Dont be Mellow When an Infant is Yellow: Deciphering Cholestasis - - PowerPoint PPT Presentation

Don’t be Mellow When an Infant is Yellow: Deciphering Cholestasis Catherine J. Goodhue, MN, RN, CPNP-PC Research Program Manager Division of Pediatric Surgery

Disclosure

• Research Coordinator of an NIH-funded U01

Grant entitled: Establishment of CHLA’s ChiLDREN (Childhood Liver Disease Research and Education Network) Clinical Center

Objectives

At the end of this presentation, the participant will be able to:

• 1. Describe at least 3 functions of the liver
• 2. Identify the most critical differential diagnoses for

cholestatic jaundice in the newborn period

• 3. Discuss the long-term treatment for an infant with

cholestatic jaundice

Functions of the Liver

• Regulates distribution

and metabolism of all nutrients from GI tract

• Bile production
• Detoxification
• Assists immune system –

filtering bacteria and

• ther “bugs”
• Assists in maintaining

normal blood circulation

What is Bilirubin?

• Formed from degradation of hemoglobin

– Newborns produce twice as much bilirubin as adults

• Heme converted to biliverdin heme oxygenase

in RES

• Biliverdin reduced to unconjugated bilirubin

and bound to albumin and sent to liver

• In liver, unconjugated bilirubin is conjugated

with glucuronic acid

• Most goes into bile and excreted into small

intestine

Physiologic Jaundice of Newborns

• Phase one

– Term infants – lasts up to 5 days with rapid rise of serum bilirubin up to 12 mg/dL – Preterm infants – lasts up to 7 days with rapid rise of serum bilirubin up to 15 mg/dL

• Phase two – bilirubin levels decline ~ 2mg/dL
• ver 2 weeks

– Preterm infants – can last more than 1 month – With exclusive breast feedings, can last more than 1 month

Hepatic Post-hepatic Neonatal Jaundice Unconjugated hyperbilirubinemia Conjugated hyperbilirubinemia Pathologic Physiologic jaundice

• f neonates

Hemolytic Non-hemolytic Intrinsic Extrinsic

1 in 2500 live births Pathologic Jaundice

All jaundiced infants should have a

fractionated bilirubin at 2 weeks of

age

• Measure both conjugated and unconjugated bilirubin
• conjugated should < 30% total bilirubin

Defining Cholestasis

• Physiologic definition: measurable decrease in

bile flow

• Pathological definition: histological presences
• f bile pigment in hepatocytes and bile ducts
• Clinical definition: accumulation in blood and

extrahepatic tissues of substances normally excreted in bile

From Suchy, Sokol, Balistreri. Liver Disease in Children, 2001

Signs and Symptoms of Cholestasis

• Jaundice
• Icterus
• Pruritus
• Dark urine
• Elevated bilirubin

level

• Elevated liver

enzymes

Case Study: Sandra

Differential Diagnosis of Cholestasis

• Neonatal hepatitis

– Idiopathic – Viral – Bacterial

• Bile duct obstruction

– Cholangiopathies

• Biliary atresia
• Alagille’s
• Choledochal cysts

– Other

• Cholelithiasis
• Tumors/masses

From Suchy et al., 2001

• Cholestatic syndromes

– PFIC – BRIC

• Metabolic disorders

– Alpha 1 antitrypsin deficiency – CF – Bile acid synthesis defects

• Toxic

– Drugs – TPN

• Miscellaneous

– Shock/hypoperfusion – ECMO

Evaluation of Cholestasis

• Detailed H & P

– Pregnancy history – Family history – Neonatal course – Extrahepatic anomalies – Stool color

• Laboratory testing

– Fractionated bilirubin – AST , ALT , Alk phos – Liver function tests – CBC – Bacterial cultures

From Suchy et al., 2001

• Timely referral to Pediatric

Hepatologist/GI and/or Pediatric Surgeon

– Abdominal ultrasound – Serologies for infections – Sweat chloride – Alpha 1 antitrypsin level and phenotype – Metabolic screen – Serum iron and ferritin – Genetic testing – X-rays – HIDA scan – Liver biopsy – IOC

More Common Causes of Conjugated Hyperbilirubinemia

• TPN-cholestasis
• Idiopathic neonatal hepatitis
• Alpha-1-antitrypsin deficiency
• Bile acid synthesis defects
• Progressive familial intrahepatic cholestasis
• Alagille’s syndrome
• Biliary atresia

TPN-associated Cholestasis

• Short gut/prematurity
• TPN developed by

Ravdin, Roads, Dudrick 1960s

• Progressive

hyperbilirubinemia assoc with prolonged TPN use

• Treatment

– Reversible in most instances with discontinuation of TPN – Cycling of TPN – Homocysteine – Parenteral Omega-3 fatty acids

Idiopathic Neonatal Hepatitis

• Unresolved conjugated hyperbilirubinemia
• “Giant cell hepatitis”
• Diagnosis of exclusion after metabolic,

infectious, genetic, or obstructive causes of cholestasis

• Up to 20% progressive, familial and worse

prognosis

Idiopathic Neonatal Hepatitis Cont

• 40% of cholestatic infants have INH
• Male: female 2:1
• Present with jaundice and acholic stools
• Recovery rates range from 60-80% for sporadic

cases; familial 20-40% recovery rate

Alpha 1 Antitrypsin Deficiency

• Inborn error of metabolism

– mutant α1-AT accumulates in the endoplasmic reticulum

leaving trypsin-mediated proteolysis uninhibited in connective tissues

• 1 in 2,000 live births in U.S.
• Homozygous α1-AT deficiency associated with

pulmonary emphysema, chronic liver disease, and hepatocellular carcinoma

A1AT Continued

• Diagnosis

– Prolonged jaundice – Neonatal hepatitis syndrome – Mild elevation AST/ALT in toddlers – Portal hypertension in child/teen – Severe liver dysfunction in child/teen – HSP

• Treatment

– Supportive management of liver dysfunction – Avoidance of cigarette smoking – Liver transplant if liver failure

Bile Acid Synthesis Defects

• 1 in 100,000
• Enzyme dysfunction at various steps of bile acid

biosynthesis

– accumulation of atypical hepatotoxic bile acid precursors. – 6 identified

• Diagnosis: mass spectrometry of urine
• Treatment: cholic acid therapy

– downregulation of intrinsic bile acid synthesis – reduction in the accumulation of toxic bile acid precursors

Progressive Familial Intrahepatic Cholestasis

• Rare inherited diseases resulting from defects

in bile synthesis and secretion

• Estimated prevalence is 1 in 70,000
• Clinical manifestations:

– Cholestasis may progress from intermittent to persistent – Pruritus may/may not be associated with jaundice; absence of jaundice may lead to delay in diagnosis – Malabsorption of fat soluble vitamins is common

Alagille Syndrome

• Cholestasis- paucity of intrahepatic bile ducts, cardiac defects,

characteristic facies, eye findings, renal anomalies, and butterfly vertebrae

• Autosomal dominant
• 1 in 100,000 live births
• Mutations in JAG1 (Notch signaling)
• Prognosis dependent on severity of CV & hepatic disease
• 15% progress to end-stage liver failure -> transplantation

Biliary Atresia

• Progressive obliterative

idiopathic cholangiopathy – Most common cause of chronic cholestasis in infants – Jaundice & acholic stools

• 1:8,000-1:12,000 live births
• F>M
• Seasonal clustering
• Lethal if untreated

Diagnosis of Biliary Atresia

• Conjugated hyperbilirubinemia
• Mildly elevated ALT

, AST with normal AST:ALT ratio

• Elevated GGT
• Ultrasound
• HIDA scan
• Liver Biopsy

Ultrasound Findings - BA

• Absent or small

gallbladder

• Cyst at the porta hepatis
• Increased echogenicity
• Nondilated intrahepatic

ducts and nonvisualized CBD

HIDA Scan

• Hepatic Technetium

99Tcmc iminodiacetic

acid

• Non-excretion into

small intestine

Liver Biopsy - BA

Portal inflammation Bile plugs Ductular proliferation

Intraoperative Cholangiogram

Kasai Procedure

Kasai and Shujitsu, 1959 Kasai, M., S. Kimura, et al. J Ped Surg, 1968 Excision of fibrotic mass in hilum of liver Drainage - Roux-en-Y portoenterostomy

Dissection of biliary remnant

Bile Pooling at Portal Plate

Timing of Diagnosis/Treatment is Key!

From Ohi R. Biliary Atresia: A Surgical Perspective. Clin Liver Disease 2000

Post-operative Management

• Antibiotic cholangitis prophylaxis
• Post-operative steroids unproven
• Analgesics
• Oral bile acid therapy
• Vitamin supplements/monitor vitamin levels
• Possible anti-pruritus therapy
• Monitor bilirubin/liver function tests
• Other therapies

– Probiotics – unproven – Herbal remedies – unproven – Omega 3 supplements - unproven

Fat Soluble Vitamins

• Vitamin A

– Integral for vision, immune function and growth

• Vitamin D

– Integral for bone health, immune function, growth, and prevention of chronic disease

• Vitamin E

– Powerful antioxidant, prevents damage to cells

• Vitamin K

– Component of many proteins in body including those involved in clotting and bone formation

Primary Care Management

• Ensure regular follow-up with hepatologist/GI
• Follow-up with surgeon as directed
• Keep childhood vaccines up to date
• Annual flu shot
• Follow growth and nutritional status

– Anthropometric measurements – Possible dietary consults if not gaining adequate weight – Avoid obesity

• Avoid unnecessary medications and remedies (OTC and

rx)

Family Education

• Contact MD if:

– Unexplained fever – Recurrent/worsening jaundice – Swollen belly or extremities – Abnormal bleeding – Can’t or won’t eat – Pale stools

Chronic Disease and the Family

• Need to work through feelings of emotional

pain and disappointment

• Blame, self-condemnation, punishment
• Reduced self-concept, self-worth
• Feelings of fear, apprehension
• Grief, “chronic sorrow”

Potential Stressors

• Strained family relationships
• Marital discord
• Increased financial strain
• Social isolation
• Medical concerns
• Differences in perceptions of child’s health
• Differing levels of grief

Living with Uncertainty

• Chronic illness = traveling on a roller coaster
• “Practicing” in chronic illness can help prepare for

minor and major setbacks

• Failed Kasai may lead to liver transplant
• Rehearsals may reduce shock; increased fear and

apprehension when transplant considered “last option”

• Transplantation provides a tangible meaning to death;

no cure, perpetuates CD cycle

• Encourage family to rely on spiritual/philosophical

beliefs that provide comfort

Progression to ESLD

Indications for Pediatric Liver Transplant

Timing of Liver Transplant

• Avoidance of liver transplant if possible
• Avoidance of protracted pre-transplant period
• Living donor liver transplant vs. split-liver

transplant

• Expedited living donor evaluation for patients

in ALF

Long-Term Implications of LVT

• Immunosuppression

– Infection – Malignancy – Toxicity

• Solutions

– Minimization of immunosuppression – Close monitoring – Biomarkers of graft acceptance/tolerance

• CHLA Outcomes

– 100% patients and graft survival for 9 consecutive reporting periods – Largest pediatric LDLT center in US – Liver transplant in JWs – Anonymous living liver donor

Family and Professional Resources

http://childrennetwork.org www.transplantliving.org www.liverfoundation.org www.alagille.org www.alpha-1.org www.alpha-1foundation.org www.classkids.org www.rarediseases.info.nih.gov www.raredisease.org http://pfic.org www.childliverdisease.org www.niddk.nih.gov www.alphanet.org