- Email: [email protected]
Neonatal jaundice
Clinics and Research in Hepatology and Gastroenterology (2012) 36, 253—256
Available online at
www.sciencedirect.com
SUMMER SCHOOL: PEDIATRIC HEPATOLOGY
Neonatal jaundice Pat McKiernan Liver Unit, Birmingham Children’s Hospital, West Midlands, United Kingdom Available online 18 May 2012
Summary Neonatal jaundice lasting greater than 2 weeks should be investigated. Pale stools and dark or yellow urine are evidence of liver disease, which should be urgently investigated. The neonatal hepatitis syndrome has many causes, and a structured approach to investigation is mandatory. It should be possible to confirm or exclude biliary atresia within one week, so that definitive surgery is not delayed unnecessarily. Babies with the neonatal hepatitis syndrome should have vigorous fat-soluble vitamin supplementation, including parenteral vitamin K if coagulation is abnormal. The prognosis for infants with idiopathic neonatal hepatitis and multifactorial cholestasis is excellent. © 2012 Elsevier Masson SAS. All rights reserved.
Prolonged jaundice is defined as jaundice lasting more than 14 days in term infants and 21 days in preterm infants. The immediate priority is to differentiate between the pathological neonatal hepatitis syndrome where there is conjugated hyperbilirubinamia, and the more benign unconjugated hyperbiliruninaemia.
Incidence The population incidence of this disorder is approximately 1:1500 live births. The largest diagnostic groups are biliary atresia, alpha -1-antitrypsin deficiency, the various forms of Progressive familial intrahepatic cholestasis (PFIC), and the multifactorial cholestasis seen in premature infants.
A history of persistently yellow urine confirms the presence of conjugated hyperbilirubinaemia. The presence of pale stools is very sensitive for liver disease and even as an isolated finding should prompt immediate investigation. An alternative presentation is with bleeding due to Vitamin K deficiency. Examination reveals hepatomegaly in most and splenomegaly in 50% of cases. Other helpful diagnostic clinical features may include stigmata of syndromic disorders, facial dysmorphic features, evidence of congenital heart disease, and manifestations of intra-uterine infection such as growth retardation or thrombocytopenia. Cutaneous cavernous haemangiomata may be associated with intrahepatic haemangiomata.
Presentation Investigations Jaundice should be clinically detectable by inspection in a well lit room with particular attention paid to scleral colour.
E-mail address: [email protected]
Total and conjugated bilirubin should be measured urgently. A level of conjugated bilirubin of >20 mol/l is pathological and must be explained. The potential causes of neonatal cholestasis are summarised in Table 1.
2210-7401/$ – see front matter © 2012 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.clinre.2012.03.018
254 Table 1
P. McKiernan Conjugated hyperbilirubinaemia
Causes of neonatal cholestasis.
Bile duct abnormalities Biliary atresia Choledochal cyst Biliary sludge Gallstones Spontaneous perforation of bile ducts Neonatal sclerosing cholangitis Infections Systemic Septicaemia Urinary tract infection Hepatitic TORCH Echo, Adeno, Coxsackie-virus Human Herpes virus-6, Varicella-zoster HIV, Hepatitis B Inherited and metabolic disorders ␣ 1-Antitrypsin deficiency Alagille’s syndrome Galactosaemia Cystic fibrosis Niemann-Pick type C Progressive familial intrahepatic cholestasis Citrin deficiency Gaucher’s disease Wolman’s disease Tyrosinaemia Zellweger’s syndrome Carbohydrate deficient glycoprotein syndrome Dubin-Johnson syndrome Rotor syndrome Bile acid synthetic disorders Aagenaes syndrome ARC syndrome (Arthrogryposis, renal tubular dysfunction and cholestasis) Endocrine disorders Hypopituitarism Hypothyroidism Hypoadrenalism Chromosomal disorders Trisomy 21, 13, 18 Turner syndrome Toxic Parenteral nutrition Foetal alcohol syndrome Vascular disorders Budd-Chiari syndrome Perinatal asphyxia Multiple haemangiomata Congestive heart failure Miscellaneous Familial haemophagocytic lymphohisticytosis
The differential diagnosis is very wide, and a structured protocol for investigation is mandatory (Fig. 1). The first priority is to recognise conditions or complications requiring immediate treatment. Subsequent investigations should be structured so that children with surgical disorders can undergo surgery as quickly as possible, while conditions
Liver Function Tests (with direct bilirubin+ GT) Alpha-1antitrypsin level and phenotype T4, TSH, cortisol, Iron and ferritin, Cholesterol and triglycerides Galactose-1-phosphateuridyl transferase TORCH serology Fasting glucose, lactate and amino acids Urinary reducing substances, amino acids, organic acids, protein/creatinine ratio
Abdominal ultrasound (4 hour fast)
Choledochal cystor dilated biliary tree
Operative cholangiogram
ERCP feasible?
Small or absent gall bladder
? Pale or Acholic stools
A1ATD, hypopituitarism, CF and Alagille excluded? Other clinical abnormalities
Yes
No
? Liver biopsy Urine bile acids Karyotype DNA s tudies Chitotriosidase
Figure 1
Investigation of neonatal cholestasis.
which may mimic biliary atresia are excluded. This should take no longer than 1 week. Subsequent third line investigations can be reserved for specific clinical circumstances, or where no other aetiology has been recognised. A fasting abdominal USS should be performed, which usually demonstrates an absent or contracted gallbladder in biliary atresia. Features of biliary atresia splenic malformation syndrome are diagnostic. Hepatobiliary isotope imaging has a high sensitivity for biliary atresia, but uses radiation, is not specific and time consuming. As a result this test is no longer routinely performed. Liver biopsy has traditionally been undertaken in most cases, and it has 90% accuracy for biliary atresia. In the term infant with acholic stools, a small or absent gallbladder, and when other conditions have been excluded, operative cholangiography should not be delayed by undertaking a liver biopsy. Liver biopsy is best reserved as a third line investigation where there is diagnostic uncertainty. The level of Gamma-glutamyl transpeptidase (GGT) levels can be useful diagnostically. Normal or low levels of GGT in the presence of cholestasis implies a failure of bile excretion at canalicular level. This may occur where there are genetic bile duct transport abnormalities, disorders of bile acid metabolism, and in ARC syndrome. The diagnostic approach to genetic disorders has been transformed by the availability of rapid microarray-based gene sequencing. These allow the rapid and affordable sequencing of multiple genes of interest including many bile acid transporters and Niemann Pick type C.
Neonatal jaundice
Medical management of cholestasis There is no unequivocal evidence that any medical treatment alters the natural history of cholestasis. Ursodeoxycholic acid (UDCA) has been shown to improve biochemical parameters, and may slow the progression of hepatic fibrosis in some types of PFIC. My personal practice is to use UDCA where cholestasis persists beyond 6 weeks and in multifactorial cholestasis and biliary atresia. The initial dose is 20 mg/kg/d in divided doses. The only common side effect is diarrhoea, which usually responds to dose reduction. UDCA should be discontinued when cholestasis has resolved. Rifampicin, Phenobarbitone and Cholestyramine are rarely indicated for cholestasis per se, but may be useful to treat associated pruritis.
255 of significant fibrosis, and certainly before portal hypertension ensues. If progressive liver disease develops, especially if accompanied by failure to thrive or pruritus, liver transplantation may be indicated.
Prognosis and outcome Prognosis is related to the underlying disorder. Most cases of idiopathic and multifactorial cholestasis will resolve, often becoming clinically and biochemically normal by 1 year of age. Approximately 25% of children with alpha-1 antitrypsin deficiency will require liver transplantation during childhood, but the majority become clinically normal by their teens. In general all children should be followed up until their first birthday, with subsequent review being on a casebased basis.
Specific treatments Practice points There are an increasing number of disorders for which specific treatment options are available, including bile acid synthetic disorders, hypopituitarism, galactosaemia and tyrosinaemia. Although individually rare, this makes screening for these disorders more important.
Nutritional management of cholestatic infants This requires a high calorie diet containing 120—150% of the Estimated Average Requirement, with an increased percentage of fat as medium chain triglyceride (MCT). It is reasonable to start with one of a number of proprietary milks containing 40—50% of fat as MCT. Additional calorie and mineral supplements will be necessary in premature infants. Where this is insufficient a modular feed, in which the individual components, calorie density and osmolality can be manipulated, should be used. Most infants with liver disease are initially hyperphagic, and supplemental enteral nutrition is usually only required in those with progressive liver disease or prematurity.
• Neonatal jaundice lasting greater than 2 weeks should be investigated. • Pale stools and dark or yellow urine are evidence of liver disease, which should be urgently investigated. • The neonatal hepatitis syndrome has many causes, and a structured approach to investigation is mandatory. • It should be possible to confirm or exclude biliary atresia within one week, so that definitive surgery is not delayed unnecessarily. • Babies with the neonatal hepatitis syndrome should have vigorous fat-soluble vitamin supplementation, including parenteral Vitamin K if coagulation is abnormal. • The prognosis for infants with idiopathic neonatal hepatitis and multifactorial cholestasis is excellent.
Fat soluble vitamins
Disclosure of interest
Large doses of oral fat soluble vitamins are needed. It is best to use individual preparations of each vitamin, as this gives complete flexibility for dose adjustment. My personal practice is to start with the following daily doses, Vitamin K 1—2 mg, Vitamin E 100 mg, Alphacalcidol 50 ng/kg and Vitamin A 2500—5000 IU. Subsequent dose adjustment should be based on blood vitamin levels and biological response. Fat soluble vitamins should be continued for at least three months after the resolution of jaundice, as it is usually at least this long before normal bile flow is established.
The author declare that he has no conflicts of interest concerning this article.
Surgical treatments The primary treatment of biliary atresia and choledochal cyst is surgical. Partial external biliary diversion can provide spectacular symptomatic relief of cholestasis, and may change the natural history of the disease in some forms of PFIC. This should be carried out before the development
Further reading Roberts EA. The jaundiced baby. In: Kelly DA, editor. Diseases of the liver and biliary system in children. 3rd ed. Oxford:Blackwell publishing; 2008, 57—105 [A comprehensive and up to date review of all aspects of neonatal jaundice with >400 references]. Francavilla R, Castellaneta SP, Hadzic N, Chambers SM, Portmann B, Tung J, et al. Prognosis of alpha-1-antitrypsin deficiency-related liver disease in the era of paediatric liver transplantation. J Hepatol 2000;32:986—92 [A large centre review of the outcome of alpha-1antirypsin deficiency]. Klomp LW, Vargas JC, van Mil SW, Pawlikowska L, Strautnieks SS, van Eijk MJ, et al. Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology 2004;40:27—38 [An example of how to do genotype phenotype correlation in genetic liver disease].
256 Gissen P, Johnson CA, Morgan NV, Stapelbroek JM, Forshew T, Cooper WN, et al. Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome. Nat Genet 2004;36:400—4 [This paper described the molecular basis of ARC syndrome and provided insights into intracellular transport systems].
P. McKiernan Bruce CK, Smith M, Rahman F, Liu ZF, McMullan DJ, Ball S, et al. Design and validation of a metabolic disorder resequencing microarray (BRUM1). Hum Mutat 2010;31:858—–65 [Describes the practical aspects of developing a microarray-based gene sequencing chip for clinical application].
Available online at
www.sciencedirect.com
SUMMER SCHOOL: PEDIATRIC HEPATOLOGY
Neonatal jaundice Pat McKiernan Liver Unit, Birmingham Children’s Hospital, West Midlands, United Kingdom Available online 18 May 2012
Summary Neonatal jaundice lasting greater than 2 weeks should be investigated. Pale stools and dark or yellow urine are evidence of liver disease, which should be urgently investigated. The neonatal hepatitis syndrome has many causes, and a structured approach to investigation is mandatory. It should be possible to confirm or exclude biliary atresia within one week, so that definitive surgery is not delayed unnecessarily. Babies with the neonatal hepatitis syndrome should have vigorous fat-soluble vitamin supplementation, including parenteral vitamin K if coagulation is abnormal. The prognosis for infants with idiopathic neonatal hepatitis and multifactorial cholestasis is excellent. © 2012 Elsevier Masson SAS. All rights reserved.
Prolonged jaundice is defined as jaundice lasting more than 14 days in term infants and 21 days in preterm infants. The immediate priority is to differentiate between the pathological neonatal hepatitis syndrome where there is conjugated hyperbilirubinamia, and the more benign unconjugated hyperbiliruninaemia.
Incidence The population incidence of this disorder is approximately 1:1500 live births. The largest diagnostic groups are biliary atresia, alpha -1-antitrypsin deficiency, the various forms of Progressive familial intrahepatic cholestasis (PFIC), and the multifactorial cholestasis seen in premature infants.
A history of persistently yellow urine confirms the presence of conjugated hyperbilirubinaemia. The presence of pale stools is very sensitive for liver disease and even as an isolated finding should prompt immediate investigation. An alternative presentation is with bleeding due to Vitamin K deficiency. Examination reveals hepatomegaly in most and splenomegaly in 50% of cases. Other helpful diagnostic clinical features may include stigmata of syndromic disorders, facial dysmorphic features, evidence of congenital heart disease, and manifestations of intra-uterine infection such as growth retardation or thrombocytopenia. Cutaneous cavernous haemangiomata may be associated with intrahepatic haemangiomata.
Presentation Investigations Jaundice should be clinically detectable by inspection in a well lit room with particular attention paid to scleral colour.
E-mail address: [email protected]
Total and conjugated bilirubin should be measured urgently. A level of conjugated bilirubin of >20 mol/l is pathological and must be explained. The potential causes of neonatal cholestasis are summarised in Table 1.
2210-7401/$ – see front matter © 2012 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.clinre.2012.03.018
254 Table 1
P. McKiernan Conjugated hyperbilirubinaemia
Causes of neonatal cholestasis.
Bile duct abnormalities Biliary atresia Choledochal cyst Biliary sludge Gallstones Spontaneous perforation of bile ducts Neonatal sclerosing cholangitis Infections Systemic Septicaemia Urinary tract infection Hepatitic TORCH Echo, Adeno, Coxsackie-virus Human Herpes virus-6, Varicella-zoster HIV, Hepatitis B Inherited and metabolic disorders ␣ 1-Antitrypsin deficiency Alagille’s syndrome Galactosaemia Cystic fibrosis Niemann-Pick type C Progressive familial intrahepatic cholestasis Citrin deficiency Gaucher’s disease Wolman’s disease Tyrosinaemia Zellweger’s syndrome Carbohydrate deficient glycoprotein syndrome Dubin-Johnson syndrome Rotor syndrome Bile acid synthetic disorders Aagenaes syndrome ARC syndrome (Arthrogryposis, renal tubular dysfunction and cholestasis) Endocrine disorders Hypopituitarism Hypothyroidism Hypoadrenalism Chromosomal disorders Trisomy 21, 13, 18 Turner syndrome Toxic Parenteral nutrition Foetal alcohol syndrome Vascular disorders Budd-Chiari syndrome Perinatal asphyxia Multiple haemangiomata Congestive heart failure Miscellaneous Familial haemophagocytic lymphohisticytosis
The differential diagnosis is very wide, and a structured protocol for investigation is mandatory (Fig. 1). The first priority is to recognise conditions or complications requiring immediate treatment. Subsequent investigations should be structured so that children with surgical disorders can undergo surgery as quickly as possible, while conditions
Liver Function Tests (with direct bilirubin+ GT) Alpha-1antitrypsin level and phenotype T4, TSH, cortisol, Iron and ferritin, Cholesterol and triglycerides Galactose-1-phosphateuridyl transferase TORCH serology Fasting glucose, lactate and amino acids Urinary reducing substances, amino acids, organic acids, protein/creatinine ratio
Abdominal ultrasound (4 hour fast)
Choledochal cystor dilated biliary tree
Operative cholangiogram
ERCP feasible?
Small or absent gall bladder
? Pale or Acholic stools
A1ATD, hypopituitarism, CF and Alagille excluded? Other clinical abnormalities
Yes
No
? Liver biopsy Urine bile acids Karyotype DNA s tudies Chitotriosidase
Figure 1
Investigation of neonatal cholestasis.
which may mimic biliary atresia are excluded. This should take no longer than 1 week. Subsequent third line investigations can be reserved for specific clinical circumstances, or where no other aetiology has been recognised. A fasting abdominal USS should be performed, which usually demonstrates an absent or contracted gallbladder in biliary atresia. Features of biliary atresia splenic malformation syndrome are diagnostic. Hepatobiliary isotope imaging has a high sensitivity for biliary atresia, but uses radiation, is not specific and time consuming. As a result this test is no longer routinely performed. Liver biopsy has traditionally been undertaken in most cases, and it has 90% accuracy for biliary atresia. In the term infant with acholic stools, a small or absent gallbladder, and when other conditions have been excluded, operative cholangiography should not be delayed by undertaking a liver biopsy. Liver biopsy is best reserved as a third line investigation where there is diagnostic uncertainty. The level of Gamma-glutamyl transpeptidase (GGT) levels can be useful diagnostically. Normal or low levels of GGT in the presence of cholestasis implies a failure of bile excretion at canalicular level. This may occur where there are genetic bile duct transport abnormalities, disorders of bile acid metabolism, and in ARC syndrome. The diagnostic approach to genetic disorders has been transformed by the availability of rapid microarray-based gene sequencing. These allow the rapid and affordable sequencing of multiple genes of interest including many bile acid transporters and Niemann Pick type C.
Neonatal jaundice
Medical management of cholestasis There is no unequivocal evidence that any medical treatment alters the natural history of cholestasis. Ursodeoxycholic acid (UDCA) has been shown to improve biochemical parameters, and may slow the progression of hepatic fibrosis in some types of PFIC. My personal practice is to use UDCA where cholestasis persists beyond 6 weeks and in multifactorial cholestasis and biliary atresia. The initial dose is 20 mg/kg/d in divided doses. The only common side effect is diarrhoea, which usually responds to dose reduction. UDCA should be discontinued when cholestasis has resolved. Rifampicin, Phenobarbitone and Cholestyramine are rarely indicated for cholestasis per se, but may be useful to treat associated pruritis.
255 of significant fibrosis, and certainly before portal hypertension ensues. If progressive liver disease develops, especially if accompanied by failure to thrive or pruritus, liver transplantation may be indicated.
Prognosis and outcome Prognosis is related to the underlying disorder. Most cases of idiopathic and multifactorial cholestasis will resolve, often becoming clinically and biochemically normal by 1 year of age. Approximately 25% of children with alpha-1 antitrypsin deficiency will require liver transplantation during childhood, but the majority become clinically normal by their teens. In general all children should be followed up until their first birthday, with subsequent review being on a casebased basis.
Specific treatments Practice points There are an increasing number of disorders for which specific treatment options are available, including bile acid synthetic disorders, hypopituitarism, galactosaemia and tyrosinaemia. Although individually rare, this makes screening for these disorders more important.
Nutritional management of cholestatic infants This requires a high calorie diet containing 120—150% of the Estimated Average Requirement, with an increased percentage of fat as medium chain triglyceride (MCT). It is reasonable to start with one of a number of proprietary milks containing 40—50% of fat as MCT. Additional calorie and mineral supplements will be necessary in premature infants. Where this is insufficient a modular feed, in which the individual components, calorie density and osmolality can be manipulated, should be used. Most infants with liver disease are initially hyperphagic, and supplemental enteral nutrition is usually only required in those with progressive liver disease or prematurity.
• Neonatal jaundice lasting greater than 2 weeks should be investigated. • Pale stools and dark or yellow urine are evidence of liver disease, which should be urgently investigated. • The neonatal hepatitis syndrome has many causes, and a structured approach to investigation is mandatory. • It should be possible to confirm or exclude biliary atresia within one week, so that definitive surgery is not delayed unnecessarily. • Babies with the neonatal hepatitis syndrome should have vigorous fat-soluble vitamin supplementation, including parenteral Vitamin K if coagulation is abnormal. • The prognosis for infants with idiopathic neonatal hepatitis and multifactorial cholestasis is excellent.
Fat soluble vitamins
Disclosure of interest
Large doses of oral fat soluble vitamins are needed. It is best to use individual preparations of each vitamin, as this gives complete flexibility for dose adjustment. My personal practice is to start with the following daily doses, Vitamin K 1—2 mg, Vitamin E 100 mg, Alphacalcidol 50 ng/kg and Vitamin A 2500—5000 IU. Subsequent dose adjustment should be based on blood vitamin levels and biological response. Fat soluble vitamins should be continued for at least three months after the resolution of jaundice, as it is usually at least this long before normal bile flow is established.
The author declare that he has no conflicts of interest concerning this article.
Surgical treatments The primary treatment of biliary atresia and choledochal cyst is surgical. Partial external biliary diversion can provide spectacular symptomatic relief of cholestasis, and may change the natural history of the disease in some forms of PFIC. This should be carried out before the development
Further reading Roberts EA. The jaundiced baby. In: Kelly DA, editor. Diseases of the liver and biliary system in children. 3rd ed. Oxford:Blackwell publishing; 2008, 57—105 [A comprehensive and up to date review of all aspects of neonatal jaundice with >400 references]. Francavilla R, Castellaneta SP, Hadzic N, Chambers SM, Portmann B, Tung J, et al. Prognosis of alpha-1-antitrypsin deficiency-related liver disease in the era of paediatric liver transplantation. J Hepatol 2000;32:986—92 [A large centre review of the outcome of alpha-1antirypsin deficiency]. Klomp LW, Vargas JC, van Mil SW, Pawlikowska L, Strautnieks SS, van Eijk MJ, et al. Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology 2004;40:27—38 [An example of how to do genotype phenotype correlation in genetic liver disease].
256 Gissen P, Johnson CA, Morgan NV, Stapelbroek JM, Forshew T, Cooper WN, et al. Mutations in VPS33B, encoding a regulator of SNARE-dependent membrane fusion, cause arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome. Nat Genet 2004;36:400—4 [This paper described the molecular basis of ARC syndrome and provided insights into intracellular transport systems].
P. McKiernan Bruce CK, Smith M, Rahman F, Liu ZF, McMullan DJ, Ball S, et al. Design and validation of a metabolic disorder resequencing microarray (BRUM1). Hum Mutat 2010;31:858—–65 [Describes the practical aspects of developing a microarray-based gene sequencing chip for clinical application].