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Acute on Chronic Liver Failure

Patrick S. Kamath, M.D.

DEFINITION ACLF, and with decompensated cirrhosis type C ACLF.

Thus, ACLF is a late stage in the natural history of chron-
Acute on chronic liver failure (ACLF) is a syndrome in ic liver disease with hepatic and extrahepatic organ
patients with chronic liver disease with or without previ- failure.
ously 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 associat- Recent studies have suggested that there are approxi-
ed with increased risk for mortality within a period of 28 mately 700,000 hospitalizations a year in the United
days and up to 3 months from onset.1 The natural histo- States for cirrhosis, 32,335 of which have ACLF (5% of
ry of chronic liver disease in a subset of patients is pro- all hospitalizations for cirrhosis).2 Among these patients
gression to cirrhosis. Cirrhosis has two broad stages. The with ACLF, approximately two-thirds are infected, com-
onset of jaundice, ascites, variceal bleeding, or hepatic pared with only approximately one-tenth of patients
encephalopathy heralds the onset of decompensated cir- without ACLF. Mortality rates from ACLF have been
rhosis; the stage where there is absence of any of these decreasing from 2001 to 2011 from approximately 65%
complications is compensated cirrhosis. When viral, drug, to currently 50% per hospitalization. The estimated
alcohol, or ischemic hepatitis, surgery, or sepsis are annual cost of treating patients with cirrhosis is US $9.9
superimposed upon chronic liver disease with or without billion per year, and for the patients with ACLF, US $1.7
either stage of cirrhosis, there is worsening of liver dis- billion. This translates to a mean hospitalization cost of
ease that may result in hepatic and extrahepatic organ US $14,894 for patients with cirrhosis and US $51,841
failure. ACLF in patients with chronic liver disease is for patients with ACLF. In contrast, the per-
termed type A ACLF, with complicated cirrhosis type B hospitalization cost for patients with congestive heart

Abbreviations: ACLF, acute on chronic liver failure; CLF, chronic liver failure; CTP, Child Turcotte Pugh.
From the Division of Gastroenterology and Hepatology, Mayo Clinic; and Department of Medicine, Mayo Clinic College of Medicine.
Potential conflict of interest: Nothing to report.
Received 5 January 2017; accepted 25 January 2017

View this article online at wileyonlinelibrary.com

C 2017 by the American Association for the Study of Liver Diseases

86 | CLINICAL LIVER DISEASE, VOL 9, NO 4, APRIL 2017 An Official Learning Resource of AASLD
REVIEW Acute on Chronic Liver Failure Kamath

failure is US $10,775, for pneumonia US $7,206, and for MANAGEMENT

sepsis US $19,330. The mean length of stay for patients
with ACLF is 16 days, compared with 5.2 days for pneu- Management focuses on reversing extrahepatic organ
monia, 5 days for congestive heart failure, and 8.8 days failure and liver failure. Liver transplantation is considered
for sepsis. Thus, the costs of treating ACLF and the mor- in selected patients. Two studies have addressed the role
tality rates are far greater than those associated with of artificial liver support in the treatment of ACLF. One
more common causes for hospitalization. study used the Prometheus device,7 and the other was
the RELIEF Study using the MARS device.8 Neither dem-
onstrated overall survival benefit. In the Prometheus
FEATURES Study, survival benefit was noted only in the presence of
a MELD score >30 and hepatorenal syndrome.
The normal hepatocyte takes up ammonia and
releases urea into the circulation. The hepatocyte also AREAS OF UNCERTAINTY
regenerates. In liver failure, when the hepatocyte is
injured, ammonia and other waste products cannot be There are several areas of uncertainty regarding various
metabolized and accumulate in the circulation. The aspects of ACLF. The definition of ACLF is not universally
injured hepatocytes attract inflammatory cells, which are accepted, with a different definition being used in Asia. The
recruited from the extracellular matrix, and inflammatory pathophysiology of ACLF is unclear, and the role of bio-
cytokines are released into the circulation. These cyto- markers for diagnosis awaits further studies. Currently used
kines also inhibit mitosis. The end result of hepatocyte prognostic scores use organ failure as a variable. Such scores
injury is waste accumulation, systemic inflammation, and are accurate for short-term mortality at a time when interven-
impaired regeneration. The systemic inflammatory tion may not reverse the downhill course. Such scores may be
response syndrome is followed by a compensatory anti- better used to exclude patients from studies. There has been
inflammatory response that results in immune suppres- some benefit in the use of granulocyte colony-stimulating
sion, second infections, sepsis, and fungemia. The end factor and erythropoietin, with decreased mortality and
result is multiple organ failure, including decreased improvement in Child Turcotte Pugh (CTP) and MELD scores,9
hepatocyte function with cholestasis and coagulopathy; but these conclusions need to be validated independently.
hepatic encephalopathy and cerebral edema; high-
output cardiac state, subclinical myocardial injury, and FUTURE DIRECTIONS
cardiomyocyte suppression; adrenal dysfunction; acute
kidney injury; acute lung injury and acute respiratory dis- Future studies should be aimed at determining wheth-
tress syndrome; and immunoparesis. er ACLF can be prevented and determining which patient
is at risk for death, which patient will benefit from inten-
sive care alone, which patient should have early liver
transplant, and the role of regenerative therapies and
Prognosis is related to a number of organ failures3 and bioartificial liver support. It is equally important, because
can be measured by the chronic liver failure (CLIF) organ ACLF is such an expensive disease to treat and so as not
failure score.4 Age and leukocytosis as variables increase to waste resources, that we be able to determine early in
the predictive accuracy of the CLIF-ACLF score, with sur- which patients treatment is likely to be futile.
vival 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 Patrick S. Kamath, M.D., Consultant in Gastroenterology and Hepa-
have high mortality risk.3 Respiratory failure is the stron- tology, Mayo Clinic, Professor of Medicine, Mayo Clinic College of
Medicine, 200 SW First Street, Rochester MN 55905. E-mail: kamath.
gest predictor of death. Patients with infection-related patrick@mayo.edu
ACLF have a high risk for delisting (42%).6 Futility of
treatment can be determined using the CLIF C score REFERENCES
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