Cholestasis

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Chapter 348 Cholestasis

348.1 Neonatal Cholestasis

H. Hesham A-kader and William F. Balistreri

Neonatal cholestasis is defined biochemically as prolonged elevation of the serum levels of conjugated bilirubin beyond the 1st 14 days of life. Jaundice that appears after 2 wk of age, progresses after this time, or does not resolve at this time should be evaluated and a conjugated bilirubin level determined. Cholestasis in a newborn can be due to infectious, genetic, metabolic, or undefined abnormalities giving rise to mechanical obstruction of bile flow or to functional impairment of hepatic excretory function and bile secretion (see Table 347-3). Mechanical lesions include stricture or obstruction of the common bile duct; biliary atresia is the prototypic obstructive abnormality. Functional impairment of bile secretion can result from congenital defects or damage to liver cells or to the biliary secretory apparatus.

Neonatal cholestasis can be divided into extrahepatic and intrahepatic disease (Fig. 348-1). The clinical features of any form of cholestasis are similar. In an affected neonate, the diagnosis of certain entities, such as galactosemia, sepsis, or hypothyroidism, is relatively simple and a part of most neonatal screening programs. In most cases, the cause of cholestasis is more obscure. Differentiation among biliary atresia, idiopathic neonatal hepatitis, and intrahepatic cholestasis is particularly difficult.

Figure 348-1 Neonatal cholestasis. Conceptual approach to the group of diseases presenting as cholestasis in the neonate. There are areas of overlap: patients with biliary atresia might have some degree of intrahepatic injury. Patients with “idiopathic” neonatal hepatitis might, in the future, be determined to have a primary metabolic or viral disease.

Mechanisms

Metabolic liver disease caused by inborn errors of bile acid metabolism or transport is associated with accumulation of atypical toxic primitive bile acids and failure to produce normal choleretic and trophic bile acids. The clinical and histologic manifestations are nonspecific and are similar to those in other forms of neonatal hepatobiliary injury. Autoimmune mechanisms may also be responsible for some of the enigmatic forms of neonatal liver injury.

Some of the histologic manifestations of hepatic injury in early life are not seen in older patients. Giant cell transformation of hepatocytes occurs commonly in infants with cholestasis and can occur in any form of neonatal liver injury. It is more common and more severe in intrahepatic forms of cholestasis. The clinical and histologic findings that exist in patients with neonatal hepatitis and in those with biliary atresia are quite disparate; the basic process is an undefined initiating insult causing inflammation of the liver cells or of the cells within the biliary tract. If bile duct epithelium is the predominant site of disease, cholangitis can result and lead to progressive sclerosis and narrowing of the biliary tree, the ultimate state being complete obliteration (biliary atresia). Injury to liver cells can present the clinical and histologic picture of “neonatal hepatitis.” This concept does not account for the precise mechanism, but it offers an explanation for well-documented cases of unexpected postnatal evolution of these disease processes; infants initially regarded as having neonatal hepatitis, with a patent biliary system shown on cholangiography, can later develop biliary atresia.

Functional abnormalities in the generation of bile flow can also have a role in neonatal cholestasis. Bile flow is directly dependent on effective hepatic bile acid excretion by the hepatocytes. During the phase of relatively inefficient liver cell transport and metabolism of bile acids in early life, minor degrees of hepatic injury can further decrease bile flow and lead to production of atypical and potentially toxic bile acids. Selective impairment of a single step in the series of events involved in hepatic excretion produces the full expression of a cholestatic syndrome. Specific defects in bile acid synthesis are found in infants with various forms of intrahepatic cholestasis (Table 348-1). Severe forms of familial cholestasis have been associated with neonatal hemochromatosis and an aberration in the contractile proteins that compose the cytoskeleton of the hepatocyte. Neonatal hemochromatosis can also be an alloimmune-mediated gestational (maternal antibodies against fetal hepatocytes) disease responsive to maternal intravenous immunoglobulin (IVIG). Sepsis is known to cause cholestasis, presumably mediated by an endotoxin produced by Escherichia coli.

Table 348-1 PROPOSED SUBTYPES OF INTRAHEPATIC CHOLESTASIS

B Disorders of bile acid biosynthesis and conjugation

1 3-oxoΔ-4-steroid 5β-reductase deficiency

2 3β-hydroxy-5-C27-steroid dehydrogenase/isomerase deficiency

3 Oxysterol 7α-hydroxylase deficiency

4 Bile acid-CoA Ligase deficiency

5 BAAT deficiency (familial hypercholanemia)

C Disorders of embryogenesis

1 Alagille syndrome (Jagged1 defect, syndromic bile duct paucity)

2 Ductal plate malformation (ARPKD, ADPLD, Caroli disease)

D Unclassified (idiopathic “neonatal hepatitis”): mechanism unknown

Note: FIC1 deficiency, BSEP deficiency, and some of the disorders of bile acid biosynthesis are characterized clinically by low levels of serum GGT despite the presence of cholestasis. In all other disorders listed, the serum GGT level is elevated.

ADPLD, autosomal dominant polycystic liver disease (cysts in liver only); ARPKD, autosomal recessive polycystic kidney disease (cysts in liver and kidney); BAAT, bile acid transporter; BRIC, benign recurrent intrahepatic cholestasis; BSEP, bile salt export pump in; GGT, γ-glutamyl transpeptidase; PFIC, progressive familial intrahepatic cholestasis.

From Balistreri WF, Bezerra JA, Jansen P, et al: Intrahepatic cholestasis: summary of an American Association for the Study of Liver Diseases single-topic conference, Hepatology 42:222–235, 2005.

Evaluation

The evaluation of the infant with jaundice should follow a logical, cost-effective sequence in a multistep process (Table 348-2). Although cholestasis in the neonate may be the initial manifestation of numerous and potentially serious disorders, the clinical manifestations are usually similar and provide very few clues about etiology. Affected infants have icterus, dark urine, light or acholic stools, and hepatomegaly, all resulting from decreased bile flow due to either hepatocyte injury or bile duct obstruction. Hepatic synthetic dysfunction can lead to hypoprothrombinemia and bleeding. Administration of vitamin K should be included in the initial treatment of cholestatic infants to prevent hemorrhage.

Table 348-2 VALUE OF SPECIFIC TESTS IN THE EVALUATION OF PATIENTS WITH SUSPECTED NEONATAL CHOLESTASIS

TEST	RATIONALE
Serum bilirubin fractionation (i.e., assessment of the serum level of conjugated bilirubin)	Indicates cholestasis
Assessment of stool color (does the baby have pigmented or acholic stools?)	Indicates bile flow into intestine
Urine and serum bile acids measurement	Confirms cholestasis; might indicate inborn error of bile acid biosynthesis
Hepatic synthetic function (albumin, coagulation profile)	Indicates severity of hepatic dysfunction
α1-Antitrypsin phenotype	Suggests (or excludes) PiZZ
Thyroxine and TSH	Suggests (or excludes) endocrinopathy
Sweat chloride and mutation analysis	Suggests (or excludes) cystic fibrosis
Urine and serum amino acids and urine reducing substances	Suggests (or excludes) metabolic liver disease
Ultrasonography	Suggests (or excludes) choledochal cyst; might detect the triangular cord (TC) sign, suggesting biliary atresia
Hepatobiliary scintigraphy	Documents bile duct patency or obstruction
Liver biopsy	Distinguishes biliary atresia; suggests alternative diagnosis

PiZZ, protease inhibitor ZZ phenotype; TSH, thyroid-stimulating hormone.

In contrast to unconjugated hyperbilirubinemia, which can be physiologic, cholestasis (conjugated bilirubin elevation of any degree) in the neonate is always pathologic and prompt differentiation is imperative. Thus the initial step is to identify the infant who has cholestasis. The next step is to recognize conditions that cause cholestasis and for which specific therapy is available to prevent further damage and avoid long-term complications such as sepsis, an endocrinopathy (hypothyroidism, panhypopituitarism), nutritional hepatotoxicity caused by a specific metabolic illness (galactosemia), or other metabolic diseases (tyrosinemia).

Hepatobiliary disease can be the initial manifestation of homozygous α₁-antitrypsin deficiency or of cystic fibrosis. Neonatal liver disease can also be associated with congenital syphilis and specific viral infections, notably echovirus and herpesviruses including cytomegalovirus (CMV). These account for a small percentage of cases of neonatal hepatitis syndrome The hepatitis viruses (A, B, C) rarely cause neonatal cholestasis.

The final and critical step in evaluating neonates with cholestasis is to differentiate extrahepatic biliary atresia from neonatal hepatitis.

Intrahepatic Cholestasis

Neonatal Hepatitis

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

Table 348-3 MOLECULAR DEFECTS CAUSING LIVER DISEASE

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.

Table 348-4 PROGRESSIVE FAMILIAL INTRAHEPATIC CHOLESTASIS

PFIC type 2 (BSEP deficiency) is mapped to chromosome 2q24 and is similar to PFIC 1 but is present in non-Amish families (Middle Eastern and European). The disease results from defects in the canalicular ATP-dependent bile acid transporter BSEP (ABCB11). The progressive liver disease results from accumulation of bile acids secondary to reduction in canalicular bile acid secretion. Mutation in ABC11 is also described in another disorder, BRIC type 2, characterized by recurrent bouts of cholestasis.

In contrast to PFIC 1 and 2, patients with PFIC type 3 (MDR3 disease) have high levels of GGT. The disease results from defects in a canalicular phospholipids flippase, MDR3 (ABCB4), which results in deficient translocation of phosphatidylcholine across the canalicular membrane. Mothers who are heterozygous for this gene can develop intrahepatic cholestasis during pregnancy.

Familial hypercholanemia (FHC) is characterized by elevated serum bile acid concentration, pruritus, failure to thrive, and coagulopathy. FHC is a complex genetic trait associated with mutation of bile acid coenzyme A (CoA): amino acid N-acyltransferase (encoded by BAAT) as well as mutations in tight junction protein 2 (encoded by TJP 2, also known as ZO-2). Mutation of BAAT, which is a bile acid–conjugating enzyme, abrogates the enzyme activity. Patients who are homozygous for this mutation have only unconjugated bile acids in their bile. Mutation of both BAAT and TJP 2 can disrupt bile acid transport and circulation. Patients with FHC usually respond to the administration of ursodeoxycholic acid.

Defective bile acid biosynthesis has been postulated to be an initiating or perpetuating factor in neonatal cholestatic disorders; the hypothesis is that inborn errors in bile acid biosynthesis lead to absence of normal trophic or choleretic primary bile acids and accumulation of atypical (hepatotoxic) metabolites. Inborn errors of bile acid biosynthesis cause acute and chronic liver disease; early recognition allows institution of targeted bile acid replacement, which reverses the hepatic injury. Several specific defects have been described, as follows.

Deficiency of Δ⁴-3-oxosteroid-5β reductase, the 4th step in the pathway of cholesterol degradation to the primary bile acids, manifests with significant cholestasis and liver failure developing shortly after birth, with coagulopathy and metabolic liver injury resembling tyrosinemia. Hepatic histology is characterized by lobular disarray with giant cells, pseudoacinar transformation, and canalicular bile stasis. Mass spectrometry is required to document increased urinary bile acid excretion and the predominance of oxo-hydroxy and oxo-dihydroxy cholenoic acids. Treatment with cholic acid and ursodeoxycholic acid is associated with normalization of biochemical, histologic, and clinical features.

Deficiency of 3β-hydroxy C₂₇-steroid dehydrogenase (3β-HSD) isomerase, the 2nd step in bile acid biosynthesis, causes progressive familial intrahepatic cholestasis. Affected patients usually have jaundice with increased aminotransferase levels and hepatomegaly; GGT levels and serum cholylglycine levels are normal. The histology is variable, ranging from giant cell hepatitis to chronic hepatitis. The diagnosis, suggested by mass spectrometry detection of C²⁴ bile acids in urine, which retain the 3β-hydroxy-Δ⁵ structure, can be confirmed by determination of 3β-HSD activity in cultured fibroblasts using 7α-hydroxy-Δ⁵ cholesterol as a substrate. Primary bile acid therapy, administered orally to downregulate cholesterol 7α-hydroxylase activity, to limit the production of 3β-hydroxy-Δ⁵ bile acids, and to facilitate hepatic clearance, has been effective in reversing hepatic injury.

Deficiency of oxysterol 7α-hydroxylase deficiency has been reported in a 10 wk old boy of parents who were first cousins. The patient presented with severe progressive cholestasis, hepatosplenomegaly, cirrhosis, and liver failure during early infancy. Although serum ALT and AST were markedly elevated, serum GGT was normal. Liver biopsy showed cholestasis with impressive giant cell transformation, bridging fibrosis, and proliferating bile ductules. Administration of cholic acid was therapeutically ineffective and UDCA resulted in deterioration in liver function tests. The patient received orthotopic liver transplant at months of age but subsequently died from disseminated Epstein-Barr virus–related lymphoproliferative disease.

Bile Acid CoA Ligase Deficiency

Conjugation with the amino acids glycine and taurine is the final step in bile acid synthesis. Two enzymes catalyze the amidation of bile acids. In the first reaction, a CoA thioester is formed by the rate-limiting bile acid-CoA ligase. The other reaction involves the coupling of glycine or taurine and is catalyzed by a cytosolic bile acid-CoA:amino acid N-acyltransferase. Several patients with bile acid-CoA ligase deficiency have been reported. The patients present with conjugated hyperbilirubinemia, growth failure, or fat-soluble vitamin deficiency and have been identified with mutation of bile acid-CoA ligase gene. Administration of conjugates of the primary bile acid, glycocholic acid may be beneficial and can correct the fat-soluble vitamin malabsorption and improve growth.

Disorders of Embryogenesis

Alagille syndrome (arteriohepatic dysplasia) is the most common syndrome with intrahepatic bile duct paucity. Bile duct “paucity” (often erroneously called intrahepatic biliary atresia) designates an absence or marked reduction in the number of interlobular bile ducts in the portal triads, with normal-sized branches of portal vein and hepatic arteriole. Biopsy in early life often reveals an inflammatory process involving the bile ducts; subsequent biopsy specimens then show subsidence of the inflammation, with residual reduction in the number and diameter of bile ducts, analogous to the “disappearing bile duct syndrome” noted in adults with immune-mediated disorders. Serial assessment of hepatic histology often suggests progressive destruction of bile ducts.

Clinical manifestations of Alagille syndrome are expressed in various degrees and can be nonspecific; they include unusual facial characteristics (broad forehead; deep-set, widely spaced eyes; long, straight nose; and an underdeveloped mandible). There may also be ocular abnormalities (posterior embryotoxon, microcornea, optic disk drusen, shallow anterior chamber), cardiovascular abnormalities (usually peripheral pulmonic stenosis, sometimes tetralogy of Fallot, pulmonary atresia, VSD, ASD, aortic coarctation), vertebral defects (butterfly vertebrae, fused vertebrae, spina bifida occulta, rib anomalies), and tubulointerstitial nephropathy. Other findings such as short stature, pancreatic insufficiency, and defective spermatogenesis can reflect or produce nutritional deficiency. The prognosis for prolonged survival is good, but patients are likely to have pruritus, xanthomas with markedly elevated serum cholesterol levels, and neurologic complications of vitamin E deficiency if untreated. Mutations in human Jagged1 gene (JAG1), which encodes a ligand for the notch receptor, are linked to Alagille syndrome.

Biliary Atresia

The term biliary atresia is imprecise because the anatomy of abnormal bile ducts in affected patients varies markedly. A more appropriate terminology would reflect the pathophysiology, namely, progressive obliterative cholangiopathy. Patients can have distal segmental bile duct obliteration with patent extrahepatic ducts up to the porta hepatis. This is a surgically correctable lesion, but it is uncommon. The most common form of biliary atresia, accounting for ∼85% of the cases, is obliteration of the entire extrahepatic biliary tree at or above the porta hepatis. This presents a much more difficult problem in surgical management. Most patients with biliary atresia (85-90%) are normal at birth and have a postnatal progressive obliteration of bile ducts; the embryonic or fetal-onset form manifests at birth and is associated with other congenital anomalies (situs inversus, polysplenia, intestinal malrotation, complex congenital heart disease) within the polysplenia spectrum (biliary atresia splenic malformation [BASM]) (Fig. 348-2) (Chapter 425.11). The postnatal onset may be an immune- or infection-mediated process.

Figure 348-2 Proposed pathways for pathogenesis of 2 forms of biliary atresia (BA). Perinatal BA can develop when a perinatal insult, such as a cholangiotropic viral infection, triggers bile duct (BD) epithelial cell injury and exposure of self-antigens or neoantigens that elicit a subsequent immune response. The resulting inflammation induces apoptosis and necrosis of extrahepatic BD epithelium, resulting in fibro-obliteration of the lumen and obstruction of the BD. Intrahepatic bile ducts can also be targets in the ongoing TH1 immune (autoimmune?) attack and the cholestatic injury, resulting in progressive portal fibrosis and culminating in biliary cirrhosis. Embryonic BA may be the result of mutations in genes controlling normal bile duct formation or differentiation, which secondarily induces an inflammatory/immune response within the common bile duct and liver after the initiation of bile flow at ∼11-13 wk of gestation. Secondary hepatocyte and intrahepatic bile duct injury ensue either as a result of cholestatic injury or as targets for the immune (autoimmune?) response that develops. The end result is intrahepatic cholestasis and portal tract fibrosis, culminating in biliary cirrhosis. Other major factors may be the role played by genetic predisposition to autoimmunity and modifier genes that determine the extent and type of cellular and immune response and the generation of fibrosis.

(From Mack CL, Sokol RJ: Unraveling the pathogenesis and etiology of biliary atresia, Pediatr Res 57:87R–94R, 2005.)

Biliary atresia has been detected in 1/10,000-15,000 live births.

Differentiation of Idiopathic Neonatal Hepatitis from Biliary Atresia

It may be difficult to clearly differentiate infants with biliary atresia, who require surgical correction, from those with intrahepatic disease (neonatal hepatitis) and patent bile ducts. No single biochemical test or imaging procedure is entirely satisfactory. Diagnostic schemas incorporate clinical, historical, biochemical, and radiologic features.

Idiopathic neonatal hepatitis has a familial incidence of ∼20%, whereas biliary atresia is unlikely to recur within the same family. A few infants with fetal onset of biliary atresia have an increased incidence of other abnormalities, such as the polysplenia syndrome with abdominal heterotaxia, malrotation, levocardia, and intra-abdominal vascular anomalies. Neonatal hepatitis appears to be more common in infants who are premature or small for gestational age. Persistently acholic stools suggest biliary obstruction (biliary atresia), but patients with severe idiopathic neonatal hepatitis can have a transient severe impairment of bile excretion. Consistently pigmented stools rule against biliary atresia. The finding of bile-stained fluid on duodenal intubation also excludes biliary atresia. Palpation of the liver might find an abnormal size or consistency in patients with biliary atresia; this is less common with idiopathic neonatal hepatitis.

Abdominal ultrasound is a helpful diagnostic tool in evaluating neonatal cholestasis because it identifies choledocholithiasis, perforation of the bile duct, or other structural abnormalities of the biliary tree such as a choledochal cyst. In patients with biliary atresia, ultrasound can detect associated anomalies such as abdominal polysplenia and vascular malformations. The gallbladder either is not visualized or is a microgallbladder in patients with biliary atresia. Children with intrahepatic cholestasis caused by idiopathic neonatal hepatitis, cystic fibrosis, or total parenteral nutrition can have similar ultrasonographic findings. Ultrasonographic triangular cord (TC) sign, which represents a cone-shaped fibrotic mass cranial to the bifurcation of the portal vein, may be seen in patients with biliary atresia (Figs. 348-3 and 348-4). The echogenic density, which represents the fibrous remnants at the porta hepatis of biliary atresia cases at surgery, may be a helpful diagnostic tool in evaluating patients with neonatal cholestasis.

Figure 348-3 Surgical findings of biliary atresia. A, Photograph of surgical specimen of obliterated extrahepatic bile ducts shows the fibrous ductal remnant (black arrowheads) in the porta hepatis, atretic gallbladder (arrow), and fibrous common bile duct (white arrowhead). The fibrous ductal remnant is a triangular cone-shaped mass. B, Schematic drawing represents the anatomic relationship between the fibrous ductal remnant and blood vessels around the porta hepatis. The triangular, cone-shaped, fibrous ductal remnant (black arrowheads, green) is positioned anterior and slightly superior to the portal vein (long arrow, blue) and the hepatic artery (short arrow, red).

(A, From Park WH, Choi SO, Lee HJ, et al: A new diagnostic approach to biliary atresia with emphasis on the ultrasonographic triangular cord sign: comparison of ultrasonography, hepatobiliary scintigraphy, and liver needle biopsy in the evaluation of infantile cholestasis, J Pediatr Surg 32:1555–1559, 1997.)

Figure 348-4 Biliary atresia in an 8 wk old male with elevated direct bilirubin. Transverse sonogram shows the triangular cord sign seen as a linear cord of echogenicity (arrowhead) along the right portal vein (RPV).

(From Lowe LH: Imaging hepatobiliary disease in children, Semin Roentgenol 43:39–49, 2008, Fig 1B.)

Hepatobiliary scintigraphy with technetium-labeled iminodiacetic acid derivatives is used to differentiate biliary atresia from nonobstructive causes of cholestasis. The hepatic uptake of the agent is normal in patients with biliary atresia, but excretion into the intestine is absent. Although the uptake may be impaired in neonatal hepatitis, excretion into the bowel eventually occurs. Obtaining a follow-up scan after 24 hr is of value to determine the patency of the biliary tree. The administration of phenobarbital (5 mg/kg/day) for 5 days before the scan is recommended because it can enhance biliary excretion of the isotope. Hepatobiliary scintigraphy is a sensitive but not specific test for biliary atresia. It fails to identify other structural abnormalities of the biliary tree or vascular anomalies. The lack of the specificity of the test and the need to wait for 5 days makes this procedure less practical and of limited usefulness in the evaluation of children with suspected biliary atresia.

Percutaneous liver biopsy is the most valuable procedure in the evaluation of neonatal hepatobiliary diseases and provides the most reliable discriminatory evidence. Biliary atresia is characterized by bile ductular proliferation, the presence of bile plugs, and portal or perilobular edema and fibrosis, with the basic hepatic lobular architecture intact. In neonatal hepatitis, there is severe, diffuse hepatocellular disease, with distortion of lobular architecture, marked infiltration with inflammatory cells, and focal hepatocellular necrosis; the bile ductules show little alteration. Giant cell transformation is found in infants with either condition and has no diagnostic specificity.

The histologic changes seen in patients with idiopathic neonatal hepatitis can occur in other diseases, including α₁-antitrypsin deficiency, galactosemia, and various forms of intrahepatic cholestasis. Although paucity of intrahepatic bile ductules may be detected on liver biopsy even in the 1st few weeks of life, later biopsies in such patients reveal a more characteristic pattern.

Management of Patients with Suspected Biliary Atresia

All patients with suspected biliary atresia should undergo exploratory laparotomy and direct cholangiography to determine the presence and site of obstruction. Direct drainage can be accomplished in the few patients with a correctable lesion. When no correctable lesion is found, an examination of frozen sections obtained from the transected porta hepatis can detect the presence of biliary epithelium and determine the size and patency of the residual bile ducts. In some cases, the cholangiogram indicates that the biliary tree is patent but of diminished caliber, suggesting that the cholestasis is not due to biliary tract obliteration but to bile duct paucity or markedly diminished flow in the presence of intrahepatic disease. In these cases, transection of or further dissection into the porta hepatis should be avoided.

For patients in whom no correctable lesion is found, the hepatoportoenterostomy (Kasai) procedure should be performed. The rationale for this operation is that minute bile duct remnants, representing residual channels, may be present in the fibrous tissue of the porta hepatis; such channels may be in direct continuity with the intrahepatic ductule system. In such cases, transection of the porta hepatis with anastomosis of bowel to the proximal surface of the transection might allow bile drainage. If flow is not rapidly established in the 1st months of life, progressive obliteration and cirrhosis ensue. If microscopic channels of patency >150 µm in diameter are found, postoperative establishment of bile flow is likely. The success rate for establishing good bile flow after the Kasai operation is much higher (90%) if performed before 8 wk of life. Therefore, early referral and prompt evaluation of infants with suspected biliary atresia is important.

Some patients with biliary atresia, even of the “noncorrectable” type, derive long-term benefits from interventions such as the Kasai procedure. In most, a degree of hepatic dysfunction persists. Patients with biliary atresia usually have persistent inflammation of the intrahepatic biliary tree, which suggests that biliary atresia reflects a dynamic process involving the entire hepatobiliary system. This might account for the ultimate development of complications such as portal hypertension. The short-term benefit of hepatoportoenterostomy is decompression and drainage sufficient to forestall the onset of cirrhosis and sustain growth until a successful liver transplantation can be done (Chapter 360).

Management of Chronic Cholestasis

With any form of neonatal cholestasis, whether the primary disease is idiopathic neonatal hepatitis, intrahepatic cholestasis, or biliary atresia, affected patients are at increased risk for progression and complications of chronic cholestasis. These reflect various degrees of residual hepatic functional capacity and are due directly or indirectly to diminished bile flow. Any substance normally excreted into bile is retained in the liver, with subsequent accumulation in tissue and in serum. Involved substances include bile acids, bilirubin, cholesterol, and trace elements. Decreased delivery of bile acids to the proximal intestine leads to inadequate digestion and absorption of dietary long-chain triglycerides and fat-soluble vitamins. Impairment of hepatic metabolic function can alter hormonal balance and utilization of nutrients. Progressive liver damage can lead to biliary cirrhosis, portal hypertension, and liver failure.

Treatment of such patients is empirical, and is guided by careful monitoring (Table 348-5). No therapy is known to be effective in halting the progression of cholestasis or in preventing further hepatocellular damage and cirrhosis.

Table 348-5 SUGGESTED MEDICAL MANAGEMENT OF PERSISTENT CHOLESTASIS

CLINICAL IMPAIRMENT	MANAGEMENT
Malnutrition resulting from malabsorption of dietary long-chain triglycerides	Replace with dietary formula or supplements containing medium-chain triglycerides
Fat-soluble vitamin malabsorption:
Vitamin A deficiency (night blindness, thick skin)	Replace with 10,000-15,000 IU/day as Aquasol A
Vitamin E deficiency (neuromuscular degeneration)	Replace with 50-400 IU/day as oral α-tocopherol or TPGS
Vitamin D deficiency (metabolic bone disease)	Replace with 5,000-8,000 IU/day of D₂ or 3-5 µg/kg/day of 25-hydroxycholecalciferol
Vitamin K deficiency (hypoprothrombinemia)	Replace with 2.5-5.0 mg every other day as water-soluble derivative of menadione
Micronutrient deficiency	Calcium, phosphate, or zinc supplementation
Deficiency of water-soluble vitamins	Supplement with twice the recommended daily allowance
Retention of biliary constituents such as cholesterol (itch or xanthomas)	Administer choleretic bile acids (ursodeoxycholic acid, 15-30 mg/kg/day)
Progressive liver disease; portal hypertension (variceal bleeding, ascites, hypersplenism)	Interim management (control bleeding; salt restriction; spironolactone)
End-stage liver disease (liver failure)	Transplantation

TPGS, D-tocopherol polyethylene glycol 1000 succinate.

Growth failure is a major concern and is related in part to malabsorption and malnutrition resulting from ineffective digestion and absorption of dietary fat. Use of a medium-chain triglyceride-containing formula can improve caloric balance.

With chronic cholestasis and prolonged survival, children with hepatobiliary disease can experience deficiencies of the fat-soluble vitamins (A, D, E, K). Inadequate absorption of fat and fat-soluble vitamins may be exacerbated by administration of the bile acid binder cholestyramine. Metabolic bone disease is common.

Serum vitamin A concentration can usually be maintained at normal levels in patients who have chronic cholestasis and who receive oral supplementation of vitamin A esters. It is essential to monitor the vitamin A status in such patients.

A degenerative neuromuscular syndrome is found with chronic cholestasis, caused by malabsorption and vitamin E deficiency; affected children experience progressive areflexia, cerebellar ataxia, ophthalmoplegia, and decreased vibratory sensation. Specific morphologic lesions have been found in the central nervous system, peripheral nerves, and muscles. These lesions are potentially reversible in children <3-4 yr of age. Affected children have low serum vitamin E concentrations, increased hydrogen peroxide hemolysis, and low ratios of serum vitamin E to total serum lipids (<0.6 mg/g for children <12 yr and <0.8 mg/g for older patients). Vitamin E deficiency may be prevented by oral administration of large doses (up to 1,000 IU/day); patients unable to absorb sufficient quantities may require administration of D-α-tocopheryl polyethylene glycol 1000 succinate orally. Serum levels may be monitored as a guide to efficacy.

Pruritus is a particularly troublesome complication of chronic cholestasis, often with the appearance of xanthomas. Both features seem to be related to the accumulation of cholesterol and bile acids in serum and in tissues. Elimination of these retained compounds is difficult when bile ducts are obstructed, but if there is any degree of bile duct patency, administration of ursodeoxycholic acid can increase bile flow or interrupt the enterohepatic circulation of bile acids and thus decrease the xanthomas and ameliorate the pruritus (see Table 348-5). Ursodeoxycholic acid therapy can also lower serum cholesterol levels. The recommended initial dose is 15 mg/kg/24 hr.

Partial external biliary diversion is efficacious in managing pruritus refractory to medical therapy and provides a favorable outcome in a select group of patients with chronic cholestasis who have not yet developed cirrhosis. The surgical technique involves resecting a segment of intestine to be used as a biliary conduit. One end of the conduit is attached to the gallbladder and the other end is brought out to the skin, forming a stoma. The main drawback of the procedure is the need to use an ostomy bag.

Progressive fibrosis and cirrhosis lead to the development of portal hypertension and consequently to ascites and variceal hemorrhage. The presence of ascites is a risk factor for the development of spontaneous bacterial peritonitis (SBP). The first step in the management of patients with ascites is to rule out SBP and restrict sodium intake to 0.5 g (∼1-2 mEq/kg/24 hr). There is no need for fluid restriction in patients with adequate renal output. Should this be ineffective, diuretics may be helpful. The diuretic of choice is spironolactone (3-5 mg/kg/24 hr in 4 doses). If spironolactone alone does not control ascites, the addition of another diuretic such as thiazide or furosemide may be beneficial. Patients with ascites but without peripheral edema are at risk for reduced plasma volume and decreased urine output during diuretic therapy. Tense ascites alters renal blood flow and systemic hemodynamics. Paracentesis and intravenous albumin infusion can improve hemodynamics, renal perfusion, and symptoms. Follow-up includes dietary counseling and monitoring of serum and urinary electrolyte concentrations (Chapters 356 and 359).

In patients with portal hypertension, variceal hemorrhage and the development of hypersplenism are common. It is important to ascertain the cause of bleeding because episodes of gastrointestinal hemorrhage in patients who have chronic liver disease may be due to gastritis or peptic ulcer disease. Because the management of these various complications differs, differentiation, perhaps via endoscopy, is necessary before treatment is initiated (Chapter 359). If the patient is volume depleted, blood transfusion should be carefully administered, avoiding overtransfusion, which can precipitate further bleeding. Balloon tamponade is not recommended in children because it can be associated with significant complications. Sclerotherapy or endoscopic variceal ligation may be useful palliative measures in the management of bleeding varices and may be superior to surgical alternatives.

For patients with advanced liver disease, hepatic transplantation has a success rate >85% (Chapter 360). If the operation is technically feasible, it will prolong life and might correct the metabolic error in diseases such as α₁-antitrypsin deficiency, tyrosinemia, and Wilson disease. Success depends on adequate intraoperative, preoperative, and postoperative care and on cautious use of immunosuppressive agents. Scarcity of donors of small livers severely limits the application of liver transplantation for infants and children. The use of reduced-size transplants and living donors increases the ability to treat small children successfully.