Alk Phos / Fibrate RCT?

[Guest guest]

From a General Surgery standpoint when someone has elevated Alk Phos

associated w/ abdominal pain we look for gallstone/gallbladder/common

bile duct (i.e. biliary) disease (i.e.inflammation) such as:

1) cholelithiasis (asymptomatic gallstones)

2) biliary colic (pain from gallstones)

3) cholecystitis (infection/inflammation of the gallbladder)

4) choledocholithiasis (stones in the Common Bile Duct) and finally

5) ascending cholangitis (infection of the Common Bile Duct).

6) tumors

Normal levels are around <125-150 depending on your lab and they do

have to be interpreted with the other LFT's. After we've ruled out a

surgical problem usually using ultrasound and CAT-scan we get GI

involved to look into cholestasis i.e hepatitis, PSC, PBC etc.

The usual extra-biliary source of Alk Phos is bone i.e. bony

metastasis from prostate cancer.

I agree with the Fibrates seem promising in the near-future.

I wonder if (HOPE) there are as of yet any Clinical trials using

fibrates for PSC? If so sign me up!

-Stefan

" Knowledge is Power "

[Guest guest]

Dear Stef;

Thanks very much for your valuable medical clarifications on alkaline

phosphatase and GGT!

Most of the clinical trials on fibrates and PBC and PSC seem to be in

Japan, and most of the work seems to have been done on PBC rather

than PSC (see for example):

Hepatol Res. 2004 Aug;29(4):216-222.

Prospective randomized crossover trial of combination therapy with

bezafibrate and UDCA for primary biliary cirrhosis.

Itakura J, Izumi N, Nishimura Y, Inoue K, Ueda K, Nakanishi H,

Tsuchiya K, Hamano K, Asahina Y, Kurosaki M, Uchihara M, Miyake S.

Division of Gastroenterology and Hepatology, Musashino Red Cross

Hospital, 1-26-1 Kyonan-cho, Musashino City, Tokyo 180-8610, Japan.

The aim of this study was to evaluate the effects of the combination

therapy with bezafibrate and ursodeoxycholic acid (UDCA) for primary

biliary cirrhosis (PBC), compared to UDCA monotherapy. Sixteen

patients with compensated PBC were divided randomly into two groups.

Group A received treatment with bezafibrate and UDCA for 6 months,

while group B received UDCA alone, treatment protocols were then

exchanged for another 6 months. The laboratory data was followed

every month. The mean levels of alkaline phosphatase (ALP) decreased

significantly more in group A than in group B in the first half of

the study. Then serum ALP levels were elevated in group A after

exchanged the therapy, but fell down in group B. Serum levels of

gamma-glutamyl transferase (GGT), immunoglobulin M and triglycerides

values were significantly lower in group B than in group A, after

changing therapies from monotherapy to combination therapy with

bezafibrate and UDCA. The mean levels of ALP, GGT and triglycerides

were significantly lower at the end of the combination therapy than

those at the end of the monotherapy. The combination therapy with

bezafibrate and UDCA significantly improves the laboratory data that

specific for PBC in comparison with UDCA monotherapy. PMID: 15288014.

For additional references on fibrates see:

http://www.psc-literature.org/fibrate.htm

Best regards,

Dave

(father of (19); PSC 07/03; UC 08/03)

> I agree with the Fibrates seem promising in the near-future.

> I wonder if (HOPE) there are as of yet any Clinical trials using

> fibrates for PSC? If so sign me up!

[Guest guest]

,

Wow I was thinking that given the relative lack of efficacy of Urso

that combination therapy might show an effect in PSC too. . . . there

must be someone is the USA looking into a clinical trial like this.

Interesting that this came out of Japan. HCC is the #1 viceral (GI)

cancer in the world, while colon cancer is #1 in the USA. The

difference is that in the far east and 3rd world countries there is a

much higher incidence of hepatitides ==> HCC. Relative to this I

wonder what the geographic distribution of PSC is? I might assume

that it is more common in Israel and Scandanavia as we spoke about. I

also wonder why more progress seems to be being made in PBC but not

PSC. . . .

Also are the fibrates FDA approved? If not what about compassionate

use 'cause right now we ain't got sh*t.

-Stef

>

> Dear Stef;

>

> Most of the clinical trials on fibrates and PBC and PSC seem to be

in

> Japan, and most of the work seems to have been done on PBC rather

> than PSC (see for example):

>

> Hepatol Res. 2004 Aug;29(4):216-222.

>

> Prospective randomized crossover trial of combination therapy with

> bezafibrate and UDCA for primary biliary cirrhosis.

>

> Itakura J, Izumi N, Nishimura Y, Inoue K, Ueda K, Nakanishi H,

> Tsuchiya K, Hamano K, Asahina Y, Kurosaki M, Uchihara M, Miyake S.

>

> Division of Gastroenterology and Hepatology, Musashino Red Cross

> Hospital, 1-26-1 Kyonan-cho, Musashino City, Tokyo 180-8610, Japan.

[Guest guest]

it is more common in Israel and Scandanavia as we spoke about. I

> also wonder why more progress seems to be being made in PBC but not

> PSC. . . .

The PBC support group is the backbone of that progress.

Andi

[Guest guest]

Dear Stef;

I've read that the Mayo clinic in Rochester may be starting a

bezafibrate study with PBC patients, but I don't know whether they

are also considering one with PSC in combination with URSO. We may

have to wait until the PSC high-dose URSO trial is completed?

As far as I am aware, fibrates are FDA approved. They have been used

in other trials related to hyperlipdemia, and there is some evidence

that they may be superior to statins:

Curr Atheroscler Rep. 2004 Mar;6(2):148-57.

The role of fibrates in managing hyperlipidemia: mechanisms of action

and clinical efficacy.

Fazio S, Linton MF.

Division of Cardiovascular Medicine, Vanderbilt University Medical

Center, 383 PRB, Nashville, TN 37232-6300, USA.

sergio.fazio@...

At a time when the lipid management guidelines give more and more

emphasis to the identification and treatment of high-risk patients

with the metabolic syndrome and diabetes, there is an obvious need to

balance the known effects of low-density lipoprotein (LDL) lowering

with the new evidence of clinical efficacy derived from the

adjustment of high-density lipoprotein (HDL) and triglyceride levels.

Whereas the statins remain the drug of choice for patients who need

to reach the LDL goal, fibrate therapy may represent the best

intervention for subjects with atherogenic dyslipidemia and an LDL

already close to goal. In addition, the concomitant use of fibrates

may significantly reduce cardiovascular risk in patients whose LDL is

controlled by statin therapy. In this review, we evaluate the

pharmacologic properties of the fibrate drugs, with particular

attention to the effects of peroxisome proliferator activated

receptor a activation in the control of dyslipidemia as well as in

the attenuation of arterial inflammation. Clinical trials of

fibrates, such as the Helsinki Heart Study, Veterans Affairs High-

density lipoprotein Intervention Trial, Diabetes Atherosclerosis

Intervention Study, and Bezafibrate Infarction Prevention trial, have

conjured up a scenario for the clinical utility of fibrates and their

possible superiority to statins in the management of obese, insulin-

resistant, and diabetic patients presenting with near-goal LDL and

inappropriate HDL and triglyceride levels. PMID: 15023300.

Bezafibrate is made by Roche, and is called " Bezalip " .

Best regards,

Dave

(father of (19); PSC 07/03; UC 08/03)

> Also are the fibrates FDA approved?

[Guest guest]

Maybe in my spare time (haha) i'll contact Roche - anyone interested

in helping? But seriously thanx - I think we have to be

the 'squicky wheel' and push for a clinical trial. I'm an impatient

(not inpatient) not willing to wait for the results of the high dose

Urso. Ask your doctor why not Mucomyst (NAC) now? Ask why not a

Fibrate now? Can they offer nothing? Typical medical docs - leave

the really tough cases to the surgeons. . . . I don't have the time

to wait - we need progress NOW!!!! Lack of evidence does not equal

lack of efficacy, safety being equal.

Just my 2cent _rant_ for the day. . . .

-Stefan, busy-bee Surgery-PGY-3 MD

PS Saw my 33wk gestational age baby-to-be's face in 3D yesterday -

now that's progress

> > Also are the fibrates FDA approved?

[Guest guest]

Dear Stef;

Great news about the baby-to-be pictures!

I do plan to contact Roche over the next month or so [depending on

progress with the new PSC Foundation that Don & Ricky & Lee & Deb &

Arne & Ali and several others (sorry if I omitted names!) are

establishing]. The initial contact will likely be to request funds

(an educational grant) to support a conference next spring [more

about that later when Don & Ricky have completed contacts with

potential speakers, and a conference site and dates are solidified].

If we establish credibility with Roche (and other drug companies

which have philanthropic programs), they may be more willing to

listen to our needs, and perhaps explore new territory?

I fully agree that we need progress NOW, and one approach is to talk

with our doctors about potential new treatments. No kidding when I

say we may know more about these potential " new " treatments than some

of our doctors do! Some of the articles on these " new " treatments

don't have Abstracts, and frankly doctors are often so busy that they

don't have time to read the literature thoroughly.

Here's the best article I've found on PSC and bezafibrate [as I

mentioned earlier, there seems to have been more work on PBC]. If you

look this article up in PubMed, you only get the title! It's not much

to go on, but it's something to consider and perhaps talk with your

doctor(s) about if you're interested in pursuing this:

Kita R, Kita-Sasai Y, Hanaoka I, Kimura T, Kokuryu H, Takamatsu S,

Osaki Y, Tomono N, Hachiya T, Shimizu T 2002 Beneficial effect of

bezafibrate on primary sclerosing cholangitis (three case reports).

Am. J. Gastroenterol. 97: 1849-1851.

TO THE EDITOR: Primary sclerosing cholangitis (PSC) is a progressive

cholestatic liver disease characterized by diffuse inflammation and

fibrosis involving intrahepatic and extrahepatic biliary ducts. The

cause of PSC remains unknown, no medical treatment has been proven to

counteract the natural progression of the disease, and liver

transplantation is the only feasible option for patients in its end

stage (1-3). Bezafibrate is a commonly used medicine for

hyperlipidemia, and several recent studies have demonstrated that

bezafibrate has the beneficial effect of lowering biliary enzymes

in primary biliary cirrhosis (PBC) (4-6). We report here three cases

of PSC treated with oral administration of bezafibrate, all of which

showed a significant reduction in biliary enzymes without side

effects. Informed consent for inclusion in this study was obtained

from each patient.

CASE 1. A 64-yr-old man was admitted to our hospital in

December, 1997 for further examination of an elevated titer

of hepatobiliary enzymes. ERCP provided evidence of multiple

irregular strictures and dilations of the intra- and extrahepatic

bile ducts. Ursodeoxycholic acid (UDCA) (600 mg/day p.o.) from

February, 1998 resulted in a reduction in hepatobiliary enzymes, but

transient exacerbation of biliary enzymes caused by cholangitis often

occurred and hepatobiliary enzymes remained high. The level of ALP

fluctuated between 650 and 850 IU/L until December, 2000. Additional

bezafibrate (400 mg/day p.o.) was started in January, 2001, when the

laboratory data showed the following results: AST (36 IU/L), ALT (28

IU/L), ALP (813 IU/L), gamma-glutamyltranspeptidase (g-GTP) (95

IU/L), and antinuclear antibody (X80) were positive and perinuclear

antineutrophil cytoplasmic antibody was negative. The level of ALP

decreased immediately and significantly after the administration

of bezafibrate and became normalized in July, 2001 (526 IU/L in

February, 426 IU/L in April, and 343 IU/L in July).

CASE 2. A 38-yr-old man was admitted to our hospital in July, 1983

for further examination of abdominal pain and tarry stool. He had

been followed up in connection with liver dysfunction for 2 yr at

another hospital. As a result of colonoscopy and ERCP examination, he

was diagnosed as having ulcerative colitis and PSC. Administration of

salazosulfapyridine improved ulcerative colitis dramatically.

Administration of UDCA (300 mg/day) was started in April, 1993, and

the biliary enzyme level decreased (ALP = 1403 IU/L and g-GTP = 575

IU/L in April; ALP = 586 IU/L and g-GTP = 178 IU/L in July, 1993).

However, the level of biliary enzymes gradually increased again

during the next 8 yr, and administration of bezafibrate (400 mg/day)

has been added since April, 2001, when the levels of hepatobiliary

enzymes were AST, 45 IU/L; ALT, 63 IU/L; ALP, 1177 IU/L; g-GTP, 731

IU/L; and total bilirubin, 0.6 mg/dl. The levels of ALP and g-GTP

decreased immediately and significantly within a few months (ALP =

610 IU/L and g-GTP = 458 IU/L in May; ALP = 592 IU/L and g-GTP = 547

IU/L in October, 2001).

CASE 3. A 78-yr-old man was admitted to our Department of

Gastroenterology for further examination regarding elevated

ALP levels in December, 2000. He had been followed up for cerebral

infarction, diabetes insipidus, and diabetes mellitus at the

Department of Endocrinology in our hospital since 1998. Biological

tests in December, 2000 showed the following: AST, 40 IU/L; ALT, 41

IU/L; ALP, 817 IU/L; g-GTP, 94 IU/L; and total bilirubin, 0.4 mg/dl.

Abdominal ultrasound and CT demonstrated multiple intrahepatic bile

duct dilations, and ERCP showed multiple strictures and dilations of

the intrahepatic bile duct. Antinuclear antibody and perinuclear

antineutrophil cytoplasmic antibody were negative. The level of ALP

has been fluctuating between 550 and 850 IU/L. Administration of

bezafibrate (400 mg/day) was started in May, 2001, when the level of

ALP was 725 IU/L, but it showed a significant decrease within a few

months (398 IU/L in June and 404 IU/L in October).

Bezafibrate is a commonly used medicine for hyperlipidemia and is

known to reduce biliary enzymes such as ALP and g-GTP (4). Several

recent studies have demonstrated that bezafibrate can lower the

levels of ALP, g-GTP, and IgM and is useful for the treatment of PBC

(5, 6). The mechanism of the protective effect of bezafibrate on the

biliary system remains unclear, but at least two possible

explanations have been proposed: 1) bezafibrate induces multidrug

resistance 3 gene expression and upregulates Pglycoprotein

expression, thus facilitating the production of biliary

phospholipids, which are secreted into bile to produce micelles with

hydrophobic toxic bile acid, resulting in the reduction of

cytotoxicity on the biliary epitheliums (5), and 2) bezafibrate works

as a ligand of the peroxisome proliferater-activated receptor alpha

and suppresses inflammation by modulating tumor necrosis factor

alpha, interleukins, nuclear factor KB, and leukotriene B4 (7).

In the study presented here, bezafibrate was administered to three

patients with PSC, whose biliary enzyme levels improved

significantly, as in the previously reported cases of PBC.

Bezafibrate was well tolerated and produced no significant side

effects in any of the cases. In a study of asymptomatic PSC (8),

Porayko et al. showed that patients with comparatively high levels of

AST or ALP had short survival times. So, medication that lowers the

level of AST or ALP is thought to be beneficial for preventing the

disease progression of PSC, whereas safety is required for long term

administration. This means that, similarly to UDCA, methotrexate, and

tacrolimus, bezafibrate could also be a promising candidate for the

treatment of patients with PSC (2, 3).

Takikawa (9) reported that there were two distinct age groups among

Japanese patients with PSC, a younger group under 40 yr and an older

group 40 yr and over. Differences in the characteristics of these

groups include frequency of complication of inflammatory bowel

disease and chronic pancreatitis and positivity of antinuclear

antibody. Of the three patients in our study, 1 and 3 belonged to the

older group and 2 to the younger group, but bezafibrate could reduce

the level of biliary enzymes in both groups of patients. Although we

could not assess the effect of bezafibrate on histological findings

in our study and the follow-up period was short, our results suggest

that bezafibrate may have a beneficial effect on biliary enzymes and

thus delay the progression of PSC when used alone or with various

combinations of other medicines such as UDCA, methotrexate, and

tacrolimus. Because PSC slowly progresses over many years, the long

term effects of bezafibrate on survival and histological improvement

need to be evaluated.

REFERENCES

1. Lee YM, Kaplan MM. Medical treatment of primary sclerosing

cholangitis. J Hepatobiliary Pancreat Surg 1999;6:361-5.

2. Lindor KD, The Mayo PSC-UDCA Study Group. Ursodiol for

primary sclerosing cholangitis. N Engl J Med 1997;336:691-5.

3. Thiel DHV, Carroll P, Elmagd KA, et al. Tacrolimus (FK506),

a treatment for primary sclerosing cholangitis: Results of an

open-label preliminary trial. Am J Gastroenterol 1995;90:455-9.

4. Day AP, Feher MD, Chopra R, et al. The effect of bezafibrate

treatment on serum alkaline phosphatase isozyme activities.

Metabolism 1993;42:839-42.

5. Iwasaki S, Tsuda K, Ueta H, et al. Bezafibrate may have a

beneficial effect in pre-cirrhotic primary biliary cirrhosis. Hepatol

Res 1999;16:12-8.

6. Kurihara T, Furukawa M, Tsuchiya M, et al. Effect of bezafi-

brate in the treatment of primary biliary cirrhosis. Curr Ther Res

Clin Exp 2000;61:74-82.

7. Devchand PR, Keller H, s JM, et al. The PPARalpha-leukotriene

B4 pathway to inflammation control. Nature 1996;384:39-43.

8. Porayko MK, Wiesner RH, LaRusso NF, et al. Patients with

asymptomatic primary sclerosing cholangitis frequently have

progressive disease. Gastroenterology 1990;98:1594-602.

9. Takikawa H. Recent status of primary sclerosing cholangitis in

Japan. J Hepatobiliary Pancreat Surg 1999;6:352-5.

Best regards,

Dave R.

(father of (19); PSC 07/03; UC 08/03)

[Guest guest]

PS Saw my 33wk gestational age baby-to-be's face in 3D yesterday - now that's progress >>>

That is very exciting! When is your baby's due date? A new years eve baby?

Blessings,

Barby-KS