Good news - fibrates MAY work

[Guest guest]

Hi, all, I actually have some good news to post! I am thrilled to

report that, today, my husband got back test results that were ALL

in the normal range.

I think this may be because of fibrates. This is certainly no

double-blind-placebo-controlled study, but based on the articles in

's website about the use of fibrates for PSC (i think primarily

in Japan), my husband started fenofibrate about six months ago. My

husband is on, and has been on for about sixteen months now, a host

of other medications - he takes almost 30 pills daily, so there is

no guarantee that the fibrates are what made a difference, but the

timing does seem to match up. His ALT, AST and GGT dipped

dramatically as soon as he started taking the high-dose Urso and the

rest of his supplements (DHA, NAC, Milk Thistle, Zinc (his liver

biopsy showed extremely high levels of copper), SAM-e and Vitamin

E), but his Alk Phos remained stubbornly just a bit outside the

normal range for more than 8 months. Earlier this year we decided

to try the fibrates - they are managed by his internist, since his

hepatologist has no experience managing this medication - and

slowly, slowly, since then, the Alk Phos has inched down towards

normal. Today it finally hit the top number in the " normal " range.

Obviously, our goal is to be square in the middle, if not bottom, of

normal, and I hope against hope that his progress continues (and

will likely turn here first if it doesn't or if g-d forbid something

bad happens). But I figured I should post this information in case

anyone else is considering fibrates to nudge that Alk Phos number

downwards.

Another thing - I found this website in April '06 and it was a

lifesaver for me - everything else I had read said my husband's

predicted " mortality " was 7 years, and I was terrified. The

information I've found here, ' g-dsend of a website, and

the truly inspiring demonstrations of courage (has everyone seen

Barb's 7/30/07 post? that woman is amazing) have been incredibly

helpful to me over the past more than a year, and I wanted to thank

every one of you that has been so generous with your

time/info./support. Can't wait until ville - maybe I'll

actually be able to get my husband to come along this time! Thanks,

Nina in Philly

[Guest guest]

Hi Nina;

Glad to hear that your husband's LFTs have normalized ... this is

good news.

Our son never did try a fibrate; we thought that fish oils would

probably be having a similar mode of action (by activating PPAR-

alpha), and his alkaline phosphatase has also slowly come back to

upper limit of normal over the last year since taking fish oils.

The latest paper on fenofibrate is interesting because it shows that

by activating PPAR-alpha, fenofibrate may also have an anti-

inflammatory effect on experimental inflammatory bowel disease (in

mice):

Gastroenterology. 2007 Jul;133(1):108-23.

Fenofibrate represses interleukin-17 and interferon-gamma expression

and improves colitis in interleukin-10-deficient mice.

Lee JW, Bajwa PJ, Carson MJ, Jeske DR, Cong Y, Elson CO, Lytle C,

Straus DS

Biomedical Sciences Division, University of California, Riverside,

California 92521-0121, USA.

BACKGROUND & AIMS: Interleukin-10 knockout (IL-10(-/-)) mice

spontaneously develop colitis characterized by T-helper cell type 1-

polarized inflammation. We tested the possible therapeutic activity

of the peroxisome proliferator-activated receptor alpha (PPARalpha)

ligand fenofibrate, and the PPARdelta ligand GW0742, in IL-10(-/-)

mice and investigated the cellular/molecular mechanisms for

fenofibrate action. METHODS: The effect of fenofibrate or GW0742 on

the progression of colitis in C3H.IL-10(-/-) mice was evaluated.

Effects of fenofibrate on cytokine and chemokine gene expression were

studied in cultured splenocytes, pathogenic T cells isolated from

C3H/HeJBir mice, and HT-29 colorectal cancer cells. RESULTS:

Treatment of C3H.IL-10(-/-) mice with fenofibrate delayed the onset

of colitis, decreased the colonic histopathology score, and decreased

colonic expression of genes encoding the inflammatory cytokines

interferon-gamma and interleukin (IL)-17. The target for fenofibrate,

PPARalpha, was expressed in lymphocytes, macrophages, and crypt and

surface epithelial cells of the colon. The mean number of lymphocytes

was decreased by more than 75% in colonic sections of fenofibrate-

treated as compared with control IL-10(-/-) mice, and fenofibrate

repressed interferon-gamma and IL-17 expression in isolated T cells.

Fenofibrate also repressed the expression of the genes encoding 3

chemokines, CXCL10, CCL2, and CCL20, and repressed CXCL10 gene

promoter activity in tumor necrosis factor-alpha-treated HT-29 cells.

In contrast to the beneficial effect of fenofibrate, the PPARdelta

ligand GW0742 accelerated the onset of colitis in IL-10(-/-) mice.

CONCLUSIONS: The immunopathology observed in IL-10(-/-) mice

resembles that seen in Crohn's disease. The novel therapeutic

activity of fenofibrate in this mouse model suggests that it may also

have activity in Crohn's disease. PMID: 17631136.

The suppression of IL-17 and interferon-gamma by fenofibrate is

consistent with suppression of inflammatory Th17 and Th1 cells, which

were discussed in the last newsletter:

http://www.pscpartners.org/NewsVol-3-1.pdf

IL-10 is normally produced by regulatory T cells (Tregs), and is

thought to be one of the main cytokines produced by Tregs to suppress

inflammation. So it is interesting that fenofibrate (by activating

PPAR-alpha) can overcome the inflammation associated with IL-10

deficiency in these IL-10 (-/-) knockout mice that are prone to

develop colitis. As was discussed earlier this week, the vitamin A

derivative, retinoic acid, plays a key role in stimulating naive T

cells to form anti-inflammatory Tregs instead of pro-inflammatory

Th17 cells. It will be interesting to see if this switch somehow

depends on PPAR-alpha?

Best regards,

Dave

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

[Guest guest]

>

> Hi, all, I actually have some good news to post! I am thrilled to

> report that, today, my husband got back test results that were ALL

> in the normal range.

>

> I think this may be because of fibrates.

Hi,

Can I be stupid and ask what are fibrates? I dint think I have ever

coem across them.

My son too has normal LFTs this week...first time for over a

year.....and I am sure it is the fish oil he has taken.

Son Dan 18 UC/PSC

[Guest guest]

I have been hearing a lot about fish oil lately, can someone tell me what brand and dosage you recommend? Thanks, cindy

-------------- Original message --------------

>> Hi, all, I actually have some good news to post! I am thrilled to > report that, today, my husband got back test results that were ALL > in the normal range.> > I think this may be because of fibrates. Hi,Can I be stupid and ask what are fibrates? I dint think I have ever coem across them.My son too has normal LFTs this week...first time for over a year.....and I am sure it is the fish oil he has taken. Son Dan 18 UC/PSC

[Guest guest]

Thanks, , I'll be sure to point this article out to the

hepatologist. You know, we did not wait a full year for the fish oil

to do its job, so there's no telling what was the final factor that

kicked it into normal, it may have been the DHA, just like it seems to

have been for . My husband's liver biopsy showed Stage III

fibrosis, however, so I just wasn't willing to wait any longer to take

every step we could - even though it means we can't be sure which

pills are doing what. tx,

nina

> The latest paper on fenofibrate is interesting because it shows that

> by activating PPAR-alpha, fenofibrate may also have an anti-

> inflammatory effect on experimental inflammatory bowel disease (in

> mice):