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Conjugated Hyperbilirubinemia

Catherine Corriveau-Bourque Preceptor : Dr. S. Gilmour


Review liver/ biliary tree anatomy + bilirubin metabolism  Develop an approach to conjugated hyperbilirubinemia  Review most common etiologies  Cholestasis : management and complications


Microscopic anatomy

Extravascular heme hemolysis (reticuloendothelial system of liver + spleen)

Bilirubin production

heme oxygenase

Intravascular hemolysis
biliverdin Hb-tetramer reductase


globin Fe heme

Hb-dimer Unconj bili





Bilirubin conjugation
BilBasolateral membrane

Bil- Alb

GST : glutathione S transferase GA : glucuronic acid





Bil- GA

Bil- GA-GST Canalicular membrane Bile duct

Bil- GA

Adapted from : Harb, R. et al. Pediatrics in Review 2007;28:83-91

Non-conj bilirubin

Bilirubin metabolism

Conj bilirubin


Hepatocytes Bile ducts

Beta glucorinidase

Portal circulation


urine stool

Age-related differences in bilirubin metabolism


increased erythrocyte turnover in infants

q 90days as opposed to q 120days

bilirubin production
neonatal : 6-8 mg/kg/24h  adult : 3-4 mg/kg/24h


immaturity of liver

decreased intracellular metabolism / conjugation slower as intestinal flora not yet established

excretion in the newborn infant

Direct vs conjugated bilirubin


Total bili measurement: spectrophotometric analysis of bilirubin cleavage in presence of accelerator (EtOH)  Accelerator needed for unconjugated bili which has a limited aqueous solubility Direct bili : rapidly reacting bili in the absence of accelerator Indirect bili = Total bili - direct bili Direct bili approximates conj bili in most cases, but the two terms do not mean the same thing

Conjugated hyperbilirubinemia

Neonates :

1 : 2500 infants, 1/3 secondary to biliary atresia Suspected when jaundice > 2 wks old, dark urine, or acholic stools Clinical significance if :
> 30Qmol/L > 20% of total bili

Older children :

Always abnormal and warranting investigation

Causes of conjugated hyperbilirubinemia

Extrahepatic disease Intrahepatic biliary disease Hepatocellular disease

Extrahepatic disease

Biliary atresia Choledochal cyst Bile duct stenosis Spontaneous perforation of the bile duct Choledocholithiasis Cholangitis Neoplasia - compression or obstruction of biliary tree Bowel obstruction

Intrahepatic biliary disease

Alagille syndrome  Congenital hepatic fibrosis  Carolis disease  Hepatic cysts  Langerhans histiocytosis  Inspissated bile

Hepatocellular Disease


Metabolic contd


AA : tyrosinemia Lipid : FA oxid defect, NiemannPick, Gaucher, Wolman Mitochondrial/ETC defect COH : galactosemia, GSD type IV, hereditary fructose intolerance Peroxisomal : Zellweger Defective bile acid synthesis : 3oxosteroid-5 b reductase def, 3 HSD

Defective prot synthesis : E1

antitrypsin def

Altered ion transport : CF Hemochromatosis Wilson Citrin deficiency

Defective canalicular secretion + transport

PFIC 1,2,3

Hepatocellular disease contd




hypoT4, panhypopit Neonatal hepatitis Dubin-Johnson Rotor Aagenaes Turner, Trisomy 18 + 21


Sepsis UTI HAV, HBV, HCV, CMV, EBV, Rubella, HSV, adenov, enterov, parvov B19, Toxoplasma, Syphilis, TB Autoimmune hepatitis SLE TPN


 Chromo D/O



Shock, hypoperfusion

General History

age jaundice onset + duration of Sx feeding Hx + diet stool Hx irritability, development, school performance birth, perinatal, PMHx


Rx travel Hx HEADS (adolescents) family Hx, consanguinity

Approach to conjugated hyperbilirubinemia


Is the child toxic? Is this a cholestatic presentation? Is this a hepatitis type picture? Does this coincide with chronic liver disease? Could this be secondary to a metabolic cause? Childs age

Is the infant acutely ill?

Sepsis especially E.coli  UTI  galactosemia, tyrosinemia, other metabolic diseases  acute biliary obstruction  acute hepatic failure

Is this a cholestatic presentation?


tea-colored urine acholic stools pruritus acute obstruction :

unwell, may have RUQ pain, emesis, poor intake insidious onset, may still look well, may still be feeding well Xanthomas/ xanthelasmas - from resulting elevated serum cholesterol levels

chronic obstruction Xanthomas :


investigations : GGT + ALP >> transaminases

Is this a hepatitis picture?

History  jaundice  malaise  +/- fever  anorexia, nausea  RUQ tenderness  Rx, (transfusions), HEADS, tattoos, piercings  travel  immunizations


fever, tachycardia jaundice, unwell RUQ pain +/- hepatomegaly


Transaminases > GGT + ALP

Chronic liver disease features?


weight loss, fatigue +/- jaundice bleeds/bruising hematemesis chronic diarrhea / steatorrhea encephalopathy


smaller, firm liver splenomegaly ascites skin : varices, spider angiomas, palmar erythema MSK : Dupuytrens contractures, nail changes, clubbing Neuro : asterixis

Spider angioma Clubbing

Palmar erythema



Caput medusae

Secondary to a metabolic cause?



Fluctuating course Increasing irritability Decreased LOC Seizures Vomiting, poor feeding FFT Multi-organ dysfxn Family Hx

abnormal odor jaundice decreased LOC eye : KF rings, cataracts abN tone, other neuro findings HSM ascites dysmorphism, microcephaly

Neonatal/Infant DDx



sepsis esp. E.coli UTIs TORCH infections acute viral hepatitis galactosemia tyrosinemia alpha1 antitrypsin def CF hypothyroidism

Drug induced Shock PFIC 1,2 Intrahepatic biliary


Bile duct paucity Biliary atresia ** Biliary hypoplasia Choledocal cyst**



** surgically treatable causes

Neonatal algorithm
Direct hyperbili R/O sepsis/ infection + UC, +/- FBC + blood C&S Diagnosis ? Newborn screen + , may need to consult metabolics -ve GI consult, LFTs, INR, albumin, viral studies, reducing substances, E1antitrypsin, abdo U/S Choledocal cyst? -ve Consider HIDA scan -ve, investigate further Consider liver Bx Consult surgery Hx, P/E, UA

Biliary obstruction?

Pf typing

E1 antitrypsin?

Differential of an acute presentation in an older child

Biliary disease  Choledochal cyst  Cholangitis - 1 or 2  Acute obstruction : stone or sludge, tumor  Parasite

Hepatocellular  Autoimmune  Viral hepatitis (HAV, HBV, HCV, EBV)  Rx, toxin

Older child algorithm

Conjugated hyperbilirubinemia AST + ALT >> GGT + ALP (hepatocellular) Viral studies Autoimmune W/U Ceruloplasmin Consider liver Bx GGT + ALP >> AST + ALT (cholestatic)

Abdominal U/S Consider MRCP/ERCP


Hepatocellular :


AST - systemic ALT - liver specific INR albumin GGT alkaline phosphatase cholesterol

CBC As needed :

Biliary :

Blood culture, UA+ UC Viral serologies Alpha-1 antitrypsin Reducing substances Coproporphyrin ANA, anti-SM Cu, ceruloplasmin, Fe, ferritin

Investigations contd

AXR : limited value

20-50% (calcified cholesterol stone or pigmented stone with Ca component) radiopaque in children - may be incidental finding sensitivity + specificity >95% for cholelithiases + sludge 30-40% sensitivity of common bile duct stones, but more easily detected dilation of ducts assessment of gallbladder wall, liver dimensions and echotexture, splenomegaly, masses, ascites Dx tool of choice for choledochal cysts Doppler

Transabdominal U/S :

Investigations contd

CT :  less sensitive than U/S in detecting stones  good assessment of complications of acute cholecystitis  evaluation of masses MRI :  Consider if obstruction still suspected and N U/S or if more detailed Dx information required  MRCP : sens >90%, spec >97% in adults, lower resolution in younger children

Investigations contd

Hepatobiliary scintigraphy


Tc 99m-labeled iminodiacetate compounds (ex. HIDA) to see uptake and excretion Phenobarbitol 5days prior to increase tracer uptake + bile flow abN is when absent gallbladder visualization in 90min

Investigations contd


good imaging modality with opportunity for intervention Invasive

Liver biopsy - if otherwise undiagnosed liver disease or to determine extent of hepatic injury / prognosis

histology electron microscopy - storage material (COH, lipid storage diseases), coarse bile (FIC1, mitoch D/O) immunohistochemistry

A few biliary diseases

Biliary atresia

Most common surgically treatable cause 1: 10,000-15,000  highest incidence in people of Asian + African origin  Females > males Presentation  Perinatal (within 2 wks of life) VS postnatal (2-8wo) Isolated (65-90%) vs assoc with situs inversus or poly/asplenia or other congenital abN

Biliary Atresia contd

Ductal involvement

Type 1 : obliteration common duct Type 2 : atresia hepatic duct with cystic structures of porta hepatis Type 3 : entire extrahepatic ductal system obstructed

Progressive periportal fibrosis and obstruction of intrahepatic portal veins -> biliary cirrhosis

Biliary atresia

May initially have N growth + weight gain Clinically,


Cholestatic Sx, liver N->enlarged->cirrhotic splenomegaly eventual development of ascites and portal HTN Conj hyperbili, ALP, GGT U/S : gallbladder contracted and not visualized Scintigraphy : absent flow from biliary tract Operative cholangiography

Investigations :

Biliary atresia contd

Kasai portoenterostomy

Time critical for procedure success, <60do Outcome dependent on absence of cirrhosis at time of operation and establishment of adequate bile flow
1/3 good bile flow 1/3 never bile flow; transplant before age 2yr 1/3 initially good flow then progressive biliary cirrhosis requiring eventual transplant

Post-op risk of cholangitis


liver transplant w/out treatment, life-span 19m from progressive liver failure

Choledochal cysts

3:1 F:M, Asian 85% type 1 Recurrent bouts abdo pain, jaundice, palpable RUQ mass Untreated, risk of cholangitis, stones, peritonitis, cholangioCa (14% by age 20y)

Choledochal cysts contd

Dx w/ clinical exam and U/S (+/- other imaging modalities) Tx : complete excision w/ Roux-en-Y hepaticojejunostomy, good prognosis life-long F/U required as at risk strictures + intrahepatic stones

Post. embryotoxon


Ductal paucity/ arteriohepatic dysplasia 1: 100 000, JAG1 on chrm 20p12, AD but low penetrance when assoc with extrahepatic findings Diagnosis may be made at any age Liver Bx : intrahepatic ductal paucity Tx : management of cholestasis


disease : congenital dilatation of large intrahepatic bile ducts in absence of other features

Clinical overlap with type V choledocal cyst visible on pre/post natal U/S


syndrome : combination of congenital hepatic fibrosis + macroscopic dilatation of large intrahepatic bile ducts complications : cholestasis, cholangitis

Congenital hepatic fibrosis

Ductal plate malformation

arrest in development leads to abnormal bile ducts that may dilate into cysts

Isolated or in conjunction w/ various disorders or syndromes especially cystic kidney diseases

Congenital hepatic fibrosis

Investigations :

U/S - kidneys, liver echotexture, Sx portal HTN MRCP - evaluation dilatations, strictures, bilomas Liver Bx - assess degree of hepatic fibrosis hepatic failure + portal HTN cholangitis periodic CBC, LFTs, coags, vit ADEK, creat/urea ATB prophylaxis ursodiol

Complications :

Supportive Tx :

Progressive familial intrahepatic cholestasis (PFIC)


Disorders of canalicular secretion + transport causing chronic cholestasis, ultimately leading to cirrhosis Autosomal recessive, M=F, rare (1:50-100,000) 10-15% liver transplant indications in children Onset generally in infancy Dx : based on liver histology, biliary lipid analysis Tx : ursodiol, surgical biliary diversion

If fail, liver transplant

PFIC1 (Bylers) epidemiology onset Clinical features All races Early infancy
More systemic : FFT, pancreatitis, steatosis, sensorineural hearing loss, watery diarrhea

PFIC2 (BDEP def) All races Early infancy

Early hepatic failure

PFIC3 (MDR3) N African European Later infancy to adolescence

May present late w/ GI bleed 2e to portal HTN, less severe pruritus

GGT Bile composition Biopsy

/N primary bile acid concentration

Canalicular cholestasis with periportal biliary metaplasia

/N primary bile acid concentration

More pronounced fibrosis + infl; giant cell hepatitis w/ hepatocellular necrosis

phospholipid concentration
Portal fibrosis, canalicular proliferation, some giant cell transformation


Since systemic, liver transplant not curative of all manifestations

Poor, increased risk HCC <1yo (AFP q 6m, U/S q yr)

= cholestasis of pregnancy. Better response to ursodiol, no reported HCC, at risk for drug toxicity

Primary sclerosing cholangitis (PSC)  Secondary cholangitis

stones, sludging  bacterial infection  surgery to biliary tract  ischemic injury  neoplasia

Primary sclerosing cholangitis

Inflammation intra/extrahepatic bile ducts -> periportal fibrosis w/ areas of alternating stenosing + dilation

Although poorly understood, immunological and genetic factors


Any age, on avg 20-40yo, 2:1 M:F 70-80% assoc w/ IBD, other infl conditions

PSC contd

pANCA (80%), ANA + anti-sm (20-50%) GGT Dx requires imaging biliary tree :

ERCP, MRCP, percutaneous focal narrowing and strictures, appearance

cholangiography beaded

Liver Bx : concentric fibrosis + edema around ducts, pericholangitis, eventual fibro-obliterative lesions

PSC contd

Treatment options:


Cholestasis management : UDCA +/- rifampin Immunosuppression : steroids, MTX, cyclosporine, Tacrolimus little effect on survival and disease progression, increased risk bacterial cholangitis Balloon dilation during cholangiography, avoid surgical repair Liver transplant - indicated if end-stage liver disease, intractable pruritus, osteoporosis
Recurrence rate : 8-20%, no identifiied risk factors

10% complicated by cholangiocarcinoma

Levy C, Lindor K. Journal of Hepatology. 2003, 38 : 24-37. Marschall H, Wagner M, et al. Gastroenterology. 2005, 129 : 476-485 Rost D, Kulaksiz H, Stiehl A. Current Treatment Options in Gastroenterology. 2007, 10: 111-119.

Metabolic causes

Neonatal Metabolic Screen


Amino acids (PKU, MUSD, CIT) Fatty acids (MCAD,LCHAD, VLCAD, CUD, TFP) Organic acids (MMA, PA, IVA, GA1, HMG, BIOT) Biotinidase TSH (detects high only, does not R/O panhypopit) 17-OH progresterone IRT (highest 2% sent for genetic analysis)

Metabolic Diseases : Age of Presentation Hepatic Failure

Infant E1-antitrypsin deficiency Bile acid synthetic D/O Cystic fibrosis Glycosylation D/O FA oxidation D/O Galactosemia Glycogen storage disease Hereditary fructose intolerance Neonatal hemochromatosis Tyrosinemia Wilsons disease Wolmans disease x x x x x x x x x x x x x x Child x x x x x Adolescent x x x



1:100,000 (1:2,000-20,000 in Qc) Type 1 : deficiency fumarylacetoacetate hydrolase Types 2+3 : upstream enzyme deficiencies Presenting features :  Chronic liver disease + cirrhosis  Acute liver failure (liver crisis), precipitated by viral or other acute illness  Renal Fanconi syndrome  Neurological crises (paresthesias, paralysis) Increased risk hepatocellular Ca Tx : low protein diet, N-TBC (blocks tyrosine metabolism), full or partial liver transplant


most freq defect Gal-1-P uridyl transferase accumulation of Gal-1-P, galactitol, galactosamine 1: 50 000 classic, 1: 10 000 all forms

Classic galactosemia

Presentation : N+V, diarrhea, FTT, +/- hemolytic anemia, jaundice, hepatomeg Sequelae : mental deficiency, renal tubular dysfxn (>fanconi), cataracts, infertility Increased risk E.coli bacteremia Dx : reducing substances +, usually detected with newborn screen -> follow up with erythrocyte GALT Tx : lactose free formulas and complete elimination of dairy products

Alpha1 antitrypsin deficiency


E1-AT: protease inhibitor; when deficient, xs neutrophil elastase activity AR, PiS + PiZ alleles

PiS : lung disease PiZZ, PiSZ : lung + liver disease


Dx : E1-AT level, protease inhibitor typing (PiZZ), liver Bx (periodic acid-Schiff (PAS) +, diastase-resistant granules) Tx : liver transplant curative

no smoking IV E1-AT from plasma for severe lung disease

Wilsons disease

ATP-dependent copper transporter, excreting Cu into bile 1: 30 000, all ethnicities generally either hepatic or CNS presentation

45% hepatic : typically 10-13yo, rarely before 3yo 35% CNS : tremor, rigidity, dysarthria 10% psychiatric : depression, new-onset school difficulties, impulsivity Other : hemolytic anemia, Fanconi syndrome, cardiomyopathy

Wilsons disease contd

Investigations :

ceruloplasmin, urinary Cu Liver biopsy : nonspecific +/- copper stores Kaiser-Fleischer rings (slit lamp) genetic testing available chelation : D-penicillamine, trientine GI binding of copper : Zn-acetate liver transplant as last resort avoid chocolate, liver, shellfish, nuts, legumes

Treatment options :


Viral Hepatitis

Hepatotropic viruses


Systemic viruses with hepatic involvement


CMV EBV HSV VZV Adenov, enterov, echov., coxsackiev, rubella, HIV

HBV interpretation
HBs-Ag Anti-HBs Anti- HBc IgM AntiHBc IgG +/+ + + + + + + HBe Ag Anti-HBe Interpretation

+ + +

+ -

susceptible Immune to HBV acute HBV infection chrn HBV HBV after seroconversion







May still be too early for detectable viremia NB. Maternal Ab can still be Vertical transmission unlikely present, suggested to repeat or viral clearance anti-HCV at >18mo A few studies have shown persistent HCV RNA + Bx or PBMCs

Any age Any age Any age

+ + +

+ + >6months

Viral clearance acute vs newly discovered chron. HCV chronic HCV

Any age

early acute infection or immunosilent HCV

Usually if patient immunocompromised, ex. HIV co-infection; ? incidence in children Described in adults with otherwise unexplained incr LFTs

Any age

- in serum + liver Bx or PBMCs

occult HCV

Autoimmune hepatitis

2-5% chronic liver disease in children Type 1 : smooth muscle Ab +/or ANA Type 2 : liver kidney microsomal Ab type 1 +/or liver cytosol Ab type 1 Certain HLA polymorphisms more susceptible may be assoc with DM I, thyroiditis, vitiligo 3 typical presentations:  50-65% - similar to acute viral hepatitis  25-35% - subacute development over 6m-2y  10% - chronic liver disease

Autoimmune hepatitis contd

Investigations :  R/O other causes hepatitis (viral, EtOH, Rx)  Igs >1.5x N especially IgG  ANA, smAb, anti LKM1at titers > 1:80  Liver Bx : hepatocellular changes w/out biliary changes, granulomas Treatment :  First line : corticosteroids, azathioprine  Second line : cyclosporine, mycophenolate  If must proceed to liver transplant, 50% recurrence

Management and complications

Ursodeoxycholic acid

hydrophilic bile acid, 3% of total bile acids proposed mechanisms of action


Protection of cholangiocytes against cytotoxicity of hydrophobic bile acids, changes composition of micelles Promote choleresis via upregulation of transporters at canalicular membrane Protection hepatocytes against bile-induced apoptosis

Nb. little effect on pruritus and resorption decreased with bile acid sequestrates (cholestyramine)
Marschall H, Wagner M, et al. Gastroenterology. 2005, 129 : 476-485. Paumgartner G, Beuers U. Hepatology. 2002, 36 : 525-531.


elimination by expression conjugation enzyme + canalicular membrane transporter

Significant pruritus

short term term safety equal to placebo  10% drug induced hepatitis w/ long term use

Marschall H, Wagner M, et al. Gastroenterology. 2005, 129 : 476-485. Tandon P, Rowe BH, et al. American Journal of Gastroenterology. 2007, 102 : 1528-1536.

Malnutrition & growth restriction

Fat and fat soluble vitamin malabsorption


can have loss of 10-30g/day fecal fat secondary to decreased intestinal bile salts vit D def. : metabolic bone disease vit A def. : night blindness, thick skin vit K def : prolonged PT vit E def : neuromuscular degeneration

Increased metabolic demand of chronic inflammation

Malnutrition & growth restriction

Requires :
closely follow growth chart  nutrition profile, bone age + density  nutritionist involvement  aggressive supplemental feeds (NG, G-tube) for adequate calories with medium chain TG-rich formula  vitamin (esp. vit. ADEK) and nutrient supplementation


Oftentimes primary concern  itching to the point of excoriations  difficult to manage and can become indication for liver transplant Unknown cause :  possibly secondary to accumulation of hydrophobic bile acids and endogenous opioids, opioidergic tone Management : often combination therapies required  Cholestyramine - 1rst line  Rifampin, opioid antagonists (naloxone, naltrexone)  Partial external biliary diversion for refractory cases  Research into 5-HT antagonists, SSRIs, leukotriene antagonists  Phenobarbital, antihistamines less effective

Cies JJ, Giamalis JN. American Journal of Health-System Pharmacy. 2007, 64 : 1157-1162. Gossard AA, Lindor KD. Canadian Journal of Gastroenterology. 2000, 14 : 93-98. Levy C, Lindor K. Journal of Hepatology. 2003, 38 : 24-37.

Common especially early in course of chrn cholestatic liver disease  No increased incidence of heart disease  Some develop xanthomas and xanthelasmas  May try UDCA or cholestyramine if cutaneous manifestations

Gossard AA, Lindor KD. Canadian Journal of Gastroenterology. 2000, 14 : 93-98.

Key points

If persistent jaundice at 2-4 wo, do a fractionated bili Time is of the essence in biliary atresia While biliary atresia and other surgical causes are important to R/O, keep an open mind in workup of neonatal conjugated hyperbili In an older child, history looking at risk factors is critical to orient diagnosis