Neonatal Hepatitis

The term neonatal hepatitis implies intrahepatic cholestasis (see Fig. 348-1), which has various forms (Tables 348-1 and 348-3).

Idiopathic neonatal hepatitis, which can occur in either a sporadic or a familial form, is a disease of unknown cause. Patients with the sporadic form presumably have a specific yet undefined metabolic or viral disease. Familial forms, on the other hand, presumably reflect a genetic or metabolic aberration; in the past, patients with α₁-antitrypsin deficiency were included in this category.

Aagenaes syndrome is a form of idiopathic familial intrahepatic cholestasis associated with lymphedema of the lower extremities. The relationship between liver disease and lymphedema is not understood and may be attributable to decreased hepatic lymph flow or hepatic lymphatic hypoplasia. Affected patients usually present with episodic cholestasis with elevation of serum aminotransferases, alkaline phosphatase, and bile acids. Between episodes, the patients are usually asymptomatic and biochemical indices improve. Compared to other types of hereditary neonatal cholestasis, patients with Aagenaes syndrome have a relatively good prognosis because >50% can expect a normal life span. The locus for Aagenaes syndrome is mapped to a 6.6cM interval on chromosome 15q.

Zellweger (cerebrohepatorenal) syndrome is a rare autosomal recessive genetic disorder marked by progressive degeneration of the liver and kidneys (Chapter 80.2). The incidence is estimated to be 1/100,000 births; the disease is usually fatal in 6-12 mo. Affected infants have severe, generalized hypotonia and markedly impaired neurologic function with psychomotor retardation. Patients have an abnormal head shape and unusual facies, hepatomegaly, renal cortical cysts, stippled calcifications of the patellas and greater trochanter, and ocular abnormalities. Hepatic cells on ultrastructural examination show an absence of peroxisomes. MRI performed in the 3rd trimester can allow analysis of cerebral gyration and myelination, facilitating the prenatal diagnosis of Zellweger syndrome.

Neonatal iron storage disease (NISD; neonatal hemochromatosis) is a rapidly progressive disease characterized by increased iron deposition in the liver, heart, and endocrine organs without increased iron stores in the reticuloendothelial system. Patients have multiorgan failure and shortened survival. Familial cases are reported, and repeated affected neonates in the same family are common. This is an alloimmune disorder with maternal antibodies directed against the fetal liver. Laboratory findings include hypoglycemia, hyperbilirubinemia, hypoalbuminemia, and profound hypoprothrombinemia. Serum aminotransferase levels may be high initially but normalize with the progression of the disease. The diagnosis is usually confirmed by buccal mucosal biopsy or MRI demonstrating extrahepatic siderosis. The prognosis is poor; liver transplantation can be curative. Despite initially encouraging reports, the use of a combination of antioxidants and prostaglandin infusion with chelation might not uniformly improve outcome in patients with NISD. Although recovery from NISD either spontaneously or with medical therapy is unusual, the potential for histologic recovery with regression of fibrosis has been reported.

Neonatal hemochromatosis seems to be a gestational alloimmune disease, and reoccurrence of severe neonatal hemochromatosis in at-risk pregnancies may be reduced by maternal treatment with weekly (beginning gestational age 18 wk) high-dose IVIG (1 g/kg) during gestation. After birth, affected neonates are treated with exchange transfusions and IVIG (1 g/kg), which improves survival and reduces the need for liver transplantation.

Disorders of Transport, Secretion, Conjugation, and Biosynthesis of Bile Acids

Progressive familial intrahepatic cholestasis type 1 (PFIC 1) or FIC1 disease (formerly known as Byler disease) is a severe form of intrahepatic cholestasis. The disease was initially described in the Amish kindred of Jacob Byler. Affected patients present with steatorrhea, pruritus, vitamin D–deficient rickets, gradually developing cirrhosis, and low γ-glutamyl transpeptidase (GGT) levels. The absence of bile duct paucity and extrahepatic features differentiate this disorder from Alagille syndrome.

PFIC 1 (FIC-1 deficiency) has been mapped to chromosome 18q12 and results from defect in the gene for F1C1 (ATP8B1; Tables 348-3 and 348-4). F1C1 is a P-type adenosine triphosphatase (ATPase) that functions as aminophospholipid flippase, facilitating the transfer of phosphatidyl serine and phosphatidyl ethanolamine from the outer to inner hemileaflet of the cellular membrane. F1C1 might also play a role in intestinal bile acid absorption, as suggested by the high level of expression in the intestine. Defective F1C1 might also result in another form of intrahepatic cholestasis: benign recurrent intrahepatic cholestasis (BRIC) type I. The disease is characterized by recurrent bouts of cholestasis, jaundice, and severe pruritus lasting from a 2 wk to 6 mo period; it can last up to 5 yr. The episodes vary from few episodes per year to 1 episode per decade and can profoundly affect the quality of life. Nonsense, frame shift, and deletional mutations cause PFIC type I; missense and split type mutations result in BRIC type I. Typically, patients with BRIC type I have normal cholesterol and GGT levels.