Unusual Causes for Acute Liver Failure: Awareness is the Key!

Acute liver failure (ALF), a rare and heterogeneous orphan disease with significantly high mortality rates, was first characterised by Trey and Davidson in 1970. Over the last few decades, considerable progress has been made in understanding the characteristics and progression of the various aetiologies implicated in ALF. Among these diverse causes, the most prominent include viral hepatitis A and E, acute reactivation or de novo hepatitis B and drug-induced liver injury (DILI) resulting from paracetamol poisoning and antituberculosis medications.[1,2] In recent times, complementary and alternative medicines, as well as herbal and dietary supplements, have emerged as leading causes of DILI.[3] Notably, yellow phosphorus poisoning significantly contributes to ALF in Southern India.[4] Here, we examine and discuss the key contentious clinical issues surrounding various unusual aetiologies of ALF [Table 1].Table 1: Etiology of Acute Liver FailureDespite being uncommon and often producing a clinically indistinguishable picture, accurately determining the underlying cause of ALF is essential, as each aetiology presents unique prognostic and treatment implications. This may sometimes require extensive investigations. Patients with acute Wilsonian crisis, de novo presentation of autoimmune hepatitis or acute Budd–Chiari syndrome can rarely present with rapidly developing liver failure. Liver failure from these causes can be phenotypic ALF if the duration of illness is <26 weeks and there are no features of overt cirrhosis. Patients with a confirmed diagnosis of Wilson’s disease, particularly women aged 5–35 years, can present with ALF due to discontinuation or poor adherence to copper-chelating therapy. The disease characteristically involves Coombs-negative haemolytic anaemia, acute intravascular haemolysis, rapid renal failure, moderate transaminase elevation and normal or very low alkaline phosphatase levels (typically under 40 IU/L). The high bilirubin to alkaline phosphatase ratio is a strong indicator, and serum copper levels may be significantly elevated due to sudden release from the damaged liver tissue. Ceruloplasmin levels may appear low or falsely normal due to its role as an acute-phase reactant. Around half of the patients will display a Kayser–Fleischer ring, although its assessment may be challenging in those with hepatic encephalopathy. In addition, the reliability of 24-h urine copper excretion can be problematic in patients with kidney dysfunction and low urine output. If the diagnosis remains ambiguous, measuring quantitative liver copper through biopsy or performing genetic testing for ATP7 B mutations should be undertaken. It is essential not to delay the liver transplantation (LT) evaluation, as the prognosis without it is significantly unfavourable.[5] While copper chelators are ineffective during an acute Wilsonian crisis, medical interventions such as plasmapheresis, albumin dialysis and continuous haemofiltration may occasionally lead to recovery and rarely replace the necessity for transplantation. Acute severe autoimmune hepatitis (AIH) has the potential to progress to ALF in about 3%–6% of patients, particularly among women, those with other autoimmune disorders and individuals with type 2 AIH. Serological assessments typically reveal elevated levels of antibodies and immunoglobulin G, though their absence does not rule out the diagnosis of AIH. Histological evaluation through liver biopsy shows centrilobular injury characterised by confluent haemorrhagic necrosis, along with prominent lymphoplasmacytic lobular inflammation, occasionally accompanied by chronic hepatitis.[6] It can be complex to diagnose a true de novo AIH-related ALF in the presence of confluent necrosis while differentiating it from exacerbations of chronic AIH or immune-mediated DILI. Consequently, acute severe AIH leading to ALF is often underrecognised, which can cause delays in essential treatment. In carefully chosen acute severe AIH-associated ALF cases, administering intravenous corticosteroids and vigilant infection surveillance significantly improves outcomes and enhances transplant-free survival. For patients who do not respond to steroids, an early consideration for LT is imperative.[7] Budd–Chiari syndrome is a notably rare cause of ALF, primarily arising from complete occlusion of the hepatic veins, resulting in severe ischaemia and widespread hepatocyte necrosis. Patients typically present with significant abdominal pain and ascites, exhibiting a predominantly hepatocellular liver injury pattern with markedly elevated aminotransferase levels, often reaching the thousands. It is imperative to assess for an underlying hypercoagulable state.[8] The cornerstone of managing Budd–Chiari syndrome is the immediate initiation of anticoagulation therapy with intravenous heparin. Historically, transplant-free survival rates were around 40%. Still, recent advancements in treatment options – such as catheter-directed thrombolysis, angioplasty, transjugular intrahepatic portosystemic shunt or direct intrahepatic portocaval shunt – have boosted these rates to an impressive 80%. However, in cases where patients do not respond to these interventions, early consideration of LT is essential.[9] Non-necrotic ALF, characterised by diffuse microvesicular steatosis, is a significant condition often seen in patients with severe mitochondrial dysfunction, whether genetic or related to pregnancy, such as acute fatty liver of pregnancy (AFLP). ALF can be associated with pregnancy in about 2.2%. Diagnosing haemolysis, elevated liver enzymes and low platelets (HELLP) versus AFLP can be challenging due to overlapping clinical features and the natural history of these disorders, as defined by the Swansea criteria. These conditions predominantly arise during the third trimester or immediately post-partum, with two-thirds of affected patients also experiencing preeclampsia or eclampsia. Pregnancy-related ALF is an obstetric emergency that demands a coordinated response from a multidisciplinary team to ensure optimal management. Prompt caesarean delivery of the foetus is crucial for facilitating spontaneous recovery. Although the condition may be reversible, those who do not improve post-delivery may require LT.[10] Moreover, complications such as hepatic bleeding, haematoma or rupture in HELLP syndrome may necessitate urgent surgical intervention. Metabolic liver diseases constitute a significant portion of ALF in the paediatric population. Despite advancements in diagnostic methods, a substantial one-third of children with paediatric ALF still present with an indeterminate cause (iPALF). These cases are associated with notably worse outcomes, as over 50% of iPALF patients progress to either death or require LT.[11] Recently, there has been a pronounced outbreak of idiopathic hepatitis in young children, initially believed to be related to adenovirus or COVID-19 infections, many necessitating emergency LT.[12] Mushroom poisoning, predominantly caused by Amanita phalloides and related species, manifests with severe abdominal pain, nausea, vomiting and diarrhoea within 6–12 h of ingestion. ALF can develop rapidly over the next 4–7 days. Amatoxins are heat-stable and water-insoluble, meaning that even a small quantity – just 1–2 medium-sized boiled mushroom caps – can deliver a lethal dose of amanitin, triggering hepatocyte apoptosis. Confirmatory testing for mushroom poisoning does not exist, making it essential to investigate a patient’s history of mushroom ingestion when they present with ALF. The Escudié’s prognostic criteria, specifically for mushroom poisoning, provide an accurate assessment of 28-day mortality and the need for LT. Most patients can survive without a transplant when treated promptly with gastric lavage, activated charcoal, intravenous hydration, silibinin dihemisuccinate, penicillin G and N-acetylcysteine, all effective in managing the situation.[13] Non-hepatotropic viruses, including herpes simplex virus types 1 and 2, varicella-zoster virus, Epstein–Barr virus, cytomegalovirus, dengue virus,[14] and adenovirus can indeed lead to ALF, particularly in immunocompromised individuals. It is important to note that there is currently no substantial evidence linking COVID-19 to the development of ALF. A considerable proportion of indeterminate ALF cases are likely due to unrecognised atypical viral infections, and routine metagenomic next-generation sequencing is a vital component of the diagnostic workup, effectively identifying novel viruses responsible for indeterminate ALF. Herpes simplex virus and varicella-zoster virus, a rare cause of ALF, are characterised by a distinctive rash, significantly elevated ALT levels exceeding 5000 IU/L and a heightened risk of death or the necessity for LT. Immediate treatment with intravenous acyclovir is essential while awaiting confirmatory serology, viral PCR and skin or mucous membrane biopsy results.[15] Significant reports of ALF associated with immune checkpoint inhibitors have been made in the past 3 to 4 years.[16] ALF can also occur following hemihepatectomy after extensive liver resection.[17] It is crucial to remain vigilant about the conditions that can mimic ALF, which are prevalent in India. Such secondary causes of ALF may include sepsis, malaria, leptospirosis, rickettsial disease, thyrotoxicosis, Still’s disease and haemophagocytic syndromes.[18] In such instances, addressing the systemic disease becomes more critical than pursuing a transplant. Ischaemic liver injury and malignant infiltration of the liver are rare secondary causes of ALF. ‘Shock liver’ arises from transient or persistent decreases in hepatic perfusion, often occurring in the context of congestive heart failure. Still, a documented episode of hypotension may not always be present. Patients with ischaemic hepatitis typically exhibit markedly elevated AST levels, often exceeding 10,000 IU/L, indicating severe hepatocellular injury. Many of these patients experience rapid clinical improvement after restoring normal haemodynamic status. The underlying condition largely dictates the prognosis, and LT is generally not indicated or necessary for ischaemic hepatitis.[19] Malignant liver infiltration accounts for only a small proportion of ALF cases. In previously undiagnosed malignancies, a high index of suspicion is essential, with diagnosis typically relying on liver or bone marrow biopsy. Treatment directed towards malignancy may be warranted; however, LT is usually not performed, and the prognosis remains poor.[20] Establishing the aetiology of ALF necessitates a thorough patient medical history and comprehensive investigation, including radiological, serological and molecular testing to meet standardised, predefined diagnostic criteria. Nonetheless, 5%–10% of patients may not have an identifiable cause of ALF even under well-vetted circumstances, resulting in what is classified as an indeterminate cause. According to the US ALF Study Group database, among 2,718 patients, 5.5% had an indeterminate aetiology. Upon review, nearly half of these cases were attributed to DILI and AIH.[21] It is crucial to consider LT in them, as spontaneous survival rates are generally poor. Given that many instances of ALF may not be diagnosed through history and other non-invasive tests, the use of transjugular liver biopsy in patients with ALF should be approached with caution. A liver biopsy is vital to rule out tumours or hepatic infiltration from extrahepatic diseases as potential causes of ALF. The primary focus for clinicians managing ALF is assessing an individual patient’s prognosis and making informed decisions about when to forgo LT for those who can thrive with medical treatment. This assessment largely hinges on accurately identifying the underlying aetiology amongst the diverse and unusual causes of ALF. Heightened awareness of these uncommon causes of ALF may facilitate earlier diagnosis and the swift implementation of tailored treatment strategies, significantly improving patient outcomes.