Infantile cholestasis refers to a pathological condition in which bile formation, secretion, and excretion are impaired due to various intrahepatic or extrahepatic causes in infants under the age of one, including neonates. Bile components fail to enter the duodenum as they normally should and instead accumulate in the bloodstream. The primary clinical manifestations include jaundice and changes in stool color, often accompanied by hepatomegaly or hepatosplenomegaly with abnormal texture. Abnormalities in liver function indicators such as elevated bilirubin, total bile acid, and transaminases are also observed. Some cases may also present with pruritus and malnutrition. In the past, this condition was referred to as "infantile hepatitis syndrome."
Etiology and Pathogenesis
The underlying causes of infantile cholestasis are diverse and complex, involving factors such as biliary abnormalities, genetic disorders, toxicity, and infections. Variations exist between countries due to geographical, genetic, and other environmental factors.
Biliary Abnormalities
Biliary Atresia
This is a progressive condition occurring in late fetal development, the early postnatal period, or during the neonatal stage. It involves obstruction of intrahepatic and extrahepatic bile ducts, blocking the bile excretion pathway. Perinatal infections, particularly viral infections, are considered major contributors to the inflammatory damage that leads to biliary atresia. Approximately 80% of cases are attributed to inflammation-related causes, while congenital bile duct developmental abnormalities account for only 10%.
Congenital Bile Duct Dilatation
This condition can be categorized into various types based on the site of dilatation. The most common form is congenital choledochal cysts, a congenital developmental anomaly caused by multiple factors. Abnormal pancreaticobiliary differentiation during embryonic development, reflux of pancreatic juice into the bile duct, distal narrowing of the common bile duct, increased bile duct pressure, and neuromuscular dysfunction of the sphincter of Oddi are considered to be the combined pathogenic mechanisms.
Congenital Intrahepatic Biliary Cystic Dilatation (Caroli Disease)
This is an autosomal recessive disorder seen more often in males and is primarily characterized by recurrent cholangitis. It can be associated with congenital hepatic fibrosis, extrahepatic bile duct dilatation, or other fibrocystic conditions.
Other Biliary Disorders
These include bile duct paucity (e.g., Alagille syndrome), biliary stenosis, viscous bile/mucus plugs, and other abnormalities.
Genetic Causes
With advancements in molecular genetic testing in clinical practice, the proportion of genetic causes identified in cholestasis cases has been increasing. A wide variety of causative genes have been implicated, and novel pathogenic genes continue to be discovered.
Carbohydrate Metabolism Disorders
These include hereditary fructose intolerance, galactosemia, and glycogen storage diseases, particularly types I, III, and IV, which are associated with infantile hepatitis syndrome.
Amino Acid and Protein Metabolism Disorders
Examples include hereditary tyrosinemia and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD).
Lipid Metabolism Disorders
Genetic defects in certain enzymes involved in lipid metabolism result in the accumulation of specific lipids in the mononuclear phagocytic system and other tissues, leading to lipid-laden histiocytic proliferation. Examples include Gaucher disease, Niemann-Pick disease, and Wolman disease.
Bile Acid and Bilirubin Metabolism Disorders
These include conditions such as congenital bile acid synthesis defects (CBAS), Rotor syndrome, and Dubin-Johnson syndrome. Deficiencies in sodium-taurocholate cotransporting polypeptide (NTCP), caused by pathogenic variants in the SLC10A1 gene, constitute an autosomal recessive disorder characterized by persistently elevated serum bile acids and, in some cases, transient cholestasis.
Endocrine Disorders
Congenital hypothyroidism can cause jaundice, with some cases presenting as cholestatic jaundice. Panhypopituitarism can manifest as severe cholestasis accompanied by hypoglycemia, with early signs often being subtle.
Other Genetic Disorders
These include progressive familial intrahepatic cholestasis (PFIC) of types 1 to 6, mitochondrial diseases, Zellweger syndrome (cerebro-hepato-renal syndrome), Aagenaes syndrome (hereditary cholestasis with lymphedema), cystic fibrosis, arthrogryposis-renal dysfunction-cholestasis syndrome, α1-antitrypsin deficiency, and chromosomal abnormalities. Cholestasis can be a prominent feature in these disorders.
Infections
This category includes both primary liver infections and systemic infections involving the liver. The TORCH complex represents major infectious agents, including Toxoplasma gondii, rubella virus, cytomegalovirus, herpes simplex virus, as well as echovirus, adenovirus, and parvovirus B19. Bacterial infections such as Staphylococcus aureus, Escherichia coli, Salmonella spp., anaerobic bacteria, and Streptococcus spp., as well as opportunistic pathogens, often involve the liver in the context of systemic infection. Urinary tract infections can also cause cholestasis, with jaundice as the sole presenting symptom in some cases. Due attention should also be given to hepatitis syndrome caused by Treponema pallidum (syphilis) and Mycobacterium tuberculosis. Additionally, vertical transmission of novel pathogens like human immunodeficiency virus (HIV) can contribute to the condition.
Toxic Effects
This category involves adverse drug effects and parenteral nutrition-associated cholestasis (PNAC).
Other Causes
These include pediatric hepatic neoplasms, neonatal hemochromatosis, systemic malignancies involving the liver (e.g., Langerhans cell histiocytosis and hemophagocytic lymphohistiocytosis).
Idiopathic Infantile Cholestasis
Cases where comprehensive evaluation fails to identify a clear cause are classified as idiopathic cholestasis. As understanding of the condition deepens and diagnostic technologies improve, the proportion of cases in this category is expected to gradually decrease.
Pathology
Although the underlying causes are diverse, the primary pathological change is nonspecific multinucleated giant cell formation. Other pathological features include bile stasis, infiltration of inflammatory cells in the liver stroma and portal areas, with the severity correlating to the disease progression. In mild cases, the normal structure of hepatic lobules is preserved, while in severe cases, structural disruption occurs, accompanied by patchy or confluent hepatic necrosis, Kupffer cell proliferation, and bile duct proliferation. As the disease progresses, fibrosis may develop around the portal areas.
Clinical Manifestations
Skin Changes
Jaundice is the initial and most prominent symptom, with skin coloration determined by the degree of bile stasis. In obstructive jaundice, the skin may appear dull or even yellow-brown. Chronic biliary obstruction over an extended period may lead to xanthomas and skin pigmentation. Petechiae, ecchymosis, or bleeding from nasal mucosa or gums may occur due to liver dysfunction and impaired synthesis of clotting factors. Some infants may also experience pronounced pruritus.
Changes in Stool and Urine Color
Stool color may lighten, resembling white clay or even grayish-white. Darkening of urine often accompanies these changes.
Hepatomegaly and/or Abnormal Liver Texture
Liver damage is often associated with an enlarged liver that feels firm and lacks obvious tenderness. Jaundice accompanied by gallbladder enlargement suggests obstruction of the distal common bile duct, which can occur in cases of gallstones, inflammation, or tumors. Severe cases can result in portal hypertension and splenomegaly. As bile stasis progresses, liver damage and dysfunction eventually worsen, potentially resulting in gastrointestinal bleeding. Twenty percent of cases may progress to biliary cirrhosis or end-stage liver failure.
Malabsorption of Fat and Fat-Soluble Vitamins and Malnutrition
Intrahepatic bile stasis reduces the amount of bile entering the intestine, leading to diarrhea, malnutrition, and poor absorption of fat-soluble vitamins. Vitamin K deficiency caused by impaired absorption and reduced synthesis due to liver dysfunction may result in coagulation disorders, manifesting as petechiae, ecchymoses, or even intracranial hemorrhage. Deficiencies in vitamins A, D, and E may contribute to symptoms such as rickets, impaired nighttime vision, or even night blindness. Malabsorption of fats and fat-soluble vitamins can result in steatorrhea. Poor protein synthesis exacerbates developmental delays and malnutrition.
Neurological and Psychological Abnormalities
Infants may present with feeding difficulties, lethargy, hypotonia, irritability, or restlessness, with severe cases potentially leading to seizures. Marked liver dysfunction may cause hyperammonemia and hepatic encephalopathy.
Special Features
Congenital cytomegalovirus (CMV) infection may present with associated chorioretinitis. Alagille syndrome may include heart murmurs and characteristic facial abnormalities. A palpable mass in the upper right abdomen may suggest a choledochal cyst. Cataracts may indicate underlying conditions such as galactosemia or hypothyroidism.
Laboratory and Auxiliary Examinations
Complete Blood Count (CBC)
Bacterial infections often present with leukocytosis, neutrophilia, and a left shift. CMV infections may exhibit elevated mononuclear cells, thrombocytopenia, anemia, or hemolysis.
Liver Function Tests (LFTs)
The levels of conjugated and unconjugated bilirubin may vary in increase and proportion. Alanine transaminase (ALT) levels are often elevated. Markers of biliary cholestasis, such as serum bile acids, gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), and 5’-nucleotidase, are typically elevated. However, specific conditions such as progressive familial intrahepatic cholestasis (PFIC) types 1 and 2 may show low or normal GGT levels. Indicators reflecting liver synthetic function, including coagulation factors, fibrinogen, and serum albumin, may be reduced. Persistent elevation of alpha-fetoprotein (AFP) suggests hepatocyte damage and regeneration.
Pathogen Screening
Testing includes markers and serological assessments for viral infections such as hepatitis viruses, CMV, Epstein-Barr virus (EBV), herpes simplex virus (HSV), rubella virus, and human immunodeficiency virus (HIV). Additional tests include Toxoplasma gondii and Treponema pallidum screening. Blood or midstream urine cultures may identify specific bacterial pathogens.
Screening for Metabolic Diseases
Tandem mass spectrometry can detect levels of amino acids and metabolites in blood and urine, aiding in the identification of disorders in amino acid and fatty acid metabolism. Thyroid-stimulating hormone (TSH) testing can detect hypothyroidism. Succinylacetone levels in urine help diagnose hereditary tyrosinemia. Galactose-1-phosphate uridyltransferase levels in blood and urine can confirm galactosemia. Reduced serum alpha-1-antitrypsin and decreased protease inhibitor activity indicate alpha-1-antitrypsin deficiency. Immunoreactive trypsinogen screening and sweat chloride tests aid in diagnosing cystic fibrosis in infants. Blood glucose measurement helps identify glycogen storage diseases involving the liver.
Genetic Testing
Over 600 causative genes for cholestasis have been identified. Techniques such as Sanger sequencing and targeted high-throughput sequencing enable the detection of relevant genetic variations, providing molecular genetic data for diagnosis and personalized treatment.
Imaging Studies
Ultrasound of the liver, gallbladder, pancreas, and spleen, as well as liver computed tomography (CT) or magnetic resonance cholangiopancreatography (MRCP), can reveal structural abnormalities or space-occupying lesions like stones.
Hepatobiliary Scintigraphy
Normal intravenous injection of 99mTc-EHIDA results in rapid uptake by hepatocytes, with clear visualization of the liver within 3 to 5 minutes. The left and right hepatic ducts appear between 5 and 10 minutes, while the gallbladder, common bile duct, and duodenum typically show radioactive signals within 15 to 30 minutes. Under normal conditions, imaging of the gallbladder and intestines occurs no later than 60 minutes. In cases of congenital biliary atresia, no radioactive signals appear in the intestines.
Biliary Drainage
Dynamic continuous duodenal drainage enables the collection of bile samples for bacterial culture and testing of bile components, such as bilirubin and bile acids, which aids in evaluating the possibility of biliary atresia.
Pathological Examination
Liver biopsy specimens obtained via percutaneous or laparoscopic methods can undergo immunohistochemistry, electron microscopy, viral culture, and enzyme analysis for pathological diagnosis.
Diagnosis
The diagnosis of infantile cholestasis is based on the criteria recommended by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN). Specifically:
- When serum total bilirubin is ≤ 85 μmol/L (5 mg/dL), direct bilirubin levels exceeding 17.1 μmol/L (1.0 mg/dL) indicate cholestasis.
- When serum total bilirubin exceeds 85 μmol/L (5 mg/dL), a direct bilirubin-to-total bilirubin ratio greater than 20% also fulfills the diagnostic criteria of cholestasis.
Infants presenting with enlarged or abnormally textured liver, along with elevated serum alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels, are diagnosed with infantile cholestatic hepatitis.
Treatment
The primary objectives of treatment are to restore bile flow, alleviate symptoms, promote growth and development, and improve quality of life.
Etiologic Treatment
Early identification of the underlying cause is critical for initiating targeted therapy in cholestasis cases amenable to specific treatments. Conditions such as biliary atresia, citrin deficiency, sepsis, urinary tract infections, hypothyroidism, and panhypopituitarism may require tailored management. Specialized formula milk is indicated for conditions like citrin deficiency, galactosemia, and tyrosinemia type I. Patients with congenital bile acid synthesis defects (CBAS) may benefit from bile acid supplementation, including cholate or chenodeoxycholic acid.
Nutritional Therapy
Nutritional therapy is indicated for all infants with cholestasis. Supplementation with medium-chain triglycerides (MCT) is beneficial in improving their nutritional status. Fat-soluble vitamins should be supplemented, with serum levels monitored regularly to prevent deficiencies.
Cholagogues for Jaundice Relief
Cholagogues are used to stimulate hepatocyte bile secretion and excretion, enhance bile flow into the intestines, reduce symptoms, and improve liver function. Commonly used medications include:
Ursodeoxycholic Acid (UDCA)
As an isomer of deoxycholic acid, UDCA promotes bile secretion, increases the bicarbonate content in bile, and reduces bile cholesterol concentration. It is extensively used in the treatment of various intrahepatic cholestatic disorders, at doses of 10–30 mg/(kg·d) administered orally in two divided doses. It is contraindicated in cases of biliary atresia or severe liver dysfunction.
Cholestyramine
This anion exchange resin binds bile acids in the intestine and increases their excretion. The dosage ranges from 0.25 to 0.50 g/(kg·d), administered before or after breakfast or in divided doses.
Phenobarbital
Phenobarbital is administered orally and enhances bile flow by improving enzyme activity and hepatobiliary excretion.
S-Adenosyl Methionine (SAMe)
As a methyl donor, SAMe methylates phospholipids in hepatic cell membranes to regulate membrane fluidity, facilitating bile acid transport. It increases bile salt uptake and excretion, promotes glutathione synthesis, and provides hepatoprotective and detoxifying effects.
Other Medications
Additional supportive therapies include hepatoprotective agents such as glucuronolactone, reduced glutathione (which promotes detoxification and synthetic functions of the liver), and silymarin, which significantly reduces liver enzyme levels. Probiotics may also be beneficial. Albumin preparations are used in cases of hypoproteinemia. Intravenous immunoglobulin is indicated for individuals with immunoglobulin deficiency and recurrent infections. In cholestasis disorders mediated by immune mechanisms, glucocorticoids may be considered after careful evaluation of the risks and benefits.
Surgical Treatment
For infants with cholestasis who do not respond adequately to medical therapy, surgical interventions such as bile diversion procedures may help alleviate clinical symptoms. In suspected cases of biliary atresia, laparoscopic or open surgical exploration should be performed as early as possible, with Kasai portoenterostomy conducted if required. Liver transplantation is an effective treatment for end-stage liver disease in infantile cholestasis. Preoperative evaluation, surgical procedures, and postoperative management require multidisciplinary collaboration.