Neonatal Hepatitis

Background

This is a broad and somewhat vague term used to describe inflammation and cellular damage within the liver during the newborn period. It is characterized by an obstructive jaundice with hyperbilirubinemia that persists beyond the immediate newborn period. The chief clinical concern is to distinguish this condition from biliary atresia which is a surgical condition and correctable condition utilizing the Kasai procedure. However, for this surgery to be successful, it must be performed prior to 2 months of life.

The pathologist may oversee numerous laboratory tests which may exclude a viral or metabolic abnormality. Occasional, a liver biopsy may be obtained. The histologic findings vary with the underlying disease process.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/Immunohistochemistry/Electron Microscopy

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

SYNONYMS Giant cell hepatitis

INCIDENCE/PREVALENCE Uncommon
Familial in 20% of cases)

AGE Premature, small for gestational age infants are at risk

SEX M > F (2:1)

GEOGRAPHY

EPIDEMIOLOGIC ASSOCIATIONS

BLOOD TRANSFUSIONS

Association between neonatal blood microtransfusions in the 1960s and hepatitis C virus infection.

De Paschale M, Casiraghi MA, Biagiotti S, Rossi U, Zanetti AR

Lancet 2000 Nov 4;356(9241):1572-3 Abstract quote
In the 1960s, a common practice in Italy was to give a few mL of blood or plasma to underweight or preterm newborns.

We postulated that this practice might be the cause of hepatitis C virus (HCV) infections seen today in adults with a negative history, and no recall of such transfusions.

We examined the transfusion files of children admitted to the Department of Paediatrics during 1968-74, and found that 613 children had been transfused within the first year of life. Of 57 traceable patients, 28 are now positive for antibodies to HCV, 17 of whom received at least one microtransfusion from a common donor who is also positive.

DISEASE ASSOCIATIONS CHARACTERIZATION

AUTOIMMUNE

INFECTION Cytomegalovirus
Hepatitis virus

METABOLIC Alpha-1 antitrypsin deficiency
Galactosemia

SPECIFIC DISEASES

DOWN SYNDROME

Severe perinatal liver disease and Down syndrome: an apparent relationship.

Ruchelli ED, Uri A, Dimmick JE, Bove KE, Huff DS, Duncan LM, Jennings JB, Witzleben CL.

Department of Pathology, Children's Hospital of Philadelphia, PA 19104.

Hum Pathol 1991 Dec;22(12):1274-80 Abstract quote
Down syndrome (DS) is not usually thought of in association with significant infantile liver disease.

We present clinical and histopathologic data from 10 patients with DS who presented with severe liver disease at birth or within the first few weeks of life, and summarize the findings of eight previously reported cases. The liver disease was fatal in all but one case. Diffuse lobular fibrosis surrounding proliferating ductular elements and residual hepatocytes characterized the pathologic findings in the liver in all patients. A large number of megakaryocytes were present in the liver in nine of 12 patients.

The phenotype of "perinatal hemochromatosis" was documented in eight of nine cases in which the presence of iron was investigated. Since only a fraction of the patients with this phenotype have DS, the patients we describe seem to represent a relatively well-defined subset of the perinatal hemochromatosis phenotype. The existence of such a subset suggests that the perinatal hemochromatosis phenotype does not represent a single etiopathogenetic disorder.

The association between DS, megakaryocytic infiltrates in the liver, and fatal subacute/chronic liver disease gives rise to the speculation that fibrosis-promoting factors and/or metabolic abnormalities, such as those resulting from a gene dosage effect, may play a role in the genesis of the liver disease, perhaps due to a particular susceptibility of fetal liver.

TT VIRUS

Three cases with TT virus infection and idiopathic neonatal hepatitis.

Tajiri H, Tanaka T, Sawada A, Etani Y, Kozaiwa K, Mushiake S, Mishiro S.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.
Intervirology 2001;44(6):364-9 Abstract quote
We present three cases of infants with idiopathic neonatal hepatitis showing diffuse intrahepatic fatty degeneration. Prolonged cholestasis has improved immediately upon intravenous administration of a high-dose gammaglobulin treatment in all three patients.

The TT virus (TTV) genome was detectable in the serum of two patients, in the duodenal fluid of one and in the liver of all three. By analyzing sequence homology, we observed that the respective TTV isolated from serum, duodenal fluid and liver tissue were completely identical in cases 2 and 3. These findings suggest that TTV infection was one of the contributing factors for neonatal cholestasis in these patients. TTV was isolated from the serum of two out of the three mothers. The viruses were either completely or almost identical in sequence to those isolated from their respective infants, suggesting that they had been transmitted from mother to infant in these 2 cases.

The patients presented here, whose livers were infected with the TTV and showed a favorable response to gammaglobulin therapy, may represent a subset of idiopathic neonatal hepatitis patients.

ULCERATIVE COLITIS

Postinfantile giant cell hepatitis complicating ulcerative colitis: a case report and review of the literature.

Labowitz J, Finklestein S, Rabinovitz M.

Department of Medicine, University of Pittsburgh School of Medicine, Pennsylvania, USA.
Am J Gastroenterol 2001 Apr;96(4):1274-7 Abstract quote
Giant cell hepatitis is common in the neonatal period. When present in adults, it is known as postinfantile giant cell hepatitis (PGCH). PGCH can arise in the context of viral, drug-related, and autoimmune disorders but, in many other cases, its etiology remains unclear.

We report a case of PGCH occurring in the setting of autoimmune hepatitis and ulcerative colitis. This case highlights the close association between PGCH and autoimmune disorders and the need to recognize it as a hepatic complication of inflammatory bowel disease.

PATHOGENESIS CHARACTERIZATION

GENERAL Mulitfactorial, dependent upon underlying disease process

LABORATORY/RADIOLOGIC/
OTHER TESTS
CHARACTERIZATION

RADIOLOGIC

LIVER SCAN

Hepatic technetium-99m-mebrofenin iminodiacetate scans and serum gamma-glutamyl transpeptidase levels interpreted in series to differentiate between extrahepatic biliary atresia and neonatal hepatitis.

Arora NK, Kohli R, Gupta DK, Bal CS, Gupta AK, Gupta SD.

Department of Pediatrics, All India Institute of Medical Sciences, New Delhi
Acta Paediatr 2001 Sep;90(9):975-81 Abstract quote
Hepatic technetium-99m-mebrofenin iminodiacetate (99mTc-mebrofenin IDA) scans and serum gamma-glutamyl transpeptidase (GGTP) have high sensitivity for extrahepatic biliary atresia (EHBA).

This study was based on the hypothesis that the interpretation of results of 99mTc-mebrofenin IDA scans and serum GGTP levels in series would result in a reduction of the false positivity observed with these tests individually. The aetiology of neonatal cholestasis in 132 study patients was: 25% (33/132) EHBA, 45.5% (60/132) neonatal hepatitis (NH) with an identifiable cause and 19.7% (26/132) idiopathic NH.

Of the various clinical, biochemical and imaging parameters that were significantly different between patient groups, sensitivity for EHBA was: serum GGTP > or = 150 IU l(-1) (100%), 99mTc-mebrofenin IDA scans (100%), pale stools (82.8%) and total serum bilirubin > or = 12 mg dl(-1) (66%). However, specificity ranged from 48.5 to 79%. Of the 63 patients who had non-excreting IDA scans, operative cholangiograms could be avoided on the basis of a specific aetiological diagnosis of NH, made concurrently, in only 9 infants. The rest (54) underwent operative cholangiograms; 21 (39%) of these had patent biliary trees and therefore underwent the procedure unnecessarily. If serum GGTP (< 150 IU l(-1)) had been used as a screen after IDA scanning in these 54 patients, operative cholangiograms could have been avoided in another 12 patients and thereafter only 9/42 (21%) of the operative cholangiograms would have been considered unnecessary.

Conclusion: A diagnostic algorithm is proposed wherein serum GGTP level (at a cut-off level that maintains 100% sensitivity for EHBA) is used in series with non-excreting 99mTc-mebrofenin IDA scans (for patients with no specific aetiological label). This strategy reduces the false positivity of individual tests.

Outcome of hepatobiliary scanning in neonatal hepatitis syndrome.

Gilmour SM, Hershkop M, Reifen R, Gilday D, Roberts EA.

Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.

J Nucl Med 1997 Aug;38(8):1279-82 Abstract quote
To evaluate the diagnostic information gained from hepatobiliary scanning in infants, we reviewed 86 consecutive infants who were < or = 4 mo old and were treated for conjugated hyperbilirubinemia at the Hospital for Sick Children in Toronto between 1985 and 1993 and who had technetium iminodiacetic hepatobiliary scanning and a percutaneous liver biopsy performed in close temporal proximity.

METHODS: Retrospective reviews of hospital charts and blinded reviews of hepatobiliary scans were performed.

RESULTS: There were 58 male and 28 female infants (age range, 2-124 days; mean = 65 days). Hepatobiliary scanning failed to show biliary excretion into the gastrointestinal tract in 53 of 86 patients. Forty of these 53 had extrahepatic biliary atresia. The remaining 33 patients demonstrated biliary excretion into the gastrointestinal tract; 24 of 33 had neonatal hepatitis. Among 13 of the 53 patients who had no evidence of biliary excretion and who also did not have extrahepatic biliary atresia, 8 had idiopathic neonatal hepatitis, 4 had interlobular bile duct paucity and 1 had total parenteral nutrition-associated cholestasis. In this large series, no patient with extrahepatic biliary atresia showed bile drainage on hepatobiliary scanning. Fifty percent of patients with interlobular bile duct paucity but no extrahepatic obstruction failed to show biliary excretion of radionuclide. Twenty-five percent of patients (8 of 32) with idiopathic neonatal hepatitis demonstrated no biliary excretion. Hepatocellular extraction was examined by semiquantitative analysis in the nondraining, nonbiliary atresia patients (12 of 53). Four of these 12 patients demonstrated poor liver extraction. Three patients had idiopathic neonatal hepatitis, and one had bile duct paucity. Therefore, four of eight neonatal hepatitis patients had normal extraction, suggesting that poor versus good liver hepatocyte clearance cannot accurately identify neonatal hepatitis.

CONCLUSION: Hepatobiliary scanning requires cautious interpretation. Nondraining scans may indicate severe neonatal hepatitis or the presence of interlobular bile duct paucity.

LABORATORY MARKERS

ALPHA FETOPROTEIN

Serum alpha-fetoprotein levels in extrahepatic biliary atresia, idiopathic neonatal hepatitis and alpha-1-antitrypsin deficiency (PiZ).

Johnston DI, Mowat AP, Orr H, Kohn J.
Acta Paediatr Scand 1976 Sep;65(5):623-9 Abstract quote
Serum alpha-fetoprotein levels were measured using a sensitive radioimmunoassay in 77 infants presenting with persistent conjugated hyperbilirubinaemia.

A breed range of alpha-fetoprotein concentrations occurred in both the 23 infants with extrahepatic biliary atresia and the 35 with idiopathic neonatal hepatitis but the 13 with alpha-1-antitrypsin deficiency had uniformly low levels. High alpha-fetoprotein concentrations (above 10 000 mug/1) favoured the diagnosis of neonatal hepatitis especially in the first ten weeks of life, but the overlap between neonatal hepatitis and extrahepatic biliary atresia was large and alpha-fetoprotein determination cannot be recommended as a reliable method for distinguishing the two conditions.

Serial alpha-fetoprotein values showed no consistent relationship with standard liver function tests and gave no guide to prognosis. There was an association between alpha-fetoprotein production and needle biopsy evidence of hepatic giant cell transformation. The uniformly low alpha-fetoprotein levels in alpha-1-antitrypsin deficient infants with neonatal hepatitis is a new observation and possible mechanisms for disordered glycoprotein release are discussed.

COAGULOPATHY

Idiopathic neonatal hepatitis associated with a fatal coagulopathy.

Patrinos ME, Hardman JM, Easa D, Harrigan R.

Department of Pediatrics, John A. Burns School of Medicine, University of Hawaii, Honolulu, USA.

J Perinatol 1999 Dec;19(8 Pt 1):599-602 Abstract quote
Idiopathic neonatal hepatitis (INH) remains a diagnosis of exclusion in the neonate with conjugated hyperbilirubinemia. The major diagnostic challenge for the clinician is to distinguish this condition from other treatable liver disorders such as biliary atresia.

Although the prognosis varies for the familial and sporadic forms of neonatal hepatitis, a poor outcome is generally distinguished by chronic and progressive liver failure. After careful review of the literature, we were unable to find a case of INH associated with a profound, irreversible coagulopathy.

Herein, we present a case with the primary presenting findings of persistent prolongation of the prothrombin time (PT) and hypofibrinogenemia, resulting in a catastrophic intracranial hemorrhage and death.

HYPERBILIRUBINEMIA

Investigation of prolonged neonatal jaundice.

Hannam S, McDonnell M, Rennie JM.

Department of Child Health, King's College Hospital, London, UK.
Acta Paediatr 2000 Jun;89(6):694-7 Abstract quote
Jaundice persisting beyond 14 d of age (prolonged jaundice) can be a sign of serious underlying liver disease. Protocols for investigating prolonged jaundice vary in complexity and the yield from screening has not been assessed.

In order to address these issues, we carried out a prospective study of term infants referred to our neonatal unit with prolonged jaundice over an 18 mo period. Infants were examined by a paediatrician and had the following investigations: a total and conjugated serum bilirubin, liver function tests, full blood count, packed cell volume, group and Coombs' test, thyroid function tests, glucose-6-phosphate dehydrogenase levels and urine for culture.

One-hundred-and-fifty-four infants were referred with prolonged jaundice out of 7,139 live births during the study period. Nine infants were referred to other paediatric specialties. One infant had a conjugated hyperbilirubinaemia, giving an incidence of conjugated hyperbilirubinaemia of 0.14 per 1,000 live births. Diagnoses included: giant cell hepatitis (n = 1), hepatoblastoma (n = 1), trisomy 9p (n = 1), urinary tract infections (n = 2), glucose-6-phosphate dehydrogenase deficiency (n = 3) and failure to regain birthweight (n = 1).

CONCLUSIONS: In conclusion, a large number of infants referred to hospital for prolonged jaundice screening had detectable problems. The number of investigations may safely be reduced to: a total and conjugated bilirubin, packed cell volume, glucose-6-phosphate dehydrogenase level (where appropriate), a urine for culture and inspection of a recent stool sample for bile pigmentation. Clinical examination by a paediatrician has a vital role in the screening process.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

GENERAL

Neonatal hepatitis--an autopsy study of 14 cases.

Shet TM, Kandalkar BM, Vora IM.

Department of Pathology, T.N. Medical College, Mumbai.

Indian J Pathol Microbiol 1998 Jan;41(1):77-84 Abstract quote
Fourteen autopsy cases of neonatal hepatitis have been studied. Of these seven cases were due to infections viz.: cytomegalovirus infection (four cases), probable cases of congenital syphilis (two cases) and neonatal herpes (one case).

The remaining seven cases were of Idiopathic Neonatal Hepatitis (INH) with giant cell change in six cases. Even in these cases (INH) there was a high index of suspicion of intrauterine or acquired infection in view of severe mononuclear inflammation in the pancreas, alimentary tract and lungs. Most of these neonates with INH had low birth weight and two were preterm pointing towards a prenatal insult.

The orcein stain and Periodic Acid Schiff (PAS) with diastase in all the cases were negative making hepatitis B virus infection and infinity 1 antitrypsin deficiency less likely. These autopsies represent the tip of the iceberg and only the severe cases of infection.

The fatal outcome could have been prevented by maternal screening for infections and earlier clinical diagnosis.

VARIANTS

HEPATIC FAILURE, ACUTE

Idiopathic neonatal giant cell hepatitis presenting with acute hepatic failure on postnatal day one.

Correa KK, Nanjundiah P, Wirtschafter DD, Alshak NS.

University of California, Los Angeles, CA, USA.
J Perinatol 2002 Apr-May;22(3):249-51 Abstract quote
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.

HISTOLOGICAL TYPES CHARACTERIZATION

GENERAL

VARIANTS

HEPATIC SIDEROSIS AND STEATOSIS

Idiopathic neonatal hepatitis presenting as neonatal hepatic siderosis and steatosis.

Tazawa Y, Abukawa D, Maisawa S, Nishinomiya F, Oyake Y, Takada G, Konno T.

Department of Pediatrics, Akita University School of Medicine, Hondo, Japan.

Dig Dis Sci 1998 Feb;43(2):392-6 Abstract quote
Idiopathic neonatal hepatitis (INH) is a heterogeneous disease of undetermined cause. We report a retrospective histologic reevaluation of INH. Sixty patients with INH were reviewed along with 32 biliary atresia (BA) patients.

Histologic findings, iron and fat deposits, giant cell transformation, portal fibrosis, and bile duct proliferation were semiquantitatively graded from 0 to 4+. Significant histologic findings were defined as > or =2+. Frequencies of patients with significant histologic findings in the INH group were compared with those of the BA group. Among the patients with significant histologic findings, those in the INH group had significantly less iron deposits (P < 0.01), portal fibrosis (P < 0.01), and bile duct proliferation (P < 0.01) than those of the BA group. A combination of significant hepatic macrovesicular steatosis and siderosis was observed in 10 INH patients but not in any BA patient (10/60 vs 0/32, P < 0.05).

Without extensive treatment, the 10 INH patients all recovered, and hepatic abnormalities normalized by the age of 12 months. In conclusion, the present study showed that the recognition of hepatic siderosis is helpful to distinguish BA from INH and that in a subset of INH patients hepatic macrovesicular steatosis and siderosis occurs.

SPECIAL STAINS/IMMUNOPEROXIDASE/
OTHER CHARACTERIZATION

SPECIAL STAINS

IMMUNOPEROXIDASE

Infantile liver giant cells: immunohistological study of their proliferative state and possible mechanisms of formation.

Koukoulis G, Mieli-Vergani G, Portmann B.

Institute of Liver Studies, King's College Hospital, Denmark Hill, SE5 9RS London, UK.

Pediatr Dev Pathol 1999 Jul-Aug;2(4):353-9 Abstract quote
The mechanism of liver giant cell formation is not clarified. Some authors consider the giant cells regenerative, others, degenerative.

Paraffin sections of 10 archival cases of idiopathic neonatal hepatitis (INH), 8 of extrahepatic biliary atresia (EHBA), and 5 normal liver samples were immunostained with two well-characterized cell proliferation markers: anti-PCNA monoclonal antibody (MAb) (clone PC-10) and MAb MIB-1, which detects Ki-67, a nuclear proliferation-related antigen. In addition, polyclonal antibody to carcinoembryonic antigen (CEA) was used to identify remnants of canalicular, therefore hepatocytic, membranes in giant cells.

Quantitative analysis of immunostaining was done by estimating PCNA and Ki-67 indices separately in giant cells and in nongiant hepatocytes. In normal samples, mean PCNA and Ki-67 indices were 1. 22% and 0.74%, respectively. In the cases of INH and EHBA, only a small minority of giant cells showed PCNA or Ki-67 staining limited to occasional peripherally located nuclei. PCNA and Ki-67 indices were significantly higher in the non-giant cell compartment. CEA staining was seen only in rare giant cells as centrally located canalicular remnants bordered by polarized nuclei, suggesting that they had been formed from rosettes through dissolution of cell membranes.

Other giant cells shared CEA-labeled canalicular membranes with mononuclear hepatocytes in rosettes. These findings indicate that the giant cells in INH and EHBA are not regenerative cells, they are not formed by amitotic division of nuclei in syncytia, and that fusion of rosette-forming hepatocytes is a possible mechanism of their formation.

ELECTRON MICROSCOPY

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES

BILIARY ATRESIA Giant multinucleated hepatocytes and altered reticulin structure are more prominent in hepatitis than in true biliary obstruction

Cholestasis is more severe with biliary atresian and may have proliferation of bile ductules

PROGNOSIS CHARACTERIZATION

GENERAL

Neonatal hepatitis: a follow-up study.

Chang MH, Hsu HC, Lee CY, Wang TR, Kao CL.

Department of Pediatrics, National Taiwan University, Republic of China.
J Pediatr Gastroenterol Nutr 1987 Mar-Apr;6(2):203-7 Abstract quote
Fifty-six patients with moderate to severe neonatal hepatitis were followed for 12 to 78 months. Two died from causes other than hepatitis itself and were free from liver disease at the time of death. Of the remaining 54 patients, seven died of hepatitis, two are living with chronic liver disease and psychomotor retardation, and 45 are living without liver disease.

High peak bilirubin levels and liver histologic findings of periportal fibrosis, moderate to severe portal inflammation, and/or diffuse giant cell transformation appear to be major factors predictive for poor outcome. Cytomegalovirus (CMV) infection was a common associated infection.

Evidence of CMV infection was found in 22 (49%) of the 45 patients studied. Three of them died, and one is still living with cirrhosis of the liver. Metabolic disorders such as alpha-1-antitrypsin deficiency, galactosemia, and aminoaciduria and/or aminoacidemia were carefully screened but were not found in these cases. A fatal case had a sibling who had died of a similar disease course. Chinese infants may have metabolic and familial cholestasis diseases requiring further investigation.

Extrahepatic biliary atresia versus neonatal hepatitis. Review of 137 prospectively investigated infants.

Mowat AP, Psacharopoulos HT, Williams R.
Arch Dis Child 1976 Oct;51(10):763-70 Abstract quote
In a prospective regional survey of neonatal hepatitis syndrome 32 infants had extrahepatic biliary atresia (EHBA) and 103 had hepatitis.

No cause for the lesion was found in infants with extrahepatic biliary atresia, but in 32 with hepatitis a specific cause was identified, 24 having genetic deficiency of the serum protein alpha1-antitrypsin. No differences were observed in parental age, mother's health in pregnancy, month of birth, birth order, or sex of the infants. Familial idiopathic hepatitis occurred in 3 of 67 sibs of patients with idiopathic hepatitis, but the 33 sibs of EHBA patients had no liver disease.

Of the infants with hepatitis, 36 were of low birthweight, less than 2.5 kg, and 23 were born prematurely. Infants with biliary atresia were all of normal birthweight and only one was born prematurely. Consideration of clinical and biochemical abnormalities in the first 2 months of life showed no differences between the two groups except that infants with EHBA were more commonly jaundiced from birth (80%) and had more frequently acholic stools (83%). The frequency of these features in patients with hepatitis being 68% and 52%.

Standard tests of liver function were not discriminatory. Percutaneous liver biopsies were diagnostic in 75% of those with EHBA and in 92% of those with hepatitis. The I131 Rose Bengal faecal excretion was less than 10% in 26 of 28 infants with EHBA and in only 5 of 18 with hepatitis. These latter two investigations together allowed a correct preoperativer diagnosis of EHBA in all instances. Bile drainage was achieved surgically in only 3 cases.

A major reason for these poor results may have been the late referral of cases for diagnosis and laparotomy, which should be performed as soon as the diagnosis is suspected and always by 70 days of age.

MALIGNANCY

Hepatocellular carcinoma following neonatal hepatitis.

Moore L, Bourne AJ, Moore DJ, Preston H, Byard RW.

Department of Histopathology, Women's and Children's Hospital, Adelaide Children's Hospital Division, North Adelaide, South Australia.
Pediatr Pathol Lab Med 1997 Jul-Aug;17(4):601-10 Abstract quote
Hepatocellular carcinoma is an uncommon malignancy in young children associated with a variety of congenital and acquired conditions. It has been generally held that idiopathic neonatal hepatitis is not an antecedent of hepatocellular neoplasia in childhood.

We report a 28-month-old girl in whom a diagnosis of neonatal giant cell hepatitis was confirmed by liver biopsy at 4 months of age who was followed up with serial liver biopsies. Hepatitis B and C virus infection and metabolic abnormalities had been excluded by appropriate testing. There was no history of parenteral nutrition. The morphologic criteria for a diagnosis of cirrhosis were satisfied in a liver biopsy undertaken at 23 months of age. At 28 months a laparotomy was performed because of continuing jaundice and the development of an abdominal mass.

Biopsy of the mass revealed a hepatocellular carcinoma. Ploidy studies showed an aneuploid tumor and a hyperdiploid karyotype was confirmed by chromosomal analysis.

This case demonstrates by sequential biopsy the progression from neonatal hepatitis to cirrhosis and hepatocellular carcinoma in a young child.

TREATMENT CHARACTERIZATION

GENERAL Dependent upon underlying disease process

Henry JB. Clinical Diagnosis and Management by Laboratory Methods. Twentieth Edition. WB Saunders. 2001.
Rosai J. Ackerman's Surgical Pathology. Eight Edition. Mosby 1996.
Sternberg S. Diagnostic Surgical Pathology. Third Edition. Lipincott Williams and Wilkins 1999.
Robbins Pathologic Basis of Disease. Sixth Edition. WB Saunders 1999.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 5th Edition. McGraw-Hill. 1999.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

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Last Updated 4/28/2003

LABORATORY/RADIOLOGIC/ OTHER TESTS	CHARACTERIZATION
RADIOLOGIC
LIVER SCAN
Hepatic technetium-99m-mebrofenin iminodiacetate scans and serum gamma-glutamyl transpeptidase levels interpreted in series to differentiate between extrahepatic biliary atresia and neonatal hepatitis. Arora NK, Kohli R, Gupta DK, Bal CS, Gupta AK, Gupta SD. Department of Pediatrics, All India Institute of Medical Sciences, New Delhi	Acta Paediatr 2001 Sep;90(9):975-81 Abstract quote Hepatic technetium-99m-mebrofenin iminodiacetate (99mTc-mebrofenin IDA) scans and serum gamma-glutamyl transpeptidase (GGTP) have high sensitivity for extrahepatic biliary atresia (EHBA). This study was based on the hypothesis that the interpretation of results of 99mTc-mebrofenin IDA scans and serum GGTP levels in series would result in a reduction of the false positivity observed with these tests individually. The aetiology of neonatal cholestasis in 132 study patients was: 25% (33/132) EHBA, 45.5% (60/132) neonatal hepatitis (NH) with an identifiable cause and 19.7% (26/132) idiopathic NH. Of the various clinical, biochemical and imaging parameters that were significantly different between patient groups, sensitivity for EHBA was: serum GGTP > or = 150 IU l(-1) (100%), 99mTc-mebrofenin IDA scans (100%), pale stools (82.8%) and total serum bilirubin > or = 12 mg dl(-1) (66%). However, specificity ranged from 48.5 to 79%. Of the 63 patients who had non-excreting IDA scans, operative cholangiograms could be avoided on the basis of a specific aetiological diagnosis of NH, made concurrently, in only 9 infants. The rest (54) underwent operative cholangiograms; 21 (39%) of these had patent biliary trees and therefore underwent the procedure unnecessarily. If serum GGTP (< 150 IU l(-1)) had been used as a screen after IDA scanning in these 54 patients, operative cholangiograms could have been avoided in another 12 patients and thereafter only 9/42 (21%) of the operative cholangiograms would have been considered unnecessary. Conclusion: A diagnostic algorithm is proposed wherein serum GGTP level (at a cut-off level that maintains 100% sensitivity for EHBA) is used in series with non-excreting 99mTc-mebrofenin IDA scans (for patients with no specific aetiological label). This strategy reduces the false positivity of individual tests.
Outcome of hepatobiliary scanning in neonatal hepatitis syndrome. Gilmour SM, Hershkop M, Reifen R, Gilday D, Roberts EA. Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada.	J Nucl Med 1997 Aug;38(8):1279-82 Abstract quote To evaluate the diagnostic information gained from hepatobiliary scanning in infants, we reviewed 86 consecutive infants who were < or = 4 mo old and were treated for conjugated hyperbilirubinemia at the Hospital for Sick Children in Toronto between 1985 and 1993 and who had technetium iminodiacetic hepatobiliary scanning and a percutaneous liver biopsy performed in close temporal proximity. METHODS: Retrospective reviews of hospital charts and blinded reviews of hepatobiliary scans were performed. RESULTS: There were 58 male and 28 female infants (age range, 2-124 days; mean = 65 days). Hepatobiliary scanning failed to show biliary excretion into the gastrointestinal tract in 53 of 86 patients. Forty of these 53 had extrahepatic biliary atresia. The remaining 33 patients demonstrated biliary excretion into the gastrointestinal tract; 24 of 33 had neonatal hepatitis. Among 13 of the 53 patients who had no evidence of biliary excretion and who also did not have extrahepatic biliary atresia, 8 had idiopathic neonatal hepatitis, 4 had interlobular bile duct paucity and 1 had total parenteral nutrition-associated cholestasis. In this large series, no patient with extrahepatic biliary atresia showed bile drainage on hepatobiliary scanning. Fifty percent of patients with interlobular bile duct paucity but no extrahepatic obstruction failed to show biliary excretion of radionuclide. Twenty-five percent of patients (8 of 32) with idiopathic neonatal hepatitis demonstrated no biliary excretion. Hepatocellular extraction was examined by semiquantitative analysis in the nondraining, nonbiliary atresia patients (12 of 53). Four of these 12 patients demonstrated poor liver extraction. Three patients had idiopathic neonatal hepatitis, and one had bile duct paucity. Therefore, four of eight neonatal hepatitis patients had normal extraction, suggesting that poor versus good liver hepatocyte clearance cannot accurately identify neonatal hepatitis. CONCLUSION: Hepatobiliary scanning requires cautious interpretation. Nondraining scans may indicate severe neonatal hepatitis or the presence of interlobular bile duct paucity.
LABORATORY MARKERS
ALPHA FETOPROTEIN
Serum alpha-fetoprotein levels in extrahepatic biliary atresia, idiopathic neonatal hepatitis and alpha-1-antitrypsin deficiency (PiZ). Johnston DI, Mowat AP, Orr H, Kohn J.	Acta Paediatr Scand 1976 Sep;65(5):623-9 Abstract quote Serum alpha-fetoprotein levels were measured using a sensitive radioimmunoassay in 77 infants presenting with persistent conjugated hyperbilirubinaemia. A breed range of alpha-fetoprotein concentrations occurred in both the 23 infants with extrahepatic biliary atresia and the 35 with idiopathic neonatal hepatitis but the 13 with alpha-1-antitrypsin deficiency had uniformly low levels. High alpha-fetoprotein concentrations (above 10 000 mug/1) favoured the diagnosis of neonatal hepatitis especially in the first ten weeks of life, but the overlap between neonatal hepatitis and extrahepatic biliary atresia was large and alpha-fetoprotein determination cannot be recommended as a reliable method for distinguishing the two conditions. Serial alpha-fetoprotein values showed no consistent relationship with standard liver function tests and gave no guide to prognosis. There was an association between alpha-fetoprotein production and needle biopsy evidence of hepatic giant cell transformation. The uniformly low alpha-fetoprotein levels in alpha-1-antitrypsin deficient infants with neonatal hepatitis is a new observation and possible mechanisms for disordered glycoprotein release are discussed.
COAGULOPATHY
Idiopathic neonatal hepatitis associated with a fatal coagulopathy. Patrinos ME, Hardman JM, Easa D, Harrigan R. Department of Pediatrics, John A. Burns School of Medicine, University of Hawaii, Honolulu, USA.	J Perinatol 1999 Dec;19(8 Pt 1):599-602 Abstract quote Idiopathic neonatal hepatitis (INH) remains a diagnosis of exclusion in the neonate with conjugated hyperbilirubinemia. The major diagnostic challenge for the clinician is to distinguish this condition from other treatable liver disorders such as biliary atresia. Although the prognosis varies for the familial and sporadic forms of neonatal hepatitis, a poor outcome is generally distinguished by chronic and progressive liver failure. After careful review of the literature, we were unable to find a case of INH associated with a profound, irreversible coagulopathy. Herein, we present a case with the primary presenting findings of persistent prolongation of the prothrombin time (PT) and hypofibrinogenemia, resulting in a catastrophic intracranial hemorrhage and death.
HYPERBILIRUBINEMIA
Investigation of prolonged neonatal jaundice. Hannam S, McDonnell M, Rennie JM. Department of Child Health, King's College Hospital, London, UK.	Acta Paediatr 2000 Jun;89(6):694-7 Abstract quote Jaundice persisting beyond 14 d of age (prolonged jaundice) can be a sign of serious underlying liver disease. Protocols for investigating prolonged jaundice vary in complexity and the yield from screening has not been assessed. In order to address these issues, we carried out a prospective study of term infants referred to our neonatal unit with prolonged jaundice over an 18 mo period. Infants were examined by a paediatrician and had the following investigations: a total and conjugated serum bilirubin, liver function tests, full blood count, packed cell volume, group and Coombs' test, thyroid function tests, glucose-6-phosphate dehydrogenase levels and urine for culture. One-hundred-and-fifty-four infants were referred with prolonged jaundice out of 7,139 live births during the study period. Nine infants were referred to other paediatric specialties. One infant had a conjugated hyperbilirubinaemia, giving an incidence of conjugated hyperbilirubinaemia of 0.14 per 1,000 live births. Diagnoses included: giant cell hepatitis (n = 1), hepatoblastoma (n = 1), trisomy 9p (n = 1), urinary tract infections (n = 2), glucose-6-phosphate dehydrogenase deficiency (n = 3) and failure to regain birthweight (n = 1). CONCLUSIONS: In conclusion, a large number of infants referred to hospital for prolonged jaundice screening had detectable problems. The number of investigations may safely be reduced to: a total and conjugated bilirubin, packed cell volume, glucose-6-phosphate dehydrogenase level (where appropriate), a urine for culture and inspection of a recent stool sample for bile pigmentation. Clinical examination by a paediatrician has a vital role in the screening process.

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
GENERAL
Neonatal hepatitis--an autopsy study of 14 cases. Shet TM, Kandalkar BM, Vora IM. Department of Pathology, T.N. Medical College, Mumbai.	Indian J Pathol Microbiol 1998 Jan;41(1):77-84 Abstract quote Fourteen autopsy cases of neonatal hepatitis have been studied. Of these seven cases were due to infections viz.: cytomegalovirus infection (four cases), probable cases of congenital syphilis (two cases) and neonatal herpes (one case). The remaining seven cases were of Idiopathic Neonatal Hepatitis (INH) with giant cell change in six cases. Even in these cases (INH) there was a high index of suspicion of intrauterine or acquired infection in view of severe mononuclear inflammation in the pancreas, alimentary tract and lungs. Most of these neonates with INH had low birth weight and two were preterm pointing towards a prenatal insult. The orcein stain and Periodic Acid Schiff (PAS) with diastase in all the cases were negative making hepatitis B virus infection and infinity 1 antitrypsin deficiency less likely. These autopsies represent the tip of the iceberg and only the severe cases of infection. The fatal outcome could have been prevented by maternal screening for infections and earlier clinical diagnosis.
VARIANTS
HEPATIC FAILURE, ACUTE
Idiopathic neonatal giant cell hepatitis presenting with acute hepatic failure on postnatal day one. Correa KK, Nanjundiah P, Wirtschafter DD, Alshak NS. University of California, Los Angeles, CA, USA.	J Perinatol 2002 Apr-May;22(3):249-51 Abstract quote 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.

PROGNOSIS	CHARACTERIZATION
GENERAL
Neonatal hepatitis: a follow-up study. Chang MH, Hsu HC, Lee CY, Wang TR, Kao CL. Department of Pediatrics, National Taiwan University, Republic of China.	J Pediatr Gastroenterol Nutr 1987 Mar-Apr;6(2):203-7 Abstract quote Fifty-six patients with moderate to severe neonatal hepatitis were followed for 12 to 78 months. Two died from causes other than hepatitis itself and were free from liver disease at the time of death. Of the remaining 54 patients, seven died of hepatitis, two are living with chronic liver disease and psychomotor retardation, and 45 are living without liver disease. High peak bilirubin levels and liver histologic findings of periportal fibrosis, moderate to severe portal inflammation, and/or diffuse giant cell transformation appear to be major factors predictive for poor outcome. Cytomegalovirus (CMV) infection was a common associated infection. Evidence of CMV infection was found in 22 (49%) of the 45 patients studied. Three of them died, and one is still living with cirrhosis of the liver. Metabolic disorders such as alpha-1-antitrypsin deficiency, galactosemia, and aminoaciduria and/or aminoacidemia were carefully screened but were not found in these cases. A fatal case had a sibling who had died of a similar disease course. Chinese infants may have metabolic and familial cholestasis diseases requiring further investigation.
Extrahepatic biliary atresia versus neonatal hepatitis. Review of 137 prospectively investigated infants. Mowat AP, Psacharopoulos HT, Williams R.	Arch Dis Child 1976 Oct;51(10):763-70 Abstract quote In a prospective regional survey of neonatal hepatitis syndrome 32 infants had extrahepatic biliary atresia (EHBA) and 103 had hepatitis. No cause for the lesion was found in infants with extrahepatic biliary atresia, but in 32 with hepatitis a specific cause was identified, 24 having genetic deficiency of the serum protein alpha1-antitrypsin. No differences were observed in parental age, mother's health in pregnancy, month of birth, birth order, or sex of the infants. Familial idiopathic hepatitis occurred in 3 of 67 sibs of patients with idiopathic hepatitis, but the 33 sibs of EHBA patients had no liver disease. Of the infants with hepatitis, 36 were of low birthweight, less than 2.5 kg, and 23 were born prematurely. Infants with biliary atresia were all of normal birthweight and only one was born prematurely. Consideration of clinical and biochemical abnormalities in the first 2 months of life showed no differences between the two groups except that infants with EHBA were more commonly jaundiced from birth (80%) and had more frequently acholic stools (83%). The frequency of these features in patients with hepatitis being 68% and 52%. Standard tests of liver function were not discriminatory. Percutaneous liver biopsies were diagnostic in 75% of those with EHBA and in 92% of those with hepatitis. The I131 Rose Bengal faecal excretion was less than 10% in 26 of 28 infants with EHBA and in only 5 of 18 with hepatitis. These latter two investigations together allowed a correct preoperativer diagnosis of EHBA in all instances. Bile drainage was achieved surgically in only 3 cases. A major reason for these poor results may have been the late referral of cases for diagnosis and laparotomy, which should be performed as soon as the diagnosis is suspected and always by 70 days of age.
MALIGNANCY
Hepatocellular carcinoma following neonatal hepatitis. Moore L, Bourne AJ, Moore DJ, Preston H, Byard RW. Department of Histopathology, Women's and Children's Hospital, Adelaide Children's Hospital Division, North Adelaide, South Australia.	Pediatr Pathol Lab Med 1997 Jul-Aug;17(4):601-10 Abstract quote Hepatocellular carcinoma is an uncommon malignancy in young children associated with a variety of congenital and acquired conditions. It has been generally held that idiopathic neonatal hepatitis is not an antecedent of hepatocellular neoplasia in childhood. We report a 28-month-old girl in whom a diagnosis of neonatal giant cell hepatitis was confirmed by liver biopsy at 4 months of age who was followed up with serial liver biopsies. Hepatitis B and C virus infection and metabolic abnormalities had been excluded by appropriate testing. There was no history of parenteral nutrition. The morphologic criteria for a diagnosis of cirrhosis were satisfied in a liver biopsy undertaken at 23 months of age. At 28 months a laparotomy was performed because of continuing jaundice and the development of an abdominal mass. Biopsy of the mass revealed a hepatocellular carcinoma. Ploidy studies showed an aneuploid tumor and a hyperdiploid karyotype was confirmed by chromosomal analysis. This case demonstrates by sequential biopsy the progression from neonatal hepatitis to cirrhosis and hepatocellular carcinoma in a young child.

Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/Immunohistochemistry/Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
SYNONYMS	Giant cell hepatitis
INCIDENCE/PREVALENCE	Uncommon Familial in 20% of cases)
AGE	Premature, small for gestational age infants are at risk
SEX	M > F (2:1)
GEOGRAPHY
EPIDEMIOLOGIC ASSOCIATIONS
BLOOD TRANSFUSIONS
Association between neonatal blood microtransfusions in the 1960s and hepatitis C virus infection. De Paschale M, Casiraghi MA, Biagiotti S, Rossi U, Zanetti AR	Lancet 2000 Nov 4;356(9241):1572-3 Abstract quote In the 1960s, a common practice in Italy was to give a few mL of blood or plasma to underweight or preterm newborns. We postulated that this practice might be the cause of hepatitis C virus (HCV) infections seen today in adults with a negative history, and no recall of such transfusions. We examined the transfusion files of children admitted to the Department of Paediatrics during 1968-74, and found that 613 children had been transfused within the first year of life. Of 57 traceable patients, 28 are now positive for antibodies to HCV, 17 of whom received at least one microtransfusion from a common donor who is also positive.

DISEASE ASSOCIATIONS	CHARACTERIZATION
AUTOIMMUNE
INFECTION	Cytomegalovirus Hepatitis virus
METABOLIC	Alpha-1 antitrypsin deficiency Galactosemia
SPECIFIC DISEASES
DOWN SYNDROME
Severe perinatal liver disease and Down syndrome: an apparent relationship. Ruchelli ED, Uri A, Dimmick JE, Bove KE, Huff DS, Duncan LM, Jennings JB, Witzleben CL. Department of Pathology, Children's Hospital of Philadelphia, PA 19104.	Hum Pathol 1991 Dec;22(12):1274-80 Abstract quote Down syndrome (DS) is not usually thought of in association with significant infantile liver disease. We present clinical and histopathologic data from 10 patients with DS who presented with severe liver disease at birth or within the first few weeks of life, and summarize the findings of eight previously reported cases. The liver disease was fatal in all but one case. Diffuse lobular fibrosis surrounding proliferating ductular elements and residual hepatocytes characterized the pathologic findings in the liver in all patients. A large number of megakaryocytes were present in the liver in nine of 12 patients. The phenotype of "perinatal hemochromatosis" was documented in eight of nine cases in which the presence of iron was investigated. Since only a fraction of the patients with this phenotype have DS, the patients we describe seem to represent a relatively well-defined subset of the perinatal hemochromatosis phenotype. The existence of such a subset suggests that the perinatal hemochromatosis phenotype does not represent a single etiopathogenetic disorder. The association between DS, megakaryocytic infiltrates in the liver, and fatal subacute/chronic liver disease gives rise to the speculation that fibrosis-promoting factors and/or metabolic abnormalities, such as those resulting from a gene dosage effect, may play a role in the genesis of the liver disease, perhaps due to a particular susceptibility of fetal liver.
TT VIRUS
Three cases with TT virus infection and idiopathic neonatal hepatitis. Tajiri H, Tanaka T, Sawada A, Etani Y, Kozaiwa K, Mushiake S, Mishiro S. Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.	Intervirology 2001;44(6):364-9 Abstract quote We present three cases of infants with idiopathic neonatal hepatitis showing diffuse intrahepatic fatty degeneration. Prolonged cholestasis has improved immediately upon intravenous administration of a high-dose gammaglobulin treatment in all three patients. The TT virus (TTV) genome was detectable in the serum of two patients, in the duodenal fluid of one and in the liver of all three. By analyzing sequence homology, we observed that the respective TTV isolated from serum, duodenal fluid and liver tissue were completely identical in cases 2 and 3. These findings suggest that TTV infection was one of the contributing factors for neonatal cholestasis in these patients. TTV was isolated from the serum of two out of the three mothers. The viruses were either completely or almost identical in sequence to those isolated from their respective infants, suggesting that they had been transmitted from mother to infant in these 2 cases. The patients presented here, whose livers were infected with the TTV and showed a favorable response to gammaglobulin therapy, may represent a subset of idiopathic neonatal hepatitis patients.
ULCERATIVE COLITIS
Postinfantile giant cell hepatitis complicating ulcerative colitis: a case report and review of the literature. Labowitz J, Finklestein S, Rabinovitz M. Department of Medicine, University of Pittsburgh School of Medicine, Pennsylvania, USA.	Am J Gastroenterol 2001 Apr;96(4):1274-7 Abstract quote Giant cell hepatitis is common in the neonatal period. When present in adults, it is known as postinfantile giant cell hepatitis (PGCH). PGCH can arise in the context of viral, drug-related, and autoimmune disorders but, in many other cases, its etiology remains unclear. We report a case of PGCH occurring in the setting of autoimmune hepatitis and ulcerative colitis. This case highlights the close association between PGCH and autoimmune disorders and the need to recognize it as a hepatic complication of inflammatory bowel disease.

HISTOLOGICAL TYPES	CHARACTERIZATION
GENERAL
VARIANTS
HEPATIC SIDEROSIS AND STEATOSIS
Idiopathic neonatal hepatitis presenting as neonatal hepatic siderosis and steatosis. Tazawa Y, Abukawa D, Maisawa S, Nishinomiya F, Oyake Y, Takada G, Konno T. Department of Pediatrics, Akita University School of Medicine, Hondo, Japan.	Dig Dis Sci 1998 Feb;43(2):392-6 Abstract quote Idiopathic neonatal hepatitis (INH) is a heterogeneous disease of undetermined cause. We report a retrospective histologic reevaluation of INH. Sixty patients with INH were reviewed along with 32 biliary atresia (BA) patients. Histologic findings, iron and fat deposits, giant cell transformation, portal fibrosis, and bile duct proliferation were semiquantitatively graded from 0 to 4+. Significant histologic findings were defined as > or =2+. Frequencies of patients with significant histologic findings in the INH group were compared with those of the BA group. Among the patients with significant histologic findings, those in the INH group had significantly less iron deposits (P < 0.01), portal fibrosis (P < 0.01), and bile duct proliferation (P < 0.01) than those of the BA group. A combination of significant hepatic macrovesicular steatosis and siderosis was observed in 10 INH patients but not in any BA patient (10/60 vs 0/32, P < 0.05). Without extensive treatment, the 10 INH patients all recovered, and hepatic abnormalities normalized by the age of 12 months. In conclusion, the present study showed that the recognition of hepatic siderosis is helpful to distinguish BA from INH and that in a subset of INH patients hepatic macrovesicular steatosis and siderosis occurs.

SPECIAL STAINS/IMMUNOPEROXIDASE/ OTHER	CHARACTERIZATION
SPECIAL STAINS
IMMUNOPEROXIDASE
Infantile liver giant cells: immunohistological study of their proliferative state and possible mechanisms of formation. Koukoulis G, Mieli-Vergani G, Portmann B. Institute of Liver Studies, King's College Hospital, Denmark Hill, SE5 9RS London, UK.	Pediatr Dev Pathol 1999 Jul-Aug;2(4):353-9 Abstract quote The mechanism of liver giant cell formation is not clarified. Some authors consider the giant cells regenerative, others, degenerative. Paraffin sections of 10 archival cases of idiopathic neonatal hepatitis (INH), 8 of extrahepatic biliary atresia (EHBA), and 5 normal liver samples were immunostained with two well-characterized cell proliferation markers: anti-PCNA monoclonal antibody (MAb) (clone PC-10) and MAb MIB-1, which detects Ki-67, a nuclear proliferation-related antigen. In addition, polyclonal antibody to carcinoembryonic antigen (CEA) was used to identify remnants of canalicular, therefore hepatocytic, membranes in giant cells. Quantitative analysis of immunostaining was done by estimating PCNA and Ki-67 indices separately in giant cells and in nongiant hepatocytes. In normal samples, mean PCNA and Ki-67 indices were 1. 22% and 0.74%, respectively. In the cases of INH and EHBA, only a small minority of giant cells showed PCNA or Ki-67 staining limited to occasional peripherally located nuclei. PCNA and Ki-67 indices were significantly higher in the non-giant cell compartment. CEA staining was seen only in rare giant cells as centrally located canalicular remnants bordered by polarized nuclei, suggesting that they had been formed from rosettes through dissolution of cell membranes. Other giant cells shared CEA-labeled canalicular membranes with mononuclear hepatocytes in rosettes. These findings indicate that the giant cells in INH and EHBA are not regenerative cells, they are not formed by amitotic division of nuclei in syncytia, and that fusion of rosette-forming hepatocytes is a possible mechanism of their formation.
ELECTRON MICROSCOPY

DIFFERENTIAL DIAGNOSIS	KEY DIFFERENTIATING FEATURES
BILIARY ATRESIA	Giant multinucleated hepatocytes and altered reticulin structure are more prominent in hepatitis than in true biliary obstruction Cholestasis is more severe with biliary atresian and may have proliferation of bile ductules