Acute on Chronic Liver Failure in the ICU: Part 1

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Liver Failure may constitute one of the least favorite disease processes for anyone routinely taking care of critically ill patients. Intensivist and hepatology circles have begun to describe a specific population known as “Acute on Chronic Liver Failure” (ACLF). These patients have chronic, progressive liver disease and then abruptly deteriorate due to any number of precipitating events (1,2). Unlike cases of acute hepatitis or paracetamol/acetaminophen overdose, the liver shut-down of ACLF is more a reaction to an inciting culprit, not the main event itself. These episodes can happen at any time, even if outpatient management is going well. Sometimes an ACLF flare is the first time someone’s chronic liver failure is recognized, especially in the medically underserved population. The resulting clinical course is often catastrophic without prompt intervention. As such, learning to identify these patients is essential.

Figure 1. Proposed Classification of ACLF superimposed on the natural history of cirrhosis. Precipitants can cause decompensation into multi-organ failure from any point in the cirrhosis cycle, whether it be from non-cirrhotic chronic liver disease (Type A), compensated cirrhosis (Type B), or End-stage/ decompensated cirrhosis (Type B). Image created by Fraser Mackay. Source: Janlan et al. Hepatol. 2014 & Bernal et al. Lancet. 2015

ACLF is Different from Acute Decompensated Cirrhosis…right?

ACLF has gone through several definitions over the last few years, and recently these definitions have coalesced around one consensus definition from the Asian Pacific Association for the Study of the Liver (APASL) (3):

“ACLF is an acute hepatic insult manifesting as jaundice (serum bilirubin of ≥ 5 mg/dL and coagulopathy (INR ≥ 1.5 or prothrombin activity < 40%) complicated within 4 weeks by clinical ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease/ cirrhosis, and is associated with a high 28-day mortality.”

That definition stemmed from the CANONIC study in 2013, where investigators prospectively identified a subset of hospitalized patients within a large group of hospitalized patients with “acute decompensated cirrhosis” with a starkly worse mortality curve (figure 2). In this study, all AD patients had a history of liver disease as well as the acute development of hepatic encephalopathy, GI hemorrhage, bacterial infection, or large volume ascites (or really any combination of these things). However, the authors found that the additional extra-hepatic organ failures would confer increased risk of death. 

Figure 2. Transplant-free survival data from the CANONIC study, comparing Acute Decompensation of cirrhosis (AD) vs. ACLF patient populations (4). Image created by Fraser Mackay.

As such, while patients with AD and ACLF share a history of chronic liver disease and acute decompensation, they differ in why they decompensate as well as to the relative degree of initial systemic collapse. Curiously, this part of the ACLF paradigm was left out of the APASL definition, mostly because the group was afraid that this would be too restrictive (since not all ACLF patients have the same degree of failure/ type of organ failure). 

That said, the practical differences between ACLF and AD (according to CANONIC as well as the EASL-CLIF and NACSELD definitions) are:

Acute on Chronic Liver Failure

Acute Decompensated Cirrhosis

History of precipitating insult (eg alcohol use, septic episode, hepatitis reactivation)

No discernable insult or injury

Hepatic AND extrahepatic organ system failure (especially AKI) and shock

Usually just hepatic failure (+/- hepatic encephalopathy)

Excessive levels of systemic inflammation, resembling sepsis/ SIRS criteria

Comparatively lower systemic inflammation

High levels of systemic circulatory dysfunction, vasoplegia, and distributive shock

Relatively little systemic circulatory dysfunction/ hypotension

HIGH short term mortality, with a small window to aggressively intervene EARLY in the clinical presentation.

Lower short term mortality, less aggressive care required in early clinical course.

More specifically, the CANONIC stratified patients ACLF by the number of organ systems in failure:


Clinical Phenotypes

28 day Mortality

90 day Mortality




-No organ failure

-Single, non-kidney organ failure (eg liver) w/o hepatic encephalopathy

-Hepatic encephalopathy only



ACLF Grade 1

-Mild Acute Kidney Injury (Cr 1.5-1.9 mg/dL)

-Mild Acute Kidney Injury w/ liver failure and/or hepatic encephalopathy



ACLF Grade 2

-Multi-organ failure (2 systems), including liver failure + more advanced AKI/ Kidney failure



ACLF Grade 3

-Multi-organ failure (3 or more systems)



Pathophysiology of ACLF and Critical Illness

The liver affects the cytokine/ immune balance in the body, and as liver health wanes, patients become immunosuppressed as their disease progresses. Similar to other immunosuppressed populations, sepsis becomes both common as well as difficult to diagnose, often presenting without classic symptoms and with initial absence of acute phase reactants or SIRS criteria. Bacterial sepsis/ infection accounts for nearly 50% of all unplanned admissions for cirrhosis patients, with spontaneous bacterial peritonitis being very common (1, 5). Once an episode of ACLF intensifies, patients can display more classic cascades of vital sign abnormalities and organ failures reminiscent of severe sepsis or distributive shock (e.g. acute kidney injury, hypotension, lactic acidosis, etc.). Unfortunately, this seems to result in a vicious feedback loop. Higher levels of inflammation and microvascular vasoconstriction cause increased capillary bed resistance in the liver as well as kidney injury, which then worsens portal hypertension, and puts the patient at risk for worse global ischemia and bacterial translocation. It’s in this dangerous feedback loop that other familiar complications of ACLF arise, among them hepato-renal syndrome (likely to be covered in a separate post altogether) and bleeding diathesis. The cycle perpetuates worsening and multiple organ system failure and creates a perfect storm that is highly challenging to weather.

Figure 3: Schematic for Acute on Chronic Liver Failure and worsening feedback cycle of MODS. Image created by Fraser Mackay.

Given that most ACLF patients do not get transplanted emergently , the end result is often stark. Hospital mortality can approach70% and when ACLF patients do survive their stay, quality of life can be negatively impacted for months if not longer (1-5, 7).

Well, that Sounds Hopeless…Not So Fast.

Even though ACLF is pretty rough, robust evidence supports that early, high quality critical care support makes a big difference in outcomes. With timely intervention, ACLF patients can recover to a reasonable baseline with meaningful quality of life (7, 9). Although a patient may not be a candidate for transplant during critical illness, he or she can make it out of the ICU and get transplanted once stabilized (10). This same body of evidence argues that caring for ACLF aggressively is not a futile exercise. Despite increasing numbers of cirrhosis diagnosis, mortality from liver disease is actually falling, largely because of good critical care (especially as it pertains to the mitigation of variceal bleeding) (8).

While there is nuance to this data and its implications, McPhail’s statement that “universal prognostic pessimism regarding admitting patients with cirrhosis to intensive care is not justified” generally holds in a large number of circumstances (6).

Managing Expectations

Family and ICU teams alike want to know about a patient’s expected outcome, but like any other disease process, it’s impossible to know how an individual case will go. There are a few tools to set expectations and help with decision-making. While these should never be used to prognosticate, they can help with communicating to specialty teams or centers and may help ground expectations during family discussions. Generally speaking, mortality in ACLF does not exceed 60% until 3 or more organ systems begin to fail.


    1. MELD Score
      This common score incorporates physiologic parameters and lab markers and can be re-calculated daily. It has been studied as a prognostic indicator but is also simply a “snapshot” in time for how the patient is doing on any given day. A MELD of 40 is bad but may improve with resuscitation. It is also used to assess transplant candidacy, so it can be helpful to have on hand when talking to hepatology or transplant colleagues.
Aiello 2017

2. Child-Pugh (CP) Score
This score speaks more to the level of dysfunction and less to what to expect at any given time point. Like the MELD score, Child-Pugh scores are used heavily to weight transplant candidacy and can certainly help communicate a clinical picture to a hepatology/ transplant service.

Source: GrepMed

3. CLIF-C ACLF score
This newer score seems to yield reproducibly good prognostication for ACLF patients, particularly when they are at their sickest. It’s not nearly as ubiquitous as CP or MELD scores, but it compares relatively well when it comes to gauging expectations about short and long-term mortality (1, 7, 8). Importantly, the original CANONIC study that derived this tool saw a large number of improvements/ resolution of ACLF (49%) and stabilizations (30%) within 3 days of presentation. As such, this tool tends to prognosticate best between days 3-7 after initial decompensation, rather than upon initial presentation.

Source: EFCLIF

What About That New Liver?

There are always a few ACLF patients that qualify for emergent transplant and make it to the OR. When it goes well, it really is like magic: all the bad labs and terribleness goes away, and the change takes place almost immediately. It’s the promise of that magic that inspires hundreds of transfers and referrals every year to liver center MICUs. The problem is that transplant during an ACLF crisis is exceedingly rare, even at high-volume centers. The extreme stresses of the OR and the long post-op course make the prospect of graft implantation in an unstable ICU patient very risky. Remember, transplant programs live and die by choosing their patients conservatively and must publicly report their metrics. Given that, it’s neither right nor reasonable to expect a cavalier or “kitchen sink” attitude from the transplant team. When you think about it, the stars really do have to align for a critically ill ACLF patient to get an emergent transplant. The ICU team must: (1) demonstrate lack of active infection, (2) resuscitate to a point where a patient would conceivably survive the operating room, (3) mitigate multi-organ failure to manageable levels, (4) establish whether family/ social dynamics are appropriate for transplant follow-up. And a compatible liver needs to be available. 

The fact that these patients do not have ready access to transplant compounds the critical nature of their clinical complexity. They tend to have longer ICU lengths of stay, spend more time on the ventilator, and slip into multi-organ failure with disturbing ease (2). Given that most ACLF patients do not receive emergent transplants, the end result is often pretty stark; hospital mortality at times approaches 70% and when ACLF patients do survive their stay, their quality of life is usually negatively impacted for months if not longer (5).

So what does all that mean? ACLF care really centers around good access to timely critical care access and aggressive support. For that, stay tuned for part 2!


  1. Bernal et al. Acute-on-chronic liver failure. Lancet 2015; 386: 1576–87
  2. Nanchal et al. Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU: Cardiovascular, Endocrine, Hematologic, Pulmonary and Renal Considerations: Executive Summary. Critical Care Med. 2020. Vol 48, No 3
  3. Sarin et al. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacifc association for the study of the liver (APASL): an update. Hepatology International 2019. 13:353–390.
  4. Moreau et al. Acute-on-Chronic Liver Failure Is a Distinct Syndrome That Develops in Patients With Acute Decompensation of Cirrhosis. Gastroenterology. 2013. 144:1426 –1437
  5. Jalan et al. Development and validation of a prognostic score to predict mortality in patients with acute-on-chronic liver failure. J Hepatol. 2014. 2014 vol. 61, 1038–1047
  6. Schmidt M, Barritt A, Orman E, Hayashi P. Decreasing mortality among patients hospitalized with cirrhosis in the United States from 2002 through 2010. Gastroenterology 2015; 148: 967–77.
  7. Engelmann et al. Validation of CLIF-C ACLF score to define a threshold for futility of intensive care support for patients with acute-on-chronic liver failure. Critical Care Med. 2018. 22:254
  8. McPhail, et al. Incidence and outcomes for patients with cirrhosis admitted to United Kingdom critical care units. Crit Care Med. 2018 May ; 46(5): 705–712.
  9. McPhail et al. Increased survival for patients with cirrhosis and organ failure in liver intensive care and validation of the chronic liver failure-sequential organ failure scoring system. Clin Gastroenterol Hepatol 2015; 13: 1353–60.
  10. Moreau, R., Gustot, T. Acute-on-chronic liver failure vs. traditional acute decompensation of cirrhosis. Journal of Hepatology 2018 vol. 69. 1384–1393.


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