Primary Sclerosing Cholangitis The Basics Carlos J RomeroMarrero

Primary Sclerosing Cholangitis: The Basics Carlos J. Romero-Marrero MD MSc Chief of Hepatology Digestive Disease and Surgical Institute Cleveland Clinic

Case scenario • 32 y/o male presents with fatigue, pruritus, abdominal pain, diarrhea. Physical examination unremarkable except for abdominal discomfort. • ALT 43, AST 39, Alk Phosphatase 700, T bili 1. 2, INR 1. 0, albumin 4. 2, AMA negative, ANA negative. Ultrasound shows mild diffuse intrahepatic biliary dilatation, no obvious masses.

Primary Sclerosing Cholangitis (PSC) • Is one of the cholestatic liver disorders • Cholestasis (“a standing still of bile”) is defined clinically as jaundice and/or itching and biochemically by varying degrees of elevation in alkaline phosphatase and bilirubin • Chronic cholestatic liver disease characterized by diffuse inflammation and fibrosis of both intraand extra-hepatic bile ducts • May lead to liver cirrhosis, portal hypertension, and liver failure

Etiology and pathogenesis of PSC • Exact causes of PSC –unknown, however believed to be multifactorial –Data supporting genetic predisposition –Familial occurrence of PSC –Association of certain haplotypes (HLA chrom 6 p 21, HLA B*08, HLA-DRB 1) with the disease – Genome wide assoc studies – 16 risk loci – Data supporting Immune-mediation –Presence of autoantibodies (ANCA, ANA, ASMA, and others) –Association with other autoimmune disorders Bacterial/toxin/viral damage and gut microbiota Smoking and coffee appear to be protective

Epidemiology of PSC • Estimated Prevalence in the US: 29, 000 (2000) • Estimated Incidence in US: 1 per 100, 000 • Males are predominantly affected (2: 1) • Occurs in 2 -7% of ulcerative colitis patients • 60 -80% of PSC cases have ulcerative colitis • Recent study in large cohort of IBD screened with MRCP found a high prevalence (25/322, 7. 8%) Bambha K et al. Gastroenterology 2003 Lunder AK, Gastroenterology 2016

Clinical Presentation of PSC • Most patients are asymptomatic at diagnosis – Cholestatic biochemical profile found incidentally in a patient with known IBD – Hypergammaglobulinemia (elevated Ig. G levels) – Positive ANA, ASMA, p. ANCA may be found • Symptomatic patients – Most common initial symptoms are abdominal pain (20%), itching (10%), jaundice (6%) and fatigue (6%) – Symptoms of bacterial cholangitis or infection in bile ducts (fever, chills, Abd pain, jaundice)

Natural history of PSC Mean Liver transplant free survival ~10 years Asymptomatic patients appear to have better survival compared to those with symptoms Bambha et al. Gastroenterology 2003

Natural history of PSC Median Liver transplant free survival was 21. 3 years in population based cohort vs. 13. 2 yrs in combined LT centers cohort Boonstra et al. Hepatology 2013

Diagnosis of PSC • Cholestatic biochemical profile • Characteristic cholangiography (multifocal strictures with segmental dilatations) • Exclusion of secondary causes –Choledocholithiasis, previous biliary surgical trauma, HIV, ischemic stricture post OLT, histiocytosis X, ischemic • Autoantibodies have no role in the diagnosis of PSC

Case scenario • 32 y/o male presents with fatigue, pruritus, abdominal pain, diarrhea. Physical examination unremarkable except for abdominal discomfort. • ALT 43, AST 39, Alk Phosphatase 700, T bili 1. 2, INR 1. 0, albumin 4. 2, AMA negative, ANA negative. Ultrasound shows mild diffuse intrahepatic biliary dilatation, no obvious masses. • What is the next best diagnostic test?

Cholangiography

Diagnosis of PSC: Imaging • MRCP: Sensitivity is around 90% and specificity is around 95% • ERCP is the gold-standard for diagnosis • Role of liver biopsy: – Not routinely necessary for the diagnosis of PSC – Often nonspecific, false negatives may occur – Helpful in cholestasis in IBD with normal cholangiogram – Useful in determining stage of fibrosis – Presence of overlap such as autoimmune hepatitis

Fibro-obliterative lesions (“onion skin”)

Special considerations: “Variant forms” • Ig. G-4 associated autoimmune cholangitis – Approximately 10% of cases of PSC – Increased serum Ig. G 4, bile duct infiltration of Ig. G 4 plasma cells – More aggressive course – May be steroid-responsive • Small duct PSC (5% of patients) – Histology typical of PSC with normal cholangiogram – Approximately 25% progress to large duct PSC – Prognosis is better than classical PSC and cholangiocarcinoma has not been described in small duct PSC • PSC with Autoimmune hepatitis features

Autoimmune hepatitis/PSC overlap • Present at a younger age (35% of children with PSC, 5% of adults) and have a worse prognosis when compared to PSC alone • Consider in patients with: – mixed elevation of liver tests + imaging consistent with PSC and serologic suggestive of autoimmune hepatitis (+ANA, + anti -smooth muscle antibody and/or +anti-LKM), elevated Ig. G levels • Need a liver biopsy for diagnosis – lymphoplasmacytic portal based infiltrates with at least moderate interface hepatitis

Algorithm for the diagnosis of PSC AASLD Guidelines Hepatology 2010; 51: 660 -678

Management of Patients with PSC No proven beneficial Medical therapy Role of Endoscopic therapy Symptoms and Specific Complications • Pruritus • Fatigue • Bone loss • Fat-soluble vitamin def. • Pre-cirrhotic portal hypertension possible • Peristomal varices

UDCA in PSC: Effects on Survival Free of Liver Transplantation 105 PSC patients (13 -15 mg/kg/d UDCA) Lindor KD, N Engl J Med 1997

High dose UDCA in PSC: 28 -30 mg/kg/d Lindor et al. Hepatology 2009

PSC: Future potential therapies • Vancomycin • Vedolizumab (immunosuppressive agent) • All-transretinoic acid (ATRA) • nor. UDCA • Obeticholic acid • Apical Sodium Dependent Bile Acid Transporter (ASBT) • Antifibrotics (simtuzumab) • Fecal microbiota transplantation

nor. UDCA improves cholestasis in patients with PSC Fickert et. J Hepatology 2017

PSC: Endoscopic therapy • Up to 40% of patients with PSC will develop dominant strictures – Stenosis with diameter <1. 5 mm in the CBD or <1 mm in HD • Repeated endoscopic interventions are often needed – Antibiotic therapy mandatory – Stents tend to occlude earlier –exchange in 2 – 3 months – Balloon dilatation alone may be preferred – Brush cytology and biopsy before endoscopic therapy to exclude malignancy • Limitations – High grade stenosis >2 cm above the bifurcation –consider percutaneous cholangiography

PSC: Liver transplantation • Only effective therapy – 40% of patients with PSC will ultimately need liver transplantation – PSC patients account for 6% of all liver transplants performed in the US – Excellent survival rates (85% at 1 year, 72% at 5 years) – However, PSC recurs in 15 -20% of cases and recurrence may be often associated with loss of the graft

Playa Flamenco, Culebra PR

Special considerations • Cholangiocarcinoma – Annual risk in PSC patients 2% – 30 -year cumulative risk: approximately 20% – 30 -50% of patients with cholangiocarcinoma are diagnosed during the following year after PSC diagnosis – Guidelines suggested for surveillance based on expert opinion: ▫ MRI/MRCP or ultrasound and Ca 19 -9 annually

Cholangioscopy: Cholangiocarcinoma

Cholangiocarcinoma –High index of suspicion required – Suspect in deteriorating clinical status, worsening liver tests, Ca 19 -9 >100 without cholangitis – Imaging –MRI/MRCP – ERCP w/ biopsy and brushings for conventional cytology and fluorescence in situ hybridization (FISH)

PSC-IBD: a unique phenotype • Extensive colitis with rectal sparing – predominantly right sided • Backwash ileitis • Mild or quiescent course • Increased colon cancer risk (RR 4 -9) and worsened overall survival vs UC only • Increased risk of pouchitis following IPAA • Increased risk of peristomal varices – avoid ileostomy in PSC patients Navaneethan U, Shen B Inflamm Bowel Dis 2010

Patient with initial diagnosis of PSC IBD Associated Symptoms Yes No Screening Colonoscopy with Biopsy Diagnosis of IBD Yearly surveillance colonoscopy for dysplasia No evidence of IBD-associated symptoms Screening colonoscopy q 5 years

Surveillance recommendations for patients with PSC – Hepatocellular carcinoma –Ultrasound every 6 months for cirrhotics – Gallbladder cancer –Annual US and early cholecystectomy if gallbladder polyps is recommended – Colon cancer – Patients with PSC & IBD –colonoscopy at diagnosis and every 1 -2 yrs – Bone health –Bone densitometry every 2 -3 years

Practical recommendations • Itching – anti-histamines +/- cholestyramine, rifampin -- >check MRCP/ERCP for dominant stricture • New onset jaundice – MRCP/ERCP • Fatigue – Not much to offer • RUQ abdominal pain, fever, jaundice – start ciprofloxacin and call me, consider ERCP • Bone health – calcium supplementation and Vitamin D • Asymptomatic – liver tests every 6 months • Cirrhosis or portal hypertension – surveillance Ultrasound and EGD (varices)

Conclusions • PSC is a rare, chronic, slowly progressive autoimmune liver disease that affects mainly young and middle-aged men, commonly associated with inflammatory bowel disease • No known medical treatment to halt the progression of disease is available; patients may benefit from endoscopic therapy and liver transplantation when appropriate • PSC is associated with a higher life-time risk of hepatobiliary and colorectal malignancies