GI Clinical Case Conference

1. GI Clinical Case Conference

2. Case Presentation 30 day old ex-39 week baby boy with prenatal ultrasound diagnosis of congenital heart disease and absent gallbladder Has had persistent and progressive cholestasis since birth Has always passed pigmented stools

3. Case Presentation Born to 35 yo G3P1 mother whose prenatal labs and serologies were unremarkable Prenatal ultrasound demonstrated VSD, aortic coarctation, hypoplastic aortic arch, interrupted inferior vena cava with azygous continuation, and absence of gallbladder No prenatal infections/complications NSVD with BW 2.94 kg, Apgars 8,9

4. Case Presentation Underwent surgical correction under cardiopulmonary bypass Surgery was uneventful with successful wean off bypass Weaned off ventilator, inotropes by POD#3 Post-op ECHO with excellent function Weaned off TPN, on full feeds by DOL#12

5. Case Presentation Post-natal ultrasound (DOL#7) revealed normal liver size/structure, no intrahepatic or extrahepatic biliary ductal abnormality, patent portal vein, spleen visualized in the LUQ, no gallbladder visualized Upper GI: No evidence of malrotation Heterotaxy � Asplenia vs. Polysplenia syndrome (multiple small spleens, absence of the intrahepatic portion of the inferior vena cava, bilateral left lung morphology, and severe congenital heart lesions: ASD, VSD, AV canal, pulmonic atresia, or TAPVRHeterotaxy � Asplenia vs. Polysplenia syndrome (multiple small spleens, absence of the intrahepatic portion of the inferior vena cava, bilateral left lung morphology, and severe congenital heart lesions: ASD, VSD, AV canal, pulmonic atresia, or TAPVR

6. Case Presentation

7. Case Presentation HR 150 � BP 78/55 � RR 46 - Wt: 3.43 kg Active, alert, nonsyndromic facies HEENT: Scleral icterus Lungs: CTA b/l CV: RRR, nl s1 and s2, II/VI SEM @ LLSB Abd: soft, liver 2 cm BCM, no splenomegaly Skin: (+) jaundice

8. Differential Diagnosis

9. Neonatal Cholestasis Biliary Atresia Choledochal Cyst Cystic fibrosis Caroli Disease Inspissated Bile Gallstones/biliary sludge Mass (hepatoblastoma, neuroblastoma) Spontaneous perforation of extrahepatic biliary tree Choledochal Cyst � Cystic dilitation of the common bile duct; treated with complete excision of the cyst and biliary bypass Caroli Disease � Rare congenital disorder of the intrahepatic bile ducts characterized by dilitation and ectasia of the intrahepatic biliary tree; often associated with ARPKDCholedochal Cyst � Cystic dilitation of the common bile duct; treated with complete excision of the cyst and biliary bypass Caroli Disease � Rare congenital disorder of the intrahepatic bile ducts characterized by dilitation and ectasia of the intrahepatic biliary tree; often associated with ARPKD

10. Neonatal Cholestasis Infectious Sepsis UTI/Pyelonephritis TORCH infections Syphilis Listeriosis Echovirus Enteroviruses Metabolic/Genetic Galactosemia Tyrosinemia Alagille Syndrome a1-Antitrypsin Deficiency Iron Storage Disease Neimann-Pick/Gaucher�s Bile acid metabolism/ transport abnormalities Sepsis � Possible endotoxinemia which affects bile synthesis (E. coli) TORCH � Toxoplasmosis, Syphilis, Rubella, CMV, HSV, Hepatitis B/C, HIV, Disorders of bile acid transport include Progressive familial intrahepatic cholestasis and Aagenaes� Syndrome Sepsis � Possible endotoxinemia which affects bile synthesis (E. coli) TORCH � Toxoplasmosis, Syphilis, Rubella, CMV, HSV, Hepatitis B/C, HIV, Disorders of bile acid transport include Progressive familial intrahepatic cholestasis and Aagenaes� Syndrome

11. Neonatal Cholestasis Systemic Disease Hypothyroidism Congestive heart failure Post-shock/asphyxia Post-NEC Neonatal lupus Drugs/Toxins Medications Parenteral nutrition Sepsis � Possible endotoxinemia which affects bile synthesis (E. coli) TORCH � Toxoplasmosis, Rubella, CMV, HSV, Hepatitis B/C, HIV, Parvovirus, Echovirus, CoxsackieSepsis � Possible endotoxinemia which affects bile synthesis (E. coli) TORCH � Toxoplasmosis, Rubella, CMV, HSV, Hepatitis B/C, HIV, Parvovirus, Echovirus, Coxsackie

12. What evaluations?

13. Work-up DISIDA Scan � Good uptake, no excretion Liver biopsy (3 wks)� Mild portal expansion, cellular and canalicular cholestasis, no significant proliferation No butterfly vertebrae or posterior embryotoxin All cultures/TORCH titers negative Neonatal screen (-) Thyroid studies WNL Liver biopsy - Equivocal A prominent, axially displaced Schwalbe's line is known as posterior embryotoxin. Galactose-1-phosphate uridyl transferase (GALT) enzyme tested WNLLiver biopsy - Equivocal A prominent, axially displaced Schwalbe's line is known as posterior embryotoxin. Galactose-1-phosphate uridyl transferase (GALT) enzyme tested WNL

14. Liver biospy Can see bile duct proliferationCan see bile duct proliferation

15. Operating Room Open liver biopsy demonstrated further portal expansion, marked proliferation of bile ducts with bile plugging No extrahepatic biliary tree observed Other findings: polysplenia, malrotation with extensive Ladd�s bands, redundant duodenum, interrupted IVC, abnormal portal vein anatomy Kasai portoenterostomy and Ladd�s procedure performed Due to no gallbladder/extrahepatic biliary tree ? No intraoperative cholangiogram was performed A Ladd's band is a peritoneal band which stretches from an incompletely rotated cecum, often causing obstruction in malrotationDue to no gallbladder/extrahepatic biliary tree ? No intraoperative cholangiogram was performed A Ladd's band is a peritoneal band which stretches from an incompletely rotated cecum, often causing obstruction in malrotation

16. Discussion

17. Neonatal Cholestasis � Frequency of Hepatic Etiologies Most babies have extrahepatic source (viral infection, TPN, etc.) Intrahepatic Cholestasis Syndromes � Include Alagille�s, PFIC Type IMost babies have extrahepatic source (viral infection, TPN, etc.) Intrahepatic Cholestasis Syndromes � Include Alagille�s, PFIC Type I

18. Biliary Atresia Progessive obliteration of the extrahepatic biliary tree Concomitant injury and fibrosis of intrahepatic bile ducts Unknown etiology Progressive fibroinflammatory cholangiopathy, total obliteration generally by 3 months of age Etiology: Focus on defect in morphogenesis, defect in prenatal circulation, Toxin exposure, Viral infection, and immunologic dysregulation; know that the group with multiple congenital anomalies have a genetic or prenatal insultProgressive fibroinflammatory cholangiopathy, total obliteration generally by 3 months of age Etiology: Focus on defect in morphogenesis, defect in prenatal circulation, Toxin exposure, Viral infection, and immunologic dysregulation; know that the group with multiple congenital anomalies have a genetic or prenatal insult

19. Epidemiology 1/8,000 � 1/18,000 live births More common in Asian populations Most common etiology of liver failure in childhood Accounts for >50% of pediatric liver transplants 80-90% have postnatal form; 10-20% embryonic 1/8000: Asian populations; 1/15000: Western countries 1/8000: Asian populations; 1/15000: Western countries

20. Clinical Presentation Jaundice Development of acholic stools Hepatomegaly +/- splenomegaly Usually well appearing, thriving Age of presentation varies Typical laboratory abnormalities Jaundice generally presents in around week 4 Acholic stools � May be pigmented intermittently early on with evolving or incomplete obstruction Conjugated bili = 3-6; elevated GGT and alk phos, usually only a minor transaminitis, generally with normal albumin, normal coags Usually no ascites, generally have compensated portal hypertensionJaundice generally presents in around week 4 Acholic stools � May be pigmented intermittently early on with evolving or incomplete obstruction Conjugated bili = 3-6; elevated GGT and alk phos, usually only a minor transaminitis, generally with normal albumin, normal coags Usually no ascites, generally have compensated portal hypertension

21. Embryonic Biliary Atresia 10-20 percent of cases Earlier onset of disease Congenital nonhepatic abnormalities Polyplenia/aspelnia Malrotation Situs inversus Interrupted IVC Congenital heart disease Poorer Prognosis No jaundice free period (typically begins as physiologic jaundice is waning), acholic stools often within first 3 weeks of life Most common is Biliary atresia splenic malformation syndrome when there is polyplenia, midline liver, malrotation, situs inversus, interrupted IVC, preduodenal portal vein) Poor prognosis: Decrease in 2 year transplant-free survival; more rapid progression of hepatobiliary disease may account for this disparity, could be due to congenital heart disease, asplenia, etc.No jaundice free period (typically begins as physiologic jaundice is waning), acholic stools often within first 3 weeks of life Most common is Biliary atresia splenic malformation syndrome when there is polyplenia, midline liver, malrotation, situs inversus, interrupted IVC, preduodenal portal vein) Poor prognosis: Decrease in 2 year transplant-free survival; more rapid progression of hepatobiliary disease may account for this disparity, could be due to congenital heart disease, asplenia, etc.

22. Diagnostic Approach History and Physical Examination Labs, infectious work-up Ultrasound DISIDA Scan Liver Biopsy Exploratory Laparotomy with Cholangiography Ultrasound: Look for other anatomic abnormalities; Absence of gallbladder is suggestive but not diagnostic, presence does not rule it out; not a great method for evaluating extrahepatic biliary tree because it�s difficult to see it in a newborn DISIDA scan: Expect to see good uptake of tracer but no excretion into the duodenum on immediate and 24 hr images; excretion essentially rules out biliary atresia, but non-excretion is not diagnostic, could be due to other forms of obstruction Liver biopsy � Preservation of basic lobular organization, prominent abnormalities in the portal tracts including edema, proliferation of bile ducts, and variable degree of fibrosis; also see bile plugs within proliferated ducts (highly suggestive) Ex-lap � Fibrotic gallbladder and diffuse fibrosis of biliary systemUltrasound: Look for other anatomic abnormalities; Absence of gallbladder is suggestive but not diagnostic, presence does not rule it out; not a great method for evaluating extrahepatic biliary tree because it�s difficult to see it in a newborn DISIDA scan: Expect to see good uptake of tracer but no excretion into the duodenum on immediate and 24 hr images; excretion essentially rules out biliary atresia, but non-excretion is not diagnostic, could be due to other forms of obstruction Liver biopsy � Preservation of basic lobular organization, prominent abnormalities in the portal tracts including edema, proliferation of bile ducts, and variable degree of fibrosis; also see bile plugs within proliferated ducts (highly suggestive) Ex-lap � Fibrotic gallbladder and diffuse fibrosis of biliary system

23. Kasai Portoenterostomy Re-establish bile drainage through patent intrahepatic ducts Anastomosis with Roux-en-Y loop of jejunum to porta hepatis Earlier = Better Careful dissection toward the hilum Roux-en-Y anastomosis is achieved with a 35-40 cm retrocolic jejunal limb, extends from hilum to the most proximal portion of jejunum Much greater success rate when Kasai is performed before 8 weeks than if it is performed afterCareful dissection toward the hilum Roux-en-Y anastomosis is achieved with a 35-40 cm retrocolic jejunal limb, extends from hilum to the most proximal portion of jejunum Much greater success rate when Kasai is performed before 8 weeks than if it is performed after

24. Post-Surgical Medical Care Prevent/Treat Cholangitis Promote Bile Flow Nutritional Support Assess for Development of Portal Hypertension 1. Occurs in approximately 50-60% of patients s/p Kasai; most common closer to Kasai -- Prevention: 3-5 days of parenteral antibiotics post-operatively, followed by 3-12 months of Bactrim prophylaxis (CHOP 12); --Aggressive monitoring for any sign of ascending cholangitis (irritability, poor feeding, fever), even before presence of jaundice or acholic stools 2. Ursodiol is commonly used to promote biliary flow although no data has proven it�s efficacy; corticosteroids are used post-operatively (known to stimulate bile flow through expression of hepatic Na-K ATPase as well as anti-inflammatory benefit. Double blind placebo study of 12 week taper after 4 mg/kg pulse is being arranged by BARC. We are using steroids sometimes. 3. Careful caloric monitoring, increased caloric intake (NG feeds, higher density formula), use of formula with MCT as fat source (Pregestemil), supplementation of fat soluble vitamins 4. Intrahepatic fibrosis and portal HTN are present at diagnose, and progresses even with good bile flow. Significant portal HTN develops in 34-76% of patients with biliary atresia. Treat varices with sclerotherapy/banding. Rarely use beta-blockers (not well studied in children). List for transplantation. Consider shunting procedure.1. Occurs in approximately 50-60% of patients s/p Kasai; most common closer to Kasai -- Prevention: 3-5 days of parenteral antibiotics post-operatively, followed by 3-12 months of Bactrim prophylaxis (CHOP 12); --Aggressive monitoring for any sign of ascending cholangitis (irritability, poor feeding, fever), even before presence of jaundice or acholic stools 2. Ursodiol is commonly used to promote biliary flow although no data has proven it�s efficacy; corticosteroids are used post-operatively (known to stimulate bile flow through expression of hepatic Na-K ATPase as well as anti-inflammatory benefit. Double blind placebo study of 12 week taper after 4 mg/kg pulse is being arranged by BARC. We are using steroids sometimes. 3. Careful caloric monitoring, increased caloric intake (NG feeds, higher density formula), use of formula with MCT as fat source (Pregestemil), supplementation of fat soluble vitamins 4. Intrahepatic fibrosis and portal HTN are present at diagnose, and progresses even with good bile flow. Significant portal HTN develops in 34-76% of patients with biliary atresia. Treat varices with sclerotherapy/banding. Rarely use beta-blockers (not well studied in children). List for transplantation. Consider shunting procedure.

25. Prognosis Approximately 50% of patients with biliary atresia require liver transplantation by 2 years Lykavieris et al. (2005) � 23% were alive with native liver at 20 years despite only 40% at 2 years Lykavieris et al. -- 20 year study of patients s/p Kasai in France from 1968-1983, demonstrated a rapid decline in first two years, followed by a slower decline over next 18 yearsLykavieris et al. -- 20 year study of patients s/p Kasai in France from 1968-1983, demonstrated a rapid decline in first two years, followed by a slower decline over next 18 years

26. Predictors of Outcome at 24 mo. Age at time of procedure Serum total bilirubin level at 3 months <2 mg/dl ? Good outcome >6 mg/dl ? Poor outcome BASM, embyronic presentation Ascending cholangitis ? Not a risk factor for poor outcome BASM was associated with much worse outcome, partially due to deaths secondary to congenital heart disease Varcieal bleeding without jaundice does not correlate with outcome Multiple episodes of cholangitis correlated with better outcome, possible because better biliary drainage may result in greater opportunity for ascending infection to occurBASM was associated with much worse outcome, partially due to deaths secondary to congenital heart disease Varcieal bleeding without jaundice does not correlate with outcome Multiple episodes of cholangitis correlated with better outcome, possible because better biliary drainage may result in greater opportunity for ascending infection to occur

27. Summary Aggressively work-up neonatal cholestasis Consider biliary atresia when other congenital anomalies are present Timely diagnosis of biliary atresia is essential Post-surgical medical management important Half of patients who undergo Kasai require liver transplant by two years of age