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Category of Report of a consensus involving international experts from Prospective, observational study in 1343 patients with Prospective, observational study in 507 Report of a consensus involving
study that led the APASL cirrhosis admitted to 29 Liver Units in 12 European countries patients with cirrhosis hospitalised in 18 international experts from the WGO
to the definition (CANONIC study), in the context of the EASL-CLIF Consortium Liver Units across the USA and Canada, in
the context of the NACSELD Consortium
Population ▸ Acute liver deterioration (see below) in patients with ▸ Patients with an acute decompensation of cirrhosis* ▸ Patients with infection at admission or ▸ Patients with chronic liver
considered in previously diagnosed or undiagnosed chronic liver ▸ Patients with prior decompensation of cirrhosis are during hospital stay† disease with or without
the definition disease (including cirrhosis) included ▸ Patients with prior decompensation of previously diagnosed cirrhosis
▸ Both compensated cirrhosis and non-cirrhotic chronic cirrhosis are included
liver disease (non-alcoholic fatty liver disease, related
chronic hepatic injury or chronic hepatitis with fibrosis,
or fibrosis due to other reasons) qualify as chronic liver
disease
Population ▸ Patients with bacterial infections ▸ Admission for scheduled procedure or treatment ▸ Outpatients with infection Not stated
excluded of the ▸ Patients with cirrhosis and known prior ▸ Hepatocellular carcinoma outside Milan criteria ▸ HIV infection
definition decompensation ( jaundice, encephalopathy or ascites) ▸ Severe chronic extrahepatic diseases ▸ Prior organ transplant
who develop acute deterioration of their clinical status ▸ HIV infection; ongoing immunosuppressive treatments ▸ Disseminated malignancies
that is either related or unrelated to precipitating
events are considered to have acute decompensation
but not ACLF
A priori criteria Experts consider the failing liver as the driver of severity ▸ Pre-specified criteria for organ failure(s) (according to the ▸ Prespecified criteria for organ failures ▸ Not developed but stated
of severity CLIF-SOFA scale; see table 2) (see table 2) CLIF-SOFA ‘is an important step
▸ Association of organ failures at enrolment and a 28-day in this direction’
transplant-free mortality of 15% or more
Basis of the Liver failure is defined as jaundice (a serum bilirubin level ▸ Absence of ACLF because 28-day mortality is <5% in ▸ Absence of ACLF: ACLF is a syndrome characterised
definition of ≥5 mg/dL) and coagulopathy (an INR of ≥1.5 or patients with: ▸ No organ failure by acute hepatic decompensation
prothrombin activity of <40%). Liver failure is complicated – No organ failure ▸ Presence of any single organ failure resulting in liver failure ( jaundice
within 4 weeks by clinical ascites and/or encephalopathy – Single organ failure in patients with a serum creatinine ▸ Presence of ACLF (called here and prolongation of the INR) and
in patients with previously diagnosed or undiagnosed level of <1.5 mg/dL and no hepatic encephalopathy infection-related ACLF) one or more extrahepatic organ
chronic liver disease (including cirrhosis) – Cerebral failure in patients with a serum creatinine level ▸ Two organ failures or more failures that is associated with
of <1.5 mg/dL increased mortality within a period
▸ ACLF grade 1 because 28-day mortality is 22% in patients of 28 days and up to 3 months from
with: onset
– Single kidney failure
– Single liver, coagulation, circulatory or lung failure that
is associated with a serum creatinine level of 1.5–
1.9 mg/dL and/or hepatic encephalopathy grade 1 or
grade 2
– Single brain failure with a serum creatinine level of 1.5–
1.9 mg/dL
▸ ACLF grade 2 because 28-day mortality is 32% in patients
with:
– Two organs failures
▸ ACLF grade 3 because 28-day mortality is 77% in patients
with:
– Three organ failures or more
Continued
Recent advances in clinical practice
Underlying chronic liver disease and triggering factors
†In the NACSELD study, definitions of infections were as follows: (1) spontaneous bacteraemia: positive blood cultures without a source of infection; (2) spontaneous bacterial peritonitis: ascitic fluid polymorphonuclear cells >250/mL; (3) lower respiratory
Prevalence of ACLF
APASL, Asian Pacific Association for the Study of the Liver; CANONIC, EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis; EASL-CLIF, European Association for the Study of Liver-Chronic Liver failure; INR, international normalised ratio; NACSELD, North
positive stool culture for Salmonella, Shigella, Yersinia, Campylobacter or pathogenic Escherichia coli; (6) soft-tissue/skin infection: fever with cellulitis; (7) urinary tract infection: urine white blood cell >15/high-power field with either positive urine Gram
▸ Type B: compensated cirrhosis
temperature >38 C or <36 C, shivering or leucocyte count >10 000/mm3 or <4000/mm3) in the absence of antibiotics; (4) Clostridium difficile infection: diarrhoea with a positive C. difficile assay; (5) bacterial enterocolitis: diarrhoea or dysentery with a
tract infections: new pulmonary infiltrate in the presence of: (i) at least one respiratory symptom (cough, sputum production, dyspnoea, pleuritic pain) with (ii) at least one finding on auscultation (rales or crepitation) or one sign of infection (core body
▸ Type A: chronic liver disease
stain or culture; (8) intra-abdominal infections: diverticulitis, appendicitis, cholangitis, etc; (9) other infections not covered above and (10) fungal infections as a separate category. Definition of each organ failure used in the NACSELD study is given in
The variety of definitions makes quite difficult to predict what
been established10
Organ failure
In the CANONIC study, the kidneys were the most common
affected organs (55.8% of patients), followed by the liver (43.6%
of patients), coagulation (27.7% of patients), the brain (24.1% of
patients), circulation (16.8% of patients) and the lungs (9.2% of
patients).9 In the NACSELD study, 55.7% had grade III–IV HE,
17.6% developed shock, 15.1% required renal replacement
The APASL definition has been used to enrol patients in
table 2.
Table 2 Examples of available definitions of organ failures used in patients with cirrhosis
Asian Pacific Association for the European Association for the Study of
Failing Study of the Liver organ failures Liver-Chronic Liver failure organ failures North American Consortium for Study of End-stage Liver
organ definition (4, 5) definition (9) Disease organ failures definition (7)
Liver Total bilirubin ≥5 mg/dL and INR ≥1.5 Bilirubin level of >12 mg/dL –
Kidney Acute Kidney Injury Network criteria Creatinine level of ≥2.0 mg/dL or renal Need for dialysis or other forms of renal replacement therapy
replacement
Brain West-Haven hepatic encephalopathy West-Haven hepatic encephalopathy grade West-Haven hepatic encephalopathy grade 3–4
grade 3–4 3–4
Coagulation INR ≥1.5 INR ≥2.5 –
Circulation – Use of vasopressor (terlipressin and/or Presence of shock defined by mean arterial pressure <60 mm Hg or
catecholamines) a reduction of 40 mm Hg in systolic blood pressure from baseline,
despite adequate fluid resuscitation and cardiac output
Respiration PaO2/FiO2 of ≤200 or SpO2/FiO2 of ≤214 Need for mechanical ventilation
or need for mechanical ventilation
FiO2, fraction of inspired oxygen; INR, international normalised ratio; PaO2, partial pressure of arterial oxygen; SpO2, pulse oximetric saturation.
Table 3 Example of studies examining the underlying cause of chronic liver disease in acute-on-chronic liver failure (ACLF)
Alcohol+viral
First author, year (ref) Country/region ACLF definition No Viral, n (%) Alcohol, n (%) n (%) Cryptogenic, n (%) Miscellaneous, n (%)
18
Du, 2005 China N/R 650 524 (81) 80 (12) 46 (7)
Xia, 201319 China # 857 602 (70) 56 (7) 149 (17) 50 (6)
Kedarisetty, 201420 Asia Pacific APASL 1363 335 (25) 645 (47) 220 (20) 106 (8)
Shi, 201521 China APASL 540 405 (75) 30 (6) 62 (11) 28 (5) 15 (3)
Wehler, 200122 Germany SOFA 143 20 (14) 108 (75) 5 (4) 10 (7)
Cholongitas, 200623 UK APASL 312 54 (17) 203 (65) 14 (5) 41 (13)
Moreau, 20139 Europe CANONIC 303 38 (12) 170 (56) 27 (9) 68 (22)
Bajaj, 20147 USA NACSELD 507 124 (25) 74 (15) 138 (27) 78 (15) 93 (18)
(#) (1) acute deterioration of pre-existing chronic liver disease; (2) extreme fatigue with severe digestive symptoms, such as obvious anorexia, abdominal distension, nausea and
vomiting; (3) progressively worsening jaundice within a short period (serum total bilirubin level ≥10 mg/dL or a daily elevation ≥1 mg/dL); (4) an obvious haemorrhagic tendency with
prothrombin activity ≤40% (approximate prothrombin time ≥18.3 s, international normalised ratio >1.50).
APASL, Asian Pacific Association for the Study of the Liver; CANONIC, EASL-CLIF Acute-on-Chronic Liver Failure in Cirrhosis; NACSELD, North American Consortium for Study of
End-stage Liver Disease; SOFA, Sequential Organ Failure Assessment.
Figure 1 Inflammation caused by microbes. Top: Microbes (bacteria, viruses, fungi) induce inflammation via two classes of molecules:
pathogen-associated molecular patterns (PAMPs) and virulence factors. Sensors of the innate immune system recognise the invading microbe via
recognition of PAMPs, which are conserved molecular patterns (structural feature recognition). Sensors are known as pattern-recognition receptors.
The second class of microbial inducers of inflammation includes a large number of virulence factors. Most of these factors are generally not
recognised by dedicated receptors but can be sensed via the effects of their activity (functional feature recognition). For example, there are bacterial
virulence factors which cause modifications and inactivation of host Rho GTPases and these alterations are sensed by the Pyrin inflammasome.
Infection may be associated with tissue damage caused by the bacteria or by the immune response to bacteria. Tissue damage can induce
inflammation which is committed to tissue repair (see text and reference32). Bottom: Proposed interventions. MELD, Model For End-Stage Liver
Disease score.
Hernaez R, et al. Gut 2017;66:541–553. doi:10.1136/gutjnl-2016-312670 545
Recent advances in clinical practice
Table 5 Examples of PRRs, their ligands (PAMPs) and their origin Table 6 Examples of DAMPs and their receptors
PRR PAMP Origin DAMP Receptor
Figure 4 Proposed algorithm for the management of patients with acute-on-chronic liver failure (ACLF) or decompensated cirrhosis. A proposed
management strategy for patients with ACLF based on mortality rate data from the CANONIC study.8 The first step is the assessment of ACLF grade
at days 3–7 after initiation of medical management, including organ support. Liver transplantation should be assessed in all patients with ACLF
because of high 90-day mortality rates (>20%). Liver transplantation should be performed as early as possible in patients with ACLF grade 2 and
grade 3 as they are at considerable risk of short-term (28-day) mortality. In the case of contraindication of liver transplantation, the presence of four
or more organ failures (OFs) or a Chronic Liver Failure Consortium (CLIF-C) ACLF score of >64 at days 3–7 after diagnosis could indicate the futility
of care. ICU, intensive care unit. Adapted from Gustot et al51 and obtained from Arroyo et al27 with permission.
transplant centre. Organ function should be monitored fre- As described above, exceedingly high CLIF-C ACLF score
quently and early treatment provided according to each specific during the course of the disease may help establish futility
organ in order to avoid a stage of multiple OF. General manage- criteria.10 51
ment should be based on current guidelines and recent reviews Data on LT and outcome in patients with ACLF are scarce and
on the management of critically ill patients with cirrhosis.52 53 interpretation may be difficult due to different ACLF definitions
Therefore, this review will focus only on specific therapies for and short series of patients. Data from the CANONIC study are
ACLF. limited as only few patients were transplanted, 9% within
28 days and 15% within 90 days after admission. In patients
Specific therapies with ACLF grade 2 or 3, survival without LT was <20%, but
Liver transplantation increased to 80% in those patients who received LT, results com-
LT represents the definitive treatment for patients with ACLF. parable with those patients transplanted without ACLF. In this
Therefore, if there are no contraindications, all patients admit- cohort, the median delay between ACLF diagnosis and LT was
ted with ACLF should be evaluated for LT. Nevertheless, the 11 (1–28) days.9 Another study that included 238 patients used
use of LT in the context of ACLF is hampered by the shortage intention-to-treat analysis and showed a 5-year post-LT survival
of donors and also by the high frequency of contraindications of >80% for patients eligible for LT.54 However, it should be
that these patients may present (‘too sick to transplant’). Due noted that LT was feasible in <25% of patients’ cohort, as many
to a high MELD score, these patients can have rapid access to patients could not be transplanted due to age, active alcoholism,
transplant. However, the final indication for LT should be active infections or other comorbidities.
reconsidered according to standard criteria such as presence of The timing of transplantation is crucial particularly in patients
active infections, comorbidities or psychological aspects and with ACLF, as these patients may provide a short window of
also according to the progression of ACLF during admission. opportunity due to the risk of development of multiorgan
550 Hernaez R, et al. Gut 2017;66:541–553. doi:10.1136/gutjnl-2016-312670
Recent advances in clinical practice
failure precluding LT. Considering the good outcomes described On this background, innovative therapies based on immuno-
so far, it could be suggested to include high-risk patients with modulatory or liver regenerative effects have been proposed as
ACLF as an indication for high urgency allocation for LT. new therapeutic approaches, including administration of
However, this may be controversial and is still not performed in granulocyte-colony stimulating factor (G-CSF) and stem cell
most countries, but it is an option that could be studied in transplantation.
future studies. G-CSF therapy in ACLF is only based on two randomised
clinical trials. Garg et al11 randomised 47 patients to 5 μg/kg
G-CSF subcutaneously (n=23) vs placebo/standard medical care
Liver support systems
(n=24) and found that the probability of survival at day 60 was
Extracorporal liver support systems, particularly albumin dialysis
66% vs 26%, respectively ( p=0.001). Other parameters such as
and/or plasma exchange have been proposed as new therapeutic
the Child-Pugh-Turcotte and SOFA scores improved and patients
options that could be used as a bridge to LT in patients with
receiving G-CSF were less likely to develop hepatorenal syn-
ACLF.55–58 These systems are aimed at improving clinical,
drome, HE or sepsis. In another study, Duan et al59 randomised
neurological and biological parameters. These improvements
55 patients with HBV-associated ACLF to G-CSF vs placebo/
could allow waiting for LT in better conditions. Trials performed
standard of care. The probability of survival at 90 days was 48%
to evaluate the usefulness of these liver support systems usually
in the G-CSF group compared with 21.4% in the placebo
include a heterogeneous population of patients with decompen-
group. Similar to the study by Garg et al, patients on G-CSF
sated cirrhosis associated with different degrees of OF.
achieved reduction in MELD score. Side effects were mild and
However, to date there are no studies evaluating these devices
expected from the use of G-CSF (nausea, vomits, fever, rash).
using the current definition of ACLF.
Overall, the use of G-CSF in patients with ACLF is still experi-
The most studied liver support devices include molecular
mental as it has been used in 102 patients but the results are
adsorbent recirculating system (MARS) and plasma separation
encouraging.
and absorption system (Prometheus), which are based on the
There is only one stem cells trial in humans. Shi et al60 using
principles of albumin dialysis. Prospective trials have shown that
an open-label controlled trial enrolled 43 hepatitis B patients
MARS is able to improve cholestasis, liver and kidney function
with ACLF to receive umbilical cord-derived mesenchymal stem
and haemodynamics in patients with decompensated cirrhosis;
cells (UC-MSC, n=24) vs 19 patients with saline as controls.
however, the effect on survival is not conclusive.56–58 A muti-
After 90 days, 79.2% on the UC-MSC survived vs 52.5% in the
centre European randomised controlled trial (RCT) of MARS
control group. MELD scores also decreased over time (in both
compared with standard medical therapy (SMT) in patients with
groups) but more in the UC-MSC (10 vs 15, p=0.04).
ACLF was recently reported (RELIEF trial). In this trial, ACLF
Self-limited fever from UC-MSC was reported, but no other sig-
was defined as bilirubin >5 mg/dL associated with at least one
nificant side effects.
of the following: HE grade 3–4, hepatorenal syndrome and bili-
Overall, both therapies (G-CSF and stem cells) showed
rubin >20 mg/dL. The most common precipitating events in
encouraging results, but the optimism is limited by the small
this population were alcohol abuse and bacterial infections. In
number of participants.
summary, there were no differences in 28-day or 90-day
transplant-free survival between MARS and SMT groups.58
Prevention of ACLF: syndrome awareness, identification of
Another multicentre European RCT evaluated Prometheus in
predisposing conditions and careful clinical examination
patients with ACLF. This was the Helios trial that defined ACLF
Nowadays, it is difficult to prevent ACLF unless the clinician is
as patients with cirrhosis and Child-Pugh score >10 and biliru-
aware of the syndrome and its clinical implications. Initiatives
bin >5 mg/dL. Results showed that the approach was safe and
such as this one, cohort studies (CANONIC, NACSELD) and
well tolerated but there is no survival benefit at 28 days.55
group consensus (APASL, WGO) help in the identification of
Overall, heterogeneity of patients and definitions and dur-
the syndrome. Borrowing terms from preventive medicine, the
ation of treatment and modalities makes difficult to evaluate the
current management of ACLF is a tertiary or, at its best, second-
usefulness of these devices particularly in patients with ACLF.
ary prevention. In other words, once ACLF have occurred, the
Therefore, further RCT with homogenous definition of the syn-
following days will determine whether the patient will undergo
drome are needed to re-evaluate the effect of liver support
recovery or not with full medical support including evaluation
systems on survival.
for liver transplant (tertiary prevention). In some occasions,
only one organ has failed and the aim is to prevent further OF
Future perspectives: pathophysiologial-based treatments involvement by providing aggressive medical care (eg, antibiotics
Considering that currently there is no specific treatment for the to prevent hepatorenal syndrome in the setting of gastrointes-
management of ACLF, research should be based on potential tinal bleeding (GIB)). Preventing other OFs is an example of
new treatments addressed to pathophysiological mechanisms secondary prevention (damage is present but aiming to reduce
leading to the development of the syndrome. Large body of evi- further damage).
dence from the last decades suggests that bacterial translocation It is the grail of ACLF treatment, however, to prevent the
(BT) and an excessive systemic inflammation are the key onset of syndrome (primary prevention). APASL has noted a
mechanisms leading to the progression of cirrhosis and the ‘golden window’, a short period of about 1 week before the
development of ACLF. Therapeutic interventions acting on BT onset of sepsis and development of extrahepatic OF in a patient
(ie, probiotics, norfloxacin, rifaximin) would probably act in the with ACLF.5 Interventions during this period are likely to
prevention of the development of ACLF rather than in the man- prevent OF and perhaps the development of ACLF (‘primary
agement of the syndrome itself once it has developed. In con- prophylaxis’). Currently, other than the thorough identification,
trast, therapeutic interventions addressed to mitigate the history, physical and pertinent laboratory/imaging studies, there
excessive systemic inflammation and to restore the immuno- are no other means to detect this ‘golden window’.
logical response should be investigated as potential treatment Prevention of ACLF should be based on treatments targeting
options. the key pathophysiological mechanisms leading to disease
Hernaez R, et al. Gut 2017;66:541–553. doi:10.1136/gutjnl-2016-312670 551
Recent advances in clinical practice
progression and development of ACLF. Evidence from the last 16 Abbas Z, Shazi L. Pattern and profile of chronic liver disease in acute on chronic
decade suggests that these key mechanisms are mainly the liver failure. Hepatol Int 2015;9:366–72.
17 Wong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second
impairment of the gut-liver axis leading to BT and systemic leading etiology of liver disease among adults awaiting liver transplantation in the
inflammation. Therefore, therapeutic interventions targeting BT United States. Gastroenterology 2015;148:547–55.
and those modulating inflammatory response (ie, norfloxacin, 18 Du WB, Li LJ, Huang JR, et al. Effects of artificial liver support system on patients
rifaximin, albumin, statins) should be investigated as potential with acute or chronic liver failure. Transplant Proc 2005;37:4359–64.
19 Xia Q, Dai X, Zhang Y, et al. A modified MELD model for Chinese pre-ACLF and
first-line treatments.
ACLF patients and it reveals poor prognosis in pre-ACLF patients. PLoS ONE
2013;8:e64379.
Acknowledgements The authors would like to thank Nicki van Berckel, for her 20 Kedarisetty CK, Sarin SK, Anand L, et al. Liver failure determines the extra-hepatic
administrative support in putting together this paper. organ failure and outcome in patients with acute-on-chronic liver failure: analysis of
Contributors RH, PG, ES and RM wrote and contributed to this paper equally. 1363 patients of AARC Data Base. Hepatology 2014;60:556A.
Final review and approval was given by all authors. 21 Shi Y, Zheng MH, Yang Y, et al. Increased delayed mortality in patients with
acute-on-chronic liver failure who have prior decompensation. J Gastroenterol
Funding Some of the work mentioned has been supported by grants awarded to Hepatol 2015;30:712–8.
PG (PI12/00330), integrated in the Plan Nacional I+D+I and co-funded by 22 Wehler M, Kokoska J, Reulbach U, et al. Short-term prognosis in critically ill
ISCIII-Subdirección General de Evaluación and European Regional Development Fund patients with cirrhosis assessed by prognostic scoring systems. Hepatology
FEDER; Agencia de Gestió d’Ajuts Universitaris I de Recerca (AGAUR) 2014/SGR 2001;34:255–61.
708; PG is a recipient of an ICREA Academia Award. Acknowledgement is made to 23 Cholongitas E, Senzolo M, Patch D, et al. Risk factors, sequential organ failure
the LiverHope project, part of the EC H2020-SC1-2016-RTD programme, number: assessment and model for end-stage liver disease scores for predicting short term
731875. mortality in cirrhotic patients admitted to intensive care unit. Aliment Pharmacol
Competing interests PG declares that he has received research funding from Ther 2006;23:883–93.
Ferring Pharmaceuticals, Grifols S.A. and Sequana Medical. He has participated on 24 Bernsmeier C, Pop OT, Singanayagam A, et al. Patients with acute-on-chronic
Advisory Boards for Ferring Pharmaceuticals, Promethera and Novartis. liver failure have increased numbers of regulatory immune cells expressing
the receptor tyrosine kinase MERTK. Gastroenterology 2015;148:
Provenance and peer review Commissioned; externally peer reviewed. 603–615.e14.
Open Access This is an Open Access article distributed in accordance with the 25 Claria J, Stauber R, Coenraad MJ, et al. Systemic Inflammation in decompensated
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which cirrhosis. Characterization and role in acute on chronic liver failure. Hepatology
permits others to distribute, remix, adapt, build upon this work non-commercially, 2016;64:1249–64.
and license their derivative works on different terms, provided the original work is 26 Sole C, Sola E, Morales-Ruiz M, et al. Systemic inflammatory response profile in
properly cited and the use is non-commercial. See: http://creativecommons.org/ acute-on-chronic liver failure and its relationship with prognosis. Sci Rep
licenses/by-nc/4.0/ 2016;6:32341.
27 Arroyo V, Moreau R, Kamath PS, et al. Acute-on-chronic liver failure in cirrhosis.
Nat Rev Dis Primers 2016;2:16041.
28 Medzhitov R. Origin and physiological roles of inflammation. Nature
REFERENCES 2008;454:428–35.
1 Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 2008;371:838–51. 29 Moreau R. The pathogenesis of ACLF: the inflammatory response and immune
2 Ginés P, Quintero E, Arroyo V, et al. Compensated cirrhosis: natural history and function. Semin Liver Dis 2016;36:133–40.
prognostic factors. Hepatology 1987;7:122–8. 30 Gustot T, Durand F, Lebrec D, et al. Severe sepsis in cirrhosis. Hepatology
3 Kjaergard LL, Liu J, ls-Nielsen B, et al. Artificial and bioartificial support systems for 2009;50:2022–33.
acute and acute-on-chronic liver failure: a systematic review. JAMA 31 Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell
2003;289:217–22. 2010;140:805–20.
4 Sarin SK, Kumar A, Almeida JA, et al. Acute-on-chronic liver failure: consensus 32 Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune
recommendations of the Asian Pacific Association for the study of the liver (APASL). system. Nat Immunol 2015;16:343–53.
Hepatol Int 2009;3:269–82. 33 Kono H, Rock KL. How dying cells alert the immune system to danger. Nat Rev
5 Sarin SK, Kedarisetty CK, Abbas Z, et al. Acute-on-chronic liver failure: consensus Immunol 2008;8:279–89.
recommendations of the Asian Pacific Association for the Study of the Liver (APASL) 34 Gabay C, Kushner I. Acute-phase proteins and other systemic responses to
2014. Hepatol Int 2014;8:453–71. inflammation. N Engl J Med 1999;340:448–54.
6 Wlodzimirow KA, Eslami S, Abu-Hanna A, et al. A systematic review on prognostic 35 Medzhitov R. Inflammation 2010: new adventures of an old flame. Cell
indicators of acute on chronic liver failure and their predictive value for mortality. 2010;140:771–6.
Liver Int 2013;33:40–52. 36 Rickard JA, O’Donnell JA, Evans JM, et al. RIPK1 regulates RIPK3-MLKL-driven
7 Bajaj JS, O’Leary JG, Reddy KR, et al. Survival in infection-related acute-on-chronic systemic inflammation and emergency hematopoiesis. Cell 2014;157:
liver failure is defined by extrahepatic organ failures. Hepatology 2014;60:250–6. 1175–88.
8 Jalan R, Yurdaydin C, Bajaj JS, et al. Toward an improved definition of 37 Christaki E, Giamarellos-Bourboulis EJ. The beginning of personalized medicine in
acute-on-chronic liver failure. Gastroenterology 2014;147:4–10. sepsis: small steps to a bright future. Clin Genet 2014;86:56–61.
9 Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a distinct 38 Cohen J, Vincent JL, Adhikari NK, et al. Sepsis: a roadmap for future research.
syndrome that develops in patients with acute decompensation of cirrhosis. Lancet Infect Dis 2015;15:581–614.
Gastroenterology 2013;144:1426–37, 1437.e1–9. 39 Byl B, Roucloux I, Crusiaux A, et al. Tumor necrosis factor alpha and interleukin
10 Jalan R, Saliba F, Pavesi M, et al. Development and validation of a prognostic score 6 plasma levels in infected cirrhotic patients. Gastroenterology 1993;104:
to predict mortality in patients with acute-on-chronic liver failure. J Hepatol 1492–7.
2014;61:1038–47. 40 Navasa M, Follo A, Filella X, et al. Tumor necrosis factor and interleukin-6 in
11 Garg V, Garg H, Khan A, et al. Granulocyte colony-stimulating factor mobilizes spontaneous bacterial peritonitis in cirrhosis: relationship with the development of
CD34(+) cells and improves survival of patients with acute-on-chronic liver failure. renal impairment and mortality. Hepatology 1998;27:1227–32.
Gastroenterology 2012;142:505–12. 41 Michelena J, Altamirano J, Abraldes JG, et al. Systemic inflammatory response and
12 Escorsell Mañosa À, Mas Ordeig A. [Acute on chronic liver failure]. Gastroenterol serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic
Hepatol 2010;33:126–34. hepatitis. Hepatology 2015;62:762–72.
13 Sargenti K, Prytz H, Nilsson E, et al. Predictors of mortality among patients with 42 Louvet A, Wartel F, Castel H, et al. Infection in patients with severe alcoholic
compensated and decompensated liver cirrhosis: the role of bacterial infections and hepatitis treated with steroids: early response to therapy is the key factor.
infection-related acute-on-chronic liver failure. Scand J Gastroenterol Gastroenterology 2009;137:541–8.
2015;50:875–83. 43 Dominguez M, Miquel R, Colmenero J, et al. Hepatic expression of CXC chemokines
14 Shi Y, Yang Y, Hu Y, et al. Acute-on-chronic liver failure precipitated by hepatic predicts portal hypertension and survival in patients with alcoholic hepatitis.
injury is distinct from that precipitated by extrahepatic insults. Hepatology Gastroenterology 2009;136:1639–50.
2015;62:232–42. 44 Medzhitov R, Schneider DS, Soares MP. Disease tolerance as a defense strategy.
15 Li H, Chen LY, Zhang NN, et al. Characteristics, diagnosis and prognosis of Science 2012;335:936–41.
acute-on-chronic liver failure in cirrhosis associated to hepatitis B. Sci Rep 45 Jamieson AM, Pasman L, Yu S, et al. Role of tissue protection in lethal respiratory
2016;6:25487. viral-bacterial coinfection. Science 2013;340:1230–4.
EDITOR’S QUIZ: GI SNAPSHOT Lim Tian-Zhi,1 Faith Leong Qi Hui,1 Ker-Kan Tan1,2
1
Division of Colorectal Surgery, University Surgical Cluster, National University Health
Don’t mistake it as a polyp! System, Singapore, Singapore
2
Department of Surgery, Yong Loo Lin School of Medicine, National University of
Singapore, Singapore, Singapore
ANSWER See page 540 for question Correspondence to Dr Lim Tian Zhi, University Surgical Cluster, 1E Kent Ridge
Inverted appendix. Road, National University Health System, Singapore 119228, Singapore;
Histology of the specimen confirmed the presence of a polyp- tian_zhi_lim@nuhs.edu.sg
oid mass with a small lumen lined by colonic type epithelium,
Contributors All three authors are responsible for the collection of clinical
surrounded by a thick muscularis wall, compatible with an information and photos, and are involved in the preparation and drafting of this
inverted appendix. Scattered endometrial type glands with manuscript.
stroma were also found extending from the mucosa to the Competing interests None declared.
serosa, compatible with endometriosis.
Provenance and peer review Not commissioned; externally peer reviewed.
Inverted appendix is an uncommon endoscopic finding but
an important consideration when faced with a polypoid lesion
in the caecal pole.1 There are only case reports of this condi-
tion, which is more common in adult females in their fourth
decade of life.1 Endometriosis is a recognised cause of inverted
To
To cite
cite Tian-Zhi
Tian-Zhi L,L, Leong
LeongQi
QiHui
HuiF,F,Tan
TanK-K.
K-K.Gut
Gut2017;66:553.
Published Online First: [ please
appendix.2
include Day Month
Received 1 August 2016 Year] doi:10.1136/gutjnl-2016-312704
The work-up for such lesions should include CT imaging of
Accepted
Received 19 August
August 2016
2016
the abdomen, endoscopic evaluation and histological sampling.
Published
Accepted 9Online First
August 8 September 2016
2016
Management of an inverted appendix include surgical resection
with a limited caecectomy2 or endoscopic removal with devices Gut 2017;66:553.
2017;0:1–13. doi:10.1136/gutjnl-2016-312704
such as endoloops.2 Endoscopic removal using diathermy loop
should not be attempted due to the potential for perforation.3 REFERENCES
Endometriosis of the appendix can also present with symptoms 1 Yan S, Yeh Y, Lai M, et al. Inverted appendix in an asymptomatic patient without
intussusception or previous appendectomy. Colorectal Dis 2010;12:339–40.
of intestinal obstruction from intussusception, symptoms mim-
2 Moradi P, Barakate M, Gill A, et al. Intussuception of the vermiform appendix due to
icking acute appendicitis or lower GI bleeding.3 endometriosis presenting as acute appendicitis. ANZ J Surg 2007;77:758–60.
In addition, the worry of an underlying mucocele of the 3 Hillman L. Gastrointestinal: Colonoscopic removal of an inverted appendix.
appendix needs to be considered given its endoscopic findings. J Gastroenterol Hepatol 2008;23:1771–1771.