REVIEW
Acute on Chronic Liver Failure
Patrick S. Kamath, M.D.
DEFINITION
Acute on chronic liver failure (ACLF) is a syndrome in
patients with chronic liver disease with or without previ-
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-
ed with increased risk for mortality within a period of 28
days and up to 3 months from onset.1 The natural histo-
ry of chronic liver disease in a subset of patients is pro-
gression to cirrhosis. Cirrhosis has two broad stages. The
onset of jaundice, ascites, variceal bleeding, or hepatic
encephalopathy heralds the onset of decompensated cir-
rhosis; 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 dis-
ease 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
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
V
86 | CLINICAL LIVER DISEASE, VOL 9, NO 4, APRIL 2017
ACLF, and with decompensated cirrhosis type C ACLF.
Thus, ACLF is a late stage in the natural history of chron-
ic liver disease with hepatic and extrahepatic organ
failure.
EPIDEMIOLOGY
Recent studies have suggested that there are approxi-
mately 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, com-
pared 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
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REVIEW
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 pneu-
monia, 5 days for congestive heart failure, and 8.8 days
for sepsis. Thus, the costs of treating ACLF and the mor-
tality rates are far greater than those associated with
more common causes for hospitalization.
PATHOPHYSIOLOGY AND CLINICAL
FEATURES
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 cyto-
kines 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 suppres-
sion, 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 dis-
tress syndrome; and immunoparesis.
PROGNOSIS
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 sur-
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
have high mortality risk.3 Respiratory failure is the stron-
gest 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
87 | CLINICAL LIVER DISEASE, VOL 9, NO 4, APRIL 2017
Acute on Chronic Liver Failure Kamath
MANAGEMENT
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 dem-
onstrated overall survival benefit. In the Prometheus
Study, survival benefit was noted only in the presence of
a MELD score >30 and hepatorenal syndrome.
AREAS OF UNCERTAINTY
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 bio-
markers 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 interven-
tion 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 DIRECTIONS
Future studies should be aimed at determining wheth-
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
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.
CORRESPONDENCE
Patrick S. Kamath, M.D., Consultant in Gastroenterology and Hepa-
tology, Mayo Clinic, Professor of Medicine, Mayo Clinic College of
Medicine, 200 SW First Street, Rochester MN 55905. E-mail: kamath.
patrick@mayo.edu
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