The Center for Autoimmune Liver Disease, Cincinnati Children s Hospital PSC Partners Seeking a Cure SAVE JON Research Accelerator

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Ross Edwards
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Chair: William Balistreri, MD Professor of Pediatrics Gastroenterology, Hepatology & Nutrition Cincinnati Children s Hospital University of Cincinnati Cincinnati, OH CME Reviewer: Deepali Tewari, MD

Pediatrics Children s Hospital of Colorado Aurora, CO Alexander G.

1 Chair: William Balistreri, MD Professor of Pediatrics Gastroenterology, Hepatology & Nutrition Cincinnati Children s Hospital University of Cincinnati Cincinnati, OH CME Reviewer: Deepali Tewari, MD Assistant Professor, Pediatric Gastroenterology and Hepatobiliary Diseases at New York Medical College Westchester, New York Faculty: Cara Mack, MD Associate Professor of Pediatrics Department of Pediatrics Children s Hospital of Colorado Aurora, CO Alexander G. Miethke, MD Assistant Professor of Pediatrics Cincinnati Children s Hospital University of Cincinnati Cincinnati, OH Tamir Miloh, MD Director of Pediatric Hepatology and Liver Transplant Medicine Texas Children s Hospital Houston, TX NASPGHAN and the NASPGHAN Foundation for sponsoring this webinar Christine and John Browner who provided support for this program The organizations who endorsed this program: The Center for Autoimmune Liver Disease, Cincinnati Children s Hospital PSC Partners Seeking a Cure SAVE JON Research Accelerator

Following the presentations we will take as many of your questions as time will allow Please submit your questions at any time during the webinar (box located directly beneath the webinar player

2 Following the presentations we will take as many of your questions as time will allow Please submit your questions at any time during the webinar (box located directly beneath the webinar player window) Registration page contains directions on how to obtain CME credit Primary Sclerosing Cholangitis (PSC) Autoimmune Hepatitis (AIH) Autoimmune Sclerosing Cholangitis (ASC) Autoimmune liver diseases (AIH,PSC and ASC) present a challenge for pediatricians and specialists Their relative rarity creates gaps re: diagnosis and management Results in severe complications: progressive disease cholangiocarcinoma

3 Describe the spectrum of Autoimmune Liver Disease in children/adolescents Review the physiology and natural history of AIH, PSC, and ASC Review the clinical presentations Describe the diagnostic approaches Explain the therapeutic strategies Review transplant options and outcomes 13 year old boy with IBD Fatigue, new onset jaundice Exam = hepatosplenomegaly Elevated CB, AST, ALT, Alk Phos US = enlarged liver, spleen Differential? AIH PSC Images courtesy of William Balistreri, MD.

features of PSC AIH PSC Chapman et al. Hepatology 2010;51:660-678.

4 Overlap AIH PSC Images courtesy of William Balistreri, MD. Children and young adults Clinical Biochemical Histological Features of AIH In presence of cholangiographic features of PSC AIH PSC Chapman et al. Hepatology 2010;51: Children and young adults Clinical Biochemical Histological Features of AIH In presence of cholangiographic features of PSC AIH ASC PSC ASC Autoimmune Sclerosing Cholangitis Chapman et al. Hepatology 2010;51:

607 cases of IBD (14% with LD): 29 PSC (10% of UC pts; 0.

9% CD) Deneau et al. Hepatology 2013;58:1392 1400.

Proportion affected 0. 6 0. 4 0. 2 PSC ASC AIH * * 0.

5 607 cases of IBD (14% with LD): 29 PSC (10% of UC pts; 0.6% CD) 44 AIH (0.4% UC; 0.3% CD) 12 ASC (2.3% UC; 0.9% CD) Deneau et al. Hepatology 2013;58: IBD PSC AIH ASC Deneau et al. Hepatology 2013;58: Proportion affected PSC ASC AIH * * Time since Dx of Liver Disease (years) Deneau et al. Hepatology 2013;58:

Proportion affected 0. 6 0. 4 0. 2 Cholangiocarcinoma in 2 of 29 PSC ASC AIH * * 0. 0 0 1 2 3 4 5 6 7 8 9 10 Time since Dx of Liver Disease (years) Deneau et al. Hepatology 2013;58:1392 1400.

6 Proportion affected Cholangiocarcinoma in 2 of 29 PSC ASC AIH * * Time since Dx of Liver Disease (years) Deneau et al. Hepatology 2013;58: Recognize New onset disease Patient with IBD Differentiate (prognosticate) Establish treatment plan Monitor Research Tamir Miloh, MD Director of Pediatric Hepatology and Liver Transplant Medicine Texas Children s Hospital

7 PSC Male predominance Most asymptomatic at presentation Symptoms related to pre-existing IBD Fatigue Abdominal pain Anorexia, weight loss, poor growth Pruritus Fever Jaundice Fat soluble vitamin deficiencies Impairment of QOL and depression AIH Female predominance Asymptomatic Symptoms related to extrahepatic immune mediated disease: thyroid, celiac, APECED Fever RUQ pain Arthralgia Jaundice Cirrhosis and portal HTN Acute hepatitis Acute liver failure Chronic Liver Disease Cirrhosis and portal HTN Drug induced AIH Overlap with PBC and PSC Recurrent AIH after LT and de novo AIH Initially unremarkable Jaundice Hepatomegaly (45%) Splenomegaly (30%) Excoriations (20%) Ascites (1%) Cirrhosis and portal hypertension

8 ALP and GGT predominance Bilirubin elevated in 40% May have evidence of ESLD panca 33%-87% IgG 4 in 10% PSC Autoimmune Ab positive up to 70% AIH ALT and AST predominance Bilirubin mostly normal May have evidence of ESLD Elevated IgG AIH type 1 ANA >1:40 ASMA >1:40 Anti F Actin AIH type 2 Anti LKM Anti LC1 Viral hepatitis Wilson s Disease Drug induced liver injury Alcohol Granulomatous hepatitis Hemochromatosis Celiac disease Non-alcoholic steatohepatitis α1-antitrypsin deficiency Secondary sclerosing cholangitis: Immunodeficiency Genetic: CF, PFIC 3 Surgery/Trauma Stone/Tumor Pancreatitis Vascular Infection US usually normal Multifocal strictures and dilation involving the intra- and/or extrahepatic biliary tract Beading Pruned tree Image courtesy of Dr. Taouli, Mount Sinai NY

9 Was considered the gold standard Used if MRCP equivocal Intervention stent balloon dilatation Screening for CC Disadvantage: Invasive, sedation, pancreatitis risk May miss intrahepatic lesions Image courtesy of Dr. McOmber, Phoenix Children s Hospital 84% sensitive in children Advantage: Non-invasive No radiation No pancreatitis risk Imaging proximal to strictures and the extraluminal abdomen Ductular proliferation Periductular inflammation Ductopenia Periductal concentric onion skin fibrosis Cholestasis Fibrosis Liver Bx needed: Small duct PSC Overlap with AIH Other diagnosis Staging Image courtesy of Dr. Thung, Mount Sinai NYC

Interface hepatitis Plasma cell infiltrate Rosette formation Bridging necrosis Fibrosis Cirrhosis Bile ducts usually spared Image courtesy of Dr. Balistreri.

10 Interface hepatitis Plasma cell infiltrate Rosette formation Bridging necrosis Fibrosis Cirrhosis Bile ducts usually spared Image courtesy of Dr. Balistreri. Interface hepatitis Plasma cell infiltrate Ductular proliferation Periductular inflammation Ductopenia Periductal concentric onion skin fibrosis Cholestasis Fibrosis Image courtesy of Dr. Balistreri. Hennes et al Hepatology 2008;48:

IBD in 53-96% of all pediatric PSC cases 5% of patients with IBD will develop PSC UC most common Pancolitis Rectal sparing Back wash ileitis Quiescent Chapman et al.

11 IBD in 53-96% of all pediatric PSC cases 5% of patients with IBD will develop PSC UC most common Pancolitis Rectal sparing Back wash ileitis Quiescent Chapman et al. Hepatology 2010;51(2): Right-sided Predominance of inflammation Pancolonic Risk of Colon CA Backwash Ileitis Mild Inflammation (often asymptomatic) Rectal sparing Hirschfield et al. Lancet 2013:392:

Crohn s colitis in approximately 10% IBD usually diagnosed first or concurrent with PSC but may present after OLT PSC course does not correlate with IBD course Recommended surveillance colonoscopy at

Abnormal in 58% within 150 months and 16% by 1 mo post-ibd diagnosis. PSC (4.3%) AIH (ASC 1.

12 Crohn s colitis in approximately 10% IBD usually diagnosed first or concurrent with PSC but may present after OLT PSC course does not correlate with IBD course Recommended surveillance colonoscopy at diagnosis Pouchitis risk: 13.8% -90% In adult PSC 10 year cumulative risk of colonic Ca: 0-10% Chapman et al. Hepatology 2010;51(2): Abnormal in 58% within 150 months and 16% by 1 mo post-ibd diagnosis. PSC (4.3%) AIH (ASC 1.7%) Non-alcoholic fatty liver disease (NAFLD) Primary biliary cirrhosis Hepatic amyloidosis Granulomatous hepatitis Portal vein thrombosis Infection Liver abscess Drug toxicity Valentino et al. Inflamm Bowel Dis 2015;21(12): children with IBD 2% IBD-LD; 21 PSC, 2 AIH, 6 Overlap IBD-LD more common in UC than in CD (4% vs. 0.8%) p < Elevation of both ALT & GGT within 90 days after dx of IBD = markedly increased likelihood of IBD-LD Goyal et al. J Pediatr Gastroenterol Nutr 2014;59(3):

Life long risk 10% 50% in first year of diagnosis Rare in pediatrics May be intrahepatic, hilar and extrahepatic Presentation: asymptomatic, abdominal pain, jaundice, weight loss Labs: marked

13 Life long risk 10% 50% in first year of diagnosis Rare in pediatrics May be intrahepatic, hilar and extrahepatic Presentation: asymptomatic, abdominal pain, jaundice, weight loss Labs: marked elevations in ALP and CA 19-9 levels Imaging: dominant biliary stricture Diagnosis: brushing cytology, FISH or biopsy Alexander Miethke, MD Assistant Professor of Pediatrics Cincinnati Children s Hospital Medical Center Autoimmune Hepatitis (AIH) Immune mediated injury against hepatocytes Association with other immune disorders: celiac disease, autoimmune thyroiditis Consequences: hepatocellular fibrosis Primary Sclerosing Cholangitis (PSC) Immune mediated injury against biliary epithelial cells Association with IBD Consequences: Ductal strictures, cholestasis, biliary fibrosis, cholangiocarcinoma

Miethke, MD Pediatric onset BILIARY LESIONS

guide approach to diagnosis and therapy of

with ALD Image concept by Alexander Miethke,

Liver Disease in Children 2014;Cambridge

Our patient with biliary injury by MRCP,

14 IgG4 AIH PSC PSC AIH IgG4 Adult onset Gheorghe et al. Eur J Gastroenterol Hepatol 2004;16(11): Gregorio et al. Hepatology 2001;33(3): Graphic concept courtesy of Alexander Miethke, MD Pediatric onset BILIARY LESIONS AIH ASC PSC RESPONSE TO STEROIDS Concept may guide approach to diagnosis and therapy of children with suspected ALD, yet it requires further support through clinical/translational studies in children with ALD Image concept by Alexander Miethke, MD and William Balistreri, MD in Suchy, et al. Liver Disease in Children 2014;Cambridge University Press: Chapter 21. Our patient with biliary injury by MRCP, elevated AST/ALT, GGT, IgG, ANA H&E acd3 Images by Rachel Sheridan MD. acd20 AIH Interface hepatitis Hepatocyte injury PSC Interlobular bile duct injury Infiltrates with T and B-lymphocyte

15 Most of patient based data stems from adults with Autoimmune Hepatitis Type I (Autoantibodies, GWAS) Primary Sclerosing Cholangitis (GWAS, lymphocyte biology) Animal models: AIH: Model of type 2 AIH PSC: Mdr2-/- without large duct disease Type 1 AIH: i.e. Cyp450 1A2 Antigens for autoantibodies Hepatocytes Graphic and concept by Alexander Miethke, MD. MHC I Type 2 AIH: CYP2D6 (recognized by LKM antibodies) -induces AIH in murine model MCH class II- single most important genetic susceptibility factor, Depends on ethnicity DRB1*0301 DRB1*0401 Variant in MHCII rs (P = ) 649 adults with Type I AIH (Netherlands), Validation cohort Dendritic cell Type I AIH (Germany) deboer et al. Gastroenterology 2014;147(2): Graphic and concept by Alexander Miethke, MD.

IL-2 CD4 CD8 TNF IL10 DC/ APC Foxp3 MH C I Webb et al. J Hepatol Jan 23. pii:s0168-8278(16)00051-92015. Liberal et al. Hepatology 2015;62(3):863-75. Graphic and concept by Alexander Miethke, MD.

16 IL-2 CD4 CD8 TNF IL10 DC/ APC Foxp3 MH C I Webb et al. J Hepatol Jan 23. pii:s (16) Liberal et al. Hepatology 2015;62(3): Graphic and concept by Alexander Miethke, MD. Activation antigenspecific cytotoxic CD8 T cells Genetic susceptibility in rare variants (Gata2, Aire) Defective Tregs (IL-2 response, IL10) CD4 Liu et al. Hepatology 2015;62(5): Béland et al. Hepatology 2015;62(5): Graphic and concept by Alexander Miethke, MD. Plasma cells NK Normal Surface proteins Impaired suppression Antibody-dependent cell-mediated cytotoxicity 1. CD11b+ B Cells suppress CD4+ T cell responses in experimental AIH 2. B cells fuel T Cell activation through Ag-presentation Association with disease SNPs on chromosome s GWAS: 3,789 European ancestry PSC cases were compared with 25,079 population controls across 130,422 single-nucleotide polymorphisms (SNPs) genotyped using Immunochip Liu et al. Nat Genetics 2013;45:

17 1.Strongest risk factor; HLA-type 2. Non-HLA genes implicate several pathways/ some overlap with IBD 3. Disease onset and disease progression estimated to be determined to 30% by inherited and to 70% by environmental factors Hov et al. Dig Dis 2011;29: Karlsen et al. Dig Dis 2015;33(suppl 2): Hirschfield et al. Gastroenterology 2013;144(7): SNPs near genes for: a. Cytokine Immune activation: IL-2, IL21, IL2RA b. T cell homeostasis: CD28, HDAC7 c. FUT2- cholangiocyte bicarbonate umbrella d. Bile acid receptor: Tgr5 Hov et al. Dig Dis 2011;29: Karlsen et al. Dig Dis 2015;33(suppl 2): Hirschfield et al. Gastroenterology 2013;144(7): Immunopathogenesis Genetic susceptibility associations 2. Dual Homing CD4+ HLA II DR3 BEC 3. Leaky Gut (rat model) DC, MP Mdr2,-/- IL-8 PRRs TLR4 Microbiome 4. Toxic Bile (mouse model) MAdCAM-1 PMN Biliary fibrosis Colon CCR5 4 7 Myofibroblasts Hydrophobicity of serum and Effector Memory Lymphocytes biliary bile acids Graphic and concept by Alexander Miethke, MD in Suchy, et al. Liver Disease in Children 2014;Cambridge University Press:Chapt 21.

18 1. Lack of commensal bacteria in germfree mdr2-/- mice: a. Higher serum ALP, ALT, Bilirubin b. Aggravated fibrosis, cholangiocyte senescence c. Decreased secondary bile acid levels (UDCA) which protected against bile duct injury in vitro 2. Fecal stool samples (n=543)- 16S rrna sequencing a. PSC subjects (n=85), HC (n=263), UC ( n=36) b. Reduced bacterial diversity in PSC compared with both control groups c. Increase of Veillonella genus in PSC Tabibian et al. Hepatology 2016;63(1): Kummen et al. Gut 2016:Feb17.pii:gutjnl IBD PSC HLA, IL-2 HLA CD28; Tgr5 Host Genetics AIH Validation of risk factors for pediatric onset ALD is urgently needed to facilitate early diagnosis, intervention and targeted disease-specific therapy Graphic and concept by Alexander Miethke, MD. Cara Mack, MD Associate Professor of Pediatrics Children s Hospital Colorado University of Colorado Denver School of Medicine

19 Corticosteroids to induce remission (2 mg/kg/day; max: 60 mg daily) Goal: biochemical and histological resolution of inflammation 3-6 months for biochemical remission Azathioprine for maintenance (1-2 mg/kg/day)+/- low dose steroid Usually minimum of 2 years of therapy prior to considering immunotherapy withdrawal. Kerkar N. and Mack CL. Autoimmune Hepatitis, in Liver Disease in Suchy, et al. Liver Disease in Children 2014;Cambridge University Press:Chapt 20; Liberal et al. J Clin Transl Hepatol 2015;3(1): May take years for histological resolution (65% of Type 1 AIH patients reach remission within 18 mons. and 80% by 3 years) Type 2 AIH rarely/never able to stop immunosuppression After proven histological normalization, withdrawal of therapy results in relapse of AIH in ~70-80% within 1 year! Kerkar N. and Mack CL. Autoimmune Hepatitis, in Liver Disease in Suchy, et al. Liver Disease in Children 2014;Cambridge University Press:Chapt 20; Liberal et al. J Clin Transl Hepatol 2015;3(1):42-52.

20 Indications: End stage liver disease who fail therapies Acute on chronic liver failure Fulminant hepatic failure (FHF) AIH accounts for 2-3% of all pediatric liver transplants in Europe and the US AIH accounts for up to 20% of all cases of pediatric FHF DiGiorgio et al. J Pediatr Gastroenterol Nutr 2015;60: Criteria Autoantibodies >1:40 Sustained rise in serum aminotransferases (>2x nl) Elevated serum immunoglobulins Compatible liver histology of AIH Corticosteroid dependency Exclusion of other causes of graft dysfunction (i.e. rejection, HCV) Mottershead et al. World J Gastroenterol 2008;14(21): Study FU (mo) n % Rec. Time to rec. Re-OLT Milkiewicz % 29 mo. 6% Ayata % d. 16% Reich % 15 mo. 12% Molmenti % Vallee % 2.5 y. 12% Heffron % Vogel % 5 y. 14% Gautam % 2.4 mo. Average: 48 mo. 30% 1 mon-5y 12% Milkiewicz et al.transplantation 1999;27;68(2): Ayata et al. Hepatology 2000;32(2): Reich et al. Hepatology 2000;32(4 Pt 1): Reich et al. Liver Transpl 2002;8(6): Molmenti et al. Liver Transpl 2002;8(6): Duclos-Vallee et al. Gut 2003;52(6): Heffron et al. Transplant Proc 2003;35(4): Vogel et al. Clin Transplant 2004;18: Gautam Liver Transpl 2006;12(12):

21 Budesonide: synthetic steroid with high first-pass metabolism in liver; therefore limits systemic side effects 207 non-cirrhotic patients (Europe) Pred/AZA vs. budesonide/aza efficient in inducing remission and superior profile of steroid-specific side effects reactivation with budesonide monotherapy Manns et al. Semin Liver Dis 2009;29(3): Prospective, double-blind randomized trial of budesonide (9mg) versus prednisone (40 mg tapered to 10 mg) plus AZA at diagnosis Results: similar biochemical remission rates between groups significantly less weight gain and other steroid side effects in budesonide group Woynarowski et al J Pediatr 2013;163: Mycophenolate mofetil (Cell Cept): blocks purine synthesis and decreases T and B cell proliferation Adult study of patients that couldn t tolerate AZA; 71% achieved remission by 3 months Pediatric study (King s College) -non-responders or couldn t tolerate AZA: ~70% achieved remission (all nonresponders had ASC) Manns et al. Semin Liver Dis 2009;29(3): Liberal et al. Hepatology 2015;62(3):

Tacrolimus: calcineurin inhibitor (inhibits T cell proliferation) few small studies suggest resolution of liver inflammation needs larger randomized trial to assess efficacy Manns et al.

22 Tacrolimus: calcineurin inhibitor (inhibits T cell proliferation) few small studies suggest resolution of liver inflammation needs larger randomized trial to assess efficacy Manns et al. Semin Liver Dis 2009;29(3): Treatment of AIH component (prednisone, AZA): 83% of patients normalized AST, 73% bilirubin, 89% nl. GGT, 92% nl. alk phos --39% weaned off AZA and 17% remain in AIH remission off immunosuppression Treatment of AIH does not alter PSC progression 17 patients with follow-up ERCP: 9 with static disease & 8 with progression of biliary strictures Gregorio et al. Hepatology 2001;33(3):

23 Immunomodulatory Methotrexate Prednisone Penicillamine Tacrolimus Cyclosporine Mycophenolate mofetil Azathioprine Infliximab Antibiotics Minocycline Metronidazole Chandok et al. Can J Gastroenterol 2012;26(5): UDCA: hydrophilic dihydroxy bile acid; ~3% of bile acid pool Displacement of hydrophobic BA Modulation of hepatocyte apoptosis Prevention of mitochondrial membrane perturbations Stimulation of BA secretion Immunomodulator Poupon. Clin Res Hepatol Gastroenterol 2012;36 Suppl 1:S subjects: age range 1-17 years Significant decrease in GGT to near normal Overall reduction in jaundice and pruritus, however not statistically significant No investigations performed regarding improvement in liver fibrosis/mrcp Gilger et al. J Pediatric Gastroenterol Nutr 2000;31:

24 IU/L ALP ALT AST GGT Mean at diagnosis Mean at 1 yr into UDCA therapy Miloh et al. Clin Gastro Hepatol 2009;7: patients (placebo or UDCA 28-30mg/kg/d) Improvement in liver tests in UDCA group ~ 2-fold increase in transplant/death in UDCA group Lindor et al. Hepatology 2009;50(3); subjects with PSC and UC (active) OV given until liver tests normalized; repeated dosing for elevated liver tests (i.e. on/ off vancomycin for many years) Significant improvement in liver tests to near normal; worsened when OV was stopped No investigations performed regarding improvement in liver fibrosis/mrcp Davies et al. J Pediatr Gastroenterol Nutr 2008;47(1):61-67.

25 9 subjects with PSC and UC (active) OV given for 6-12 months Significant improvements in liver tests and increased Tregs/ anti-inflammatory cytokines with decreased proinflammatory cytokines Subjective analysis of liver biopsy results 6-12 months after treatment: 5 biopsies normal and 4 with mild/residual inflammation or fibrosis Abarbanel et al. J Clin Immunol 2013;33(2): Previous studies: all PILOT studies with small numbers very unique population (active colitis at time of PSC treatment) Side effects of oral vancomycin: potential for creating highly resistant colonic bacteria (harmful around liver transplant) allergic reaction risk (low) of kidney dysfunction or hearing loss Need for multi-centered randomized placebo controlled or comparative effectiveness trial of OV ~500 liver transplants per year in children ~2.6% of pediatric transplants due to PSC (10-20 per year) Recurrence of PSC post transplant: 5 large retrospective studies in pediatric PSC ; 208 patients; FU 5.8 yrs % pts. with recurrent PSC: range 0-31%, mean 17% Wilschanski et al. Hepatology 1995;22: Gregorio et al. Hepatology 2001;33: Feldstein et al. Hepatology 2003;38: Miloh et al. Clin Gastroenterol Hepatol 2009;7: Deneau et al. Hepatology 2013;58:

26 Randomized, comparative effectiveness trial of OV vs. UDCA for pediatric PSC Efficacy of LUM001, an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTi), in patients With PSC Norursodeoxycholic Acid in the Treatment of PSC Miethke et al. Hepatology 2016;63: Dawson et al. Hepatology 2016;63: Must be considered in all children with new onset jaundice or elevated AST/ALT: Most patients with PSC are asymptomatic at the time of diagnosis and found through screening of patients with IBD Differential of AIH from ASC or PSC is based on biochemistry, imaging, and liver histology

27 The pathogenesis remains elusive: HLA-type is the strongest genetic risk factor for PSC and AIH Non-HLA genetic risk factors differ between AIH and PSC; thus these are distinct entities Interrelationship of the intestinal microbiota, bile acids, and cholangiocyte injury in PSC may reveal potent therapeutic targets Standard therapy for AIH (and AIH component of ASC) = corticosteroids and azathioprine In historical treatment trials of PSC no strategies demonstrated definitive efficacy High rate of recurrence post liver transplant Clear need for multi-center randomized placebo controlled or comparative effectiveness trials NOTE: link to download the slide deck in a PDF format we will post a recorded version of the webinar on the NASPGHAN website ( Obtain CME credit through the link posted on registration page

28 To our faculty for sharing their wisdom with us To NASPGHAN and the NASPGHAN Foundation for sponsoring this program To Chris and John Browner for providing support and to the organizations which endorsed this program To all participants in tonight s webinar Good Night

Pediatric PSC A children s tale

Pediatric PSC A children s tale September 8 th PSC Partners seeking a cure Tamir Miloh Assistant Professor Pediatric Hepatology Mount Sinai Hospital, NY Incidence Primary Sclerosing Cholangitis (PSC) ;