (HRS) and a MELD score greater than

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Table 1

Liver transplant in ACLF

Ref.

Study

n

Mean MELD score

Hospital mortality (%)

Overall survival (n)

One-year survival (%)

Five-year survival Rate (%)

[63••] [64] [58] [65]

Finkenstedt et al. 2013 Duan BW et al. 2013 Xing T et al. 2013 Lin KH et al 2013

33 100 133 54

28 32 28 24

N/A 20 21.8 N/A

28 80 104 50

84.8 80 78.1 92.6

82 74.1 72.8 N/A

[66] [67] [68]

Liu CL et al. 2003 Ling Qi et al. 2012 Bahirwani R et al. 2011 Chan AC et al. 2009 Wang ZX et al. 2007 TOTAL

32 36 126 N/A 157 32.8

6.3 16.7 25.5

28 92 117

88 73 74.5

84 N/A N/A

149 37 42 33 826

4.7 16.7

142 35 676

95.3 83.3 83.3

90 NA 80.6

[48] [69]

NA Data not available, HE hepatic encephalopathy, DDLT deceased donor liver transplant, LDLT live donor liver transplant

30 at admission showed a survival benefit [74]. The results of the largest randomized trial of the use of artificial liver support systems in patients with ACLF (the RELIEF study) [75] considering MARS for 189 patients showed a decrease in serum creatinine level (p < 0.02) and bilirubin level (p < 0.001) with improvement of hepatic encephalopathy (from grade II–IV to grade 0–I; 62.5 vs. 38.2 %; p = 0.07) at day 4, but without any survival benefit. A recent meta-analysis [76] considering studies from 1973 to 2012 showed a decrease in mortality in patients with ACLF treated with artificial liver support systems. But in all these studies, the patients at inclusion were quite heterogenous, and no well-defined criteria were taken into consideration at enrolment, hence a proper RCT with a large sample is needed to derive a conclusion (Table 2). Table 2

Bio-Artificial Liver (BAL) Support The main purpose of BAL is to supplement the hepatocyte function until recovery of liver failure. The present data on BAL for ACLF are limited and have been extrapolated from ALF patients. The core of BAL is the bioreactor, which is available in various forms, mainly for clinical trial, and none is commercially available for clinical use [80, 81]. Common sources of hepatocytes in the bioreactors include isolation of primary hepatocytes, hepatocytes derived from cadaveric livers deemed unsuitable for transplantation or immortalized human hepatocytes developed via spontaneous transformation, telomerase constructs introduction or retroviral transfection, or the C3A line, a sub-clone of the HepG2 hepatoblastoma cell line. The common BAL include the AMC-BAL Bioreactor, the HepatAssist device (a

ACLF and artificial liver support system (ALSS)

Ref. Study

Study population

n

Trial design

[77] Ash et al. 1994

ACLF ALF ACLF – severe alcoholic hepatitis (9 MARS, 9 control)

56

Liver dialysis vs. SMT

[78]

[79]

[75]

[74]

Device

Clinical results

Hemodiabsorption Improved HE and hemodynamic profile. Increased bleeding in patients with DIC. Sen et al. 2004 18 MARS+SMT vs. SMT MARS Improvement of HE. No hemodynamic changes. No changes in plasma cytokines and ammonia levels Laleman et al. 2006 ACLF – severe 18 MARS+SMT vs. MARS Better hemodynamic improvement alcoholic hepatitis Prometheus+SMT With less bilirubin reduction or SMT alone (3 days) than Prometheus Banares et al. 2013 ACLF: Bil > 20 mg/ 189 MARS+SMT vs. SMT MARS No changes in survival. dl and/or HE Up to 10 sessions (6–8 h) Improvement in HE. greater than Improvement in HRS. grade II and/or HRS No differences in overall adverse events. Kribben et al. 2012 ACLF 145 Prometheus+SMT vs. Prometheus No changes in overall survival. SMT Survival benefit in post-hoc analysis in type Up to 8–11 sessions I HRS and MELD score >30.

ALF Acute liver failure, ACLF acute-on-chronic liver failure, SMT standard medical therapy, MARS molecular adsorbent recirculating system, HE hepatic encephalopathy, HRS hepato-renal syndrome, DIC disseminated intravascular coagulation

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Multiple doses, Subcutaneous 4 weeks G-CSF+Darbopoietin α Double- blinded RCT Kedarisetty CK et al. Gastro 2015 104

Total (55) 29 Treatment 26 Placebo

Severe Alcoholic hepatitis Open RCT Singh V et al. Am J Gastroenterol 2014 103


G-CSF HBV related ACLF RCT Duan XZ et al. WJG 2013 102


G-CSF ACLF(APASL) Double -blinded RCT Garg et al. Gastro 2012 101


Liver disease Study design Cases Study Ref.

Mesenchymal Stem Cells or Multipotent Mesenchymal Stromal Cells (MSCs) Therapy Therapies with MSCs have been extensively investigated in small animal models to treat both acute and chronic liver injuries. Therapeutic benefits of these MSCs could be due to the ability of these cells to differentiate into hepatocyte-like cells, to reduce inflammation, and to enhance tissue repair at the site of injury [87–89]. Use of autologous BM MSC in ACLF is not possible due to the emergency needs, and the data on MSC transplantation are limited. Only a single study has yet used umbilical cord-

Trials of G-CSF–mobilized hematopoietic stem cell transplant in patients with liver disease

Hepatocyte Transplantation Clinical use of adult hepatocytes and fetal hepatic progenitor cells have shown transient clinical benefits in metabolic liver diseases and ALF, but with very limited benefits in CLD [84] and ACLF. Recently, Wang et al [85] have shown significant improvements in the survival of ACLF patients with intrasplenic hepatocyte transplantation. Of the 7 ACLF patients with