Perinatal/Neonatal Case Presentation &&&&&&&&&&&&&& Idiopathic Neonatal Giant Cell Presenting With Acute Hepatic Failure on Postnatal Day One

Kimberley K. Correa, BS presented in the first postnatal day (PND) with fulminant hepatic Prathiba Nanjundiah, MD failure. David D. Wirtschafter, MD Najeeb S. Alshak, MD CASE REPORT A 2.83-kg term black male was born by normal spontaneous vaginal delivery to a 34-year-old, gravida 4, para 2, TAB 1 woman We report a term male infant presenting on postnatal day 1 with fulminant with A-positive blood type. The mother was RPR-negative, hepatitis hepatic failure. Described congenital infection, metabolic disorders, and B surface antigen-negative, HIV-negative, chlamydia-negative, cardiovascular etiologies of acute neonatal failure were assessed and gonorrhea-negative, and rubella-immune. During pregnancy, the eliminated. A liver biopsy on postnatal day 10 showed neonatal giant cell mother had two gynecological cytology exams, both within normal hepatitis (NGCH) with an unusual degree of fibrosis for this early postnatal limits. The infant presented with 3+ thick meconium; the APGAR age. NGCH is a clinical diagnosis of cholestatic disorders of unknown scores were 8 and 9 at 1 and 5 minutes, respectively. Physical etiology in the newborn, and, to our knowledge, has not been previously examination at birth was normal. At 5 hours of life, the infant had associated with immediate neonatal hepatic failure. The giant cell blood glucose of 24 mg/dl by chemstrip, which improved to 55 mg/ transformation is a common response to a variety of insults and only rarely dl following feeding. Before assessing bilirubin results, the infant occurs beyond the neonatal period. Most cases present with cholestatic was circumcised without complications. There was no significant and varying degrees of coagulopathy, and, many, as in this case, family history of perinatal deaths or liver disease. show progressive resolution. At 30 hours of life, the infant was noted to have scleral icterus. Journal of Perinatology (2002) 22, 249 – 251 DOI: 10.1038/sj/jp/7210670 Total and direct bilirubin was 26.6 and 15.1 mg/dl, respectively, and on repeat were 25.5 and 14.5 mg/dl. The infant was admitted to the neonatal intensive care unit (NICU) for a work-up of direct hyperbilirubinemia. Other than jaundice, the physical examination INTRODUCTION was normal. There was no evidence of hepatosplenomegaly, petechial Neonatal giant cell hepatitis (NGCH) and idiopathic neonatal lesions or mucosal bleeding. Initial laboratory studies indicated a white blood cell count of hepatitis (INH), are used synonymously as a clinical diagnosis of 3 3 infant cholestatic disorders of unknown etiology. Patients usually 15.1Â10 /mm , with 66% neutrophils, 26% lymphocytes, 8% present with cholestatic jaundice, dark urine, light or acholic monocytes, and 8 nucleated red blood cells. The patient’s blood type stools, and hepatomegaly. The degree of hepatic synthetic was O positive, and the direct Coombs test was negative. The hematocrit was 64.7%, hemoglobin was 22.5 g/dl, and platelet count dysfunction is variable, manifesting in varying degrees of 3 3 coagulopathy. NGCH is differentiated from other cholestatic was 103Â10 /mm . etiologies by liver biopsy. Formation of giant hepatocytes appears Coagulation studies were found to be significantly abnormal. The to be a common response to a variety of insults to the infant infant consistently had prolonged prothrombin (PT), elevated INR liver, but it is rarely seen beyond the neonatal period. We report and partial thromboplastin (PTT) times. PT at 40 hours of life was on an infant, diagnosed with NGCH by liver biopsy, who 22.5 seconds (normal 13 to 20 seconds), INR was 2.3 (normal 0.8 to 1.2) and PTT was 47 seconds (normal 30 to 45 seconds). The D- dimer assay for disseminated intravascular coagulation (DIC) was University of California ( K.K.C., D.D.W. ), Los Angeles, CA, USA; Department of / negative. ( P.N. ), Kaiser Permanente Medical Center, Los Angeles, CA, USA; University of Southern California ( P.N. ), Los Angeles, CA, USA; Department of Pediatrics / The work-up for anatomical, infectious, and metabolic causes of ( D.D.W. ), Kaiser Permanente Medical Center, Los Angeles, CA, USA; and Department of direct hyperbilirubinemia showed the following: Liver enzymes were and Laboratory ( N.S.A. ), Kaiser Permanente Medical Center, Los Angeles, CA, USA. elevated; alkaline phosphatase was 854 U/l (normal <420 U/l), Address correspondence and reprint requests to David D. Wirtschafter, MD, Department of ALT was 124 U/l (normal 5 to 35 U/l), and AST was 281 U/l Pediatrics / Neonatology, Southern California Permanente Medical Group, 4867 Sunset Boulevard, Los Angeles, CA 90027, USA. (normal 10 to 40 U/l). The blood ammonia level was 180 mol/l

Journal of Perinatology 2002; 22:249 – 251 # 2002 Nature Publishing Group All rights reserved. 0743-8346/02 $25 www.nature.com/jp 249 Correa et al. Neonatal Giant Cell Hepatitis and Fulminant Hepatic Failure

(normal 100 to 200 mol/l). These enzymes remained elevated throughout the hospital stay. Serum alpha-fetoprotein was 284,000 ng/ml (seven times SD>mean). Ferritin levels were elevated on PND 5 (1191 ng/ml), PND 6 (2491 ng/ml), and PND 7 (1926 ng/ml) (normal 10 to 300 ng/ml). Transferrin was 158 mg/dl (normal 171 to 302 mg/dl). Serum TIBC was 188 g/dl (normal 250 to 420 g/dl). An abdominal ultrasound on PND 3 did not show either a choledochal cyst or biliary dilatation. An abdominal and chest MRI on PND 3 had no significant findings, including no T2-weighted findings indicative of neonatal hemochromatosis. The infant was assessed for congenital infectious etiologies of acute hepatic failure. Antibiotics were administered for 2 days Figure 2. Portal and parenchymal fibrosis of mild to moderate degree pending the blood culture results (negative). Immunoglobulin (Masson’s trichrome stain, 400Â). M titer was 10.3 mg% (normal <19 mg%). Urine was negative for cytomegalovirus (CMV) and herpes simplex virus by fluorescent in situ hybridization. Opthalmology exam showed no indication of portal and parenchymal fibrosis of mild to moderate degree. See chorioretinitis. Stool for viral cultures were negative. Total serum Figures 1 and 2. protein and albumin were 5.1 g/dl (normal 6.0 to 8.0 g/dl) and The patient was discharged home on PND 14, on Progestamil 3.12 g/dl (normal 3.3 to 4.8 g/dl), respectively. Long bone survey formula, supplements of vitamins A, D, E, and K, and was negative for any signs of infection. Serology for hepatitis A, ursodeoxycholic acid. At 3 months of age, the infant’s coagulation hepatitis B, hepatitis C, and VDRL were all negative. A parvovirus B19 studies had normalized (PT -10.2 seconds, INR -1.0). Liver studies polymerase chain reaction (PCR) analysis was negative. The infant remained abnormal: alkaline phosphatase -472 U/l, ALT -136 U/l, was assessed for metabolic disorders, including , and total and direct bilirubin -2.1 mg/dl and 1.2 mg/dl, tyrosinemia, and phenylketonuria. Urine was negative for reducing respectively. A follow-up alpha-one-antitrypsin phenotype analysis, substances and organic acids. The infant was found to have amino at 4 months of age, revealed MV genotype, which is not known to be acidemia consistent with hepatic dysfunction. Phenotype analysis for associated with disease. At 5 months, the infant’s total and direct alpha-1-antitrypsin did not match the known prototypes (e.g., MM bilirubin had normalized, and the AST, ALT and PT continued to or ZZ). improve. At 8 months of age, the serum concentration of fasting bile On PND 9, the patient was treated with vitamin K and fresh frozen acids was 32.7 g/dl (normal 0 to 60.0 g/dl). Fast atom plasma infusions in preparation for liver biopsy the next day. The bombardment mass spectrometry (FAB-MS) of the urine revealed liver biopsy showed (1) NGCH with moderate inflammatory activity normal urinary bile acid excretion. At 11 months of age, physical and with moderate extramedullary hematopoiesis, (2) minimal examination of the infant revealed a soft, nondistended abdomen, increase in stainable iron by the iron stain methodology, and (3) with the liver palpable 2 cm below the costal margin and a barely palpable spleen tip. At present, the infant receives ursodeoxycholic acid and is doing well on Prosobee and solid foods. Growth and development (both motor and social) are normal, and all major milestones have been successfully achieved.

DISCUSSION Progressive jaundice, elevated serum liver enzymes, coagulopathies, and hypoglycemia characterize fulminant hepatic failure in patients of any age. Potential etiologies of acute hepatic failure in the neonate have recently been reviewed.1 Infectious etiologies include herpes simplex virus, echovirus, coxsackie virus, adenovirus, Epstein-Barr virus, hepatitis B virus, and rarely cytomegalovirus. Metabolic etiologies include galactosemia, tyrosinemia, hereditary fructose Figure 1. Giant cell transformation of hepatocytes with associated intolerance, cytochrome chain defects, Zellweger syndrome, neonatal moderate portal and parenchymal inflammation and extramedullary hemochromatosis, and alpha-one-antitrypsin deficiency. Ischemia hematopoiesis (H and E stain, 400Â). and abnormal perfusion, resulting from congenital heart disease,

250 Journal of Perinatology 2002; 22:249 – 251 Neonatal Giant Cell Hepatitis and Fulminant Hepatic Failure Correa et al.

cardiac sequelea, severe asphyxia, and myocarditis, can also cases failed to detect HPV, but did detect Epstein-herpesvirus 6 cause fulminant hepatic failure in the neonate.1 All of these described (HHV6) in 4. causes of acute hepatic failure were excluded in this infant, as was We speculate that the NGCH and fulminant hepatic failure seen in the more recently reported entity of 3-oxosteroid 5-beta-reductase this infant resulted from an infectious etiology, perhaps HPV or deficiency that produces neonatal liver failure, hemochromatosis, HHV6. The PCR test for HPV DNA could not be performed due to and a predominance of atypical bile acid metabolites on FAB-MS inadequate liver tissue in this case. We recommend that HPV, HHV6 exam of the urine.2 and CMV PCR testing of liver tissue be included in the work-up of the NGCH usually presents with cholestatic jaundice. Dark urine, neonate presenting with fulminant hepatic failure. light or acholic stools, hepatomegaly, and varying degrees of coagulopathy may also be seen. Infectious agents causing giant cell transformation include congenital infection (TORCH organ- References isms), hepatitis with hemolytic anemia, paramyxovirus (syncytial 1. Whitington PF. Fulminant hepatic failure in children. In: Suchy FJ, editor. Liver Disease in Children. St. Louis: Mosby-Year Book; 1994. pp. 180–213. giant cell hepatitis), hepatitis with rubeola infection, and hepatitis 2. Shneider BL, Setchell KDR, Whitington PF, Neilson KA, Suchy FJ. Delta-3- with HIV infection. Ductal cholestasis resulting from oxosteroid 5-beta-reductase deficiency causing neonatal liver failure and or hypoplasia, or a choledochal cyst can also cause formation of hemochromatosis. J Pediatr 1994;124:234–8. giant cells, as can metabolic diseases such as neonatal 3. Koukoulis G, Mieli-Vergani G, Portmann B. Infantile liver giant cells: hemochromatosis, alpha-one-antitrypsin deficiency, galactosemia, immunohistological study of their proliferative state and possible and Niemann-Pick disease, and inborn errors of bile acid mechanisms of formation. Pediatr Dev Pathol 1999;2:353–9. metabolism, such as 3-beta-hydroxysteroid dehydrogenase/iso- 4. Balistreri WF. Neonatal giant cell hepatitis. In: Hoofnagle JH, Goodman Z, merase or 3-oxo-steroid 5-beta-reductase deficiencies.1 editors. Liver Biopsy Interpretation for the 1990’s: Clinicopathological NGCH presenting with fulminant hepatic failure and this degree Correlations in Liver Disease. Chicago: American Association for the Study of of fibrosis early in the neonatal period, as in our case, is highly Liver Diseases; 1991. pp. 76–106. unusual. Liver biopsy distinguishes NGCH from other etiologies. 5. Nishinomiya F, Abukawa D, Takada G, Tazawa Y. Relationships between Histologically, NGCH can be identified by severe panlobular disarray clinical and histological profiles of non-familial idiopathic neonatal hepatitis. Acta Paediatr Jpn. 1996;38:242–7. due to the transformation of many or most hepatocytes to 3,4 6. Sandor T, Surinya M, Monus Z. Familial occurrence of giant cell hepatitis in multinucleated giant cells by still uncertain mechanisms. infancy. Acta Hepato-Gastroenterol (Stuttgart) 1976;23:101–4. 5,6 Sporadic and familial cases of NGCH have been described. 7. Moore L, Bourne AJ, Moore DJ, Preston H, Byard RW. Hepatocellular 7 Some have been associated later with hepatocellular carcinoma. carcinoma following neonatal hepatitis. Pediatr Pathol Lab Med. 8 Clayton et al. reported a case of familial NGCH with decreased bile 1997;17:601–10. acid synthesis that was consistent with a defect in bile acid synthesis. 8. Clayton PT, Casteels M, Mieli-Vergani G, Lawson AM. Familial giant cell Human papilloma virus (HPV) has recently been linked to NGCH. hepatitis with low bile acid concentrations and increased urinary excretion of Drut et al.9 detected the presence of HPV DNA through polymerase specific bile alcohols: a new inborn error of bile acid synthesis? Pediatr Res chain reaction (PCR) in seven of seven clinical presentations of 1995;37:424–31. NGCH, whereas liver samples from normal and CMV infected 9. Drut R, Gomez MA, Drut RM, Lojo MM. Human papillomavirus–associated were negative for HPV DNA. Patients positive for HPV DNA had all neonatal giant cell hepatitis (NGCH). Pediatr Pathol Lab Med. 1996;16: presented clinically within 72 hours of birth and were found to have 403–12. 10. Drut R, Dut RM, Gomez MA, Rua EC, Lojo MM. Presence of human elevated serum transaminases and cholestatic jaundice. A progressive, papillomavirus in extrahepatic biliary atresia. J Pediatr Gastroenterol Nutr spontaneous recovery was described in six cases. In a follow-up 1998;27:530–5. 10 study, Drut et al. found HPV DNA amplification in 16 of 18 patients 11. Domiati-Saad R, Dawson DB, Margraf LR, Finegold MJ, Weinberg AG, Rogers with extrahepatic biliary atresia (EBA). BB. Cytomegalovirus and human herpesvirus 6, but not human 11 Domiati-Saad et al. have recently challenged the hypothesized papillomavirus, are present in neonatal giant cell hepatitis and extrahepatic association between HPV and NGCH and/or EBA. PCR analyses of 19 biliary atresia. Pediatr Dev Pathol 2000;3:367–73.

Journal of Perinatology 2002; 22:249 – 251 251