Cholestasis in Neonates and Young Infants

Cholestasis in neonates and young infants is conjugated hyperbilirubinemia in the 1st 3 months of life due to impaired bile excretion. Biliary tract malformations involving the gallbladder and bile duct are grouped into cystic and noncystic obliterative cholangiopathies, the most common of which is biliary atresia. Less common causes include the genetic Alagille syndrome, infectious causes, and metabolic disorders. Clinical presentation is with obstructive jaundice. Ultrasonography and MRCP are useful diagnostic tools, and a prenatal diagnosis is sometimes made with ultrasonography. Cystic causes frequently require surgery to correct the defect and allow for normal child growth. Liver transplantation may be needed in cases of biliary atresia with portal hypertension.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Cholestasis in neonates and young infants is conjugated hyperbilirubinemia in the 1st 3 months of life due to impaired bile excretion.

Etiology

Biliary tract Biliary tract Bile is secreted by hepatocytes into thin channels called canaliculi. These canaliculi lead into slightly larger interlobular bile ductules, which are part of the portal triads at the "corners" of hepatic lobules. The bile leaves the liver via the right and left hepatic ducts, which join together to form the common hepatic duct. Gallbladder and Biliary Tract malformations involving the gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract and bile duct are grouped into cystic and noncystic obliterative cholangiopathies, the most common of which is biliary atresia. Less common causes include the genetic Alagille syndrome, infectious causes, and metabolic disorders.

  • Obstructive causes:
    • Biliary atresia
    • Choledochal cysts
    • Other obstructive causes:
      • Stones
      • Tumors
      • Neonatal sclerosing cholangitis
  • Infectious causes:
    • TORCH infections:
      • Toxoplasmosis
      • Other ( syphilis Syphilis Syphilis is a bacterial infection caused by the spirochete Treponema pallidum pallidum (T. p. pallidum), which is usually spread through sexual contact. Syphilis has 4 clinical stages: primary, secondary, latent, and tertiary. Syphilis)
      • Rubella
      • Cytomegalovirus (CMV)
      • Herpes simplex virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview ( HSV HSV Herpes simplex virus (HSV) is a double-stranded DNA virus belonging to the family Herpesviridae. Herpes simplex virus commonly causes recurrent infections involving the skin and mucosal surfaces, including the mouth, lips, eyes, and genitals. Herpes Simplex Virus 1 & 2)
    • Viral infections:
      • Echovirus Echovirus Echoviruses are single-stranded positive-sense RNA viruses belonging to the genus Enterovirus. Transmission is most commonly through the fecal-oral route. The majority of patients are asymptomatic. Patients who are symptomatic can exhibit a wide range of illnesses ranging from nonspecific URIs and exanthems to severe and life-threatening illnesses. Picornaviridae: Echovirus
      • Adenovirus Adenovirus Adenovirus (member of the family Adenoviridae) is a nonenveloped, double-stranded DNA virus. Adenovirus is transmitted in a variety of ways, and it can have various presentations based on the site of entry. Presentation can include febrile pharyngitis, conjunctivitis, acute respiratory disease, atypical pneumonia, and gastroenteritis. Adenovirus
      • Parvovirus B19 Parvovirus B19 Primate erythroparvovirus 1 (generally referred to as parvovirus B19, B19 virus, or sometimes erythrovirus B19) ranks among the smallest DNA viruses. Parvovirus B19 is of the family Parvoviridae and genus Erythrovirus. In immunocompetent humans, parvovirus B19 classically results in erythema infectiosum (5th disease) or "slapped cheek syndrome." Parvovirus B19
    • Neonatal urinary tract Urinary tract The urinary tract is located in the abdomen and pelvis and consists of the kidneys, ureters, urinary bladder, and urethra. The structures permit the excretion of urine from the body. Urine flows from the kidneys through the ureters to the urinary bladder and out through the urethra. Urinary Tract infection
  • Genetic causes:
    • Alagille syndrome (syndromic paucity of the interlobular bile ducts)
    • Alpha-1 antitrypsin deficiency
    • Progressive familial intrahepatic cholestasis
    • Cystic fibrosis Cystic fibrosis Cystic fibrosis is an autosomal recessive disorder caused by mutations in the gene CFTR. The mutations lead to dysfunction of chloride channels, which results in hyperviscous mucus and the accumulation of secretions. Common presentations include chronic respiratory infections, failure to thrive, and pancreatic insufficiency. Cystic Fibrosis
  • Metabolic disorders/inborn errors of metabolism:
    • Carbohydrate metabolism: galactosemia Galactosemia Galactosemia is a disorder caused by defects in galactose metabolism. Galactosemia is an inherited, autosomal-recessive condition, which results in inadequate galactose processing and high blood levels of monosaccharide. The rare disorder often presents in infants with symptoms of lethargy, nausea, vomiting, diarrhea, and jaundice. Galactosemia
    • Amino acids: tyrosinemia
    • Lipids: 
      • Niemann-Pick type C
      • Gaucher disease Gaucher disease Gaucher Disease (GD) is an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase enzyme activity, resulting in accumulation of glucocerebroside in cells and certain organs. The disease is categorized into 3 types with variable clinical presentation. Gaucher Disease type 2
    • Disorders of bile acid metabolism
  • Toxic
    • Intestinal failure–associated liver disease (parenteral nutrition)
    • Drugs
Gallbladder and biliary tract

Normal biliary tract anatomy

Image by Lecturio.

Biliary Atresia

Biliary atresia is an idiopathic, progressive, fibrotic obliteration of the extrahepatic biliary tree that presents with biliary obstruction within the 1st 3 months of life.

  • Classification:
    • Neonatal form (80%–90% of patients):
      • Isolated biliary atresia
      • Neonate is normal at birth; progressive obliteration of extrahepatic bile ducts develops within weeks.
    • Embryonic or fetal form:
      • Present at birth
      • Associated with other congenital anomalies (situs inversus, polysplenia, intestinal malrotation Intestinal malrotation Intestinal malrotation is a congenital anomaly that results from failure of the GI tract to undergo normal rotation around the mesenteric vessels during embryologic development. This condition can result in several anatomic patterns characterized by abnormal location and attachments of the abdominal cavity's intestines. Intestinal Malrotation, heart disease)
    • Severity of obstruction:
      • Noncorrectable: obliteration of the entire extrahepatic biliary tree is seen in approximately 85% of cases
      • Surgically correctable form (less common): distal segmental bile duct obliteration with patent extrahepatic ducts 
  • Epidemiology:
    • 1 in 10,000–15,000 live births
    • More common in the East Asian population
    • Unlikely to occur within the same family
  • Etiology: pathogenesis is unknown, but several mechanisms have been implicated:
    • Viral
    • Toxin-mediated inflammatory response
    • Genetic factors
    • Immune etiologies
  • Pathophysiology:
    • Perinatal insult (possible viral infection) causes bile duct injury.
    • Immunologic response → inflammatory infiltration and obstruction
    • Epithelial proliferation → progressive sclerosis → obliteration of extrahepatic biliary ducts and atresia in the 1st few months of life
    • Cholestasis → hepatocellular injury with secondary cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
  • Clinical presentation:
    • May not be present at birth and may appear over the 1st 2 weeks
    • May show normal appetite and growth during early weeks
    • Variable degrees of:
      • Jaundice, scleral icterus
      • Dark urine (bilirubinuria)
      • Acholic (pale) stools 
      • Hepatomegaly 
      • Splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly may gradually develop owing to portal hypertension Portal hypertension Portal hypertension is increased pressure in the portal venous system. This increased pressure can lead to splanchnic vasodilation, collateral blood flow through portosystemic anastomoses, and increased hydrostatic pressure. There are a number of etiologies, including cirrhosis, right-sided congestive heart failure, schistosomiasis, portal vein thrombosis, hepatitis, and Budd-Chiari syndrome. Portal Hypertension.
    • Physiologic jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice (indirect hyperbilirubinemia; resolves within 2 weeks) returns after 8 weeks (direct hyperbilirubinemia, pathologic)
    • Cardiac murmurs may suggest associated anomalies.
  • Diagnosis:
    • Screening in high-risk populations: stool color cards
    • Labs:
      • Total and direct (conjugated) bilirubin: both elevated
      • Obstructive pattern of liver enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes: significant elevation of alkaline phosphatase, mild elevation of ALT and AST
    • Abdominal ultrasonography may identify:
      • Other causes of neonatal cholestasis
      • Associated anomalies such as polysplenia
      • Hypoplastic or absent gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract
      • Triangular cord sign: represents the fibrous ductal remnant of the extrahepatic bile duct in biliary atresia
    • MRCP may be indicated for preoperative evaluation. 
    • Percutaneous liver biopsy:
      • Most valuable test
      • Shows proliferation and plugging of bile ductules with relatively intact lobular structure
  • Management:
    • Exploratory laparotomy Laparotomy Laparotomy is an open surgical exploration of the abdomen, usually through a single large incision. Laparotomy and Laparoscopy + direct cholangiography (preferably before 8 weeks of life)
    • Surgically correctable lesions are corrected.
    • Noncorrectable lesions: treated in the short term with a portoenterostomy (Kasai procedure)
      • The liver is anastomosed to a piece of intestine, allowing multiple small bile duct remnants to empty into the intestine. 
      • This procedure delays the onset of cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis and allows for normal growth. 
      • Most individuals with noncorrectable lesions eventually develop portal hypertension Portal hypertension Portal hypertension is increased pressure in the portal venous system. This increased pressure can lead to splanchnic vasodilation, collateral blood flow through portosystemic anastomoses, and increased hydrostatic pressure. There are a number of etiologies, including cirrhosis, right-sided congestive heart failure, schistosomiasis, portal vein thrombosis, hepatitis, and Budd-Chiari syndrome. Portal Hypertension and recurrent hepatic dysfunction. 
      • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver transplantation done later is curative.

Related videos

Alagille Syndrome

Alagille syndrome is a genetic disorder characterized by a paucity of bile ducts in the liver, leading to cholestasis. This syndrome also affects other organs.

  • Etiology:
    • Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance mutations in the JAG1 gene in > 90% of patients
    • Others have mutations in the NOTCH2 gene.
  • Clinical presentation:
    • Hepatic manifestations:
      • Paucity of interlobular bile ducts
      • Chronic cholestasis (in 90%)
      • Jaundice
      • Cirrhosis
      • Pruritus (80%)
      • Xanthomas
    • Cardiac murmur or anomalies in 85%–91%, most commonly pulmonic stenosis
    • Renal dysplasia
    • Butterfly vertebrae
    • Typical facial features:
      • “Triangular” facies with prominent forehead, broad nasal bridge, and pointed chin 
      • Deep-set eyes
    • Other minor abnormalities in growth and intellectual disability
  • Diagnosis:
    • Lab findings:
      • Conjugated hyperbilirubinemia
      • Elevated liver enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes (aminotransferases) and disproportionately increased gamma-glutamyl transpeptidase (GGTP)
    • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver biopsy: reduced number of interlobular bile ducts
    • Genetic testing to confirm gene mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations
  • Management: 
    • Cholestatic liver disease is of variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables severity; may stabilize by school age.
    • Medical management of pruritus to improve quality of life:
      • Ursodeoxycholic acid
      • Bile acid sequestrants (cholestyramine, colesevelam)
      • Refractory to medical treatment in approximately 40% of patients; surgery with biliary diversion or liver transplantation may be indicated.
    • Complication: portal hypertension Portal hypertension Portal hypertension is increased pressure in the portal venous system. This increased pressure can lead to splanchnic vasodilation, collateral blood flow through portosystemic anastomoses, and increased hydrostatic pressure. There are a number of etiologies, including cirrhosis, right-sided congestive heart failure, schistosomiasis, portal vein thrombosis, hepatitis, and Budd-Chiari syndrome. Portal Hypertension later in childhood
    • Prognosis: In a study of 293 individuals, transplant-free survival was 24% up to age 18.
Histology_of_normal_and_defective_intrahepatic_bile_ducts.

A: Fetal liver at 16 weeks of development showing focal dilations (arrows) in the biliary epithelial cell precursors surrounding the portal vein (PV).
B: Mature liver showing bile ducts ( BD BD Blount’s disease (BD) is an orthopedic childhood disorder characterized by outward bowing of the leg due to abnormal ossification of the medial aspect of the tibial epiphysis. Blount’s disease mostly affects children of African descent and tends to debut at approximately 1–3 years of age. Blount’s Disease (BD)) and hepatic artery (HA) embedded in the periportal mesenchyme in a characteristic arrangement known as the “portal triad.” Hepatocytes arranged in chords surround the portal triad.
C: The portal triad region from an individual with Alagille syndrome shows ductal cysts rather than normal bile ducts due to defects in ductal plate remodeling.

Image: “Histology of normal and defective intrahepatic bile ducts” by Smallbot. License: CC BY 3.0

Choledochal Cysts

Choledochal cysts are congenital bile duct anomalies that cause abnormal enlargement and obstruction of the intrahepatic and/or extrahepatic bile ducts.

  • Classification:
    • Type I (90%–95% of cases): a saccular or fusiform cystic dilation of the extrahepatic biliary duct
    • Type II: a diverticulum of the common bile duct 
    • Type III (choledochocele): a cyst in the common bile duct in the duodenal wall
    • Type IV: involves dilation of both intrahepatic and extrahepatic ducts 
    • Type V (least common): multiple cystic dilations of intrahepatic ducts
  • Etiology: 
    • Unknown, likely > 1 mechanism
    • May be congenital (most common) or acquired (rare) after cholecystectomy Cholecystectomy Cholecystectomy is a surgical procedure performed with the goal of resecting and extracting the gallbladder. It is one of the most common abdominal surgeries performed in the Western world. Cholecystectomy is performed for symptomatic cholelithiasis, cholecystitis, gallbladder polyps > 0.5 cm, porcelain gallbladder, choledocholithiasis and gallstone pancreatitis, and rarely, for gallbladder cancer. Cholecystectomy: Approaches and Technique
    • Associated with a variety of other anatomic abnormalities:
      • Abnormal pancreatobiliary junction
      • Biliary, duodenal, or colonic atresia
      • Double common bile duct
      • Imperforate anus
      • Ventricular septal defect
      • Aortic hypoplasia
  • Epidemiology: 
    • Incidence in Western countries: 1 in 100,000–150,000
    • Higher incidence in Japan: about 1 in 1000
    • Female to male ratio is 3–4:1
    • Most often diagnosed in infancy or childhood, but sometimes in adulthood
  • Clinical presentation:
    • Infants: 
      • Obstructive jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice
      • Palpable mass
      • Acholic stools
      • Hepatomegaly
      • Cysts may be an incidental finding on prenatal ultrasonography
    • Children (majority present at < 10 years): 
      • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
      • Jaundice 
      • Palpable mass
      • Nausea and vomiting
      • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
      • Pruritus
      • Weight loss
      • Bouts of acute pancreatitis Acute pancreatitis Acute pancreatitis is an inflammatory disease of the pancreas due to autodigestion. Common etiologies include gallstones and excessive alcohol use. Patients typically present with epigastric pain radiating to the back. Acute Pancreatitis; occasionally acute cholangitis Acute Cholangitis Acute cholangitis is a life-threatening condition characterized by fever, jaundice, and abdominal pain which develops as a result of stasis and infection of the biliary tract. Septic shock, liver abscess, and multi-organ dysfunction are potential serious complications. Acute Cholangitis
  • Diagnosis:
    • Laboratory studies:
      • Direct (conjugated) hyperbilirubinemia 
      • Obstructive pattern of liver enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes: significant elevation of alkaline phosphatase, mild elevation of ALT and AST
    • Ultrasonography 
    • MRCP for preoperative assessment 
  • Treatment: primary cyst excision + biliary enteric (Roux-en-Y) anastomosis
  • Complications:
    • If the obstruction is not relieved (especially in infancy), severe liver dysfunction and coagulopathy may rapidly ensue.
    • Higher risk of cholangiocarcinoma if proper resection is not performed

References

  1. Wildhaber, B.E. (2012). Biliary atresia: 50 years after the first Kasai. ISRN Surg. DOI: 10.5402/2012/132089
  2. Erlichman, J., Loomes, K.M. (2021). Causes of cholestasis in neonates and young infants. UpToDate. Retrieved December 15, 2021, from https://www.uptodate.com/contents/causes-of-cholestasis-in-neonates-and-young-infants
  3. Kamath, B.M., Ye, W., et al. (2020). Outcomes of childhood cholestasis in Alagille syndrome: results of a multicenter observational study. Hepatology Commun 4:387–398. DOI: 10.1002/hep4.1468
  4. Erlichman, J., Loomes, K.M. (2021). Biliary atresia. UpToDate. Retrieved December 15, 2021, from https://www.uptodate.com/contents/biliary-atresia
  5. Topazian, M. (2021). Biliary cysts. UpToDate. Retrieved December 15, 2021, from https://www.uptodate.com/contents/biliary-cysts

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