Acute-on-Chronic Liver Failure

Introduction

Cirrhosis had traditionally been classified into two stages: compensated cirrhosis and decompensated cirrhosis. Within the period of compensated cirrhosis, the major risks for mortality are cardiovascular disease, stroke, and extrahepatic malignancy. However, the majority of patients with compensated cirrhosis progress to decompensated disease, which is characterized by jaundice, ascites, variceal bleeding, or hepatic encephalopathy. A finer stratification includes four stages of cirrhosis: stage 1, compensated cirrhosis without either varices or ascites; stage 2, compensated cirrhosis with varices that have not bled but without ascites; stage 3, ascites without variceal bleeding; and stage 4, variceal bleeding with or without ascites. Because infection is recognized as an independent risk factor for mortality, cirrhosis with sepsis has been proposed as the fifth stage of cirrhosis.

More recently, the concept of acute-on-chronic liver failure (ACLF) has been proposed as the preterminal pathway in the natural history of chronic liver disease. Multiple organ failure and an increased risk for mortality are key to the diagnosis of ACLF. Indeed, patients with compensated cirrhosis and even patients with chronic liver disease without cirrhosis may also develop multiple organ failure with high mortality risk. ACLF requires a precipitating event (identified or unidentified), underlying chronic liver disease, and rapid progression to multiorgan dysfunction characterized by a high short-term mortality. The current understanding of ACLF (definitions and pathophysiology), associated extrahepatic organ dysfunction, current prognostic markers, predictive models, and potential therapies are discussed in this chapter, recognizing that this is a rapidly evolving area of discovery.

Definition

For an optimal definition of ACLF, identification of the subset of patients with chronic liver disease or cirrhosis with abrupt decompensation to extrahepatic organ failure and an elevated risk for short-term mortality is essential. Indeed, the mortality risk should be substantially higher than the expected natural progression of cirrhosis. Compared with the general population, patients with compensated cirrhosis have a fivefold increase (hazard ratio [HR], 4.7; 95% confidence interval [CI], 4.4-5.0) and persons with decompensated cirrhosis have a 10-fold increase (HR, 9.7; 95% CI, 8.9-10.6) in risk of death. The median 1-year survival was 83% in persons with compensated cirrhosis and between 36% and 80% for persons with decompensated cirrhosis in a recent population-based study of Danish alcoholic cirrhotic patients. On the other hand, median survival in patients with infection-related ACLF is only approximately 35 days. In a recent study, cirrhotic patients with ACLF had 90-day mortality rates of 34% versus 1.9% for chronic decompensation.

There are currently many separate definitions of ACLF including an interim definition of ACLF arrived at following a joint European Association for the Study of the Liver–American Association for the Study of Liver Diseases (EASL-AASLD) meeting. ACLF is characterized by immune paralysis, akin to changes seen in severe sepsis. Patients with ACLF may also have clinical features in common with acute liver failure (ALF). However, ALF occurs in subjects without underlying chronic liver disease and is characterized by onset of coagulopathy and encephalopathy within 8 weeks of onset of symptoms. On the other hand, both ACLF and ALF may be associated with cerebral edema which is not seen in decompensated cirrhosis without ACLF.

Three separate definitions have been derived from multicenter efforts from the Asia-Pacific region, Europe, and North America. The Asia-Pacific Association for the Study of the Liver (APASL), defined ACLF as an “acute hepatic insult manifesting as jaundice (bilirubin >5 mg/dL) and coagulopathy (INR >1.5) complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease.” Reactivation of hepatitis B and superinfection with hepatitis E virus infection on NAFLD are important causes of ACLF in that region, but a significant proportion of cases continue to be due to alcoholic hepatitis. The European Association for the Study of the Liver–Chronic Liver Failure (EASL-CLIF) consortium defined ACLF as a failure of hepatic or extrahepatic organs associated with a 28-day mortality greater than 15%. ACLF was further characterized into three grades. Grade 1: this group was further subdivided into (1) patients with kidney failure as the only organ failure; (2) patients with kidney dysfunction (1.5-1.9 mg/dL) and/or mild to moderate hepatic encephalopathy along with single organ failure of either liver, coagulation, circulation, or respiratory systems; and (3) patients with hepatic encephalopathy along with kidney dysfunction (1.5-1.9 mg/dL). Grade 2 comprised patients with two or more organ failures and grade 3 comprised patients with three or more organ failures. The 28-day mortality was 22%, 32%, and 77%, respectively, in grade 1, grade 2, and grade 3 ACLF. It is important to emphasize that the majority of subjects in the EASL-CLIF study had ACLF in the setting of alcoholic liver disease. Viral or drug-induced hepatitis as precipitating events were extremely infrequent; no precipitating event was found in 44% of cases. There was a high prevalence of bacterial infection. The overall transplant-free mortality was 34% at 28 days and 51% at 90 days.

The North American Consortium for the Study of End-Stage Liver Disease (NACSELD) recently examined survival in sepsis- or infection-related ACLF. Organ failures were defined as the presence of either shock (cardiac failure), grade 3 or grade 4 hepatic encephalopathy (brain failure), need for dialysis (kidney failure), or need for mechanical ventilation (pulmonary failure). ACLF due to sepsis was defined as two or more organ failures in the presence of liver failure. Overall half of the population (total 507 patients) had hepatitis C and 16% had a nosocomial infection. Thirty-day mortality increased in parallel with the number of extrahepatic organ failures: 27%, 49%, 64%, and 77% for one, two, three, and four extrahepatic organ failures, respectively.

It is recognized that the definition of the individual organ failure was different between the EASL-CLIF and NACSELD consortia. The interval between the precipitating event and organ failure, the emphasis on extrahepatic organ failure, especially infection, and the definition of chronic were different across the three iterations of ACLF. In order to consolidate the complementary definitions, a working group on behalf of the World Gastroenterology Organization proposed the following definition: ACLF is a “syndrome in patients with chronic liver disease with or without previously diagnosed cirrhosis which is characterized by acute hepatic decompensation resulting in liver failure (jaundice and prolongation of the INR [International Normalized Ratio]) and one or more extrahepatic organ failures that is associated with increased mortality within a period of 28 days and up to 3 months from onset.” The proposal also included classifying ACLF based on whether it occurs in patients with chronic liver disease but without cirrhosis (Type A, e.g., reactivation of hepatitis B); in patients with compensated cirrhosis (Type B, e.g., acute alcoholic hepatitis in a patient with cirrhosis); or in patients with decompensated cirrhosis (Type C, e.g., infection in a patient with a history of ascites) ( Fig. 21-1 ). Current definitions are suboptimal in that the diagnosis is made only after the onset of organ failure, which might be too late for effective interventions.

Precipitating Events

Precipitating events differ based on underlying liver disease and region of the world. In noncirrhotic chronic liver disease the precipitating event is a major hepatic injury, such as reactivation of chronic hepatitis B, superimposed acute hepatitis A or hepatitis E infection in the East, or drug-induced liver injury superimposed upon nonalcoholic fatty liver disease in the West. In compensated cirrhosis the precipitating event is primarily hepatic, such as alcoholic hepatitis or drug-induced hepatitis. In decompensated cirrhosis extrahepatic events such as infection may be the precipitating event, though in a significant population no recognizable precipitating event occurs.

Data from the Department of Veterans Affairs in the United States suggest that patients with either underlying chronic liver disease or with diabetes are at higher risk for liver failure with superimposed viral hepatitis. Whereas these patients might have ACLF, distinction of ACLF from ALF may be possible only on liver biopsy. Furthermore, the drug-induced liver injury (DILI) network in the United States demonstrated that DILI is more likely to lead to liver failure in patients with diabetes. This suggests that drug-induced liver injury superimposed on NAFLD may be an important cause of ACLF in the West.

Though alcoholic hepatitis, DILI and infections are reportedly more common causes of ACLF in western centers, they remain a major cause of ACLF in the East. Given that approximately half of subjects with cirrhosis admitted to the hospital have evidence of infection or sepsis and a further 25% develop nosocomial infections with high inpatient hospital mortality, infection plays an overwhelming role in the natural history of ACLF. There are also differences in long-term survival in patients with hepatic precipitants (e.g., viral hepatitis) as compared with extrahepatic precipitants such as bacterial infection (1-year mortality 63.9% vs. 74.6%).

Prevalence

The prevalence of ACLF is hard to assess given the variation in definitions of ACLF, but it ranges from 12% to 40% among hospitalized cirrhotic patients. In the European multicenter study, the prevalence was 31%. In the NACSELD cohort, the prevalence of infection associated ACLF was 24.4% (>2 organ failures). In a European population-based cirrhotic cohort (2001-2010), the prevalence of infection-related ACLF was 24%. In a single-center prospective nationwide inception cohort study in Italy, ACLF was observed in 12% of hospitalized cirrhotic patients.

Natural History

In data from European centers ( n = 338), approximately 50% had resolution or improvement in their ACLF, 20% had worsening of their clinical course, and 30% had a steady or fluctuating course. Patients with grade 1 ACLF had the highest resolution and lowest degree of worsening (resolution 54.5%). The prognosis was worst in grade 3 ACLF (resolution 16%). The time course assessing improvement, resolution, or worsening was determined within 48 hours in 40%, 3 to 7 days in 15%, and 8 to 28 days in another 15% of the population.

The mortality rate of patients with infection-associated ACLF may be as high as 50%, depending on the number of extrahepatic organ failures. Approximately one half of the hospitalizations of cirrhotic patients are due to infections; indeed a further 20% to 40% of patients develop nosocomial infections. The most prevalent infections in patients hospitalized with cirrhosis are urinary tract infection (UTI) and spontaneous bacterial peritonitis (SBP).

Economic Burden

There are limited data on the cost of ACLF as it is hard to accurately separate out subjects with ACLF from those with non-ACLF-related decompensated liver disease among patients hospitalized with cirrhosis. In one estimate of the Nationwide Inpatient Sample (NIS) in the United States using the NACSELD definition of ACLF as more than two extrahepatic organ failures, the mean cost per ACLF patient hospitalization was twice as high as that for non-ACLF cirrhosis patients (approx. $32,000 for ACLF patients, compared with $16,000 for non-ACLF cirrhosis patients). In addition, it does not appear that there has been a significant reduction in mortality in patients with ACLF during the past 2 decades, with mortality in the nationwide sample approaching 50%.