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![Differential Diagnosis of Neonatal and Infantile
Cholestasis
INTRAHEPATIC CHOLESTASIS
SYNDROMES
“Idiopathic” neonatal hepatitis
Alagille syndrome
Intrahepatic cholestasis (progressive
familial intrahepatic cholestasis [PFIC])
FIC-1 deficiency
Bile salt export pump (BSEP)
deficiency
MDR3 deficiency
Tight junction protein 2 deficiency
Farnesoid X receptor (FXR) mutations
Familial benign recurrent cholestasis
associated with lymphedema (Aagenaes
syndrome)
ARC (arthrogryposis, renal dysfunction, and
cholestasis) syndrome
Caroli disease (cystic dilation of intrahepatic
ducts)](https://image.slidesharecdn.com/neonatalhepatitis-250630160249-e12db4d0/75/approach-to-hepatitis-and-liver-dysfunction-in-neonates-21-2048.jpg)
approach to hepatitis and liver dysfunction in neonates
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- 2. Contents Physiologic jaundice ofnewborn Pathologic jaundice in newborn Neonatal cholestasis Neonatal hepatitis Causes of neonatal cholestasis / hepatitis Approach to patient with neonatal cholestasis Brief description of common causes of neonatal hepatitis.
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- 4. Introduction Physiologic jaundice inthe newborn Results from normal physiologic delay in bilirubin conjugation Reflects an increase in the levels of unconjugated bilirubin, Is transient and Of no clinical consequence.
- 5. Introduction Jaundice in neonateshould be evaluated if Persists Appears Continues to progress or Does not resolve by 14 days of life
- 6. Differential Diagnosis ofUnconjugated Hyperbilirubinemia in neonate Hemolytic Disease Non Hemolytic Disease Immune hemolysis Rh & ABO incompatibility Congenital spherocytosis Sickle cell anemia Infantile pyknocytosis Hemangioma Neonatal jaundice (physiologic) Hereditary Crigler-Najjar & Gilbert disease Breast milk jaundice Pyloric stenosis Antibiotic administration
- 7. Neonatal cholestasis Jaundice withelevated levels of conjugated bilirubin is Never physiologic and Almost always signifies underlying disease within the hepatobiliary system. Neonatal cholestasis is defined as prolonged elevation of conjugated bilirubin levels. Liver dysfunction in the infant, regardless of the cause, is commonly associated with bile secretory failure and cholestatic jaundice.
- 8. Introduction The subsequent damageto the liver is due to multiple factors, including toxic effects of various retained biliary components. The term Neonatal hepatitis / giant cell hepatitis / neonatal hepatocellular cholestasis is used for the constant morphologic change seen in intrahepatic cholestasis as a result of various etiologies.
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- 10. Neonatal hepatitis Though allthese are grouped together, all of them are not necessarily inflammatory conditions, thus contrary their nomenclature as ‘hepatitis’. The condition usually presents in the First few weeks of birth with jaundice, Bilirubinuria Pale stools(acholic) and High serum alkaline phosphatase.
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- 12. Morphologic features The histologicfeatures of neonatal hepatitis are: 1. Loss of normal lobular architecture of the liver. 2. Presence of prominent multinucleate giant cells derived from hepatocytes. 3. Mononuclear inflammatory cell infiltrate in the portal tracts with some periportal fibrosis. 4. Cholestasis in small proliferated ductules in the portal tract and between necrotic liver cells.
- 13. Biliary atresia The conditionmay, have various grades of destruction ranging from complete absence of bile ducts termed atresia, to reduction in their number called paucity of bile ducts. Depending upon the portion of biliary system involved, biliary atresias may be extrahepatic or intrahepatic.
- 14. Extrahepatic Biliary Atresia Themain histologic features are – 1. Inflammation & fibrous obliteration of the extrahepatic ducts with absence of bile in them. 2. Ductular proliferation and periductular inflammation. 3. Cholestasis and bile thrombi in the portal area. 4. Periportal fibrosis and later secondary biliary cirrhosis. 5. Transformation of hepatic parenchyma to neonatal (giant cell) hepatitis in 15% of cases. α-1-antitrypsin deficiency - similar appearance.
- 15. Intrahepatic Biliary Atresia Themicroscopic features are as follows: 1. Paucity of intrahepatic bile ducts. 2. Cholestasis. 3. Inflammation and fibrosis in the portal area, eventually leading to cirrhosis.
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- 17. Relative Frequencies ofVarious Disorders of Neonatal Cholestasis Disorder Frequency (%) Idiopathic neonatal hepatitis 30-35 Extrahepatic biliary atresia 30 α1-Antitrypsin deficiency 7-10 Intrahepatic cholestatic syndromes (Alagille syndrome, PFIC, others) 5-6 Hepatitis (CMV, rubella, HSV, others) 3-5 Choledochal cyst 2-4 Bacterial sepsis 2 Endocrinopathy (hypothyroidism, panhypopituitarism) ≈1 Galactosemia ≈1 Inborn errors of bile acid metabolism ≈1 Other metabolic disorders ≈1
- 18. Differential Diagnosis ofNeonatal and Infantile Cholestasis INFECTIOUS Generalized bacterial sepsis Viral hepatitis Hepatitides A, B, C, D, E Cytomegalovirus Rubella virus Herpesviruses: herpes simplex, human herpesvirus 6 and 7 Varicella virus Coxsackievirus Echovirus INFECTIOUS Reovirus type 3 Parvovirus B19 HIV Adenovirus Others Toxoplasmosis Syphilis Tuberculosis Listeriosis Urinary tract infection
- 19. Differential Diagnosis ofNeonatal and Infantile Cholestasis TOXIC Sepsis Parenteral nutrition related Drug, dietary supplement, herbal related METABOLIC Disorders of amino acid metabolism Tyrosinemia Disorders of lipid metabolism Wolman disease Niemann-Pick disease (type C) Gaucher disease Cholesterol ester storage disease Disorders of carbohydrate metabolism Galactosemia Fructosemia Glycogenosis IV Disorders of bile acid biosynthesis
- 20. Differential Diagnosis ofNeonatal and Infantile Cholestasis Other metabolic defects α1 -Antitrypsin deficiency Cystic fibrosis Hypopituitarism Hypothyroidism Zellweger (cerebrohepatorenal) syndrome Wilson disease Gestational alloimmune liver disease (previously neonatal iron storage disease ) Indian childhood cirrhosis/infantile copper overload Congenital disorders of glycosylation Mitochondrial hepatopathies Citrin deficiency GENETIC OR CHROMOSOMAL Trisomies 17, 18, 21
- 21. Differential Diagnosis ofNeonatal and Infantile Cholestasis INTRAHEPATIC CHOLESTASIS SYNDROMES “Idiopathic” neonatal hepatitis Alagille syndrome Intrahepatic cholestasis (progressive familial intrahepatic cholestasis [PFIC]) FIC-1 deficiency Bile salt export pump (BSEP) deficiency MDR3 deficiency Tight junction protein 2 deficiency Farnesoid X receptor (FXR) mutations Familial benign recurrent cholestasis associated with lymphedema (Aagenaes syndrome) ARC (arthrogryposis, renal dysfunction, and cholestasis) syndrome Caroli disease (cystic dilation of intrahepatic ducts)
- 22. Differential Diagnosis ofNeonatal and Infantile Cholestasis MISCELLANEOUS Shock and hypoperfusion Associated with enteritis Associated with intestinal obstruction Neonatal lupus erythematosus Myeloproliferative disease (trisomy 21) Hemophagocytic lymphohistiocytosis (HLH) COACH syndrome (coloboma, oligophrenia, ataxia, cerebellar vermis hypoplasia, hepatic fibrosis) Cholangiocyte cilia defects
- 23. Differential Diagnosis ofNeonatal and Infantile Cholestasis EXTRAHEPATIC DISEASES Biliary atresia Sclerosing cholangitis Bile duct stricture/stenosis Choledochal–pancreaticoductal junction anomaly Spontaneous perforation of the bile duct Choledochal cyst Mass (neoplasia, stone) Bile/mucous plug (“inspissated bile”)
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- 25. Flow chart for evaluationof neonatal cholestasis
- 26. Diagnosis The stools ofa patient with well-established biliary atresia are acholic, but early in the course of incomplete or evolving biliary obstruction, the stools may appear normal or only intermittently pigmented (coloration of feces with secretions and epithelial cells).
- 27. Diagnosis A critical stepin evaluating neonates with cholestasis is to differentiate extrahepatic biliary atresia from neonatal hepatitis. Life threatening but treatable disorders such as bacterial infection and a number of inborn errors of metabolism must be excluded.
- 28. Evaluation of theInfant With Cholestasis HISTORY AND PHYSICAL EXAMINATION Details of family history, pregnancy, presence of extrahepatic anomalies, and stool color TESTS TO ESTABLISH THE PRESENCE AND SEVERITY OF LIVER DISEASE Fractionated serum bilirubin analysis Liver biochemical tests (AST, ALT, alkaline phosphatase, 5′-nucleotidase, GGTP) Tests of liver function (prothrombin time, partial thromboplastin time, coagulation factors, S. albumin level, S. ammonia, serum cholesterol level, blood glucose TESTS FOR INFECTION CBC Bacterial cultures of blood, urine, and other sites if indicated Viral cultures Serologic tests (HBsAg, TORCH, EBV, parvovirus B19, HIV, others) Paracentesis if ascites
- 29. Evaluation of theInfant With Cholestasis METABOLIC AND GENETIC STUDIES α1-Antitrypsin level and phenotype if level is reduced Metabolic screen (urine and serum amino acids, urine organic acids) Urine for reducing substances RBC galactose-1-phosphate uridyl transferase activity - galactosemia Serum iron and ferritin levels Sweat chloride analysis Thyroid hormone, thyroid-stimulating hormone (evaluation of hypopituitarism as indicated) Urine and serum analysis of bile acids and bile acid precursors Genetic studies for Alagille syndrome and progressive familial intrahepatic cholestasis
- 30. Evaluation of theInfant With Cholestasis IMAGING STUDIES US of liver and biliary tract (first) Hepatobiliary scintigraphy MRCP Radiography of long bones and skull for congenital infection and of chest for lung and cardiac disease Percutaneous or endoscopic cholangiography (rarely indicated) PROCEDURES Bone marrow examination and skin fibroblast culture for suspected storage disease Duodenal intubation to assess fluid for bile pigment Percutaneous liver biopsy (for light and electron microscopic examination, enzymologic evaluation) Exploratory laparotomy and intraoperative cholangiography
- 31. Approach to evaluation Standardliver biochemical tests usually show variable elevations in serum direct bilirubin, aminotransferase, alkaline phosphatase, and lipid levels. Unfortunately, no single test has proved to have satisfactory discriminatory value, because at least 10% of infants with intrahepatic cholestasis have bile secretory failure sufficient to lead to an overlap in diagnostic test results with those suggestive of biliary atresia.
- 32. Approach to evaluation Genomicsequencing is identifying new defects that were previously labeled as idiopathic neonatal hepatitis.
- 33. USG US can beused to assess the size and echogenicity of the liver. Even in neonates, Define the presence and size of the gallbladder, Detect stones and sludge in the bile ducts and gallbladder, and Demonstrate cystic or obstructive dilatation of the biliary system. Extrahepatic anomalies can also be identified.
- 34. USG A triangular cordor band-like periportal echogenicity (≥3 mm), - a cone-shaped fibrotic mass cranial to the portal vein, specific US finding in the early diagnosis of biliary Atresia. The gallbladder “ghost” triad, defined as Gallbladder length less than 1.9 cm, Lack of smooth or complete echogenic mucosal lining with an indistinct wall, and Irregular or lobular contour, has been proposed as an additional criterion for biliary atresia.
- 35. CT CT provides informationsimilar to that obtained by US but is less suitable in patients younger than 2 years of age because of Exposure to radiation, The paucity of intra-abdominal fat for contrast, and The need for heavy sedation or general anesthesia.
- 36. MRCP MRCP - widelyused to assess the biliary tract in all age groups. In some patients with biliary atresia, Nonvisualization of the bile duct and Demonstration of a small gallbladder have been characteristic MRCP findings. MRCP can accurately define choledochal cysts and has emerged as the procedure of choice in the diagnosis of PSC.
- 37. MRCP Contrary to previousreports, false-positive and false-negative findings occur with MRCP. Differentiation of severe intrahepatic cholestasis from biliary atresia may be difficult because the ability of MRCP to delineate the extrahepatic biliary tract depends on bile flow.
- 38. Hepatobiliary scintigraphic imaging Theuse of hepatobiliary scintigraphic imaging agents such as 99mTc iminodiacetic acid derivatives may be helpful in differentiating extrahepatic biliary atresia from other causes of neonatal Jaundice. Unfortunately, a 1997 study showed that in 50% of patients who had a paucity of interlobular bile ducts but no extrahepatic obstruction, biliary excretion of radionuclide was absent.
- 39. Hepatobiliary scintigraphic imaging Inpatients who had idiopathic neonatal hepatitis, 25% also demonstrated no biliary excretion. Nevertheless, the modality remains useful for assessing cystic duct patency in patients with a hydropic gallbladder or cholelithiasis.
- 40. ERCP ERCP may beuseful in evaluating children with extrahepatic biliary obstruction and has been performed successfully in cholestatic neonates. Considerable technical expertise - general anesthesia. Interventional ERCP is commonly used to dilate biliary strictures and to remove common bile duct stones in children.
- 41. PTC PTC may beof value in visualizing the biliary tract in selected patients, but the technique is more difficult to perform in infants than in adults because the intrahepatic bile ducts are small and because most disorders that occur in infants do not result in dilatation of the biliary tract.
- 42. Percutaneous liver biopsy Percutaneousliver biopsy is particularly valuable in evaluating cholestatic patients and can be undertaken in even the smallest infants with only sedation and local anesthesia. For example, a diagnosis of extrahepatic biliary atresia can be made based on clinical and histologic criteria in 90% to 95% of patients.
- 43. Percutaneous liver biopsy Liverbiopsy is also valuable in demonstrating bile duct paucity or biliary damage from drugs or viruses.
- 45. Exploration When doubt aboutthe diagnosis persists, the patency of the biliary tract can be examined directly by a mini laparotomy and operative cholangiography.
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- 49. Idiopathic neonatal hepatitis Idiopathicor cryptogenic neonatal hepatitis is a descriptive term for children with Prolonged cholestasis and Typical histologic changes who are Not found to have any known infectious, metabolic, or other cause of their hepatic disease.
- 50. Idiopathic neonatal hepatitis Thediagnosis is applied to children without evidence of mechanical obstruction. Historically, a diagnosis of neonatal hepatitis would be assigned to approximately 65% of children presenting with liver aminotransferase level elevations and cholestasis.
- 51. Idiopathic neonatal hepatitis However,with the advent of improved understanding of the metabolic and genetic factors contributing to the mechanism of disease, the number of children given a diagnosis of neonatal hepatitis has decreased. It can occur in either a sporadic or familial form. Sporadic form presumably - undefined metabolic or viral disease
- 52. Idiopathic neonatal hepatitis Familialforms - presumably reflect a genetic or metabolic aberration. The mainstay of therapy are to manage the consequences of cholestasis. Currently no specific therapies available. These infants have a good prognosis overall, with spontaneous resolution occurring in most.
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- 54. α1-Antitrypsin deficiency α1-Antitrypsin deficiencypresents with clinical findings indistinguishable from neonatal hepatitis. Most frequent genetic cause(1 in 3000) of liver disease in children and a leading metabolic disorder requiring liver transplantation. Autosomal recessive
- 55. α1-Antitrypsin deficiency The presentationof children with liver involvement is bimodal with 1. Early presentation of cholestasis (within the first 1 month to 2 months of life) and 2. Older children presenting with advanced, chronic disease manifesting itself as portal hypertension, hematemesis, or cryptogenic cirrhosis.
- 56. α1-Antitrypsin deficiency The distinctivehistologic finding of homozygous PiZZ A1AT deficiency is the presence of PAS-positive, diastase resistant eosinophilic globules in the endoplasmic reticulum of affected livers. Diagnosis is best achieved by determination of the A1AT phenotype by isoelectric focusing or by agarose gel electrophoresis at an acidic pH.
- 57. α1-Antitrypsin deficiency Management Currently, thereis no specific therapy for A1AT deficiency– associated liver disease. Supportive care - nutritional and vitamin replacement while cholestasis persists is important. Liver transplant - excellent survival in children and adults. Autophagy-enhancing drugs, such as carbamazepine, have been shown to decrease hepatic accumulation. Gene therapy and autologous cell–based therapies
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- 59. Alagille syndrome Syndromic Paucityof the Interlobular Bile Ducts or Arteriohepatic Dysplasia Autosomal dominant or sporadic Most common syndrome with intrahepatic bile duct paucity. absence or marked reduction in the number of interlobular bile ducts in the portal triads, with normal-size branches of portal vein and hepatic arteriole.
- 60. Alagille syndrome Biopsy inearly life often reveals an inflammatory process involving the bile ducts; Subsequent biopsy specimens then show subsidence of the inflammation, with residual reduction in the number and diameter of bile ducts, analogous to the disappearing bile duct syndrome noted in adults with immune-mediated disorders.
- 61. Alagille syndrome Associated abnormalitiesin some (syndromic) types include Peripheral pulmonic stenosis or other cardiac anomalies; Hypertelorism; unusual facies with deep-set eyes, prominent forehead, and a pointed chin; butterfly vertebrae; and a defect of the ocular limbus (posterior embryotoxon). Cholestasis is variable but is usually lifelong and associated with hypercholesterolemia and severe pruritus.
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- 64. Alagille syndrome May progressto end-stage liver disease. Antipruritic ursodeoxycholic acid – (variable results), hydroxyzine, diphenhydramine, rifampin, naltrexone, and cholestyramine alone or in combination.
- 65. Alagille syndrome Severe pruritus(with or without xanthomas), biliary diversion - relieve symptoms does not prevent progression of liver disease. Indications for transplant include Complications of end-stage liver disease, Severe complications of chronic cholestasis such as failure to thrive, refractory cholestasis, and pruritus, and recurrent fractures.
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- 67. PFIC The PFIC syndromesare characterized by presence of Chronic, unremitting hepatocellular cholestasis, An occurrence pattern consistent with autosomal recessive inheritance, and A characteristic combination of clinical, biochemical, and histologic features. Exclusion of identifiable metabolic or anatomic disorders,
- 68. Inherited Syndromes ofProgressive Cholestasis Genetic defects - abnormal folding of proteins, defects in the synthesis of bile acids, disruption in canalicular transport, and abnormal formation and flow of bile Common to all forms - history of jaundice, pruritus, failure to thrive, and fat-soluble vitamin deficiency, which may occur at different times and with different severity. Cirrhosis may develop within 5 years to 10 years, leading to liver failure.
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- 70. PFIC Management Medical therapy -Ursodeoxycholic acid, Rifampin and cholestyramine Optimization of nutritional status, and management of complications of chronic liver disease constitute the main avenues of treatment. Surgical interventions, - biliary diversion and ileal bypass, to decrease the enterohepatic circulation of bile acids, used with varying success to treat patients with PFIC and intractable pruritus.
- 71. PFIC Liver transplant shouldbe considered in patients with Complications of end-stage liver disease Hepatocellular carcinoma Intractable and refractory pruritus
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- 74. References Sleisenger and Fordtran’sGastrointestinal and Liver Disease 11 th edition. Zakim and Boyer’s Hepatology: A Textbook of Liver Disease Seventh Edition Nelson Textbook of Pediatrics 21 Edition
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- 76. 1. Physiologic jaundiceof newborn is characterised by A. Unconjugated hyperbilirubinemia B. Conjugated hyperbilirubinemia C. Both A and B D. None
- 77. 2. Which isnot a cause of neonatal cholestasis A. Neonatal lupus erythematosus B. Mitochondrial hepatopathies C. Hereditary pyknocytosis D. Cystic fibrosis
- 78. 3. Which isnot included in neonatal hepatitis A. Listeriosis B. Fructosemia C. Biliary atresia D. Hemophagocytic lymphohistiocytosis
- 79. 4. The gallbladder“ghost” triad is found in A. Cholecystitis B. Biliary atresia C. Phrygian cap D. Torsion of GB
- 80. 5. Most frequentgenetic cause of liver disease in children- A. Wilsons B. Cystic fibrosis C. PFIC2 D. α1-Antitrypsin deficiency
- 81. 6. Bile SaltExcretory Protein(BSEP) deficiency is found in A. PFIC 1 B. PFIC 2 C. PFIC 3 D. PFIC 4
- 82. 7. Periodic acid–Schiff-positive,diastase resistant eosinophilic globules in the endoplasmic reticulum of liver are associated with A. Alagille syndrome B. Wilsons disease C. α1-Antitrypsin deficiency D. Cystic fibrosis
- 83. 8. Elevated GGTis found in A. PFIC 1 B. PFIC 2 C. PFIC 3 D. PFIC 4
- 84. 9. Identify theassociated syndrome with the radiograph shown A. α1-Antitrypsin deficiency B. Alagille syndrome C. Byler disease D. COACH syndrome
- 85. 10. Autophagy-enhancing drugs,such as carbamazepine, have been shown to decrease hepatic accumulation in A. PFIC B. Cystic fibrosis C. α1-Antitrypsin deficiency D. Wilsons disease.