Latest PSC Research. Joseph A Odin, MD, PhD

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2 Latest PSC Research Joseph A Odin, MD, PhD Associate Professor of Medicine Director, New York Autoimmune Liver Disease Programs at Mount Sinai School of Medicine September 8, 2009

3 Outline Very Quick Overview Biliary Anatomy and Physiology The Basics of Primary Sclerosing Cholangitis Current Research Studies

What is primary sclerosing cholangitis (PSC)? Bile is a liquid made in the liver. Bile ducts are tubes that carry bile out of the liver to the gallbladder and small intestine.

4 What is primary sclerosing cholangitis (PSC)? Bile is a liquid made in the liver. Bile ducts are tubes that carry bile out of the liver to the gallbladder and small intestine. In the intestine, bile helps break down fat in food. PSC may damage and block bile ducts inside and outside the liver. In PSC, inflammation of the bile ducts may lead to scar formation and narrowing of the ducts over years to decades. As scarring increases, the ducts become blocked. As a result, bile builds up in the liver and damages liver cells. Eventually, scar tissue may spread throughout the liver, causing cirrhosis and liver failure.

5 What causes PSC? Genetic Polymorphisms combined with Environmental Factors CFTR HLA p16(ink4a) SXR MMP3 CCR5 Bile duct inflammation and scarring ICAM-1 Colitis polys Blockage of bile ducts Infections/Cancer (12%) Cirrhosis (20%) Transplant (5%) Chlorinated hydrocarbons Obesity/DM Gallstones Tobacco

6 What are the symptoms of PSC? Fatigue Itching Jaundiced skin/yellow eyes Dark urine/pale stool Fever/Chills (bile infections) Symptoms of vitamin A, D, E, K deficiency Cirrhosis related symptoms

7 Who is at risk for PSC? Only 10 in 100,000 people have PSC. Most people with PSC are adults but the disease also affects children. The average age at diagnosis is 40. PSC is more common in men (60%) than women (40%). Having family members with PSC increases a person s risk for PSC up to ten-fold. Having ulcerative colitis or crohn s colitis increases a person s risk for getting PSC.

8 Where Do They Live in NYC?

9 PSC Clusters in Light Blue St. Paul Milwaukee Denver Chicago Chicago PSC AIH PBC PSC

10 Colitis and PSC Few (7%) with ulcerative colitis or crohn s colitis have PSC Most (70-90%) with PSC have at least mild colitis Either disease occurs first Liver transplantation does not prevent colitis Colon removal does not prevent PSC except possibly PSC recurrence after transplantation

11 How is PSC diagnosed? Blood tests (raised alkaline phosphatase) Radiologic imaging of bile ducts (narrowing or stricturing of ducts typical with dilated areas) Liver biopsy may not be needed for diagnosis, but may be needed for prognosis Must then rule out secondary biliary cirrhosis (e.g. gallstone disease or intra-arterial chemotherapy as causes of bile duc damage)

12 Radiologic Imaging Normal PSC liver liver DILATED STRICTURE Common bile duct Common bile duct

13 How is PSC treated? No treatment is clearly proven to cure or slow down progression of PSC -Use of ursodiol or actigall is controversial -Milk thistle may be helpful Treatments are available to relieve symptoms -Cholestyramine, etc. for itching -Antibiotics for biliary infections (cholangitis) -Vitamins and herbal supplements -Bile duct stents for strictures

14 Cholangiocarcinoma (Bile Duct Cancer) Frequency- 1-2% per year. Not related to duration of disease Screen yearly as soon as diagnosed with PSC Screen method- ERCP/MRCP, CA19-9, CEA Treatment- Resection v. ablation v. systemic chemo Recurrence rate- very high even after transplant

15 Transplantation There is a severe shortage of donor livers. Some states have more donors/patient. Recipients MELD score, based on his/her blood test results, determines who is the next recipient of a liver from a deceased donor. Living liver donors must be closely related to or associated with the recipient. In New York, 25 MELD points are given to those with PSC who have been hospitalized for two episodes of cholangitis.

After-Transplantation Post-transplant survival- very high (>80% after 1 year). Poor prognosis only if incidental cholangiocarcinoma detected in the removed liver.

16 After-Transplantation Post-transplant survival- very high (>80% after 1 year). Poor prognosis only if incidental cholangiocarcinoma detected in the removed liver. Rejection prevention- standard drugs are used. Recurrence of PSC- 23% in 5y, but re-transplantation is rare until >15 years after 1 st transplantation. Colon removal may help prevent PSC recurrence.

17 Recent Clinical Trials for PSC-I TITLE Sponsor Goal Contact High-Dose Urso in Primary Sclerosing Cholangitis (28-30 mg/kg/day) Mayo Clinic NIDDK Prolong time to cirrhosis, transplant, and death Completed-negative PMID: Erlotinib for Chemoprevention in Trisomy 7 Positive Primary Sclerosing Cholangitis Mayo Clinic Genentech Cholangiocarcinoma prevention blechacz.boris@ma yo.edu Cholangioscopy Using Narrow Band Imaging (NBI) Mayo Clinic Cholangiocarcinoma detection baron.todd@mayo.e du Docosahexaenoic Acid (DHA) in PSC Beth Israel Deaconess Med. Center Decreased liver blood tests Active, not recruiting Probiotics in Patients With Primary Sclerosing Cholangitis Netherlands Decreased liver blood tests & QOL Completed-negative PMID:

18 Recent Clinical Trials for PSC-II TITLE Sponsor Goal Contact Minocycline in Primary Sclerosing Cholangitis (PSC) Mayo Clinic Decreased liver blood tests & QOL Completed-positive PMID: Budesonide for PSC Mayo Clinic NIDDK Decreased liver blood tests Completed-negative PMID: Vancomycin for PSC Mass. General Hospital Decreased liver blood tests & QOL Melissa at (617) Milk Thistle, 140 mg orally three times daily Mayo Clinic Decreased liver blood tests Completed-positive PMID: High Dose Vitamin D3 for PSC Mount Sinai Medical Center Decreased liver blood tests & QOL edu

19 Clinical Studies TITLE Sponsor Center Goal Cholangiocarcinoma-associated serum micrornas in primary sclerosing cholangitis: Identification and prognostic potential. PSCpartners UC Davis Early detection of cholangiocarcinoma Aberrant homing of lymphocytes to the liver in patients with primary sclerosing cholangitis; the missing link between colon and liver PSCpartners C. Y. Ponsioen, MD Amsterdam, NE Understand how PSC develops PSC Resource Of Genetic Risk, Environment and Synergy Studies (PROGRESS) PSCpartners Mayo Clinic Identify Risk Factors for PSC Histologic Predictors of PSC in those with Ulcerative Colitis Not yet active Mount Sinai Medical Center Identify Disease Markers

20 Points to Remember Primary sclerosing cholangitis (PSC) damages and scars bile ducts inside and outside the liver. The cause of PSC is not known. PSC can lead to vitamin deficiencies, infections, bile duct cancer, cirrhosis, liver failure, and the need for a liver transplant. Many people with PSC also have ulcerative or crohn s colitis, inflammatory bowel diseases. PSC treatments are primarily of benefit for symptom relief and complication prevention. Research continues to find a cure.

22 Lifestyle and Nutrition in PSC Moderator: Douglas Dieterich, M.D. Professor of Medicine Mount Sinai School of Medicine Panelists: Nancy Bach, M.D. Clinical Professor of Medicine Mount Sinai School of Medicine, Franklin Klion, M.D. Clinical Professor of Medicine Mount Sinai School of Medicine Miloh Tamir, M.D. Assistant Professor of Pediatrics Mount Sinai School of Medicine

23 Scenario One A 60 kg, jaundiced, 18 year old woman recently diagnosed with PSC by imaging with MRCP and has very high serum alkaline phosphatase levels and itching. Does she need a biopsy? What if her AST and ALT levels are also high? Would you prescribe ursodiol? If yes, how much? How do you treat the itching?

24 Scenario Two A 55 year old fitness instructor was recently diagnosed with PSC after an evaluation for mild fatigue. His alkaline phosphatase was slightly high and he had an abnormal ERCP. Otherwise he feels fine and has no other medical problems. He does not want any drugs and prefers a holistic approach to PSC. What alternative therapies or special diet would you recommend (e.g. fish oil, vitamin D, milk thistle)? What lifestyle changes would you recommend? Should he still drink champagne at special celebrations?

25 Scenario Three A thirty year old woman with PSC for 5 years taking ursodiol (20 mg/kg/day; three actigall pills in the AM and PM) and milk thistle wants to have a child and seeks your advice. Is it safe for her to become pregnant? What do you advise regarding her medications? What is the risk of PSC developing in her children?

26 Scenario Four A healthy 60 year old man diagnosed with both mild colitis and mild PSC thirty years ago has suddenly had two brief episodes of cholangitis in the past three months along with a ten pound weight loss. His last imaging of his liver and colonoscopy were five years ago. What possible causes of his cholangitis come to mind? How frequently should he have imaging of his liver and a colonoscopy? Along with cirrhosis, a single, benign narrowing (stricture) is seen in his left bile duct. What would you recommend? If despite being stented, he is hospitalized twice more in six months with cholangitis, would you recommend transplantation? He wants to know how he can get a transplant quickly and whether the disease would come back after transplantation.

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) ;