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Autoimmune Hepatitis

Autoimmune hepatitis is characterized by chronic unexplained hepatocellular inflammation. Usually histologically we see interface autoimmune hepatitis hepatitis. Oftentimes these patients have hypergammaglobulinemia. 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. This standard approach has served us well, and importantly, in patients receiving corticosteroids with or without azathioprine who have autoimmune hepatitis, ten-year survival is 

However, this combination is not universally effective and side effects are common. Only about three-fourths of patients who receive corticosteroids with or without azathioprine will enter remission from their autoimmune hepatitis.

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

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

Steatohepatitis 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. Now some series are suggesting that the transplant centers have 1-2% of their patients undergoing transplantation for NASH. There is no effective therapy that’s standard for these patients. Weight loss is frequently advocated but for many of these patients with obesity it’s seldom successful. They’ve been trying to lose weight essentially all their life. I think the other thing that’s been frustrating when weight loss is advocated is oftentimes patients who are told to lose weight and do so, but do so quickly, may actually have what appears to be histologic

There have been a variety of drugs that have been tested or currently undergoing evaluation. Vitamin E in obese kids has looked quite successful. These kids tend to have vitamin E deficiency for unexplained reasons. When vitamin E has been used in patients, adult patients, with NASH however, the results have not been so promising. Although the studies have oftentimes been obscured by use of vitamin E in combination with various other antioxidants.

Betaine is a drug that’s approved for use in homocystinuria in animal models of fatty liver. It led to improvement, and in an ongoing clinical trial - that we have a pilot study - has led to improved biochemistry’s and in two patients, in whom liver biopsies have been repeated after a year, histologic improvement as well. This drug is taken as a powder. It’s unpleasant to take and it’s relatively expensive. I don’t know what its role will be. Troglitazone - I’ll show you a little more information about that in a minute - is Rezulin the new oral hypoglycemic agent and in a small study this looked promising. I’ll also show you some information about ursodeoxycholic acid used in a pilot study for treatment of NASH.

In a study from the University of Virginia six obese patients who are not diabetic but had nonalcoholic steatohepatitis received troglitazone for up to four months. Four of these six normalized their ALT, the test that’s usually most abnormal in NASH patients. This was sustained for at least three months, even after the troglitazone was stopped. So the patients received it for up to four months. The drug was stopped, and when they were followed for up to three months later, they still had improvement in biochemistry’s. These patients had stable weight during this time. I think it’s also important, before I get too enthusiastic about troglitazone or Rezulin, is to recall that the severe hepatotoxicity that can occur with this disease. We’ve seen some patients, now being reported, undergoing liver transplantation. We had an experience with one of our patients with NASH who had been receiving this for management of her diabetes, and had a bilirubin that rose to 55. It’s now back down to under 2, but it does mean that troglitazone is something that ought to be probably used cautiously or at least only currently in the context of trials.

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. The shaded area here shows the 95% confidence interval for the change over one year. A modest change in alkaline phosphatase, ALT and gamma GT. Importantly, there is some modest reduction in the grade of fat in biopsies. This is really all the evidence that is available supporting ursodeoxycholic acid alone for NASH. Recently a study was reported that looked at the use of