This document discusses metabolic liver disease presenting with cholestasis. It begins by defining cholestasis and describing the differences between intrahepatic and extrahepatic cholestasis. In neonates, a metabolic etiology is often the cause of cholestasis and can include conditions like galactosemia or tyrosinemia. The document then examines various etiologies of cholestasis across different age groups. It provides details on progressive familial intrahepatic cholestasis (PFIC), benign recurrent intrahepatic cholestasis (BRIC), and intrahepatic cholestasis of pregnancy. The document emphasizes the importance of early identification of treatable metabolic causes of chole

1. Metabolic liver disease
presenting with cholestasis
Anshu Srivastava
Department of Pediatric Gastroenterology
SGPGIMS, Lucknow

2. Cholestasis (Greek-bile stoppage)
Reduction or absence of bile flow into duodenum
Intrahepatic •Impairment of bile
secretion at the level of
bile ductules (ductular
cholestasis)
•Functional defect in
Extrahepatic bile formation at
hepatocyte level
(hepatocellular
Chronic if > 6mo duration chlestasis)
Etiology: differs across ages
Alkaline phosphatase >1.5ULN, GGT> 3ULN*

3. Neonatal cholestasis: metabolic etiology?
Metabolic etiology
Presenting as liver failure
West:2000-2006 Galactosemia
Tyrosinemia
N Haemachromatosis
Mitochondrial/FAOD
Nieman Pick C
HFI
Others
PFIC/ BASD
Cystic Fibrosis
AATD X
Citrin deficiency
Peroxisomal disorders (Zellweger)
Nieman Pick A, Wolmans disease
Cong Disorders Glycosylation
Gaucher’s etc
Clin Liver Dis 2006;10:27-53

4. Neonatal cholestasis
Others (n-53) (Jan 2007 –Dec 2009)
NH 20%
n=224
BA
UTI/sepsis Non syndromic PILBD
2(0.8%) 2( 0.8%)
Metabolic
21(9.3%) ~14%
18( 8%) Galactosemia
Tyrosenemia
NH/others
TORCH
10(4.4%)
Progressive familial
Intrahepatic cholestasis

5. Etiology of Intrahepatic cholestasis
older children and adults
Hepatocellular Cholangiocellular
•AVH •PBC
•Drug/TPN related •PSC
•Alcoholic steatohepatitis •Ig G4 associated cholangitis
•Sepsis •Cystic Fibrosis
•Infiltrative-metastasis, •Ductal plate malformation-caroli,
Lymphoma, sarcoidosis hamartoma
•CHF/NRH •GVHD
•Metabolic-PFIC, BRIC, ICP •Vanishing bile duct- drugs/ idiopathic
•Paraneoplastic -renal Ca, •Sec sclerosing cholangitis –AIDS,
lymphoma vasculitis etc

6. Clinical features of cholestatic syndrome
Liver disease Reduced bile in intestine
• Cirrhosis causing malabsorption
• Portal hypertension • Vitamin A-night blindness
• D-osteomalacia
Accumulation of bile • E- neuromyelopathy
constituents • K-bleeding tendency
• Bilirubin- jaundice • Calcium-
• Bile acids ostemalacia/osteoporosis
• Pruritogens- pruritus • Fat- steatorrhea, FTT
• Lipids-zanthomata
• Copper-KF ring rare

7. Intrahepatic cholestasis
General management
• Calories: adequate, ~125% of RDA in children
• MCT oil supplement (formula/diet)
• Fat soluble vitamins (A, D, E, K)
• Osteoporosis: Calcium, DEXA for
monitoring, bisphosphonates
• Pruritus: cholestyramine/ Rifampicin/ naltrexone/ UDCA/
ondansetron?, gabapentin?/ plasmapheresis/ MARS
• Specific treatment: BASD, PFIC etc
• Liver transplantation

8. Bile secretion

9. F1C1/ ATP8B1 (18q 21-22)
• Lipid flippase transports phosphotidyl serine from exoplasmic to
cytoplasmic leaflet of canalicular membrane of hepatocyte.
• Less stable canalicular membrane leads to impaired BSEP function
• PFIC 1/ BRIC 1 and ICP
BSEP/ ABCB 11 ( 2q24)
• Primary transporter responsible for bile salt secretion
• PFIC 2/ BRIC 2/ ICP
MDR 3/ ABCB4 (7q 21)
• Canalicular phospholipid translocator causes excretion of
phosphatidyl choline in bile.
• Low PC in bile causes high biliary cholesterol saturation index
• PFIC3/ ICP/ LPAC/ transient neonatal cholestasis/ drug induced
cholestasis.

10. Progressive familial intrahepatic cholestasis
(PFIC)
• AR inheritance, three types 1-3
• Clues- consanguinity, cholestasis of pregnancy in
mother, affected sibling
• Pruritus, jaundice, hepato- splenomegaly, pigmented
stools
• Initial episodes of severe cholestasis followed by
disease-free intervals, but eventually it becomes non
remitting.
• Disease is typically progressive, leading to
cirrhosis/portal hypertension/ESLD and death
J Pediatr 2007;150:556-9 J Gastroenterol Hepatol 1999; 14: 594-99

11. PFIC 1 PFIC 2 PFIC 3
Onset First few mo First few mo Late infancy (~30%)/
Childhood/ adults
ESLD First decade rapid, first few years I-II decade
Extra hepatic Pancreatitis, diarrhea, none none
hearing loss, short
stature, Abn sweat
chloride
γGT N/ low N / low Raised
Liver biopsy Bland cholestasis Giant cell hepatitis, Bile ductular proli-
Hepatocellular necrosis, feration Inflammatory
portal fibrosis infiltrate, fibrosis
E microscopy Granular bile Amorphous bile -
AFP N increased N
Serum bile acids Raised ++ Raised ++ Raised +
Bile: Primary BS Reduced Severely reduced Normal
Biliary phospho- Normal Normal Reduced
lipids

12. PFIC1 and 2 : differentiation
Type I (n-61) Type II (n-84)
ALT/AST + ++ higher
Serum bile acids + ++ higher
Bx giant cells 7% 73% more
Gall stones no 32%
Portal hypertension less More
HCC no 4/84
Growth failure more less
Extrahepatic +++ no
Presentation similar
Type I is a multisystem disease
Type II more severe hepatobiliary disease/ gall stones/HCC/ cholangioCa
J Hepatol 2010;53:170-78// Hepatology 2010;51:1645-55

13. Immunostaining and PFIC
• BSEP and MDR3 antibodies used for immunostaining
• Absence of canalicular or mild immunostaining favors gene
defect
• Normal staining does not exclude gene defect as mutation
may induce loss of function but normal synthesis.
Normal `MDR3 staining no MDR 3 staining
Genetic testing “Gold standard” for diagnosis
Orphanet J of Rare Diseases 2009; 4:1-12

14. PFIC: management
Drug Low High Mechanism of action
C+ partial GGT GGT
response PFIC PFIC
UDCA 22+12 20+14 Replaces endogenous
More in type III cytotoxic BA
98 46
biliary PL/ total ~30% ~70% Induces expression of
lipids>7% predicts ABCB11/ABCB4
response
Rifampicin 0+3 - CYP3A4 induction, 6α
17 hydroxylation of BS and urinary
~16% excretion
Cholestyramine 0+0 2+2 Reduced reabsorption of BS in
34 16 intestine
~25% Stimulates fecal BS excretion
Complete-normalization of transmainases or/ bilirubin/relief of pruritus
Partial- some improvement J Hepatol 2010;52:258-71

15. PFIC and partial biliary diversion
Reduces enterohepatic circulation
External-
jejunal conduit between GB & skin stoma
Internal-
Ileocolonic anastomosis (ileal bypass)
Jejunal conduit between Gb and colon
- successful (LFT/ pruritus) in ~81% cases
- stops progression and even resolution
of histologic changes
- significant fibrosis/cirrhosis predicts failure
- choice between procedures? No RCT
- ensure fluid/electrolyte balance in PEBD
-Ileal
bypass-recurrence within 1y due to ileal adaptation
-Nasobiliary drainage may select responders to biliary diversion
Hep 2006;43:51-53, Clin liv Dis 2000;4:831-8/ J Ped surg 2009;44:821-27/
Ped Surg Int 2010;26:831-34/ Hepatol 2006;43:51-53

16. Saudi J Gastroenterol 2011;17:212-4

17. PFIC and Liver Transplantation
• Reserved for patients with ESLD/ no response to other
therapy
• Survival rate 75-100% (similar to EHBA)
• Guarded prognosis in type1,diarrhea may worsen after
transplant when biliary bile salt secretion is restored with
severe hepatic steatosis
HCC monitoring should be done
from 1st year of life especially in PFIC2
Pediatr Transplant 2006;10:570-74/ 2007;11:634-40// liver transpl 2002;8:714-16/ 2009;15:610-18

18. Benign recurrent intrahepatic cholestasis
(BRIC)
• Recurrent attacks of jaundice, pruritus, steatorrhoea and ± wt loss
• Pruritus precedes jaundice (diff AVH)
• Each attack 2wk-18mo, mean ~3mo
• Improvement in appetite heralds resolution of attack
• Asymptomatic period b/w attacks 1mo-30y, average once every 2y
• Attacks start mostly before 20y of age
• Most cases sporadic, family history in upto 50%
• No progression to CLD
• Attacks often precipitated by acute gastroenteritis.
• Factors causing onset and resolution of cholestatic event ? unclear.
Infection---related endotoxemia----post transcriptional down
regulation of human BSEP
Ann Hepatol 2010;9:207-10, Gastroenterol 2004;127:379-84

19. • Prototype is BRIC 1 (ATP8B1), BRIC 2 and 3 also described
• Location of mutation determines presentation as PFIC 1 or BRIC 1
• Mutation in highly conserved portion in PFIC I and non conserved area
which encodes for non critical portion of the FIC1 protein in BRIC 1

20. BRIC: treatment
• Correction of coagulopathy if any
• Symptomatic treatment of pruritus-
rifampicin, cholestyramine, UDCA, naltrexone
• Nasobiliary drainage-
effect within 24-48hrs, response in 7/9cases*
Drugs may be tried for 4-8wks to assess response
• Plasmapheresis
• MARS important in refractory cases**
• Liver transplantation??
Hepatol 2006;43;51-53*// Eur J Gast Hep 2005;17:585-8**

21. Intrahepatic cholestasis of pregnancy
Pathogenesis- mutation in BSEP/MDR3,
- higher estrogen and progesterone metabolites
Higher incidence is seen in twin pregnancies (20%-22%)
Late II-III trimester pruritus with mild jaundice
Pruritus affects the palms and soles and worsens at night
Constitutional symptoms: anorexia, malaise, abdominal pain
Pale stools, dark urine and steatorrhea may occur
Mild increase in ALT/AST, normal to raised GGT
Raised serum bile acids >10 µmol/L (gold standard)
Symptoms resolve within 48 h and biochemical abnormalities within 2-
8 wk of delivery.
Recurs in subsequent pregnancy or with OCP
Sem Liv dis 2010;30:134-46/Hepatology 2004;40:467e74
/Postgrad Med J 2010;86:160e164 / WJG 2009 ; 15: 2049-2066

22. Foetal complications
• Sudden IUD 3.5%, meconium stained liquor 16-50% ,
preterm labour 30-40%
• risk of adverse fetal outcomes increases with increasing
levels of maternal serum bile acids
Management:
• UDCA, effective in 70-80%, safe,
• Target fasting BA <40 µmol/L
• Vitamin K
• Topical treatment with aqueous cream with 2% menthol
• Elective delivery at 37wk pregnancy as most IUD occur
at/after 37wks

23. Bile acid synthesis defects
• Uncommon, ~2% of liver disease in infancy
• Nine defects identified.
• Commonest 3 beta hydroxy delta 5 C27steroid
dehydrogenase def (AR)
• Commonest presentation with neonatal cholestasis
• Most present with jaundice, hepatomegaly, steatorrhea ,
FTT , vitamin ADEK deficiency in first 3y of life
• Untreated cirrhosis and ESLD by 5y of age
JPGN 2010;50:61-66

24. Diagnosis:
• N GGT, reduced serum bile acids
• ALT/AST/ blirubin raised, low plasma cholesterol
• Liver biopsy giant cell hepatitis, steatosis
• Abnormal BA in urine by FAB-MS (fast atom bombardment mass
spectrometry) or ESLMS (electrospray ionisation tandem mass
spectrometry)
UDCA interferes with detection of abnormal BA so should be
stopped 5days before testing
• Skin biopsy-fibroblast culture and enzyme estimation
Treatment:
• Chenodeoxy cholic acid with/ without cholic acid
• Monitor by amount of abnormal BA in urine
• Excellent response with improvement in histology
J Inherit Metab dis 2011;34:593-604

25. Cystic fibrosis
• Accounts ~0.7% of NCS
• Presents at 1-2mo age, jaundice, hepatosplenomegaly, pale stools,
• h/p portal expansion, periportal steatosis, biliary proliferation
• Jaundice clears in majority by 7-8mo of age, few patients
progress to overt CLD
• ~30% have CF associated liver disease: fatty liver, focal/
multilobular biliary cirrhosis
• Meconium ileus, use of TPN, pancreatic insufficiency, severe
genotype, and males have increased risk of liver disease
• Diagnosis:
sweat chloride, genetic testing
• Treatment:
UDCA, supportive,
liver transplantation
JPGN 2006;43:s49-55/ Arch Dis Child 1999;81:125–128

26. Approach to cholestasis
step I: Differentiate extrahepatic and intrahepatic
history, physical examination and imaging
(USG/ CT, ERCP, MRCP, EUS)
intra hepatic extra hepatic
Evaluate as per cause
GGT
HIGH
LOW/ NORMAL
PFIC I/II BASD Pruritus +nt -nt
PFIC III Cyst Fibrosis
Pruritus +++ ±
AATD citrin def
Serum BA raised normal/low
Alagille synd others
Liver biopsy

27. Clues to differential diagnosis
Zellweger synd
AAT: PAS+diastase
resistant globules

28. Conclusions
• Long list of metabolic causes of cholestasis
• Early identification of the treatable conditions is
a priority
• “Pattern of presentation” helps in making the
differential diagnosis
• Team approach of pediatrician, geneticist,
gastroenterologist and good metabolic lab
crucial for diagnosis and management

29. Thanks