Objectives
Review liver/ biliary tree anatomy + bilirubin metabolism Develop an approach to conjugated hyperbilirubinemia Review most common etiologies Cholestasis : management and complications
Anatomy
Microscopic anatomy
Bilirubin production
RBC
heme oxygenase
biliverdin
Intravascular hemolysis
biliverdin Hb-tetramer reductase
bilirubin
Hb
globin Fe heme
MJ
Hb-Haptoglobin
Liver
Bilirubin conjugation
BilBasolateral membrane
Bil- Alb
Hepatocyte
Bil-GST
Hepatocyte
Bil GST GA
Bil
UGT1A1 GST
Bil- GA
cMOAT
Bil- GA
Non-conj bilirubin
Bilirubin metabolism
Conj bilirubin
Kidney
Portal circulation
Bowel
urine stool
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
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
http://emedicine.medscape.com/article/178757-overview
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 :
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
Alagille syndrome Congenital hepatic fibrosis Carolis disease Hepatic cysts Langerhans histiocytosis Inspissated bile
Hepatocellular Disease
Metabolic
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
antitrypsin def
PFIC 1,2,3
Endocrine
Infectious
Familial
Sepsis UTI HAV, HBV, HCV, CMV, EBV, Rubella, HSV, adenov, enterov, parvov B19, Toxoplasma, Syphilis, TB Autoimmune hepatitis SLE TPN
Autoimmune
Chromo D/O
Iatrogenic
Shock, hypoperfusion
General History
age jaundice onset + duration of Sx feeding Hx + diet stool Hx irritability, development, school performance birth, perinatal, PMHx
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
Sepsis especially E.coli UTI galactosemia, tyrosinemia, other metabolic diseases acute biliary obstruction acute hepatic failure
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
History jaundice malaise +/- fever anorexia, nausea RUQ tenderness Rx, (transfusions), HEADS, tattoos, piercings travel immunizations
P/E
Investigations
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
Palmar erythema
Leuconychia
Ascites
Caput medusae
History
P/E
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
Infectious
sepsis esp. E.coli UTIs TORCH infections acute viral hepatitis galactosemia tyrosinemia alpha1 antitrypsin def CF hypothyroidism
Metabolic
Extrahepatic
Endocrine
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?
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
Investigations
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
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
ERCP :
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
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
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
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 :
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
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)
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
Alagille
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
Carolis
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
arrest in development leads to abnormal bile ducts that may dilate into cysts
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 :
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
PFIC1 (Bylers) epidemiology onset Clinical features All races Early infancy
More systemic : FFT, pancreatitis, steatosis, sensorineural hearing loss, watery diarrhea
phospholipid concentration
Portal fibrosis, canalicular proliferation, some giant cell transformation
prognosis
= cholestasis of pregnancy. Better response to ursodiol, no reported HCC, at risk for drug toxicity
Cholangitis
Primary sclerosing cholangitis (PSC) Secondary cholangitis
stones, sludging bacterial infection surgery to biliary tract ischemic injury neoplasia
Inflammation intra/extrahepatic bile ducts -> periportal fibrosis w/ areas of alternating stenosing + dilation
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 :
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
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
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)
Tyrosinemia
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
Galactosemia
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
E1-AT: protease inhibitor; when deficient, xs neutrophil elastase activity AR, PiS + PiZ alleles
Dx : E1-AT level, protease inhibitor typing (PiZZ), liver Bx (periodic acid-Schiff (PAS) +, diastase-resistant granules) Tx : liver transplant curative
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
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 :
Hepatitis
Viral Hepatitis
Hepatotropic viruses
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
Age
<2mo
Anti-HCV
+
HCV RNA
-
Interpretation
Uninterpretable
Comments
2-17mo
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
+ + +
+ + >6months
Any age
Usually if patient immunocompromised, ex. HIV co-infection; ? incidence in children Described in adults with otherwise unexplained incr LFTs
Any age
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
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
Cholestasis
Management and complications
Ursodeoxycholic acid
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.
Rifampin
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.
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
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
Pruritus
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.
Hypercholesterolemia
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
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
Questions??