atresia vias biliares

7/31/2019 Atresia Vias Biliares

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Biliary atresia

Barbara Anne Haber, MDa, Pierre Russo, MDb,*aDivision of Gastroenterology and Nutrition, The Childrens Hospital of Philadelphia,

34th and Civic Center Boulevard, Philadelphia, PA 19104, USAbPathology Department, The Childrens Hospital of Philadelphia,

34th and Civic Center Boulevard, Philadelphia, PA 19104, USA

Biliary atresia (BA) is a progressive, idiopathic, necroinflammatory

process initially involving a segment or all of the extrahepatic biliary tree. As

the disease progresses, the extrahepatic bile duct lumen is obliterated and

bile flow is obstructed, resulting in cholestasis and chronic liver damage.

With time, the intrahepatic biliary system becomes involved. BA occurs with

an estimated frequency of 1 in 8 to 15,000 live births, which results in 250 to

400 new cases per year in the United States [1]. It is the most common causeof neonatal jaundice for which surgery is indicated; it is also the most

common indication for liver transplantation in children.

If not corrected, BA is uniformly fatal within the first 2 years of life [2,3].

More than a century has passed since the first descriptions of congenital

obliteration of the bile ducts by Thompson [4] yet a clear understanding of this

diseases etiology and pathogenesis remains lacking. Successful treatment

also remains elusive. The first surgical repair was introduced in 1916 by

Holmes [5], who discussed a bilioenteric anastomosis and introduced the

clinical classification of correctable and noncorrectable types. In 1928,the first surgery was reported in which the patient survived [6]. The next

significant therapeutic advance occurred in 1959, when Morito Kasai

introduced the hepatoportoenterostomy (a similar surgery is performed

today). The only other new therapy introduced has been liver transplantation.

For those patients who do not achieve drainage from hepatoportoenter-

ostomy, liver transplantation is performed. Transplantation is also performed

in those who develop complications of progressive liver disease such as

growth failure, cirrhosis, or refractory cholangitis.

Optimal timing of hepatoportoenterostomy is crucial in determiningoutcome after the first surgery. It is believed that a window of opportunity

occurs at approximately 4 to 8 weeks of age, because surgical and nonsurgical

Gastroenterol Clin N Am

32 (2003) 891911

* Corresponding author.

E-mail address: [email protected] (P. Russo).

0889-8553/03/$ - see front matter 2003 Elsevier Inc. All rights reserved.

doi:10.1016/S0889-8553(03)00049-9
mailto:[email protected]:[email protected]


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entities are more easily distinguished at this age. The waiting period permits

nonsurgical etiologies of neonatal jaundice to be sufficiently eliminated from

the differential diagnosis while still allowing for the option of surgicalintervention before a point of desperate illness. BA is clearly a progressive

disease, and despite hepatoportoenterostomy at an appropriate age two

thirds of children in the United States still require liver transplantation.

Etiology

At least two different forms of BA are recognized. However, it is possible

that the BA phenotype represents the final common pathway of several

etiologies [2,3,7]. The more common of the two forms is the perinatal or

postnatal form, which accounts for the majority of all cases. These children

typically appear healthy at birth; their weights are average and they have

pigmented stools. Jaundice develops at some variable interval postnatally;

typical timing is between 2 to 6 weeks of age. Because of the frequency of

breast milk jaundice, the diagnosis can be me missed unless a fractionated

bilirubin is obtained. The less common presentation is the embryonic or

fetal form, which occurs in 10% to 35% of cases [7]. These children are

cholestatic at birth; 10% to 20% have associated congenital anomalies.

Neither of the two forms is thought to be inherited, because HLA identical

twins discordant for BA have been described and recurrence within the same

family is exceedingly rare [8,9].

The pathogenesis of BA remains a mystery. The relative infrequency of

the disease in any one center makes investigation of large numbers of cases

difficult. Most of the causal theories and research to date can be divided into

five areas: (1) defects resulting from a viral infection or toxin exposure; (2)

defects in morphogenesis; (3) genetic predisposition; (4) defects in prenatal

circulation; and (5) immune or autoimmune dysregulation.

Viral/toxin

An acquired viral infection or toxin exposure has been the most-pursued

theory of BA etiology. The demonstration of timespace clusteringcom-

bined with the fact that the disease appears to be acquired postnatally most

frequentlyhas led researchers to look for events that might occur after

birth, such as virus or toxin exposure. Initial reports described a higherincidence of BA in rural rather than urban areas, as well as a seasonal

variation in which the winter months were predominating [10,11]. This

epidemiologic information has been called into question by a more recent

study in France that found no seasonal variation [12]. In animals, strong

evidence comes from reported outbreaks of an epidemic of BA among lambs

in 1964 and 1988 by Harper et al [13]. In each time period there was

892 B.A. Haber, P. Russo / Gastroenterol Clin N Am 32 (2003) 891911


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a correlation with a drought and a change of grazing patterns by pregnant

ewes. In 1964, 60 of a flock of 400 died, and 300 lambs died in 1988.

Autopsies revealed an enlarged, firm, dark liver with a shrunken fibroticgallbladder. No specific infectious or toxic agent was identified, however.

During the past 20 years, numerous studies exploring a viral etiology

were published, though none have been fully substantiated. The common

hepatotropic viruses A, B and C have all been investigated and none have

been implicated in BA [14,15]. Rubella has been examined, but there have

been no increases in BA during epidemics. Drut et al [16] found evidence of

human papilloma virus types 6 and 18 by nested polymerase chain reaction

in archived tissue from patients with BA and with neonatal hepatitis, though

these findings could not be duplicated by others [17]. This is just thebeginning of a long list of unsuccessful endeavors.

The most promising candidate viruses have been reovirus, rotavirus, and

cytomegalovirus. Of these three, the evidence for a role by infection with

reovirus type 3, a double-stranded RNA virus, has been the most

compelling. A relatively high prevalence of reovirus type 3 antibodies has

been detected in infants with BA [18] and neonatal hepatitis [19]. Reovirus

particles have been reported in bile duct remnants by immunohistochemistry

and electron microscopy [20,21], though this finding has been disputed [22].

Similarities between a weanling mouse model of infection and humandisease have been proposed [23,24], and reovirus particles were found in the

biliary tract of a rhesus monkey that developed BA [25]. Recently, Tyler et

al [26] have demonstrated the presence of reovirus RNA by polymerase

chain reaction in 55% of frozen tissues of patients with BA (except,

interestingly, those with associated polysplenia), as well as in 78% of

specimens from patients with choledochal cysts (versus 21% of specimens

from other hepatobiliary diseases). A similar search using archived paraffin-

embedded material was negative [27].

Much of the difficulty in interpreting findings is attributable to theamount of contradictory results, which is most likely due to differences in

experimental design. Riepenhoff-Talty et al [28] found evidence of rotavirus

type C in liver tissues of patients with BA. They also reported the

development of extrahepatic biliary obstruction in mice inoculated with

group A rotavirus, and immunization of the newborn pups appeared to be

protective [29]. However, a separate study by Bobo et al [30] could find no

evidence for rotavirus A, B, or C in hepatobiliary samples. Studies by

Fischler et al [31] have implicated infection with cytomegalovirus in the

pathogenesis of BA and other neonatal cholestatic disorders, as had earlierstudies by Tarr [32] and Hart [33]. Other investigators, however, have

reported no evidence of the virus in hepatobiliary samples [34,35].

As stated above, the difficulties in the interpretation of this data is in part

due to different techniques, sample size, the frequent occurrence of many of

these infections in neonates, and the likelihood that BA may represent the

final common path of several different types of injuries.

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Defective morphogenesis

The hypothesis that BA represents a defect in morphogeneis is

especially appealing for cases of the embryonic form, in which there is

a high frequency of associated congenital anomalies. These children are

thought to have a different disease than those who have the postnatal

form. Some authors have reported a poorer overall prognosis for these

patients [3638], although this is not well substantiated [39,40]. In the

series reported by Davenport et al [37], children with associated anomalies

had a lower birth weight and a higher incidence of maternal diabetes

compared with nonsyndromic cases. The most frequently reported associa-

tion is with polysplenia syndrome, which is noted in 5% to 20% of patients

with BA [39,4143]. Polysplenia syndrome is a disorder of laterality

development [44]. The reported anomalies are numerous and include

polysplenia, double spleen, asplenia, portal vein anomalies, situs inversus,

malrotation, cardiac anomalies, annular pancreas, immotile cilia syn-

drome, doudenal atresia, esophageal atresia, polycystic kidney, cleft palate

and jejunal atresia. Some authors have observed a histologic appearance

suggestive of ductal plate malformation and segmental agenesis of bile

ducts in the livers of infants with the fetal form [40]. This finding raises the

possibility that in some instances the defect in BA may result from ab-

normal interactions of a growth factor at a particular time of development

[45].

Recently, a mouse model has been described that results in a similar

constellation of defects. The inversin mouse (Inv) has either a deletion or

a recessive insertional mutation in the proximal region of chromosome 4,

resulting in anomalous development of the hepatobiliary system, as well as

anomalies of visceral organ symmetry [46,47]. The mice experienced com-

plete situs inversus, severe jaundice, and death in the first weeks of life. The

human inversin gene has been mapped to chromosome 9q, although no

mutation of that gene was detected in a series of cases with BA and laterality

disorders [48].

Further support of the theory that BA is a defect in morphogenesis is its

relationship to choledochal cysts. Landing [49] proposed that biliary atresia,

choledochal cysts, and neonatal hepatitis formed a continuum that he

termed infantile cholangiopathies. He viewed the relationship as different

degrees of response to an inflammatory process. Injury to the bile duct

epithelial cells that in turn led to obliteration would result in biliary atresia;

if the injury only caused weakening of the bile duct wall, a choledochal cyst

would develop. Further supportive evidence has included cystic dilatation

of a segment of the extrahepatic biliary tree observed by preoperative

ultrasound in patients with BA [50,51] and antenatal ultrasound demon-

strating cystic dilitation similar to that seen with choledochal cyst, in

patients found to have BA [52,53]. Lastly, evolution from an apparent

choledochal cyst to BA has been also been reported [54].



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Genetic

BA is not thought to be a heritable disorder, but it is likely that genetics is

a factor. Potential gene candidates include those genes implicated in

laterality such as inversin and CFC; Jagged 1, which is responsible for bile

duct paucity in Alagille syndrome; and background genes, such as the

HLA genes. In the fetal form, the associated anomalies and the similarities

with Inv mouse suggest that a large gene defect or alteration in gene

expression at a critical time of development accounts for the anomalies. A

recent study demonstrated an increased frequency of Jagged 1 mutations in

cases of BA [55]; the mutations reported are identical to those found in

Alagille syndrome. This work raises the possibility that the Jagged 1 gene

may be involved at different stages of biliary development. In the other

instances, as with many diseases, a specific genetic background may be

necessary for the manifestation or acquisition of disease. The increased

association with certain HLA loci and its early onset suggests a genetic

susceptibility to an acquired insult [5658]. Reports of the occurrence of BA

with other cholestatic diseases within families lends further credence to the

possibility of shared etiologic features among these entities, possibly

modulated by the timing and severity of the insult. BA and neonatal

hepatitis have been reported in siblings [33], as has BA and intrahepatic

paucity of bile ducts [59]. Familial associations of BA with dilatation of the

biliary tree and malformation of the pancreaticobiliary junction [60],

sclerosing cholangitis [61], and with North American Indian cirrhosis [62]

have also been reported.

Vascular etiology

There is a frequent association in BA between abnormalities of the portal

vein and hepatic artery. This association has raised the question of an

ischemic insult to the biliary tree in utero. The bile ducts receive their bloodsupply exclusively from the hepatic arterial circulation. Interruptions of this

flow account for bile duct damage in liver transplantation in humans as well

as in a fetal sheep model [63,64]. In animal models, the lesion resembles the

less common correctable variant of BA.

Immunologic/autoimmune dysfunction

Many studies support a role for immune dysfunction in BA. The central

concept is that after a particular insult (eg, a viral or toxin exposure) the

biliary epithelium expresses inappropriate antigens on the surface of the

bile duct epithelia, which in the proper genetic milieu are recognized

by circulating T lymphocytes. These cells then elicit a cellular immune

injury, resulting in inflammation and fibrosis of the bile duct epithelium.

Like a number of autoimmune diseases, there appears to be a female



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predominance in BA and aberrant HLA expression in bile duct epithelium.

It has been proposed that some insult to the fetus or neonate leads to

abnormal expression of antigens in bile duct epithelium [1]. Support for sucha theory comes from T cell subset ratios that are more suggestive of an

immune or metabolic pathogenesis than an infectious one. For example, the

subsets are more akin to a1-antitrypsin deficiency than hepatitis B-related

inflammation of the liver [65].

At present, there is evidence supporting a number of aspects of the

immune cascade, including antigen expression and presentation, T cell

activation, Kupffer cell activation, cytokine release, and apoptosis. A

number of HLA associations have been reported. Silveira et al [66] reported

an association with the HLA-B12 allele and the haplotypes A9-B5 and A28-B35. The increase in HLA-B12 occurred most frequently in those without

other anomalies. In a different ethnic group, Kobayashi et al [67] reported

associations with A33, B44, and DR6. Further support of an immune

mechanism is the finding of abnormal expression of HLA-DR, a class II

antigen, in biliary epithelium in patients with BA. Normally only major

histocombatibility complex class I antigens are expressed by bile duct

epithelium. When aberrant expression is present, it is possible that the

biliary epithelium is behaving as an antigen-presenting cell in the immune

pathway and thus directly activates T lymphocytes. The activation of T cellsrequires adhesion to the antigen-presenting cell through intercellular

adhesion molecules (ICAMs). ICAM expression by biliary epithelium in

BA has been reported both by Broome et al [68] and Dillon et al [69]. Lastly,

Davenport et al [70] have demonstrated that activated and proliferating

helper T cells and natural killer cells are present in the liver and in bile ducts

in BA.

Taken together, there is evidence of abnormal antigen expression in the

livers of children with BA, as well as evidence that T cell activation and

cytotoxicity play some role in causing injury. The damage may also be medi-ated through Kupffer cells. Recent histologic studies have demonstrated

increased numbers and size of Kupffer cells in liver tissue of BA patients

[71], and Davenport et al [70] have reported a poorer prognosis in children

with increased CD68+ cells (Kupffer cells) in the biliary remnant.

Expression of FAS ligand in bile duct epithium in BA patients has also

been reported and may play a role in apoptotic injury [72].

Anatomy and histopathology

The destructive inflammatory process that underlies BA may involve

a short segment of a duct, an entire duct, or the entire system. There is

obliteration or discontinuity of the hepatic or common bile ducts for any

length between the porta hepatis to the duodenum. Many different classi-

fications of BA have been proposed over the years. All essentially rec-

ognize three broad types of lesions. The most comprehensive classification



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children are healthy and thriving, so pediatricians can easily be misled.

Diagnosis is made by pursuing a series of serologic, urine, and imaging

studies. When suspicion becomes high, a liver biopsy or intraoperativecholangiogram is recommended.

Box 1 shows that a broad differential needs to be considered in the

evaluation of a child with neonatal cholestasis. Because the timing of

surgery is crucial, the diagnostic approach is often to proceed with the

evaluation, even if all the tests have not returned. Attempts have been made

to develop easy tests that reliably predict BA. Recently, the triangular cord

sign seen on ultrasound has been reported to have a positive predictive

value of 95% [82]. If the reliability and reproducibility of this test is

established, it will likely become a standard in the evaluation.At this point, if suspicion is high, more invasive tests are recommended.

The choices are liver biopsy, endoscopic retrograde cholangiopancreatog-

raphy, magnetic resonance cholangiogram, or operative cholangiogram.

The liver biopsy is used to discriminate between intra- and extrahepatic

causes of cholestasis and to determine the appropriateness of surgical

exploration.

Liver biopsy

In experienced hands, the accuracy rate of interpretation of liver biopsies

in neonatal cholestasis is high (probably > 90%) [83]. The accuracy rate

of interpretation of needle and open liver biopsies is roughly the same,

assuming the needle biopsy is adequate [84]. The main purpose of the biopsy

is to distinguish obstructive from nonobstructive causes of cholestasis.

Histology alone cannot discriminate between biliary atresia and other causes

of obstruction, such as a choledochal cyst. However, a diagnosis of

obstruction mandates surgical exploration, and biliary atresia is by far the

most frequent cause of obstructive jaundice in the neonate. As in any area ofdiagnostic pathology, close collaboration with the clinical team is essential

to diagnosis.

Diagnostic changes for BA noted on biopsy include expansion of the

portal spaces with proliferation of bile ductules and interlobular bile ducts

with bilirubinostasis, which is the presence of bilirubin pigment in bile plugs

(Fig. 1). Bile duct proliferation with bile plugs is the most specific finding for

biliary obstruction and is the finding with the strongest discriminating value

[83]. Edema and some fibrosis are present in the portal tracts, accompanied

by an inflammatory infiltrate, which frequently represents myelopoiesis.Variable degrees of extramedullary hematopoiesis, canalicular and hepato-

cellular cholestasis, ballooning, and giant cell transformation of hepatocytes

may also be observed in the lobule.

A major pitfall in the interpretation of these biopsies is overreading

milder degrees of bile duct and ductular proliferation [85]. Lesser degrees

of bile duct proliferation, even with bile stasis, may occur in other



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Box 1. Differential diagnosis of neonatal and infantile

cholestasis

Neonatal hepatitis

Idiopathic NH

Viral NH

CMV

Herpes

Rubella

Reovirus

Adenovirus

Enteroviruses

Parvovirus B19

Paramyxovirus

Hepatitis B

HIV

Bacterial and parasitic

Bacterial sepsis

UTI

Syphilis

Listeriosis

Toxoplasmosis

Tuberculosis

MalariaBile duct obstruction

Cholangiopathies

Biliary atresia

Choledochal cysts

Nonsyndromic paucity

Alagille syndrome

Sclerosing cholangitis

Spontaneous duct perforation

Caroli disease

Congenital hepatic fibrosis

Bile duct stenosis

Other

Inspissated bile/mucus

Cholelithiasis

Tumors

Masses

Cholestatic syndromes

PFIC

Type 1 Byler P-type ATPaseType 2 Canalicular bile acid Tx

Type 3 MDR3 deficiency

Aagenaes cholestasis lymphedema

N. Am. Indian cholestasis

(continued on next page)


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Nielsen Greenland Eskimo cholestasis

Benign recurrent intrahepatic cholestasis

DubinJohnson MRP2 cMOAT deficiency

Rotor syndrome

Metabolic disorders

a1-antitrypsin deficiency

Cystic fibrosis

Neonatal iron storage disease

Endocrinopathies

Hypopituitarism

Hypothyroidism

Amino acid disorders

Tyrosinemia

HypermethionemiaMevalonate kinase deficiency

Lipid disorders

Niemann-Pick A, B

Niemann-Pick C

Gaucher

Wolman

Cholesterol ester storage ds

Urea cycle disorders

Arginase deficiency

Carbohydrate disorders

Galactosemia

Fructosemia

Glycogen storage IV

Mitochondrial disorders

Oxidative phosphorylation

Peroxisomal disorders

Zellweger

Infantile refsum

Other enzymopathies

Bile acid synthetic disorders

3b-hydroxysteroid dehydrogenase/i

D4-3-oxosteroid 5b-reductase

Oxosterol 7a-hydroxylase

Toxic

Drugs

Parenteral alimentation

Aluminum

Miscellaneous associations

Shock/hypoperfusion

Histiocytosis X

Neonatal lupus erythematosus

Indian childhood cirrhosis

Autosomal trisomies 17, 18, 21

Graft v host disease


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nonobstructive disorders (eg, cytomegalovirus infection [86];a1-antitrypsindeficiency [87]; early Alagille syndrome [88]; total parenteral nutrition

[89,90]; cystic fibrosis, especially in young infants [91,92]; and sepsis [93]).

Furthermore, the earliest histologic changes associated with BA may be

relatively nonspecific, and biopsies too early in the course of the disease may

result in a falsely negative diagnosis [94]. In any instance when a strong

clinical suspicion of obstruction exists, early biopsies with nonspecific

changes should be followed by a repeat biopsy.

Endoscopic retrograde cholangiopancreatography and magneticresonance cholagiogram

Endoscopic retrograde cholangiopancreatography has been advocated as

a relatively noninvasive method (compared with surgical exploration) to

determine biliary obstruction. However, the technical difficulties of this

procedureas well as the fact that few institutions possess appropriately

Fig. 1. Typical findings of biliary atresia on a liver biopsy from a 7-week-old patient with

cholestasis. There is portal tract expansion, with characteristic bile duct and ductular

proliferation with the presence of bile plugs in the lumen of biliary structures (arrows). Some

fibrosis and inflammation is also noted. Hepatocytes in the lobule are variably ballooned, with

retention of bile pigment, and some multinucleated forms may be observed, but generally less

than in non-specific neonatal giant cell hepatitis. Extramedullary hematopoiesis in liver

sinusoids is a frequent concomitant finding.



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sized equipmenthas made this an infrequent choice. Even in skilled centers

the failure rate is 3% to 14% and the morbidity ranges from 0.8% to 7%

[95]. Magnetic resonance cholangiogram has also been suggested as analternative to intraoperative cholangiogram. The sensitivity has been

reported to be 90%, specificity 77%, and accuracy 82% [96], yet most

centers are still not skilled at this test in this age group.

It remains for the present that if the biopsy is suggestive of obstruction,

most physicians then proceed with an intraoperative cholangiogram.

Box 1 lists the massive differential that is considered in the evaluation of

neonatal cholestasis. Fig. 2 shows the algorithm for diagnosis. As stated

previously, evaluation often proceeds despite the fact that more sophisti-

cated laboratory tests have yet to be completed. It is of utmost importancethat a rapid diagnosis of BA is made so that a hepatoportoenterostomy is

performed in a timely manner if needed.

If a cholangiogram is consistent with BA, a surgical hepatoportenter-

ostomy is recommended. Initially, the two most important prognostic

factors in determining surgical outcome are the age at operation and the

surgeons experience [97]. All in the field agree that children who have initial

surgery after 100 days of age have a worse outcome; what is less clear is

whether or not there are advantages to operating earlier than 40 to 60 days

of age. A Kings College study examined the outcomes of children who hadtheir initial surgery at less than 40 days of age, between 41 and 60 days of

age, between 61 and 99 days of age, and 100 days or more [98]. The study

measured survival with native liver at 1 year of age and yielded a 90%

success rate for all groups under 100 days and a 60% success rate for the 100

days or later group.

Management after portoenterostomy

After surgery, the management of a child with BA is aimed at optimizing

nutrition, promoting choleresis, and preventing inflammation. Children are

given antibiotics immediately postoperatively, and when bowel sounds

return a diet that is easily digested is given.

Nutrition and vitamins

Malnutrition and growth retardation result from a combination of

factors including fat malabsorption from decreased intestinal bile salts,organomegaly or ascites. The child might not be able to meet the increased

metabolic demands of a liver with chronic inflammation. Typically a formula

high in medium chain triglycerides (MCT) is chosen to overcome some of

the fat malabsorption. Previously used formulas with more than 80% MCT

were deficient in long chain fatty acids, especially linoleic acid. The more

recently developed formulas contain approximately 60% MCT and provide



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Fig

.2.

Algorithm

forevaluationo

fneonataljaundice.



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essential fatty acids. This choice will allow dietary fat to be absorbed

without a substantial need for micelle formation, which may be impaired. If

a child does not sustain adequate growth, supplementation is achieved byincreasing the caloric density of the formula; if necessary, nasogastric

feedings are implemented to guarantee intake. Infants may have caloric

requirements in excess of 150 kcal/kg/day. Growth is usually monitored by

following length and weight and head circumference. However, there is

good evidence that this may underrecognize nutritional issues because of the

issues of organomegaly and fluid retention. Midarm circumference and

triceps skinfold measured by a technician trained in anthropometry may be

a better way to detect true lean body and fat mass [99].

Protein is typically not restricted in a childs diet unless encephalopa-thy is present. Protein intake aids in achieving positive nitrogen balance,

and the type of caseine protein typical of most infant formulas is well

tolerated. Monitoring of proteins such as albumin, retinol binding

protein, and PT provides an index of protein balance and hepatic synthetic

function.

Fat soluble vitamins are closely monitored and supplemented as needed

[100]. Some institutions routinely provide supplements for vitamins A, D, E,

and K until the total bilirubin is below 2 mg/dL; however, no unified

standard has been adopted. Vitamin A deficiency is rare, but its toxicitywhen administered inappropriately has made it the most commonly

monitored vitamin, and it is only supplemented when deficient. The goal

of therapy is low normal serum levels of 400 to 500 lm/mL. Vitamin D is

normally ingested in the diet, but is highly dependent on bile salt

solubilization for absorption [101,102]. Dietary vitamin D is hydroxylated

at the 25 position in the liver, followed by hydroxylation at the 1 position by

the kidney to form the active hormone. Usual supplementation is with 25-

OHD, which is the most common form found in the circulation. Because

there is no impairment of the hydroxylation in the kidney, this is thepreferred and safer form. However, if rickets is present, the active hormone

1,25-(OH)2D is administered with close monitoring of calcium and

phosphorous levels [101]. Vitamin E deficiency is found in BA, and

supplementation can be successfully achieved with d-alpha-tocopherol poly-

ethylene glycol [103105]. Lastly, Vitamin K is critical for activation of

clotting factors II, VII, IX, and X. Two naturally occurring forms of vitamin

K exist. K1 is of dietary origin, and K2 is synthesized by intestinal bacteria.

Monitoring PT is standard and is an easy method of assessing vitamin K

status [100,106]. Other nutrients that may need to be monitored includeiron, zinc, and cholesterol. Iron may become deficient because of inadequate

dietary content, chronic inflammation with poor iron use, and gastrointes-

tinal blood loss. Zinc is sometimes depleted in malabsorptive states and has

been associated with poor linear growth. Cholesterol is often elevated in

chronic cholestasis, with some patients developing cutaneous deposits in the

form of xanthomas.



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Choleresis and decreasing inflammation: steroids, antibiotics,

and ursodeoxycholic acid

In the initial postoperative period, the major objective is to prevent

postoperative cholangitis. Administration of a combination of antibiotics

and possibly steroids is recommended. The use of steroids has been adopted

from the Japanese, who use steroids routinely. Prednisolone is given in-

travenously for 4 days, followed by oral administration until the total

bilirubin is less than 2.0 mg/dL. Some centers in the United States have

adopted this practice, but there has yet to be a well-designed controlled

study. In one study, 25 infants were studied retrospectively after a 6-week

course of steroids. The measured outcome was survival with native liver. At

a mean follow-up of 50 months, 88% still had their native liver [107].

Progression of liver disease is also thought to be related to repeated bouts

of cholangitis; therefore, one clinical approach is to aggressively treat

cholangitis. Cholangitis typically occurs in the first year of life [108]. Reports

from the 1980s suggest that the incidence of cholangitis ranges from 50% to

more than 90%. Our more recent experience is significantly less (un-

published data). Some hospitals routinely use antibiotic prophylaxis for the

first year of life; however, some argue that the risk of developing resistant

intestinal flora outweighs any proven benefits. The diagnosis is made by

percutaneous liver biopsy and confirmed by blood culture. The suspicion

should be raised in any child with fever, irritability, leukocytsosis, or an

unexplained change in liver enzymes. Unfortunately, the diagnosis is

complicated by the frequency of childhood febrile diseases (eg, otitis media,

viral illnesses). When no specific source is identified and clinical suspicion

exists, broad spectrum antibiotics should be used to cover enteric organisms.

Ursodeoxycholic acid is routinely given to promote choleresis and to

prevent scarring [109]. There is no documented efficacy in BA; however, it is

considered a well-tolerated medicine with potential benefit. Its use stems

from the literature regarding PBC, AIH, and rat models of fibrosis.

Ursodeoxycholic acid is a naturally occurring dihydroxy bile acid with

known choleretic properties. It undergoes extensive enterohepatic recycling.

Following conjugation and biliary secretion, the drug is hydrolyzed to active

ursodiol. Several large, well-designed studies in adults with primary biliary

cirrhosis have demonstrated its usefulness and tolerability. Ursodeoxycholic

acid significantly lowers serum levels of alkaline phosphatase, alanine

aminotransferase, and aspartate aminotransferase at a dose of 13 to 15 mg/

kg/day in adults with PBC [110112]. With this chemical improvement,

there has also been documented reduction in disease progression based on

histology and mortality [113]. Few subjects in these studies have had to

discontinue drug administration because of adverse events. The literature

regarding the efficacy of ursodeoxycholic acid in preventing fibrosis is

fledgling, although a bile duct-ligated rat model of fibrosis has demonstrated

benefit [114].



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Summary

BA is a rare disease of unclear etiology; nevertheless, its impact in the

field of pediatric hepatology is significant. It is the most common surgically

correctable cause of neonatal cholestasis and is the most common pediatric

disease referred for liver transplantation. Little progress has been made with

regard to improving outcome or understanding its pathogenesis in the past

decade. Fortunately, however, a national, government-sponsored collabo-

rative endeavor has begun that will hopefully make a significant impact

upon the progress of designing new treatments for BA and develop a better

understanding of its pathogenesis.

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