Fish oils and inhibition of cholangiocarcinoma

[Guest guest]

Cancer Res. 2008 Jan 15;68(2):553-60.

Cyclooxygenase-2-derived prostaglandin E2 activates beta-catenin in

human cholangiocarcinoma cells: evidence for inhibition of these

signaling pathways by omega 3 polyunsaturated fatty acids.

Lim K, Han C, Xu L, Isse K, Demetris AJ, Wu T

http://www.ncbi.nlm.nih.gov/pubmed/18199552

" utilization of omega 3-PUFAs may represent an effective and safe

therapeutic approach for the chemoprevention and treatment of human

cholangiocarcinoma. "

Dave

(father of (22), PSC 07/03, UC 08/03

[Guest guest]

I've never taken omega-3's before, and this looks like yet another good

reason to add them to my regimen.... Does anyone have a recommendation

for a specific formulation/dosage that seems to work well for you?

Genevieve

UC 1983, J-Pouch 1999, PSC 12/07

[Guest guest]

Hi Genevieve;

My 22 year-old son [~153 lbs] takes 3 x 1000 mg soft gel capsules of

Carlson's Super Omega-3 fish oils per day. Each capsule contains 300

mg of eicosapentaenoic acid (EPA) and 200 mg docosahexaenoic acid

(DHA):

http://www.carlsonlabs.com/pdf/products/SuperOmega-3_Oils.pdf

We chose this product because it is tested for purity, and is

guaranteed to be free of mercury, PCB and other contaminants.

A good recent article on dietary omega 3's and the science behind

them, can be found here:

The science behind dietary omega-3 fatty acids

Marc E. Surette, PhD

CMAJ • January 15, 2008; 178 (2)

http://www.cmaj.ca/cgi/content/full/178/2/177

The generally recommended amount of omega 3's seems to be ~ 500 to

1000 mg per day, not to exceed 3000 mg per day.

Since taking fish oils [together with high-dose ursodiol, rifampin

and asacol, vitamin supplements and folic acid], 's LFT's have

normalized, his colon now shows very little evidence of ulcerative

colitis, and his acne has cleared up. We're hoping that this " anti-

inflammatory cocktail " will help keep the UC and PSC at bay, and by

suppressing inflammation will decrease the risk of colon and bile-

duct cancer ... we can but hope!

Best regards,

Dave

(father of (22); PSC 07/03; UC 08/03)

[Guest guest]

Thanks so much for all the info, !

Genevieve

UC 1983, J-Pouch 1999, PSC 12/07

[Guest guest]

Hi -

Thank you for the information on fish oil and the current pub med ref. of Jan 08 from University of Pittsburg. That was very encouraging to read. I am a spouse not the one afflicted with this disease. My husband (PSC-1996), is very hesitant to do anything short of the Ursodiol (300mg x 3/dy) prescribed by his Gastro doctor.

He has had repeat ERCPs (13 or 14) with dilation for a dominant stricture in the common bile duct(6mm at the hilum) and intrahepatict duct strictures (right and left). His LFTs are elevated: AlkPhos 133, AST117, ALT167, GGT403. Despite this he has been assymptomatic, for the most part. He has never had pain or difficulty after his ERCPs, however they have never chosen to place a stent in and said they would not recommend this.

Our GI does not believe in anything like diet or alternative treatments. I have heard about the benefits of Milk Thistle. Have you considered this in your son's case? What is the Rifampin? is this for the UC? My husband does not take a Vit Supplement nor does he take folic acid.

Would appreciate any information on those supplements. Thanks, Kate Piazzi

To: From: rhodesdavid@...Date: Sat, 19 Jan 2008 01:28:07 +0000Subject: Re: Fish oils and inhibition of cholangiocarcinoma

Hi Genevieve;My 22 year-old son [~153 lbs] takes 3 x 1000 mg soft gel capsules of Carlson's Super Omega-3 fish oils per day. Each capsule contains 300 mg of eicosapentaenoic acid (EPA) and 200 mg docosahexaenoic acid (DHA):http://www.carlsonlabs.com/pdf/products/SuperOmega-3_Oils.pdfWe chose this product because it is tested for purity, and is guaranteed to be free of mercury, PCB and other contaminants.A good recent article on dietary omega 3's and the science behind them, can be found here:The science behind dietary omega-3 fatty acidsMarc E. Surette, PhD CMAJ • January 15, 2008; 178 (2)http://www.cmaj.ca/cgi/content/full/178/2/177The generally recommended amount of omega 3's seems to be ~ 500 to 1000 mg per day, not to exceed 3000 mg per day. Since taking fish oils [together with high-dose ursodiol, rifampin and asacol, vitamin supplements and folic acid], 's LFT's have normalized, his colon now shows very little evidence of ulcerative colitis, and his acne has cleared up. We're hoping that this "anti-inflammatory cocktail" will help keep the UC and PSC at bay, and by suppressing inflammation will decrease the risk of colon and bile-duct cancer ... we can but hope!Best regards,Dave (father of (22); PSC 07/03; UC 08/03)

[Guest guest]

Hi Kate;

My son does not take milk thistle, but others in the group do.

takes rifampin (rifampicin) because it is very effective in

alleviating his itching (pruritus). Although it is an antibiotic, it

has an important secondary effect of activating a receptor called the

pregnane X receptor (PXR) [also known as the steroid and xenobiotic

receptor (SXR)] in the gut and liver. The activation of PXR increases

the expression of a number of enzymes of bile transport and

metabolism, leading to more effective detoxification and excretion of

bile acids. For example, PXR is known to protect against liver injury

caused by lithocholic acid:

Staudinger JL, Goodwin B, SA, Hawkins-Brown D, MacKenzie KI,

LaTour A, Liu Y, Klaassen CD, Brown KK, Reinhard J, Willson TM,

Koller BH, Kliewer SA 2001 The nuclear receptor PXR is a lithocholic

acid sensor that protects against liver toxicity. Proc. Natl. Acad.

Sci. U.S.A. 98: 3369-3374.

http://www.ncbi.nlm.nih.gov/pubmed/11248085

It has been suggested that rifampin (by activating PXR) may serve a

complementary role to ursodiol in stimulating bile transport and

metabolism/detoxification in cholestatic liver disease:

Marschall HU, Wagner M, Zollner G, Fickert P, Diczfalusy U, Gumhold

J, Silbert D, Fuchsbichler A, Benthin L, Grundstrom R, Gustafsson U,

Sahlin S, Einarsson C, Trauner M 2005 Complementary stimulation of

hepatobiliary transport and detoxification systems by rifampicin and

ursodeoxycholic acid in humans. Gastroenterology 129: 476-485.

http://www.ncbi.nlm.nih.gov/pubmed/16083704

It's known that the PXR is down regulated in ulcerative colitis:

Langmann T, Moehle C, Mauerer R, Scharl M, Liebisch G, Zahn A,

Stremmel W, Schmitz G 2004 Loss of detoxification in inflammatory

bowel disease: dysregulation of pregnane X receptor target genes.

Gastroenterology 127: 26-40.

http://www.ncbi.nlm.nih.gov/pubmed/15236169

The PXR gene has been implicated as an inflammatory bowel disease

susceptibility gene:

Dring MM, Goulding CA, Trimble VI, Keegan D, AW, Brophy KM,

Smyth CM, Keeling PWN, O'Donoghue D, O'Sullivan M, O'Morain C, Mahmud

N, Wikstrom AC, Kelleher D, McManus R 2006 The pregnane X receptor

locus is associated with susceptibility to inflammatory bowel

disease. Gastroenterology 130: 341-348.

http://www.ncbi.nlm.nih.gov/pubmed/16472590

and certain variants of PXR gene seems to influence the rate of

progression/survival of PSC:

Karlsen TH, Lie BA, Frey Froslie K, Thorsby E, Broome U, Schrumpf E,

Boberg KM 2006 Polymorphisms in the steroid and xenobiotic receptor

gene influence survival in primary sclerosing cholangitis.

Gastroenterology 131: 781-787.

http://www.ncbi.nlm.nih.gov/pubmed/16952547

Recently it has been suggested that PXR has anti-inflammatory and

anti-fibrotic effects because it inhibits nuclear factor kappa B

(NFkB ... this is activated in inflammatory bowel disease):

Shah Y, Ma X, Morimura K, Kim I, FJ 2007 Pregnane X receptor

activation ameliorates DSS-induced IBD via inhibition of NF{kappa}B

target gene expression. Am. J. Physiol. Gastrointest. Liver Physiol.

292: G1114-G1122.

http://www.ncbi.nlm.nih.gov/pubmed/17170021

Xie W, Tian Y 2006 Xenobiotic receptor meets NF-kappaB, a collision

in the small bowel. Cell. Metab. 4: 177-178.

http://www.ncbi.nlm.nih.gov/pubmed/16950133

Zhou C, Tabb MM, EL, Grun F, Verma S, Sadatrafiei A, Lin M,

Mallick S, Forman BM, Thummel KE, Blumberg B 2006 Mutual repression

between steroid and xenobiotic receptor and NF-kappaB signaling

pathways links xenobiotic metabolism and inflammation. J. Clin.

Invest. 116: 2280-2289

http://www.ncbi.nlm.nih.gov/pubmed/16841097

Axon A, Cowie DE, Mann DA, MC 2007 A mechanism for the anti-

fibrogenic effects of the pregnane X receptor (PXR) in the liver:

Inhibition of NF-kappaB? Toxicology Dec 23 [Epub ahead of print].

http://www.ncbi.nlm.nih.gov/pubmed/18194834

It's also been suggested that PXR is necessary for liver regeneration:

Dai G, He L, Bu P, Wan YJ 2007 Pregnane X receptor is essential for

normal progression of liver regeneration. Hepatology. Dec 31 [Epub

ahead of print].

http://www.ncbi.nlm.nih.gov/pubmed/18167061

Why does take folic acid? It's thought that without adequate

folate this can lead to elevated levels of homocysteine, which can

then promote thrombosis

Chowers Y, Sela BA, Holland R, Fidder H, Simoni FB, Bar-Meir S 2000

Increased levels of homocysteine in patients with Crohn's disease are

related to folate levels. Am. J. Gastroenterol. 95: 3498-3502.

http://www.ncbi.nlm.nih.gov/pubmed/11151883

and low folate levels can be a risk factor for colon cancer:

Brockton NT 2006 Localized depletion: the key to colorectal cancer

risk mediated by MTHFR genotype and folate? Cancer Causes Control 17:

1005-1016.

http://www.ncbi.nlm.nih.gov/pubmed/16933051

takes Centrum Silver in order to try to avoid the depletions

of fat soluble vitamins that can occur during the course of PSC:

nsen RA, Lindor KD, Sartin JS, LaRusso NF, Wiesner RH 1995 Serum

lipid and fat-soluble vitamin levels in primary sclerosing

cholangitis. J. Clin. Gastroenterol. 20: 215-219.

http://www.ncbi.nlm.nih.gov/pubmed/7797830

We're particularly concered about vitamin D (deficiencies can result

in osteoporosis), and vitamin A. I could spend hours talking about

vitamin A ... but I wont bore you. I would just like to say that

vitamin A and its metabolite, retinoic acid, may have dramatic

effects on the immune system, and intestinal barrier functions:

Austenaa LM, Carlsen H, Ertesvag A, G, Blomhoff HK,

Blomhoff R 2004 Vitamin A status significantly alters nuclear factor-

kappaB activity assessed by in vivo imaging. FASEB J. 18: 1255-1257.

http://www.ncbi.nlm.nih.gov/pubmed/15180954

Mora JR, Iwata M, Eksteen B, Song SY, Junt T, Senman B, Otipoby KL,

Yokota A, Takeuchi H, Ricciardi-Castagnoli P, Rajewsky K, DH,

von Andrian UH 2006 Generation of gut-homing IgA-secreting B cells by

intestinal dendritic cells. Science 314: 1157-1160.

http://www.ncbi.nlm.nih.gov/pubmed/17110582

Mora JR, von Andrian UH 2004 Retinoic acid: an educational " vitamin

elixir " for gut-seeking T cells. Immunity 21: 458-460.

http://www.ncbi.nlm.nih.gov/pubmed/15485623

Elias KM, ce A, son TS, s G, Kanno Y, Shevach EM,

O'Shea JJ 2007 Retinoic acid inhibits Th17 polarization and enhances

FoxP3 expression through a Stat-3/Stat-5 independent signaling

pathway. Blood Oct 19 [Epub ahead of print].

http://www.ncbi.nlm.nih.gov/pubmed/17951529

Elitsur Y, Neace C, Liu X, Dosescu J, Moshier JA 1997 Vitamin A and

retinoic acids immunomodulation on human gut lymphocytes.

Immunopharmacology 35: 247-253.

http://www.ncbi.nlm.nih.gov/pubmed/9043938

Saurer L, McCullough KC, Summerfield A 2007 In vitro induction of

mucosa-type dendritic cells by all-trans retinoic acid. J Immunol.

2007 Sep 15;179(6):3504-14.

http://www.ncbi.nlm.nih.gov/pubmed/17785784

Mucida D, Park Y, Kim G, Turovskaya O, I, Kronenberg M,

Cheroutre H 2007 Reciprocal Th-17 and regulatory T cell

differentiation mediated by retinoic acid. Science 317: 256-260.

http://www.ncbi.nlm.nih.gov/pubmed/17569825

Osanai M, Nishikiori N, Murata M, Chiba H, Kojima T, Sawada N 2007

Cellular retinoic acid bioavailability determines epithelial

integrity: role of retinoic acid receptor alpha agonists in colitis.

Mol. Pharmacol. 71: 250-258.

http://www.ncbi.nlm.nih.gov/pubmed/17035595

Best regards,

Dave

(father of (22); PSC 07/03; UC 08/03)

[Guest guest]

THis will be a good question for the experts at the conference.Should people be on rifampin with the urso?Bill takes cipro everyday for the pouchitis but not rifampin.I guess I wonder if he should switch antibiotics.Thanks for posting this , Dave.LeeHi Kate;My son does not take milk thistle, but others in the group do. takes rifampin (rifampicin) because it is very effective in alleviating his itching (pruritus). Although it is an antibiotic, it has an important secondary effect of activating a receptor called the pregnane X receptor (PXR) [also known as the steroid and xenobiotic receptor (SXR)] in the gut and liver. The activation of PXR increases the expression of a number of enzymes of bile transport and metabolism, leading to more effective detoxification and excretion of bile acids. For example, PXR is known to protect against liver injury caused by lithocholic acid:

[Guest guest]

Dear Dave,

If I recall well, there was some research going on to test the effect

of either EPA or DHA in PSC? I saw that Carlson also sells fish-oils

with more EPA or more DHA. Was there any reason you chose Super Omega-

3 type with a more balanced mix of EPA and DHA?

With lots of respect for your dedication,

Gerard

> My 22 year-old son [~153 lbs] takes 3 x 1000 mg soft gel capsules

of

> Carlson's Super Omega-3 fish oils per day. Each capsule contains

300

> mg of eicosapentaenoic acid (EPA) and 200 mg docosahexaenoic acid

> (DHA):

>

> http://www.carlsonlabs.com/pdf/products/SuperOmega-3_Oils.pdf

[Guest guest]

Thank you so much for that detailed response. I will review the articles you cited myself. I am putting together some of the new information to meet and discuss with my husband's GI doctor. I can't tell you how much I appreciate your feedback. It is very helpful to me to direct my efforts at researching questions.

Yours very truly,

Kate Piazzi, wife of Chris(PSC,97)

To: From: rhodesdavid@...Date: Sun, 20 Jan 2008 01:11:33 +0000Subject: Re: Fish oils and inhibition of cholangiocarcinoma

Hi Kate;My son does not take milk thistle, but others in the group do. takes rifampin (rifampicin) because it is very effective in alleviating his itching (pruritus). Although it is an antibiotic, it has an important secondary effect of activating a receptor called the pregnane X receptor (PXR) [also known as the steroid and xenobiotic receptor (SXR)] in the gut and liver. The activation of PXR increases the expression of a number of enzymes of bile transport and metabolism, leading to more effective detoxification and excretion of bile acids. For example, PXR is known to protect against liver injury caused by lithocholic acid:Staudinger JL, Goodwin B, SA, Hawkins-Brown D, MacKenzie KI, LaTour A, Liu Y, Klaassen CD, Brown KK, Reinhard J, Willson TM, Koller BH, Kliewer SA 2001 The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc. Natl. Acad. Sci. U.S.A. 98: 3369-3374. http://www.ncbi.nlm.nih.gov/pubmed/11248085It has been suggested that rifampin (by activating PXR) may serve a complementary role to ursodiol in stimulating bile transport and metabolism/detoxification in cholestatic liver disease:Marschall HU, Wagner M, Zollner G, Fickert P, Diczfalusy U, Gumhold J, Silbert D, Fuchsbichler A, Benthin L, Grundstrom R, Gustafsson U, Sahlin S, Einarsson C, Trauner M 2005 Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Gastroenterology 129: 476-485. http://www.ncbi.nlm.nih.gov/pubmed/16083704It's known that the PXR is down regulated in ulcerative colitis:Langmann T, Moehle C, Mauerer R, Scharl M, Liebisch G, Zahn A, Stremmel W, Schmitz G 2004 Loss of detoxification in inflammatory bowel disease: dysregulation of pregnane X receptor target genes. Gastroenterology 127: 26-40.http://www.ncbi.nlm.nih.gov/pubmed/15236169The PXR gene has been implicated as an inflammatory bowel disease susceptibility gene:Dring MM, Goulding CA, Trimble VI, Keegan D, AW, Brophy KM, Smyth CM, Keeling PWN, O'Donoghue D, O'Sullivan M, O'Morain C, Mahmud N, Wikstrom AC, Kelleher D, McManus R 2006 The pregnane X receptor locus is associated with susceptibility to inflammatory bowel disease. Gastroenterology 130: 341-348. http://www.ncbi.nlm.nih.gov/pubmed/16472590and certain variants of PXR gene seems to influence the rate of progression/survival of PSC:Karlsen TH, Lie BA, Frey Froslie K, Thorsby E, Broome U, Schrumpf E, Boberg KM 2006 Polymorphisms in the steroid and xenobiotic receptor gene influence survival in primary sclerosing cholangitis. Gastroenterology 131: 781-787. http://www.ncbi.nlm.nih.gov/pubmed/16952547Recently it has been suggested that PXR has anti-inflammatory and anti-fibrotic effects because it inhibits nuclear factor kappa B (NFkB ... this is activated in inflammatory bowel disease):Shah Y, Ma X, Morimura K, Kim I, FJ 2007 Pregnane X receptor activation ameliorates DSS-induced IBD via inhibition of NF{kappa}B target gene expression. Am. J. Physiol. Gastrointest. Liver Physiol. 292: G1114-G1122. http://www.ncbi.nlm.nih.gov/pubmed/17170021Xie W, Tian Y 2006 Xenobiotic receptor meets NF-kappaB, a collision in the small bowel. Cell. Metab. 4: 177-178.http://www.ncbi.nlm.nih.gov/pubmed/16950133Zhou C, Tabb MM, EL, Grun F, Verma S, Sadatrafiei A, Lin M, Mallick S, Forman BM, Thummel KE, Blumberg B 2006 Mutual repression between steroid and xenobiotic receptor and NF-kappaB signaling pathways links xenobiotic metabolism and inflammation. J. Clin. Invest. 116: 2280-2289http://www.ncbi.nlm.nih.gov/pubmed/16841097Axon A, Cowie DE, Mann DA, MC 2007 A mechanism for the anti-fibrogenic effects of the pregnane X receptor (PXR) in the liver: Inhibition of NF-kappaB? Toxicology Dec 23 [Epub ahead of print].http://www.ncbi.nlm.nih.gov/pubmed/18194834It's also been suggested that PXR is necessary for liver regeneration:Dai G, He L, Bu P, Wan YJ 2007 Pregnane X receptor is essential for normal progression of liver regeneration. Hepatology. Dec 31 [Epub ahead of print]. http://www.ncbi.nlm.nih.gov/pubmed/18167061Why does take folic acid? It's thought that without adequate folate this can lead to elevated levels of homocysteine, which can then promote thrombosisChowers Y, Sela BA, Holland R, Fidder H, Simoni FB, Bar-Meir S 2000 Increased levels of homocysteine in patients with Crohn's disease are related to folate levels. Am. J. Gastroenterol. 95: 3498-3502. http://www.ncbi.nlm.nih.gov/pubmed/11151883and low folate levels can be a risk factor for colon cancer:Brockton NT 2006 Localized depletion: the key to colorectal cancer risk mediated by MTHFR genotype and folate? Cancer Causes Control 17: 1005-1016. http://www.ncbi.nlm.nih.gov/pubmed/16933051 takes Centrum Silver in order to try to avoid the depletions of fat soluble vitamins that can occur during the course of PSC:nsen RA, Lindor KD, Sartin JS, LaRusso NF, Wiesner RH 1995 Serum lipid and fat-soluble vitamin levels in primary sclerosing cholangitis. J. Clin. Gastroenterol. 20: 215-219. http://www.ncbi.nlm.nih.gov/pubmed/7797830We're particularly concered about vitamin D (deficiencies can result in osteoporosis), and vitamin A. I could spend hours talking about vitamin A ... but I wont bore you. I would just like to say that vitamin A and its metabolite, retinoic acid, may have dramatic effects on the immune system, and intestinal barrier functions:Austenaa LM, Carlsen H, Ertesvag A, G, Blomhoff HK, Blomhoff R 2004 Vitamin A status significantly alters nuclear factor-kappaB activity assessed by in vivo imaging. FASEB J. 18: 1255-1257. http://www.ncbi.nlm.nih.gov/pubmed/15180954Mora JR, Iwata M, Eksteen B, Song SY, Junt T, Senman B, Otipoby KL, Yokota A, Takeuchi H, Ricciardi-Castagnoli P, Rajewsky K, DH, von Andrian UH 2006 Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314: 1157-1160.http://www.ncbi.nlm.nih.gov/pubmed/17110582Mora JR, von Andrian UH 2004 Retinoic acid: an educational "vitamin elixir" for gut-seeking T cells. Immunity 21: 458-460.http://www.ncbi.nlm.nih.gov/pubmed/15485623Elias KM, ce A, son TS, s G, Kanno Y, Shevach EM, O'Shea JJ 2007 Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood Oct 19 [Epub ahead of print].http://www.ncbi.nlm.nih.gov/pubmed/17951529Elitsur Y, Neace C, Liu X, Dosescu J, Moshier JA 1997 Vitamin A and retinoic acids immunomodulation on human gut lymphocytes. Immunopharmacology 35: 247-253. http://www.ncbi.nlm.nih.gov/pubmed/9043938Saurer L, McCullough KC, Summerfield A 2007 In vitro induction of mucosa-type dendritic cells by all-trans retinoic acid. J Immunol. 2007 Sep 15;179(6):3504-14. http://www.ncbi.nlm.nih.gov/pubmed/17785784 Mucida D, Park Y, Kim G, Turovskaya O, I, Kronenberg M, Cheroutre H 2007 Reciprocal Th-17 and regulatory T cell differentiation mediated by retinoic acid. Science 317: 256-260.http://www.ncbi.nlm.nih.gov/pubmed/17569825Osanai M, Nishikiori N, Murata M, Chiba H, Kojima T, Sawada N 2007 Cellular retinoic acid bioavailability determines epithelial integrity: role of retinoic acid receptor alpha agonists in colitis.Mol. Pharmacol. 71: 250-258.http://www.ncbi.nlm.nih.gov/pubmed/17035595Best regards,Dave (father of (22); PSC 07/03; UC 08/03)

[Guest guest]

Hi ,Is 's hepatologist on board with the supplements he takes? If so, how did that happen? Did you take all these articles to the doctor so he/she could review them? My hepatologist is very opposed to supplements because they are so unregulated and tested, and he's worried about liver toxicity. I think he sees a few cases each year of liver failure due to use of supplements.Marie

To: From: rhodesdavid@...Date: Sun, 20 Jan 2008 01:11:33 +0000Subject: Re: Fish oils and inhibition of cholangiocarcinoma

Hi Kate;

My son does not take milk thistle, but others in the group do.

takes rifampin (rifampicin) because it is very effective in

alleviating his itching (pruritus). Although it is an antibiotic, it

has an important secondary effect of activating a receptor called the

pregnane X receptor (PXR) [also known as the steroid and xenobiotic

receptor (SXR)] in the gut and liver. The activation of PXR increases

the expression of a number of enzymes of bile transport and

metabolism, leading to more effective detoxification and excretion of

bile acids. For example, PXR is known to protect against liver injury

caused by lithocholic acid:

Staudinger JL, Goodwin B, SA, Hawkins-Brown D, MacKenzie KI,

LaTour A, Liu Y, Klaassen CD, Brown KK, Reinhard J, Willson TM,

Koller BH, Kliewer SA 2001 The nuclear receptor PXR is a lithocholic

acid sensor that protects against liver toxicity. Proc. Natl. Acad.

Sci. U.S.A. 98: 3369-3374.

http://www.ncbi.nlm.nih.gov/pubmed/11248085

It has been suggested that rifampin (by activating PXR) may serve a

complementary role to ursodiol in stimulating bile transport and

metabolism/detoxification in cholestatic liver disease:

Marschall HU, Wagner M, Zollner G, Fickert P, Diczfalusy U, Gumhold

J, Silbert D, Fuchsbichler A, Benthin L, Grundstrom R, Gustafsson U,

Sahlin S, Einarsson C, Trauner M 2005 Complementary stimulation of

hepatobiliary transport and detoxification systems by rifampicin and

ursodeoxycholic acid in humans. Gastroenterology 129: 476-485.

http://www.ncbi.nlm.nih.gov/pubmed/16083704

It's known that the PXR is down regulated in ulcerative colitis:

Langmann T, Moehle C, Mauerer R, Scharl M, Liebisch G, Zahn A,

Stremmel W, Schmitz G 2004 Loss of detoxification in inflammatory

bowel disease: dysregulation of pregnane X receptor target genes.

Gastroenterology 127: 26-40.

http://www.ncbi.nlm.nih.gov/pubmed/15236169

The PXR gene has been implicated as an inflammatory bowel disease

susceptibility gene:

Dring MM, Goulding CA, Trimble VI, Keegan D, AW, Brophy KM,

Smyth CM, Keeling PWN, O'Donoghue D, O'Sullivan M, O'Morain C, Mahmud

N, Wikstrom AC, Kelleher D, McManus R 2006 The pregnane X receptor

locus is associated with susceptibility to inflammatory bowel

disease. Gastroenterology 130: 341-348.

http://www.ncbi.nlm.nih.gov/pubmed/16472590

and certain variants of PXR gene seems to influence the rate of

progression/survival of PSC:

Karlsen TH, Lie BA, Frey Froslie K, Thorsby E, Broome U, Schrumpf E,

Boberg KM 2006 Polymorphisms in the steroid and xenobiotic receptor

gene influence survival in primary sclerosing cholangitis.

Gastroenterology 131: 781-787.

http://www.ncbi.nlm.nih.gov/pubmed/16952547

Recently it has been suggested that PXR has anti-inflammatory and

anti-fibrotic effects because it inhibits nuclear factor kappa B

(NFkB ... this is activated in inflammatory bowel disease):

Shah Y, Ma X, Morimura K, Kim I, FJ 2007 Pregnane X receptor

activation ameliorates DSS-induced IBD via inhibition of NF{kappa}B

target gene expression. Am. J. Physiol. Gastrointest. Liver Physiol.

292: G1114-G1122.

http://www.ncbi.nlm.nih.gov/pubmed/17170021

Xie W, Tian Y 2006 Xenobiotic receptor meets NF-kappaB, a collision

in the small bowel. Cell. Metab. 4: 177-178.

http://www.ncbi.nlm.nih.gov/pubmed/16950133

Zhou C, Tabb MM, EL, Grun F, Verma S, Sadatrafiei A, Lin M,

Mallick S, Forman BM, Thummel KE, Blumberg B 2006 Mutual repression

between steroid and xenobiotic receptor and NF-kappaB signaling

pathways links xenobiotic metabolism and inflammation. J. Clin.

Invest. 116: 2280-2289

http://www.ncbi.nlm.nih.gov/pubmed/16841097

Axon A, Cowie DE, Mann DA, MC 2007 A mechanism for the anti-

fibrogenic effects of the pregnane X receptor (PXR) in the liver:

Inhibition of NF-kappaB? Toxicology Dec 23 [Epub ahead of print].

http://www.ncbi.nlm.nih.gov/pubmed/18194834

It's also been suggested that PXR is necessary for liver regeneration:

Dai G, He L, Bu P, Wan YJ 2007 Pregnane X receptor is essential for

normal progression of liver regeneration. Hepatology. Dec 31 [Epub

ahead of print].

http://www.ncbi.nlm.nih.gov/pubmed/18167061

Why does take folic acid? It's thought that without adequate

folate this can lead to elevated levels of homocysteine, which can

then promote thrombosis

Chowers Y, Sela BA, Holland R, Fidder H, Simoni FB, Bar-Meir S 2000

Increased levels of homocysteine in patients with Crohn's disease are

related to folate levels. Am. J. Gastroenterol. 95: 3498-3502.

http://www.ncbi.nlm.nih.gov/pubmed/11151883

and low folate levels can be a risk factor for colon cancer:

Brockton NT 2006 Localized depletion: the key to colorectal cancer

risk mediated by MTHFR genotype and folate? Cancer Causes Control 17:

1005-1016.

http://www.ncbi.nlm.nih.gov/pubmed/16933051

takes Centrum Silver in order to try to avoid the depletions

of fat soluble vitamins that can occur during the course of PSC:

nsen RA, Lindor KD, Sartin JS, LaRusso NF, Wiesner RH 1995 Serum

lipid and fat-soluble vitamin levels in primary sclerosing

cholangitis. J. Clin. Gastroenterol. 20: 215-219.

http://www.ncbi.nlm.nih.gov/pubmed/7797830

We're particularly concered about vitamin D (deficiencies can result

in osteoporosis), and vitamin A. I could spend hours talking about

vitamin A ... but I wont bore you. I would just like to say that

vitamin A and its metabolite, retinoic acid, may have dramatic

effects on the immune system, and intestinal barrier functions:

Austenaa LM, Carlsen H, Ertesvag A, G, Blomhoff HK,

Blomhoff R 2004 Vitamin A status significantly alters nuclear factor-

kappaB activity assessed by in vivo imaging. FASEB J. 18: 1255-1257.

http://www.ncbi.nlm.nih.gov/pubmed/15180954

Mora JR, Iwata M, Eksteen B, Song SY, Junt T, Senman B, Otipoby KL,

Yokota A, Takeuchi H, Ricciardi-Castagnoli P, Rajewsky K, DH,

von Andrian UH 2006 Generation of gut-homing IgA-secreting B cells by

intestinal dendritic cells. Science 314: 1157-1160.

http://www.ncbi.nlm.nih.gov/pubmed/17110582

Mora JR, von Andrian UH 2004 Retinoic acid: an educational "vitamin

elixir" for gut-seeking T cells. Immunity 21: 458-460.

http://www.ncbi.nlm.nih.gov/pubmed/15485623

Elias KM, ce A, son TS, s G, Kanno Y, Shevach EM,

O'Shea JJ 2007 Retinoic acid inhibits Th17 polarization and enhances

FoxP3 expression through a Stat-3/Stat-5 independent signaling

pathway. Blood Oct 19 [Epub ahead of print].

http://www.ncbi.nlm.nih.gov/pubmed/17951529

Elitsur Y, Neace C, Liu X, Dosescu J, Moshier JA 1997 Vitamin A and

retinoic acids immunomodulation on human gut lymphocytes.

Immunopharmacology 35: 247-253.

http://www.ncbi.nlm.nih.gov/pubmed/9043938

Saurer L, McCullough KC, Summerfield A 2007 In vitro induction of

mucosa-type dendritic cells by all-trans retinoic acid. J Immunol.

2007 Sep 15;179(6):3504-14.

http://www.ncbi.nlm.nih.gov/pubmed/17785784

Mucida D, Park Y, Kim G, Turovskaya O, I, Kronenberg M,

Cheroutre H 2007 Reciprocal Th-17 and regulatory T cell

differentiation mediated by retinoic acid. Science 317: 256-260.

http://www.ncbi.nlm.nih.gov/pubmed/17569825

Osanai M, Nishikiori N, Murata M, Chiba H, Kojima T, Sawada N 2007

Cellular retinoic acid bioavailability determines epithelial

integrity: role of retinoic acid receptor alpha agonists in colitis.

Mol. Pharmacol. 71: 250-258.

http://www.ncbi.nlm.nih.gov/pubmed/17035595

Best regards,

Dave

(father of (22); PSC 07/03; UC 08/03)

Helping your favorite cause is as easy as instant messaging. You IM, we give. Learn more.

[Guest guest]

Hi Marie;

's hepatologist has no problem with him being on this " cocktail " .

's hepatologist prescribed high-dose ursodiol, asacol, Centrum

Silver, extra folic acid, and rifampin. The only treatment that his

hepatolgist did not prescribe was fish oils, but his hepatologist is

entirely comfortable with him taking this because of the health

benefits of fish oils, and their excellent safety profile. We did not

have to show any papers to 's hepatologist to have the high-dose

ursodiol, rifampin, asacol, Centrum Silver and extra folic acid

prescribed ... these were all suggested by his hepatologist.

Best regards,

Dave

(father of (22); PSC 07/03; UC 08/03)

[Guest guest]

Hi ,

Gosh, I wish you could send a couple of hepatologists like that to

Finland...

On a serious note, 's coctail sounds very interesting. I think I

know what the other medications/supplements are but what is Centrum

Silver? Sorry if I just missed the info in earlier posts.

Taru-Mari

mother of Eemeli (10) PSC 07/2003

" " wrote:

> 's hepatologist has no problem with him being on

this " cocktail " .

> Dave

> (father of (22); PSC 07/03; UC 08/03)

[Guest guest]

Dear Gerard;

There is currently a trial, in progress, on the effects of

docosahexaenoic acid (DHA) in PSC:

http://www.clinicaltrials.gov/ct2/show/NCT00325013

I havn't seen any results from this trial yet, but I'll keep you

posted if I hear anything official (i.e. written by the investigator,

Dr. Freedman at Harvard).

The rationale for this trial is as follows:

When mice defective in the cystic fibrosis transmembrane conductance

regulator (CFTR), a gene encoding a chloride transport protein

expressed in the gut and liver (cholangiocytes), are given colitis,

they develop a sclerosing cholangitis resembling human PSC:

Blanco PG, Zaman MM, Junaidi O, Sheth S, Yantiss RK, Nasser IA,

Freedman SD 2004 Induction of colitis in cftr-/- mice results in bile

duct injury. Am. J. Physiol. Gastrointest. Liver Physiol. 287: G491-

G496.

http://www.ncbi.nlm.nih.gov/pubmed/15064232

These mice are protected from bile duct injury when given oral DHA.

If you look closely at the data shown in this paper (specifically,

Fig. 6 of Blanco et al (2004)), you'll see that there is a similar

protective effect when the mice are given eicosapentaenoic acid

(EPA), but the standard deviation (error) is a bit larger in this

treatment, and the results are not considered statistically

significant!

Freedman's group has since shown that " dietary DHA resulted in highly

significant amelioration of the severity of liver disease in the Cftr

(-/-) mice, primarily a reduction in the degree of peri-portal

inflammation " :

Beharry SA, Ackerely C, Corey M, Kent G, Heng YM, Christensen H, Luk

C, Yantiss RK, Nasser IA, Zaman M, Freedman SD, Durie PR 2007 Long-

term docosahexaenoic acid therapy in a congenic murine model of

cystic fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 292:

G839-G848.

http://www.ncbi.nlm.nih.gov/pubmed/17095751

The CFTR-deficient mice have an impaired regulation of the receptor

peroxisome proliferator-activated receptor-alpha (PPARa); a defect

that is reversed by DHA:

Pall H, Zaman MM, Andersson C, Freedman SD 2006 Decreased peroxisome

proliferator activated receptor alpha is associated with bile duct

injury in cystic fibrosis transmembrane conductance regulator-/-

mice. J. Pediatr. Gastroenterol. Nutr. 42: 275-281.

http://www.ncbi.nlm.nih.gov/pubmed/16540796

Freedman's group has speculated that PSC may be associated with

ulcerative colitis (UC) in a heterozygous CFTR background, meaning

that just one copy of the mutant CFTR gene is sufficient to render UC

patients susceptible to PSC:

Sheth S, Shea JC, Bishop MD, Chopra S, Regan MM, Malmberg E,

C, Ricci R, Tsui LC, Durie PR, Zielenski J, Freedman SD 2003

Increased prevalence of CFTR mutations and variants and decreased

chloride secretion in primary sclerosing cholangitis. Hum. Genet.

113: 286-292.

http://www.ncbi.nlm.nih.gov/pubmed/12783301

Moreover, CFTR channel function seems to be impaired in children with

PSC:

Pall H, Zielenski J, Jonas MM, Dasilva DA, Potvin KM, Yuan, XW, Huang

Q, Freedman SD 2007 Primary sclerosing cholangitis in childhood is

associated with abnormalities in cystic fibrosis-mediated chloride

channel function. J. Pediatr. 151: 255-259.

http://www.ncbi.nlm.nih.gov/pubmed/17719933

So it seems reasonable to test whether DHA may be of benefit in PSC

patients. Trials are also underway in cystic fibrosis:

Van Biervliet S, Van Biervliet JP, Robberecht E, Christophe A 2005

Docosahexaenoic acid trials in cystic fibrosis: a review of the

rationale behind the clinical trials. J. Cyst. Fibros. 4: 27-34.

http://www.ncbi.nlm.nih.gov/pubmed/15752678

I've heard (through the grapevine) that Dr. Freedman believes that

there may be some competition between DHA and EPA, and that is why he

is testing DHA alone, rather than fish oils (i.e. an EPA + DHA

combination).

We began giving fish oils (EPA + DHA) for several reasons.

First, we were intrigued by reports of beneficial effects of fibrates

on PBC and PSC patients, see page 2 of our newsletter:

http://www.pscpartners.org/NewsVol-1-2.pdf

Fibrates are activators of PPARa (mentioned above) and this receptor

in turn increases the activity of the biliary phospholipid pump

(MDR3). Mice deficient in this pump develop sclerosing cholangitis

resembling human PSC:

Fickert P, Fuchsbichler A, Wagner M, Zollner G, Kaser A, Tilg H,

Krause R, Lammert F, Langner C, Zatloukal K, Marschall HU, Denk H,

Trauner M 2004 Regurgitation of bile acids from leaky bile ducts

causes sclerosing cholangitis in Mdr2 (abcb4) knockout mice.

Gastroenterology 127: 261-274.

http://www.ncbi.nlm.nih.gov/pubmed/15236191

We therefore looked for " natural " activators of PPARa, and came

across fish oils (including EPA) as good candidates:

Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown PJ,

Sternbach DD, Lehmann JM, Wisely GB, Willson TM, Kliewer SA, Milburn

MV 1999 Molecular recognition of fatty acids by peroxisome

proliferator-activated receptors. Mol Cell. 3: 397-403.

http://www.ncbi.nlm.nih.gov/pubmed/10198642

Sampath H, Ntambi JM 2005 Polyunsaturated fatty acid regulation of

genes of lipid metabolism. Annu. Rev. Nutr. 25: 317-340.

http://www.ncbi.nlm.nih.gov/pubmed/16011470

We read that fish oils have potent anti-inflammatory effects, in part

by activating PPAR's, and in part by competing out arachidonic acid

in membranes, and preventing the production of many pre-inflammatory

lipids derived from arachidonic acid:

Simopoulos AP 2002 Omega-3 fatty acids in inflammation and autoimmune

diseases. J. Am. Coll. Nutr. 21: 495-505.

http://www.ncbi.nlm.nih.gov/pubmed/12480795

Some of the anti-inflammatory effects of fish oils may be due to

their oxidation products that activate PPARa, and which then inhibit

nuclear factor kappaB :

Mishra A, Chaudhary A, Sethi S 2004 Oxidized omega-3 fatty acids

inhibit NF-kappaB activation via a PPARalpha-dependent pathway.

Arterioscler. Thromb. Vasc. Biol. 24: 1621-1627.

http://www.ncbi.nlm.nih.gov/pubmed/15231516

Both EPA and DHA give rise to potent anti-inflammatory molecules that

are involved in resolving inflammation, and protecting from

inflammation (resolvins and protectins):

Serhan CN, Chiang N 2007 Endogenous pro-resolving and anti-

inflammatory lipid mediators: a new pharmacologic genus. Br. J.

Pharmacol. Oct 29 [Epub ahead of print].

http://www.ncbi.nlm.nih.gov/pubmed/17965751

Transgenic mice that naturally produce both EPA and DHA are resistant

to colitis:

Hudert CA, Weylandt KH, Lu Y, Wang J, Hong S, Dignass A, Serhan CN,

Kang JX 2006 Transgenic mice rich in endogenous omega-3 fatty acids

are protected from colitis. Proc. Natl. Acad. Sci. U.S.A. 103: 11276-

11281.

http://www.ncbi.nlm.nih.gov/pubmed/16847262

And there is evidence that DHA and/or EPA may protect against colon

cancer:

Nowak J, Weylandt KH, Habbel P, Wang J, Dignass A, Glickman JN, Kang

JX 2007 Colitis-associated colon tumorigenesis is suppressed in

transgenic mice rich in endogenous n-3 fatty acids. Carcinogenesis

28: 1991-1995.

http://www.ncbi.nlm.nih.gov/pubmed/17634405

son LA, Nguyen DV, Hokanson RM, Callaway ES, Isett RB,

ND, Dougherty ER, Wang N, Lupton JR, Carroll RJ, Chapkin RS 2004

Chemopreventive n-3 polyunsaturated fatty acids reprogram genetic

signatures during colon cancer initiation and progression in the rat.

Cancer Res. 64: 6797-6804.

http://www.ncbi.nlm.nih.gov/pubmed/15374999

Fan YY, Spencer TE, Wang N, Moyer MP, Chapkin RS 2003 Chemopreventive

n-3 fatty acids activate RXRalpha in colonocytes. Carcinogenesis 24:

1541-1548.

http://www.ncbi.nlm.nih.gov/pubmed/12844485

This last article indicated a new possible mode of action of omega-3

fatty acids, namely activation of the retinoid X receptor (RXRa).

Pall et al (2006) acknowledge in their discussion, that the effects

of DHA on bile-duct injury in CFTR mice might well be due to

activation of RXRa, in addition to PPARa. RXRa is a key partner for

many of the nuclear recptors in the liver, including the pregnane X

receptor (PXR) that I mentioned yesterday!

Other reasons for taking fish oils include, protection of epithelial

barrier function in the gut:

Li Q, Zhang Q, Wang M, Zhao S, Xu G, Li J 2008 n-3 Polyunsaturated

fatty acids prevent disruption of epithelial barrier function induced

by proinflammatory cytokines. Mol. Immunol. 45: 1356-1365.

http://www.ncbi.nlm.nih.gov/pubmed/17936906

Li Q, Zhang Q, Zhang M, Wang C, Zhu Z, Li N, Li J 2008 Effect of n-3

polyunsaturated fatty acids on membrane microdomain localization of

tight junction proteins in experimental colitis. FEBS J. 275:411-201.

http://www.ncbi.nlm.nih.gov/pubmed/18167140

and prevention of cholangiocarcinoma:

Lim K, Han C, Xu L, Isse K, Demetris AJ, Wu T 2008 Cyclooxygenase-2-

derived prostaglandin E2 activates beta-catenin in human

cholangiocarcinoma cells: evidence for inhibition of these signaling

pathways by omega 3 polyunsaturated fatty acids. Cancer Res. 68: 553-

560.

Because both EPA and DHA have these multitude of anti-inflammatory

and potentially protective effects, we put on fish oils in

order to get the benefits of both the EPA and DHA.

has suffered from dyslexia is a child, and this paper suggests

that it may even help in this condition:

Lindmark L, Clough P 2007 A 5-month open study with long-chain

polyunsaturated fatty acids in dyslexia. J. Med. Food. 10: 662-666.

http://www.ncbi.nlm.nih.gov/pubmed/18158838

Best regards,

Dave

(father of (22); PSC 07/03; UC 08/03)

[Guest guest]

Dear Taru-Mari;

Centrum Silver is a multi-vitamin

http://www.centrum.com/product_detail.aspx?productid=CENTRUMSLVR & panel=tablets

This multi-vitamin was chosen primarily because of it's high vitamin D content and low iron (Fe) [at least no iron is listed in the ingredients!]. When first diagnosed he was found to have high iron, and it was speculated that he might have hemochromatosis (iron overload). We still don't like the fact that it has copper (since PSCers often tend to accumulate copper in the liver):

Aaseth J, sen Y, Aadland E, Fausa O, Schrumpf E 1995 Hepatic retention of copper and selenium in primary sclerosing cholangitis. Scand. J. Gastroenterol. 30: 1200-1203.

Best regards,

Dave R.

>what is Centrum Silver?

[Guest guest]

Dear ,

Thank you very much for the quick response. I have been wanting to

find a multivitamin for our son but all the ones here seem to have

vitamin D in them, and that is already being prescribed to him in the

calcium+vitamin D supplement which, by the way, is the only

supplement our doctors prescribe to him. Eemeli's vitamin D levels

were just checked and they are ok with the current supplement. The

doctors do not want to prescribe any multivitamin but just say Eemeli

will be fine if he maintains a healthy diet.

Eemeli has finally been on high-dose urso for a month now in addition

to the azathioprine, and this combination seems to control the

earlier fluctuating liver enzyme values rather well. When I get the

chance next time, I am going to ask about the multivitamins again. We

do already give Eemeli fish oil, and the product seems to be close to

the product you have chosen for . Although the fish oil has not

been prescribed by the doctors, they are ok with Eemeli taking it.

All the best to and thank you very much for all the research

you do and share with the group.

Taru-Mari

mother of Eemeli (10), PSC 07/2003

[Guest guest]

Freedman has a patent on "Methods for modulating PPAR biological activity for the treatment of diseases caused by mutations in the CFTR gene" (31-Oct-2005)

http://www.patentdebate.com/PATAPP/20060160867

PSC is included in the list of disease caused by defects in the CFTR gene. DHA and fibrates are listed as compounds covered by the patent that induce PPARa, or act as PPARa agonists (activators).

To see an overview of Freedman's thoughts on PSC, CFTR, pancreatitis, pain, and DHA, I can recommend this presentation:

Pancreatitis and Primary Sclerosing Cholangitis: Targeting the Cystic Fibrosis Gene and the Brain D. Freedman, MD, PhD 28 Mar 2006

from the "Digital Atlas of Video Education - Gastroenterology (The DAVE Project)" (no connection with this Dave!)

Best regards,

Dave R.

[Guest guest]

,

I assume that if my doctor won't okay taking fish oils, that eating a lot of fish would be helpful?

Marie

To: From: rhodesdavid@...Date: Mon, 21 Jan 2008 03:12:54 +0000Subject: Re: Fish oils and inhibition of cholangiocarcinoma

Dear Gerard;There is currently a trial, in progress, on the effects of docosahexaenoic acid (DHA) in PSC:http://www.clinicaltrials.gov/ct2/show/NCT00325013I havn't seen any results from this trial yet, but I'll keep you posted if I hear anything official (i.e. written by the investigator, Dr. Freedman at Harvard). The rationale for this trial is as follows:When mice defective in the cystic fibrosis transmembrane conductance regulator (CFTR), a gene encoding a chloride transport protein expressed in the gut and liver (cholangiocytes), are given colitis, they develop a sclerosing cholangitis resembling human PSC:Blanco PG, Zaman MM, Junaidi O, Sheth S, Yantiss RK, Nasser IA, Freedman SD 2004 Induction of colitis in cftr-/- mice results in bile duct injury. Am. J. Physiol. Gastrointest. Liver Physiol. 287: G491-G496.http://www.ncbi.nlm.nih.gov/pubmed/15064232These mice are protected from bile duct injury when given oral DHA. If you look closely at the data shown in this paper (specifically, Fig. 6 of Blanco et al (2004)), you'll see that there is a similar protective effect when the mice are given eicosapentaenoic acid (EPA), but the standard deviation (error) is a bit larger in this treatment, and the results are not considered statistically significant!Freedman's group has since shown that "dietary DHA resulted in highly significant amelioration of the severity of liver disease in the Cftr(-/-) mice, primarily a reduction in the degree of peri-portal inflammation":Beharry SA, Ackerely C, Corey M, Kent G, Heng YM, Christensen H, Luk C, Yantiss RK, Nasser IA, Zaman M, Freedman SD, Durie PR 2007 Long-term docosahexaenoic acid therapy in a congenic murine model of cystic fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 292: G839-G848. http://www.ncbi.nlm.nih.gov/pubmed/17095751 The CFTR-deficient mice have an impaired regulation of the receptor peroxisome proliferator-activated receptor-alpha (PPARa); a defect that is reversed by DHA:Pall H, Zaman MM, Andersson C, Freedman SD 2006 Decreased peroxisome proliferator activated receptor alpha is associated with bile duct injury in cystic fibrosis transmembrane conductance regulator-/- mice. J. Pediatr. Gastroenterol. Nutr. 42: 275-281. http://www.ncbi.nlm.nih.gov/pubmed/16540796Freedman's group has speculated that PSC may be associated with ulcerative colitis (UC) in a heterozygous CFTR background, meaning that just one copy of the mutant CFTR gene is sufficient to render UC patients susceptible to PSC:Sheth S, Shea JC, Bishop MD, Chopra S, Regan MM, Malmberg E, C, Ricci R, Tsui LC, Durie PR, Zielenski J, Freedman SD 2003 Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis. Hum. Genet. 113: 286-292. http://www.ncbi.nlm.nih.gov/pubmed/12783301Moreover, CFTR channel function seems to be impaired in children with PSC:Pall H, Zielenski J, Jonas MM, Dasilva DA, Potvin KM, Yuan, XW, Huang Q, Freedman SD 2007 Primary sclerosing cholangitis in childhood is associated with abnormalities in cystic fibrosis-mediated chloride channel function. J. Pediatr. 151: 255-259. http://www.ncbi.nlm.nih.gov/pubmed/17719933So it seems reasonable to test whether DHA may be of benefit in PSC patients. Trials are also underway in cystic fibrosis:Van Biervliet S, Van Biervliet JP, Robberecht E, Christophe A 2005 Docosahexaenoic acid trials in cystic fibrosis: a review of the rationale behind the clinical trials. J. Cyst. Fibros. 4: 27-34.http://www.ncbi.nlm.nih.gov/pubmed/15752678I've heard (through the grapevine) that Dr. Freedman believes that there may be some competition between DHA and EPA, and that is why he is testing DHA alone, rather than fish oils (i.e. an EPA + DHA combination).We began giving fish oils (EPA + DHA) for several reasons. First, we were intrigued by reports of beneficial effects of fibrates on PBC and PSC patients, see page 2 of our newsletter:http://www.pscpartners.org/NewsVol-1-2.pdfFibrates are activators of PPARa (mentioned above) and this receptor in turn increases the activity of the biliary phospholipid pump (MDR3). Mice deficient in this pump develop sclerosing cholangitis resembling human PSC:Fickert P, Fuchsbichler A, Wagner M, Zollner G, Kaser A, Tilg H, Krause R, Lammert F, Langner C, Zatloukal K, Marschall HU, Denk H, Trauner M 2004 Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (abcb4) knockout mice. Gastroenterology 127: 261-274. http://www.ncbi.nlm.nih.gov/pubmed/15236191We therefore looked for "natural" activators of PPARa, and came across fish oils (including EPA) as good candidates:Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown PJ, Sternbach DD, Lehmann JM, Wisely GB, Willson TM, Kliewer SA, Milburn MV 1999 Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell. 3: 397-403. http://www.ncbi.nlm.nih.gov/pubmed/10198642Sampath H, Ntambi JM 2005 Polyunsaturated fatty acid regulation of genes of lipid metabolism. Annu. Rev. Nutr. 25: 317-340. http://www.ncbi.nlm.nih.gov/pubmed/16011470We read that fish oils have potent anti-inflammatory effects, in part by activating PPAR's, and in part by competing out arachidonic acid in membranes, and preventing the production of many pre-inflammatory lipids derived from arachidonic acid:Simopoulos AP 2002 Omega-3 fatty acids in inflammation and autoimmune diseases. J. Am. Coll. Nutr. 21: 495-505. http://www.ncbi.nlm.nih.gov/pubmed/12480795Some of the anti-inflammatory effects of fish oils may be due to their oxidation products that activate PPARa, and which then inhibit nuclear factor kappaB :Mishra A, Chaudhary A, Sethi S 2004 Oxidized omega-3 fatty acids inhibit NF-kappaB activation via a PPARalpha-dependent pathway.Arterioscler. Thromb. Vasc. Biol. 24: 1621-1627. http://www.ncbi.nlm.nih.gov/pubmed/15231516Both EPA and DHA give rise to potent anti-inflammatory molecules that are involved in resolving inflammation, and protecting from inflammation (resolvins and protectins):Serhan CN, Chiang N 2007 Endogenous pro-resolving and anti-inflammatory lipid mediators: a new pharmacologic genus. Br. J. Pharmacol. Oct 29 [Epub ahead of print].http://www.ncbi.nlm.nih.gov/pubmed/17965751Transgenic mice that naturally produce both EPA and DHA are resistant to colitis:Hudert CA, Weylandt KH, Lu Y, Wang J, Hong S, Dignass A, Serhan CN, Kang JX 2006 Transgenic mice rich in endogenous omega-3 fatty acids are protected from colitis. Proc. Natl. Acad. Sci. U.S.A. 103: 11276-11281. http://www.ncbi.nlm.nih.gov/pubmed/16847262And there is evidence that DHA and/or EPA may protect against colon cancer:Nowak J, Weylandt KH, Habbel P, Wang J, Dignass A, Glickman JN, Kang JX 2007 Colitis-associated colon tumorigenesis is suppressed in transgenic mice rich in endogenous n-3 fatty acids. Carcinogenesis 28: 1991-1995.http://www.ncbi.nlm.nih.gov/pubmed/17634405son LA, Nguyen DV, Hokanson RM, Callaway ES, Isett RB, ND, Dougherty ER, Wang N, Lupton JR, Carroll RJ, Chapkin RS 2004 Chemopreventive n-3 polyunsaturated fatty acids reprogram genetic signatures during colon cancer initiation and progression in the rat. Cancer Res. 64: 6797-6804. http://www.ncbi.nlm.nih.gov/pubmed/15374999Fan YY, Spencer TE, Wang N, Moyer MP, Chapkin RS 2003 Chemopreventive n-3 fatty acids activate RXRalpha in colonocytes. Carcinogenesis 24: 1541-1548.http://www.ncbi.nlm.nih.gov/pubmed/12844485This last article indicated a new possible mode of action of omega-3 fatty acids, namely activation of the retinoid X receptor (RXRa). Pall et al (2006) acknowledge in their discussion, that the effects of DHA on bile-duct injury in CFTR mice might well be due to activation of RXRa, in addition to PPARa. RXRa is a key partner for many of the nuclear recptors in the liver, including the pregnane X receptor (PXR) that I mentioned yesterday! Other reasons for taking fish oils include, protection of epithelial barrier function in the gut:Li Q, Zhang Q, Wang M, Zhao S, Xu G, Li J 2008 n-3 Polyunsaturated fatty acids prevent disruption of epithelial barrier function induced by proinflammatory cytokines. Mol. Immunol. 45: 1356-1365.http://www.ncbi.nlm.nih.gov/pubmed/17936906Li Q, Zhang Q, Zhang M, Wang C, Zhu Z, Li N, Li J 2008 Effect of n-3 polyunsaturated fatty acids on membrane microdomain localization of tight junction proteins in experimental colitis. FEBS J. 275:411-201.http://www.ncbi.nlm.nih.gov/pubmed/18167140and prevention of cholangiocarcinoma:Lim K, Han C, Xu L, Isse K, Demetris AJ, Wu T 2008 Cyclooxygenase-2-derived prostaglandin E2 activates beta-catenin in human cholangiocarcinoma cells: evidence for inhibition of these signaling pathways by omega 3 polyunsaturated fatty acids. Cancer Res. 68: 553-560.Because both EPA and DHA have these multitude of anti-inflammatory and potentially protective effects, we put on fish oils in order to get the benefits of both the EPA and DHA. has suffered from dyslexia is a child, and this paper suggests that it may even help in this condition:Lindmark L, Clough P 2007 A 5-month open study with long-chain polyunsaturated fatty acids in dyslexia. J. Med. Food. 10: 662-666.http://www.ncbi.nlm.nih.gov/pubmed/18158838Best regards,Dave (father of (22); PSC 07/03; UC 08/03) Connect and share in new ways with Windows Live. Get it now!

[Guest guest]

Hi Marie;

Marine fish are a great source of omega-3's. Many health professionals advocate eating such fish or taking fish oil supplements. Please read this article and I hope you will be reassured that I'm not crazy:

The science behind dietary omega-3 fatty acids

Marc E. Surette, PhD

CMAJ. 2008 January 15; 178(2): 177–180

http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed & pubmedid=18195292

Best regards,

Dave R.

>> > ,> > I assume that if my doctor won't okay taking fish oils, that eating a lot of fish would be helpful?> Marie

[Guest guest]

Those delightful burps really do go away after a week or two. Also, flax seed seems to help me keep "regular" as well as containing some omega-3. Enjoy. Don Please be a blood/organ donor

Never miss a thing. Make Yahoo your homepage.