Acute-on-Chronic Liver Failure: A New and Important Entity in the ICU




© Springer International Publishing AG 2018
Davide Chiumello (ed.)Practical Trends in Anesthesia and Intensive Care 2017https://doi.org/10.1007/978-3-319-61325-3_8


8. Acute-on-Chronic Liver Failure: A New and Important Entity in the ICU



Gianni Biancofiore1, 2  


(1)
Transplant Anesthesia and Critical Care Department, Azienda Ospedaliera Universitaria Pisana, Pisana, Italy

(2)
Anesthesiolgy and Critical Care, University School of Medicine, Pisa, Italy

 



 

Gianni Biancofiore



Traditionally two types of liver failure were recognized: acute liver failure (ALF), characterized by a rapid deterioration of the liver function in the absence of a preexisting liver disease, and the progression with a slow deterioration over time of preexisting end-stage liver disease leading to an acute hepatic insult [1]. Recently, a new clinical form of liver failure has been described: Acute-on-chronic liver failure (ACLF). This new entity is characterized by acute complications of compensated or even decompensated cirrhosis with a high rate of organ failure and a high short-term mortality rate. ACLF is now an increasingly recognized entity in both the hepatology and critical care literature and poses several challenges to clinicians. In fact, the liver’s position at the apex of multiple synthetic, detoxifying, metabolic, immunological, and hormonal processes predisposes patients with ACLF to a number of complications. The present review aims at summarizing the most updated knowledge about this particularly severe syndrome.


8.1 Definition of ACLF


Until 2013, there was no shared, established, evidence-based definition of ACLF, and the only published definitions were based on expert opinion. Moreover, the used definitions of ACLF differed between Eastern and Western countries. In Asia, the following liver-centered definition has been suggested: an acute hepatic insult manifesting as jaundice (serum bilirubin level > 5 mg/dL) and coagulopathy (international normalized ratio [INR] >1.5) complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease [2]. In Europe and the USA, a different definition of ACLF was used identifying ACLF as an acute deterioration of liver function in patients with cirrhosis which usually is associated with a precipitating event and results in the failure of one or more organs and high short-term mortality rates [3]. Finally, the sequential organ failure assessment (SOFA) score was also used to diagnose organ failures in patients with cirrhosis admitted to the intensive care unit [4].

Since diagnostic criteria of ACLF were based in both definitions on personal expert opinions rather than on objective data, in 2009, a group of European investigators decided to create the Chronic Liver Failure (CLIF) Consortium with the objective of stimulating research on complications of cirrhosis. The Consortium was endorsed by the European Association for the Study of the Liver (EASL) resulting in the EASL-CLIF Consortium. One of the first decisions by the Steering Committee of the Consortium was to perform a multicenter, prospective, observational study in patients with an acute decompensation of cirrhosis. This study was named CLIF Acute-on-Chronic Liver Failure in Cirrhosis (CANONIC) study and aimed at assessing the prevalence, diagnostic criteria, precipitating events, natural course, and prognosis of ACLF. The CANONIC study prospectively enrolled 1343 patients with cirrhosis hospitalized in 29 liver units from 8 European countries between February and September 2011. Enrolled patients were hospitalized for at least 1 day and had an acute development of large ascites, hepatic encephalopathy, gastrointestinal hemorrhage, bacterial infections, or any combination of these [5]. For the diagnosis of organ failures, investigators used a modified SOFA scale, called the CLIF-SOFA scale, which had been designed specifically by the Writing Committee of the CANONIC study before the onset of this study. The CLIF-SOFA scale assesses the function of six organ systems (liver, kidneys, brain, coagulation, circulation, and lungs) but also takes into consideration some specificities of cirrhosis. Each organ system receives a subscore ranging from zero (normal) to four (most abnormal). A total CLIF-SOFA score ranging from 0 to 24 can thus be calculated. Notably, all variables included in the CLIF-SOFA are easy to obtain in every hospital.

In the CANONIC study, three types of risk factors obtained from the CLIF-SOFA score at enrollment were found to be related to high 28-day mortality rate: (1) the presence of two organ failures or more, (2) the presence of one organ failure when the organ that failed was the kidney, and (3) the coexistence of a single “non-kidney” organ failure with kidney dysfunction (i.e., serum creatinine level ranging from 1.5 to 1.9 mg/dL) and/or mild to moderate hepatic encephalopathy [5].

Based on the findings from the CANONIC study, four stages of ACLF can be nowadays recognized:


  1. A.


    No ACLF. This group comprises three subgroups: (1) patients with no organ failure, (2) patients with a single “non-kidney” organ failure (i.e., single failure of the liver, coagulation, circulation, or respiration) who had a serum creatinine level > 1.5 mg/dL and no hepatic encephalopathy, and (3) patients with single cerebral failure who had a serum creatinine level > 1.5 mg/dL.

     

  2. B.


    ACLF grade 1. This group includes three subgroups: (1) patients with single kidney failure; (2) patients with single failure of the liver, coagulation, circulation, or respiration who had a serum creatinine level ranging from 1.5 to 1.9 mg/dL and/or mild to moderate hepatic encephalopathy; and (3) patients with single cerebral failure who had a serum creatinine level ranging from 1.5 to 1.9 mg/dL.

     

  3. C.


    ACLF grade 2. This group includes patients with two organ failures.

     

  4. D.


    ACLF grade 3. This group includes patients with three organ failures or more.

     

These results show that ACLF is a new clinical entity that is distinct from decompensated cirrhosis.


8.2 Prevalence, Risk Factors, and Prognosis of ACLF (According to the CANONIC Study)


The prevalence of ACLF in the CANONIC Study was 30% (20% at admission and 10% during hospitalization), and the overall 28-day and 90-day mortality rates were 33% and 51%, respectively. Mortality rates in patients without ACLF were low (28-day, 1.9%; 90-day, 10%). The prevalence and 28-day and 90-day mortality rates associated with the different grades of ACLF were 15.8%, 22%, and 41%, respectively, in ACLF-1; 10.9%, 32%, and 55% in ACLF-2; and 4.4%, 73%, and 78% in ACLF-3 [5].

Patients with ACLF were significantly younger than those without ACLF, and the main etiologies were alcoholism (60%), hepatitis C (13%), and alcoholism plus hepatitis C (10%). In only 5% of patients, the main etiology was cirrhosis associated with hepatitis B virus (HBV) infection. The commonest organ failure in patients with ACLF was renal failure (56%) with liver coagulation and cerebral, circulatory, and respiratory failures (44%, 28%, 24%, 17%, and 9%, respectively) also very frequent. The prevalence of circulatory and respiratory failure was significant only in patients with ACLF-3. Most importantly, patients with ACLF showed systemic inflammation (high count of C-reactive protein and leukocyte concentration) which was independent on the presence or absence of recognized bacterial infections. Patients with no history of decompensated cirrhosis developed a more severe form of ACLF than patients with previous episodes of decompensation (28-day mortality of 42% vs. 29%).

The most common precipitating events were bacterial infections and active alcoholism. In patients with ACLF the prevalence of alcoholic cirrhosis (60%) was higher than the prevalence of active alcoholism, indicating that alcoholic hepatitis accounts for only part of cases of ACLF associated with alcoholic cirrhosis. There was a small proportion of other precipitating events. As a trigger, gastrointestinal hemorrhage was less frequent in patients with ACLF than in patients without ACLF, suggesting that hemorrhage, if not associated to other complications (i.e., active drinking and/or bacterial infections), is not related to ACLF development. Finally, a significant proportion of patients developing ACLF did so in the absence of any identifiable trigger. Mortality was independent of the presence and type of precipitating events, indicating that although triggers are important in the development of ACLF, mortality depends on other factors, such as the clinical course and number of organ failure [5, 6].

Regarding the prognostic relevance of ACLF, some findings have been reported as significant in determining patient outcomes [5]:


  1. A.


    Among patients who are admitted for an acute decompensation and subsequently die, multiorgan failure (i.e., ACLF grade 3) is present in all patients before death.

     

  2. B.


    The interval between the diagnosis of ACLF and death is 12.0 ± 7.5 days for ACLS grade 1, 11.0 ± 8.0 days for ACLS grade 2, and 8.0 ± 6.1 days for ACLS grade 3. Therefore, the greater the number of organ failures at diagnosis the shorter the time to death.

     

  3. C.


    ACLF is not a temporally fixed syndrome. For example, 50% of patients with ACLF grade 1 at diagnosis improve and survive whereas one-third progress to ACLF grade 3 and die. A majority of patients with ACLF grade 3 at diagnosis acquire new organ failures and die. However, 16% of patients with ACLF grade 3 at diagnosis progress to a no ACLF status.

     

  4. D.


    The finding that patients without any organ failure on admission have a 28-day mortality rate of approximately 5% and not 0% is explained by the fact that some of these patients develop in-hospital ACLF, which progresses to ACLF grade 3 and death. Conversely, patients who do not have ACLF on admission and remain free of this syndrome during the following 28 days have a very low short-term mortality rate (1.9%).

     

Another very important finding from the CANONIC study needs to be outlined: the fact that the presence or absence or the type of precipitating event is not related to the severity of ACLF and the short-term mortality rate [5]. Therefore, precipitating events are important in the occurrence of the syndrome but once it develops the prognosis depends on the number of organ failures. This observation indicates that the severity of ACLF probably depends more on the individual response to the precipitating event [6]. Finally, in almost half of patients enrolled in the CANONIC study with ACLF, the syndrome develops in the absence of a prior history of decompensation or has developed within a few weeks after the first episode of decompensation. This finding outlines that ACLF is not a terminal event in a long-lasting history of decompensated cirrhosis.


8.3 ACLS is Caused by a Derangement of the Inflammatory Pathway


The CANONIC study results clearly show that white cell count and plasma C-reactive protein (CRP) levels are higher in patients with ACLF than in those without indicating higher degree of systemic inflammation in the former patients [5]. Furthermore, the higher white cell count or CRP levels the higher the number of failing organs. All in all, these findings suggest that organ failures may result from an excessive inflammatory response, for which the term immunopathology was proposed [7]. Although the precise mechanisms involved in ACLF have yet to be clarified, the immune system seems to play a predominant role in the setting of cirrhosis. The homeostatic role of the liver in the systemic immune response is already well known, [8, 9] and the definition of “cirrhosis-associated immune dysfunction” which includes the main syndromic abnormalities of immune function, immunodeficiency and systemic inflammation, well depicts the key role of the immune system in this setting [10]. The immune dysfunction in cirrhosis is a dynamic condition which leads to oscillation from predominantly pro-inflammatory to predominantly immunodeficient situations, is multifactorial, and reflects a complex interaction between many systems predisposing these patients to infections [10]. It is thought that this susceptibility is not due to an only sole responsible factor but rather to the concomitant presence of various facilitating mechanisms such as portal hypertension with portosystemic shunting (thus impairing detoxification and reticuloendothelial system phagocytic activity), increased gut permeability and bacterial overgrowth (all of them increases the risk of bacteremia and the occurrence of endotoxemia), albumin and lipoprotein dysfunction, or aberrant toll-like receptor expression in hepatic Kupffer cells [1]. Moreover, comparing septic patients to ACLF patients, Wasmuth et al. formulated the concept of “sepsis- like immune paralysis” based on a profoundly decreased production of TNF-α and low monocyte HLA-DR expression in both groups. They also postulated that this cellular immune impairment could contribute to increased mortality [11]. Endotoxins have also been proposed to play a role in mediating the full activation of neutrophils, which paradoxically would render them unable to act against the insult. The role that cytokines play in ACLF remains a key point in the pathogenesis of the inflammatory response. Elevated serum levels of many cytokines including TNF-α, sTNF-αR1, sTNF-αR2, interleukin (IL)-2, IL-2R, IL-4, IL-6, IL-8, IL-10, and interferon-α has been described. In particular IL-6 and TNF-α had been proposed to have a dual action, producing hepatocyte death and also enhancing hepatocyte proliferation through a complex interplay with Kupffer cells and hepatocytes [1]. This entire cascade eventually leads to hepatocyte death and liver dysfunction. It has also been outlined that hepatocytes apoptosis rather than necrosis can be the predominant mode of cell death in ACLF, as high levels of some apoptosis markers occurs in ACLF patients [12].


8.4 Clinical Features of ACLF



8.4.1 Infections


Although the CANONIC study showed that the trigger of ACLF is not related to an infection in the 70% of cases, the presence of innate immune dysfunction in this class of patients can be inferred from susceptibility to infections: 30–50% of cirrhotic patients presented bacterial infections upon their admission or during hospitalization. The most common bacterial infections were spontaneous bacterial peritonitis (25%), urinary tract infections (20%), pneumonia (15%), and spontaneous bacteremia (12%). In a study of 184 cirrhotic patients from King’s College Hospital, 67 (36%) developed bloodstream infection (BSI) a median of 8 days after admission; BSI was independently associated with higher ICU mortality [13]. This may support the hypothesis that following the initial cytokine storm responsible for acute decompensation and multiorgan dysfunction, these patients enter a later phase of monocyte immunoparalysis (compensatory anti-inflammatory response), which further alters their susceptibility to sepsis and predisposes them to a higher rate of second infection and increased mortality [14, 15]. Finally, it is important to outline that data from a large multicenter study suggested that cirrhotic patients with septic shock, including those on mechanical ventilation or receiving renal replacement therapy, have benefited from the progress in septic shock and organ failures management obtained in recent years in the general population indicating that it is justified to admit ACLF patients to ICU [16].


8.4.2 Kidney Injury


Acute kidney injury (AKI) in critically ill cirrhotic patients is common and often multifactorial.

Renal complications of ACLF can be due to low flow state, infections, nephrotoxic drugs, and chronic diseases such as hypertension and diabetes which can predispose patients to chronic renal failure. However, the characteristic renal complication of end-stage liver diseases is the hepatorenal syndrome (HRS) which is characterized by splanchnic arterial vasodilatation leading to renal vasoconstriction in the setting of a low flow state due to decreased systemic vascular resistance [17, 18]. Although the incidence of HRS is unknown, especially in relation to other causes of renal failure, it is estimated to be 40% over a 5-year period in patients with cirrhosis and ascites [19]. There are two different forms of HRS, type 1 and type 2. Although HRS is associated with a very poor prognosis, overall the natural progression of the disease differs significantly based on the type, with type 1 experiencing a median survival of 2 weeks and type 2 exhibiting median survivals of 3–6 months. Diagnosis of HRS involves the demonstration of low glomerular filtration rate in the absence of shock, infection, fluid losses, and nephrotoxic agents, with no improvement after discontinuation of diuretics and administration of 1.5 L fluid and proteinuria of less than 500 mg/dL, with no ultrasonographic evidence of obstruction or intrinsic parenchymal disease [17, 18]. Recently, a consensus conference proposed that cirrhosis-associated AKI should be defined by an increase in serum creatinine by more than 50% from the stable baseline value in less than 6 months or by 0.3 mg/dl (27 mmol/l) in less than 48 h [20].


8.4.3 Cardiovascular Derangements


Hemodynamic changes observed in patients with end-stage liver disease are characterized by humoral and nervous dysregulation secondary to autonomic nervous system activation and include increased cardiac output, peripheral vasodilatation, decreased systemic vascular resistance (SVR), and decreased oxygen extraction. Circulatory failure in cirrhotic patients with ACLF is distributive in nature and characterized by a greater decrease in arterial pressure associated with signs of impaired tissue perfusion. Marked splanchnic vasodilatation results in a state of effective hypovolemia with water and sodium retention [19, 21]. Although mechanisms for this autonomic nervous system activation are still poorly understood, it has been associated with higher mortality. In addition to hemodynamic changes, a decline in cardiac function termed cirrhotic cardiomyopathy has also been described [21]. This is characterized by a combination of diastolic and systolic dysfunction. Cirrhotic cardiomyopathy can be associated with a prolonged QT interval and can lead to an increased risk of ventricular arrhythmias/sudden cardiac death.


8.4.4 Neurological Derangements


The most common manifestation is a confusional syndrome superimposed on varying degrees of cognitive impairment that can even evolve to coma [22]. Precipitating factors, such as infection or electrolyte abnormalities, may enhance the disturbances attributable to liver failure or exert a direct effect on the brain. Important contributing factors are the systemic inflammatory response, circulatory dysfunction, and failure of other organs [6]. The activation of inflammatory mediators, such as cytokines, may enhance the effects of neurotoxins such as ammonia. Neuroinflammation increases blood-brain barrier permeability and, by generation of nitric oxide and prostanoids, causes astrocyte swelling. Other cerebrovascular abnormalities include disturbances of neurotransmission, injury to astrocytes, energy impairment, brain edema, loss of autoregulation, and brain atrophy. In cirrhosis, cerebral edema is an uncommon finding; however, cases of increased intracranial pressure have been identified [22, 23]. Patients with ACLF are also more vulnerable to central pontine myelinolysis which has been reported even with relatively modest elevations in sodium in this population. However, the most common cause of changes in mental status is hepatic encephalopathy, a disease process thought to be caused by astrocyte swelling and cerebral edema due to the synergistic effects of excess ammonia and inflammation, although the precise underlying molecular mechanisms are unclear. Hepatic encephalopathy is rarely solely due to worsening liver function, rather a precipitating cause almost always is responsible and determining this precipitant is key to management [19].


8.4.5 Respiratory Derangements


Pulmonary vascular issues affecting patients with ACLF can be divided into two distinct abnormalities: hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH). Hepatopulmonary syndrome is characterized by intrapulmonary vasodilation leading to a ventilation/perfusion mismatch with resultant hypoxemia that can be found in up to 40% of patients with end-stage liver disease. Diagnosis is based on its identification identify either through pulse oximetry or on arterial blood gas and the demonstration of an intrapulmonary shunt (which can usually be demonstrated with contrast echocardiography) if there is a normal chest x-ray and pulmonary function tests [24]. Portopulmonary hypertension is the presence of pulmonary arterial hypertension due to increased pulmonary vascular resistance and pulmonary vasoconstriction leading to right heart failure in the setting of advanced liver disease. The disease is largely believed to be underdiagnosed as a cause of dyspnea and decreased exercise capacity. Doppler echocardiography is a highly sensitive tool for detecting portopulmonary hypertension, using a right heart catheterization for confirmation and definitive diagnosis. The diagnosis is made if mean pulmonary arterial pressure is >25 mm Hg or left ventricular end-diastolic pressure <15 mm Hg in the setting of liver disease or portal hypertension. In general, the presence of portopulmonary hypertension is a poor prognostic sign [24, 25]. Moreover, pulmonary function can also be compromised by direct mechanical effects of hydrothorax and abdominal ascites on diaphragmatic movement. Hydrothorax is defined as a significant pleural effusion, usually >500 mL in a patient with end-stage liver disease, exclusive of primary cardiac or pulmonary disease. A pleural effusion is observed in approximately 5% of patients with ACLF. Various mechanisms have been proposed such as decreased osmotic pressure, leakage of plasma from azygous venous system, and lymph leakage from the thoracic duct, although the prevailing thought is direct transport into pleural space through diaphragmatic defects [19]. Finally, the presence of an exaggerated inflammatory response, coupled with a relative immunocompromised state likely can predispose patients to acute lung injury. The risk of aspiration pneumonia is also high because of altered consciousness, swallowing dysfunction, gastric stasis, increased intra-abdominal pressure due to ascites, and ileus resulting from infection and electrolyte abnormalities [22].

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Apr 10, 2018 | Posted by in Uncategorized | Comments Off on Acute-on-Chronic Liver Failure: A New and Important Entity in the ICU

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