New ACG Guidelines Offer Key Advice on Acute Liver Failure

Nancy S. Reau, MD


September 25, 2023

Acute liver failure (ALF) is a rare condition occurring in people without preexisting liver disease that can result in hepatic failure. Although potentially reversible, it can rapidly progress, making early recognition and appropriate management imperative.

The American College of Gastroenterology (ACG) convened a team of experts with the goal of helping clinicians recognize and treat ALF, resulting in practice guidelines recently published in the American Journal of Gastroenterology.

To find out more about best practices surrounding ALF, Medscape contributor Nancy S. Reau, MD, chief of the hepatology section at Rush University Medical Center in Chicago, spoke with one of the guidelines' authors, Alexandra Shingina, MD, MSc, a transplant hepatologist in the Department of Medicine, Vanderbilt University Medical Center in Nashville, Tennessee.

Definition and Differentiation

Please remind us of the definition of ALF and why each component is important to have (eg, having increased enzymes alone doesn't count).

ALF is a much-dreaded severe complication of liver injury that, as the name implies, develops over a short period of time; at most, it's 26 weeks. It can lead to life-threatening complications, such as cerebral edema and multiorgan failure.

The liver has a tremendous reserve and regeneration ability and can handle a lot of inflammation without its synthetic function being affected. It is only when the latter is compromised — judged by an elevated INR of over 1.5 — that the liver's ability to metabolize toxins gets affected. People can develop confusion related to liver disease or hepatic encephalopathy (HE).

A combination of these findings is what defines ALF, which carries a poor prognosis without treatment and liver transplantation in some cases.

How do you distinguish ALF from acute-on-chronic liver failure (ACLF) in a patient with chronic liver disease?

Patients with chronic liver disease experience a slow deterioration in liver function that leads to symptoms of end-stage liver disease, such as variceal bleeding, ascites, spontaneous bacterial peritonitis, and HE. Even with development of these symptoms, the immediate mortality is lower for decompensated liver disease than for ALF, which is why patients with ALF receive top priority of the liver transplant waitlist (status 1A).

However, development of an acute insult, such as infection or bleeding, in preexisting chronic liver disease can lead to development of ACLF, which has been elegantly described by Bajaj and colleagues in the most recent ACG guidelines on ACLF.

Currently, patients with ACLF do not receive priority on transplant waitlists outside of the Model for End-Stage Liver Disease (MELD) score.

ACLF can appear very similar to ALF but with subtle differences, which we have summarized in Table 6 of our guidelines.

In brief, documentation of preexisting liver disease is the most reliable factor to distinguish ALF from ACLF, and all efforts should be made to obtain records form previous encounters with the healthcare system. Presence of bona fide portal hypertension, including portosystemic varices and skin findings of spider angiomas, can point a clinician toward ACLF. But, it can still be a hard call to make. The whole clinical, laboratory, and imaging characteristics should be reviewed to make that determination.

In addition, certain disease etiologies can still lead to development of ALF even with preexisting liver disease. These include Wilson disease, autoimmune hepatitis, and Budd-Chiari syndrome.

Special Considerations for Clinicians

Grade 2 HE triggers an evaluation in the intensive care unit, but clinicians may fail to recognize this vital transition. Why is the presence of HE so important to recognize?

The pathophysiology of HE in ALF is complex and not well described, but we do know that development of the HE portends a poor prognosis in ALF.

Development of grade 2 HE, which is marked by lethargy, disorientation, inappropriate behavior, and asterixis, indicates a rapidly failing synthetic function of the liver. In the absence of a readily correctable cause, this will progress to grade 3 encephalopathy, which usually requires intubation.

This progression can happen extremely fast, within 1-2 hours, which is why patients need to be monitored very closely.

Imaging can sometimes be misleading. ALF can appear to be cirrhotic or as nodularity. Can you help clinicians differentiate when massive collapse is present vs "normal liver disease" or other radiographic findings?

It may be hard to distinguish a cirrhotic-appearing liver and a "shrunken"-looking liver due to massive intrahepatic collapse. Findings of severe portal hypertension would argue toward the cirrhotic etiology. However, ascites and splenomegaly can be seen in ALF, especially ALF of subacute presentation.

Liver biopsy has not been consistently used in ALF and is reserved for ruling out contraindications to transplant, rather than assessment of fibrosis.

In the setting of an acute liver insult, the degree of inflammation and parenchymal collapse frequently interferes with the assessment of fibrosis on a trichrome stain and may not be as helpful.

Once again, a complete clinical picture must be considered to make a call of whether or not presentation can be attributed to ALF vs ACLF.

The guidelines point out the differences between MELD and King's College Criteria (KCC). Which system should you use, and when? Or should both scores be calculated in all patients?

Traditionally, KCC was the most used prognostic model for predicting the need for liver transplantation in acetaminophen (APAP) and non-APAP–induced ALF. However, it was originally developed in the 1980s, and its performance characteristics in more modern patient populations have been questioned. The main shortcoming of KCC, according to published meta-analyses, is that its sensitivity seems to be limited.

A specific recommendation of which score to use cannot be based on existing literature; however, if a patient does not fulfill KCC criteria, MELD could be calculated for increased sensitivity.

For a gastroenterologist practicing at a nontransplant center, the development of HE would be the most important prognostic factor that should trigger transfer to a transplant center.

Advice for General Management of ALF

Continuous renal replacement therapy (CRRT) is recommended in persons at risk for cerebral edema. Can you discuss the prognostic value of ammonia in ALF and when CRRT should be considered? And if you start CRRT, should lactulose and rifaximin continue?

Unfortunately, we could not identity supporting evidence for lactulose and rifaximin use in patients with ALF. Practices tend to be very center-specific.

There are several studies that describe the effect of CRRT on plasma ammonia levels in patients with ALF and ACLF, with largely indirect evidence pointing toward the utility of CRRT in the prevention of cerebral edema and short-term mortality.

In these guidelines, we advocate for early consideration of CRRT for hyperammonemia, specifically even in the absence of other CRRT indications. A specific ammonia cutoff was difficult to identify.

Clinical presentation (high-grade HE, fulminant ALF) in conjunction with multidisciplinary discussions should guide CRRT decisions in these patients.

Infection is common in these patients. The guidelines recommend against empirical antibiotics. Is there a role for surveillance cultures?

Infections are extremely common in patients presenting with ALF, although up to one third of patients do not develop any clinical signs of infections. Despite that, there is no evidence to suggest that empirical antibiotic therapy improves mortality in patients with ALF. However, the above-mentioned statistics understandably make clinicians uncomfortable with doing no infection surveillance at all.

The expert opinion supports doing surveillance cultures, but the exact frequency cannot be specified. Per our group discussion, every 2-3 days may be a reasonable interval, but this is not based on any specific evidence.

Given that APAP is in the differential diagnosis for most acute liver injury and ALF, is there ever a reason to not give N-acetylcysteine (NAC)?

NAC has now been shown to improve outcomes not only for APAP-related ALF but also for other causes of ALF, as well as acute alcoholic hepatitis. With a fairly low side-effect profile, there is rarely a contraindication for NAC (outside of a previous anaphylactic reaction).

One consideration for clinicians is that NAC comes with fair bit of volume. So, if the patient is not a candidate for CRRT and develops an acute kidney injury, care must be taken to balance the anti-inflammatory benefits of NAC with volume overload leading to increased intracranial pressures of NAC infusion.

Do you have any final takeaways for clinicians?

We want to stress the importance of early contact with a liver transplant center. The mundane realities are that hospitals are always full, and we would advise the referring provider to contact as many transplant hospitals as possible to arrange for the expedited transfer of a patient.

Nancy S. Reau, MD, is chief of the hepatology section at Rush University Medical Center in Chicago and a regular contributor to Medscape. She serves as editor of Clinical Liver Disease, a multimedia review journal, and recently as a member of, a web-based resource from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America, as well as educational chair of the AASLD hepatitis C special interest group. She continues to have an active role in the hepatology interest group of the World Gastroenterology Organisation and the American Liver Foundation at the regional and national levels.

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