Acute on chronic liver failure (ACLF) is characterized by the acute deterioration of liver function in a patient with compensated chronic liver disease mainly stable liver cirrhosis. It is commonly associated with an acute precipitating event, such as infection/sepsis, acute upper gastrointestinal bleeding, ischaemia, superimposed liver injury caused by alcohol, hepatotoxic drugs, reactivation or co-infection with a hepatitis virus. ACLF is accompanied by a disturbed function of several extrahepatic organs leading to multi-organ failure and death within few days or weeks in the majority of patients.
Acute on chronic liver failure (ACLF) encompasses patients with previously well-compensated liver disease in whom an acute decompensation of liver function occurs because of a precipitating event. There are emerging data on the presentation and course of patients with this profile of liver disease; a clear definition based on precise diagnostic criteria, however, remains difficult to establish. In a high percentage of patients, ACLF is associated with the development of multi-organ failure leading to high in-hospital mortality despite costly intensive care therapy. Liver transplantation remains the only curative therapeutic option for the majority of these patients. Therefore, early identification of the precipitating events inducing ACLF and better understanding of the underlying mechanism are key issues for the prevention and treatment of ACLF. However, although there is increasing evidence that cytokines play a major role in the development of ACLF, the pathophysiology remains complex and poorly understood.
Proposed working definitions
Although ACLF is a more common condition than acute liver failure (ALF), much more interest was focused on ALF in the past. In contrast to ALF, ACLF constitutes a poorly defined entity mainly because of the extreme heterogeneity in the mode of presentation. Therefore, a clear definition of ACLF is lacking. In particular, the differentiation between ACLF and chronic hepatic decompensation as a result of the progression of the underlying liver disease remains difficult. Probably the most important difference between both entities is the potentially reversible nature of ACLF if the precipitating factor can be controlled. The following working definition of ACLF was proposed by the London group in 2002: ‘Acute deterioration in liver function over a period of 2–4 weeks, usually associated with a precipitating event, leading to severe deterioration in clinical status with jaundice and hepatic encephalopathy (HE) and/or hepatorenal syndrome (HRS) with a high SOFA/APACHE II score.’ (1). A similar definition was recommended by APASL in 2009: ‘Acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease’ (2).
Multi-organ failure as a consequence of cirrhosis
Multi-organ failure plays a central role in the clinical course of ACLF. Basically all organ systems can be affected, particularly circulation, brain, kidneys and liver. Hyperbilirubinemia is almost invariably present. As already mentioned, jaundice is considered an essential criterion of ACLF. In addition, the reduction of the hepatic synthetic functions, especially decreases in the production of co-agulation factors and albumin resulting in a haemorrhagic diathesis, oedema and increasing ascites, is a major clinical finding in the setting of ACLF. Characteristic changes occur in the circulation of cirrhotics, which become more aggravated during ACLF including peripheral arterial vasodilatation, reduced renal blood flow, increased portosystemic shunting and high cardiac output (hyperdynamic circulation). These phenomena are thought to be secondary to a reduction in vascular responsiveness and down regulation of receptors leading to hyporesponsive vasoconstriction. Consequently, circulatory failure in ACLF is characterized by the impossibility to obtain adequate mean arterial blood pressure with volume expansion and the need for vasopressors. Changes in renal blood flow are already seen at early stages of cirrhosis. Intense renal vasoconstriction occurs in patients with advanced cirrhosis, especially in those with refractory ascites, which may lead to the development of a HRS. It is one of the most dangerous complications of ACLF, from which the chances of recovery is extremely poor. In particular, the type-1 HRS, a rapidly progressive impairment of renal function, has a very poor prognosis. As the HRS syndrome is one of the most important issues in the setting of ACLF, it will be discussed in more detail in a separate article of this issue. HE may be either a precipitating factor or a consequence of ACLF. Apart from jaundice hepatic HE is probably the most apparent manifestation of ACLF. Aspiration pneumonia and acute respiratory failure are the most severe complications of HE. Adrenal insufficiency is frequently seen in patients with cirrhosis and septic shock (3). It may contribute to the development of multi-organ failure.
Acute on chronic liver failure constitutes a clinical picture in which two simultaneous – acute and chronic – insults occur. Whether the prognosis of the patient depends on the degree of the acute or the chronic insults or the combination of both is unknown. At present two categories of prognostic models are used: firstly, those evaluating the severity of liver disease and secondly those evaluating the dysfunction of several organ systems. It has been shown that liver function is not the main determinant of the outcome of patients with decompensated cirrhosis, thus liver-specific scoring systems, such as the Child–Pugh or the MELD score, have limitations to accurately predict the outcome of patients with ACLF (4). Organ failure scores, such as the APACHE II and SOFA score, are more helpful in predicting survival. A recent meta-analysis showed that the SOFA score had the best predictive ability (5). However, there is still an ongoing surge for better and more accurate predictive models.
SIRS – a key player in acute on chronic liver failure
Inflammation and neutrophil dysfunction are of major importance regarding the pathophysiology of ACLF. In particular, cytokines are believed to play a central role in ACLF. There is increasing evidence that the systemic inflammatory response syndrome (SIRS), characterized by a predominantly pro-inflammatory cytokine profile [interleukin-6, tumour necrosis factor (TNF)α], causes the transition from a stable cirrhosis to ACLF. It has been shown that SIRS is associated with more severe encephalopathy, an increased incidence of bacterial infections and renal failure (6). Therefore, it has been expected that anti-inflammatory agents may help to inhibit the deleteriously increased pro-inflammatory cytokine response and improve patient outcome. Unfortunately, the medical attempts to control the inflammatory response in cirrhotic patients with anti-TNFα agents were dismal. As bacterial infection is the major cause of death in patients with decompensated liver cirrhosis, the complex interaction between SIRS and sepsis seems to be central in the pathophysiology of ACLF.
Prevention and therapy
Major improvements have been achieved in the management of several malignant, infectious or cardiovascular diseases, however, the mortality of decompensated liver cirrhotic patients after hospital admission has not markedly improved over the last decades (7). Organ failure has a major impact on the outcome of cirrhotic patients. The in-hospital mortality shows a dramatic increase with the number of different organ system failures. Therefore, any condition or precipitating factor which can cause ACLF should be recognized as early as possible or, even better, should be avoided in order to prevent the development of multiple organ failures. A recent paper has demonstrated that patients with ACLF have high short-term mortality but those who survived the acute exacerbation showed a comparable long-term survival to that of patients with decompensated cirrhosis (8). Additionally, a randomized, controlled study has shown that primary prophylaxis with norfloxacin reduced the incidence of spontaneous bacterial peritonitis, delayed the development of HRS and improved patient survival (9).
Liver transplantation remains the only definitive therapeutic option for patients who do not improve with supportive measurements to sustain life. In contrast to patients with ALF, there is currently no possibility to put ACLF patients on a ‘high-urgency’ list. As a consequence, the mortality of these patients on the waiting list is exceptionally high. Thus, several (extracorporeal) liver support devices have been used either to give the patient additional time for recovery or to serve as a ‘bridge’ to liver transplantation. So far, studies have failed to show any survival benefit of these liver support devices in patients with ACLF. These studies and other topics regarding liver devices will be discussed in more detail in separate articles of this issue. There are almost no data available regarding the accurate long term outcome of patients transplanted for ACLF. A recent retrospective study from Hong Kong showed that the survival rates of patients with ACLF are similar to those transplanted for other liver conditions (10). However, these data have to be interpreted with caution especially when transferring these results to western transplant centers for two reasons: firstly, more than half of the patients with ACLF had an acute exacerbation of chronic hepatitis B and secondly, living donor liver transplantation was performed in the majority of patients.
In conclusion, despite several advances in the understanding of liver diseases, the management of patients with ACLF remains a significant clinical challenge. In the majority of patients ACLF is associated with multi-organ failure and, consequently, the prognosis is very poor. A better understanding of the pathophysiology and the definition of predictive factors in order to identify patients who may develop ACLF after a precipitating event as early as possible are of major importance to improve the outcome of these patients.
Conflict of interest: There are no conflicts of interest of the author with regard to any of the techniques or material mentioned in the present manuscript. The author has no relationship at all with any of the companies, nor does he hold shares.