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

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