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Primary Biliary Cirrhosis

Primary biliary cirrhosis is chronic cholestatic liver disease. It primarily affects middle-aged women, 90% of the patients affected are women. Anti- mitochondrial antibodies are found in virtually all of these patients. A variety of other autoimmune conditions can complicate this disease. Ursodeoxycholic acid is a bile acid which alters the bile acid pool. It has some properties that suggest it is cytoprotective, and it also has some features that make it seem like it might be immuno-modulatory. It has been approved now, about 15 months ago, by the FDA for treatment of PBC. It’s been shown to be safe and effective. These patients, once started, probably need life-long therapy.

The same is true for primary biliary cirrhosis. If the drug is stopped, even after 10 years, the liver biochemistry’s start looking like untreated disease. So life-long therapy is probably going to be necessary. There is no doubt that ursodeoxycholic acid improves liver tests. It’s been shown in a Canadian study to now reduce pruritus. We’ve shown that is slows the progression to cirrhosis. Over a five year period, the risk of developing cirrhosis is cut to about 25% with ursodeoxycholic acid therapy.

I think because it slows the progression to cirrhosis and also prevents the development of varices, again over a four year period, it reduces the risk of developing varices by three to fourfold. Also most importantly, it improves survival free of liver transplantation.

This slide shows the effects of ursodiol compared to patients initially randomized to placebo and then receiving ursodiol on average for the last year. This is data from three large studies using the same dose, 13-15 mg per kilogram of Urso and showing a statistically significant survival benefit. One of the things people ask about is which of these patients ought to receive ursodeoxycholic acid? The data that we had was a large enough data set that we were able to break it into three groups. Those with low bilirubin, moderate bilirubin elevations and substantially raised bilirubin elevations.

I think one of the things that’s important to recall is that when treating people with PBC with ursodeoxycholic acid an adequate dose needs to be used. In this study we compared three different doses, 150 patients were randomized, either 5-7 mg, 13-15 mg or 22-25 mg per kilogram per day. Duodenal bile acid enrichment was considerably greater in the patients.

Liver biochemistry is improved in all groups but more impressively in the patients receiving the two higher doses. The Mayo risk score, which is a reasonable predictor of prognosis - even in the face of ursodiol therapy.

A variety of drugs have been used as adjuvants; steroid ursodeoxycholic acid, colchicine although it has excellent tolerability, was not efficacious. Methotrexate has had, in a couple of the pilot studies that have been presented, a fair amount of toxicity. There’s a large U.S. multi-center trial that is currently ongoing. Over 200 patients are entered into that. The dose of methotrexate is a little bit lower and it is gradually tapered upward. In that study the tolerability seemed better.

Cholesarcosine, a synthetic bile acid which is designed to increase the percentage of ursodiol in the bile was poorly tolerated and didn’t seem effective in a small pilot study. Corticosteroids have been tested. Most often the corticosteroids are well tolerated. Occasionally they can worsen the bone disease. Their efficacy is somewhat marginal.

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. And because of the therapy that was evaluated was so effective - that is, corticosteroids with or without azathioprine - there really has been a paucity of new studies over the past 30 years.

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.

Ursodeoxycholic acid now seems to be a popular therapy for patients with NASH but the data upon which these decisions have been based are relatively sparse. Twenty-four patients were treated for up to a year with the dose that would be used for treating PBC, 13-15 mg per kilogram. Modest improvement in alkaline phosphatase. This shows, the line here, shows no change.