The Acute Liver Failure Study Group (ALFSG) is a clinical research network funded by the National Institutes of Health since 1997, to gather important prospective data and biosamples on this rare condition. Acute liver failure (ALF) is estimated to develop in 2000 individuals in the United States per year. In each instance, severe injury to liver cells evolves over days to weeks, without cirrhosis being present, yielding the hallmark features — abnormal coagulation testing (prolonged prothrombin time, measured at (PT/INR) and abnormal mental functioning (hepatic encephalopathy). Outcomes vary, but nearly 29% die while another 22% undergo liver transplantation. The network enrolls patients meeting the above criteria at 13 sites in North America (see map). Since each patient, by definition, has altered mental functioning, consent must be provided by next of kin or someone with medical power of attorney; all information gathered is de-identified and the ALFSG consortium holds a Certificate of Confidentiality from the National Institute of Mental Health.

Various Causes

The causes of ALF are shown in the bar graph below. The most common cause (etiology) of ALF in North America is acetaminophen liver toxicity, in most instances the result of overdosing at a single time point (suicide attempt) or over time when seeking pain relief (unintentional overdose). Acetaminophen (abbreviated APAP), is a very common pain reliever found in innumerable over-the-counter medications (Tylenol®, Nyquil®, TylenolPM®) and prescription opioid combination medications (Vicodin®, Percocet®).

Causes of acute liver failure graph

Since APAP is a dose-related toxin, most severe liver injuries are the result of dosing above the recommended package labeling. However, there may be some instances where acetaminophen taken within the package instructions can cause severe acute liver injury and even fatalities. Other causes of ALF include toxicity secondary to prescription drugs, herbal and dietary supplements, hepatitis A and B. In a small percentage of cases (less than 10%) the cause cannot be delineated (indeterminate).

ALFSG has published more than 80 papers on various aspects of ALF with colleagues within and outside of ALFSG (see publications tab for a complete list with links to the papers). The group has also developed two apps: Acute Liver Failure Checklist and Acute Liver Failure Prognostic Index. The former provides a list of diagnostic considerations and tests to be performed as well as initial management suggestions. The latter provides a method of calculating the likelihood of survival that is to be used in conjunction with clinical judgment and other modalities. It is not to be used as a substitute for the overall clinical judgment of these critically ill patients. Both these web applications (apps) can be found at the Apple app store.

As of December 2016, over 3,000 patients had been enrolled in the overall registry. Improvements in outcomes have been observed over the first 16 years the study has been in operation as outlined in our recent overview paper (Reuben A, et al. Ann Intern Med 2016;164:724-32). While the severity of illness and the mix of etiologies have not declined, the numbers requiring listing for transplantation, those transplanted and those dying of ALF all declined over the 16-year period. In this context, it was interesting to note that use of ICU measures such as mechanical ventilation, plasma and red blood cell transfusions and blood pressure support medication use all declined during this same period suggesting that good care of the comatose patient does not necessarily involve very aggressive measures.

In another recent paper, we examined the outcomes of patients listed for transplantation due to acute liver failure. Perhaps not surprisingly, those with acetaminophen toxicity that were listed were more severely ill, and less likely to receive a liver transplant than those with drug-induced liver injury, autoimmune hepatitis or hepatitis B, for example. In fact, most with acetaminophen overdoses had an outcome (death, transplant or recovery) by day 4 following admission, emphasizing how rapidly deterioration can occur as well as recovery. This study published in Liver Transplantation (Reddy KR et al Liver Transplant 2016;22:505-15) was the cover article in the April 2016 issue.  

Group photo
Members of the Acute Liver Failure Study Group