What Is Known/What Is New
What Is Known
- Acute liver failure has a high mortality in the pediatric population.
- Neonatal hemochromatosis, viral infection, and metabolic/mitochondrial conditions are common causes of acute liver failure in infants.
What Is New
- Age-specific criterion for acute liver failure limited to the neonate within the first 30 days of life identifies important clinical and biochemical patterns of presentation.
- Neonates with acute liver failure have reduced survival with their native liver and lower rates of liver transplantation than older infants.
- Higher alpha-fetoprotein values are present in neonates with acute liver failure that survive with their native liver.
Neonatal acute liver failure (ALF) is a rare disease with high mortality ranging between 50% and 80% without liver transplantation (1–4). Although liver transplantation in infants can achieve similar outcomes as older children, overall prognosis remains poor (5). Prior reports on ALF in infancy have used varying ages of inclusion from 90 to 365 days of life (2–4,6), and identified genetic and mitochondrial etiologies as one of the most common etiologies of ALF in older infants (2). The neonatal period, however, ends at 30 days after birth thereby limiting application of data from these studies to neonates.
In addition, variation in reported prevalence and outcomes for neonatal ALF may be in part because of difficulties in applying diagnostic criteria of ALF to the neonate. Embedded within the diagnosis of ALF is the presence of hepatic encephalopathy, which is particularly challenging to identify in infants. To establish pediatric-specific criteria, the Pediatric Acute Liver Failure Study Group (PALFSG) defined ALF as an acute impairment of liver synthetic function with an international normalized ratio (INR) ≥1.5 with encephalopathy or ≥2.0 without encephalopathy (7). Although clinical experience suggests the normal INR for premature infants may be higher than full-term newborns and older children (7,8), different “normal” parameters for the neonate have not been established, and we continue to define neonatal ALF by the PALFSG criteria.
The primary aim of our study was to advance the understanding of ALF in the neonate by using age-specific criteria limited to the first 30 days of life. We identified differences in the prevalence of etiologies, presenting features, and outcomes in neonatal ALF as compared with prior reports in older infants. We further compare trends in laboratory values by etiology and outcome. Findings from our study may facilitate recognition of patterns of presentation by etiology to improve early diagnosis and management to reduce associated morbidity and mortality.
We performed a retrospective chart review of infants with a diagnosis of neonatal ALF at Ann & Robert H. Lurie Children's Hospital of Chicago between January 1, 2008 and December 31, 2018. We identified infants ≤30 days of life that received a code suggestive of ALF during an encounter at Lurie Children's Hospital. We searched for the following ICD-10 codes and their conversion to ICD-9 codes according to the date of the encounter: acute and subacute hepatic failure (with or without coma), hepatic failure unspecified (with or without coma), liver disease unspecified, and toxic liver disease unspecified. To account for cases that may not have received general codes for liver failure during their primary encounter, we also collected patients by etiology-specific ICD-9/10 codes and problems entered in the patient history as inpatients (<30 days of life) or seen for outpatient follow-up (<6 months of age). Diagnoses included hemophagocytic lymphohistocytosis (HLH), enterovirus or echovirus infection, herpes simplex viral (HSV) infection, adenovirus infection, ornithine transcarbamylase (OTC) deficiency, tyrosinemia, galactosemia, mitochondrial disease, and gestational alloimmune liver disease (GALD) or neonatal hemochromatosis (NH). As cytomegalovirus and Epstein-Barr virus are not common etiologies for neonatal ALF, these were not integrated into the etiology-specific search criteria. Patients with an INR ≥2.0 for greater than 24 hours were included in the study. These criteria excluded patients without underlying liver synthetic dysfunction that demonstrated transient consumptive coagulopathy or Vitamin-K responsive coagulopathy on serial labs. The search using general hepatic failure codes pulled 38 patients who met inclusion criteria and the search by etiology-specific codes pulled 9 patients who met criteria of which 5 were new (2 from inpatient and 3 from outpatient encounters). The study was approved by the Institutional Review Board at Ann and Robert H. Lurie Children's Hospital of Chicago.
We extracted data from the electronic medical record for all patients including: demographic information; laboratory values for markers of liver injury and synthetic function; etiology-specific work-up; treatment received; and patient outcomes of liver transplantation, death, or survival with native liver (SNL). The etiology of neonatal ALF was assigned as recorded by the treating physicians during the patients’ hospital course. Etiologies were classified as GALD-NH, viral infection, HLH, genetic (metabolic or mitochondrial disease), ischemia, Trisomy 21-associated myelodysplasia (TAM), or not identified. As Lurie Children's is a large referral center for congenital cardiac disease, ischemia was further separated into cardiac-associated ischemia for infants with a history of underlying cardiac disease, such as transposition of the great arteries, critical aortic coarctation or valvular stenoses, superior ventricular tachycardia, hypoplastic left heart syndrome, and double outlet right ventricle. Other cases of ischemia were classified based on chart review that revealed history of perinatal event or thrombosis leading to ischemic injury. NH was diagnosed by clinical, imaging, and histologic features during the inpatient presentation and classified as GALD-NH if no alternate etiology for NH was identified. Patients without a definitive underlying etiology of neonatal ALF were labeled as “not identified.” We considered a patient to have a complete work-up for neonatal ALF if the following tests were sent: AFP or ferritin to evaluate for GALD-NH; testing for adenovirus, enterovirus, and HSV for the most common viral etiologies; ferritin and soluble interleukin-2 receptor (sIL-2R) for HLH; and serum amino acids and urine organic acids for evaluation of genetic etiologies.
Patient data was grouped by underlying etiology for analyses. Descriptive statistics for demographic and clinical patient variables are reported as medians with interquartile range (IQR) for continuous variables and frequencies/proportions for categorical variables. Differences in laboratory values upon presentation of ALF were calculated by ANOVA with the Bonferroni post hoc test for multiple comparisons. HLH was excluded from this analysis because of a sample size of 1. Outcomes were compared using the Mann-Whitney test. Survival rates were estimated by the Kaplan-Meier method and the median survival is reported for the full cohort, viral infection, and GALD-NH. Statistical comparisons and survival analyses were conducted in Prism 8.1.2 (GraphPad Software, San Diego, CA) and SAS 9.4 (SAS Institute Inc., Cary, NC).
Forty-three patients met inclusion criteria for neonatal ALF during the study period (Table 1). Overall, 51% of patients were boys and 49% were girls. The median birth weight across all etiologies was 2755 g (IQR 2287–3196 g) with an overall incidence of preterm birth of 28% (12/43) of which 50% (6/12) were born at less than 32 weeks of gestation. The median age of presentation with ALF was at 3.0 days (IQR 1.0–8.0 days). Across all etiologies, overall mortality was 65% including data captured until last contact with all survivors (median age of 1079 days, IQR 649–2456 days). Median age of death occurred at 20 days (IQR 13–71 days).
TABLE 1 -
Patient demographics by etiology of neonatal acute liver failure
||M : F
||Median birth weight,g (IQR)
||Median age at presentation, days (IQR)
||Median age at death, days (IQR)
||5 : 5
||4 : 5
|Cardiac-associated ischemia (7)
||3 : 4
|Other ischemia (6)
||6 : 0
||3 : 1
|T21-associated myelodysplasia (3)
||1 : 2
||0 : 1
|Not identified (3)
||0 : 3
||22 : 21
F = female; GALD = gestational alloimmune liver disease; HLH = hemophagocytic lymphohistiocytosis; M = male; n = number; NH = neonatal hemochromatosis; T21 = Trisomy 21.
∗Preterm is defined as less than 37 weeks gestational age.
†Missing data on 1 patient.
Among all patients, viral infection was the most common identified etiology occurring in 23% of patients, followed by GALD-NH (21%), cardiac-associated ischemia (16%), other ischemia (14%), genetic etiologies (9%), TAM (7%), HLH (2%), and not identified (7%). HSV constituted 70% of viral diagnoses and enterovirus accounted for the remaining 30%. Among genetic etiologies, 2 patients had OTC deficiency, 1 had a mitochondrial disorder, and 1 was diagnosed with galactosemia. When assessing characteristics of neonatal ALF by etiology, preterm birth was least common among infants with viral infection (10%, n = 1/10), genetic etiologies (0%, n = 0/4), and unidentified causes (0%, n = 0/3). Median birth weight was lowest among patients with noncardiac causes of ischemia at 709.5 g (IQR 580.0–3449 g). Overall median age at presentation was 3.0 days (IQR 1.0–8.0 days) for the entire cohort.
Laboratory, Imaging, and Histology Findings by Etiology
Six patients (14%) received a complete laboratory work-up for at least 3 of the primary etiologies of neonatal ALF. Patients without an identified cause were tested for the most etiologies (average of 2.3 etiologies tested per patient) whereas TAM, cardiac-associated ischemia, and other causes of ischemia received the most limited evaluation (average of 0.3, 0.4, and 0.7 etiologies tested per patient, respectively). Among all patients, GALD-NH was the most commonly investigated cause for neonatal ALF (67%, n = 29) followed by genetic (35%, n = 15). Complete testing for all viral etiologies was performed in only 9% of patients (n = 4), with adenovirus screening performed the least.
We next evaluated laboratory data at the time of presentation of neonatal ALF to determine trends by etiology. All reported aminotransferase and bilirubin values were obtained within 27 hours of the first recorded INR (Fig. 1). At presentation, infants with cardiac-associated ischemia had the highest INR (4.5, IQR 2.2–5.9), followed by viral etiologies (4.1, IQR 2.9–6.8) (Fig. 1A) whereas peak values of INR over the disease course were highest for viral infection (6.7, IQR 5.2–10) and GALD-NH (6.7, IQR 3.9–10). Viral infection had significantly higher alanine aminotransferase (ALT) (1179 IU/L, IQR 682.8–1585 IU/L) values at presentation in comparison to all other etiologies (P < 0.05 for multiple comparisons) (Fig. 1B). Direct bilirubin was greater than 3.0 mg/dL in HLH, GALD-NH, noncardiac ischemia, and not identified etiologies (Fig. 1C). In total, 56% of patients (n = 24/43) had an alpha-fetoprotein (AFP) value and 67% (n = 29/43) had a ferritin value recorded. The median AFP was highest among patients with GALD-NH (82,896 ng/mL, IQR 9344–141,933 ng/mL) whereas ferritin was highest in viral infection (51,000 ng/mL, IQR 1648–100,000 ng/mL) (Fig. 1D).
Of the 9 patients with a diagnosis of GALD-NH, 3 had positive iron staining on buccal biopsy, 4 had extra-hepatic iron deposition on autopsy, 1 had a history of a previously affected sibling, and 1 patient with insufficient sample on buccal biopsy was diagnosed by clinical presentation alone. Magnetic resonance imaging (MRI) reports from 3 patients with GALD-NH demonstrated extra-hepatic iron deposition in only 1 case. Liver biopsy was performed during work-up for neonatal ALF in a total of 6 patients at a mean of 45 ± 39 days of life with diagnoses of GALD-NH (n = 1), HLH (n = 1), genetic etiology identified as a mitochondrial disorder (n = 1), unidentified etiology (n = 2), and cardiac-associated ischemia with prominent cholestasis (n = 1). One patient with an unidentified etiology that had an indeterminate diagnosis of HLH had pancreatic iron deposition on autopsy. Although the autopsy in this patient demonstrated NH and would influence recommendations for gestational intravenous immunoglobulin (IVIG) in future pregnancies, the patient remained categorized as unidentified in the present study for the rationale described in methods.
Outcomes for Infants With Neonatal Acute Liver Failure
All infants with neonatal ALF secondary to a viral illness (n = 10) received empiric acyclovir at a mean of 0.6 ± 1.3 days from presentation beginning at 6.9 ± 2.0 days of life. Although acyclovir was initiated in 2 of the 7 patients with HSV after a positive laboratory result, treatment began within 1 day of documented ALF. Of the patients without a viral etiology, 36% (n = 12/33) received acyclovir. Infants with GALD-NH received their first dose of IVIG at 4.2 ± 4.7 days from presentation beginning at 8.2 ± 10 days of life. An additional 5 of 9 patients with GALD-NH received double volume exchange transfusion at 9.0 ± 5.0 days of life. Liver transplantation was performed in 1 patient with a diagnosis of GALD-NH at 40 days of life but died secondary to post-transplant complications at 54 days of life. A second patient with OTC deficiency received a liver transplant at 287 days of life and was alive at last follow-up.
Evaluation of laboratory values that may be associated with outcome demonstrated that SNL patients had a significantly higher median AFP level of 134,715 ng/mL (IQR 17,483–214,100 ng/mL) than those who died or received a liver transplant (median 15,968 ng/mL, IQR 5599–31,448 ng/mL) (P = 0.04) (Fig. 2A and B). Other laboratory values tested did not reach statistical significance (Fig. 2A).
Across all etiologies, survival was poor with 28 of 43 patients (65%) alive at 30 days and 14 (33%) alive at 1 year (Fig. 3A). Additional 2 patients were alive at last contact but did not reach 1-year follow-up. Survival was highest in those with unidentified etiologies at 67%. Of the 12 patients who died after 30 days of life, 50% (n = 6) were on life-sustaining measures at 30 days including mechanical ventilation, pressor support, dialysis, or extracorporeal membrane oxygenation. Cumulative median survival for the entire cohort was 74 days (95% confidence interval 23–262 days) (Fig. 3B). Despite timely initiation of medical therapy for HSV and GALD-NH, survival remained low for these sub-groups with a median survival of 17 days for patients with viral infection and 74 days for GALD-NH.
This is the first study to report on neonatal ALF limited to the specific age range of birth to 30 days of life. Viral infection and GALD-NH were the most common etiologies of neonatal ALF, which contrasts with genetic etiologies as the leading cause for neonatal ALF in older infants (21–43%) (2–4,6). Our results also support a role for etiology-specific patterns of clinical presentation in neonatal ALF. Significantly elevated aminotransferases on presentation suggest viral infection, whereas coagulopathy with low aminotransferases are common in GALD-NH. Additionally, the clinical characteristics of both preterm birth and low-birth weight were most frequent among ischemic causes of neonatal ALF.
Despite diagnostic advances, identifying the underlying etiology of ALF in the critically ill neonate remains challenging. In our study, 3 infants (7%) had an unidentified etiology similar to previous reports of 6.4% to 33.3% (2–4,6). Although diagnostic liver biopsy can be performed safely in older children with ALF (9), this can be technically challenging in small neonates with coagulopathy. In addition, comprehensive laboratory testing requires a high blood volume making completion of diagnostic testing more difficult to achieve (10). Further diagnostic challenges arise from shared clinical features between etiologies. The presence of extra-hepatic iron deposition that is central to the diagnosis of GALD-NH can also occur in other etiologies of neonatal ALF including TAM and other blood dyscrasias, deoxyguanosine kinase deficiency, severe perinatal infection with hepatic necrosis, and congenital HLH (11). Among infants without an identified etiology in our study, 1 case that was indeterminate for HLH also had extra-hepatic iron deposition on autopsy. As there is no single serologic test for GALD-NH, diagnosis continues to rely on clinical-pathologic findings. In the case of infants with unidentified etiologies that do not fully fit the clinical spectrum of GALD-NH, yet have NH by imaging or tissue evaluation, future treatment with gestational IVIG is recommended in subsequent pregnancies (12,13). Despite these ongoing challenges, we propose an algorithm for work-up and treatment of neonatal ALF based on the etiology-specific laboratory trends shown in our study (Fig. 4). Further research is needed to increase the precision and ease of diagnostic testing to achieve an accurate and timely diagnosis and improve outcomes.
Our findings also demonstrate higher mortality for neonatal ALF than has been observed in older infants. Despite medical therapy, SNL in our cohort was low at 33%; however, only 5% received a liver transplant. This finding is similar to a recent report in infants before 3 months of age (4); however, our data contrasts with prior studies reporting spontaneous survival of 60% (2) and (50)% (6) in infants up to 90 and 120 days, respectively. This difference is likely in part because of the higher prevalence of viral infection in neonates as compared with metabolic and genetic etiologies in older infants, of which some have better survival with dietary or medical treatment. In addition, we observed reduced incidence of liver transplantation for neonatal ALF (5%) compared with reports in older infants of 8% to 29% (2–4,6). Although there are comparable outcomes for liver transplantation in infants with ALF ≤90 days of life and older children (3), liver transplantation in neonatal ALF carries additional technical challenges, and overwhelming viral infection remains a contraindication to liver transplantation. Furthermore, while transplantation for NH has been shown to have similar outcomes as medical therapy and liver transplantation for other etiologies of ALF (12,14,15), there are no reliable predictors for SNL. In contrast to a recent report identifying total bilirubin as a predictor of outcome in infants up to 3 months of age with liver failure (4), we demonstrate only a higher AFP present in SNL patients. Although AFP was only measured as part of the diagnostic work-up in our patients, this finding is similar to data in adults with ALF that has shown correlation between persistently elevated or rising AFP levels and good outcome (16,17). Further research is needed to determine the significance of AFP levels in neonatal ALF and identify additional etiology-specific prognostic markers that may facilitate timely decisions for liver transplant in those that may not respond to medical therapy.
Although our study significantly contributes to current literature on neonatal ALF, we acknowledge several limitations of our study. As a retrospective review, identification of patients with neonatal ALF relied upon coding in the medical record. We queried multiple ICD-9 and ICD-10 codes that would be used to describe ALF; however, it remains possible we may not have captured all patients meeting inclusion criteria. We also recognize the limitation of a small sample size because of the rarity of the condition and the heterogeneity of clinical presentation between etiologies that prevents predictive modeling without a larger cohort. Additionally, larger multi-center studies are needed to address differences that may have been observed because of center variation. Lastly, the duration of the study period was designed to capture an optimal number of patients with available medical records; however, advances in diagnostic evaluation and treatment strategies evolved over the 11-year period and may have differentially impacted patient data.
Overall, this study is the first to characterize ALF specifically in the neonate within the first 30 days of life. We demonstrate that this patient population has a different prevalence of etiologies than older infants and has an overall lower SNL. Viral infection and GALD-NH represent the 2 most dominant causes of neonatal ALF and can be distinguished by unique clinical and laboratory features. Despite diagnostic advances, a proportion of cases remain without an identified etiology. We propose this more stringent definition for neonatal ALF for future studies to allow for prognostic stratification to ultimately improve patient outcomes.
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