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REVIEW ARTICLE

Prolonged neonatal jaundice:

When to worry and what to do

Susan M Gilmour MD FRCPC

SM Gilmour. Prolonged neonatal jaundice: When to worry and what to do. Paediatr Child Health 2004;9(10):700-704.

Neonatal jaundice persisting beyond 14 days of age is a common clin- ical scenario. The vast majority of affected children have a benign unconjugated hyperbilirubinemia, but included in this clinical pres- entation is a group of neonates with conjugated hyperbilirubinemia and liver disease. Early identification of liver disease improves the infant’s outcome, especially for those with extrahepatic biliary atre- sia. The present paper reviews the approach to the neonate with pro- longed jaundice, including clinical presentation, when to proceed with initial investigations, timing of referral, further investigations and management, and provides an overview of the more common causes of neonatal cholestatic liver disease.

Key Words: Cholestatic liver disease; Neonatal jaundice

La jaunisse néonatale prolongée : Quand s’inquiéter et quoi faire

La jaunisse néonatale qui persiste plus de 14 jours de vie constitue un scénario clinique courant. La majorité des enfants atteints souffrent d’hyperbilirubinémie bénigne non conjuguée, mais cette présentation clinique inclut également un groupe de nouveau-nés atteints d’hyperbilirubinémie conjuguée et de maladie hépatique. Un dépistage précoce de la maladie hépatique améliore l’issue du nourrisson, surtout s’il souffre d’atrésie extrahépatique des voies biliaires. Le présent examen permet d’analyser la démarche à adopter à l’égard du nouveau-né atteint d’une jaunisse prolongée, y compris sa présentation clinique, le moment de procéder aux premiers examens, le moment convenable pour procéder à l’aiguillage, les examens plus approfondis et la prise en charge, et fournit un aperçu des causes les plus courantes de maladie hépatique cholestatique néonatale.

P ersistent jaundice in the neonate is defined as jaundice that lasts longer than 14 to 21 days (1). It can occur in

up to 15% of all newborns (2). The vast majority of these neonates have benign unconjugated hyperbilirubinemia but one in 2500 live births has cholestatic liver disease (3). The difficult task facing primary care providers is discriminating between serious conjugated hyperbilirubinemia and benign unconjugated jaundice because in the early stage, the infants can look very well except for their jaundice. Early identification of infants with cholestatic liver disease is crit- ical so that a correct diagnosis is made and the appropriate therapy is instituted. The most compelling evidence for the importance of early detection is the condition of extrahepatic biliary atre-

sia. It is the single most common cause of neonatal liver disease (4). Without therapy, its natural course is very poor, with less than 10% survival by the third year (5). Survival and outcome are improved with a Kasai portoenterostomy to restore bile drainage. The most important predictor of success is early age at operation (5), preferably 60 days of age or younger (6). Exploring all causes of the diagnostic and management dilemma of neonatal jaundice is beyond the scope of this article. Rather, the article will focus on the issue of the jaundiced infant in an outpatient setting, including initial management, interpretation of findings and timing of refer-

ral, as well as review some of the more common causes of cholestatic liver disease.

PRESENTATION Clinically, most patients with cholestatic liver disease have jaundice, dark urine and pale stools, but otherwise look well. The presence of pale stools is a sensitive marker for liver dis- ease, but parental reports of the history of stool colour may be misleading because the stool colour may be influenced by oral intake. Infants with severe liver disease may also present with encephalopathy, which might be difficult to diagnose in the neonatal period because it may manifest with nonspe- cific poor feeding and sleep disturbances. Another presenta- tion of severe liver disease is bleeding and bruising due to vitamin K deficiency. Far less common is the presentation of seizures, either from hypocalcemia secondary to vitamin D deficiency or from hypoglycemia. A thorough physical examination may provide evidence of cholestatic liver disease and its underlying etiology. Some helpful features may include dysmorphic faces (Alagille’s syndrome), evidence of congenital heart disease (Alagille’s syndrome, biliary atresia), an abdominal mass (choledochal cyst, tumour), hepatomegaly/splenomegaly (found with obstruction, inflammation, a storage disorder or tumour), failure to thrive and an abnormal respiratory examination (cystic fibrosis). In addition, the neuromuscular examination

Division of Pediatric Gastroenterology/Nutrition, Stollery Children’s Hospital, University of Alberta, Edmonton, Alberta Correspondence: Dr S Gilmour, Division of Pediatric Gastroenterology/Nutrition, Stollery Children’s Hospital 2C3 WMC, University of Alberta, Edmonton, Alberta T6G 2R7. Telephone 780-407-3339, fax 780-407-3507, e-mail sgilmour@cha.ab.ca

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Paediatr Child Health Vol 9 No 10 December 2004

TABLE 1 Differential diagnosis of neonatal cholestatic liver disorders

Structural Extrahepatic biliary atresia Choledochal cyst Caroli’s syndrome Choledocholithiasis Alagille’s syndrome Nonsyndromic bile duct paucity Undersized extrahepatic biliary system (biliary hypoplasia) Neonatal sclerosing cholangitis

Infection Viral

Prolonged neonatal jaundice

TABLE 2 Initial investigations for conjugated hyperbilirubinemia

Blood

Liver panel: aspartate aminotransferase, alanine aminotransferase,

alkaline phosphatase, gamma-glutamyl transpeptidase, total bilirubin,

conjugated bilirubin and albumin

Coagulation studies (prothrombin time/international normalized ratio,

partial thromboplastin time)

Complete blood count and differential with smear

Toxoplasmosis, other infections, rubella, Cytomegalovirus infection and

herpes simplex (TORCH) serology

Blood culture

- Cytomegalovirus

Hepatitis B surface antigen

- Herpes simplex

Glucose/serum lactate/serum amino acids/ammonia

- Adenovirus

Thyroxine, thyroid-stimulating hormone

- Enterovirus

Iron studies, ferritin

- Parvovirus B19

Galactosemia screen

- Hepatitis B virus

Bacterial infection (sepsis or remote from liver [eg, urinary tract infection]) Toxoplasmosis Syphilis

Metabolic

Alpha-1-antitrypsin deficiency

Galactosemia Tyrosinemia Hereditary fructose intolerance

Glycogen storage disease type IV Lipid storage disease

- Niemann-Pick disease type A

- Niemann-Pick disease type C

- Gaucher’s disease

- Wolman’s disease

Mitochondrial enzymopathies (including fatty acid oxidation disorders) Peroxisomal disorders (eg, Zellweger syndrome) Bile acid synthesis disorders Progressive familial intrahepatic cholestasis syndromes

- FIC-1 protein deficiency (PFIC 1)

- Bile salt export pump deficiency (PFIC 2)

- MDR3 protein deficiency (PFIC 3)

North American Indian familial cholestasis

Urea cycle defects

Genetic

Cystic fibrosis

Trisomy 21

Trisomy 18

Neoplastic

Neuroblastoma

Hepatoblastoma

Histiocytosis X

Toxic Drug induced Total parenteral nutrition

Endocrine

Panhypopituitarism

Hypothyroidism

Immune Neonatal lupus erythematosus

Vascular Budd-Chiari syndrome Congestive heart failure Hepatic hemagiomatosis

Idiopathic

Paediatr Child Health Vol 9 No 10 December 2004

Urine

Reducing substances

Organic acids

Bacterial culture

Urine Cytomegalovirus (positive result before four weeks of age is highly

suggestive of congenital Cytomegalovirus)

Imaging

Abdominal ultrasound (evaluate for mass, choledochal cyst, small

gallbladder, triangular cord sign)

may reveal hypotonia or abnormal reflexes (as with mito- chondrial disorders and vitamin E deficiency).

INITIAL EVALUATION Because the differential diagnosis of neonatal conjugated hyperbilirubinemia is very broad (Table 1), it is important to have a structured approach to its investigation. The most important investigation is to determine whether the infant with prolonged jaundice has liver disease or benign jaun- dice. The timing of initial investigations should occur between two to four weeks of age (1,6,7). The fractionation of the total serum bilirubin into its conjugated (direct) and unconjugated (indirect) components is the most important initial investigation. The bilirubin may be reported as indirect/direct or conjugated/unconjugated bilirubin, depending on the method used in the laboratory. Definitions of elevated conjugated hyperbilirubinemia may be based on absolute values in the context of a predominantly unconju- gated hyperbilirubinemia (more than 35 µmol/L) or the per- centage of total bilirubin (more than 15%) (8), but for practical purposes, and because of laboratory variation, any elevation of conjugated bilirubin should be considered abnormal, and warrants further investigations and a referral to a paediatric gastroenterologist. Initial investigations that may be ordered by the primary care physician are outlined in Table 2. It is important to rule out conditions that require immediate treatment, such as infection, inborn errors of metabolism, hypothyroidism and identification of patients with liver failure as evidenced by hepatic synthetic dysfunction. After these potential

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Conjugated hyperbilirubinemia Initial investigations (Table 2 ) Other Investigations • Sweat chloride •
Conjugated
hyperbilirubinemia
Initial investigations
(Table 2 )
Other Investigations
• Sweat chloride
• Alpha-1-antitrypsin
phenotype
• Urine bile acid
metabolites
• Chest X-ray
Abdominal ultrasound
Choledochal cyst Dilated biliary tree Surgery
Choledochal cyst
Dilated biliary tree
Surgery
Normal or small gallbladder Hepatobiliary scan Liver biopsy
Normal or small
gallbladder
Hepatobiliary scan
Liver biopsy
or small gallbladder Hepatobiliary scan Liver biopsy Bile duct proliferation Bile plugs No excretion
Bile duct proliferation Bile plugs No excretion hepatobiliary scan
Bile duct proliferation
Bile plugs
No excretion
hepatobiliary scan

Laparotomy and

intraoperative

cholangiogram

Biliary hypoplasia Alagille’s syndrome • Ophthalmology • Echocardiogram • Genetic counselling
Biliary hypoplasia
Alagille’s syndrome
• Ophthalmology
• Echocardiogram
• Genetic
counselling
Neonatal hepatitis No excretion hepatobiliary
Neonatal hepatitis
No excretion
hepatobiliary
scan Follow with medical therapy until 8 weeks No clinical improvement or worse May rebiopsy,
scan
Follow with
medical therapy
until 8 weeks
No clinical
improvement or
worse
May rebiopsy,
rescan or
laparotomy to
rule out
extrahepatic
biliary atresia

Excretion

hepatobiliary

scan Medical therapy
scan
Medical therapy

Figure 1) Flow chart for the investigation and management of conjugated hyperbilirubinemia

diagnoses have been eliminated, the most important differ- ential diagnosis is biliary atresia.

FURTHER INVESTIGATIONS The approach to the diagnostic evaluation and manage- ment of the infant with conjugated hyperbilirubinemia is outlined in Figure 1.

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Abdominal ultrasound Abdominal ultrasound may be performed before and/or after referral to paediatric gastroenterology. It is a very sen- sitive method for diagnosing choledochal cysts and for detailing the anatomical abnormalities associated with the embryonic form of extrahepatic biliary atresia (midline liver, polysplenia or asplenia). While a small or absent gallbladder

Paediatr Child Health Vol 9 No 10 December 2004

is suggestive of extrahepatic biliary atresia, it is not diagnos- tic. Although extrahepatic biliary atresia is an obstructive process, it is important to note that bile duct dilation is not ordinarily a feature of biliary atresia. Some literature (9) suggests that the ‘triangular cord sign’ (an echogenic area in the porta hepatis) is very specific for biliary atresia, although the demonstration of this finding is very operator- dependent, limiting its widespread use (9).

Hepatobiliary scanning The nuclear medicine imaging procedure of hepatobiliary scanning uses technetium-labelled iminodiacetic deriva- tives. Infants should receive three to five days of pheno- barbital (5 mg/kg/day) to promote hepatocellular uptake of the tracer. Serial images are obtained evaluating hepa- tocellular uptake and biliary excretion into the small intestine. Hepatobiliary scanning is almost 100% sensitive for extrahepatic biliary atresia because the excretion of tracer into the small bowel almost always rules out biliary atresia. Unfortunately, a nondraining scan is not specific and it can have many different etiologies (10). Although the test has poor specificity, it is useful when the liver biopsy is nondiagnostic.

Liver biopsy Liver biopsy is the most informative investigation in the evaluation of neonatal conjugated hyperbilirubinemia, with many centres reporting over 90% accuracy for biliary atresia (1). Some histological findings include bile ductular prolif- eration, bile plugging and portal fibrosis in biliary atresia, parenchymal inflammatory infiltrate and giant cell transfor- mation in neonatal hepatitis, and portal duct hypoplasia with Alagille’s syndrome. Further immunostaining, histo- chemistry and electron microscopy can assist in the diagno- sis of other disorders, such as alpha-1-antitrypsin deficiency and some storage disorders.

SPECIFIC DISORDERS On completion of the investigations outlined in Table 2 and Figure 1, the etiology of neonatal conjugated hyper- bilirubinemia tends to fall into one of five groups: biliary atresia (30%), idiopathic neonatal hepatitis (25%), intra- hepatic cholestasis (including Alagille’s syndrome) (15%) and a collection of infectious and rare disorders (11,12) (approximately 30%).

Extrahepatic biliary atresia Extrahepatic biliary atresia is the progressive obliteration of the extrahepatic bile ducts that leads to fibrosis and damage of the intrahepatic bile ducts. The incidence is 1:8000 to 1:15,000 live births (7). It is the most common disease requiring liver transplantation in childhood. The cause of the inflammation and biliary destruction is unknown, although many mechanisms have been impli- cated, including immunological, viral (Cytomegalovirus [CMV] and Reovirus type 3), ischemic or genetic mecha- nisms, as well as toxic bile acids (8,13). Extrahepatic

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Prolonged neonatal jaundice

biliary atresia is usually classified into two phenotypes. The embryonic form is found in 10% to 20% of patients and is associated with other anomalies, including splenic mal- formation, abnormalities of the portal vein and inferior vena cava, situs inversus and congenital heart disease. The perinatal form is by far the most common. These patients typically present with a history of being well at birth and

for their first few weeks, with jaundice appearing after the first week of life. The gold standard for diagnosis of extrahepatic biliary

atresia is laparotomy with an intraoperative cholangiogram.

The treatment is a Kasai portoenterostomy in which the

atretic extrahepatic tissue is removed and a Roux-en-Y jeju-

nal loop is anastomosed to the hilum where patent bile ducts have been dissected. The success of this operation is greatly influenced by the age of the child at the time of sur- gery, with the greatest success seen when surgery is per- formed before 60 days of age (5,6).

Infections

CMV is the most common cause of congenital infection,

and 60% to 80% of symptomatic children can have

hepatosplenomegaly and jaundice (7). CMV affects the cen- tral nervous system, and affected patients may present with microcephaly, intracranial calcifications and chorioretinitis.

CMV rarely results in cirrhosis and chronic liver disease.

Other TORCH infections (Toxoplasmosis, Other infec- tions, Rubella, Cytomegalovirus infection and Herpes sim- plex) may have hepatosplenomegaly and jaundice as part of the congenital infection. Hepatotropic viruses (hepatitis A, B and C) rarely cause neonatal jaundice. Hepatitis B and C are vertically trans-

mitted and are usually subclinical, although hepatitis B may

cause a neonatal hepatitis. Conjugated hyperbilirubinemia may occur with bacterial

sepsis, especially urinary tract infection (14), and this must

be ruled out with the initial investigations.

Alagille’s syndrome Alagille’s syndrome has the feature of portal bile duct hypoplasia. The genetic basis for this syndrome is a muta- tion in the jagged 1 gene on chromosome 20p (15). Alagille’s syndrome is an autosomal dominant disorder with variable penetrance and up to 50% of patients show new mutations. The syndrome has variable penetrance with heterogeneity of clinical manifestations. There are five

major clinical features:

• chronic cholestasis;

• faces with a broad forehead, recessed eyes and a small chin;

• vertebral anomalies, including butterfly vertebrae;

• cardiac anomalies (most commonly peripheral pulmonary stenosis); and

• ocular abnormalities, including posterior embryotoxon.

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Other clinical findings include renal abnormalities, developmental delay, growth retardation and vascular abnormalities. Infants usually present with neonatal cholestasis and the characteristic facies, although these may be difficult to recognize in the neonatal period. If children with the syndrome present with jaundice, the prognosis is that 50% will die or require a transplant by 10 years of age.

Alpha-1-antitrypsin deficiency Alpha-1-antitrypsin deficiency is a common inherited cause of neonatal conjugated hyperbilirubinemia. It is a common protease inhibitor that is produced in hepatocytes. Approximately 1:2000 to 1:3000 individuals is homozygous for the Z mutation, and the ZZ phenotype is associated with neonatal liver disease and adult emphysema. Only 10% to 15% of infants with the ZZ phenotype will present with liv- er disease. The mechanism for the liver disease and why this minority of infants with the ZZ phenotype have jaundice are unclear. Liver disease seems to be related to hepatocyte accumulation of abnormal alpha-1-antitrypsin, along with inefficient excretion and some other undefined modifying factors (1).

Idiopathic neonatal hepatitis After biliary atresia, the most common diagnosis is idio- pathic neonatal hepatitis. Although no specific etiology can be demonstrated, these infants are more likely to have been born prematurely, be the product of a complicated pregnancy or have intrauterine growth retardation (1). The typical liver biopsy has hepatocyte giant cell transformation with inflammation. Prognosis is usually very good with 75% to 90% of cases resolved by one year (16). Predictors of poor prognosis include acholic stool, jaundice beyond six months, hepatomegaly, family history and a liver biopsy with severe inflammation (1).

MANAGEMENT Intensive supportive therapy is required for all infants with cholestatic liver disease. Much of the management can be provided through a co-care model between the primary care physician and the paediatric gastroenterologist. One of the most important issues is nutritional support. Infants with cholestatic liver disease require high calorie diets with 120% to 150% of the estimated average requirements (17), and because of the lack of bile flow, they require an increased percentage of medium chain triglycerides. Infants must be followed closely, with adjustments of the caloric density and medium chain triglycerides content of the diet based on growth. Some infants may require nasogastric tube feeds to meet nutritional requirements. Fat-soluble vitamins must also be supplemented with aqueous preparations. Current recommendations are alpha-tocopherol (vitamin E) 25 IU/kg/day plus a twice daily dose of a liquid multivitamin supplement (eg, Poly-Vi-Sol, Mead Johnson and Company, USA) and 1 mg/day to 2 mg/day of vitamin K. The dose should be titrated based on

measurements of serum levels of vitamins A, D and E, and the results of coagulation studies. To promote bile flow and decrease the pruritus of

cholestasis, ursodeoxycholic acid is used. The usual dose is

20 mg/kg/day. Further treatment of pruritus due to cholesta-

sis may include cholestyramine to bind intestinal bile acids and prevent reabsorption, or rifampin (5 mg/kg/day to

10 mg/kg/day).

The infants also require frequent monitoring by both their primary care physician and their paediatric gastroen- terologist to assess for progression or resolution of their liver disease. Follow-up evaluation of physical findings, hepatic synthetic function, transaminases and evidence of portal hypertension are used to assess the progression of the liver disease.

SUMMARY Early detection of infantile cholestatic liver disease is one of the greatest challenges facing the primary care provider. Although many infants are jaundiced beyond 14 days, it is imperative that they be investigated to facilitate early diagno- sis and implementation of therapy. The most important meas- ure in any infant persistently jaundiced beyond two weeks of age is the conjugated bilirubin level. Any elevation in bilirubin level should prompt investigations and immediate referral to a paediatric gastroenterologist.

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