In this case series, three patients had ultra-rapid whole genome sequencing (WGS). Case 1 identified PRF1 mutation consistent with familial HLH, Case 2 identified variants in FDXR implicated in a mitochondrial disorder and Case 3, found pathogenic mutations in ASL associated with agrininosuccinic aciduria.
The authors argue that ultra-rapid WGS which can provide information in as little as 12 hours and typically provides actionable results within 3 days. should be a first-line approach and would identify nearly all causative genetic reasons for neonatal acute liver failure. While GALD and viral etiologies would not be found, if there are no genetic causes, this would support the “initiation of empiric therapy.”
In this retrospective study with 1807 neonates and 890 infants (31-120 days) with ALF (identified in two large databases between 2004-2018), the key findings:
Neonates had higher death rates (46% alive without liver transplant, compared to 53% of infants who were alive without liver transplant)
Both groups had low liver transplant rates, with neonates less likely to be transplanted: 2% vs 6.4% (P<0.001)
Infants had higher rates of “unidentified” as etiology whereas neonates had higher rates of GALD and viral infections. Cardiac etiologies causing ALF were common in both groups, 24% of neonates and 18% of infants.
My take: Rapid genomic testing is very useful in infants/neonates with ALF. This population has a high mortality rate and a low rate of receiving liver transplants. Reducing the size for split liver donation could help with organ availability (see next post).
This single-center retrospective study with 43 patients (over 11 year timeframe) identified etiology and outcomes for neonatal acute liver failure (NALF).
Etiologies included viral infection (23%), gestational alloimmune liver disease with neonatal hemochromatosis (GALD-NH) (21%), cardiac-associated ischemia (16%), other ischemia (14%), genetic etiologies (9%), Trisomy 21-associated myelodysplasia (TAM) (7%), hemophagocytic lymphohistiocytosis (HLH) (2%), and not identified (7%)
Infants with viral etiologies had the highest alanine aminotransferase (ALT) at presentation (1179 IU/L, interquartile range [IQR] 683–1585 IU/L) in contrast to low levels in GALD-NH (23 IU/L, IQR 18–64 IU/L)
Across all etiologies, only 33% were alive at 1 year
Among laboratory values at presentation, alpha-fetoprotein (AFP) was significantly higher in patients that survived with their native liver (P = 0.04)
Figure 4 provides a helpful management algorithm for NALF. Figure 4 is similar to the slide below (shared by lead author).
-Consider empiric acyclovir in those with INR >/= 2.0 in the first 30 days of life
-In those with normal to low elevation of aminotransferases, consider empiric IVIG while undergoing workup. Part of workup should include either MRI or lip biopsy for GALD
-In those with moderate to severe elevation of aminotransferases, workup should include assessment for viral, HLH and genetic etiologies. Fulminant viral hepatitis or HLH likely with Ferritin levels >10,000. Hypoglycemia and hyperammonemia is suggestive of metabolic/mitochondrial disorder
-Liver biopsy may be needed if etiologies not identified
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I recently had the opportunity to review the topic of neonatal cholestasis with my neonatal colleagues. I reviewed two related conditions: parenteral nutrition associated liver disease (PNALD) and neonatal acute liver failure (NALF). Some of the material incorporates recommendations from NASPGHAN cholestasis guidelines and from NASPGHAN cholestasis slidesets. Much of the slideset information is publicly available on a YouTube lecture by Dr. Linda Book (link at bottom).
Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.