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).
Full lecture: Neonatal Cholestasis for Neonatologists
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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.
A recent review (SA Taylor, PF Whittington. Liver Transplantation 2016; 22: 677-85) provides several important concepts for practitioners who may need to manage neonatal acute liver failure.
The most common etiologies (in parenthesis the approximate percentage of cases in their experience):
- Gestational alloimmune liver disease (GALD) (60-90%)
- Viral hepatitis (20-30%)-particularly HSV, followed by HHV-6, and rarely CMV
- Hemophagocytic lymphohistiocytosis (HLH) (<10%)
- Mitochondrial hepatopathy (<5%)
- Rare causes include galactosemia, hereditary tyrosinemia type 1, and hereditary fructose intolerance. (<1%) In addition, bile acid synthetic defect 5-beta-reductase deficiency can cause neonatal liver failure.
While INR ≥2.0 was used in the PALF studies as a primary defining feature of liver failure, since an INR of 2.0 can occur in the normal newborn, the authors recommend using an INR≥ 3.0 for neonatal liver failure.
Their Table 1 helps provide some important differences, Distinguishing features:
- With GALD, ALT values are typically <100 due to underdeveloped hepatic parenchyma and ferritin is typically >800 and <7000. IUGR is frequent (70-90%) as is hypoglycemia. Hepatosplenomegaly is uncommon.
- With viral infections and HLH, ALT values are typically high, ferritin often very high, hepatosplenomegaly is common. IUGR is rare.
- With mitochondrial disorders, ALT typically is between 100-500, ferritin levels are variable, and IUGR occurs in 20-30%. A distinguishing feature is lactate: pyruvate ratio and ketone body ratios.
- By thinking carefully about the reasons for liver failure in the neonatal period and not trying to examine for every possible liver disease, the use of these variables can expedite the evaluation and decrease the cost. Genetic testing is not recommended due to the slow turnaround time, “and many diseases that are prominent causes of cholestatic disease …just do not cause NALF.”
With regard to treatment, the authors advocate use of IVIG if suspicion for GALD. If workup (lip biopsy and/or MRI) confirms GALD then exchange transfusion and repeat IVIG is recommended.
My take: This reference should be helpful when managing a neonate with severe liver disease.
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Set from the Musical “Beautiful”
A previous post discusses gestational alloimmune liver disease (GALD) (The more you know the more you see) and provides a number of references. Additional insight into GALD comes from a recent case report (Pediatrics 2012; 129: e1076-79).
In this report, ascites is recognized in utero at 29 weeks. This ascites was determined to be due to compression of the vena cava by hypertrophy of the hepatic caudate lobe. When the patient was delivered at 34 weeks gestation, additional testing revealed normal coagulation parameters, peak ferritin level of 750 ng/ml at day 19, and a nodular liver on ultrasonography. The patient underwent a liver biopsy via minilaparotomy which confirmed cirrhosis but did not show evidence of iron overload. Tests for a multitude of other liver diseases were negative. Liver biopsy stains demonstrated C5b-9 complex in >95% of hepatocytes after treatment with monoclonal antibody. The detection of a high level of C5b-9 neoantigen is highly specific for GALD. Clinically, the patient had spontaneous recovery.
Take home points:
1. While iron overload is a hallmark of GALD, it is likely a consequence and not a cause of this severe liver disease.
2. Identifying atypical GALD cases allows the institution of immunotherapy during future pregnancies which reduces the recurrence risk.
3. The phenotypic spectrum of GALD includes the following:
- Neonatal liver failure with iron overload
- Fetal liver failure and/or death with or without iron overload
- Liver cirrhosis and mild neonatal liver disease without iron overload. These patients likely require special stains (call Peter Whittington for these patients)
And the more you see, the more you know. Case in point: gestational alloimmune liver disease (GALD), also referred to as congenital alloimmune hepatitis (CAH) which itself is often referred to as neonatal hemochromatosis (NH). Now, GALD is more readily identifiable and has better treatments to prevent progression to liver-related complications. A recent study (J Pediatr 2011; 159: 612-16) shows that GALD can result in fetal death; this finding is a relatively logical extension from the work in this area over the last decade but would not have been feasible without the prior recognition that most cases of neonatal hemochromatosis stem from GALD.
GALD is mediated by fetal complement via activation of the terminal complement cascade. The presence of C5b-9 complex, an antigen that is part of this cascade, is unique to cases of NH and allows diagnosis, particularly in case in which extrahepatic siderosis is not present. In the reference above, a retrospective study enabled autopsies of six stillborn fetuses and two extreme premature infants who had family histories compatible with NH (along with appropriate controls); the autopsy cases were identified as having GALD– based on liver immunostains with C5b-9 complex. The implications of this study for pediatricians:
- When faced with a newborn with coagulopathy or liver failure with family history of stillbirth, consider linking the events immediately & evaluate for NH. However, this clue has limited utility as NH is the most frequent reason for liver failure in newborns; though, many newborns with liver failure are often treated for sepsis prior to consideration of NH.
- Establishing a proper diagnosis, allows management of subsequent pregnancies. GALD is extremely likely to recur in subsequent pregnancies & can be treated by administration of IVIG to expectant at-risk mothers.
- -J Pediatr 2011; 159: 813. Study of ALF in young infants. 38% were indeterminate, ~14% NH, 12% herpes. n=148. 60% survived w/o OLT, 24% died, 16% OLT
- -Hepatology 2010; 51: 2061 (edit 1888). Fetal hepatocyte injury involves terminal complement cascade –very good article from Whittington et al. NH being renamed ‘congenital alloimmune hepatitis’
- -J Pediatr 2009; 155: 566-71. n=16. 75% with good outcome –Rx’d with IVIG (1gm/kg) and exchange transfusion (7 had double volume ET and 6 had less). Appeared to reduce need for liver transplant. Some response with regard to hypoglycemia was fairly quick but most parameters like coagulopathy improved slowly ~2 weeks. Previous historical survival ~36%. (5 of 10 w transplant and 2 of 9 w/o transplant).
- -Pediatrics 2008; 121: e1615. Weekly IVIG during pregnancy after 18th week of gestation very effective in preventing severe NH
- -Hepatology 2006; 43: 654. Review by Whitington. MRI detects disease in ~90%. Mucosal biopsy abnl in about 2/3rds of patients. Explains iron homeostasis and alloimmunity.
- -Liver Tx 2005; 11: 1323 (ed), 1417. Medical treatment ineffective, try transplant. “All who drink of this remedy recover in a short time except those whom it does not help, who all die. It is obvious, therefore, that it fails only in incurable cases.” –Galen, circa 100AD
- -JPGN 2005; 40: 544. NH is probably an alloimmune dz.
- -Lancet 2004; 364: 1690-8.