Introduction
Acute liver failure (ALF) is a life-threatening syndrome characterized by a rapid onset of liver dysfunction and hepatic encephalopathy in individuals without pre-existing chronic liver disease. Its etiology is multifaceted, encompassing viral infections, drug-induced liver injury (DILI), toxins, autoimmune conditions, metabolic disorders, and vascular events. A significant and persistent clinical challenge, however, is the high proportion of ALF cases classified as having an "indeterminate" etiology, meaning the underlying cause remains unknown. This review critically analyzes the global prevalence and implications of indeterminate ALF, arguing that a determinate diagnosis is paramount for initiating specific therapies that could potentially avert the need for liver transplantation.
The Global Burden of Indeterminate Etiology
An analysis of 67 ALF cohorts from around the world reveals a startlingly wide range of indeterminate cases, from 2% to 100%, with an average of 30%. This problem is particularly pronounced in pediatric populations, where the average rate is 47% (range: 22%-100%), compared to 26% (range: 2%-78%) in adult cohorts. The higher rate in children is often attributed to undiagnosed rare genetic diseases. Furthermore, cohorts studied before the widespread availability of sophisticated diagnostic tools, such as polymerase chain reaction for viral detection, consistently show higher rates of indeterminacy, highlighting the impact of diagnostic capabilities.
Consequences of Diagnostic Uncertainty
The classification of ALF as "indeterminate" is not a benign label; it carries grave clinical consequences. The primary issue is that the lack of a firm diagnosis precludes the initiation of a specific, potentially effective therapy. For treatable conditions such as Wilson disease, autoimmune hepatitis (AIH), drug-induced autoimmune hepatitis (DIAIH), or specific viral infections, this diagnostic delay or failure means a window of opportunity for medical intervention is lost. Consequently, patients are often managed supportively until their condition deteriorates to the point where liver transplantation becomes the only life-saving option. Data confirm the poor prognosis for these patients, with studies showing transplant-free survival rates as low as 20-23% in adults.
Re-evaluation Efforts and Persistent Shortcomings
Recognizing this problem, some studies have attempted to re-adjudicate cases initially deemed indeterminate. For instance, a re-evaluation by the US Acute Liver Failure Study Group (ALFSG) successfully assigned new, specific diagnoses to nearly half of the re-assessed indeterminate cases. These new diagnoses included acetaminophen toxicity, AIH, and various viral infections. However, this review critically notes that these re-evaluation efforts were often hampered by the use of non-validated diagnostic methods, such as the opinion-based US Drug-Induced Liver Injury Network (DILIN) tool, rather than robust, validated algorithms like the Roussel Uclaf Causality Assessment Method (RUCAM). This underscores a systemic issue in the initial diagnostic workup of ALF at many centers.
A Call for Prospective and Standardized Diagnostics
The high and persistent rate of indeterminate ALF is identified as an avoidable pitfall in clinical hepatology. To address this, the review calls for a paradigm shift towards prospective, systematic diagnostic protocols for every patient presenting with severe acute liver injury or ALF. The proposed approach must integrate a comprehensive battery of tests, including:
Specific serological and molecular testing for a broad range of hepatotropic and non-hepatotropic viruses.
Autoimmune markers and globulin levels.
Genetic sequencing, especially in pediatric cases.
The rigorous application of validated causality assessment tools like the updated RUCAM for suspected DILI and DIAIH.
Conclusion
In conclusion, a determinate etiology of ALF is a crucial prerequisite for optimal patient management. The unacceptably high global rates of indeterminate ALF often reflect diagnostic inadequacy rather than a truly unknown cause. By implementing thorough, early, and standardized diagnostic evaluations, clinicians can identify treatable causes of severe liver injury. This allows for the timely initiation of targeted therapies, which can halt disease progression, improve spontaneous recovery, and ultimately reduce the need for liver transplantation. The focus must therefore be on strengthening pre-transplant diagnostic modalities to turn the tide on this longstanding clinical challenge.
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The study was recently published in the Journal of Clinical and Translational Hepatology .
The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study's novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.
