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Primary Sclerosing Cholangitis

Primary sclerosing cholangitis, this is a cholestatic liver disease. It has fibrotic stricture in the bile ducts. It is more common in men. Not like primary biliary cirrhosis, which affects women 90% of the time, and most of these patients have underlying colitis. Here’s ERCP showing a cholangiogram in a patient with primary sclerosing cholangitis, and here’s a view of an MR cholangiogram, which is an emerging new technology. This shows pancreatic duct here, bile duct and then shows changes intrahepatically that would be consistent with primary sclerosing cholangitis. This technique is relatively new. It’s non-invasive, does not use any radiation and uses no contrast, so it has a lot of advantages compared to invasive cholangiography. The disadvantage of it, however, is the lack of application of therapeutic options. In a study that we’ve recently completed, about 70% of the patients with primary sclerosing cholangitis required endoscopic manipulation during the time of their cholangiogram. So MR cholangiogram is a very useful test, diagnostically.

Patients with primary sclerosing cholangitis, it turns out, frequently require sampling. Sampling either with brushes or biopsies, dilatation, or stone extraction. So the role of MR cholangiography and invasive cholangiography is still being worked through, but it does have a lot of promise as a simple diagnostic study.

There are no proven treatments for patients with primary sclerosing cholangitis. The ones not in italics have all been tested in randomized controlled trials and none of these - even though some of the numbers are small - have been proven efficacious. Nicotine and pentoxifylline in pilot studies do not look effective. You heard yesterday about the relationship of smoking and ulcerative colitis, smoking and PSC. Patients with PSC are less apt to be smokers so we thought if nicotine might be useful in colitis, and there’s the same relationship to smoking there, why don’t we try it in PSC? It didn’t work. An elegant animal model of cholangitis by Steve Leckman of University of North Carolina showed the importance of tumor necrosis factor in developing a lesion that looked like PSC. We used pentoxifylline, a weak TNF inhibitor, to see if it may have any beneficial effect in humans.

The use of ursodeoxycholic acid in patients with primary sclerosing cholangitis I think is controversial. Some of the earlier small studies suggested benefit. One randomized study in 14 patients suggested histologic improvement. During the largest study, liver tests were improved but the clinical course was unaltered. In a slide or two I’ll show you that higher doses might be promising. This shows some of the modest biochemical improvement seen comparing placebo to ursodiol at one and two years. Alkaline phosphatase, AST and bilirubin. Unfortunately, when we looked at survival free of treatment failure there really wasn’t any advantage to using the ursodiol compared to the placebo therapy.

We’ve been involved with a couple of other pilot studies, three other pilot studies. You heard about budesonide yesterday as a synthetic steroid with fewer side effects. One of our concerns in patients with liver disease is that the hepatic metabolism that we count on to reduce the systemic side effects might not be occurring. In this graph we compare liver biochemistry’s, changes in liver biochemistry’s, at six months from the placebo trial. The standard dose of ursodiol’s trial, budesonide, perphenadone, which is a new anti-fibrotic agent, and high dose of ursodiol, 25-30 mg per kilogram, and I think that in this tabulation, you can see that the most promising of these agents looks to be high dose ursodeoxycholic acid. We are in the process of completing this study and have recently submitted a proposal for a long term, randomized trial.

Autoimmune hepatitis can be characterized as chronic unexplained hepatocellular inflammation. Usually histologically we see interface hepatitis, or the old term as piecemeal necrosis. The various autoantibodies, oftentimes these patients have hypergammaglobulinemia. The initial therapy evaluations occurred about 30 years ago, over 30 years ago.

I’m almost embarrassed to show you this slide because this is really the survey of studies looking at new therapies for patients with autoimmune hepatitis. You can see the small number of patients that are studied. The first and the last study are really looking at alternatives to azathioprine as corticosteroid-sparing agents. These studies looked at 6-mercaptopurine, which is the active moiety to which azathioprine is metabolized, to be used instead of azathioprine for those patients, those few patients, who cannot tolerate azathioprine. This looked like, in these three patients, an acceptable alternative. Cyclophosphamide, Cytoxan, a cancer cytotoxic drug, was also used in three patients along with corticosteroids instead of azathioprine and appeared to offer some benefit. Cyclosporine and ursodeoxycholic acid have been tested as primary therapies, but again just in a very small number of patients in both of these series, however these agents look promising. Cyclosporine has a number of toxicities but in this study of the five patients, four patients entered remission, the fifth patient required liver transplantation. Ursodeoxycholic acid in a low dose has recently been reported in a Japanese study to lead to a fairly frequent induction of biochemical remission and some histologic remission as well, most likely. But again, the number of patients is quite small.

Steatohepatitis. This is characterized by maculovesicular steatosis. These patients tend to have lobular and portal inflammation. They may have Mallory’s hyalin, fibrosis or cirrhosis. Really an appearance that resembles alcoholic liver disease. But in the absence of a history of alcohol abuse. This is a common disorder. Depending upon the degree of obesity in a population it may affect up to 1-2% of given populations. Diabetes, obesity and hyperlipidemia are risk factors for this entity. Some of these patients will have iron overload, especially with severe disease, but this may be a secondary phenomenon much as Jack described in his talk on hemochromatosis. Occasionally these patients require liver transplantation.