PBC / secondary sclerosing cholangitis

[Guest guest]

One of Braden's doctors thinks he can't have Primary sclerosing

cholangitis because he has had his bile ducts manipulated so much and

so that means he has secondary sclerosing cholangitis. He has had his

bile ducts manipulated so much because he has had strictues and

obstructions so frequently. He had beading on his MRCPs then

strictures that required balon dilations and a year of very frequent

stent replacements, several huge cuts with his endoscopic

sphincterotomies to establish bile flow has mural thickening of his

common bile walls, intrahepatic duct dilation, intrahepatic duct

" hardening/thickening " and small duct PSC on his biopsy- but large

duct PSC findings on his MRCPs and ERCPs. He has had 13 ERCPs for

obstructions.

My doctor is looking for PBC with me and I am waiting on

antimitochondrial antibody tests. I have autoimmune issues

inflammatory bowel problems ( no official dx yet), had bridging

fibrosis on a biopsy 7 years ago- biopsy was done after several years

of elevated LFTs, had cholestatsis of pregnancy and HELLP syndrome

with my pregnacy and increased EOS on a subsequent biospy, have edema

terrible itching and fatigue....

My daughter has intermittent colicky epigastric pain and has a dilated

common bile duct per MRCP at 4 mm (this was when she was 8)and normal

is supposed to be 1 mm and my other son has had elevated LFTs GGT, ALT

AST and some intermittent biliary type pain too....

Anyone want to take a stab at what an underlying problem could be for

all of us ??

[Guest guest]

>

> One of Braden's doctors thinks he can't have Primary sclerosing

> cholangitis because he has had his bile ducts manipulated so much and

> so that means he has secondary sclerosing cholangitis. He has had his

> bile ducts manipulated so much because he has had strictues and

> obstructions so frequently. He had beading on his MRCPs then

> strictures that required balon dilations and a year of very frequent

> stent replacements, several huge cuts with his endoscopic

> sphincterotomies to establish bile flow has mural thickening of his

> common bile walls, intrahepatic duct dilation, intrahepatic duct

> " hardening/thickening " and small duct PSC on his biopsy- but large

> duct PSC findings on his MRCPs and ERCPs. He has had 13 ERCPs for

> obstructions.

> My doctor is looking for PBC with me and I am waiting on

> antimitochondrial antibody tests. I have autoimmune issues

> inflammatory bowel problems ( no official dx yet), had bridging

> fibrosis on a biopsy 7 years ago- biopsy was done after several years

> of elevated LFTs, had cholestatsis of pregnancy and HELLP syndrome

> with my pregnacy and increased EOS on a subsequent biospy, have edema

> terrible itching and fatigue....

> My daughter has intermittent colicky epigastric pain and has a dilated

> common bile duct per MRCP at 4 mm (this was when she was 8)and normal

> is supposed to be 1 mm and my other son has had elevated LFTs GGT, ALT

> AST and some intermittent biliary type pain too....

>

> Anyone want to take a stab at what an underlying problem could be for

> all of us ??

>

Looks like I do not have elevated antimitochondrial antibody but I do

have very low iron but the capacity to absorb it well according to the

tests I just had done and found out about today. So it looks likely

that I am having some type of GI bleeding ???

[Guest guest]

This is a tough question, but I think it would be helpful to take a

look at the literature on cholestasis of pregnancy, which you have

indicated that you have had.

There may be a genetic predisposition to intrahepatic cholestasis of

pregnancy, and some of the genes involved may include the bile acid

sensor, farnesoid X receptor (FXR):

_________________

Gastroenterology. 2007 Aug;133(2):507-16.

Functional variants of the central bile acid sensor FXR identified in

intrahepatic cholestasis of pregnancy.V

an Mil SW, Milona A, Dixon PH, Mullenbach R, Geenes VL, Chambers J,

Shevchuk V, GE, Lammert F, Glantz AG, Mattsson LA, Whittaker J,

MG, White R, on C

Maternal and Fetal Disease Group, Institute of Reproductive and

Developmental Biology, Imperial College London, London, England.

BACKGROUND AND AIMS: Intrahepatic cholestasis of pregnancy (ICP) is

characterized by liver impairment, pruritus, and elevated maternal

serum bile acids. It can cause premature delivery and intrauterine

death. Bile acid synthesis, metabolism, and transport are regulated

by the bile acid sensor FXR, and we hypothesized that genetic

variation in FXR confers susceptibility to ICP. METHODS: The coding

regions and intron/exon boundaries of FXR were sequenced in 92

British ICP cases of mixed ethnicity. Subsequently, a case-control

study of allele frequencies of these variants in 2 independent

cohorts of Caucasian ICP patients and controls was performed.

Variants were cloned into an FXR expression plasmid and tested in

functional assays. RESULTS: We identified 4 novel heterozygous FXR

variants (-1g>t, M1V, W80R, M173T) in ICP. W80R was not present in

Caucasians and M1V was detected uniquely in 1 British case. M173T

and -1g>t occur both in Caucasian cases and controls, and we found a

significant association of M173T with ICP (OR, 3.2; 95% confidence

interval, 1.1-11.2; P = .02) when the allele frequencies of both

Caucasian cohorts were analyzed together. We demonstrate functional

defects in either translation efficiency or activity for 3 of the 4

variants (-1g>t, M1V, M173T). CONCLUSIONS: This is the first report

of functional variants in FXR. We propose that these variants may

predispose to ICP, and because FXR has a central role in regulating

bile and lipid homeostasis they may be associated with other

cholestatic and dyslipidemic disorders. PMID: 17681172.

_________________

and/or the MDR3 (ABCBA) gene that encodes a phospholipid export pump

in the liver:

_________________

Semin Liver Dis. 2007 Feb;27(1):77-98.

MDR3 (ABCB4) defects: a paradigm for the genetics of adult

cholestatic syndromes.

Trauner M, Fickert P, Wagner M

Laboratory of Experimental and Molecular Hepatology, Division of

Gastroenterology and Hepatology, Department of Internal Medicine,

Medical University of Graz, Austria.

Because ATP-binding cassette (ABC) transporters are important for

normal bile secretion, hereditary and acquired ABC transporter

defects play a central role in the pathogenesis of cholestasis.

Defects of the phospholipid export pump MDR3 (ABCC4) result in

impaired biliary excretion of phosphatidylcholine and a variety of

cholestatic syndromes ranging from progressive familial intrahepatic

cholestasis in neonates to biliary cirrhosis in adults. Moreover,

MDR3 mutations predispose to cholestasis of pregnancy and drug-

induced cholestasis. Because MDR2 (rodent orthologue of human MDR3)

knockout mice develop sclerosing cholangitis, it is attractive to

speculate that MDR3 defects could also play an important role in

cholangiopathies in humans. Indeed, MDR3 variants could play a role

as modifier gene in primary biliary cirrhosis and primary sclerosing

cholangitis, but their exact role needs further clarification.

Impaired biliary phosphatidylcholine excretion has also been reported

in total parenteral nutrition-induced cholestasis and bile duct

injury following liver transplantation, but a genetic basis for these

findings remains to be explored. Several drugs for the treatment of

cholestatic liver diseases target MDR3 expression and function,

further underscoring the clinical significance of this transport

system. PMID: 17295178.

_________________

If you have a genetic variant of FXR or MDR3 that you then passed on

to your children, they might also be predisposed to cholestatic liver

disease that might resemble PSC? In fact Trauner has proposed

that variants in the MDR3 gene in humans might contribute to PSC

(when the equivalent mouse gene is defective, the mice develop bile

duct injury resembling sclerosing cholangitis).

Ursodiol seems to be beneficial in intrahepatic cholestasis of

pregnancy:

_________________

Orphanet J Rare Dis. 2007 May 29;2:26.

Intrahepatic cholestasis of pregnancy.

Pusl T, Beuers U

Department of Gastroenterology & Hepatology, AMC, University of

Amsterdam, The Netherlands. thomas.pusl@...

Intrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder

characterized by (i) pruritus with onset in the second or third

trimester of pregnancy, (ii) elevated serum aminotransferases and

bile acid levels, and (iii) spontaneous relief of signs and symptoms

within two to three weeks after delivery. ICP is observed in 0.4-1%

of pregnancies in most areas of Central and Western Europe and North

America, while in Chile and Bolivia as well as Scandinavia and the

Baltic states roughly 5-15% and 1-2%, respectively, of pregnancies

are associated with ICP. Genetic and hormonal factors, but also

environmental factors may contribute to the pathogenesis of ICP.

Intrahepatic cholestasis of pregnancy increases the risk of preterm

delivery (19-60%), meconium staining of amniotic fluid (27%), fetal

bradycardia (14%), fetal distress (22-41%), and fetal loss (0.4-

4.1%), particularly when associated with fasting serum bile acid

levels > 40 micromol/L. The hydrophilic bile acid ursodeoxycholic

acid (10-20 mg/kg/d) is today regarded as the first line treatment

for intrahepatic cholestasis of pregnancy. Delivery has been

recommended in the 38th week when lung maturity has been established.

PMID: 17535422.

_________________

Best regards,

Dave

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

[Guest guest]

>

> This is a tough question, but I think it would be helpful to take a

> look at the literature on cholestasis of pregnancy, which you have

> indicated that you have had.

>

> There may be a genetic predisposition to intrahepatic cholestasis of

> pregnancy, and some of the genes involved may include the bile acid

> sensor, farnesoid X receptor (FXR):

> _________________

-

THANK YOU THANK YOU THANK YOU

You are an amazing guy !!!!!!

>