Acute on chronic liver failure (2017)

Watch a video presentation of this article Watch the interview with the author Acute on chronic liver failure (ACLF) is a syndrome in patients with chronic liver disease with or without previously diagnosed cirrhosis characterized by acute hepatic decompensation resulting in liver failure (jaundice and prolongation of the international normalized ratio), and one or more extrahepatic organ failures, that is associated with increased risk for mortality within a period of 28 days and up to 3 months from onset.1 The natural history of chronic liver disease in a subset of patients is progression to cirrhosis. Cirrhosis has two broad stages. The onset of jaundice, ascites, variceal bleeding, or hepatic encephalopathy heralds the onset of decompensated cirrhosis; the stage where there is absence of any of these complications is compensated cirrhosis. When viral, drug, alcohol, or ischemic hepatitis, surgery, or sepsis are superimposed upon chronic liver disease with or without either stage of cirrhosis, there is worsening of liver disease that may result in hepatic and extrahepatic organ failure. ACLF in patients with chronic liver disease is termed type A ACLF, with complicated cirrhosis type B ACLF, and with decompensated cirrhosis type C ACLF. Thus, ACLF is a late stage in the natural history of chronic liver disease with hepatic and extrahepatic organ failure. Recent studies have suggested that there are approximately 700,000 hospitalizations a year in the United States for cirrhosis, 32,335 of which have ACLF (5% of all hospitalizations for cirrhosis).2 Among these patients with ACLF, approximately two-thirds are infected, compared with only approximately one-tenth of patients without ACLF. Mortality rates from ACLF have been decreasing from 2001 to 2011 from approximately 65% to currently 50% per hospitalization. The estimated annual cost of treating patients with cirrhosis is US $9.9 billion per year, and for the patients with ACLF, US $1.7 billion. This translates to a mean hospitalization cost of US $14,894 for patients with cirrhosis and US $51,841 for patients with ACLF. In contrast, the per-hospitalization cost for patients with congestive heart failure is US $10,775, for pneumonia US $7,206, and for sepsis US $19,330. The mean length of stay for patients with ACLF is 16 days, compared with 5.2 days for pneumonia, 5 days for congestive heart failure, and 8.8 days for sepsis. Thus, the costs of treating ACLF and the mortality rates are far greater than those associated with more common causes for hospitalization. The normal hepatocyte takes up ammonia and releases urea into the circulation. The hepatocyte also regenerates. In liver failure, when the hepatocyte is injured, ammonia and other waste products cannot be metabolized and accumulate in the circulation. The injured hepatocytes attract inflammatory cells, which are recruited from the extracellular matrix, and inflammatory cytokines are released into the circulation. These cytokines also inhibit mitosis. The end result of hepatocyte injury is waste accumulation, systemic inflammation, and impaired regeneration. The systemic inflammatory response syndrome is followed by a compensatory anti-inflammatory response that results in immune suppression, second infections, sepsis, and fungemia. The end result is multiple organ failure, including decreased hepatocyte function with cholestasis and coagulopathy; hepatic encephalopathy and cerebral edema; high-output cardiac state, subclinical myocardial injury, and cardiomyocyte suppression; adrenal dysfunction; acute kidney injury; acute lung injury and acute respiratory distress syndrome; and immunoparesis. Prognosis is related to a number of organ failures3 and can be measured by the chronic liver failure (CLIF) organ failure score.4 Age and leukocytosis as variables increase the predictive accuracy of the CLIF-ACLF score, with survival being unusual in patients with a CLIF-ACLF score >64 in the absence of liver transplantation.5 In general, patients with two or more extrahepatic organ failures have high mortality risk.3 Respiratory failure is the strongest predictor of death. Patients with infection-related ACLF have a high risk for delisting (42%).6 Futility of treatment can be determined using the CLIF C score with patients with four or more organ failures at almost invariable risk for mortality.5 Management focuses on reversing extrahepatic organ failure and liver failure. Liver transplantation is considered in selected patients. Two studies have addressed the role of artificial liver support in the treatment of ACLF. One study used the Prometheus device,7 and the other was the RELIEF Study using the MARS device.8 Neither demonstrated overall survival benefit. In the Prometheus Study, survival benefit was noted only in the presence of a MELD score >30 and hepatorenal syndrome. There are several areas of uncertainty regarding various aspects of ACLF. The definition of ACLF is not universally accepted, with a different definition being used in Asia. The pathophysiology of ACLF is unclear, and the role of biomarkers for diagnosis awaits further studies. Currently used prognostic scores use organ failure as a variable. Such scores are accurate for short-term mortality at a time when intervention may not reverse the downhill course. Such scores may be better used to exclude patients from studies. There has been some benefit in the use of granulocyte colony-stimulating factor and erythropoietin, with decreased mortality and improvement in Child Turcotte Pugh (CTP) and MELD scores,9 but these conclusions need to be validated independently. Future studies should be aimed at determining whether ACLF can be prevented and determining which patient is at risk for death, which patient will benefit from intensive care alone, which patient should have early liver transplant, and the role of regenerative therapies and bioartificial liver support. It is equally important, because ACLF is such an expensive disease to treat and so as not to waste resources, that we be able to determine early in which patients treatment is likely to be futile.