Rajneesh AR et al

Calicut Medical Journal 2011; 9(2):e6

Review Article

Acute on Chronic Liver Failure

Rajneesh AR, Kavitha Rangan, Varghese Thomas Department of Gastroenterology ,Calicut Medical College _______________________________________________________________________________________ Introduction In 2002, Rajiv Jalan and colleagues came with the Liver failure can develop either acutely in the definition of ACLF based on SOFA absence of any pre-existing liver disease or as acute (sequential organ failure assessment) and APACHE on chronic liver failure (ACLF) which denotes an 7 scoring. They acute deterioration of known or unknown chronic liver defined ACLF as an acute disease or as a gradual decompensation of an enddeterioration in the liver function over a period of two stage liver disease. Acute liver failure is a well defined weeks, which is usually associated with a precipitating and well understood clinical entity and connotes a event leading to severe deterioration in clinical status very poor outcome. with jaundice and hepatic encephalopathy and or ACLF is also a serious condition with varied etiology hepatorenal syndrome with a high SOFA or APACHE 6 and manifestations and with a high mortality rate. This II score. Acute liver failure has widely accepted term was first used in 1995 to describe a syndrome definition (AASLD definition) that includes evidence of where two insults to the liver are operating coagulation abnormality, usually an INR >1.5, and any 1 simultaneously, one chronic and the other acute . degree of mental alteration (encephalopathy) in a There is limited data on the entity of ACLF in English patient without preexisting cirrhosis and with an 2 literature. The Asia Pacific Association for the Study illness of <26 weeks duration . APASL defined liver of the Liver (APASL) set up a Working Party on ACLF failure in ACLF as jaundice (serum bilirubin 5 mg/dL in 2004 with a mandate to study and analyze the [85 mol/L]) and coagulopathy (INR 1.5 or various aspects of this clinical entity and to develop Prothrombin activity <40%) which are mandatory, consensus guidelines on ACLF relevant to the which is complicated within four weeks by ascites and disease pattern and clinical practice. APASL defined or encephalopathy determined by physical 2 ACLF as acute hepatic insult manifesting as jaundice examination. and coagulopathy, complicated within 4 weeks by Constituents of ACLF ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver Constituents of acute events included infectious and 2 disease. non infectious etiologies and also unknown hepatotoxic etiologies. Among the infectious Definition of ACLF etiologies, the predominant ones were Hepatotropic Terms like hyperacute liver failure (<7days), acute and non-hepatotropic viruses. Reactivation of liver failure (8-28 days), subacute liver failure (> 28 hepatitis B (overt or occult) or hepatitis C, other 3 days) have been proposed . On the other hand, the infectious agents afflicting the liver which included time line for fulminant and subfluminant hepatic failure Spirochetal, protozoal, helminthic or fungal organisms 4 (<2 week) and late onset hepatic failure (>8 weeks) which directly infect the liver, while bacterial or 5. has also been reported There is no consistent parasitic infection may spread to the liver from other 7 definition of ACLF in the literature. Each study on sites . ACLF has used its own definition and there is no The major etiological agents responsible for unanimity in these definitions in terms of criteria for precipitating ACLF are quite distinct in the East and liver failure, criteria for the acute event precipitating the West. Alcohol and drugs constitute the majority of ACLF and the criteria for the diagnosis of underlying acute insults in the West while infectious etiologies chronic liver disease. As most of these studies were predominate in the East. The difference in the on patients who required liver support devices or liver etiologies of ACLF between the East and the West transplantation, these studies were essentially also reflects the differences in the etiology of the included more sick patients in the definition and underlying chronic liver disease in the different patients having a milder course were generally geographical regions. Among the infectious etiologies, excluded from this definition. reactivation of hepatitis B virus infection is one of the
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major causes of ACLF in the Asian region. The other very important infectious etiology of the acute event is superinfection with hepatitis A and E, predominantly 8,9,10 in patients in the Indian sub-continent The non infectious etiologies included were active alcohol drinking within the last 4 weeks, use of hepatotoxic drugs, herbs, flare of autoimmune hepatitis or Wilsons disease, surgical intervention, variceal bleed. Among the non-infectious etiologies, alcoholic hepatitis is the major cause of acute deterioration in stable known or unknown chronic liver disease, more often in the western countries. Hepatotoxic drugs and herbal indigenous medicines are important causes for liver failure in the Asia11 Pacific region. Among the etiologies for chronic liver disease in ACLF, alcoholic cirrhosis constitutes 50-70% of all the underlying liver diseases of ACLF in the western countries while hepatitis B related cirrhosis constitutes about 10-15% of all the cases. However, in most of the Asian countries, hepatitis B constitutes 70% and 13alcohol only about 15% of all the etiologies of ACLF 22 . Autoimmune liver disease, Wilsons disease, metabolic liver disease and chronic cholestatic liver disease constitute only minority of patients. NASH, irrespective of stage of fibrosis, has been included as an underlying chronic liver disease in ACLF. However, since simple steatosis may not always be progressive, it was not included as an underlying chronic liver disease for ACLF. Pathophysiology of ACLF
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ACLF is a state of severe functional failure of neutrophils in a proportion of patients with cirrhosis and alcoholic hepatitis and that these defects are associated with increased risk of infection, organ 15,24,25 failure, and mortality. The clinical importance of these neutrophil abnormalities, which are identified by a high resting oxidative burst greater than or equal to 55% and a reduced phagocytic capacity (relative geometric mean fluorescence intensity <42%), are highlighted by the observation of increased risk of infection and the association with organ failure and 24 mortality in these patients Inflammation and oxidative stress also induce production of nitric oxide (NO), which appears to cause the circulatory and renal disturbances of liver failure. There is increasing evidence that the mediators of inflammation (e.g., proinflammatory cytokines, NO, and oxidative stress) could modulate the effect of hyperammonaemia in precipitating encephalopathy. The liver plays a prominent role in the metabolism of asymmetric dimethyl-l-arginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase. Hepatocellular damage is a main determinant of elevated ADMA concentration in advanced alcoholic cirrhosis. By inhibiting NO release from vascular endothelium, ADMA might oppose the peripheral vasodilation caused by excessive NO production in severe cirrhosis. Plasma ADMA and stereo-isomer symmetric dimethylarginine (SDMA) are significantly high in alcoholic hepatitis patients and in nonsurvivors. High ADMA and SDMA are markers of poor prognosis in ACLF patients. DAS: (dimethyl arginine score) of >1.23 indicates higher 26-28 mortality Sepsis and ACLF Sepsis plays an important role in the progression and management decisions of ACLF, but whether it itself acts as an initial precipitating event was debatable. The existing literature from the United Kingdom and the United States has included sepsis as an integral cause for the development of ACLF. However, it was argued that sepsis alone might not directly cause an acute hepatic insult but could result in worsening of the condition of the patient. Furthermore, sepsis per se can cause organ failure in cirrhotic patients without direct hepatic derangements.

Main pathophysiological mechanism described are presence of SIRS (systemic inflammatory response syndrome), proinflammatory cytokine release, endotoxemia, neutrophilic dysfunction, and also due to increased nitric oxide levels. Systemic inflammatory response, characterized by a predominantly proinflammatory cytokine profile, causes the transition from stable cirrhosis to ACLF. Pro-inflammatory cytokines are believed to mediate hepatic inflammation, apoptosis and necrosis of liver cells, cholestasis, and fibrosis. Wasmuth etal demonstrated that patients with ACLF have immunological defects 15 that are comparable to those in patients with sepsis.

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Figure 1 shows the complex interplay between various factors and cytokines Role of cytokines There is elevated levels of many cytokines including TNF-alpha, IL-2, IL-4, IL-6, IL-8, IL-10, and IFN . Cytokines such as TNF- and IL-6 may also promote liver regeneration by inducing acute-phase proteins and hepatic proliferation and by exhibiting antiapoptotic effects. Elevated levels of circulating cytokines in ACLF may be the result of increased production due to endotoxemia, cytokine release by necrotic liver cells, and/or reduced hepatic removal. TNF- can induce apoptosis of hepatocytes, especially in alcoholic liver disease when hepatocytes are sensitized to TNF-- induced apoptosis. Recent studies suggest that the transition from a stable cirrhotic condition to the burst of an acute decompensation leading to liver failure is based on an acute systemic inflammatory response, mainly 29,30 mediated by cytokines . Karvellas et al analysed 184 patients of ACLF, of which Infection was documented in 67 (36%) patients. Gram negative organisms contributed 58%, gram positive organisms in 36% and fungal in 6% 31 cases. Fibrin deposition and thrombosis within the microvasculature is now appreciated to play a pivotal role in the hepatocellular injury observed in viral hepatitis. Activated endothelial cells and macrophages express distinct cell-surface procoagulants, including a novel prothrombinase, Fgl2/fibroleukin, which are important for both the initiation and localization of fibrin deposition. There is a critical role for Fgl2/fibroleukin in the pathophysiology of viral hepatitis. Human fgl2 (hfgl2) was detected in 21 of 23 patients (91%) with severe 32 ACLF due to hepatitis B . There was a positive correlation between hfgl2 expression and the severity of the liver disease as indicated by the levels of bilirubin. The measurement of hfgl2/fibroleukin expression in PBMC may serve as a useful marker to monitor the severity of acute on chronic hepatitis B 31-33 and a target for therapeutic intervention . Hemodynamics in ACLF There is reduction in vascular responsiveness and desensitisation to vasoconstrictors and effects of 34 vasodilating factors (NO). ACLF patients with small varices had HVPG values [13.2 mmHg ( 5.5)] comparable to compensated cirrhotics; those with large varices had HVPG comparable to 35 decompensated cirrhotics [18.2 mmHg ( 6.5)]. The data clearly showed that patients with small varices and lower HVPG levels have a higher chance of recovery after the acute insult settles down. HVPG of ACLF patients ranges between those with compensated and decompensated chronic liver disease. Large varices in patients with ACLF reflects high HVPG resulting in poor prognosis. Higher liver blood flow levels in ACLF patients correlate with higher mortality.

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Histology in ACLF There is scarcity of histological data on ACLF. Prognosis and treatment depends upon the etiology along with the extent of parenchymal collapse and stage of fibrosis. Liver biopsy is a good predictor of outcome in patients with ACLF. Transjugular liver biopsy is relatively safe and is the best approach to 36 get a liver biopsy. Two patterns of liver histological injury were observed. The first pattern is characterized by hepatocyte ballooning, rosette formation, type I cholestasis, moderate to severe interface activity and variable fibrosis (Pattern I). The second histological pattern is characterized by marked ductular proliferation, coarse inspissated bile plugs (type 2 cholestasis), higher stage of fibrosis and variable activity (Pattern II). On clinical correlation, pattern I was observed in majority of patients who had recovered, while, Pattern II was a feature of all 2,36 patients who had died. Differentiating acute liver failure and chronic hepatitis with flare is based on findings of fibrous bands (spurs and bridges) and ductular proliferation. Features of cholestasis and bile duct proliferation are more common in patients with acute injury (classical features of acute hepatitis along with cellular and ductular cholestasis are indicative of acute injury). Differentiation between cirrhosis with acute deterioration and compensated cirrhosis is based on the presence of necrosis and features of acute hepatitis in the former group of patients. It was proposed that the diagnostic stains for fibrosis and necrosis be mentioned. It was also proposed that connective tissue stains (especially Shikatas orcein) should be done in all such cases for differentiating necrosis from fibrosis. ACLF is characterized by massive injury on the chronic preexisting liver diseases, thus the regeneration of ACLF may involve hepatic progenitor cell activation because (i) it is believed that a threshold of 50% loss of hepatocytes, associated with a significant decrease in the proliferative activity of remaining mature hepatocytes, is needed for 37 extensive hepatic progenitor cell activation , and (ii) impairment of liver regeneration is observed in chronic liver diseases, including non-alcoholic fatty liver disease, cirrhosis, chronic hepatic infection, malnutrition, with increased cell death, delayed 38 mitosis and slower return of normal hepatic mass. Role of prognostic scores in ACLF Several prognostic scoring systems have been developed for patients with chronic liver disease as well as for patients admitted to an intensive care unit. Two categories of prognostic models are commonly used: first, those evaluating the severity of illness: Acute Physiology and Chronic Health Evaluation (APACHE) II and III, Simplified Acute Physiology Score (SAPS) II and Mortality Prediction Model (MPM) II, which are most used, and second, models quantifying organ dysfunction and failure: Logistic Organ Dysfunction System, Multiple Organ Dysfunction Score, Organ System Failure (OSF) and Sequential Organ Failure Assessment (SOFA). In a 13 meta-analysis by Cholangitas et al , general- ICU models had better performance in cirrhotic populations compared with Child- Turcotte-Pugh (CTP) score; OSF and SOFA had the best predictive ability. SOFA had relatively better prognostic value. SOFA at 48 h > 10 predicted mortality in 93% of patients (13). ADMA (Asymmetric dimethylarginine), SDMA and their combined sum, which is termed as dimethylarginine score, were reported as better predictors of outcome compared with CTP score, MELD and Maddrey's discriminant-function. Elevated dimethylarginines may serve as important biological markers of deleterious outcome in alcoholic 28 hepatitis . Mortality Severity depends on severity of acute and chronic insult plus the etiology Mortality for cirrhosis was 7%, ALF- 2.7% and ACLF 4.7% in one study(40). 3-month mortality for ACLF was predicted using MELD score (41). MELD score of 2029 Mortality 56.0% score of 3039 76.5% score over 40 98.2% Management of ACLF Management depends upon the severity and type of injury. The three main modalities used in the treatment of ACLF are Antiviral drugs, Artificial support systems and Liver transplantation.Antiviral drugs- HBV reactivation is common (14-50%) following chemotherapy and is associated with a high mortality (5-12%) despite prompt anti-viral treatment. Antiviral therapy should be initiated in patients with ACLF due to hepatitis B (Irrespective of DNA & ALT status). Lamivudine for shorter course and other new drugs for longer course should be given depending
37-40

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upon the situation. Prophylactic treatment recommended before Chemotherapy (2, 42-44). is months. Earlier intervention if hepatorenal syndrome develops, However, liver transplantation should not be performed when there is HRS with anuria. Results of liver transplantation are better when HRS has been partially controlled by terlipressin. Hemodynamic instability and high dose inotrope requirement (sepsis, bleeding), Severe bacterial infection, Fungal infection, and Refractory cerebral edema or intracranial bleeding are the conditions in which transplant is not be considered. The use of liver graft of sufficient graft weight for the recipient and with 2. uniform venous outflow is preferred Chan etal concluded that Liver transplantation for acute-on-chronic liver failure is life-saving, and the survival rates it attains are similar to those attained by transplantation for other liver conditions. Among 149 patients with ACLF who underwent Liver transplantation, 5 year survival rates were 93.2% for patients with acute exacerbation of chronic hepatitis B and 90.5% for cirrhotic patients with acute 40 deterioration . Conclusions In summary, acute on chronic liver failure is a distinct clinical entity. There is now sufficient data on the presentation and course of patients with this profile of liver failure, but data from India is very scarce. After APASL guidelines, there is uniformity in definitions and management aspects. But there are lots of queries regarding the inclusion and exclusion criterias which may be challenged in the near future after arrival of many studies. With the availability of newer information, specially correlated with liver histology would help to further improve our understanding of this disease entity in the future.

Role of MARS (MOLECULAR ADSORBENT RECIRCULATING SYSTEM) in ACLF MARS serve as a bridge to transplantation. Endogenous albumin bound toxins, (Eg: Aromatic amino acids, bilirubin, bile acids, digoxin like substances, endogenous benzodiazepines, indols, mercaptans, middle and short chain fatty acids, NO, phenols, prostacyclins, Tryptophan) that accumulate in liver failure are removed by MARS. It also help by lowering the levels of proinflammatory cytokines TNF, IL-10, and IL-6 that may perpetuate the liver damage and extend the inflammatory cascade to other organs (45). MARS treatment efficiently removed TNF-, IL-6, IL-8, interleukin-gamma, and 46 IL-4 in one study by Guo etal . The measurable changes noted after MARS are Reduction in serum bilirubin, Improvement in encephalopathy, Child-Turcotte-Pugh score, Increase in systemic vascular resistance, Mean arterial pressure, Decrease in cardiac output, Improvement in Cerebral blood flow and cerebral perfusion and renal function (2,3,45,46). Finally 4 RCTs, Comprising 67 patients showed that there is no survival benefit for MARS, but it improves Hepatic encephalopathy in 2 ACLF . Liver transplantation in ACLF There is scarcity of data on liver transplant in ACLF. Orthotopic liver transplantation remains the only definitive therapy for patients who do not improve with supportive measures to sustain life. Liver transplantation should be performed according to prognostic scores suggesting death within the next 3

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Corresponding Author Varghese Thomas Professor and Head Department of Gastroenterology Calicut Medical College drvarghesethomas@gmail.com

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