Re: PSC - The arteriosclerosis of the bile duct (LONG reply to Nina)

[Guest guest]

I am far from science-y, so I apologize in advance if this is

completely wrong - and I trust someone with a better mind for this

stuff will correct me.

If I understand what I've been reading on a basic level, what I think

it means is that in people without the damaged gene, nutrients come

into the body and are transformed into proteins - the genes you have

determine which proteins your body makes. The proteins that are

running around in your body, then, work on other nutrients/molecules

to produce an array of fatty acids that can have other functions.

The normal " balance " of fatty acids in the body is caused by the

normal balance of proteins which, of course, goes back to the genes.

Again, this is my probably grade-school-level of understanding about

this, but what I gather from my reading is that the effect of the

normal balance is a certain viscosity of bodily fluid - i.e. the goop

that lines tissue like the lungs our, in the case of PSC, the biliary

tract. Normally that goop is of a certain consistency, like maybe a

thick stew? (i know that's gross, sorry). What happens with people

who have the damaged gene, then, is that they don't make the normal

array of proteins - they make more of some and less of others becuase,

again, the kinds of proteins you have are determined by the genes.

Therefore, with our " off " ratio of proteins what we end up with is

more of some fatty acids (i.e. the ones that tend to lead to

inflammation and are " sticky " ) and less of others (in my understanding

these are akin to the " good cholesterol " that makes thicker liquid

more " slippery " ). What I think happens with the DHA hypothesis is

that you realize that one of the key imbalances is a lack of adequate

DHA, so you basically just ingest enough DHA to normalize the

balance. In my (loony) imagination, it's like adding cooking oil to

honey.

Fibrates, although I have no idea how, supposedly reduce the amount of

bad cholesterol in the blood and increase the amount of good

cholesterol. I imagine this works much the same way, like replacing

the lumpy, animal-lard-like stuff from the body with slick, olive-oil-

type stuff so that the liquid (e.g. blood, maybe bile) that goes

through the channels (e.g. arteries, maybe biliary tract) is less

likely to stick to the walls and create strictures.

Also, in addition to the actual liquidity of the bile, I THINK that

the imbalance of fatty acids which means that PSCers have a much

higher concentration of acids that cause inflammation is the " toxic "

bile that gets talked about.

SO, in terms of why the PSC would come back? I would imagine it's

because you're talking about the entire balance of molecules in your

whole body, not just your liver. If every last molecule with DNA is

encouraging a certain balance, just having the molecules in your liver

encourage a difference one probably wouldn't outweigh it, at least in

my mind. The super-confusing question for me is why it would NOT come

back for people who've had colectomies - and I can only suppose that i

guess the key amount of the transcription that causes this balance

problem takes place in the colon?

Anyway, that's my best-guess explanation for what I think I understand

of this stuff - again I can vouch for nothing, and eagerly await a

real answer from someone who took at least a single science class

after high school. tx,

nina

> If CFTR was the cause for most PSC, don't you think that we wouldnt

have a 20% chance of PSC reoccuring after transplant?

[Guest guest]

I guess what I was gettting at was that if it was due to a CFTR mutation that many other systems in the body would be affected. CFTR is linked to Cystic Fibrosis which expresses itself as pancreatitis, lung disease, liver disease, and sterility in men. THis is due to the fact that CFTR handles the trafficing of a cholride channel to the surface of the cells (specifically the apical side that opens into a lumen such a duct). When the Cl channle is not trafficed it can't secrete chloride into the lumen. Normally, when chloride is secreted into the lumen or duct water will follow due to osmosis. However, since no chloride (Cl) can be secreted due to the CFTR water doesn't follow into the ducts. This will cause problems in moving things along like bile in the liver, the enzymes in the pancreas, and sperm in the testicles b/c that is the sole job of water in the lumen and ducts which isn't getting there in the CFTR mutation. My

point being, that if PSC was due to a CFTR mutaiton then I would expect this mutation to announce itself as the other problems listed above, maybe not all but at least some. The possibility that a mutation in CFTR would cause only one organ problem is very minimal, but I do recognize that it is a small possibility. Another point why I doubt its CFTR behind PSC is due to the reoccurance after transplantation. There are many genetic problems such as Polycystic Kideny Disease and antitrypis deficiency (a primary liver disease followed by secondary lung disease due to the lack of production of a protein by the liver) that are corrected and don't reoccur after tranplantation. This is becuase the new organ doesn't contain the crummy gene that lead to the bad protein. In the case of PSC if it was CFTR then that protein would not be mutated in the new transplant which lead to no reoccurance after

transplantation. That fact that 20% of people with PSC cand have a reoccurance to the disease does not point to a primary genetic problem with the cells of our body. Rather, this points to something in the environment that remains after the a new liver is transplatned. I think much of the evidence that is pointing to the Pregnane X Receptor (PXR), aka steroid xenobiotic receptor in humans, is more credible due to the fact that it is primarly expressed in the intestine (UC and Crohns) and the liver (PSC). As we know, PXR is involved in the expression of MDR that is important in pumping out toxins from the cell so they don't die. PXR has been shown to be induced by a wide variety of steriod like substances, such a rifampin, fish oils, ursidiolo, and the list goes on and on. I would even bet that vancomycin may be shown to upregulate this receptor and that's why the vancomycin study showed promise in some people. It has also

been shown that bacterial products can down regulate MDR. Specifically it has been show that a substance termed LPS from gram negative bacteria (which are the majority of your normal flora of the gut) can downregulate MDR and since LPS is a steriod like molecule I wuold be bet that it is working through downregulating PXR leading to the MDR in the liver specifcally affecting the bile ducts more. This would make sense because hepatic portal system (the veins that take all the nutrients and toxins from you intestine goes straight to the liver without passing go and travel directly next to the bile ducts in the liver) This would leave the bile ducts and surrounding liver cells to receive the most toxins in the most concentrated form b/c of the vicinity of each other. I'm not saying LPS is doing it, but I am will to be that a toxin/toxins from the altered normal flora is causing this damage. This would explain the reoccurance after

transplant, but it doesn't expalin why it doesn't reoccure to all that are transplanted becuase the gut microflora wouldn't have changed that I could think of due to a tranplant. Just some thoughts......anybody that would love to add to this I would greatly appreciate the feed back...... I wrote this very fast so please forgive any spelling errors as I am studying for a biochem test.nlr_psc wrote: I am far from science-y, so I apologize in advance if

this is completely wrong - and I trust someone with a better mind for this stuff will correct me. If I understand what I've been reading on a basic level, what I think it means is that in people without the damaged gene, nutrients come into the body and are transformed into proteins - the genes you have determine which proteins your body makes. The proteins that are running around in your body, then, work on other nutrients/molecules to produce an array of fatty acids that can have other functions. The normal "balance" of fatty acids in the body is caused by the normal balance of proteins which, of course, goes back to the genes. Again, this is my probably grade-school-level of understanding about this, but what I gather from my reading is that the effect of the normal balance is a certain viscosity of bodily fluid - i.e. the goop that lines tissue like the lungs our, in the case of PSC, the biliary

tract. Normally that goop is of a certain consistency, like maybe a thick stew? (i know that's gross, sorry). What happens with people who have the damaged gene, then, is that they don't make the normal array of proteins - they make more of some and less of others becuase, again, the kinds of proteins you have are determined by the genes. Therefore, with our "off" ratio of proteins what we end up with is more of some fatty acids (i.e. the ones that tend to lead to inflammation and are "sticky") and less of others (in my understanding these are akin to the "good cholesterol" that makes thicker liquid more "slippery"). What I think happens with the DHA hypothesis is that you realize that one of the key imbalances is a lack of adequate DHA, so you basically just ingest enough DHA to normalize the balance. In my (loony) imagination, it's like adding cooking oil to honey. Fibrates, although I have no idea how,

supposedly reduce the amount of bad cholesterol in the blood and increase the amount of good cholesterol. I imagine this works much the same way, like replacing the lumpy, animal-lard-like stuff from the body with slick, olive-oil-type stuff so that the liquid (e.g. blood, maybe bile) that goes through the channels (e.g. arteries, maybe biliary tract) is less likely to stick to the walls and create strictures. Also, in addition to the actual liquidity of the bile, I THINK that the imbalance of fatty acids which means that PSCers have a much higher concentration of acids that cause inflammation is the "toxic" bile that gets talked about. SO, in terms of why the PSC would come back? I would imagine it's because you're talking about the entire balance of molecules in your whole body, not just your liver. If every last molecule with DNA is encouraging a certain balance, just having the molecules in your liver

encourage a difference one probably wouldn't outweigh it, at least in my mind. The super-confusing question for me is why it would NOT come back for people who've had colectomies - and I can only suppose that i guess the key amount of the transcription that causes this balance problem takes place in the colon? Anyway, that's my best-guess explanation for what I think I understand of this stuff - again I can vouch for nothing, and eagerly await a real answer from someone who took at least a single science class after high school. tx,nina> If CFTR was the cause for most PSC, don't you think that we wouldnt have a 20% chance of PSC reoccuring after transplant?

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[Guest guest]

Hi Ross;

In the patent by Freedman he indicated something to the effect

that CFTR may " cause " PSC .... I think what he should really have

said is that mutations in CFTR are associated with increased risk of

acquiring PSC, or are associated with increased susceptibility to

PSC. If you look closely at his paper in Human Genetics (2003) he

states that simply being a carrier of a mutant CFTR allele (i.e.

having one normal copy of the gene and one mutant copy of the gene)

can be a risk factor for PSC.

Hum Genet. 2003 Aug;113(3):286-92.

Increased prevalence of CFTR mutations and variants and decreased

chloride secretion in primary sclerosing cholangitis.

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

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

Department of Medicine, Beth Israel Deaconess Medical Center/Harvard

Medical School, Dana 532, 330 Brookline Avenue, Boston, MA 02215, USA.

Primary sclerosing cholangitis (PSC) and cystic fibrosis (CF) are

both slowly progressive cholestatic liver diseases characterized by

fibro-obliterative inflammation of the biliary tract. We hypothesized

that dysfunction of the CF gene product, cystic fibrosis

transmembrane conductance regulator (CFTR), may explain why a subset

of patients with inflammatory bowel disease develop PSC. We

prospectively evaluated CFTR genotype and phenotype in patients with

PSC ( n=19) compared with patients with inflammatory bowel disease

and no liver disease ( n=18), primary biliary cirrhosis ( n=17), CF (

n=81), and healthy controls ( n=51). Genetic analysis of the CFTR

gene in PSC patients compared with disease controls (primary biliary

cirrhosis and inflammatory bowel disease) demonstrated a

significantly increased number of mutations/variants in the PSC group

(37% vs 8.6% of disease controls, P=0.02). None of the PSC patients

carried two mutations/variants. Of PSC patients, 89% carried the

1540G-variant-containing genotypes (resulting in decreased functional

CFTR) compared with 57% of disease controls ( P=0.03). Only one of 19

PSC patients had neither a CFTR mutation nor the 1540G variant. CFTR

chloride channel function assessed by nasal potential difference

testing demonstrated a reduced median isoproterenol response of 14 mV

in PSC patients compared with 19 mV in disease controls ( P=0.04) and

21 mV in healthy controls ( P=0.003). These data indicate that there

is an increased prevalence of CFTR abnormalities in PSC as

demonstrated by molecular and functional analyses and that these

abnormalities may contribute to the development of PSC in a subset of

patients with inflammatory bowel disease. PMID: 12783301.

Having only copy of the mutant allele is not usually sufficient to

cause lung problems. But it can result in increased risk of

pancreatitis:

Hum Mutat. 2005 Oct;26(4):303-7. Increased risk of idiopathic chronic

pancreatitis in cystic fibrosis carriers.

Cohn JA, Neoptolemos JP, Feng J, Yan J, Jiang Z, Greenhalf W, McFaul

C, Mountford R, Sommer SS

Department of Medicine, Durham Veterans Administration and Duke

University Medical Center, Durham, North Carolina 27710, USA.

Cohn0001@...

Cystic fibrosis (CF) is a recessive disease caused by mutations of

the CF transmembrane conductance regulator (CFTR) gene. The risk of

idiopathic chronic pancreatitis (ICP) is increased in individuals who

have CFTR genotypes containing a CF-causing mutation plus a second

pathogenic allele. It is unknown whether the risk of ICP is increased

in CF carriers who have one CF-causing mutation plus one normal

allele. In this study, 52 sporadic cases of ICP were ascertained

through the European Registry of Hereditary Pancreatitis and Familial

Pancreatic Cancer. Individuals with pathogenic cationic trypsinogen

mutations were excluded. DNA was comprehensively tested for CFTR

mutations using a robotically enhanced, multiplexed, and highly

redundant form of single-strand conformation polymorphism (SSCP)

analysis followed by DNA sequencing. Fifteen subjects had a total of

18 pathogenic CFTR alleles. Eight subjects had common CF-causing

mutations. This group included seven CF carriers in whom the second

CFTR allele was normal (4.3 times the expected frequency, P=0.0002).

Three subjects had compound heterozygotes genotypes containing two

pathogenic alleles (31 times the expected frequency, P<0.0001). A

variant allele of uncertain significance (p.R75Q) was detected in

eight of the 52 ICP subjects and at a similar frequency (13/96) in

random donors. ICP differs from other established CFTR-related

conditions in that ICP risk is increased in CF carriers who have one

documented normal CFTR allele. Having two CFTR mutations imparts a

higher relative risk, while having only one mutation imparts a higher

attributable risk. PMID: 16134171.

In my opinion, being a carrier of a mutant CFTR allele cannot be the

sole " cause " of PSC because in this case there would be a much higher

incidence of PSC. The susceptibility would have to occur only in

combination with some other condition, such as IBD (which in turn may

be under complex genetic control). Thus, one rational explantion is

that IBD together with a mutant CFTR allele is a strong risk factor

for PSC. Perhaps the fact that about 5% of ulcerative colitis

patients develop PSC is attributable to an approximately 5% CFTR

mutant allele carrier status in the general population? But if this

is true, why don't Crohn's patients develop PSC at the same rate as

UC patients? Well, it has recently been shown that carrying a mutant

CFTR allele seems to be protective against Crohn's disease, for

reasons which are as yet unknown:

Inflamm Bowel Dis. 2006 Dec 19; [Epub ahead of print]

Potential role for the common cystic fibrosis DeltaF508 mutation in

Crohn's disease.

Bresso F, Askling J, Astegiano M, Demarchi B, Sapone N, Rizzetto M,

Gionchetti P, Lammers KM, de Leone A, Riegler G, Nimmo ER, Drummond

H, Noble C, Torkvist L, Ekbom A, Zucchelli M, Lofberg R, Satsangi J,

Pettersson S, D'Amato M

Strategic Research Center IRIS, Karolinska Institutet.

Background: Inflammatory bowel disease (IBD) is an epithelial barrier

disease that is thought to result from a dysregulated interaction

with bacteria in the intestine of genetically predisposed

individuals. The cystic fibrosis transmembrane conductance regulator

(CFTR), which is mutated in the autosomal recessive disease cystic

fibrosis, modulates gut permeability, mucus production, and

epithelial interactions with bacteria. The cystic fibrosis DeltaF508

mutation is commonly found in the general population and has been

shown to result in a reduced number of CFTR molecules at the surface

of epithelial cells. Given the important biological functions of CFTR

in the intestine, we tested whether this mutation is of relevance to

IBD.Methods: Using DNA heteroduplex analysis, we investigated the

distribution of DeltaF508 heterozygosity in 2568 subjects from three

independent cohorts of Italian, Swedish, and ish IBD patients

and controls.Results: In all three cohorts an association between

DeltaF508 and Crohn's disease (CD) was observed. Specifically,

DeltaF508 heterozygosity was markedly underrepresented in CD patients

from Italy and Sweden (P = 0.021 and 0.027 versus controls,

respectively), while stratification for disease location revealed an

absence of DeltaF508 carriers among ish CD patients with right-

sided colitis (P = 0.023 versus all other locations). Conclusions:

DeltaF508 heterozygosity might exert a protective effect in CD.

(Inflamm Bowel Dis 2007). PMID: 17206681.

I realize this is a very heavy scientific discussion. For the benefit

of non-scientific audience, I'd like to make an analogy that PSC is

like being struck by lightining. Imagine that a risk factor for being

struck by lightning would be wearing a metal helmet (carrying a

mutant CFTR allele). This might not be too bad if you stayed indoors!

But if you went out to a golf course in the middle of a thunder

storm, watch out!! So imagine a second risk factor, such as belonging

to a golf club, and actively playing golf (IBD). Those with a golf

cart (Crohn's) might be able to wear a metal helmet (mutant CFTR)

without getting stuck by lightning because they spend more time off

the ground. Having a golf cart (Crohns') would appear to be

protective. Those without a golf cart (UC) and wearing a metal helmet

(mutant CFTR) would have a much higher probability of being struck by

lighting because they spend more time in contact with the ground. Men

play golf more often than women, and so the incidence of being struck

by lightning on a golf course is twice as high in men as in women.

Being a male golfer without a golf cart and wearing a metal helmet,

and then going out to play golf in a thunderstorm results in a high

risk of being struck by lightning.

Best regards,

Dave

(father of (21); PSC 07/03; UC 08/03)