Clinical characteristics and outcomes of acute liver failure in neonates: a retrospective cohort in China

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We attempted to analyze a NALF cohort to improve the prognosis of this disease. We included all patients diagnosed with NALF at our institution between 2016 and 2021 and retrospectively reviewed their electronic records. NALF was defined as an INR ≥ 2.0 due to liver disease 28 days after birth. Comparisons were made according to etiology and outcome. The Kaplan-Meier method was used to estimate survival. Fifty-eight patients were included in this study. Etiologies included hypoxic/ischemic injury (29.3%), infection (27.6%), gestational alloimmune liver disease with neonatal hemochromatosis (GALD-NH) (10.3%), inherited metabolic diseases (5.2%), hemophagocytic lymphohistiocytosis (1.7%), other etiologies (12.1%), and unidentified causes (13.8%). Enteroviruses constituted 87.5% of the viral infections, whereas herpes simplex virus accounted for no infections. The median INR was significantly lower in the infection group than in the GALD-NH group ( P < 0.05 for multiple comparisons). At the last follow-up, none of the patients had undergone liver transplantation, and the overall mortality rate was 50%. Liver function completely recovered in 31% of the patients, all of whom survived. The overall median survival time was 48 days; 26 days for hypoxic/ischemic injury and 43 days for GALD-NH. The incidence of cholestasis was significantly greater among surviving patients ( P = 0.018). Conclusions : Hypoxic/ischemic injury and infection are the predominant etiologies of NALF in China. The overall prognosis of NALF is poor, but its short-term prognosis is determined by the etiology. Liver failure Hepatology Neonate Perinatal asphyxia Neonatal hemochromatosis Figures Figure 1 Figure 2 What is Known/New What is Known : 1. Neonatal acute liver failure (NALF) is a rare disorder with limited cohort studies, especially in China. 2. Gestational alloimmune liver disease, viral infections (especially herpes simplex virus), metabolic diseases and ischemic insults are common etiologies of NALF, which are significantly different from other populations. 3. There are no reliable biochemical markers to predict the outcome of NALF. What is New : 1. In this first report on a Chinese NALF cohort, we demonstrate that hypoxic/ischemic injury and infection (excluding herpes simplex virus) are the predominant etiologies of NALF. 2. The overall prognosis of NALF is poor, and its etiology determines the short-term outcome. Introduction Acute liver failure (ALF) is an altered state characterized by a sudden loss of liver function without any previous liver disease, and the incidence and etiology of this disease vary according to age group and geographic region [ 1 , 2 ] . Neonatal acute liver failure (NALF) refers to ALF that occurs within the first 4 weeks of life and includes neonatal cirrhosis as a result of liver damage in the fetus [ 3 ] . The etiological spectrum and clinical features of NALF, as a rare disease with high mortality, are significantly different from other populations [ 1 , 3 ] . However, most of the published reports of ALF include pediatric and neonatal populations [ 2 , 4 , 5 ] , with limited data for neonates [ 6 – 9 ] . There are no data on Chinese newborns with ALF. Therefore, we retrospectively analyzed the etiologies, clinical features, therapeutic treatments and outcomes of patients diagnosed with NALF in China. The results of this study could contribute to early diagnosis and effective treatment to improve the outcomes of NALF patients. Methods This was a retrospective study. We reviewed all coagulation tests performed in the Neonatology Department of the Children’s Hospital of Fudan University between January 1, 2016, and December 31, 2021, to identify patients that fit the NALF definition via a ‘catch-all’ approach. The inclusion criteria in our study were inpatients (term infants aged ≤ 28 days and preterm infants with a postmenstrual age less than 44 weeks) with an international normalized ratio (INR) ≥ 2.0. The exclusion criteria were as follows: no underlying liver synthetic dysfunction presenting as transient consumptive coagulopathy, vitamin K responsive coagulopathy, congenital coagulation factor deficiency and neoplasms. Patients with chronic liver disease presenting as NALF (NALF-CLD) were defined as those with liver failure who presented splenomegaly, ascites and congenital cirrhosis on ultrasound. In the absence of liver transplantation (LT), liver failure resolution was considered when the INR was 15 (in this case, 15 was the assumed value for statistical analysis). The upper limits for the detection of alpha-fetoprotein (AFP) and ferritin were 121000 ng/mL and 2000 ng/mL, respectively (in these patients, 121000 and 2000 ng/mL were the assumed values for statistical analysis). We collected the following data from electronic medical records: demographic information, clinical manifestations, laboratory and imaging results, clinical interventions, and outcomes. Statistical Analysis The statistical analysis was performed using SPSS 22.0 statistical software (SPSS, Inc., Chicago, IL, USA). Continuous variables are presented as medians with interquartile ranges (IQRs), and categorical variables are presented as percentages. Differences in laboratory values among patients with different etiologies were calculated by the Kruskal-Wallis test with Bonferroni post hoc correction for multiple comparisons. Hemophagocytic lymphohistiocytosis (HLH) was excluded from the above analysis due to the sample size of 1. The Mann-Whitney test and Fisher’s exact test were used to compare outcomes. The Kaplan-Meier method was applied to estimate the median survival times of the entire cohort, infection cohort and gestational alloimmune liver disease with neonatal hemochromatosis (GALD-NH) cohort. A P value < 0.05 was considered to indicate statistical significance. Results Demographics Fifty-eight patients with NALF were ultimately included in this study (Table 1 ). Overall, 36.2% (21/58) of the patients were born preterm (median gestational age at birth: 38 weeks; IQR: 35–39 weeks), and 44.8% (26/58) were boys. The median birth weight was 2800 g (IQR: 2195–3300 g). The median age at ALF diagnosis was 4 days (IQR: 1-13.3 days); 69% (40/58) of the patients were diagnosed within the first 7 days after birth, and 27.6% (16/58) were diagnosed on the first day after birth. Three premature infants (all born at less than 29 weeks of gestational age) were diagnosed with ALF 28 days after birth (all diagnosed at less than 39 weeks of postmenstrual age). Table 1 Patients’ demographics and clinical features by etiology of neonatal acute liver failure (NALF) Etiology, n M:F Preterm Birth weight (g) Age at diagnosis of ALF (days) Problems during pregnancy Family history Bleeding NALF-CLD MODS Hypoxic/ischemic (17) 7:10 41.2% (7/17) 2800 (2030–3465) 1 (1-3.5) 64.7% (11/17) 23.5% (4/17) 47.1% (8/17) 0% 82.4% (14/17) Infection (16) 2:14 37.5% (6/16) 2610 (1985-3063.8) 7.5 (5-18.3) 43.8% (7/16) 6.25% (1/16) 31.3% (5/16) 0% 62.5% (10/16) GALD-NH (6) 2:4 16.7% (1/6) 2800 (2570–3225) 5.5 (3–13) 0% 33.3% (2/6) 66.7% (4/6) 16.7% (1/6) 83.3% (5/6) Inherited metabolic diseases (3) 1:2 0% 3220 (2800-) 2 (2-) 0% 66.7% (2/3) 66.7% (2/3) 0% 66.7% (2/3) HLH (1) 1:0 0% 3600 14 0% 100% (1/1) 0% 0% 100% (1/1) Other etilologies (7) 6:1 71.4% (5/7) 2280 (1425–3300) 3 (1–4) 57.1% (4/7) 28.6% (2/7) 57.1% (4/7) 0% 28.6% (2/7) Unknown (8) 7:1 25% (2/8) 2825 (2350–3300) 4.5 (1.5–24.5) 12.5% (1/8) 25% (2/8) 37.5% (3/8) 50% (4/8) 50% (4/8) Total (58) 26:32 36.2% (21/58) 2800 (2195–3300) 4 (1-13.3) 39.7% (23/58) 24.1% (14/58) 44.8% (26/58) 8.6% (5/58) 65.5% (38/58) Data are expressed as median (IQR) or percentage. CLD chronic liver disease, F female, HLH hemophagocytic lymphohistiocytosis, GALD-NH gestational alloimmune liver disease with neonatal hemochromatosis, M male, MODS multiple organ dysfunction syndrome Etiology Hypoxic/ischemic injury was the most common identified etiology, occurring in 29.3% (17/58) of the patients, followed by infection (27.6%, 16/58), GALD-NH (10.3%, 6/58), inherited metabolic diseases (IMDs) (5.2%, 3/58), HLH (1.7%, 1/58), and other etiologies (12.1%, 7/58). In addition, 13.8% (8/58) of the patients had an unidentified cause (Table 1 ). In the hypoxic/ischemic group, eleven (19%, 11/58) patients experienced severe perinatal hypoxia-ischemia, whereas the other six patients (10.3%, 6/58) experienced cardiac-associated ischemia or hypovolemic shock. The etiologies observed in the infection group included eight (13.8%, 8/58) cases of viral infection, five (8.6%, 5/58) cases of bacterial infection, two (3.4%, 2/58) cases of fungal infection and one (1.7%, 1/58) case of congenital tuberculosis. Enterovirus infection accounted for 87.5% (7/8) of the viral infections, and rubella virus infection accounted for the remaining 12.5% (1/8). The IMD group in our series included three patients: one with a urea cycle disorder, one with carnitine palmitoyltransferase II deficiency, and one with hereditary fructose intolerance. Among the patients with other etiologies, four had focal liver lesions, one had portal vein thrombosis, one had intrahepatic portosystemic shunts, and one had adrenocortical insufficiency. Clinical Features A total of 39.7% (23/58) of the patients presented with problems during gestation: twelve (eleven with perinatal hypoxia-ischemia) had fetal distress, six had infection risk factors such as maternal fever, vaginal bleeding and premature rupture of membranes, three had oligohydramnios, and one had intrauterine growth retardation; focal liver lesions indicated by magnetic resonance imaging (MRI) were described in one fetus. A total of 24.1% (14/58) of the patients had a family history of repeated miscarriages, neonatal death or ALF in siblings (Table 1 ). Patients diagnosed with NALF were in critical condition, and 65.5% (38/58) of the patients presented with multiple-organ insufficiency syndrome. Bleeding was a common complication (44.8%, 26/58) involving the gastrointestinal tract (27.6%, 16/58), lungs (12.1%, 7/58), intracranial space (10.3%, 6/58), skin (5.2%, 3/58), adrenal glands (3.4%, 2/58), and intraperitoneal cavity (1.7%, 1/58). Five patients (8.6%, 5/58) presented with NALF-CLD, including four patients with unidentified etiologies and one patient with GALD-NH. Laboratory Data Figure 1 shows the laboratory data during hospitalization for neonates with different etiologies. The distributions of the INR and alanine aminotransferase (ALT), total bilirubin (TB), direct bilirubin (DB) and ammonia levels differed for each etiological group, and the differences were statistically significant (all p values less than 0.05). The median INR in the infection group (4.2, IQR: 3.5–5.7) was significantly lower than that in the GALD-NH group (13.5, IQR: 9.4–15) ( P < 0.05 for multiple comparisons) (Fig. 1 A). The unknown cause group had significantly lower ALT levels (57.1 IU/L, IQR: 30-179.8 IU/L) than did the IMD (977 IU/L, IQR: 429.5-1885.3 IU/L) and infection (472.3 IU/L, IQR: 191-756.4 IU/L) groups ( P < 0.05 for multiple comparisons) (Fig. 1 B). Compared with those in the GALD-NH and unknown cause groups, the TB (65.6 µmol/L, IQR: 30-156.7 µmol/L) and DB (11.1 µmol/L, IQR: 7-15.4 µmol/L) levels were significantly lower in the hypoxic/ischemic injury group ( P 200 µmol/L). Compared with those in the GALD-NH (214 µmol/L, IQR: 176–339 µmol/L) and unknown cause (227 µmol/L, IQR: 176-281.4 µmol/L) groups, the ammonia levels in the hypoxic/ischemic injury group (109 µmol/L, IQR: 87.7-126.3 µmol/L) were significantly lower ( P < 0.05 for multiple comparisons) (Fig. 1 D). A total of 31% of the patients (n = 18/58) had a recorded AFP value, and 46.6% (n = 27/58) had a recorded ferritin value. No significant difference was found in the AFP value ( P = 0.18) or in the ferritin level ( P = 0.3) among the different etiological groups (Fig. 1 E-F). Of the six patients diagnosed with GALD-NH, all had extrahepatic iron deposition on MRI. No patients underwent liver biopsy during follow-up due to critical conditions, family member refusal or spontaneous recovery. Treatment and Outcomes Only 6.9% (4/58) of the patients, including two with viral infection, received empiric acyclovir after symptom onset. All infants with GALD-NH received intravenous immunoglobulin beginning at the onset of illness, but none of the patients received double volume exchange transfusion due to improvement or death. During the follow-up period, no patients underwent LT due to spontaneous recovery, family refusal or death prior to transfer to a regional liver unit. At the last follow-up, liver function had completely recovered in eighteen patients (31%, 18/58) (median duration of liver failure: 10.5 days, IQR: 3.5–17.5 days), and all of those patients survived, 50% (9/18) of whom were in the infection group. The overall mortality rate was 50% (29/58) at the last contact with all survivors (median age: 34.5 days, IQR: 7-141 days). The survival rate was greater in the infection (62.5%, 10/16), other etiology (71.4%, 5/7) and unknown cause (62.5%, 5/8) groups (Fig. 2 A). The cumulative median survival time for the whole cohort was 48 days (95% CI: 0.0-140.7 days) (Fig. 2 B), with a median survival time of 26 days (95% CI: 0.0-62.9 days) for the hypoxic/ischemic injury group and 43 days (95% CI: 0.0-125.8 days) for the GALD-NH group. The DB level in the patients who survived was significantly greater than that in the patients who died ( P = 0.025), and the incidence of cholestatic liver injury in the surviving patients (69%, 20/29) was significantly greater than that in the deceased patients (38%, 11/29) ( P = 0.018). Other characteristics were not significantly different between patients who survived and patients who died (Table 2 ). Table 2 Patients features of different outcomes Survival (IQR; n) Death (IQR; n) P value Birth weight (g) 2850 (2375–3300; 29) 2650 (2030–3235; 29) 0.379 Gestational age (weeks) 38.4 (35.6–39.2; 29) 37.4 (33.9–38.3; 29) 0.146 Age at diagnosis (days) 4 (2-10.5; 29) 5 (1–14; 29) 0.912 INR 4.3 (3.6–6.6; 29) 5.7 (3.9–10.8; 29) 0.118 ALT (IU/L) 242 (102.3-497.9; 29) 203.9 (112.8–324; 29) 0.423 DB (µmol/L) 108.9 (26.5-214.5; 29) 20.4 (11-140.6) 0.025 Ammonia (µmol/L) 166 (107.1–224; 23) 204 (132.2-308.3; 20) 0.113 AFP (ng/mL) 60651 (42324–121000; 13) 4820.9 (2267.4-75051; 5) 0.125 Ferritin (ng/mL) 2000 (1223.8–2000; 16) 2000 (1741–2000; 11) 0.582 AFP Alpha-fetoprotein, ALT Alanine aminotransferase, DB Direct bilirubin, INR International normalized ratio, TB Total bilirubin Discussion To our knowledge, this is the first study to report on Chinese neonates with ALF. In our study, hypoxic/ischemic injury, especially perinatal hypoxia-ischemia, predominated among the etiologies of NALF, which was consistent with the findings of Zozaya et al. [ 7 ] . Infection, the second most common etiology in our series, included not only viral infections, which have been highlighted in previous studies [ 6 , 8 ] , but also bacterial and fungal infections. We agree with Zozaya et al. [ 7 ] that a case of NALF can be considered secondary to septicemia only if the Pediatric Acute Liver Failure Study Group criteria are fully met when the pathogen is isolated from a blood culture sample. Surprisingly, herpes simplex virus, the most common virus that causes NALF [ 6 , 8 ] , was not found in our series; our results showed that the most common virus was enterovirus. According to the published literature, the indeterminate etiology rate among neonates is approximately 5%-32% [ 6 – 9 ] . In our study, 13.8% of the patients had an unidentified cause. The primary pathogenic mechanism, such as hypoxic/ischemic injury or infection, can be quickly diagnosed by recognizable clinical scenarios and laboratory test results. NH, mainly caused by GALD, can be diagnosed by positive MRI or oral mucosal biopsy findings of extrahepatic siderosis, but a negative finding cannot exclude GALD [ 10 , 11 ] . The definitive confirmation of GALD is positive C5b-9 staining by liver biopsy; however, its use as a routine diagnostic tool is unfeasible. Compared with ALF, metabolic disorders rarely cause NALF. However, this may not actually be the case. Metabolic diseases are a major category of disease and can be easily diagnosed through metabolic screening and next-generation sequencing; however, others diseases (such as mitochondrial disorders) require more invasive operations for definitive diagnosis, such as muscle or liver biopsy [ 12 ] . In our study, medical exome sequencing [ 13 ] or trio whole-exome sequencing (trio-WES) was performed for neonates with a suspected genetic metabolic disease or an unknown causes of ALF, resulting in the diagnosis of three patients. One girl developed severe hyperlactacidemia complicated with liver, heart, and kidney symptoms immediately after birth, so mitochondrial disease was suspected. Although the trio-WES results were negative, mitochondrial DNA sequencing or biopsy of clinically relevant tissue was not performed. Despite advances in diagnostic techniques, an extensive diagnostic work-up is not easily performed for critically ill newborns. Storing blood, urine, and liver tissue samples for future studies is strongly recommended for patients with unknown causes of ALF. The fetal-neonatal continuum of liver disease is defined by the fact that some causes of neonatal liver failure actually begin with fetal liver disease [ 3 ] . As early as 2001, Jackson et al. [ 14 ] proposed that neonatal liver failure (liver failure at 60 days of age, according to their definition) be categorized as “acute hepatocellular necrosis” or “chronic liver disease (CLD)” (that is, the extension of fetal liver disease). The Clinical Practice Guidelines of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition suggest that pediatric ALF be subclassified into “pure” forms of ALF and CLD presenting with a phenotype of ALF [ 1 ] . In our study, five infants developed splenomegaly, ascites and cirrhosis on ultrasound in the neonatal period, suggesting chronic liver injury. GALD predominated in the NALF-CLD group [ 3 , 14 ] . Of the five patients in our study, only one was diagnosed with NH-associated GALD, but the remaining four patients had unknown etiologies and did not undergo further liver biopsy during follow-up due to critical conditions or family member refusal. Despite prompt medical therapy, the survival with native liver (SNL) rate in our study was low (50%), consistent with previous reports of approximately 33–47.8% [ 6 – 9 ] . LT is the only option for treating ALF when standard medical therapy fails [ 15 ] . Antala et al. conducted a multicenter retrospective study on peritransplant outcomes in NALF patients and reported a lower rate of LT (2.0% vs. 6.4%; P < 0.001) in these patients than in older infants (31–120 days old). However, risk factors for death or transplant and posttransplant outcomes were similar between neonates and older infants. Therefore, further studies are needed to better optimize decision algorithms for LT in NALF patients and improve outcomes [ 9 , 15 ] . There are no reliable biochemical markers for predicting SNL. Zozaya et al. [ 7 ] demonstrated that higher ALT levels and INR values at diagnosis could predict poor prognosis in the short term. Borovsky et al. [ 6 ] reported that only a higher AFP level was present in SNL patients. However, our study showed that the incidence of cholestasis and the DB level were significantly greater in SNL patients. This result may be explained by the fact that severe perinatal hypoxia-ischemia was the main cause of ALF in our study, which resulted in multiple-organ failure in the infants shortly after birth. Therefore, we agree with Squires et al. [ 2 ] that the etiology of ALF determines the short-term outcome. Identifying the etiology of ALF is crucial for quickly instituting disease-specific therapies for treatable disorders and selecting patients who may benefit from LT. One limitation of our study is that it was a single-center study with a small sample size due to the rarity of the disease and the diversity of etiologies, which led to predictive analysis in the absence of a larger cohort. However, multicenter studies are needed to address the sample size limitation and differences in results due to regional specificity. Overall, this study is the first to report on neonates with ALF in China. We demonstrated that hypoxic/ischemic injury and infection are the predominant causes of ALF in this population and can be easily distinguished by unique clinical and laboratory profiles. The population had an overall low SNL rate, and a proportion of the patients did not have a clear etiology. However, further research is needed to maximize the accuracy and accessibility of diagnostic tests and minimize their invasiveness to achieve accurate and timely diagnosis and improved outcomes. Abbreviations AFP Alpha-fetoprotein ALF Acute liver failure ALT Alanine aminotransferase CLD Chronic liver disease DB Direct bilirubin GALD-NH Gestational alloimmune liver disease with neonatal hemochromatosis HLH Hemophagocytic lymphohistiocytosis LT Liver transplantation IMD Inherited metabolic diseases INR International normalized ratio IQR Interquartile range NALF Neonatal acute liver failure SNL Survival with native liver TB Total bilirubin WES Whole-exome sequencing Declarations Competing interests The authors have no relevant financial or non-financial interests to disclose. Author Contributions Guoqiang Cheng, Peng Zhang and Suhua Xu conceptualized and designed the study. Material preparation, data collection and analysis were performed by Suhua Xu, Peng Zhang, Mengmeng Ge and Yuanyuan Shan. The first draft of the manuscript was written by Suhua Xu and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Funding There was no funding for the study. Ethics approval This retrospective study was conducted on already available data and was approved by the Medical Ethics Committee of the Children’s Hospital of Fudan University institutional review board and conducted under the Declaration of Helsinki principles (approval reference: No (2021) 491; December 8, 2021). Consent to participate Informed consent was obtained from the legal guardians of all participants included in the study. References Di Giorgio A, Bartolini E, Calvo PL et al (2021) Diagnostic Approach to Acute Liver Failure in Children: A Position Paper by the SIGENP Liver Disease Working Group. Dig Liver Dis 53(5):545–557. https://doi:10.1016/j.dld.2021.03.004 Squires RJ, Shneider BL, Bucuvalas J et al (2006) Acute liver failure in children: the first 348 patients in the pediatric acute liver failure study group. 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Case Rep Pediatr 2017:7432859. https://doi:10.1155/2017/7432859 Debray FG, de Halleux V, Guidi O, Detrembleur N, Gaillez S, Rausin L, Goyens P, Pan XM, Whitington PF (2012) Neonatal liver cirrhosis without iron overload caused by gestational alloimmune liver disease. PEDIATRICS 129 (4):e1076-e1079. https://doi:10.1542/peds.2011-0568 Gorman GS, Chinnery PF, DiMauro S et al (2016) Mitochondrial diseases. Nature Reviews Disease Primers 2:16080. https://doi:10.1038/nrdp.2016.80 Yang L, Wei Z, Chen X, et al (2022) Use of medical exome sequencing for identification of underlying genetic defects in NICU: Experience in a cohort of 2303 neonates in China. Clin Genet 101(1):101–109. https://doi:10.1111/cge.14075 Jackson R, Roberts EA (2001) Identification of neonatal liver failure and perinatal hemochromatosis in Canada. 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Cite Share Download PDF Status: Published Journal Publication published 29 Apr, 2024 Read the published version in European Journal of Pediatrics → Version 1 posted Editorial decision: Revision requested 03 Mar, 2024 Reviews received at journal 03 Mar, 2024 Reviews received at journal 18 Feb, 2024 Reviewers agreed at journal 13 Feb, 2024 Reviewers agreed at journal 12 Feb, 2024 Reviewers invited by journal 31 Jan, 2024 Editor assigned by journal 31 Jan, 2024 Submission checks completed at journal 31 Jan, 2024 First submitted to journal 21 Jan, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3886832","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":270315264,"identity":"6bf31873-97aa-4f31-ab0e-1da7dd370b4e","order_by":0,"name":"Suhua Xu","email":"","orcid":"","institution":"Children's Hospital, Shanghai Jiaotong University, Shanghai Children's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Suhua","middleName":"","lastName":"Xu","suffix":""},{"id":270315265,"identity":"1fd966ef-511a-4233-bf03-0e89103a4bef","order_by":1,"name":"Peng Zhang","email":"","orcid":"","institution":"Children’s Hospital of Fudan University, National Children’s Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Peng","middleName":"","lastName":"Zhang","suffix":""},{"id":270315266,"identity":"f03c5a54-78e2-4770-a103-bde470606280","order_by":2,"name":"Mengmeng Ge","email":"","orcid":"","institution":"Children’s Hospital of Fudan University, National Children’s Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mengmeng","middleName":"","lastName":"Ge","suffix":""},{"id":270315267,"identity":"92a59e35-15d7-43f2-a4dd-243befd86aa8","order_by":3,"name":"Yuanyuan Shan","email":"","orcid":"","institution":"Children’s Hospital of Fudan University, National Children’s Medical Center","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuanyuan","middleName":"","lastName":"Shan","suffix":""},{"id":270315268,"identity":"0f05cac6-77ad-4ff2-bb6a-590a9fb062b1","order_by":4,"name":"Guoqiang Cheng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIiWNgGAWjYHACNijNfOADlG1ArBa2xBmkauExJE6LvHvyswcfd9Qy8E8787GZp8wuj4G9eZsEQ80dnFoMzzwzN5x55jiDxO3cjc0855KLGXiOlUkwHHuGW8uMHDZp3rZjDAbSudsf87YxJzZI5JhJMDYcxq/lL1hLzsNm3rb6xAb5N/i1yEsAtTC21YC0MAK1HAbawoNfiwHPMzPJ3rYDQL+kGTbOOXc8sY0nrdgi4RgeW9qTn0n8bKtj4J+d/LDhTVl1Yj/74Y03PtTgseVAAog6XN8AEwFHTQJODUBbGsCydXiUjIJRMApGwYgHAKqtU2U+NmDoAAAAAElFTkSuQmCC","orcid":"","institution":"Children’s Hospital of Fudan University, National Children’s Medical Center","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Guoqiang","middleName":"","lastName":"Cheng","suffix":""}],"badges":[],"createdAt":"2024-01-22 03:44:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3886832/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3886832/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00431-024-05567-7","type":"published","date":"2024-04-30T00:50:29+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":50521752,"identity":"fe45ce68-6821-4962-8ae7-e38189e5c89b","added_by":"auto","created_at":"2024-02-01 19:12:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":446900,"visible":true,"origin":"","legend":"\u003cp\u003eMedian laboratory values of infants with acute liver failure during neonatal hospitalization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A)\u003c/strong\u003e The INR in the infection group (4.2) was significantly lower than that in the GALD-NH group (13.5). \u003cstrong\u003e(B)\u003c/strong\u003e Patients with an unknown etiology had significantly lower ALT levels (57.1 IU/L) than did those with an IMD (977 IU/L) or infection (472.3 IU/L). \u003cstrong\u003e(C)\u003c/strong\u003eThe HI group had a significantly lower DB levels (11.1 μmol/L) than did the GALD-NH and unknown cause groups (127.6 and 138.4 μmol/L, respectively).\u003cstrong\u003e (D)\u003c/strong\u003e Ammonia levels in the HI group (109 μmol/L) were significantly lower than those in the GALD-NH and unknown cause groups (214 and 227 μmol/L, respectively). \u003cstrong\u003e(E-F)\u003c/strong\u003e There was no significant difference in AFP (P = 0.18) or ferritin (P = 0.3) levels among the different etiological groups. \u003cem\u003eAFP\u003c/em\u003e Alpha-fetoprotein, \u003cem\u003eALT\u003c/em\u003e Alanine aminotransferase, \u003cem\u003eDB\u003c/em\u003e Direct bilirubin, \u003cem\u003eGALD-NH\u003c/em\u003e Gestational alloimmune liver disease with neonatal hemochromatosis, \u003cem\u003eHI\u003c/em\u003eHypoxic/ischemic injury, \u003cem\u003eIMD\u003c/em\u003eInherited metabolic diseases, \u003cem\u003eINR\u003c/em\u003eInternational normalized ratio, \u003cem\u003eInfect\u003c/em\u003eInfection, \u003cem\u003eTB\u003c/em\u003e Total bilirubin. ∗\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05 for multiple comparisons\u003c/p\u003e","description":"","filename":"Fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-3886832/v1/1fad71937e05328b2972c1bb.png"},{"id":50521751,"identity":"031960e8-d5fa-4066-b7d5-a664c2c5a0c4","added_by":"auto","created_at":"2024-02-01 19:12:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":188672,"visible":true,"origin":"","legend":"\u003cp\u003eOutcomes of neonatal acute liver failure patients. \u003cstrong\u003e(A)\u003c/strong\u003e The overall mortality rate was 50% (29/58) at the last contact with all the survivors. The mortality rate was greater than 50% in the GALD-NH (83.3%, 5/6), HLH (100%, 1/1) and IMD (66.7%, 2/3) groups. \u003cstrong\u003e(B)\u003c/strong\u003e The cumulative median survival time for the whole cohort was 48 days (95% CI: 0.0-140.7 days). \u003cem\u003eGALD-NH\u003c/em\u003e Gestational alloimmune liver disease with neonatal hemochromatosis, \u003cem\u003eHI\u003c/em\u003eHypoxic/ischemic injury, \u003cem\u003eHLH\u003c/em\u003e Hemophagocytic lymphohistiocytosis, \u003cem\u003eIMD\u003c/em\u003e Inherited metabolic diseases\u003c/p\u003e","description":"","filename":"Fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-3886832/v1/6c2ae4ea2ce4cd330b5e7f44.png"},{"id":55697688,"identity":"9a294a95-a183-43c6-9f19-3ffb7c0a09c0","added_by":"auto","created_at":"2024-05-02 02:20:38","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":782025,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3886832/v1/d210bd38-3530-4e8a-bc71-55c89e1fcb88.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical characteristics and outcomes of acute liver failure in neonates: a retrospective cohort in China","fulltext":[{"header":"What is Known/New","content":"\u003cp\u003e\u003cstrong\u003eWhat is Known\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003e1. Neonatal acute liver failure (NALF) is a rare disorder with limited cohort studies, especially in China.\u003c/p\u003e\n\u003cp\u003e2. Gestational alloimmune liver disease, viral infections (especially herpes simplex virus), metabolic diseases and ischemic insults are common etiologies of NALF, which are significantly different from other populations.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e3. There are no reliable biochemical markers to predict the outcome of NALF.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWhat is New\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003e1. In this first report on a Chinese NALF cohort, we demonstrate that hypoxic/ischemic injury and infection (excluding herpes simplex virus) are the predominant etiologies of NALF.\u003c/p\u003e\n\u003cp\u003e2. The overall prognosis of NALF is poor, and its etiology determines the short-term outcome.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eAcute liver failure (ALF) is an altered state characterized by a sudden loss of liver function without any previous liver disease, and the incidence and etiology of this disease vary according to age group and geographic region \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Neonatal acute liver failure (NALF) refers to ALF that occurs within the first 4 weeks of life and includes neonatal cirrhosis as a result of liver damage in the fetus \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe etiological spectrum and clinical features of NALF, as a rare disease with high mortality, are significantly different from other populations \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. However, most of the published reports of ALF include pediatric and neonatal populations \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e, with limited data for neonates \u003csup\u003e[\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. There are no data on Chinese newborns with ALF. Therefore, we retrospectively analyzed the etiologies, clinical features, therapeutic treatments and outcomes of patients diagnosed with NALF in China. The results of this study could contribute to early diagnosis and effective treatment to improve the outcomes of NALF patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis was a retrospective study. We reviewed all coagulation tests performed in the Neonatology Department of the Children\u0026rsquo;s Hospital of Fudan University between January 1, 2016, and December 31, 2021, to identify patients that fit the NALF definition via a \u0026lsquo;catch-all\u0026rsquo; approach. The inclusion criteria in our study were inpatients (term infants aged\u0026thinsp;\u0026le;\u0026thinsp;28 days and preterm infants with a postmenstrual age less than 44 weeks) with an international normalized ratio (INR)\u0026thinsp;\u0026ge;\u0026thinsp;2.0. The exclusion criteria were as follows: no underlying liver synthetic dysfunction presenting as transient consumptive coagulopathy, vitamin K responsive coagulopathy, congenital coagulation factor deficiency and neoplasms.\u003c/p\u003e \u003cp\u003ePatients with chronic liver disease presenting as NALF (NALF-CLD) were defined as those with liver failure who presented splenomegaly, ascites and congenital cirrhosis on ultrasound. In the absence of liver transplantation (LT), liver failure resolution was considered when the INR was \u0026lt;\u0026thinsp;1.4. In our laboratory, a coagulation test indicating \"no clot formation\" was defined as an INR\u0026thinsp;\u0026gt;\u0026thinsp;15 (in this case, 15 was the assumed value for statistical analysis). The upper limits for the detection of alpha-fetoprotein (AFP) and ferritin were 121000 ng/mL and 2000 ng/mL, respectively (in these patients, 121000 and 2000 ng/mL were the assumed values for statistical analysis). We collected the following data from electronic medical records: demographic information, clinical manifestations, laboratory and imaging results, clinical interventions, and outcomes.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThe statistical analysis was performed using SPSS 22.0 statistical software (SPSS, Inc., Chicago, IL, USA). Continuous variables are presented as medians with interquartile ranges (IQRs), and categorical variables are presented as percentages. Differences in laboratory values among patients with different etiologies were calculated by the Kruskal-Wallis test with Bonferroni post hoc correction for multiple comparisons. Hemophagocytic lymphohistiocytosis (HLH) was excluded from the above analysis due to the sample size of 1. The Mann-Whitney test and Fisher\u0026rsquo;s exact test were used to compare outcomes. The Kaplan-Meier method was applied to estimate the median survival times of the entire cohort, infection cohort and gestational alloimmune liver disease with neonatal hemochromatosis (GALD-NH) cohort. A \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered to indicate statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDemographics\u003c/h2\u003e \u003cp\u003eFifty-eight patients with NALF were ultimately included in this study (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Overall, 36.2% (21/58) of the patients were born preterm (median gestational age at birth: 38 weeks; IQR: 35\u0026ndash;39 weeks), and 44.8% (26/58) were boys. The median birth weight was 2800 g (IQR: 2195\u0026ndash;3300 g). The median age at ALF diagnosis was 4 days (IQR: 1-13.3 days); 69% (40/58) of the patients were diagnosed within the first 7 days after birth, and 27.6% (16/58) were diagnosed on the first day after birth. Three premature infants (all born at less than 29 weeks of gestational age) were diagnosed with ALF 28 days after birth (all diagnosed at less than 39 weeks of postmenstrual age).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatients\u0026rsquo; demographics and clinical features by etiology of neonatal acute liver failure (NALF)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEtiology, n\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM:F\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePreterm\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBirth weight (g)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAge at diagnosis of ALF (days)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eProblems during pregnancy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eFamily history\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBleeding\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNALF-CLD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eMODS\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypoxic/ischemic (17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7:10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41.2% (7/17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2800 (2030\u0026ndash;3465)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1 (1-3.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e64.7% (11/17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e23.5% (4/17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e47.1% (8/17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e82.4% (14/17)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfection (16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2:14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.5% (6/16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2610 (1985-3063.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.5 (5-18.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e43.8% (7/16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6.25% (1/16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e31.3% (5/16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e62.5% (10/16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGALD-NH (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2:4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16.7% (1/6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2800 (2570\u0026ndash;3225)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.5 (3\u0026ndash;13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e33.3% (2/6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e66.7% (4/6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e16.7% (1/6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e83.3% (5/6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInherited metabolic diseases (3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1:2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3220 (2800-)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 (2-)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e66.7% (2/3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e66.7% (2/3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e66.7% (2/3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHLH (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1:0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3600\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e100% (1/1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e100% (1/1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther etilologies (7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6:1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e71.4% (5/7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2280 (1425\u0026ndash;3300)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (1\u0026ndash;4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e57.1% (4/7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e28.6% (2/7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e57.1% (4/7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e0%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e28.6% (2/7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnknown (8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7:1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25% (2/8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2825 (2350\u0026ndash;3300)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.5 (1.5\u0026ndash;24.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12.5% (1/8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e25% (2/8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e37.5% (3/8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e50% (4/8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e50% (4/8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal (58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26:32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.2% (21/58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2800 (2195\u0026ndash;3300)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4 (1-13.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e39.7% (23/58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e24.1% (14/58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e44.8% (26/58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e8.6% (5/58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e65.5% (38/58)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"10\"\u003eData are expressed as median (IQR) or percentage. \u003cem\u003eCLD\u003c/em\u003e chronic liver disease, \u003cem\u003eF\u003c/em\u003e female, \u003cem\u003eHLH\u003c/em\u003e hemophagocytic lymphohistiocytosis, \u003cem\u003eGALD-NH\u003c/em\u003e gestational alloimmune liver disease with neonatal hemochromatosis, \u003cem\u003eM\u003c/em\u003e male, \u003cem\u003eMODS\u003c/em\u003e multiple organ dysfunction syndrome\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eEtiology\u003c/h2\u003e \u003cp\u003eHypoxic/ischemic injury was the most common identified etiology, occurring in 29.3% (17/58) of the patients, followed by infection (27.6%, 16/58), GALD-NH (10.3%, 6/58), inherited metabolic diseases (IMDs) (5.2%, 3/58), HLH (1.7%, 1/58), and other etiologies (12.1%, 7/58). In addition, 13.8% (8/58) of the patients had an unidentified cause (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In the hypoxic/ischemic group, eleven (19%, 11/58) patients experienced severe perinatal hypoxia-ischemia, whereas the other six patients (10.3%, 6/58) experienced cardiac-associated ischemia or hypovolemic shock. The etiologies observed in the infection group included eight (13.8%, 8/58) cases of viral infection, five (8.6%, 5/58) cases of bacterial infection, two (3.4%, 2/58) cases of fungal infection and one (1.7%, 1/58) case of congenital tuberculosis. Enterovirus infection accounted for 87.5% (7/8) of the viral infections, and rubella virus infection accounted for the remaining 12.5% (1/8). The IMD group in our series included three patients: one with a urea cycle disorder, one with carnitine palmitoyltransferase II deficiency, and one with hereditary fructose intolerance. Among the patients with other etiologies, four had focal liver lesions, one had portal vein thrombosis, one had intrahepatic portosystemic shunts, and one had adrenocortical insufficiency.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eClinical Features\u003c/h2\u003e \u003cp\u003eA total of 39.7% (23/58) of the patients presented with problems during gestation: twelve (eleven with perinatal hypoxia-ischemia) had fetal distress, six had infection risk factors such as maternal fever, vaginal bleeding and premature rupture of membranes, three had oligohydramnios, and one had intrauterine growth retardation; focal liver lesions indicated by magnetic resonance imaging (MRI) were described in one fetus. A total of 24.1% (14/58) of the patients had a family history of repeated miscarriages, neonatal death or ALF in siblings (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePatients diagnosed with NALF were in critical condition, and 65.5% (38/58) of the patients presented with multiple-organ insufficiency syndrome. Bleeding was a common complication (44.8%, 26/58) involving the gastrointestinal tract (27.6%, 16/58), lungs (12.1%, 7/58), intracranial space (10.3%, 6/58), skin (5.2%, 3/58), adrenal glands (3.4%, 2/58), and intraperitoneal cavity (1.7%, 1/58). Five patients (8.6%, 5/58) presented with NALF-CLD, including four patients with unidentified etiologies and one patient with GALD-NH.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eLaboratory Data\u003c/h2\u003e \u003cp\u003eFigure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the laboratory data during hospitalization for neonates with different etiologies. The distributions of the INR and alanine aminotransferase (ALT), total bilirubin (TB), direct bilirubin (DB) and ammonia levels differed for each etiological group, and the differences were statistically significant (all p values less than 0.05). The median INR in the infection group (4.2, IQR: 3.5\u0026ndash;5.7) was significantly lower than that in the GALD-NH group (13.5, IQR: 9.4\u0026ndash;15) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for multiple comparisons) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). The unknown cause group had significantly lower ALT levels (57.1 IU/L, IQR: 30-179.8 IU/L) than did the IMD (977 IU/L, IQR: 429.5-1885.3 IU/L) and infection (472.3 IU/L, IQR: 191-756.4 IU/L) groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for multiple comparisons) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Compared with those in the GALD-NH and unknown cause groups, the TB (65.6 \u0026micro;mol/L, IQR: 30-156.7 \u0026micro;mol/L) and DB (11.1 \u0026micro;mol/L, IQR: 7-15.4 \u0026micro;mol/L) levels were significantly lower in the hypoxic/ischemic injury group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for multiple comparisons) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). Ammonia was measured in 74.1% (43/58) of the patients, and 39.5% (17/43) had hyperammonemia (\u0026gt;\u0026thinsp;200 \u0026micro;mol/L). Compared with those in the GALD-NH (214 \u0026micro;mol/L, IQR: 176\u0026ndash;339 \u0026micro;mol/L) and unknown cause (227 \u0026micro;mol/L, IQR: 176-281.4 \u0026micro;mol/L) groups, the ammonia levels in the hypoxic/ischemic injury group (109 \u0026micro;mol/L, IQR: 87.7-126.3 \u0026micro;mol/L) were significantly lower (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 for multiple comparisons) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD). A total of 31% of the patients (n\u0026thinsp;=\u0026thinsp;18/58) had a recorded AFP value, and 46.6% (n\u0026thinsp;=\u0026thinsp;27/58) had a recorded ferritin value. No significant difference was found in the AFP value (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.18) or in the ferritin level (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.3) among the different etiological groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE-F).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eOf the six patients diagnosed with GALD-NH, all had extrahepatic iron deposition on MRI. No patients underwent liver biopsy during follow-up due to critical conditions, family member refusal or spontaneous recovery.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eTreatment and Outcomes\u003c/h2\u003e \u003cp\u003eOnly 6.9% (4/58) of the patients, including two with viral infection, received empiric acyclovir after symptom onset. All infants with GALD-NH received intravenous immunoglobulin beginning at the onset of illness, but none of the patients received double volume exchange transfusion due to improvement or death. During the follow-up period, no patients underwent LT due to spontaneous recovery, family refusal or death prior to transfer to a regional liver unit.\u003c/p\u003e \u003cp\u003eAt the last follow-up, liver function had completely recovered in eighteen patients (31%, 18/58) (median duration of liver failure: 10.5 days, IQR: 3.5\u0026ndash;17.5 days), and all of those patients survived, 50% (9/18) of whom were in the infection group. The overall mortality rate was 50% (29/58) at the last contact with all survivors (median age: 34.5 days, IQR: 7-141 days). The survival rate was greater in the infection (62.5%, 10/16), other etiology (71.4%, 5/7) and unknown cause (62.5%, 5/8) groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). The cumulative median survival time for the whole cohort was 48 days (95% CI: 0.0-140.7 days) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB), with a median survival time of 26 days (95% CI: 0.0-62.9 days) for the hypoxic/ischemic injury group and 43 days (95% CI: 0.0-125.8 days) for the GALD-NH group.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe DB level in the patients who survived was significantly greater than that in the patients who died (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.025), and the incidence of cholestatic liver injury in the surviving patients (69%, 20/29) was significantly greater than that in the deceased patients (38%, 11/29) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.018). Other characteristics were not significantly different between patients who survived and patients who died (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatients features of different outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSurvival (IQR; n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDeath (IQR; n)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth weight (g)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2850 (2375\u0026ndash;3300; 29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2650 (2030\u0026ndash;3235; 29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.379\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational age (weeks)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38.4 (35.6\u0026ndash;39.2; 29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37.4 (33.9\u0026ndash;38.3; 29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.146\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge at diagnosis (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (2-10.5; 29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (1\u0026ndash;14; 29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.912\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.3 (3.6\u0026ndash;6.6; 29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.7 (3.9\u0026ndash;10.8; 29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.118\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALT (IU/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e242 (102.3-497.9; 29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e203.9 (112.8\u0026ndash;324; 29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.423\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDB (\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e108.9 (26.5-214.5; 29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20.4 (11-140.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmmonia (\u0026micro;mol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e166 (107.1\u0026ndash;224; 23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e204 (132.2-308.3; 20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.113\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAFP (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60651 (42324\u0026ndash;121000; 13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4820.9 (2267.4-75051; 5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.125\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFerritin (ng/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2000 (1223.8\u0026ndash;2000; 16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2000 (1741\u0026ndash;2000; 11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.582\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003eAFP\u003c/em\u003e Alpha-fetoprotein, \u003cem\u003eALT\u003c/em\u003e Alanine aminotransferase, \u003cem\u003eDB\u003c/em\u003e Direct bilirubin, \u003cem\u003eINR\u003c/em\u003e International normalized ratio, \u003cem\u003eTB\u003c/em\u003e Total bilirubin\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo our knowledge, this is the first study to report on Chinese neonates with ALF. In our study, hypoxic/ischemic injury, especially perinatal hypoxia-ischemia, predominated among the etiologies of NALF, which was consistent with the findings of Zozaya et al. \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Infection, the second most common etiology in our series, included not only viral infections, which have been highlighted in previous studies \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e, but also bacterial and fungal infections. We agree with Zozaya et al. \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e that a case of NALF can be considered secondary to septicemia only if the Pediatric Acute Liver Failure Study Group criteria are fully met when the pathogen is isolated from a blood culture sample. Surprisingly, herpes simplex virus, the most common virus that causes NALF \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e, was not found in our series; our results showed that the most common virus was enterovirus.\u003c/p\u003e \u003cp\u003eAccording to the published literature, the indeterminate etiology rate among neonates is approximately 5%-32% \u003csup\u003e[\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. In our study, 13.8% of the patients had an unidentified cause. The primary pathogenic mechanism, such as hypoxic/ischemic injury or infection, can be quickly diagnosed by recognizable clinical scenarios and laboratory test results. NH, mainly caused by GALD, can be diagnosed by positive MRI or oral mucosal biopsy findings of extrahepatic siderosis, but a negative finding cannot exclude GALD \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. The definitive confirmation of GALD is positive C5b-9 staining by liver biopsy; however, its use as a routine diagnostic tool is unfeasible. Compared with ALF, metabolic disorders rarely cause NALF. However, this may not actually be the case. Metabolic diseases are a major category of disease and can be easily diagnosed through metabolic screening and next-generation sequencing; however, others diseases (such as mitochondrial disorders) require more invasive operations for definitive diagnosis, such as muscle or liver biopsy \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. In our study, medical exome sequencing \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e or trio whole-exome sequencing (trio-WES) was performed for neonates with a suspected genetic metabolic disease or an unknown causes of ALF, resulting in the diagnosis of three patients. One girl developed severe hyperlactacidemia complicated with liver, heart, and kidney symptoms immediately after birth, so mitochondrial disease was suspected. Although the trio-WES results were negative, mitochondrial DNA sequencing or biopsy of clinically relevant tissue was not performed. Despite advances in diagnostic techniques, an extensive diagnostic work-up is not easily performed for critically ill newborns. Storing blood, urine, and liver tissue samples for future studies is strongly recommended for patients with unknown causes of ALF.\u003c/p\u003e \u003cp\u003eThe fetal-neonatal continuum of liver disease is defined by the fact that some causes of neonatal liver failure actually begin with fetal liver disease \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. As early as 2001, Jackson et al. \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e proposed that neonatal liver failure (liver failure at 60 days of age, according to their definition) be categorized as \u0026ldquo;acute hepatocellular necrosis\u0026rdquo; or \u0026ldquo;chronic liver disease (CLD)\u0026rdquo; (that is, the extension of fetal liver disease). The Clinical Practice Guidelines of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition suggest that pediatric ALF be subclassified into \u0026ldquo;pure\u0026rdquo; forms of ALF and CLD presenting with a phenotype of ALF \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. In our study, five infants developed splenomegaly, ascites and cirrhosis on ultrasound in the neonatal period, suggesting chronic liver injury. GALD predominated in the NALF-CLD group \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. Of the five patients in our study, only one was diagnosed with NH-associated GALD, but the remaining four patients had unknown etiologies and did not undergo further liver biopsy during follow-up due to critical conditions or family member refusal.\u003c/p\u003e \u003cp\u003eDespite prompt medical therapy, the survival with native liver (SNL) rate in our study was low (50%), consistent with previous reports of approximately 33\u0026ndash;47.8% \u003csup\u003e[\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. LT is the only option for treating ALF when standard medical therapy fails \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Antala et al. conducted a multicenter retrospective study on peritransplant outcomes in NALF patients and reported a lower rate of LT (2.0% vs. 6.4%; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) in these patients than in older infants (31\u0026ndash;120 days old). However, risk factors for death or transplant and posttransplant outcomes were similar between neonates and older infants. Therefore, further studies are needed to better optimize decision algorithms for LT in NALF patients and improve outcomes \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThere are no reliable biochemical markers for predicting SNL. Zozaya et al.\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e demonstrated that higher ALT levels and INR values at diagnosis could predict poor prognosis in the short term. Borovsky et al.\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e reported that only a higher AFP level was present in SNL patients. However, our study showed that the incidence of cholestasis and the DB level were significantly greater in SNL patients. This result may be explained by the fact that severe perinatal hypoxia-ischemia was the main cause of ALF in our study, which resulted in multiple-organ failure in the infants shortly after birth. Therefore, we agree with Squires et al. \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e that the etiology of ALF determines the short-term outcome. Identifying the etiology of ALF is crucial for quickly instituting disease-specific therapies for treatable disorders and selecting patients who may benefit from LT.\u003c/p\u003e \u003cp\u003eOne limitation of our study is that it was a single-center study with a small sample size due to the rarity of the disease and the diversity of etiologies, which led to predictive analysis in the absence of a larger cohort. However, multicenter studies are needed to address the sample size limitation and differences in results due to regional specificity.\u003c/p\u003e \u003cp\u003eOverall, this study is the first to report on neonates with ALF in China. We demonstrated that hypoxic/ischemic injury and infection are the predominant causes of ALF in this population and can be easily distinguished by unique clinical and laboratory profiles. The population had an overall low SNL rate, and a proportion of the patients did not have a clear etiology. However, further research is needed to maximize the accuracy and accessibility of diagnostic tests and minimize their invasiveness to achieve accurate and timely diagnosis and improved outcomes.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAFP \u0026nbsp; Alpha-fetoprotein\u003c/p\u003e\n\u003cp\u003eALF \u0026nbsp;Acute liver failure\u003c/p\u003e\n\u003cp\u003eALT \u0026nbsp;Alanine aminotransferase\u003c/p\u003e\n\u003cp\u003eCLD \u0026nbsp;Chronic liver disease\u003c/p\u003e\n\u003cp\u003eDB \u0026nbsp;Direct bilirubin\u003c/p\u003e\n\u003cp\u003eGALD-NH \u0026nbsp; Gestational alloimmune liver disease with neonatal hemochromatosis\u003c/p\u003e\n\u003cp\u003eHLH \u0026nbsp; Hemophagocytic lymphohistiocytosis\u003c/p\u003e\n\u003cp\u003eLT \u0026nbsp;Liver transplantation\u003c/p\u003e\n\u003cp\u003eIMD \u0026nbsp;Inherited metabolic diseases\u003c/p\u003e\n\u003cp\u003eINR \u0026nbsp; International normalized ratio\u003c/p\u003e\n\u003cp\u003eIQR \u0026nbsp; Interquartile range\u003c/p\u003e\n\u003cp\u003eNALF \u0026nbsp;Neonatal acute liver failure\u003c/p\u003e\n\u003cp\u003eSNL \u0026nbsp;Survival with native liver\u003c/p\u003e\n\u003cp\u003eTB \u0026nbsp;Total bilirubin\u003c/p\u003e\n\u003cp\u003eWES \u0026nbsp;Whole-exome sequencing\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting interests\u0026nbsp;\u003c/strong\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e Guoqiang Cheng, Peng Zhang and Suhua Xu conceptualized and designed the study. Material preparation, data collection and analysis were performed by Suhua Xu, Peng Zhang, Mengmeng Ge and Yuanyuan Shan. The first draft of the manuscript was written by Suhua Xu and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e There was no funding for the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e This retrospective study was conducted on already available data and was approved by the Medical Ethics Committee of the Children\u0026rsquo;s Hospital of Fudan University institutional review board and conducted under the Declaration of Helsinki principles (approval reference: No (2021) 491; December 8, 2021).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate\u003c/strong\u003e Informed consent was obtained from the legal guardians of all participants included in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDi Giorgio A, Bartolini E, Calvo PL et al (2021) Diagnostic Approach to Acute Liver Failure in Children: A Position Paper by the SIGENP Liver Disease Working Group. 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HEPATOLOGY 68(6):2338\u0026ndash;2347. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi:10.1002/hep.30116\u003c/span\u003e\u003cspan address=\"https://doi:10.1002/hep.30116\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Liver failure, Hepatology, Neonate, Perinatal asphyxia, Neonatal hemochromatosis","lastPublishedDoi":"10.21203/rs.3.rs-3886832/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3886832/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCurrently, no literature is available regarding neonatal acute liver failure (NALF), as a rare disease with high mortality, in China. We attempted to analyze a NALF cohort to improve the prognosis of this disease. We included all patients diagnosed with NALF at our institution between 2016 and 2021 and retrospectively reviewed their electronic records. NALF was defined as an INR ≥ 2.0 due to liver disease 28 days after birth. Comparisons were made according to etiology and outcome. The Kaplan-Meier method was used to estimate survival. Fifty-eight patients were included in this study. Etiologies included hypoxic/ischemic injury (29.3%), infection (27.6%), gestational alloimmune liver disease with neonatal hemochromatosis (GALD-NH) (10.3%), inherited metabolic diseases (5.2%), hemophagocytic lymphohistiocytosis (1.7%), other etiologies (12.1%), and unidentified causes (13.8%). Enteroviruses constituted 87.5% of the viral infections, whereas herpes simplex virus accounted for no infections. The median INR was significantly lower in the infection group than in the GALD-NH group (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05 for multiple comparisons). At the last follow-up, none of the patients had undergone liver transplantation, and the overall mortality rate was 50%. Liver function completely recovered in 31% of the patients, all of whom survived. The overall median survival time was 48 days; 26 days for hypoxic/ischemic injury and 43 days for GALD-NH. The incidence of cholestasis was significantly greater among surviving patients (\u003cem\u003eP\u003c/em\u003e = 0.018).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: Hypoxic/ischemic injury and infection are the predominant etiologies of NALF in China. The overall prognosis of NALF is poor, but its short-term prognosis is determined by the etiology.\u003c/p\u003e","manuscriptTitle":"Clinical characteristics and outcomes of acute liver failure in neonates: a retrospective cohort in China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-01 19:12:25","doi":"10.21203/rs.3.rs-3886832/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-03-03T07:25:19+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-03-03T06:08:23+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-02-18T14:39:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"774299cc-a40d-4e23-9654-2c2472f44d00","date":"2024-02-13T11:38:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"87492294-cde0-4825-bd0d-abf8298476a2","date":"2024-02-12T05:00:33+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-31T08:56:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-31T05:18:26+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-01-31T05:16:38+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Pediatrics","date":"2024-01-22T03:42:29+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e448ccf4-4382-486a-a140-667b725d5625","owner":[],"postedDate":"February 1st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-05-02T00:50:29+00:00","versionOfRecord":{"articleIdentity":"rs-3886832","link":"https://doi.org/10.1007/s00431-024-05567-7","journal":{"identity":"european-journal-of-pediatrics","isVorOnly":false,"title":"European Journal of Pediatrics"},"publishedOn":"2024-04-30 00:50:29","publishedOnDateReadable":"April 30th, 2024"},"versionCreatedAt":"2024-02-01 19:12:25","video":"","vorDoi":"10.1007/s00431-024-05567-7","vorDoiUrl":"https://doi.org/10.1007/s00431-024-05567-7","workflowStages":[]},"version":"v1","identity":"rs-3886832","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3886832","identity":"rs-3886832","version":["v1"]},"buildId":"cTy_lsJlmDsVRNrSptgXS","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}