This report of the first 348 children in the PALF data set highlights a number of important observations: 1) HE is not an absolute requirement to establish the diagnosis of ALF in children; 2) a specific diagnosis was not made in almost half of all infants and children; 3) the etiologies of ALF in children differ from those seen in adults,(16
) with children having more indeterminate cases and fewer APAP and viral-induced cases; and 4) short-term outcome varied among diagnostic groups.
HE is difficult to assess in children and, in fact, may never become clinically apparent in the setting of ALF.(3
) However, coagulopathy is an independent risk factor for death or need for liver transplantation in ALF.(17
) Therefore, we chose to include children without HE in our study, but only when a significant uncorrectable coagulopathy was present. HE remains an important predictor of outcome(18
) and, similar to other studies in the post-liver transplant era, only 25% of our children with a peak HE of grade 3–4 had a spontaneous recovery. However, it is equally important to note that of 79 children with non-APAP ALF who never developed clinically detectable HE, death (8/79) or liver transplant (8/79) occurred in 20%. Our data support a definition of pediatric ALF that does not require HE.
An indeterminate cause of ALF was assigned to 54% of children < 3 years of age and 49% overall. Factors that may influence the intensity of the diagnostic evaluation in children with ALF include prioritization of the etiologic possibilities, blood volumes required for diagnostic studies, and the rapid evolution of disease to transplant or death. Thus, all potential diagnostic studies were not performed on each patient. The indeterminate group may include patients who were “under-evaluated” for known causes of ALF as well as those with novel infectious, immune, autoimmune, metabolic or genetic disorders.
An infectious agent was identified in only 6% of patients in this series. Herpes simplex virus and Epstein Barr virus were the most common identifiable infections in children <3 years and ≥3 years, respectively. Hepatitis A and B are commonly associated with ALF in adults(19
), however we identified only three cases of Hepatitis A, one case of Hepatitis C and no cases of Hepatitis B. Nevertheless, these infections are common causes of ALF in children living in endemic areas where hepatitis A can represent up to 40% of ALF cases.(20
) Respiratory viruses, enterovirus, or perhaps medications used for symptomatic treatment of these conditions might be implicated given the surge of cases in the winter months however, these viruses were rarely identified.
AIH presenting as ALF accounted for 6% of patients, occurred in all age groups and should therefore be considered early in the diagnostic evaluation to enable timely initiation of corticosteroid treatment.(21
) A metabolic cause for ALF was established in 18% of children <3 years of age. Unfortunately, diagnostic criteria for several conditions are not well-established and special attention to proper collection and transport of biological specimens to specialized research laboratories is needed. Wilson disease and defects or deficiencies in mitochondrial function and metabolism (i.e., mitochondrial hepatopathies) were the most common metabolic conditions identified in our study.
Acute APAP toxicity is the most common identifiable cause of ALF in children ≥ 3 y/o (21%), but the frequency is even higher in adults (40%).(22
) Instances involving prolonged or inappropriate dosing, so-called therapeutic misadventures,(23
) are not easily captured by this study. APAP-protein adducts are formed when the usual mechanisms of APAP metabolism and excretion are exhausted and the reactive APAP metabolite binds to important intracellular proteins resulting in cell death. Detection of these adducts in serum may serve as a biomarker of APAP toxicity.(24
Non-APAP drug-related ALF was recognized only in the older age group in our series. Drug-related hepatotoxicity is relatively common in children, particularly those taking neuroleptic medications, yet ALF is rare.(25
) The mechanism of injury leading to ALF is thought to be an idiosyncratic reaction in most cases; however, children with ALF related to valproic acid should be evaluated for an underlying mitochondrial disorder.(27
)In addition, polymorphisms of genes associated with drug detoxification or cytokine expressions may enhance a patient’s susceptibility to liver injury. (28
Patient outcome was influenced by a number of factors including age, diagnosis, the degree of HE, and severity of the coagulopathy. The risk of death or liver transplant was highest among children <3 years of age. While the numbers are relatively small, patients with Grade IV HE at enrollment experienced a higher rate of spontaneous recovery than those who progressed to Grade IV during the course of the study (50% vs. 20%). At the same time, 20% of children who never experienced clinical HE either died or received a liver transplant. Logistic regression analysis identified total bilirubin ≥ 5 mg/dl, INR ≥ 2.55 and HE to be risk factors to predict death or liver transplant.
In summary, this multicenter, multinational database has confirmed that APAP induced ALF has an excellent outcome when HE is absent(30
), demonstrated the etiologies of ALF in children are age-dependent and differ from those in adults, and identified AIH as an important cause of ALF in all ages of children. Unfortunately, the majority of cases of ALF in children are indeterminate. Therefore, improvement in diagnosis will require a focused search for treatable causes that prioritizes diagnostic conditions known to cause ALF. Newer techniques to identify children with an underlying metabolic disease, APAP toxicity, and immune dysregulation will likely improve our ability to establish a diagnosis in these seriously ill children.