 Abstract | | |
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 |
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 | |  |
We would like to thank Ms. Gloria D. Palacay for her secretarial assistance.
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Correspondence Address:
Asaad M.A Abdullah
Department of Paediatrics, College of Medicine & KKUH, P.O. Box 89828, Riyadh 11692
Saudi Arabia
 Source of Support: None, Conflict of Interest: None  | Check |
PMID: 19864861 
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