Elsevier

Journal of Hepatology

Volume 69, Issue 2, August 2018, Pages 406-460
Journal of Hepatology

Clinical Practice Guidelines
EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis

https://doi.org/10.1016/j.jhep.2018.03.024Get rights and content

Summary

The natural history of cirrhosis is characterised by an asymptomatic compensated phase followed by a decompensated phase, marked by the development of overt clinical signs, the most frequent of which are ascites, bleeding, encephalopathy, and jaundice. The following Clinical Practice Guidelines (CPGs) represent the first CPGs on the management of decompensated cirrhosis. In this context, the panel of experts, having emphasised the importance of initiating aetiologic treatment for any degree of hepatic disease at the earliest possible stage, extended its work to all the complications of cirrhosis, which had not been covered by the European Association for the Study of the Liver guidelines, namely: ascites, refractory ascites, hyponatremia, gastrointestinal bleeding, bacterial infections, acute kidney injury, hepatorenal syndrome, acute-on-chronic liver failure, relative adrenal failure, cirrhotic cardiomyopathy, hepatopulmonary syndrome, and porto-pulmonary hypertension. The panel of experts, produced these GPGs using evidence from PubMed and Cochrane database searches providing up to date guidance on the management of decompensated cirrhosis with the only purpose of improving clinical practice.

Introduction

When the panel of experts nominated by the European Association for the Study of the Liver (EASL) governing board began work to update the Clinical Practice Guidelines (CPGs) on ascites, spontaneous bacterial peritonitis (SBP), and hepatorenal syndrome (HRS),1 it became obvious that all other complications of decompensated cirrhosis had to be covered. Within this framework, a formal definition of decompensated cirrhosis was sought. The natural history of cirrhosis is characterised by a silent, asymptomatic course until increasing portal pressure and worsening liver function produce a clinical phenotype. In the asymptomatic phase of the disease, usually referred to as compensated cirrhosis, patients may have a good quality of life, and the disease may progress undetected for several years. Decompensation is marked by the development of overt clinical signs, the most frequent of which are ascites, bleeding, encephalopathy, and jaundice. Following the first appearance of any of these, the disease usually progresses more rapidly towards death or liver transplantation (LT). This phase of the disease has been designated “decompensated cirrhosis”.2 Progression of the decompensated disease may be further accelerated by the development of other complications such as rebleeding, acute kidney injury (AKI), with or without the features of HRS, hepato-pulmonary syndrome (HPS), portopulmonary hypertension (PPHT), cirrhotic cardiomyopathy (CCM), and bacterial infections. Indeed, the development of bacterial infections as well as hepatocellular carcinoma may accelerate the course of the disease at any stage, but especially in decompensated cirrhosis.3 Having defined the potential field of action, and having emphasised the importance of initiating aetiologic treatment for any degree of hepatic disease at the earliest possible stage, the panel decided to extend the work to all those complications of cirrhosis which have not yet been covered by EASL guidelines, namely: gastrointestinal (GI) bleeding, bacterial infections other than SBP, acute-on-chronic liver failure (ACLF), adrenal failure, HPS, PPHT and CCM. In doing so, we have had to deal with the recommendations regularly proposed by very well recognised international expert groups who have worked in the field of GI bleeding or ascites and ascites-related complications for many years. Given their extreme importance in clinical practice, only specific aspects of their recommendations were further developed in an attempt to give a more integrated view of the pathophysiology and management of patients with decompensated cirrhosis. Thus, this document can no longer be considered an update of earlier guidelines, but rather the first CPG on the management of decompensated cirrhosis with the sole purpose of improving clinical practice.

Section snippets

Guidelines development process

A panel of hepatologists with a great interest in decompensated cirrhosis, approved by the EASL Governing Board, wrote and discussed this CPG between March 2017 and February 2018. The guidelines were independently peer reviewed, and all contributors to the CPG disclosed their conflicts of interest by means of a disclosure form provided by the EASL Office prior to work commencing. The EASL Ethics Committee reviewed the composition of the panel to eliminate the potential for real or perceived

Pathophysiology of decompensated cirrhosis

The transition from compensated asymptomatic cirrhosis to decompensated cirrhosis occurs at a rate of about 5% to 7% per year.4 Once decompensation has occurred, cirrhosis becomes a systemic disease, with multi-organ/system dysfunction.5 At this stage, patients become highly susceptible to bacterial infections because of complex cirrhosis-associated immune dysfunction, which involves both innate and acquired immunity.6 In turn, patients with bacterial infections are burdened by severe

Management of decompensated cirrhosis

Ideally, the strategy of management of patients with decompensated cirrhosis should be based on preventing cirrhosis progression (i.e. further decompensation) rather than treating complications as they occur. The ultimate treatment for decompensated cirrhosis would be one that targets primarily the pathological alterations within the liver with the aim of restoring the integrity of liver architecture by suppressing inflammation, causing fibrosis regression, regularising the portal and arterial

Effects of suppression of aetiological factor on outcome of decompensated cirrhosis

Removal of the aetiological factor(s) causing liver injury is an important cornerstone in the management of cirrhosis. This approach is clearly effective in preventing decompensation and improving outcome in patients with compensated cirrhosis. However, results in patients with decompensated cirrhosis are less efficacious and probably depend, among other factors, on the actual status of liver disease at the time of removing the aetiological factor of liver injury. For example, although in some

Effects of targeting key pathogenic events in prevention of cirrhosis progression

Several strategies have been evaluated to prevent disease progression in patients with decompensated cirrhosis, including i) targeting microbiome abnormalities and BT, to improve gut-liver axis; ii) improving the disturbed circulatory function; iii) treating the inflammatory state; and iv) targeting portal hypertension.

Administration of rifaximin has been shown to reduce the risk of development of several complications of cirrhosis besides hepatic encephalopathy in retrospective studies and

Ascites

Ascites is the most common cause of decompensation in cirrhosis, as 5% to 10% of patients with compensated cirrhosis per year develop this complication.29 The mainstay of ascites formation is renal sodium retention due to the activation of sodium retaining systems, such as the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system. The resulting positive fluid balance ultimately leads to extracellular fluid volume expansion. Reduced effective volaemia secondary to splanchnic

Definition and pathophysiology

Hyponatremia is common in patients with advanced cirrhosis, and has been arbitrarily defined as serum sodium concentration lower than 130 mmol/L.[141], [142] However, according to guidelines on hyponatremia in the general patient population,143 reductions below 135 mmol/L should also be considered. Patients with hyponatremia have a poor prognosis, as it is associated with increased mortality[144], [145] and morbidity, particularly neurological complications,[146], [147] and reduced survival

Pathophysiology

Variceal haemorrhage (VH) occurs because of the rupture of the variceal wall due to excessive wall tension. Variceal wall tension is an intrinsic property of the vessel wall that opposes the expansive force determined by variceal transmural pressure, which depends on portal pressure and vessel size. Tissue support surrounding the varix may counteract the increase in variceal pressure and size, protecting the wall from rupture.161 Once variceal wall rupture occurs, the amount of bleeding is

Bacterial infections

The risk of bacterial infection in cirrhosis is caused by multiple factors that include liver dysfunction, portosystemic shunting, gut dysbiosis, increased BT, cirrhosis-associated immune dysfunction,[237], [238] and genetic factors This immune defect facilitates BT, induced by increased intestinal permeability and gut bacterial overgrowth observed in cirrhosis.239 Genetic immune defects can contribute to the high risk of bacterial infections in cirrhosis, particularly SBP. Cirrhotic patients

Definition and diagnosis

Renal impairment in patients with cirrhosis was defined more than 30 years ago by an SCr value ≥1.5 mg/dl because this value was considered an index of GFR ≤40 ml/min.32 The use of SCr in the evaluation of renal function in patients with cirrhosis, has several well-known limitations. However, the diagnosis of renal dysfunction in liver disease is still based on it.[32], [299] The diagnosis should be based on different diagnostic categories including chronic kidney disease (CKD) and acute renal

Definitions and pathophysiology

Since the CANONIC study, the first major international observational study characterising the syndrome of ACLF,3 a large number of publications have described the association of this syndrome with different clinical, diagnostic and therapeutic approaches. ACLF occurs in 30% of admitted patients[3], [399] and in 25% of outpatients,400 and is a major cause of death in cirrhosis, with an approximately 50% mortality rate.400 Even though there is an ongoing debate regarding the definition of ACLF,

Precipitating events

The precipitating events vary between different populations, geographic areas and aetiologies. While in Western countries (Europe, North and Latin America) bacterial infection, followed by active alcohol intake or binge are major precipitating events,[3], [412], [413] in Eastern countries (Asia, Pacific region) the exacerbation of hepatitis B, followed by alcohol or bacterial infections are the major causes of AD and ACLF development.[414], [415], [416] But there are a number of other insults,

Definition and pathophysiology

Relative adrenal insufficiency (RAI) is a condition of inadequate cortisol response to stress in the setting of critical illness,435 also named as “Critical Illness Related Corticosteroid Insufficiency” (CIRCI).436 RAI has also been described in patients with cirrhosis and, although it is mainly present in critically ill patients with sepsis or septic shock (68.9%), it also affects non-critically ill cirrhotic patients (41.8%), including those with compensated cirrhosis.[437], [438], [439],

Definition and pathophysiology

Cirrhotic cardiomyopathy (CCM) refers to chronic cardiac dysfunction in a patient with established cirrhosis, characterised by a blunted contractile response to stress (pharmacological/surgical or inflammatory) and an altered diastolic relaxation, often associated with electrophysiological abnormalities such as prolongation of the QTc interval. These phenomena occur in the absence of any other cardiac disease.457 Systemic inflammation is thought to be key in inducing myocardial dysfunction

Definitions and clinical manifestations

The association of chronic liver disease with respiratory symptoms and hypoxia is well recognised. Four main pulmonary complications may occur in patients with chronic liver disease: pneumonia, hepatic hydrotorax, HPS and PPHT. HPS is defined as a disorder in pulmonary oxygenation, caused by intrapulmonary vasodilatation and, less commonly, by pleural and pulmonary arteriovenous communications occurring in the clinical setting of portal hypertension.[498], [499] It is most commonly diagnosed in

Conclusions

These guidelines on the management of patients with decompensated cirrhosis were developed based on a new pathophysiological background that offers the opportunity for more comprehensive therapeutic or prophylactic approaches to manage the disease. The knowledge of the key pathophysiologic mechanisms makes it possible nowadays to counteract the progression of cirrhosis and so to prevent its complications. This represents a step forward, shifting our approach from treating the complications of

Conflict of interest

Paolo Angeli: Consultancy fee from Sequana Medical AG, Gilead Italy and Biovie; Patent inventor from Biovie; Research grant from Gilead; Speaker’s fee from Bhering, Kedrion 2016. Mauro Bernardi: Consultancy fee from CLS Behring GmbH, Baxter Healthcare SA, Grifols SA; Speaker’s fee from CLS Behring GmbH, Baxter Healthcare SA, PPTA Europe, Octapharma AG, Gilead Sciences, AbbVie Italia. Wim Laleman: Speaker’s fee for Gore, Norgine, 4C, Abbvie, Sirtex; Consultancy fee for AbbVie, Gilead, MSD,

Acknowledgments

We would like to thank Alessandra Brocca Dr, Marta Tonon MD, Husain-Syed Faeq MD for the great editorial work. We acknowledge ICREA for the ACADEMIA AWARD given to Pere Ginès. We would like to thank the reviewers of this Clinical Practice Guideline for their time and critical reviewing: EASL Governing Board, Alexander Gerbes, Thierry Gustot, Guadalupe Garcia-Tsao.

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