This document discusses a case of neonatal liver failure that was ultimately diagnosed as neonatal hemochromatosis. It provides background on neonatal liver failure and outlines the diagnostic challenges. It describes the patient's presentation and initial workup. Additional testing revealed elevated ferritin and iron saturation levels suggestive of hemochromatosis, though initial MRI and liver biopsy were negative. Confirmation came from a salivary gland biopsy showing iron deposits. The discussion reviews genetic and metabolic causes of neonatal liver failure and highlights the difficulty in diagnosis given tests may not be fully sensitive or specific.

1. Neonatal liver failure: a genetic and metabolic perspective
Margarita Sifuentes Saenz, Johan Van Hove and Gunter Scharer
Division of Clinical Genetics and Metabolism, Liver failure in newborns can present formidable diagnostic challenges. The
Department of Pediatrics, University of Colorado
Denver, Colorado, USA presentation of neonatal liver failure is variable and the initial assessment is crucial in the
determination of potentially treatable causes. We present a case of neonatal
Correspondence to Margarita Sifuentes Saenz, 13121
E. 17th Ave, Mail Stop 8400, Ed2S, Aurora, CO 80045, hemochromatosis, review genetic and metabolic causes of neonatal liver failure, and
USA outline an updated differential diagnosis of neonatal liver failure. In addition, we propose
Tel: +1 303 724 2339;
e-mail: saenz.margarita@tchden.org a comprehensive initial work-up of neonatal liver failure, and review current treatments
for neonatal hemochromatosis.
Current Opinion in Pediatrics 2010, 22:241–245
Keywords
neonatal cholestasis, neonatal hemochromatosis, neonatal hypoglycemia, neonatal
liver failure
Curr Opin Pediatr 22:241–245
ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins
1040-8703
suggestive of an infectious cause. Further evaluation
Introduction revealed direct hyperbilirubinemia, and prolonged
Neonatal liver failure is an acute clinical circumstance prothrombin time (PT), indicating liver dysfunction.
that presents diagnostic challenges. The presentation is Echocardiogram and head, abdominal, and renal ultra-
variable, but symptoms commonly include: hypoglyce- sounds were all normal. On day of life 4, disseminated
mia, coagulopathy, jaundice, cholestasis, and/or poor intravascular coagulopathy (DIC) was noted, with
feeding. Initial assessment is crucial for the timely identi- increased PT, decreased fibrinogen, increased D-dimers
fication of treatable conditions, such as tyrosinemia, and low platelets, along with elevated transaminases and
galactosemia, fatty acid oxidation defects, and fructose oliguria. However, the patient began to feed vigorously
metabolism abnormalities, since identification of these and i.v. glucose infusion was discontinued.
disorders may lead to clinical improvement if treatment is
initiated quickly in the face of fulminant liver failure On day of life 11, hypoglycemia returned. Lactate, cortisol,
[1,2]. Furthermore, the consideration for a liver transplant growth hormone, and thyroid function tests were normal.
may be altered in some metabolic disorders [3–5]. Review of newborn screening results by tandem mass
spectrometry showed only nondiagnostic elevations of
Neonatal hemochromatosis is among the most common C16 and C18 : 1 long chain acylcarnitines, prompting car-
causes of acute liver failure (ALF) in the neonatal age nitine supplementation. Further testing of serum and urine
group [3,6–8], but is not easily confirmed by standard were consistent with liver dysfunction (elevated 4-hydro-
biochemical, hematologic, or genetic tests. Neonatal xyphenyllactate, 4-hydroxyphenylpyruvate, methionine,
hemochromatosis is a severe multiorgan disease of peri- and tyrosine), with marked increases in alpha-fetoprotein.
natal onset [6,9] associated with extrahepatic siderosis (in Serum ferritin was 3068 ng/dl (ref 22–151), and iron satur-
thyroid, pancreas, heart, salivary glands) [3]. Most live- ation was 95% (ref 20–55%). On day of life 17, the patient
born patients exhibit evidence of in-utero insult (intra- was treated with desferrioxamine over 3 days. Selenium,
uterine growth retardation and oligohydramnios) and vitamin E, and N-acetylcysteine were also initiated. An
many are born premature [1,3,4,6,9–12]. Untreated, neo- abdominal magnetic resonance imaging (MRI) did not
natal hemochromatosis is often fatal [9,13]. show evidence of hepatic iron accumulation and liver
biopsy staining for iron was negative. On day of life 21, a
salivary gland biopsy confirmed scattered, rare iron depos-
Case report its, and thus neonatal hemochromatosis as the underlying
The patient was a term male with birth weight appro- cause. A double volume exchange was performed on the
priate for gestational age, born after an uncomplicated following day with the objective of removing maternal
pregnancy via vaginal delivery at 39 weeks gestation. On alloantibodies, followed by intravenous immunoglobulin
day of life 2, the infant was noted to have lethargy, poor (IVIG) administration.Alimentumwas the primary formula
oral intake, hypoglycemia (<5 mg/dl), and hypothermia. for the first 6 months of life and by 9 months of age there was
Intravenous (i.v.) antibiotics and i.v. glucose at 3.6 mg/kg/ clinical resolution of liver damage, as supported by clinical
min were initiated. Postnatal laboratory studies were not presentation and laboratory studies.
1040-8703 ß 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MOP.0b013e328336ebe1
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

2. 242 Case report
A review of the patient’s pedigree did not reveal a history Table 2 Differential diagnosis of nongenetic causes of neonatal
of similar problems in the extended family. Maternal liver failure [2–4,6,22,23]
obstetric history was not suggestive of neonatal hemo- Infectious
Hepatitis A, B, C
chromatosis; no previous pregnancies were reported with HSV types 1 and 2
neonatal liver failure. HHV 6, 7, 8
CMV
Enterovirus
Parvovirus
Discussion Syphilis
High mortality rates in neonatal liver failure have Rubella
prompted clinicians and researchers to re-evaluate diag- Toxoplasmosis
Coxsackie
nostic approaches to the potential causes and available Adenovirus
treatment modalities. Apart from the large group of Bacterial
infections, trauma, malignancies, and hematologic dis- HIV
Tumor
orders, an increasing number of genetic and metabolic Thalassemia, particularly alpha
causes can be associated with neonatal liver failure. In Endocrine abnormalities – panhypopituitary,
addition, endocrine dysfunction and immunologic dis- hypocortisolism, growth hormone deficiency
Hypoxic ischemic injury, includes trauma
orders need to be considered, as well as a number of still Drug exposure
unidentified causes. Tables 1 and 2 highlight the differ- Hemophagocytic lymphohistiocytosis
ential diagnosis of a newborn with acute liver failure. Unknown
Table 3 provides an approach to evaluation of an infant
with liver failure. suspicion for neonatal hemochromatosis [3,6], but only
prolonged pursuit of additional studies enabled confir-
In the case presented here, the impaired hepatic syn- mation of the correct diagnosis by pathology exam of
thetic function with increased alpha-fetoprotein, elev- salivary gland tissue [24,25]. There was delay in the
ated ferritin, and iron binding capacity saturation raised initiation of treatment, which could be explained by
the patient’s unique phenotype – lacking a history of
Table 1 Differential diagnosis of genetic/metabolic causes of prematurity or intrauterine growth retardation and the
neonatal liver failure [6,14–21] normal abdominal MRI and liver biopsy findings. There-
Carbohydrate disorders fore, the diagnostic work-up focused initially on common
Galactosemia infectious and rarer metabolic causes. This case illus-
Fructose-1,6-bisphosphatase deficiency trates the difficulty in reaching a definite diagnosis
Hereditary fructose intolerance
Congenital disorder of glycosylation type Ib with diarrhea, Ia, Ik because the confirmatory tests (MRI of the abdomen,
Glycogen storage disease type IV and IX liver biopsy, and salivary gland biopsy) do not have
Transaldolase deficiency complete sensitivity and specificity.
Amino acid disorders
Tyrosinemia
Urea cycle defects Increased ferritin is not specific for neonatal hemochro-
Citrin defect matosis in the setting of neonatal liver failure [3,11,30],
S-adenosylhomocysteine-hydrolase deficiency
Fatty acid oxidation disorders with a number of disorders characterized by iron over-
Long-chain 3-hydroxy-acyl-CoA dehydrogenase deficiency load. In particular, familial hemophagocytic lymphohis-
Multiple acyl-CoA dehydrogenase deficiency tiocytosis (FHLH) is clinically indistinguishable from
Carnitine-palmitoyl-transferase I and II deficiency
Carnitine-acylcarnitine translocase deficiency neonatal hemochromatosis. The mimicking stems from
Energy metabolism disorders profound hypoglycemia, hepatosplenomegaly, coagulo-
Mitochondrial DNA depletion, including deoxyguanosine kinase pathy, and marked hyperferritinemia. However, dis-
deficiency (DGUOK) respiratory chain defects
GRACILE syndromea tinguishing features are found in pathologic specimens;
TRMU (tRNA 5-methylaminomethyl-2-thiouridylate FHLH does not have iron accumulation in extrahepatic
methyltransferase) or hepatic tissues, alpha-fetoprotein is normal in FHLH,
EFG1 (mitochondrial elongation factor G1)
Other and meningeal lymphohistiocytic infiltrate, if present,
Bile acid synthesis defect with cholestasis; specifically is characteristic [22]. GRACILE (growth retardation,
D4-3-oxosteroid-5D-reductase aminoaciduria, cholestasis, iron overload, lactacidosis,
Mevalonic aciduria
Peroxisomal biogenesis disorders and early death) syndrome is a recessively inherited
Neonatal hemochromatosis lethal disease characterized by fetal growth retardation,
Niemann–Pick disease type C lactic acidosis, aminoaciduria, cholestasis, and abnormal-
Wolman
Alpha1antitrypsin deficiency ities in iron metabolism. The molecular bases for GRA-
Cerebrotendinous xanthomatosis CILE syndrome are mutations in BCS1L, a mitochondrial
a
Growth retardation, aminoaciduria, cholestasis, iron overload, lactaci- inner membrane protein, and a chaperone necessary for
dosis, and early death. the assembly of mitochondrial respiratory chain complex
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

3. Neonatal liver failure a genetic and metabolic perspective Saenz et al. 243
Table 3 Diagnostic tests to consider in neonatal liver failure [3,5,13,17,20,24–27]
Test Condition(s) identified
A. First tier screen
A.1) General serum/urine studies
Comprehensive metabolic panel Metabolic acidosis, hepatocellular damage
Complete blood count Anemia, infection, coagulopathy
Urine analysis Ketosis, infection, hydration status
Ammonia Urea cycle defects, liver failure
Lactate Mitochondrial[28], perfusion abnormalities
Coagulation panel Liver failure (synthetic function)
Ferritin NH, FHLH, GRACILE significantly elevated
TIBC and iron saturation NH, elevated
A.1) Infectious screen
HSV PCR Herpes simplex viral infection[29]
Nasal swab with DFA Viral infections
Enterovirus PCR and culture Enterovirus infection
Hepatitis B Hepatitis B infection
Blood culture Bacteremia
Urine culture Urinary tract infection
CSF cell count, culture Infection
HIV Human immunodeficiency virus
infection
A.2) Follow-up level 2 (if tier 1 test results raise suspicion for NH)
Imaging studies:
Abdominal MRI NH, þ/À iron deposits
A.3) Follow-up level 3 (if tier 1 test suggestive of NH and tier 2 is inconclusive)
Biopsy:
Salivary gland biopsy NH, iron deposits
Liver biopsy NH, iron deposits, various pathology
B. Second Tier (if A.1 screen is negative)
B.1) Specific biochemical screen/studiesa
Serum amino acids Aminoacidopathies
Acylcarnitine profile Fatty acid oxidation defects
Galactose-1-phosphate Galactosemia
Urine reducing substances Galactosemia, hereditary fructose
intolerance
Transferrin glycosylation analysis Congenital disorders of glycosylation
Alpha-fetoprotein Tyrosinemia I, NH, DGUOK
Succinylacetone Tyrosinemia type I
Urine polyols Transaldolase deficiency
Urine bile acids Defect in bile acid synthesis
Very long chain fatty acids Zellweger
Liver aldolase (biopsy req) Hereditary fructose intolerance
Serum alpha-1-antitrypsin Alpha-1-antitrypsin deficiencya
Urine orotic acid Ornithine transcarbamylase deficiency
B.2) Follow-up level 2, (if biochemical screen is negative)
Biopsy:
Skin biopsy Niemann–Pick C, Glycogen storage disease
Muscle biopsy Respiratory chain dysfunction
B.3) Follow-up level 3,
Genetic studies:
DNA testing Mitochondrial DNA depletion, single
gene defects
CSF, cerebrospinal fluid; DFA, direct fluorescent antibody; NH, neonatal hemochromatosis; PCR, polymerase chain reaction; TIBC, total iron binding
capacity.
a
Molecular or enzymatic confirmatory testing may be necessary, as is the case with the majority of genetic conditions.
III [30]. Other respiratory chain disorders causing early [11]. However, increased iron-binding capacity saturation
neonatal liver failure can have alpha-fetoprotein levels can also be observed in other conditions, such as chronic
as high as those seen in deoxyguanosine kinase deficiency hemolysis and repeated transfusions.
mutations in the DGUOK gene. Transaldolase defici-
ency has been described with liver fibrosis/cirrhosis Magnetic resonance imaging of the abdomen is one of the
and evidence of early fetal involvement in some patients most useful diagnostic tools [29,33], but hepatic siderosis is
(intrauterine growth restriction, oligohydramnios, renal not always present [9], as demonstrated in our patient. The
dysgenesis [31,32]). Increased saturation of iron binding hallmark of neonatal hemochromatosis is extrahepatic
capacity (>80%) is considered a more specific indicator siderosis with sparing of the reticuloendothelial system.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

4. 244 Case report
Therefore, in the face of severe coagulopathy, salivary monary circulatory overload, whereas desferrioxamine
gland biopsy is a safer alternative to a liver biopsy [24,26]. increases the risk for infection [9,10,34]. Antioxidant
However, the interpretation of results warrants caution, as therapy has included selenium, N-acetylcysteine and a-
salivary gland siderosis has also been documented in other tocopherol, polyethylene glycol succinate [6,10,22,36].
unrelated conditions such as tyrosinemia, parvovirus B19 Results have been mixed, with few reports of survivors
and rubella infection, renal–hepatic–pancreatic cystic with medical treatment only [1,11]. Liver transplantation
dysplasia, and a-thalassemia. The latter diagnoses are has been successful as the definitive management in a
often supported or ruled out by other clinical and labora- portion of survivors [3,9].
tory evidence [13].
The genetics of neonatal hemochromatosis is currently Conclusion
unknown and not linked to the adult-onset forms (i.e. Caution must be exercised in laboratory interpretation of
mutations in the HFE gene) [6,8,11,28] or juvenile forms hepatic dysfunction in neonates [14]. The atypical pres-
of hemochromatosis. Still, there is the possibility of entation of neonatal hemochromatosis presented here
marked variability in penetrance of a dominant gene that highlights the necessity of including abdominal MRI,
has yet to be identified [9]. However, the greater than serum ferritin, and salivary gland biopsy early in the
fifty percent recurrence [3], no affected parents of neo- diagnostic evaluation of neonatal liver failure. Long-term
natal hemochromatosis patients, no aunts or uncles of follow-up is required in this case but highlights a positive
neonatal hemochromatosis patients with affected off- outcome in a condition with typically poor prognosis. We
spring, and fathers of neonatal hemochromatosis patients recommend case by case consideration, with our recom-
who have not had recurrence with new partners all defy a mendations as a guide to metabolic and genetic consider-
dominant inheritance. It has also been documented that ations.
women with multiple affected children have had differ-
ent partners for those patients [6,10,11]. There is no clear
sex predilection or an increased rate of neonatal hemo- References
chromatosis in any particular ethnicity. Other potential
1 Ekong UD, Melin-Aldana H, Whitington PF. Regression of severe fibrotic liver
genetic causes include gonadal mosaicism for new and disease in 2 children with neonatal hemochromatosis. J Pediatr Gastroenterol
dominant mutations that are lethal in spermatogenesis Nutr 2008; 46:329–333.
only [13], mitochondrial DNA mutations, or maternal 2 Vohra P, Haller C, Emre S, et al. Neonatal hemochromatosis: the importance
of early recognition of liver failure. J Pediatr 2000; 136:537–541.
transmission of an imprinted gene.
3 Rodrigues F, Kallas M, Nash R, et al. Neonatal hemochromatosis -medical
treatment vs. transplantation: the King’s experience. Liver Transplant 2005;
The theory of alloimmunity as cause for neonatal hemo- 11:1417–1424.
chromatosis has been recurrent in the scientific literature 4 Whitington PF, Kelly S, Ekong UE. Neonatal hemochromatosis: fetal liver
disease leading to liver failure in the fetus and newborn. Pediatr Transplant
[7,10]. An alloimmune process requires exposure of a fetal 2005; 9:640–645.
antigen at some point in the pregnancy, with no maternal 5 Sigurdsson L, Reyes J, Kocoshis S, et al. Neonatal hemochromatosis: out-
‘self’-recognition [28]. On the basis of this hypothesis, comes of pharmacologic and surgical therapies. J Pediatr Gastroenterol Nutr
1998; 26:85–89.
maternal treatment for neonatal hemochromatosis with
6 Boyd RL, Bahtia J, Clark JH. Neonatal hemochromatosis. Emedicine 2008;
IVIG beginning at 18 weeks gestation was started [3,6– 1–15.
9,28,34]. Clinical outcomes after IVIG infusions are 7 Brodsky D. Intrauterine Immunoglobulin in the prevention of neonatal hemo-
improved, as reflected in decreased severity of disease chromatosis. NeoReviews 2008; 9:e218–e222.
and improved survival rate. Recurrence in subsequent 8 Marron-Corwin MJ, Ford E. Index of suspicion. NeoReviews 2006; 7:e627–
e629.
pregnancies, however, is not decreased [12]. This success- 9 Grabhorn E, Richter A, Burdelski M. Neonatal hemochromatosis: long-term
ful effect has provided further evidence for the alloim- experience with favorable outcome. Pediatr 2006; 118:2060–2065.
mune theory. 10 Ekong UD, Kelly S, Whitington P. Disparate clinical presentation of neonatal
hemochromatosis in twins. Pediatr 2005; 116:e880–e884.
11 Whitington PF. Fetal and infantile hemochromatosis. Hepatol 2006; 43:654–
Neonatal hemochromatosis is often a fatal condition, if left 660.
untreated. However, there is little consensus on the most 12 Whitington PF, Malladi P. Neonatal hemochromatosis: is it an alloimmune
effective treatment and there are few studies that review disease? J Pediatr Gastroenterol Nutr 2005; 40:544–549.
long-term outcome in patients not treated with liver trans- 13 Murray K, Kowdley KV. Neonatal hemochromatosis. Pediatr 2001; 108:960–
964.
plantation [10]. Therapeutic options include iron chela-
14 Shneider BL. Neonatal liver failure. Curr Opin Pediatr 1996; 8:495–501.
tion, supportive therapy with antioxidants, postnatal
15 van der Meer SB, Janssen A, Bakker JA, et al. Neonatal liver failure with
exchange transfusion, IVIG therapy [35], and liver trans- micronodular cirrhosis due to mitochondrial disease. J Inherit Metab Dis
plantation [3,4,11,34]. Iron chelation has been performed 2002; 25 (suppl 1):88.
with desferrioxamine and prostaglandin E1. However, 16 Fernandes J, Saudubray JM, Van den Berghe G, et al. Clinical approach to
inherited metabolic diseases. In: Ferandes J, Saudubray J-M, van den Berghe G,
prostaglandin administration poses a risk in the neonate Walter JH, editors. Inborn metabolic diseases, 4th ed. Heidelberg: Springer
for persistent patent ductus arteriosus and resultant pul- Medizin Verlag; 2006. pp. 7–13 and 44.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

5. Neonatal liver failure a genetic and metabolic perspective Saenz et al. 245
17 Wong L-J, Brunetti-Pierri N, Zhang Q, et al. Mutations in the MPV17 gene are 27 Mclean P, Davison S. Neonatal liver failure. Semin Neonatol 2003; 8:393–
responsible for rapidly progressive liver failure in infancy. Hepatol 2007; 401.
46:1218–1227.
28 Whitington PF, Hibbard JU. High-dose immunoglobulin during pregnancy
18 Ueki I, Kimura A, Chen H-L, et al. SRD5B1 gene analysis needed for the for recurrent neonatal hemochromatosis. Lancet 2004; 364:1690–
accurate diagnosis of primary 3-oxo-D 4-steroid 5 b-reductase deficiency. 1698.
J Gastroenterol Hepatol 2009; 24:776–785.
29 Udell IW, Barshes NR, Voloyiannis T, et al. Neonatal hemochromatosis:
19 Siafakas CG, Jonas MM, Perez-Atayde AR. Abnormal bile acid metabolism radiological and histological signs. Liver Transplant 2005; 11:998–1000.
and neonatal hemochromatosis: a subset with poor prognosis. J Pediatr ¨¨
30 Visapaa I, Fellman V, Vesa J, et al. GRACILE syndrome, a lethal metabolic
Gastroenterol Nutr 1997; 25:321–326.
disorder with iron overload, is caused by a point mutation in BCS1L. Am J
20 Zeharia A, Shaag A, Pappo O, et al. Acute infantile liver failure due to Hum Genet 2002; 71:863–876.
mutations in the TRMU gene. Am J Hum Genet 2009; 85:401–407.
31 Wamelink MMC, Struys EA, Valayannopoulos V, et al. Retrospective detec-
21 Rutledge JC. Progressive neonatal liver failure due to type C Niemann Pick tion of transaldolase deficiency in amniotic fluid: implications for prenatal
disease. Pediatr Pathol 1989; 9:779–784. diagnosis. Prenat Diagn 2008; 28:460–462.
22 Al-Jasmi F, Abdelhaleem M, Stockley T, et al. Novel mutation of the perforin 32 Sundaram SS, Bove KE, Lovell MA, et al. Mechanisms of disease: inborn
gene and maternal uniparental disomy 10 in a patient with familial hemopha- errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol 2008;
gocytic lymphohistiocytosis. J Pediatr Hematol Oncol 2008; 30:621–624. 5:456–468.
23 Verma A, Dhawan A, Zuckerman M, et al. Neonatal herpes simplex virus 33 Hayes AM, Jaramillo D, Levy HL, et al. Neonatal hemochromatosis: diagnosis
infection presenting as acute liver failure: prevalent role of herpes simplex with MR imaging. Am J Radiol 1992; 159:623–625.
virus type I. J Pediatr Gastroenterol Nutr 2006; 42:282–286.
34 Leonis M, Balistreri W. Neonatal hemochromatosis: it’s OK to say ‘NO’ to
24 Smith SR, Shneider BL, Magid M. Minor salivary gland biopsy in neonatal antioxidant-chelator therapy. Liver Transplant 2005; 11:1323–1325.
hemochromatosis. Arch Otolaryngol Head Neck Surg 2004; 130:760–763.
35 Silas R, Sharma A, Veldman A. Neonatal liver failure: how many cases of
25 Lee WS, Mckiernan PJ, Kelly DA. Serum ferritin level in neonatal fulminant liver neonatal hemochromatosis have you missed? J Paediatr Child Health 2009;
failure. Arch Dis Child Fetal Neonatal Ed 2001; 85:F226. 45:s1; A111.
26 Chan KC, Edelman M, Fantasia JE. Labial salivary gland involvement in 36 Flynn DM, Mohan N, McKiernan P, et al. Progress in treatment and outcome
neonatal hemochromatosis: a report of 2 cases and review of literature. Oral for children with neonatal hemochromatosis. Arch Dis Child Fetal Neonatal Ed
Surg Oral Med Oral Pathol Oral Radiol Endod 2008; 106:e27–e30. 2003; 88:124–127.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.