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

[Guest guest]

,

Thanks so much for taking the time to find information pertaining to my questions. I have found it all very interesting. You are correct. CF was ruled out with the sweat test. I will be sure and ask about the anti-mitochondrial antibody test. I just want to get an actual name or reason for this disease, but I know that since I'm in the very beginning of this game I could have a long road until then. Plus, our doc says we might never find out which disease it actually is. I wonder what the statistics are concerning patients with out an exact name for their liver disease.I'm sure this is very trying on a person's patience and understanding.

Warm thoughts to all,

son, Nick (9) liver disease 09

Subject: Re: Intro and questions ...cpl more questions.To: Date: Tuesday, March 24, 2009, 2:32 PM

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 EJDepartment 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 EARoyal Cornwall Hospital Trust, Cornwall Gastrointestinal Unit, Truro, TR1 3LJ, UK. hyder.hussaini@ rcht.cornwall. nhs.ukDrug-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 MLaboratory 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)