PSC: a care-giver s perspective
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1 PSC: a care-giver s perspective PSC Partners Seeking a Cure; Denver, CO; April 30, 2005 David and Judy Rhodes (father and mother of Steven (19); PSC 07/03; UC 08/03)
2 Advice from a care-giver: 1. Read about the disease and its many complications 2. Be aware of symptoms at different stages 3. Be aware of side-effects of medications 4. Know how the medications work 5. Encourage good nutrition, and healthy life-style 6. Keep detailed medical records 7. Join a PSC support group
3 A compilation of www resources & scientific literature on PSC and allied diseases Access to >24,500 abstracts on PSC, IBD & autoimmune diseases Scientific literature organized by keyword, authors, and dates Collected ~ 8,000 full papers since July 2003 Web site requests = 10,000 per month (1,900 distinct hosts served per month) as of April 2005 Updated weekly (approx. 300 new abstracts per week)
4 Medications/Supplements that Steven is Taking: Ursodiol (ursodeoxycholic acid; UDCA; URSO) Rifampin (rifampicin) Fish Oil Vitamins (Centrum Silver) Folic acid Spinach Asacol (a 5-aminosalicylic acid)
5 Ursodeoxycholic acid (ursodiol; URSO; UDCA) A bile acid originally identified in bear bile (bear family = Ursidae) First used in Western medicine to treat/dissolve gallstones Improves bile flow; preserves activity of bile salt export pump Competes with deoxycholic acid (DCA), a toxic bile acid Prevents cell death caused by DCA accumulation Tends to lower ALT and AST (and ALP to some extent) Anti-inflammatory effects (due to interaction with the glucocorticoid receptor (GR)) Evidence growing that it protects against colon cancer & cholangiocarcinoma In PBC, significantly delays time to liver transplant In PSC, studies still in progress with high-dose ursodiol
6 Transport Polarity of Normal Hepatocytes and Bile-Duct Epithelial Cells (Cholangiocytes) BSEP activity decreased by DCA BSEP Ursodiol preserves BSEP activity Bile Salt Export Pump Trauner, M. et al. N Engl J Med 1998;339:
7 Many of the pumps involved in bile transport in the liver are regulated by molecular switches BSEP Ursodiol preserves bile salt export pump (BSEP) activity BSEP MDR1 MDR3 PXR PPARa Rifampin Fish Oil
8 Multidrug Resistance 1 MDR1 decreased in UC due to decrease of PXR activity PXR activated by rifampin MDR1 gene mutations linked to some cases of UC (also activates enzymes of bile metabolism)
9 Chrencik JE, Orans J, Moore LB, Xue Y, Peng L, Collins JL, Wisely GB, Lambert MH, Kliewer SA, Redinbo MR (2005) Structural disorder in the complex of human PXR and the macrolide antibiotic rifampicin. Mol. Endocrinol. Feb 10 [Epub ahead of print] Rifampin (rifampicin) interacts with, and activates the PXR (pregnane X receptor). PXR is a switch that regulates a number of bile transporters and enzymes of bile metabolism. Here rifampin is shown binding to PXR.
10 Kliewer SA, Willson TM (2002) Regulation of xenobiotic and bile acid metabolism by the nuclear pregnane X receptor. J. Lipid Res. 43: The pregnane X receptor (PXR) activates bile transporters, increases bile acid hydroxylation (promoting urinary excretion) and inhibits one pathway of cholesterol metabolism to bile acids
11 PXR Rifampin Rifampin interacts with, and activates the PXR (pregnane X receptor), inhibiting the Neutral pathway of bile acid synthesis
12 Multidrug Resistance 3 MDR3 Mice deficient in MDR3 develop SC MDR3 regulated by PPARa; activated by fibrates Fibrates lower ALP and GGT in PBC and PSC Other activators of PPARa include DHA; a component of fish oil
13 Essential Fats: Metabolism and Dietary Sources Safflower oil Corn oil Soy bean oil Omega-6 O C- OH 18:2n6 linoleic acid, LA competition for 6 and 5 desaturase and elongation enzymes Omega-3 O C- OH 18:3n3 linolenic acid, LNA Canola oil Walnuts Flax seed Leaf plants Meat, Organs 20:4n-6, arachidonic acid AA pro-inflammatory O C- OH Series 2 Prostaglandins Thromboxanes Series 4 Leukotrienes Series 3 Prostaglandins Thromboxanes Series 5 Leukotrienes platelet activity immune responses smooth muscle many other functions O C- OH 20:5n-3, eicosapentaenoic acid, EPA Fish Seafood Seaweed 22:6n-3, docosahexaenoic acid, DHA (brain, retina, testis) anti-inflammatory O C- OH
14
15 Take Home Message: Fish Oils are Anti-Inflammatory
16 5-Methylthioadenosine (anti-inflammatory) Various acceptors Methylated-acceptors S-Adenosylmethionine (SAMe) S-Adenosylhomocysteine (pro-inflammatory) Alterations in severe ulcerative colitis Glutathione (anti-oxidant) Methionine Dimethylglycine Tetrahydrofolate Homocysteine Betaine (spinach) Methyl-tetrahydrofolate Steven takes folic acid and eats spinach Folic acid Serine Glycine
17 Components of the inflammation signaling pathway in IBD Toll-like Receptor NOD2/ CARD15 Nuclear Factorkappa B inflammation Tumor Necrosis Factor Alpha
18 Bacterial products asacol urso fish oils inflammation TNFa inhibitors e.g. infliximab, etanercept Mutations in these genes linked to IBD; mostly Crohn s Anti-inflammatory medications
19 NIDDK Action Plan for Liver Disease Research: Autoimmune Liver Disease
20
21 In Memory of Shauna Saunders Shauna Saunders, a sixth-year doctoral student in the Department of Economics, died Dec. 3, 2004 at Duke University Hospital. A burgeoning force in her field, a devoted teacher and a wit with a shoe obsession, Shauna struggled with a chronic liver disease she carried since childhood even as her body broke down and multiple liver transplants at Duke fell through. She was 29.
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