The Acute Liver Failure Study Group (ALFSG) has maintained, since 1998, a clinical registry now numbering more than 3,400 patients who have been enrolled over this period of time at 32 sites over the 22-year period. The study is now closed, and the database locked. This study has provided critical information on all forms of ALF with detailed clinical histories and laboratory and outcome data available. A searchable public use website is accessible via NIDDK for data prior to 2010. In the next year, the searchable database will be updated with data through the end of the study. All the patient information is thoroughly de-identified in strict accordance with HIPAA regulations.
Enrollment criteria for the study were as follows:
Acute Liver Injury (no hepatic encephalopathy)
- If presumed acetaminophen etiology: acute hepatic illness < 2 weeks, with INR ≥ 2.0, alanine aminotransferase (ALT) of ≥ 10X ULN.
- If presumed non-acetaminophen etiology: acute hepatic illness of < 26 weeks, with INR ≥ 2.0, ALT of ≥ 10X ULN, total bilirubin of ≥ 3.0 mg/dL.
- Hospitalized patient
- Written informed consent from the patient
- Altered mentation of any degree (=ALF)
Acute Liver Failure (must have hepatic encephalopathy of some degree)
- Acute liver failure (fulminant or sub-fulminant; liver-related illness).
- Altered mentation of any degree (presumed not due to sedation alone).
- Evidence of moderately severe coagulopathy (INR ≥ 1.5) and
- Presumed acute illness onset of less than 26 weeks.
- Written informed consent from the patient’s LAR or family member if patient is considered encephalopathic.
- Known cirrhosis
- Illness longer than 28 weeks
Much earlier, ALFSG performed the NAC trial between 2001 and 2006, testing whether N-acetylcysteine, the antidote for acetaminophen overdoses is of use in the management of other forms of acute liver failure. That study was analyzed and the results published in 2009. See publications list (Lee WM et al Gastroenterology 2009;137:856-864). Several other publications highlight the apparent benefit of NAC; however, use of NAC for non-acetaminophen ALF is not an FDA-approved indication.
Between 2012 and 2016, we conducted a study in partnership with Ocera Therapeutics, Inc., of the Safety and Tolerability of Ornithine Phenylacetate for management of hepatic encephalopathy in the setting of ALF. This was not an efficacy study but meant to determine safety and tolerability. Study results are available in the following article: Stravitz RT, et al. Hepatology 2018; 67:1003-13. In brief, OPA appeared to be safe and to effectively lower ammonia levels in patients with ALF at the highest dose studied, 20 gm/day. Preliminary results were presented in November 2016 at the AASLD meeting in Boston; the manuscript with full study results in currently submitted and under review.
ALFSG has concluded two interesting studies as outlined below: MBT and ROTEM. Results are currently being analyzed and have not been published for either study. The group has evaluated the Methacetin Breath Test (MBT), a method to determine hepatic functional mass (how much functioning liver is remaining) in order to help predict need for transplantation. 13C-methacetin is a medication containing a non-radioactive isotope, that is taken in a small dose (75 mg) and converted by the liver into 13CO2, which is then excreted via the lungs and its percent excretion compared to normal standards to reflect the amount of liver impairment present. It can be performed daily to aid in determining risk of death and the need for liver transplantation. This is not a therapy trial, but involves giving the test substance so does involve this small dose of medication that is converted to acetaminophen. Several precautions are in place to assure that there is no acetaminophen toxicity related to its ingestion.
This is an open label, non-randomized study to determine the value of the 13C-Methacetin Breath Test System in predicting the 21-day outcome of patients diagnosed with acute liver failure.
Inclusion Criteria (Abbreviated)
- Men & women, ages 18-70 (have not reached their 71st birthday).
- Severe Acute Liver Injury with INR ≥ 1.5
- Presence of any degree of hepatic encephalopathy
- Duration of illness < 26 weeks
- Enrolled in the ALFSG Registry
- Written informed consent from the patient or patient’s legally authorized representative or family member
Exclusion Criteria (Abbreviated)
- History of chronic liver disease or evidence of cirrhosis (unless clinically acute Wilson disease or autoimmune ALF)
- ALF due to Budd-Chiari Syndrome, caused by malignancy or by known or suspected herpes simplex virus requiring acyclovir therapy
- Liver transplantation prior to enrollment (Note: Listing for LT does not preclude participation in the trial.)
- Pre-existing New York Heart Association stage III/IV heart failure
- Severe obstructive lung disease or shock or severe ARDS
- History of chronic renal failure requiring hemodialysis or chronic hemodialysis prior to hospital admission for ALF
- Previous extensive bowel resection or upper GI bleeding at enrollment
- Allergic to acetaminophen
- Contra-indicated enteral drugs or fluids, no appropriately placed naso/orogastric tube in situ, or cannot tolerate taking substrate orally
- Received amiodarone or an HMG-CoA reductase inhibitors (Statins) 30 days prior to enrollment
- Consumption of: any of the drugs that may interfere with the metabolism of 13C-Methacetin in the 48 hours; alcohol in the last 24 hours; and smoking cigarettes in the 8 hours prior to study enrollment
- Pregnant or breastfeeding women
ALFSG is performing a separate study simultaneously that again is not a therapeutic intervention trial, but is to determine the nature of clotting in the setting of acute liver failure. Classically, it has been thought that patients with ALF were at great risk of bleeding because of markedly altered coagulation parameters such as the prothrombin time/INR test. Although PT/INR is abnormal there are other compensatory changes in clotting in the ALF setting that likely counteract the loss of clotting factors due to the damaged liver, setting up a re-balanced coagulation system that may not be all that abnormal overall. Thromboelastography is a dynamic method for testing the adequacy of an individual’s clotting mechanism, that requires only a small blood sample to perform. There is little data to date in the setting of ALF and the present study should help answer whether coagulation is abnormal in ALF and, if so, in what settings and how much.
Each ALFSG patient enrolled into the registry will be eligible for the ROTEM test that will be performed daily on days 1,2,3 5 and 7 of the study period.
No additional therapy trials are contemplated at present. Future possibilities include the use of liver assist devices or transplantation of hepatocytes. Stay tuned.