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Cholestasis in Children and Adults: Similarities and differences
Broide Efrat M.DAssaf Harofeh Medical center
Differential Diagnosis of Cholestasis in Children Versus Adults
Adults
Extrahepatic biliary obstruction Extrahepatic biliary atresiaExtra hepatic biliary atresia25 percent (range 2 to 55 percent)Idiopathic neonatal hExtrahepatic biliary atresia25 percent (range 2 to 55 percent)Idiopathic neonatal hepatitis25 percent (range 4 to 45 percent)Infectious hepatitis (eg, CMV)11 percent (range 3 to 38 percent)Parenteral nutrition-associated 6 percent (range 7 to 30 percent)Metabolic disease (eg, galactosemia)4 percent Alpha-1-antitrypsin deficiency 4 percent Alagille syndrome1 percent Progressive familial intrahepatic cholestasisepatitis25 percent (range 4 to 45 percent)Infectious hepatitis (eg, CMV)11 percent (range 3 to 38 percent)Parenteral nutrition-associated 6 percent (range 7 to 30 percent)Metabolic disease
(eg, galactosemia)4 percent Alpha-1-antitrypsin deficiency4 percent Alagille syndrome1 percent Progressive familial intrahepatic cholestasis
Choledocholithiasis (most common)
Malignant obstruction
Biliary strictures
Primary sclerosing cholangitis
Complications after invasive procedures
Chronic pancreatitis
Biliary anastomotic stricture (OLT)
Infections
HIV
Intra Hepatic Cholestasis
Drug and toxins
PSC
Intrahepatic cholestasis of pregnancy
TPN
All types of liver disease
Hepatitis: viral, chronic, alcoholic, Cirrhosis
Children
Extrahepatic biliary atresia
Idiopathic neonatal hepatitis
Infectious hepatitis
CMVTPN
Metabolic disease
Galactosemia
Tyrosinemia
A1AT Def
CF
Alagille syndrome
Progressive familial intrahepatic cholestasis
PFIC1
PFIC2
PFIC3
BMC Pediatrics 2015; 15:192
PSC and PBC are the most commonly recognized cholestatic liver disease in the adult population
Biliary atresia and Alagille syndrome are commonly recognized in the pediatric population
In infants, the causes are usually congenital or inherited -usually jaundice
In adult patients “silent” progressive cholestatic liver disease for years prior to development of symptoms such as jaundice and pruritus
Clin Liver Dis 20 (2016) 67–77
PSC in Children versus Adults
The incidence in children - 0.23 cases/100,000 person-years1.11 / 100,000 in adults (Canada), male predominance (62%)
Cholangiocarcinoma in children-extremely rare
May associated with immunodeficiencies, neoplasms (eg,Langerhans cell histiocytosis), trauma, cystic fibrosis and sicklecell
SC may have strong features of autoimmunity (autoimmune SC)
Histologic changes of SC with no radiologic changes (small duct)Curr Gastroenterol Rep (2010) 12:195–202
Autoimmune Sclerosing Cholangitis in Children
Often associated with florid autoimmune features: elevated titres of ANA and SMA; elevated IgG; and interface hepatitis
This variant of PSC is diagnosed in 1.4–17% PSC patients
The same prevalence as AIH-1 in childhood
Similar proportion of boys and girls
IBD present in 45% of children with ASC
pANCA-in 74% of patients with ASC
Evolution from AIH to ASC
AIH and ASC - the same pathogenic process
Sclerosing Cholangitis in Children and Adolescents
AIH /PSC overlapping syndrome in adults
Bile duct injury and ductular reaction are very common (83%) in newly diagnosed AIH and cannot be predicted biochemically
Bile duct injury may subside in the majority of treated AIH cases while DR tends to persist during follow up
Part of the spectrum of AIH with dissimilar responses to treatment and do not necessarily an overlap syndrome)
Liver int 2016
Overlap syndrome AIH/PSC-outcome
Accepted to constitute a variant of the primary disorder, mostly PSC,
In all patients, the original diagnosis was AIH
All patients insufficiently responded to immunosuppressive therapy and eventually showed typical signs of a large duct PSC
Increasing evidence for a better outcome of PSC/AIH overlap compared to classical PSC
This would indicate that immunosuppression may benefit both conditions
Journal of Hepatology1 2014
Rare but severe cholangiopathy presented by jaundice , pale stool
Most develop end stage liver disease requiring LT
Must be considered in the DD of a cholestatic infant after exclusion of EHBA
The liver histology similar to biliary atresia, except that patent bile ducts with the characteristic changes seen in SC are demonstrated
Noenatal Sclerosing Cholangitis
Absence of cystic kidney disease
2 had small cysts
One-end stage renal disease
Exons analysis revealed the mutations-genetically heterogenous
No expression of DCDC2 in the biliary system
Absence of cilia at EM====NEW BILIARY CILIOPATHY
ESPGHAN 2016
Prognosis of PSC
In adults: 31% of 174 died-underlying liver disease and cholangiocarcinoma, 10% OLT
In all models : age and bilirubin prediction prognostic factors
In childhood –rate of progression-unclear OLT in 15-33% of pediatric patients
Cholangiocarcinoma in the graft post liver transplantation -never reported
Immunomodulatory effect of vancomycin on Treg in pediatric inflammatory bowel disease and primary sclerosing cholangitis
Vancomycin affect TNF-α pathways, an immunomodulator; separate from its function as an antibiotic
OV administration may result in the induction of regulatory T (Treg) cells (anti-inflammatory properties)
OV was an effective treatment for concomitant PSC and IBD in children
J Clin Immunol. 2013 February
Long-term treatment of primary sclerosing cholangitis in children with oral vancomycin: an immunomodulating
antibiotic
14 children - improvement in ALT (P = 0.007), GGT (P = 0.005), ESR (P = 0.008), and clinical symptoms with oral vancomycintreatment
IBD, liver histology and radiology - improved
There was less improvement noted in the patients with cirrhosis when compared with the patients without cirrhosis
JPGN 2008
Vancomycin in Adults
35 patients with PSC - 4 groups: vancomycin 125 mg or 250 mg four times/day, or metronidazole 250 mg or 500 mg three times/day for 12 weeks
Vancomycin appears to be the better-tolerated drug
Both low and high-dose vancomycin groups achieved significant decrease in ALKP
The low-dose group normalisation of ALKP
The low-dose group other biochemical improvements, a decrease in Mayo PSC risk score, Bilirubin and CRP
Aliment Pharmacol Ther. 2013
PFIC
PFIC 1 and 2 seem to be more comparable, usually in the first months of life and normal values of serum GGT
PFIC 3 usually manifests in the first year of life, but can also develop later such as adolescence or adulthood
Penetrated mutations in genes encoding proteins associated with hepatocellular transporting system
Progressive Familial Intrahepatic Cholestasis
J Clin Experimental Hepatology 2014; 4: 25-36
PFIC1
Byler Disease, defect in ATP8B1 gene on chromosome 18 FIC1
Overload of bile acids in hepatocyte, reduced secretion , increased ileal absorption
Down regulation of Bile Salt Export Pump, CFTR
Milder presentation-BRIC1= ICP only partially impaired protein function
Progressive cholestasis, pruritus, steatorrhea, poor growth
PFIC2
Recurrent cholestasis, pruritus
BSEP deficiency (ABCB11) gene mutation
Normal or low GGT
Lack of extra hepatic manifestations
Mutation in 2q24 chromosome
Molecular defect: export of bile salt into canalicular
PFIC3
ABCB4 gene encoding multidrug resistance class III (MDR3) protein, located on chromosome 7 (7q21)
MDR3 is expressed in canalicular membrane of hepatocytes
Responsible for biliary secretion of phospholipids
Neutralizing the detergent effect of hydrophobic bile salts
Result in injury of biliary epithelium and bile canaliculi, and cholestasis
Milder phenotypes of PFIC3 present as ICP , cholesterol gall stone disease, drug induced cholestasis, adult idiopathic cirrhosis, and transient neonatal cholestasis
In some patients the disease may present as a clinical continuum, starting with gall stone disease going on to cholestasis and biliary cirrhosis
Elevation of gamma-glutamyl transferase in adult: Should we think about progressive familiar intrahepatic cholestasis?
• PFIC 3 patients - recurrent pruritus and/or jaundice, high levels ofserum -GT (x10)
• The family history may reveal ICP in their mothers, a relation between genetic defects in MDR3 and ICP
• Herheterozigous carrier state of ABCB4 gene mutation
MDR3 deficiency should be looked for in young adults with unexplained biliary cirrhosis
Identification of MDR3 mutations in affected patients and within families is essential for prenatal diagnosis
Digestive and Liver Disease 48 (2016) 203–205
Alagille Syndrome
Autosomal dominant, variable expression localized to the JAG1 gene (20p12)
Occurs in approximately one in 70 000 live births
JAG1 gene product functions as a ligand for the notch-1 receptor
Estimated 20-year survival rates - 80% for those not requiring liver transplantation, 60% for those requiring transplantation, significant intra-cardiac lesions 40%
Alagille syndrome in adult patients: it is never too late
Renal disease caused by AGS probably is under diagnosed in adult patients
AGS should be considered in the differential diagnosis of proteinuric renal disease
First presentation in adults with Biliary Cirrhosis
Clin Kidney J. 2013 Jun;6(3):295-9Int J Obstet Anesth. 2011 Oct;20(4):355-8
Orthotopic liver transplantation for adultswith Alagille syndrome
Clin Transplant 2012: 26: E94–E100
More pediatric patients with cholestatic liver disease are surviving into adulthood and are being followed by adult hepatologists
Adult-AGS patients had a significantly higher rate of encephalopathy, lower serum albumin, and higher serum creatinine in comparison with P-AGS
One- and five-yr patient and graft survival in A-AGS were not significantly different in comparison with P-AGS or (A-AGS patient survival: 95.5%, 90.9%, P-AGS: 88. 7%, 86.2%,
Idiopathic Adulthood Ductopenia
Idiopathic adulthood ductopenia (IAD)-unknown origin
Affect predominant young adults
Clinical and biochemical of cholestasis
Diagnosis by histology-interlobular bile duct loss in less than 50% of the portal tracts (mild) ≥50% (severe)
Treatment mild cases symptomatic, severe OLT
Arch Intern Med 2008Gastroenterology Report 3 (2015)
Hepatotoxicity in Adults and children
THANKS