Colestasis Neonatal Semin[1].04

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Neonatal Cholestasis

Sridevi Venigalla, MD, and Glenn R. Gourley, MD

Any infant who is jaundiced beyond two to three weeks of life should be evaluated for

neonatal cholestasis. Neonatal cholestasis is defined as accumulation of bile substances in

blood due to impaired excretion. These infants should always have fractionated serum

bilirubin levels checked to differentiate the conjugated hyperbilirubinemia of cholestasis

from unconjugated hyperbilirubinemia that is usually benign and spontaneously resolves.

Conjugated hyperbilirubinemia, pale stools and dark urine are the cardinal features of

neonatal cholestasis. The differential diagnosis of cholestasis is extensive and a systematic

approach is helpful to quickly establish the diagnosis. Biliary atresia is a common cause of

neonatal cholestasis and affected infants need surgery before 60 days of life for better

prognosis. Premature infants have multifactorial cholestasis and need a modified approach

to the evaluation of cholestasis. Management of cholestasis is mostly supportive, consist-

ing of medical management of complications of chronic cholestasis like pruritus andnutritional support for malabsorption and vitamin deficiency.

Semin Perinatol 28:348-355 2004 Elsevier Inc. All rights reserved.

KEYWORDS neonate, jaundice, direct hyperbilirubinemia, cholestasis, obstructive jaundice,

conjugated hyperbilirubinemia

Jaundice is a common clinical finding in the first 1 to 2weeks after birth and usually resolves spontaneously. Anyinfant who is jaundiced beyond 2 to 3 weeks after birth needsfurther evaluation to rule out neonatal cholestasis. Neonatalcholestasis is defined as impaired canalicular biliary flow re-sulting in accumulation of biliary substances (bilirubin, bileacids and cholesterol) in blood and extrahepatic tissues. It isclinically manifested by conjugated hyperbilirubinemia andshould be differentiated from unconjugated hyperbiliru-binemia which is usually benign.1 The incidence of neonatalcholestasis is estimated around 1 in 2500 live births.2,3 Themost common causes of neonatal cholestasis are biliary atre-sia and idiopathic neonatal hepatitis.

Pathophysiology

The normal process of bile production involves two main

processes: uptake of bile acids by hepatocytes from the bloodand excretion of bile acids into the biliary canaliculus. Uptakeof bile acids from sinusoidal blood is an active process at thesinusoidal membrane of the hepatocytes. Na taurocholate

cotransporting polypeptide (NTCP) and organic anion trans-porting proteins (OATP) are the two main receptors involvedin the uptake of conjugated bile acids by the liver cells. Thesereceptors are also responsible for the transport of other an-ions like drugs and toxins through the hepatocellular mem-brane.

At the biliary canaliculus, bile salt export pump (BSEP)and the multidrug resistant proteins MRP2 and MDR3 areinvolved in the secretion of bile acids into bile. These pumpsare present in the canalicular membrane.

In newborn infants, the biliary system is both structurallyand functionally immature making them more susceptible tocholestasis. In hepatitis and sepsis, there is down regulationof the NTCP and OATP receptors resulting in decreased bileproduction and cholestasis. Various genetic defects in thetransporter proteins have been recognized in familial cho-lestasis syndromes, eg, mutation of BSEP gene in progressive

familial intrahepatic cholestasis type 2 (PFIC), defect in theMDR3 in PFIC type 3.

Classification ofNeonatal Cholestasis

The differential diagnosis of neonatal cholestasis is extensiveand can be classified based on the anatomic location of thepathology into extrahepatic and intrahepatic causes. Biliaryatresia and choledochal cyst are examples of extrahepatic

Department of Pediatrics, Oregon Health & Science University, Portland,

OR.

Address reprint requests to: Glenn R. Gourley, MD, Oregon Health & Sci-

ence University, 707 SW Gaines Road, Mailcode: CDRCP, Portland, OR

97239-2998. E-mail: [email protected]

348 0146-0005/04/$-see front matter 2004 Elsevier Inc. All rights reserved.doi:10.1053/j.semperi.2004.09.008


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causes while common intrahepatic causes include idiopathicneonatal hepatitis, infections, 1-antitrypsin deficiency andother metabolic disorders.2-6 The different causes of cholesta-sis can also divided into broad etiological categories like in-fectious, metabolic, toxic, chromosomal, vascular disordersand bile duct anomalies (Table 1).

Clinical Presentation

An infant with cholestasis usually presents with prolongedjaundice, pale stools and dark urine. Acholic stools are acardinal feature of cholestasis and should be promptly eval-uated. Some infants may present with signs of coagulopathydue to deficiency of clotting factors or vitamin K deficiency.Neurological abnormalities like irritability, lethargy, seizuresand poor feeding may indicate either sepsis or metabolicdisorders.

Physical examination is remarkable for jaundice. Hepato-megaly is common. Splenomegaly may be seen in infants

with advanced liver disease. Other physical findings mayinclude growth retardation seen in congenital infectionsand syndromic facial dysmorphisms. Choledochal cyst canpresent as a mass in the right upper quadrant.

Evaluation of Cholestasis

Any infant presenting with jaundice beyond 2 weeks afterbirth should be immediately evaluated for cholestasis.7 Adetailed history (including family history, pregnancy anddelivery history and postnatal course) and physical exam-ination could provide clues to a specific diagnosis. Breast-

fed infants who can be reliably monitored and have anotherwise normal history and physical examinationshould be reevaluated at 3 weeks of age and if still jaun-diced, have fractionated serum bilirubin levels checked atthat time.7 Once cholestasis is established, further inves-tigations should be done in a stepwise manner to establishthe specific cause of cholestasis (Fig. 1). The investigationsshould first rule out conditions requiring immediate inter-vention like sepsis, metabolic disorders like galactosemia,glycogen storage disorders and other endocrinopathies.Once they have been excluded, the next step is to look forbiliary atresia. It is important to establish or rule out bili-

ary atresia early because of better prognosis if the patientundergoes surgical intervention before 60 days of life. Ifbiliary atresia has been excluded, further investigationsshould be done to establish the cause of intrahepatic cho-lestasis (Table 2). The potentially extensive evaluation ofan infant with cholestasis (Fig. 1 and Table 2) should beindividualized to efficiently and promptly establish a di-agnosis. The approach suggested in Fig. 1 should beadapted to the clinical presentation.

Laboratory InvestigationsThe most important initial investigation is fractionated serum

bilirubin levels. Conjugated hyperbilirubinemia is defined asconjugated or direct bilirubin level more than 1 mg/dL whenthe total bilirubin is less than 5 mg/dL or more than 20% of

Table 1 Differential Diagnosis of Neonatal Cholestasis

1) Idiopathic neonatal hepatitis2) Infections

Viral:CytomegalovirusRubellaReovirus3AdenovirusCoxsackie virus

Human herpes virus 6Varicella zosterHerpes simplexParvovirusHepatitis B and CHuman immuno-deficiency virus

Bacterial: sepsisUrinary tract infectionSyphilisListeriosisTuberculosis

Parasitic: ToxoplasmosisMalaria

3) Bile duct anomaliesBiliary atresiaCholedochal cystAlagille syndrome

Non syndromic bile duct paucityInspissated bile syndromeCaroli syndromeCholedocholithiasisNeonatal sclerosing cholangitisSpontaneous common common bile duct perforation

4) Metabolic disorders1-antitrypsin deficiencyGalactosemiaGlycogen storage disorder type IVCystic fibrosisHemochromatosisTyrosinemiaArginase deficiencyZellwegers syndromeDubin-Johnson syndromeRotor syndrome

Hereditary fructosemiaNiemann Pick disease, type CGauchers diseaseBile acid synthetic disordersProgressive familial intrahepatic cholestasisNorth American Indian familial cholestasisAagenaes syndromeX-linked adreno-leukodystrophy

5) EndocrinopathiesHypothyroidismHypopituitarism (Septo-optic dysplasia)

6) Chromosomal disordersTurners syndromeTrisomy 18Trisomy 21Trisomy 13Cat-eye syndrome

Donahues syndrome (Leprechauns)7) Toxic

Parenteral nutritionFetal alcohol syndromeDrugs

8) VascularBudd-Chiari syndromeNeonatal asphyxiaCongestive heart failure

9) NeoplasticNeonatal leukemiaHistiocytosis XNeuroblastomaHepatoblastomaErythrophagocytic lymphohistiocytosis

10) MiscellaneousNeonatal lupus erythematosus

Le foie vide (infantile hepatic non regenerativedisorder)

Indian childhood cirrhosis

Neonatal cholestastis 349


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Figure 1 An approach to a full term or premature infant with cholestasis (modified, used with permission 3).


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the total bilirubin level if the total bilirubin is greater than 5mg/dL

Serum transaminases, alanine aminotransferase (ALT)and aspartate aminotransferase (AST), are sensitive indi-

cators of hepatocellular injury but are neither specific norof prognostic value. Alkaline phosphatase is found in the

liver, bone and kidney. Elevated levels can be seen inbiliary obstruction, but is not specific and other sources of

theelevation like bone disease need to be ruled out. -Glu-tamyl transpeptidase (GGT) is an enzyme in biliary epi-

thelium. Elevated levels are highly sensitive for cholestaticdisorders like biliary atresia, 1-antitrypsin deficiency,

Alagille syndrome and idiopathic neonatal hepatitis. How-ever, normal levels are seen in progressive familial intra-hepatic cholestasis (PFIC).

Radiological InvestigationsAbdominal UltrasoundReal-time abdominal ultrasonography is the most useful ini-tial imaging study in the evaluation of neonatal cholestasis.Ultrasonography can assess the size and appearance of theliver and gall bladder including visualization of gallstonesand biliary sludging. An ultrasound examination can estab-lish the diagnosis of choledochal cyst or demonstrate a smallor absent gall bladder that suggests biliary atresia. The trian-gular cord sign that represents a fibrous cone of tissue at theporta hepatis is highly specific for biliary atresia.8,9 Bile ductdilation is not seen in biliary atresia.

Hepatobiliary ScintigraphyHepatobiliary scintigraphy using technetium labeled imino-diacetic acid derivatives is helpful in distinguishing biliaryatresia from other causes of cholestasis. Normal uptake intohepatocytes but delayed excretion is seen in biliary atresia,while in neonatal hepatitis the uptake of the isotope into the

hepatocytes is delayed but the excretion is normal. Pretreat-ment with phenobarbital (5 mg/kg/d for 5 days) improvessensitivity by increasing the biliary excretion of the isotope.10

Magnetic Resonance Cholangiography (MRC)MRC using T2-weighted turbo spin-echo sequences is beingused to assess the biliary tract. Non- visualization of the com-mon bile duct and presence of small gall bladder have beennoted in biliary atresia. More studies are required to provereliability of this modality.11

Endoscopic Retrograde Cholangiography (ERC)This can be useful in evaluation of infants with biliary ob-

struction. However the need for high technical expertise andgeneral anesthesia for the study limits its feasibility.

Duodenal Aspirate AnalysisDuodenal fluid is obtained by either placing a tube or a stringin the duodenum and the aspirate is analyzed for bilirubinconcentration. In biliary obstruction, the bilirubin concen-tration of the aspirate is not greater than the serum bilirubinconcentration. There has been some data showing the sensi-tivity of this test similar to that of hepatobiliary scintigraphy.This test has limited use because it is more invasive, but canbe a cheaper alternative when other tests are unavailable.7

Liver BiopsyLiver biopsy is the single most definitive investigation in theevaluation of neonatal cholestasis. Typical findings in biliaryatresia include bile duct proliferation, bile plugs and portaltract edema and fibrosis. These findings should be differen-tiated from those seen in idiopathic neonatal hepatitis thatinclude diffuse cell swelling, giant cell transformation andfocal hepatocellular necrosis.

Management of Cholestasis

Medical management of cholestasis is mostly supportive anddoes not alter the natural course of the disease. It is aimedmostly at treating the complications of chronic cholestasis

Table 2 Evaluation of an Infant with Cholestasis

1) Initial investigations: Establish cholestasis and

determine severity of liver disease

a) Detailed history and physical examination (include

family and pre and post natal history, stool color)

b) Fractionated serum bilirubin levels

c) Tests of liver injury (AST, ALT, Alkaline phosphatase,

GGT)d) Liver function tests (Serum albumin, Prothrombin

time, Serum ammonia, Blood glucose)

2) Detect conditions that require immediate treatment

a) Complete blood count, bacterial cultures (blood and

urine) to rule out sepsis

b) Serum T4 and TSH to rule out hypothyroidism

c) To detect metabolic conditions: (Urinalysis, Urine

reducing substance, urine organic acids, urine and

serum amino acids, urine succinylacetone, galactose-

1-phosphate uridyl transferase, serum lactate, serum

iron and ferritin levels)

d) VDRL and viral serologies and cultures

3) Differentiate extrahepatic disorders from intrahepatic

causes of cholestasis

a) Ultrasonography

b) Hepatobiliary scintigraphy

c) Percutaneous liver biopsy (histology, electron

microscopy, immunohistochemistry)

d) Exploratory laparotomy with intraoperative

cholangiogram

4) Establish other specific diagnoses

a) Serum 1-antitrypsin levels and phenotype

b) Sweat chloride for cystic fibrosis

c) Urine and serum for bile acids and precursors

d) Genetic testing for Alagille syndrome and PFIC

syndromes.

e) X-rays of skull and long bones to look for congenitalinfection, chest x-ray for heart disease, eye exam for

posterior embryotoxon or choreoretinitis

f) Bone marrow examination and skin fibroblast culture

for storage disorders

AST, Aspartate transferase; ALT, Alanin e trans ferase ; GGT,

Gamma glutamyl transpeptidase; T4, Thyroid hormone, Thy-

roxine; TSH, Thyroid stimulating hormone; VDRL, Venereal

Disease Research Laboratory; PFIC, Progressive familial in-

trahepatic cholestasis.



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like pruritus, malabsorption and nutritional deficiencies andportal hypertension.

PruritusThe cause of pruritus in cholestasis is unclear but decreasingthe levels of bile acids in blood has shown improvement ofsymptoms. The various drugs used for this purpose throughdifferent mechanisms of actions decrease the bile acid levels.

Ursodeoxycholic acid (UDCA) is a hydrophilic bile acidand acts by altering the bile pool by replacing the hydropho-bic bile acids. UDCA is generally used as first line therapy forpruritus due to cholestasis, parenteral nutrition induced cho-lestasis and in biliary atresia. The dosage is 10 to 20 mg/kg/din divided doses. The most common side effect is diarrheaand resolves with dosage reduction.

Rifampin inhibits the bile acid uptake by the hepatocytesand also induces the hepatic microsomal enzymes. Dosage is10 mg/kg/d. Side effects include hepatotoxicity and severaldrug interactions.

Phenobarbital stimulates bile acid independent flow, en-hances bile acid synthesis, induces hepatic microsomal en-zymes and hence lowers the circulating bile acid levels. Doses

of 3 to 10 mg/kg/d have been used. Sedation and behavioralside effects limit its use.

Cholestyramine, an anion exchange resin, binds bile acidsin the intestinal lumen, thus blocking the enterohepatic cir-culation of bile acids and increasing their excretion. It alsodecreases the negative feedback to the liver, promoting theconversion of cholesterol to bile acids like cholic acid thatacts as a choleretic. It is used in long-term management ofintrahepatic cholestasis and hypercholesterolemia. Doses of0.25 to 0.5 g/kg/d are generally used. Side effects includehyperchloremic metabolic acidosis and increased steator-rhea. Cholestyramine is usually avoided in infants with a

portoenterostomy for biliary atresia due to concerns of risk ofaccumulation of the drug at the anastomosis causing an ob-struction.

Nutritional ManagementNutritional assessment should start at the initial visit and thegrowth parameters including weight and height for age andweight for height measurements should be closely followed.Long chain fatty acids are not well absorbed and this leads tomalnutrition and fat-soluble vitamin deficiency. Mediumchain triglycerides (MCT) are more readily absorbed and area better source of fat calories. These infants should be startedon a formula containing MCT like Pregestimil or Alimentum.

If oral intake is not sufficient, patients may be started onnocturnal enteral feeds. Due to steatorrhea and increasedenergy expenditure, the caloric intake goal should be 125%of recommended dietary allowance based on ideal bodyweight. Some infants may need additional calories forcatch-up growth if there is already significant malnutritionpresent.

The intestinal absorption of fat-soluble vitamins (A, D, Eand K) requires the presence of bile acids. Doses of at leasttwo to four times the recommended daily allowance aregiven. Vitamin supplementation should continue at least 3months after resolution of jaundice (Table 3).

Neonatal Phototherapy in CholestasisThe bronze infant syndrome is an important but uncommoncomplication of phototherapy that occurs in some infantswith cholestasis and is described as a dark, grayish-browndiscoloration of the skin, serum,and urine caused by a poorlyunderstood accumulation of porphyrins and other metabo-lites. This syndrome is generally benign and if there is a needfor phototherapy, direct hyperbilirubinemia should not be acontraindication. However, since the products of photother-apy are excreted in bile, cholestasis can reduce the effective-ness of phototherapy. In infants receiving phototherapy who

develop the bronze infant syndrome, the American Academyof Pediatrics recommends that exchange transfusion shouldbe considered if the total serum bilirubin (TSB) is in the

Table 3 Medical and Nutritional Management of Cholestasis

Drug Dose Side Effects

Ursodeoxycholic acid 10-20 mg/kg/day Diarrhea, Hepatotoxicity

Rifampin 10 mg/kg/day Hepatotoxicity, Drug interactions

Phenobarbital 3-10 mg/kg/day Sedative effects, Behavioral changes

Cholestyramine 0.25-0.5 gm/kg/day Constipation, steatorrhea

Hyperchloremic metabolic acidosis

Vitamin A (Aquasol A) 5000-25,000 IU/day Hepatotoxicity, Hypercalcemia

Pseudotumor cerebri

Vitamin D

Cholecalciferol 2500-5000 IU/day Hypercalcemia

25-OH cholecalciferol 3-5 mcg/kg/day Nephrocalcinosis

Vitamin K (Phytonadione) 2.5-5 mg every other day

Vitamin E Potentiation of vitamin K deficiency

coagulopathy

Aquasol E 50-400 IU/day

TPGS (d-alpha tocopheryl polyethylene

glycol-1000 succinate)

15-25 IU/kg/day Diarrhea

Hyperosmolality (with TPGS)

Water soluble vitamins Twice the recommended daily

allowance

352 S. Venigalla and G.R. Gourley


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intensive phototherapy range and phototherapy does notpromptly lower the TSB. Because of the paucity of data, firmrecommendations cannot be made, however, the direct se-rum bilirubin should not be subtracted from the TSB concen-tration in making decisions about exchange transfusions.1

Specific DiseasesBiliary AtresiaBiliary atresia is an idiopathic inflammatory process involv-ing the bile ducts resulting in obstruction of the biliary tract,chronic cholestasis and progressive fibrosis and eventually tobiliary cirrhosis. It accounts for approximately one-third ofthe cases of neonatal cholestasis and is the most commoncause of liver transplantation in children.

The incidence of biliary atresia has been estimated to beabout 1:15,000. It is worldwide in distribution and occurs inall races, though more commonly in nonwhites. The etiologyof biliary atresia is still unclear. Various studies have sug-gested a possible relationship between biliary atresia and viralinfections like reovirus 3, rotavirus C and cytomegalovirusbut this has not been conclusively proven. Increased risk ofbiliary atresia in family members of an affected individual hasbeen noted and may suggest genetic etiology. Studies haveshown that severe jaundice and death within 1 week of lifeoccurs in the inv mouse, a transgenic mouse with deletion ofthe inversin gene and is associated with biliary atresia andcomplete abdominal situs inversus.

There are two forms of biliary atresia: (1) isolated biliaryatresia, the more common form, also known as peri- or post-natal form, (2) biliary atresia associated with situs inversus

and polysplenia syndrome, also known as the fetal or embry-onic form. The polysplenia syndrome includes situs inversus,poly- or asplenia, cardiovascular malformations and anoma-lies of the portal vein and hepatic artery. Biliary atresia mayalso be anatomically classified into 3 types: type 1 atresiainvolving common bile duct and a patent proximal system;type 2 atresia involving the hepatic duct but with patentproximal ducts; and type 3 atresia involving the right and lefthepatic ducts at the porta hepatitis.

These children are usually born at term after a normalpregnancy and are normal at birth and have appropriateweight gain early in the course of the disease. These infants

usually present with prolonged jaundice, acholic stools andlater develop failure to thrive, pruritus and coagulopathy.They may also present with bleeding or bruising from vita-min K deficiency. Physical examination is remarkable forhepatomegaly. Splenomegaly, ascites and other features ofcirrhosis may be seen late in the disease process.

EvaluationIn addition to a good history and physical examination, asystematic approach to the evaluation of jaundice in theseinfants will help establish the diagnosis of biliary atresia.Early diagnosis and treatment (Kasai procedure), before the

age of 60 days, is important for better prognosis.Laboratory investigations show conjugated hyperbiliru-

binemia, elevated serum transaminases and alkaline phos-

phatase levels. -Glutamyl transpeptidase (GGT) levels aremarkedly elevated. Vitamin K malabsorption may cause mildcoagulopathy.

Abdominal ultrasound usually shows an absent or smallgall bladder. Presence of a normal gall bladder however doesnot rule out biliary atresia. In infants with polysplenia, anultrasound can also demonstrate the vascular anomalies in

the liver, hepatomegaly and multiple spleens. The triangularcord sign (an echogenic area in porta hepatis) on ultrasoundis highly specific for biliary atresia. If the ultrasound is incon-clusive, hepatobiliary scintigraphy may be helpful in deter-mining the patency of the extra-hepatic biliary system. Evi-dence of radioactivity in the duodenum establishes thepatency of the biliary system and rules out biliary atresia. Theidentification of bile acids and bilirubin by near infrared re-flectance spectroscopy (NIRS) of homogenized stool speci-mens is 100% sensitive and around 92% specific for biliaryatresia.

When radiological studies are inconclusive, a liver biopsy

can provide the diagnosis in about 94 to 97% of the cases.The classic pathologic finding is the presence of bile ductproliferation. This finding in combination with a polymor-phonuclear exudate and cholestasis is highly suggestive ofmechanical obstruction and warrants a laparotomy and chol-angiogram. Liver biopsy done early in the disease process(less than 6 weeks age) can sometimes be inconclusive and arepeat biopsy should be done in these cases.7 1-Antitrypsindeficiency has similar presentation and should be ruled outbefore laparotomy.12,13

Management

The standard treatment of biliary atresia is the Kasai hepato-portoenterostomy with intraoperative cholangiogram to con-firm the site of the obstruction before surgery. The surgeryinvolves removal of the atretic tissue and a Roux-en-Y anas-tomosis made between the jejunum and the hilum of theliver. The success of the surgery is based on the anatomicalfindings, luminal size of the bile ducts at surgery, age atsurgery and the experience of the surgeon. The success ofsurgery is shown by the excretion of bile and improvement of

jaundice. The most significant predictive factor of long-termprognosis is resolution of jaundice. Patients who remain

jaundiced usually die or have liver transplantation by 8 years

age. Jaundice-free patients have a 10 year survival of almost90%.In addition to the surgical management, patients should

also receive supportive care for cholestasis, including supple-mentation of fat-soluble vitamins and high calorie diet.

Complications of the Kasai Procedure(1) Ascending CholangitisThis is the most common postoperative complication seenwith the Kasai procedure, occurring in at least 50% of infantsin the first two years following surgery. Patients present withfever, abnormal liver function tests, worsening jaundice and

an elevated ESR. Blood cultures are not always positive andthe organisms are usually Gram-negative rods, though Gram-positive rods like Hemophilus influenza have also been iden-



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tified. Treatment is aggressive with broad-spectrum intrave-nous antibiotics. In patients with refractory cholangitis,prophylactic oral antibiotics like oral neomycin or tri-methoprim-sulfamethoxazole have shown some success indecreasing the rates of cholangitis.14

(2) Portal Hypertension

By 5 years of age, about 40 to 80% of the patients developportal hypertension and varices. These patients present withsplenomegaly, ascites, variceal bleeding or return of jaundice.In 20% of the patients who develop portal hypertension,portal vein thrombosis has been noted and could be second-ary to ongoing inflammation and cholangitis. In patients withvariceal bleeding, sclerotherapy or variceal ligation can bedone. Variceal hemorrhage may lead to rapid decline of liverfunction and the patient may need liver transplantation.

Idiopathic Neonatal Hepatitis

Idiopathic neonatal hepatitis, also known as giant cell hepa-titis, accounts for approximately one-third of the cases ofneonatal cholestasis. It is diagnosed by the presence of theclassic pathological findings and the absence of any identifi-able cause of cholestasis. There are two different categories:sporadic cases and familial cases that could likely suggest anundiagnosed genetic or metabolic disease. These infants usu-ally have low birth weight. Jaundice is present within the firstweek of life. Acholic stools are usually absent unless there issevere cholestasis. On physical examination, liver is enlargedand firm in consistency. Serum bilirubin and transaminasesare mildly elevated.

Liver biopsy usually shows lobular disarray with hepato-cellular swelling (ballooning), focal hepatic necrosis and gi-ant cell transformation with evidence of extramedullary he-matopoiesis.

Management is usually supportive with nutritional sup-port, vitamin supplementation and treatment of complica-tions of cholestasis. Prognosis is variable with sporadic caseshaving very good prognosis with 90% resolution by age 1year and relatively poor prognosis in familial cases suggestingsome inborn errors.

Cholestasis in Premature Infants

Cholestasis is a common finding in very low birth weightinfants and is multifactorial in etiology. The biliary tract isstructurally and functionally immature in these infants lead-ing to an exaggerated physiologic cholestasis of infancy. Inaddition, other risk factors like perinatal hypoxia,15 paren-teral nutrition, sepsis, and poor enteral feedings can contrib-ute to cholestasis. In premature infants biliary atresia is un-common, so a modified schematic for evaluation may befollowed (Fig. 1). Hepatobiliary scintigraphy and liver biopsyshould be delayed until the infants corrected gestational age(CGA) is at term and the weight is more than 2 kg. Liverbiopsy is indicated in the presence of acholic stools, cholesta-

sis which persists beyond CGA of 2 months and in patientswho have a nonexcreting hepatobiliary scan.

Cholestasis is a complication of parenteral nutrition (PN)

in preterm infants. Though a clear etiology has not beenidentified, it is felt that the immaturity of the enterohepaticcirculation plays a role in the pathogenesis. Risk factors forthe development of parenteral nutrition associated liver dis-ease include prematurity, sepsis, early initiation and in-creased duration of parenteral nutrition, lack of enteral feeds,over feeding and preexisting liver disease.

Clinical findings include conjugated hyperbilirubinemiawith increasing levels 2 weeks after initiation of PN, eleva-tions of serum transaminases. Management includes cessa-tion of parenteral feeds and transitioning to full enteral feeds.In infants who are not tolerating full enteral feeds, manage-ment includes trophic enteral feeds, making changes to PNsubstrates, eg, limiting glucose intake to 15 g/kg/d, supple-mentation with taurine and glutamine, limiting intake oflipid emulsions and cycling of the PN to12 hrs/d. Medicalmanagement includes ursodeoxycholic acid to increase bileacid excretion. Cholecystokinin-octapetide and the cholecys-tokinin analog, ceruletide, may prevent cholelithiasis or liver

disease in patients receiving PN by stimulating gallbladdercontraction.16

1-Antitrypsin (1AT) Deficiency

This is the most common inherited cause of neonatal cho-lestasis. 1AT is a protease inhibitor produced in the liver.The deficiency is caused by mutations in the gene found onchromosome 14. More than 75 different phenotypes of1ATare named according to migration characteristics on poly-acrylamide gels, based on differences in isoelectric point (Pi),with M normal and Z most deficient.17 The incidence of ho-

mozygous PiZZ that is associated with neonatal liver diseaseand adult emphysema is 1 in 2000 live births in Europeanand North American populations. Only 15% of PiZZ neo-nates develop clinical disease within the next 20 years. Themechanism of liver disease is accumulation of the defectivemolecule in the liver.

Clinical presentation is very similar to biliary atresia. Theseinfants also have intrauterine growth retardation and aremore likely to develop coagulopathy. Diagnosis is confirmedby documenting low plasma 1AT levels and determining1AT phenotype.

Management is mostly supportive with nutritional supple-mentation. Prognosis is related to the severity of the liverdisease. In children with progressive liver disease, liver trans-plantation has shown good survival rates of 90% at 1 year and80% at 5 years.18 Prospects for therapy include attempts toblock1AT accumulation in the liver or increase the turnoverof the accumulated abnormal 1AT protein.19

Progressive FamilialIntrahepatic Cholestasis (PFIC)

PFIC is a group of genetic disorders that show progressiveintrahepatic cholestasis. All these disorders have an autoso-

mal recessive inheritance.PFIC-1 is caused by mutation in the FIC 1 gene and is the

original Byler disease described in the descendants of an

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Amish American family. The FIC1 gene is expressed in thecanalicular membranes. Patients present with episodic cho-lestasis in the first month of life. Diarrhea, pancreatitis anddeficiency of fat-soluble vitamins are seen. Serum GGT levelsare normal. Liver biopsy shows bile duct paucity. Electronmicroscopy shows granular appearance of bile present in thecanaliculus. Management is mostly supportive. Surgical

methods like ileal exclusion, partial external biliary diversionhave been tried. Cirrhosis is seen by end of first decade of lifeand liver transplantation is needed with hepatic decompen-sation and is usually needed around the second decade of life.

PFIC-2 is caused by a defect in the canalicular bile saltexcretory pump (BSEP). Clinical presentation is similar toPFIC 1 except for the absence of pancreatitis in this condi-tion. Liver biopsy shows more inflammation and electronmicroscopy shows amorphous bile. Management is againsupportive. Prognosis is worse, with patients requiring livertransplantation in the first decade of life.20

PFIC-3 is caused by a defect in the canalicular phospho-

lipids transporter, MDR3. Clinical presentation is similar toPFIC-1 but is delayed until early adulthood. There is a historyof cholestasis of pregnancy in the mother. GGT is markedlyelevated and bile analysis shows high bile acid to phospho-lipid ratio. Liver biopsy may mimic biliary atresia but thebiliary tract is patent. Treatment is mostly supportive andprognosis is variable.21

Alagille Syndrome

Alagille syndrome is an autosomal dominant disorder char-acterized by paucity of the interlobular bile ducts. The inci-dence is reported to be 1 in 100,000 births. It is also knownas Watson-Alagille syndrome, arteriohepatic dysplasia, syn-dromic bile duct paucity (SBDP), syndromic intrahepatic bil-iary hypoplasia, intrahepatic biliary atresia and intrahepaticbiliary dysgenesis. Alagille syndrome is caused by mutationsin the human Jagged 1 gene that has been mapped to chro-mosome 20p12. This gene encodes a ligand for the Notchsignaling pathway.

Clinically, this syndrome is characterized by chronic cho-lestasis; characteristic facies with a broad forehead, small chinand saddle nose with bulbous tip and hypertelorism; skeletalanomalies including butterfly vertebrae, curved phalanges andshort ulna; cardiac anomalies most commonly peripheral pul-

monic stenosis andalsoincluding tetralogy of Fallot,pulmonaryatresia, truncus arteriosus and VSD; and ocular anomalies likeposterior embryotoxon and optic nerve drusen. Other findingsinclude renal abnormalities like ectopic kidney, small kidneys,multicystic kidneys, renal artery stenosis; mental retardationand developmental delay; growth retardation and pancreaticinsufficiency.

Infants usually present with neonatal cholestasis. It may bedifficult to differentiate from biliary atresia initially becausein some cases initial liver biopsy may show bile duct prolif-eration. The characteristic facies may not be evident in thenewborn period.

Management is mostly supportive with nutritional supportand treatment of pruritus. Supplementation of fat-solublevitamins and pancreatic enzymes are needed.

More than half of the children presenting with neonatalcholestasis progress to cirrhosis and require liver transplan-

tation by age 10. Care should be taken when evaluating par-ents for matched living donor due to increased incidence of

the subclinical disease in family members. There have been

reports of hepatocellular carcinoma in patients with Alagillesyndrome.22

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Colestasis Neonatal Semin[1].04