**2. Clinical Features**

ACLF has typical clinical features based on the definition used, on which its prevalence also depends. In the European cohort, the prevalence of the syndrome was 23% among patients with AD of cirrhosis at admission and 8.3% of patients developed it during hospitalization within a period of days (maximum of two weeks). In outpatients with cirrhosis, the incidence of the syndrome is about 40% at 10 years [11]. As confirmed by the PREDICT (PREDICTing Acute-on-Chronic Liver Failure) study, another large-scale European prospective investigation designed to identify predictors of this syndrome, patients with ACLF were younger, showed higher levels of white blood cells and C-reactive protein (CRP) and had a greater prevalence of bacterial infections, severe alcoholic hepatitis, variceal bleeding, drug-induced encephalopathy as precipitants, with respect to patients without ACLF [2,12,13]. Moreover, the PREDICT study demonstrated that the clinical course of AD that leads to ACLF is distinct from the other forms of AD of cirrhosis [12]. The 28-day mortality significantly rises with the increase in the number of OFs, ranging from 4.7% for patients without ACLF to 22%, 32% and 77% for patients with ACLF grade 1, 2 and 3, respectively [2].

In a validation study of NACSELD definition of ACLF, in which 2675 patients with AD of cirrhosis related or not to infection were included, the prevalence of ACLF was 10% and 30-day mortality rate was significantly different between patients with or without the syndrome (41% vs. 7%, respectively) [14]. In a recent study, the NACSELD criteria were demonstrated to be less sensitive compared to EASL-CLIF criteria in diagnosing ACLF [15].

When using NACSELD criteria, only about 40% of patients with a diagnosis of ACLF based on EASL-CLIF criteria were classified as affected by the syndrome, probably because the NACSELD definition considers only more severe patients and because it could be influenced by the medical strategies available in the different centers (renal replacement therapy (RRT), mechanical ventilation, use of vasopressors) [10,16].

In a cohort of patients with HBV-related AD of cirrhosis, the prevalence of ACLF was 30.2% according to the COSSH ACLF definition. As in the European cohort, patients with ACLF were younger, had a more severe grade of systemic inflammation (as demonstrated by higher levels of white blood cells and CRP) and more frequently had a bacterial infection (associated or not with HBV reactivation) as precipitant compared to those without ACLF, with a significantly higher short-term mortality (52.1% vs. 4.3%) [6]. Although EASL-CLIF and COSSH definitions of ACLF are very similar, clinical characteristics of patients are quite different, because of the higher prevalence of intra-hepatic precipitants in the Chinese cohort (most often HBV reactivation) with respect to the European cohort [16], with liver and coagulation failure being more frequent in the former and kidney and brain failure more frequent in the latter [4]. As expected, a flare of HBV infection was the most frequent trigger of ACLF in studies using AARC criteria [9,17]. In a study using AARC ACLF criteria which enrolled patients with HBV-related ACLF, about 32% had a bacterial or fungal infection as a complication. The 28-day mortality rate was 27.8% [18].

#### **3. Pathophysiology**

The pathophysiology of ACLF is yet to be fully understood. To date, ACLF is considered the extreme expression of systemic inflammation that drives AD of cirrhosis [19]. Systemic inflammation is characterised by activation of the immune system that leads to increased circulating levels of inflammatory mediators and, if severe, proliferation of neutrophils, monocytes and dendritic cells [20]. The mechanism of systemic inflammation depends on the precipitant of ACLF [3]. The recognition of pathogen-associated molecular patterns (PAMPs) activates the innate immune system by pattern-recognition receptors (PRR) in case of bacterial infection or translocation of viable bacteria and bacterial products through the intestinal wall [19,21]. Exceeding inflammation can cause direct tissue damage and necrotic cell death, resulting in the release of damage-associated molecular patterns (DAMPs) that perpetuate inflammation acting on PRR [21]. DAMPs are also released when an injury acts directly on the liver, as in case of alcoholic hepatitis or ischemia due to variceal haemorrhage [22,23]. This overactivation of the immune cells requires a large amount of energy sustained by reallocation of nutrients. This causes a reduced availability of substrates for other organ systems that leads to OFs by severe mitochondrial dysfunction and impaired energy production [19]. Moreover, recent findings suggest that systemic inflammation can explain and act with the traditionally accepted organ-specific mechanisms of AD (portal hypertension, hyperammonaemia, endogenous vasoconstrictors system and arterial blood volume) in determining OFs [19]. Blood metabolomics offers a new insight into the pathophysiology of systemic inflammation in patients with ACLF and could be an intriguing starting point to uncover new potential therapeutic targets [24]. Figure 1 summarizes the pathophysiology of ACLF.

**Figure 1.** Pathophysiology of ACLF. PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; PRR, pattern-recognition receptors; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system.

#### **4. Prognostic Stratification**

ACLF is a dynamic syndrome that can resolve, improve or worsen in a few days [25]. Outcomes for ACLF patients are strictly related both to severity of liver disease and to severity and number of OFs. Because ACLF patients may be considered for urgent Intensive Care Unit (ICU) referral and/or liver transplantation (LT), different consortia developed prognostic scores [16]. EASL-CLIF proposed the CLIF-C ACLF score, which demonstrated more accuracy in predicting death than MELD (Model for end-stage Liver Disease), MELD-Na (Model for end-stage Liver Disease-Sodium), Child-Pugh and CLIF-C OF scores [17]. CLIF-C ACLF score captures both intra- and extra-hepatic OFs but has a subjective element in the scoring of hepatic encephalopathy and a "ceiling effect" with INR, serum creatinine and bilirubin (for example, a patient with serum bilirubin 25 mg/dL has the same prognosis of a patient with serum bilirubin 12 mg/dL) [16]. The NACSELD organ failure score is simple to use but considers only the sickest patients. The AARC-ACLF score was found to be superior to MELD and CLIF-SOFA in predicting short-term mortality [26] but, as with CLIF-C ACLF score, has subjective elements and suffers from a "ceiling effect" for the considered laboratory values [16]. The COSSH-ACLF score showed higher predictive value for short-term mortality than other scores (MELD, MELD-Na, Child-Pugh, CLIF-C OF and CLIF-C ACLF) in patients with HBV-ACLF [6]. Recently, a simplified version of this score (COSSH-ACLF II) demonstrably improved prognostic accuracy and sensitivity for patients with HBV-ACLF. The COSSH-ACLF II score also allows easy division of patients into three different strata with significantly different 28-day mortality rates [27]. The COSSH-ACLF scores also include a subjective element in hepatic encephalopathy evaluation.

Prognosis is more accurately estimated when the scores are applied at 3 to 7 days than at time of diagnosis [25,28]. These findings are in keeping with the dynamic nature of ACLF. Prognostic scores have also been applied to determine futility of treatments in ACLF patients [28,29]. Thus, it is necessary to overcome the above-mentioned limitations by creating models based only on objective, verifiable and continuous variables [16]. Finally, among OFs not actually included in the prognostic scores, relative adrenal insufficiency (RAI) has been shown to have a similar prognostic value for non-kidney OFs. RAI could be considered to better stratify patients with ACLF in clinical practice [30].

## **5. Management of ACLF**

Principles of treatment of ACLF are summarized in Table 2.

#### *5.1. Admission to Intensive Care Unit*

The referral of patients with ACLF to ICU should be neither delayed nor denied only because of the underlying chronic liver disease or the possibility of poor prognosis in patients with OF(s) [31,32]. In fact, several findings suggest that acceptable survival rates can be achieved in patients with cirrhosis admitted to ICU [33]. In such a setting, CLIF-C OF and CLIF-C ACLF scores perform better than generally used and liver specific scores [31,34].

**Table 2.** Principles of treatment of ACLF [3]. ICA, International Club of Ascites; AKI, acute kidney injury; HRS, hepatorenal syndrome; RRT, renal replacement therapy; LT, liver transplantation; NSAID, non-steroidal anti-inflammatory drugs; MAP, mean arterial pressure; SBP, spontaneous bacterial peritonitis; LVP, large volume paracentesis; DVT deep-vein thrombosis; PaO2 FiO2 SpO2 ACLF, acute-on-chronic liver failure.


\* See ref. [34].

#### *5.2. Treating Organ Failures*

Acute kidney injury (AKI) should be treated with volume expansion with albumin and withdraw from diuretics and beta-blockers [35]. If there is no response after two days of volume expansion and hepatorenal syndrome (HRS)-AKI criteria are met [36], terlipressin given by continuous infusion should be started [37]. Response to terlipressin is inversely related to the number of OFs at baseline and to the creatinine value at the start of the treatment [38,39]. There are scarce data about the role of RRT in patients with ACLF. In a recent study in patients with type 1 HRS and no response to vasoconstrictors, RRT did not improve survival at 30 and 180 days [40]. To date, RRT should be considered as a bridge to LT in selected patients. A target of mean arterial pressure ≥ 65 mmHg should be reached within the first hours in patients with circulatory failure. Crystalloids and 5% albumin solution should be preferred over saline solutions as resuscitation fluids. Starches formulations should be avoided [4]. Norephinephrine is the first-line vasopressor agent [41]. Terlipressin demonstrated a better alternative in one study in patients with cirrhosis and septic shock [42]. Infusion of blood products should be considered only if clinically significant bleeding or invasive procedures in patients with coagulation failure. Respiratory failure should be treated with oxygen supplementation and ventilation, if needed. Intubation should be considered to prevent aspiration pneumonia in patients with severe hepatic encephalopathy by using short-acting sedative agents. Other measures include lactulose and enemas to clear the bowel and the treatment of the underlying cause [4,35].
