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Metabolic liver disease presenting with cholestasis talk anshu srivastava
- 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
- 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