Acute-on-Chronic Liver Failure: Conceptual Framework and Clinical Controversies

Evidence supporting the concept of acute-on-chronic liver failure underscores the complex pathophysiology and clinical challenges in its recognition and management, addressing controversies surrounding its existence and diagnostic criteria to improve clinical outcomes in affected patients.

March 2021

Acute decompensated liver cirrhosis (ADLC) and acute-on-chronic liver failure (ACLF) are 2 important conditions seen in patients with chronic liver disease who decompensate acutely.

ADLC refers to the development of ascites, encephalopathy, gastrointestinal bleeding, or any combination of these disorders in patients with cirrhosis.

ACLF refers to a syndrome associated with an elevated short-term risk of death (i.e., death less than 28 days after hospitalization) in patients with ADLC.

Three main features characterize this syndrome:

  1. It occurs in the context of intense systemic inflammation.
     
  2. It frequently develops in close temporal relationship with precipitating proinflammatory events (e.g., infections or alcoholic hepatitis).
     
  3. They are associated with the failure of one or more organs.

There is extensive literature recognizing ACLF as a clinical entity (e.g., 8 randomized therapeutic trials are currently enrolling patients with ACLF), but some doubt the existence of the syndrome. On the other hand, the definitions proposed for ACLF differ from each other.

Definition of acute-on-chronic liver failure

Although definitions of ACLF differ, most take into account the role of hepatic and extrahepatic precipitating events and include extrahepatic organ failures.

The European definition, proposed by the Consortium of the European Association for the Study of the Liver–Chrome Liver Failure (EASL-CLIF), which includes extrahepatic organ failures, applies only to patients with ADLC, with or without prior decompensation, and does not excludes extrahepatic precipitating events.

The definition is based on a prospective investigation involving 1,343 consecutive patients hospitalized for CHADA. Organ failures are identified by using the modified Sequential Morgan Failure Assessment score (EASL-CLIF Consortium point system), which considers liver, kidney, and brain function, as well as coagulation, circulation, and breathing, which allows patients to be stratified into subgroups with different risks of death.

Coagulation is included in the score because coagulation may not only reflect the degree of liver failure in patients with severe systemic inflammation or sepsis.

The European definition includes patients with a high risk of death up to 28 days after hospital admission (patients with renal failure alone; those with non-renal organ failure alone, if associated with renal or brain dysfunction; and, those with ≥ 2 organic failures.

According to the number of organ failures at the time of diagnosis, patients with ADLC were stratified into 4 prognostic grades: without ACLF and with ACLF grades 1, 2, and 3.

In a study involving 1,322 prospectively enrolled patients, the Chinese Group of the Study of Severe Hepatitis B developed a definition for ACLF due to hepatitis B virus. This definition is very similar to the European definition of ACLF.

Like the European definition, the American Consortium for the Study of End-Stage Liver Disease definition of ACLF applies only to patients with ADLC and does not exclude extrahepatic precipitating events.

On the other hand, it considers organ failure (defined by shock, grade 3 or 4 hepatic encephalopathy, or need for dialysis or mechanical ventilation) as components of the syndrome. The definition is based on an investigation of 507 patients with cirrhosis and ongoing infection.

The definition of ACLF was based on the presence of ≥2 extrahepatic organ failures. This definition has been validated in a large North American cohort of infected and uninfected patients with cirrhosis.

Unlike the other definitions, the Asian Pacific Association for the Study of the Liver definition does not include extrahepatic organ failure. Rather, the definition is based on the opinions of experts who considered  ACLF as acute liver damage (e.g., hepatitis B virus reactivation or acute alcoholic hepatitis), manifesting with jaundice and coagulopathy, and within 4 weeks it is complicated by clinical ascites, encephalopathy, or both.

The definition applies only to patients without a history of decompensation and those with chronic non-cirrhotic liver disease. Consequently, patients with prior decompensation and those with ADLC are not included in the definition.

Extrahepatic injuries, such as sepsis or gastrointestinal bleeding, are not considered conditions that precipitate ACLF , but are considered complications of this syndrome. Extrahepatic organ failures are considered the progressive manifestations of ACLF or the infectious complications, but not as components of the syndrome.

Clinical features

In a European study that used European criteria and included patients hospitalized with ADLC, ACLF was present in 22.6% of patients on admission, and in another 8.3% it developed during hospitalization.

Newly developed ACLF occurred days after hospitalization (maximum interval, 2 weeks), indicating that ACLF in patients with cirrhosis occurs simultaneously with, or following, acute decompensation.

ACLF was particularly prevalent in patients with alcoholic cirrhosis; 60% of patients had precipitating hepatic conditions (alcoholic hepatitis), extrahepatic precipitating conditions (most commonly infections), or both. The fact that 40% of the remaining patients did not have a clinically identifiable precipitating event is consistent with the idea that ACLF may occur for as yet unknown reasons.

In patients with ACLF , the 28-day and 90-day transplant-free mortality rates were 32.8% and 51.2%, respectively, and in patients without ACLF , the rates were 1.8% and 9.8%. 8%, respectively. The prevalence of ACLF and the associated mortality rate were also high in large-scale studies conducted outside Europe but using European criteria.

It has been discovered that in a few days the disorder can have a variable course of resolution, improvement or worsening or follow a constant evolution. Consequently, the prognosis for patients with each grade of ACLF was less accurate when estimated 3 to 7 days from the time of diagnosis than when estimated later.

In a North American study that used the North American definition of ACLF in patients hospitalized non-selectively for CHAD, the prevalence of ACLF was 10%, and the 30-day mortality rate was 41% (vs. 7% mortality in the absence of the syndrome). ). Therefore, the prevalence differs depending on the definition used.

In Asia, a common precipitant of ACLF is an outbreak of hepatitis B virus infection. In a study using the Asia Pacific ACLF criteria, 76% of patients with cirrhosis and hepatitis B virus-related ACLF hepatitis B had complications, including bacterial or fungal infection (32% of patients), hepatorenal syndrome (15%), and gastrointestinal bleeding (9%). Mortality rates in transplant-free patients at 28 and 90 days were 27.8% and 40.0%, respectively.

A Veterans Health Administration study involving a large series of patients with compensated cirrhosis investigated the newly developed ACLF and compared the Asia Pacific and European definitions.

The incidence rate of ACLF was 5.7 cases/1000 person-years according to the Asia Pacific Criteria and 20.1/1000 person-years with the European criteria. Mortality rates at 28 and 90 days after ACLF were 41.9% and 56.1%, respectively, with the Asia Pacific criteria and 37.6% and 50.4%, respectively, with the European definition.

Pathophysiology

The pathophysiology of ACLF is largely unknown but systemic inflammation is believed to be involved.

Patients with ACLF have intense systemic inflammation and oxidative stress, unlike patients who have acute decompensation but without organ failure.

ACLF studies have shown that systemic inflammation directly correlates with the severity of the syndrome; The greater the intensity of systemic inflammation, the greater the number of organ failures and the higher the short-term mortality.

Bacterial infections and acute alcoholic hepatitis are two precipitants of systemic inflammation that are frequently associated with ACLF . The mechanisms by which gastrointestinal bleeding can precipitate ACLF are less clear. However, severe hemorrhage can cause ischemic hepatitis, which produces cellular necrosis and release of inflammatory stimuli.

On the other hand, gastrointestinal bleeding confers a predisposition to the development of bacterial infections. In 40% of patients with cirrhosis, who have systemic inflammation and ACLF without any identifiable precipitating condition, translocation of bacterial byproducts from the intestinal lumen into the systemic circulation may occur.

Therapeutic principles

The Model for End-Stage Liver Disease score with the addition of serum sodium level (MELD-Na), in addition to scores based on the number of organs in failure, provides prognosis. accurate for individual patients with ACLF . The main therapeutic principle is to diagnose and treat the precipitating event and then provide supportive therapy.

Organ support should be done in an intensive care unit, with care supervised by expert hepatologists, which may benefit patients with life-threatening failure of 1 or multiple organs, who do not respond to standard therapy.

Many therapeutic recommendations are based on clinical practice or studies involving critically ill patients without cirrhosis. In the future, different therapies can be validated, depending on the precipitating event (hepatic or extrahepatic.

Treatment of the precipitating event

> Bacterial or fungal infection

The prevalence of infections, whether precipitating or complications of the syndrome, is almost 50% in patients with ACLF  and 70% in patients with ≥3 organ failures. The most common causative microbes are bacteria, but fungal infection can also occur.

Treatment of infections should be started as soon as possible. The choice of antimicrobial therapy. It is based on the isolated organism (if any), the suspected site of infection, the site of acquisition, and local antimicrobial susceptibility patterns.

> Acute varicose hemorrhage

Standard medical treatment includes the combination of a safe vasoconstrictor (terlipressin, somatostatin, or analogues such as octreotide or vapreotide, administered from the time of admission and maintained for 2 to 5 days) and endoscopic therapy (preferably endoscopic ligation of the varicose veins, performed during diagnostic endoscopy, less than 12 hours after admission), along with short-term antibiotic prophylaxis, with ceftriaxone. The only vasoconstrictor currently available in the US is octreotide.

> Alcoholic hepatitis

Prednisolone therapy is indicated for patients with severe alcoholic hepatitis. The Lille score is used for early identification of patients who do not respond to treatment. The score is calculated based on age, bilirubin and albumin values, prothrombin time, baseline renal function, and change in bilirubin levels between days 0 and 7 of prednisolone therapy.

The score ranges from 0 to 1. A score ≥0.45 on the seventh day of treatment indicates that there is no improvement in response to prednisolone and that the probability of short-term survival is low, compared to patients who respond. ; treatment should be discontinued.

A score <0.45 indicates a positive response to treatment, which should be continued for 28 days. The response to prednisolone is negatively correlated with the number of organ failures at baseline.

>  Reactivation of the hepatitis B virus

In all patients with hepatitis B virus infection at presentation, administration of nucleoside or nucleotide analogues should be initiated immediately, while awaiting confirmation of infection, based on the level of viral DNA. Potential antiviral medications such as tenofovir, tenofovir, alafenamide, or entecavir should be used.

Supportive therapy

> Cardiovascular support

In Western countries, the most common acute organ injury is that of the kidney.

Management of ACLF in patients with acute kidney injury includes diuretic withdrawal and volume expansion (with intravenous albumin), as well as urinalysis to determine whether the kidney injury is acute tubular necrosis or type 1 hepatorenal syndrome.

If there is no response to volume expansion, treatment with a vasoconstrictor (terlipressin or norepinephrine) should be initiated, particularly if urinalysis points to type 1 hepatorenal syndrome. The likelihood of a renal response to vasoconstrictor therapy is inversely related. with the number of organs in failure at the beginning of the study. For the treatment of persistent shock, the first-line vasopressor agent is norepinephrine .

> Treatment of encephalopathy

If the airway cannot be protected, intubation is necessary.

Initial treatment is with lactulose , taking care not to cause profuse diarrhea. A useful adjunct to oral lactulose is the administration of enemas to cleanse the intestine. When severe hepatic encephalopathy is refractory to lactulose, albumin dialysis can be used.

> Extracorporeal liver support

Two large randomized trials showed that albumin dialysis, compared with standard medical treatment, did not improve the short-term survival of patients with IHA. More recently, the extracorporeal liver assist device incorporating hepatocytes was found to be no more effective than standard care.

Randomized trials are currently underway to evaluate plasma exchange (e.g., APACHE) and strategies targeting albumin exchange and endotoxin removal (DIALIVE trial) in patients with ACLF .

> Liver transplant

The 1-year survival rate after liver transplantation in patients with ACLF and 1 or 2 organ failures does not differ significantly from the rate in patients without ACLF .

For patients with ≥3 failing organs, the 1-year post-transplant survival rate can reach 80%, compared with a <20% survival rate in non-transplanted patients. These data provide compelling evidence in favor of transplantation for patients with ACLF .

Conclusions

  • ACLF is a syndrome that affects patients with chronic liver disease and is characterized by intense systemic inflammation, organ failure and poor prognosis; it often develops in close association with precipitating events.
     
  • It is still unclear whether extrahepatic organ failure is a component of the syndrome or a consequence of its progression.
     
  • The potential role of bacterial infections as precipitating conditions also continues to be debated.
     
  • Acute-on-chronic liver failure is a great challenge for physicians and a stimulus for research in the field of cirrhosis.