We report a term male infant presenting on postnatal day 1 with fulminant hepatic failure. Described congenital infection, metabolic disorders, and cardiovascular etiologies of acute neonatal liver failure were assessed and eliminated. A liver biopsy on postnatal day 10 showed neonatal giant cell hepatitis (NGCH) with an unusual degree of fibrosis for this early postnatal age. NGCH is a clinical diagnosis of cholestatic disorders of unknown etiology in the newborn, and, to our knowledge, has not been previously associated with immediate neonatal hepatic failure. The giant cell transformation is a common response to a variety of insults and only rarely occurs beyond the neonatal period. Most cases present with cholestatic jaundice and varying degrees of coagulopathy, and, many, as in this case, show progressive resolution.
Neonatal giant cell hepatitis (NGCH) and idiopathic neonatal hepatitis (INH), are used synonymously as a clinical diagnosis of infant cholestatic disorders of unknown etiology. Patients usually present with cholestatic jaundice, dark urine, light or acholic stools, and hepatomegaly. The degree of hepatic synthetic dysfunction is variable, manifesting in varying degrees of coagulopathy. NGCH is differentiated from other cholestatic etiologies by liver biopsy. Formation of giant hepatocytes appears to be a common response to a variety of insults to the infant liver, but it is rarely seen beyond the neonatal period. We report on an infant, diagnosed with NGCH by liver biopsy, who presented in the first postnatal day (PND) with fulminant hepatic failure.
A 2.83-kg term black male infant was born by normal spontaneous vaginal delivery to a 34-year-old, gravida 4, para 2, TAB 1 woman with A-positive blood type. The mother was RPR-negative, hepatitis B surface antigen-negative, HIV-negative, chlamydia-negative, gonorrhea-negative, and rubella-immune. During pregnancy, the mother had two gynecological cytology exams, both within normal limits. The infant presented with 3+ thick meconium; the APGAR scores were 8 and 9 at 1 and 5 minutes, respectively. Physical examination at birth was normal. At 5 hours of life, the infant had blood glucose of 24 mg/dl by chemstrip, which improved to 55 mg/dl following feeding. Before assessing bilirubin results, the infant was circumcised without complications. There was no significant family history of perinatal deaths or liver disease.
At 30 hours of life, the infant was noted to have scleral icterus. 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 was normal. There was no evidence of hepatosplenomegaly, petechial lesions or mucosal bleeding.
Initial laboratory studies indicated a white blood cell count of 15.1×103/mm3, with 66% neutrophils, 26% lymphocytes, 8% monocytes, and 8 nucleated red blood cells. The patient's blood type was O positive, and the direct Coombs test was negative. The hematocrit was 64.7%, hemoglobin was 22.5 g/dl, and platelet count was 103×103/mm3.
Coagulation studies were found to be significantly abnormal. The infant consistently had prolonged prothrombin (PT), elevated INR and partial thromboplastin (PTT) times. PT at 40 hours of life was 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 negative.
The work-up for anatomical, infectious, and metabolic causes of direct hyperbilirubinemia showed the following: Liver enzymes were elevated; alkaline phosphatase was 854 U/l (normal <420 U/l), ALT was 124 U/l (normal 5 to 35 U/l), and AST was 281 U/l (normal 10 to 40 U/l). The blood ammonia level was 180 μmol/l (normal 100 to 200 μmol/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 μg/dl (normal 250 to 420 μg/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 pending the blood culture results (negative). Immunoglobulin 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 chorioretinitis. Stool for viral cultures were negative. Total serum protein and albumin were 5.1 g/dl (normal 6.0 to 8.0 g/dl) and 3.12 g/dl (normal 3.3 to 4.8 g/dl), respectively. Long bone survey was negative for any signs of infection. Serology for hepatitis A, hepatitis B, hepatitis C, and VDRL were all negative. A parvovirus B19 polymerase chain reaction (PCR) analysis was negative. The infant was assessed for metabolic disorders, including galactosemia, tyrosinemia, and phenylketonuria. Urine was negative for reducing substances and organic acids. The infant was found to have amino acidemia consistent with hepatic dysfunction. Phenotype analysis for alpha-1-antitrypsin did not match the known prototypes (e.g., MM or ZZ).
On PND 9, the patient was treated with vitamin K and fresh frozen plasma infusions in preparation for liver biopsy the next day. The liver biopsy showed (1) NGCH with moderate inflammatory activity and with moderate extramedullary hematopoiesis, (2) minimal increase in stainable iron by the iron stain methodology, and (3) portal and parenchymal fibrosis of mild to moderate degree. See Figures 1 and 2.
The patient was discharged home on PND 14, on Progestamil formula, supplements of vitamins A, D, E, and K, and ursodeoxycholic acid. At 3 months of age, the infant's coagulation studies had normalized (PT -10.2 seconds, INR -1.0). Liver studies remained abnormal: alkaline phosphatase -472 U/l, ALT -136 U/l, and total and direct bilirubin -2.1 mg/dl and 1.2mg/dl, respectively. A follow-up alpha-one-antitrypsin phenotype analysis, at 4 months of age, revealed MV genotype, which is not known to be associated with disease. At 5 months, the infant's total and direct bilirubin had normalized, and the AST, ALT and PT continued to improve. At 8 months of age, the serum concentration of fasting bile acids was 32.7 μg/dl (normal 0 to 60.0 μg/dl). Fast atom bombardment mass spectrometry (FAB-MS) of the urine revealed normal urinary bile acid excretion. At 11 months of age, physical examination of the infant revealed a soft, nondistended abdomen, 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.
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 intolerance, cytochrome chain defects, Zellweger syndrome, neonatal hemochromatosis, and alpha-one-antitrypsin deficiency. Ischemia and abnormal perfusion, resulting from congenital heart disease, cardiac surgery sequelea, severe asphyxia, and myocarditis, can also cause fulminant hepatic failure in the neonate.1 All of these described causes of acute hepatic failure were excluded in this infant, as was the more recently reported entity of 3-oxosteroid 5-beta-reductase deficiency that produces neonatal liver failure, hemochromatosis, and a predominance of atypical bile acid metabolites on FAB-MS exam of the urine.2
NGCH usually presents with cholestatic jaundice. Dark urine, light or acholic stools, hepatomegaly, and varying degrees of coagulopathy may also be seen. Infectious agents causing giant cell transformation include congenital infection (TORCH organisms), hepatitis with hemolytic anemia, paramyxovirus (syncytial giant cell hepatitis), hepatitis with rubeola infection, and hepatitis with HIV infection. Ductal cholestasis resulting from biliary atresia or hypoplasia, or a choledochal cyst can also cause formation of giant cells, as can metabolic diseases such as neonatal hemochromatosis, alpha-one-antitrypsin deficiency, galactosemia, and Niemann-Pick disease, and inborn errors of bile acid metabolism, such as 3-beta-hydroxysteroid dehydrogenase/isomerase or 3-oxo-steroid 5-beta-reductase deficiencies.1
NGCH presenting with fulminant hepatic failure and this degree of fibrosis early in the neonatal period, as in our case, is highly unusual. Liver biopsy distinguishes NGCH from other etiologies. Histologically, NGCH can be identified by severe panlobular disarray due to the transformation of many or most hepatocytes to multinucleated giant cells by still uncertain mechanisms.3,4
Sporadic and familial cases of NGCH have been described.5,6 Some have been associated later with hepatocellular carcinoma.7 Clayton et al.8 reported a case of familial NGCH with decreased bile acid synthesis that was consistent with a defect in bile acid synthesis.
Human papilloma virus (HPV) has recently been linked to NGCH. Drut et al.9 detected the presence of HPV DNA through polymerase chain reaction (PCR) in seven of seven clinical presentations of NGCH, whereas liver samples from normal and CMV infected infants were negative for HPV DNA. Patients positive for HPV DNA had all presented clinically within 72 hours of birth and were found to have elevated serum transaminases and cholestatic jaundice. A progressive, spontaneous recovery was described in six cases. In a follow-up study, Drut et al.10 found HPV DNA amplification in 16 of 18 patients with extrahepatic biliary atresia (EBA).
Domiati-Saad et al.11 have recently challenged the hypothesized association between HPV and NGCH and/or EBA. PCR analyses of 19 cases failed to detect HPV, but did detect Epstein-herpesvirus 6 (HHV6) in 4.
We speculate that the NGCH and fulminant hepatic failure seen in this infant resulted from an infectious etiology, perhaps HPV or HHV6. The PCR test for HPV DNA could not be performed due to inadequate liver tissue in this case. We recommend that HPV, HHV6 and CMV PCR testing of liver tissue be included in the work-up of the neonate presenting with fulminant hepatic failure.
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Correa, K., Nanjundiah, P., Wirtschafter, D. et al. Idiopathic Neonatal Giant Cell Hepatitis Presenting With Acute Hepatic Failure on Postnatal Day One. J Perinatol 22, 249–251 (2002). https://doi.org/10.1038/sj.jp.7210670
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