Saudi Journal of Gastroenterology
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Year : 1995  |  Volume : 1  |  Issue : 1  |  Page : 12-15
Conjugated hyperbilibubinaemia in infancy (Infantile Cholestasis)

Department of Paediatrics, College of Medicine & KKUH, P.O. Box 89828, Riyadh 11692, Saudi Arabia

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The finding of high conjugated bilirubin needs prompt evaluation to rule out liver or bile duct pathology. If assessment of total and direct bilirubin is carried routinely in any infant whose jaundice persists for more than 2 weeks, early identification of a group of children who need corrective surgery for atresia of the extra hepatic bile duct is possible. The aim of this review is to look at common causes of infantile cholestasis with emphasis on evaluation, diagnosis, complications, treatment and outcome of infant with neonatal cholestasis.

How to cite this article:
Abdullah AM. Conjugated hyperbilibubinaemia in infancy (Infantile Cholestasis). Saudi J Gastroenterol 1995;1:12-5

How to cite this URL:
Abdullah AM. Conjugated hyperbilibubinaemia in infancy (Infantile Cholestasis). Saudi J Gastroenterol [serial online] 1995 [cited 2022 Aug 8];1:12-5. Available from:

Infantile cholestasis is defined as Jaundice result­ing from failure of excretion of conjugated biliru­bin from the hepatocyte into the duodenum. It is characterized by elevated direct reacting bilirubin more than 15 percent of the total [1],[2] . It must always be considered as a pathological state. Clin­ically, conjugated hyperbilirubinemia is charac­terized by jaundice, acholic stools, dark urine and hepatomegaly. [3]

The differential diagnosis of conjugated hyper­bilirubinemia includes abnormalities of the biliary tree like biliary atresia, choledocal cyst, Caroli's syndrome. biliary hypoplasia and spontaneous perforation of the extrahepatic ducts [4] ; or it might be secondary to intrahepatic cholestasis which may be caused by neonatal hepatitis, inborn error of metabolism in infancy, and total parenteral nut­rition. [5]

Extrahepatic biliary atresia:

Biliary atresia is a rare familial condition, it is associated with abnormalities of the portal struc­tures or polysplenia or situs inversus in around 25% of cases. The condition is believed to result from multifactorial etiology, particularly post­natal infection with reovirus type 3. The incidence of biliary atresia is 0.8-1/10000 live birth and it causes cholestasis in 20% of infants with conju­gated hyperbilirubinaemia. [6] Clinically, babies usually present with cholestasis 2-3 weeks after birth, and their birth weight is appropriate for ges­tation age, hepatomegaly is usually found on clin­ical examination. [7] The stool is clay color and pruritis is rare before 5 months of age. Laboratory investigations usually show raised total and direct serum bilirubin, serum aminotrasferases, alkaline phosphatase and gamma-glutamyl transpep­tidase. Liver histopathology shows bile duct pro­liferation bile lakes, cellular infiltrate, and fibrous tissue.

T99c-labelled compounds of Iminodiacetic acid (e.g. DISIDA, HIDA) are simple ways of show­ing bile duct patency in suspected biliary atresia. [8] Abdominal ultrasound occasionally shows dilated proximal ducts within the liver, if the gallbladder is unidentified by ultrasound this may indicate obliteration of its lumen. Both percutaneous liver biopsy, DISIDA Scan and percutaneous cholan­giography support a diagnosis of biliary atresia. Other investigations which may be helpful in biliary atresia is Endoscopic Retrograde Cholan­gio Pancreatography which may demonstrate patency of extrahepatic bile duct. [9] In most cases of biliary atresia, exploratory laparotomy is help­ful in confirming the diagnosis. Early biliary atresia require Kasai portoenterostomy around 6 weeks of age. [10] Post operative cholangitis is a well recognized complication of Kasai operation and usually it is treated with ampicillin and an aminoglycoside with or without clindamycin. [11] Other complications include portal hypertension and fat soluble vitamin malabsorption which respond to fat soluble vitamin supplement. [4] Liver transplantation can be life saving and should be done before the onset of irreversible hepatic decompensation. [4]

Another cause of extra hepatic cholestasis in infancy is choledochal cyst which is diagnosed by abdominal ultrasound and once the diagnosis is confirmed, surgical excision is the best therapy. [12] Spontaneous perforation of the bile duct in infancy lead to conjugated hyperbilirubinaemia, biliary ascites and peritonitis. Abdominal paracentesis usually confirms the presence of bile stained ascites.[13]

Paucity of interlobular bile ducts:

A well recognized cause of persistent conju­gated hyperbilirubinaemia is paucity of interlobu­lar bile ducts which maybe either an isolated find­ing or associated with syndromes. Alagille syn­drome is a typical example of these conditions. This syndrome is associated with malformations like vertebral anomalies (butterfly appearance of vertebra), growth retardation, systolic murmur due to peripheral pulmonary stenosis, and a characteristic facial appearance which include prominent forehead with deeply set, widely sepa­rated eyes, straight nose and small pointed chin. It is also associated with mental retardation and hypogonadism. [3] The diagnosis is confirmed by percutaneous liver biopsy. [13]

Neonatal hepatitis:

Another major cause of conjugated hyper­bilirubinaemia is neonatal hepatitis which results from inflammation of the hepatocyte in utero. [14] It is either idiopathic in the majority of cases [[15] or secondary to infection with Gram negative bac­teria like  Escherichia More Details coli or viral infection (like cytomegalovirus, herpes virus, rubella, hepatitis viruses) or it might be secondary to infection with toxoplasma gondii. [16] Clinically babies with neonatal hepatitis which is due to congenital infec­tion are usually small for gestational age, with jaundice hepatosplenomegaly, microcephaly and skin rashes. [16]

An important cause of cholestasis in preterm babies is total parenteral nutrition which is also associated with multiple risk factor such as pre­maturity, abdominal surgery, sepsis, hypoxic episodes and parenteral nutrition more than 2 weeks duration, [17] the etiology of total parentral nutrition cholestasis is multifactorial and might be secondary to lack of enteral feeding, excess calories, aminoacid excess and or imbalance or nutrient deficiency such as taurine, carnitine or choline deficiency. [17]

Metabolic Causes:

Inborn errors of metabolism should be consi­dered in any case of neonatal cholestasis. Disor­ders of carbohydrate metabolism which lead to cholestasis include galactosemia which is due to deficiency of the enzyme galactose-1-phosphate uridyl transferase and inherited as an autosomal recessive disorder. Clinically it present with jaun­dice, vomiting, hepatomegaly, hypoglycemia and intolerance to lactose containing formula. Late manifestations are cataract and mental retarda­tion. The diagnosis is suspected by finding positive reducing substances in the urine and confirmed by low galactose-1-phosphate uridyl transferase in red blood cells. Early removal of lactose from the diet usually leads to resolution of symptoms. [18] Another carbohydrate disorder which is associated with cholestasis is hereditary fructose intolerance which is due to deficiency of fructose­1-phosphate aldolase, it is also inherited as autosomal recessive and it leads to intolerance to fruit or sucrose containing food. It presents with vomiting, hepatomegaly and hypoglycemia. The diagnosis is usually confirmed by enzyme assay in liver tissue. The treatment is usually fructose and sucrose free diet. [19]

Tyrosinemia is a disorder of amino acid metabolism which is due to deficiency of fumaryl acetoacetate and inherited as autosomal recessive. Clinically it presents with jaundice, hepatomegaly and hepatic failure, it leads to ele­vated tyrosine and methionine in plasma and suc­cinyl acetone in urine. [19]

Alpha-one-Antitrypsin deficiency may present with neonatal cholestasis, acholic stool and hepatomegaly, liver biopsy shows characteristic periodic acid-schiff-positive diastases-resistant granules. The diagnosis is usually confirmed by protease inhibitor phenotyping and measurement of serum alpha one antitrypsin concentration. [20]

Disorder of lipid metabolism that lead to cholestasis include Niemann-pick disease, Gaucher dis­ease, Wolman disease and cholesterol ester dis­ease. Clinically these disorder present with cholestasis and hepato cellular dysfunction. [14]

Zellweger syndrome is due to defective peroxi­some biogenesis, it is inherited as autosomal recessive. It presents with neonatal cholestasis, hypotonia, abnormal faces with hypertelorism, epicanthal folds, and prominent forehead. Mental retardation and renal cortical cysts are associated findings. Defects in multiple peroxisomal path­ways, elevated very long chain fatty acids in plasma, pipecolic aciduria, plasmalogen defects and absent peroxisomes on electron microscopy have been described. [19] A high trihydroxy cop­rostanic acid (an atypical bile acid) is found in dis­orders of bile acid metabolism which are inherited as autosomal recessive. [20]

Cystic fibrosis is a rare cause of neonatal choles­tasis. It is associated with meconium ileus, meconium peritonitis or intestinal atresia. [20] Other rare causes of neonatal cholestasis are neonatal hypothyroidism and hypopituitarism. [2]

In addition to investigations which are done to exclude biliary atresia, babies with neonatal cholestasis need work up to look for the cause of neonatal hepatitis. This work up may include liver function test, serum and urine aminoacid chromatography, stool for bilirubin, urine and blood culture, TORCH screen, urine for reducing substances, TSH, T4, growth hormone assay abdominal ultrasound, HIDA scan after 5 days phenobarbitone administration and percutaneous liver biopsy. [21]

Apart from Kasai portoenterostomy and liver transplantation for biliary atresia, [22] infant with cholestasis need adequate nutritional support such as adequate protein, calories and fat soluble vitamins. Cholestyramin and phenobarbitone might help in the treatment of pruritus. [23] Ursodeoxycholate (relatively hydrophilic, ter­tiary bile acid with less intrinsic toxicity than endogenous bile acid) might also be effective in pruritus. [24]

In the past, the long term prognosis for infants with intrahepatic cholestasis and patent extra hepatic biliary tracts is worse with alpha-one-anti­trypsin deficiency, scanty interlobular ducts and familial idiopathic neonatal hepatitis. [25],[26] How­ever, recently the prognosis improved should liver transplantation be available at the appropriate time. Babies who made complete recovery from all physical and biochemical evidence of liver dis­ease may remain well for a long time. [27] .

   Acknowledgement Top

We would like to thank Ms. Gloria D. Palacay for her secretarial assistance.

   References Top

1.Maisels MJ. Jaundice in the newborn. Pediatr Rev 1982; 3: 305-19.  Back to cited text no. 1    
2.Mowat AP. Hepatitis and cholestasis in infancy in: Mowat liver disorder in childhood, 2nd edition. London, Butterworths 1987; 37-88.  Back to cited text no. 2    
3.Alagille D. Management of chronic cholestasis in child­hood. Semin Liv Dis 1987; 7: 254-62.  Back to cited text no. 3    
4.Ryckman FC, Noseworthy J. Neonatal cholestasis con­ditions requiring surgical reconstruction. Semin Liv Dis 1987: 7: 134-54.  Back to cited text no. 4    
5.Heubi JE, Daugherty CC. Neonatal cholestasis: An approach for the practicing pediatrician. Curr Probl Pediatr 1990; 5: 234-95.  Back to cited text no. 5    
6.Johnston Dl. Extra hepatic biliary atresia/choledochal cyst. Curr Probl Paediatr 1991; 1: 216-7.  Back to cited text no. 6    
7.Mowat AP, Psacharopoulos HT, Williams R. Extra hepatic biliary atresia versus neonatal hepatitis. Review of 137 prospectively investigated infants. Arch Dis Child 1976; 51: 763-70.  Back to cited text no. 7    
8.Dick MC. Mowat AP. Biliary scintigraphy with DIS­IDA, a simpler way of showing bile duct in suspected biliarv atresia. Arch Dis Child 1986:6L 191-2.  Back to cited text no. 8    
9.Nelson R. Managing biliary atresia: Referral before 6 weeks is vital. Br Med J 1989; 298: 1471.  Back to cited text no. 9    
10.Levy J, Altman RP. Biliary atresia. Pediatr Ann 1985; 14: 481-5.  Back to cited text no. 10    
11.Wilkinson ML, Mieli-Vergani G, Ball C, Portman B, MOwat AP. Endoscopic retrograde cholangiopan­creatography in infantile cholestasis. Arch Dis Child 1991: 66: 121-3.  Back to cited text no. 11    
12.Kamath KR. Abnormalities of the biliary tree. Clin Gas­troenterol 1986: 15: 157-72.  Back to cited text no. 12    
13.Mowat AP. Biliary disorders in childhood. Semin Liv Dis 1982: 2: 271-81.  Back to cited text no. 13    
14.Rosenthal Ph, Sinatra F. Jaundice in infancy. Pediatr Rev 1989; 11: 79-86.  Back to cited text no. 14    
15.Sepherd R. Hepatic and biliary disorders in infancy and childhood. Medicine International 1990: 83: 3454-9.  Back to cited text no. 15    
16.Fitzgerald JF. Cholestatic disorders of infancy. Pediatr Clin North Am 1988; 35: 357-73.  Back to cited text no. 16  [PUBMED]  
17.Sheard NF. Kleinman RE. TPN cholestasis in premature infants. the role of parenteral nutrition solutions. Pediatr Ann 1987: 16: 243-52.  Back to cited text no. 17    
18.Abdullah AMA. Galactosemia in a Saudi child. Med Sci Res 1993: 21: 841-2.  Back to cited text no. 18    
19.Waber L. Inborn errors of metabolism. Pediatr Ann 1990; 19: 105-18.  Back to cited text no. 19  [PUBMED]  
20.Gartner LM. Cholestasis of the newborn. Pediatr Rev 1983; 5: 163-71.  Back to cited text no. 20    
21.Hull J. Kelly DA. Investigation of prolonged neonatal jaundice. Curt Probl Pediatr 1991; 1: 228-30.  Back to cited text no. 21    
22.Shaw BW. Wood PR. Kaufman SS, et al. Liver trans­plantation therapy for children: Part I. J Pediatr Gas­troenterol Nut 1988: 7: 157-66.  Back to cited text no. 22    
23.Novak DA, Balistreri WF. Management of the child with chronic cholestasis. Pediatr Ann 1985; 14: 488-92.  Back to cited text no. 23  [PUBMED]  
24.Reichert J. Pharmacologic treatment of cholestasis. Semin Liver Dis 1993: 13: 302-15.  Back to cited text no. 24    
25.Odievre M, Madchouel M, Landrieu P, Alagille D, Eliot N. Long term prognosis for infants with intrahepatic cholestasis and patent extrahepatic biliary tract. Arch Dis Child 1981: 56: 373-6.  Back to cited text no. 25    
26.Danks DM, Campbell PE, Smith AL, Rogers J. Prog­nosis for babies with neonatal hepatitis. Arch Dis Child 1977; 52: 368-72.  Back to cited text no. 26  [PUBMED]  
27.Deutsch J. Smith AL. Danks DM, Campbell PE. Long term prognosis for babies with neonatal liver disease. Arch Dis Child 1985; 60: 447-51.  Back to cited text no. 27    

Correspondence Address:
Asaad M.A Abdullah
Department of Paediatrics, College of Medicine & KKUH, P.O. Box 89828, Riyadh 11692
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

PMID: 19864861

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