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 fewer than 26 weeks.
- Written informed consent from the patient’s LAR or family member if the 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 were 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, the 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., on the Safety and Tolerability of Ornithine Phenylacetate for the 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. The group evaluated the Methacetin Breath Test (MBT), a method to determine the hepatic functional mass (how much functioning the liver is remaining) to help predict the 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 the risk of death and the need for liver transplantation. Several precautions were in place to assure that there is no acetaminophen toxicity related to methacetin ingestion since it is metabolized briefly to acetaminophen.
The 13C-Methacetin breath test (MBT) is a non-invasive, quantitative test of hepatic metabolic function. This prospective, multicenter study aimed to determine the utility of initial and serial 13C- MBT results for predicting 21-day outcomes in adults with acute liver failure (ALF) and non-acetaminophen acute liver injury (ALI).
Methods: The 13C-MBT Breath ID device (Exalenz Biosciences) provided the percent dose recovery (PDR) throughout 60 minutes after administration of 13C methacetin solution as the change in exhaled 13CO2/ 12CO2 compared to pre-ingestion ratio on study days 1, 2, 3, 5, and 7 after enrollment. Results were correlated with 21-day transplant-free survival and other prognostic indices.
Results: 280 subjects were screened for enrollment between May 2016 and August 2019. The mean age of the 62 enrolled patients with adequate data was 43 years, 79% were Caucasian and 76% had ALF with the remaining 24% having ALI. The mean PDR peak on Day 1 or 2 was significantly lower in non-survivors compared to transplant-free survivors (9.1 vs 2.3, p < 0.0001). In addition, serial peak PDRs were consistently lower in non-survivors vs survivors (p < 0.0001). The AUROC of the 13C-MBT in the combined cohort was 0.88 (95% CI: 0.79-0.97) and higher than that provided by King’s College (AUROC= 0.70) and MELD scores (AUROC=0.83). The 13C-MBT was well tolerated with only 2 gastrointestinal adverse events reported.
Conclusions: The 13C-MBT provides a promising estimate of the likelihood of hepatic recovery in ALF and ALI patients. The use of the PDR peak data from the 13C-MBT point of care test may assist with medical decision-making and help avoid unnecessary transplantation in critically ill ALF and ALI patients.
Full Results of the MBT study were published: Fontana RJ, et al. Prognostic Value of the C-Methacetin Breath Test in Adults with Acute Liver Failure and Non-Acetaminophen Acute Liver Injury. Hepatology. 2021 Mar 3. doi: 10.1002/hep.31783. Epub ahead of print. PMID: 33660316.
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.
Background & Aims. Despite an abnormal hemostatic profile, patients with acute liver injury and failure (ALI/ALF) experience bleeding complications uncommonly. Rotational thromboelastometry (ROTEM), which assesses clot formation in whole blood, was explored to determine whether abnormal hemostasis contributes to bleeding events, illness severity, or outcome.
Approach & Results. 200 patients were recruited from sites of the ALF Study Group. Blood collected daily for up to 5 days was analyzed using ROTEM delta® devices. Consistent with standard laboratory evidence of hypercoagulability (median INR 2.9 and platelet count 144x109/L), patients frequently exhibited ROTEM parameters outside of the normal range (73% and 62% had abnormalities in clot formation from extrinsic and intrinsic clotting cascades, respectively); however, measures of clot stability were generally normal. Eighteen patients (9%) experienced bleeding events, in whom clot initiation, assembly, and firmness were more severely deranged than patients without bleeding. Abnormal ROTEM parameters were more frequently observed in patients with non-acetaminophen (APAP) ALI/ALF than those with APAP ALI/ALF (clot initiation (P<0.001), assembly (P=0.02), firmness at 10 min (P=0.05), and maximal firmness (P=0.06)). Patients with more severe systemic complications (high-grade hepatic encephalopathy and the need for renal replacement therapy) also had a higher incidence of abnormal ROTEM parameters. Finally, more hypercoagulable ROTEM parameters were observed in patients who died or underwent liver transplantation than in those who survived with their native liver (clot initiation (P=0.005), stiffness at 10 min (P=0.05), and maximal stiffness by fibrin assembly (P=0.004)).
Conclusions. In patients with ALI/ALF, abnormal hemostasis by ROTEM is frequent and proportional to disease severity. Whether the increased bleeding risk associated with abnormal ROTEM indicates hemostatic failure or is a proxy for disease severity requires additional study.
Full Results of the ROTEM study were published: Stravitz RT, et al. Coagulopathy, Bleeding Events, and Outcome According to Rotational Thromboelastometry in Patients with Acute Liver Injury/Failure. Hepatology. 2021 Feb 26. doi:10.1002/hep.31767. Epub ahead of print. PMID: 33636020.
No additional therapy trials are contemplated at present. Future possibilities include the use of liver assist devices or transplantation of hepatocytes. Stay tuned.