Re: Intro and questions ...cpl more questions.

[Guest guest]

Sandi, and all

PSC was first mentioned to my husband and me by Nick's pediatric liver

specialist Dr. Jack at Children's Mercy Hospital in Kansas City.

I contacted this hospital because they have a pediatric liver care center and

Dr. is the director. After conducting and reviewing the liver biopsy,

MRI, CAT w/ contrast, sweat chloride test, upper and lower GI Scopes, and also

he sent off to Mayo for 's disease, and and a few other things. This is

when we were told he was leaning toward PSC. But, after the ERCP done by a

doctor that I can't remember his name. They said it was not PSC, but was severe

liver disease. Something was or had cause fibrosis of the smaller bile ducts and

had caused a lot of them to dissapear. Also, said no telling how long this has

been going on. I think they mean this is secondary to something else. Anyway, I

figured Dr. was familiar with PSC since he was the one who initially

mentioned it to us.

I guess I should ask about this at our next visit. I think I'm just not asking

the right or spicific enough questions. Anyone have any thoughts on some real

essential questions I should be sure and ask the doc? Though I cannot say enough

about Dr. and his hep. coordinator, Gayla Cheadle.

Thanks,

Son, Nick(9)liver disease 09

>

>

> ,

>

> Hi! I hope you and your son are both having extremely good days!

>

> I'm not sure I can offer you any advice, but I can provide a sympathetic ear

if you need one. You say you're not sure if you belong here. If you need our

help and/or we can answer questions for you or give you peace of mind, you are

more than welcome to be here and you absolutely do belong. That's one of the

things I love so much about this site, not only is there an amazing array of

knowledge and experience in this group, but I honestly think it's made up of

some of the nicest, most compassionate and most caring people I've ever had the

privilege of talking to.

>

> I am curious. You mention taking your son to several doctors. Were any of

them specialists in PSC? PSC can be incredibly tricky to diagnose from my

experience and from what I understand of it. Is there anyone nearby or anyone

you can go to who might have some experience in that area who can give you some

answers and some more peace of mind?

>

> Best of luck to you both!

>

> Sandi in VA/Rochester

>

[Guest guest]

Dear ;

Sorry to hear about your young son's liver disease. It is so difficult

diagnosing PSC because there are so many other diseases that resemble it. In

your son's case, where only the small bile ducts seem to be dissappearing, the

most obvious alternatives would be cystic fibrosis (presumably this would have

been ruled out by the sweat test?), and primary biliary cirrhosis (an

anti-mitochondrial antibody test might have ruled this out?). But then there are

all these other secondary causes of sclerosing cholangitis to consider:

________________________________________

Hepatology. 2006 Nov;44(5):1063-74.

Sclerosing cholangitis: a focus on secondary causes.

Abdalian R, Heathcote EJ

Department of Medicine, University Health Network, Toronto Western Hospital,

University of Toronto, Toronto, Ontario, Canada.

Secondary sclerosing cholangitis (SSC) is a disease that is morphologically

similar to primary sclerosing cholangitis (PSC) but that originates from a known

pathological process. Its clinical and cholangiographic features may mimic PSC,

yet its natural history may be more favorable if recognition is prompt and

appropriate therapy is introduced. Thus, the diagnosis of PSC requires the

exclusion of secondary causes of sclerosing cholangitis and recognition of

associated conditions that may potentially imitate its classic cholangiographic

features. Well-described causes of SSC include intraductal stone disease,

surgical or blunt abdominal trauma, intra-arterial chemotherapy, and recurrent

pancreatitis. However, a wide variety of other associations have been reported

recently, including autoimmune pancreatitis, portal biliopathy, eosinophillic

and/or mast cell cholangitis, hepatic inflammatory pseudotumor, recurrent

pyogenic cholangitis, primary immune deficiency, and AIDS-related

cholangiopathy. This article offers a comprehensive review of SSC. PMID:

17058222.

full text available at:

http://www3.interscience.wiley.com/cgi-bin/fulltext/113412026/PDFSTART

________________________________________

The primary immune deficiencies that can be associated with sclerosing

cholangitis include immunoglobulin A deficiency, and hyper- IgM syndrome.

Drug-induced vanishing bile-duct syndrome is also a possibility to consider:

________________________________________

Expert Opin Drug Saf. 2007 Nov;6(6):673-84.

Idiosyncratic drug-induced liver injury: an overview.

Hussaini SH, Farrington EA

Royal Cornwall Hospital Trust, Cornwall Gastrointestinal Unit, Truro, TR1 3LJ,

UK. hyder.hussaini@...

Drug-induced liver injury (DILI) encompasses a spectrum of clinical disease

ranging from mild biochemical abnormalities to acute liver failure. The majority

of adverse liver reactions are idiosyncratic, occurring in most instances 5-90

days after the causative medication was last taken. The diagnosis of DILI is

clinical, based on history, probability of the suspect medication as a cause of

liver injury and exclusion of other hepatic disease. DILI can be hepatocellular

(predominant rise in alanine transaminase), cholestatic (predominant rise in

alkaline phosphatase) or mixed liver injury. An elevated bilirubin level more

than twice the upper limit of normal in patients with hepatocellular liver

injury implies severe DILI, with a mortality of approximately 10% and with an

incidence rate of 0.7-1.3 per 100,000. Although acute liver failure is rare,

13-17% of all acute liver failure cases are attributed to idiosyncratic drug

reactions. Response to drug withdrawal may be delayed up to 1 year with

cholestatic liver injury with occasional subsequent progressive cholestasis

known as the vanishing bile duct syndrome. Overall, chronic disease may occur in

up to 6% even if the offending drug is withdrawn. Antibiotics and NSAIDs are the

most common cause of DILI. Statins rarely cause significant liver injury whereas

antiretroviral therapy is associated with hepatotoxicity in 10% of treated

patients. Multiple mechanisms of DILI have been implicated, including

TNF-alpha-activated apoptosis, inhibition of mitochondrial function and

neoantigen formation. Risk factors for DILI include age, sex and genetic

polymorphisms of drug-metabolising enzymes such as cytochrome P450. In patients

with human immunodeficiency virus, the presence of chronic viral hepatitis

increases the risk of antiretroviral therapy hepatotoxicity. Over the next

decade, the combination of accurate case ascertainment of DILI via clinical

networks and the application of genomics and proteomics will hopefully lead to

accurate prediction of risk of DILI, so that pharmacotherapy can be optimised

with avoidance of adverse hepatic events. PMID: 17967156.

________________________________________

Genetic deficiencies in certain bile transport proteins such as MDR3 are yet

another potential cause:

________________________________________

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.

________________________________________

Is there any history in your family of drug-induced cholestatis, or cholestasis

of pregnancy?

This is my no means an exhaustive list of secondary causes, but it might help

you formulate some questions to ask?

Best regards,

Dave

(father of (23); PSC 07/03; UC 08/03)

[Guest guest]

Dear ;

Sorry to hear about your young son's liver disease. It is so difficult

diagnosing PSC because there are so many other diseases that resemble it. In

your son's case, where only the small bile ducts seem to be dissappearing, the

most obvious alternatives would be cystic fibrosis (presumably this would have

been ruled out by the sweat test?), and primary biliary cirrhosis (an

anti-mitochondrial antibody test might have ruled this out?). But then there are

all these other secondary causes of sclerosing cholangitis to consider:

________________________________________

Hepatology. 2006 Nov;44(5):1063-74.

Sclerosing cholangitis: a focus on secondary causes.

Abdalian R, Heathcote EJ

Department of Medicine, University Health Network, Toronto Western Hospital,

University of Toronto, Toronto, Ontario, Canada.

Secondary sclerosing cholangitis (SSC) is a disease that is morphologically

similar to primary sclerosing cholangitis (PSC) but that originates from a known

pathological process. Its clinical and cholangiographic features may mimic PSC,

yet its natural history may be more favorable if recognition is prompt and

appropriate therapy is introduced. Thus, the diagnosis of PSC requires the

exclusion of secondary causes of sclerosing cholangitis and recognition of

associated conditions that may potentially imitate its classic cholangiographic

features. Well-described causes of SSC include intraductal stone disease,

surgical or blunt abdominal trauma, intra-arterial chemotherapy, and recurrent

pancreatitis. However, a wide variety of other associations have been reported

recently, including autoimmune pancreatitis, portal biliopathy, eosinophillic

and/or mast cell cholangitis, hepatic inflammatory pseudotumor, recurrent

pyogenic cholangitis, primary immune deficiency, and AIDS-related

cholangiopathy. This article offers a comprehensive review of SSC. PMID:

17058222.

full text available at:

http://www3.interscience.wiley.com/cgi-bin/fulltext/113412026/PDFSTART

________________________________________

The primary immune deficiencies that can be associated with sclerosing

cholangitis include immunoglobulin A deficiency, and hyper- IgM syndrome.

Drug-induced vanishing bile-duct syndrome is also a possibility to consider:

________________________________________

Expert Opin Drug Saf. 2007 Nov;6(6):673-84.

Idiosyncratic drug-induced liver injury: an overview.

Hussaini SH, Farrington EA

Royal Cornwall Hospital Trust, Cornwall Gastrointestinal Unit, Truro, TR1 3LJ,

UK. hyder.hussaini@...

Drug-induced liver injury (DILI) encompasses a spectrum of clinical disease

ranging from mild biochemical abnormalities to acute liver failure. The majority

of adverse liver reactions are idiosyncratic, occurring in most instances 5-90

days after the causative medication was last taken. The diagnosis of DILI is

clinical, based on history, probability of the suspect medication as a cause of

liver injury and exclusion of other hepatic disease. DILI can be hepatocellular

(predominant rise in alanine transaminase), cholestatic (predominant rise in

alkaline phosphatase) or mixed liver injury. An elevated bilirubin level more

than twice the upper limit of normal in patients with hepatocellular liver

injury implies severe DILI, with a mortality of approximately 10% and with an

incidence rate of 0.7-1.3 per 100,000. Although acute liver failure is rare,

13-17% of all acute liver failure cases are attributed to idiosyncratic drug

reactions. Response to drug withdrawal may be delayed up to 1 year with

cholestatic liver injury with occasional subsequent progressive cholestasis

known as the vanishing bile duct syndrome. Overall, chronic disease may occur in

up to 6% even if the offending drug is withdrawn. Antibiotics and NSAIDs are the

most common cause of DILI. Statins rarely cause significant liver injury whereas

antiretroviral therapy is associated with hepatotoxicity in 10% of treated

patients. Multiple mechanisms of DILI have been implicated, including

TNF-alpha-activated apoptosis, inhibition of mitochondrial function and

neoantigen formation. Risk factors for DILI include age, sex and genetic

polymorphisms of drug-metabolising enzymes such as cytochrome P450. In patients

with human immunodeficiency virus, the presence of chronic viral hepatitis

increases the risk of antiretroviral therapy hepatotoxicity. Over the next

decade, the combination of accurate case ascertainment of DILI via clinical

networks and the application of genomics and proteomics will hopefully lead to

accurate prediction of risk of DILI, so that pharmacotherapy can be optimised

with avoidance of adverse hepatic events. PMID: 17967156.

________________________________________

Genetic deficiencies in certain bile transport proteins such as MDR3 are yet

another potential cause:

________________________________________

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.

________________________________________

Is there any history in your family of drug-induced cholestatis, or cholestasis

of pregnancy?

This is my no means an exhaustive list of secondary causes, but it might help

you formulate some questions to ask?

Best regards,

Dave

(father of (23); PSC 07/03; UC 08/03)