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  • 1. Neonatal liver failure: a genetic and metabolic perspectiveMargarita Sifuentes Saenz, Johan Van Hove and Gunter ScharerDivision of Clinical Genetics and Metabolism, Liver failure in newborns can present formidable diagnostic challenges. TheDepartment of Pediatrics, University of ColoradoDenver, 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 neonatalCorrespondence to Margarita Sifuentes Saenz, 13121E. 17th Ave, Mail Stop 8400, Ed2S, Aurora, CO 80045, hemochromatosis, review genetic and metabolic causes of neonatal liver failure, andUSA outline an updated differential diagnosis of neonatal liver failure. In addition, we proposeTel: +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 evaluationIntroduction revealed direct hyperbilirubinemia, and prolongedNeonatal 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, disseminatedmia, coagulopathy, jaundice, cholestasis, and/or poor intravascular coagulopathy (DIC) was noted, withfeeding. Initial assessment is crucial for the timely identi- increased PT, decreased fibrinogen, increased D-dimersfication of treatable conditions, such as tyrosinemia, and low platelets, along with elevated transaminases andgalactosemia, fatty acid oxidation defects, and fructose oliguria. However, the patient began to feed vigorouslymetabolism abnormalities, since identification of these and i.v. glucose infusion was discontinued.disorders may lead to clinical improvement if treatment isinitiated 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 ofNeonatal 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 urinegroup [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 patientborn 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. Anmany are born premature [1,3,4,6,9–12]. Untreated, neo- abdominal magnetic resonance imaging (MRI) did notnatal 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 underlyingThe patient was a term male with birth weight appro- cause. A double volume exchange was performed on thepriate for gestational age, born after an uncomplicated following day with the objective of removing maternalpregnancy via vaginal delivery at 39 weeks gestation. On alloantibodies, followed by intravenous immunoglobulinday of life 2, the infant was noted to have lethargy, poor (IVIG) administration.Alimentumwas the primary formulaoral intake, hypoglycemia (<5 mg/dl), and hypothermia. for the first 6 months of life and by 9 months of age there wasIntravenous (i.v.) antibiotics and i.v. glucose at 3.6 mg/kg/ clinical resolution of liver damage, as supported by clinicalmin 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.0b013e328336ebe1Copyright © 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 complexCopyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
  • 3. Neonatal liver failure a genetic and metabolic perspective Saenz et al. 243Table 3 Diagnostic tests to consider in neonatal liver failure [3,5,13,17,20,24–27]Test Condition(s) identifiedA. 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 pathologyB. 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 defectsCSF, cerebrospinal fluid; DFA, direct fluorescent antibody; NH, neonatal hemochromatosis; PCR, polymerase chain reaction; TIBC, total iron bindingcapacity.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 saturationneonatal liver failure can have alpha-fetoprotein levels can also be observed in other conditions, such as chronicas 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 theand 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. Thedysgenesis [31,32]). Increased saturation of iron binding hallmark of neonatal hemochromatosis is extrahepaticcapacity (>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. 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