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. Over the past 22 years, the group based at UT Southwestern Medical Center in Dallas has enrolled more than 2,631 patients in North America with acute liver failure and 857 with acute liver injury (ALI). Acute liver failure (ALF) is defined as a severe form of acute liver injury characterized by rapid onset over days and weeks in the absence of underlying cirrhosis, leading to abnormal coagulation with prolongation of the prothrombin time (INR ≥ 1.5) in the presence of altered mentation. ALI is defined as a severe acute liver injury with an INR ≥ 2.0 and no encephalopathy (altered mental functioning, drowsiness, or coma). ALF is estimated to develop in 2000 individuals in the United States per year and ALI in another 2-4000 individuals. Outcomes vary, but nearly 29% die while another 22% undergo liver transplantation, the remaining 51% survive and in general recover fully. The group comprised 33 sites around the US and Canada over the 22 years of the study. More than 100 original research articles have been generated to date by investigators and collaborators from around the world (see publications tab). In addition to maintaining and storing the data and bio-samples for more than 3,400 unique patients, the network conducted several clinical trials: N-acetylcysteine for non-acetaminophen acute liver failure, ornithine phenyl acetate for management of ALF-related encephalopathy, a pilot study using rotational thromboelastography as a dynamic measure of coagulation and a separate study using C13 labeled methacetin breath testing to determine outcomes in ALF patients being considered for transplantation.
A unique feature of ALF and ALI is that there are a variety of causes, all of which share similar clinical features (coagulopathy, encephalopathy, susceptibility to infection, and bleeding) regardless of cause. The most frequent causes are acetaminophen overdose, drug-induced liver injury, autoimmune hepatitis, and viral hepatitis B, but less common causes include acute fatty liver of pregnancy, ischemia/shock, Wilson disease, heat stroke, and metastatic cancer.
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.
ALFSG closed enrollment in its registry on August 31, 2019, and the study is now complete. The database is locked; however, opportunities remain for investigators to access data and bio-samples for approved studies of this patient population. A two-day symposium entitled Acute Liver Failure: Science and Practice, was scheduled for March 30-31, 2022 on the UT Southwestern Campus (see separate tab for more details).
Various Causes
The causes of ALF are shown in the bar graph (right). 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®).
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, and hepatitis A and B. In a small percentage of cases (less than 10%) the cause cannot be delineated (indeterminate).
Causes of acute liver failure, as recorded by the site principal investigator in the US Adult Acute Liver Failure Study Group Registry 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 in the Apple app store. The Acute Liver Failure Checklist has a web version available for those who may not have an iPhone® or iPad® platform.
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 the 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.