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This is Episode Six of “Autoimmune Disease: Pieces of the Picture.” Dr. Jama Darling talks about autoimmune hepatitis, the importance of liver biopsy, how it is different from other types of hepatitis, and treatments of the disease. Dr. Darling is an Assistant Professor of Medicine in the Division of Gastroenterology and Hepatology.

Jama Darling, MD

“When we have diagnosed a patient with autoimmune hepatitis, one of the most common questions I get is, ‘I’ve never done drugs or had a blood transfusion. I don’t drink alcohol—why on earth do I have hepatitis?

I explain to the patient that they don’t have a virus, they don’t have a blood-blood transmission virus like hepatitis C, it isn’t due to a behavior such as excess alcohol intake.. Their immune system is recognizing something in the liver as unwanted and trying to get rid of it, and this is of no fault of their own.”

– Jama Darling, MD

Ron Falk, MD: Hello, and welcome to the Chair’s Corner from the Department of Medicine at the University of North Carolina.

Welcome to our series where we are exploring topics related to autoimmune diseases, to help patients and their loved ones understand and manage their condition. Today we’re going to focus on autoimmune hepatitis. We welcome Dr. Jama Darling who is an Assistant Professor of Medicine in our Division of Gastroenterology and Hepatology. Dr. Darling specializes in the treatment of hepatitis and other chronic liver diseases. Welcome, Jama.

Jama Darling, MD: Thank you.

Autoimmune hepatitis & how it is diagnosed

Falk: What on earth is autoimmune hepatitis? What do those words really mean?

Darling: Autoimmune hepatitis is a chronic liver disease. It can affect any aged patient, any ethnicity, it can affect either sex, usually has a female-to-male predominance of about 3:1. Hepatitis just means inflammation of the liver.

Falk: Remind me again, what does the liver do?

Darling: The liver does a lot of important things. For one, it metabolizes nutrients from the gut, it makes bile which helps you digest fats, it makes a lot of important proteins, specifically—all of your clotting factors except for one, and proteins that help fluids stay in the right spaces. It also detoxifies certain drugs or medications.

Falk: When you inflame a liver, just like when you inflame any other organ, the suffix is “-it is;” the liver is the hepatic system, so hepatitis which is inflammation of the liver from any number of causes.

Darling: Absolutely. The liver is made up of liver cells or hepatocytes, and it’s made up of small and large bile ducts, and for the most part it implies that this is inflammation of the liver cells themselves, the hepatocytes. It is usually manifested as elevated liver enzymes, so AST, ALT—these are blood tests and it is reflective of turnover of liver cells.

Falk: The liver can be affected by a number of factors. One can get hepatitis from alcohol, one can get hepatitis from a number of drugs, one can get hepatitis from certain viruses. What’s the most common of those entities?

Darling: Viral hepatitis is an easy one to check for. That’s routinely done with a blood test. Normally we’ve eliminated viral causes of liver inflammation.

Falk: Hepatitis C and hepatitis B. And the one on the ads on the news are for treatment for hepatitis C.

Darling: Correct. That one has certainly gotten press lately. Alcohol, that’s a different form of hepatitis. Usually a good history will tell us if that’s a factor. We also look for genetic or metabolic causes of liver disease, or drugs. It turns out that autoimmune hepatitis is actually more of a diagnosis of exclusion. There are diagnostic criteria for autoimmune hepatitis – we usually look for autoantibodies, of which anti-nuclear antibody, anti-smooth muscle antibody, several others. We look for immunoglobulin levels. We look for absence of a virus in the liver. Last, but certainly not least, we look at histology of the liver. Histology of the liver consistent with the diagnosis. Actually, the hallmark of autoimmune hepatitis is the diagnostic histology. A biopsy is actually an essential part of the diagnosis because twenty percent of the patients will not have circulating antibodies and normal immunoglobulins. The liver biopsy is a very important part of the diagnosis.

Falk: When you do a liver biopsy under ultrasound guidance, and they’re pretty safe procedures.

Darling: Absolutely. This is one of the forms of chronic liver disease where a biopsy is very important. A liver biopsy is a safe procedure, it’s a subcutaneous or through the skin biopsy. It involves usually an ultrasound guidance, and it can be done either with or without sedation, but it’s always done with a local anesthesia.

Falk: There can be a stigma with liver disease that’s really associated with something that they’ve done to themselves – have drunk too much alcohol, or taken a drug that’s hurt them, but really in autoimmune hepatitis in which your body is reacting to the liver, the patient has no reason to think for a moment that they’ve caused this, and it’s something to figure out.

Darling: When we have diagnosed a patient with autoimmune hepatitis, one of the most common questions I get is, “If never done drugs or had a blood transfusion. I don’t drink alcohol—why on earth do I have hepatitis?” The perception is, I explain to the patient that they don’t have a virus, they don’t have a blood-blood transmission virus like hepatitis B or hepatitis C, it isn’t due to a behavior such as excess alcohol intake but this is the way they’re built, basically. Their immune system is recognizing something in the liver as unwanted and trying to get rid of it, and this is of no fault of their own.

Falk: If we could figure out what caused any autoimmune disease, it would be a pathway to figuring out a cure.

Symptoms of autoimmune hepatitis

Falk: Patients with autoimmune hepatitis—you describe them as asymptomatic, they don’t know it’s happening, but something there are associated symptoms, right? Everyone with autoimmune disease is fatigued or tired. What else would a patient with autoimmune hepatitis—what other kinds of symptoms might appear?

Darling: There’s a huge spectrum of presentation with autoimmune hepatitis, from asymptomatic with minor liver enzyme elevations to a much more dramatic presentation in which the person’s liver is really not functioning well. These patients usually present with mild jaundice, meaning they have yellowing of the eyes and darkening of urine, they can present confused—the liver processes a lot of toxins and the toxins build up if the liver’s not working. They can also present quite ill in full liver failure. So there’s a huge spectrum.

The majority of the patients that we see have liver enzyme elevations but they can have a little bit of nausea, they can have a little bit of discomfort in their right upper abdomen, they can have a lot of fatigue which they didn’t realize was associated with autoimmune hepatitis. They may have periodically noticed darkening of the urine or mild yellowing of the eyes, but it sort of waxes and wanes—this is characteristic of autoimmune liver disease. A lot of patients take a number of years to be diagnosed because it does spontaneously remit in some patients. Hence, up to a third of patients at the time of diagnosis will actually have cirrhosis of the liver or bad scarring in the liver, as if this process has been going on for quite some time.

Falk: Like many autoimmune diseases, there is a relapsing and remitting course, and a waxing and waning course. Since most autoimmune diseases come and go, and you’ve just described beautifully that patients can have mild disease almost on presentation have a very aggressive liver disease, arguing that prompt referral to somebody who treats liver disease it’s pretty important to find out where on that spectrum you are.

Darling: Yes, if you present to the hospital with liver dysfunction and actually have fulminant liver failure, the patients do need to be referred promptly to a liver center. Also, if it’s not clearly obvious, the etiology of the underlying cause for liver enzyme dysfunction, these patients we would like to see sooner rather than later. Hepatitis is not a particularly common disorder and often times can be missed by the general gastroenterologist.

Falk: Or primary care provider.

Treatments available for autoimmune hepatitis

Falk: So the reason why you want to see someone earlier in their course, is due to you want to make a correct diagnosis, and if they have an autoimmune disease, you’d like to treat them. What kind of treatments are available now?

Darling: We definitely like to see these patients where we can intervene sooner rather than later because it is a reversible process oftentimes, even if the patient has advanced fibrosis or early cirrhosis.

Falk: Scarring of the liver, in other words, and the disease process is no longer inflammation. We use the word “cirrhosis” or scarring, the liver has scarred like a cut on the skin.

Darling: Right, and when a patient has cirrhosis, we often describe it as bad scarring in the liver. The liver may continue to do its job, but it doesn’t have good reserve if it is badly scarred. In regards to treatment for autoimmune hepatitis, steroids or prednisone is a mainstay of treatment. Often it works as a therapeutic and diagnostic therapy.

Falk: In other words, if you get better when you’ve been given prednisone, you would wonder then if that person had autoimmune hepatitis.

Darling: Actually, sometimes a patient may have negative serologies or blood tests and the biopsy is consistent with, but not classic for, autoimmune liver disease. If the patient is given a trial of steroids and they improve very rapidly, this is a good indication that this is autoimmune hepatitis. Steroids have been the mainstay, but long term therapy with steroids has its disadvantages like side effects over time. We usually try to use a steroid sparing agent to complement, or be able to lower the dose of the steroids or the prednisone. We usually use azathioprine – that is the medication that probably we all have the most experience with, and if the patient is intolerant of azathioprine or mercaptopurine, another form of azathioprine, we can use another drug that works similarly called mycophenolate mofetil.

Falk: So there are plenty of options.

Darling: Absolutely. There are a number of different drugs that allow us to lower the dose of prednisone over time. I think this is both a response-driven therapy and a patient-individualized therapy.

Falk: So by response-driven, you’re looking to see whether or not those blood tests that tell you whether the liver is being damaged are improving or going back to normal.

Darling: Yes, normalization of liver enzymes, specifically the AST and the ALT, the immunoglobulins have been elevated, we look for normalization of the immunoglobulins.

Falk: If you start a patient on one of these immunosuppressives, is that a lifelong therapy or can you stop the drug at some point in time?

Darling: That is certainly a frequently asked question, because these are immune-modulating therapies. Ideally once you start a patient on therapy for autoimmune hepatitis, they should stay on a minimum of three years. That is three years of stable dose of medication with normal liver enzymes. If the patient has no evidence of cirrhosis and has done very well after three years of therapy, often times we will try to decrease the immunosuppression. Unfortunately, only about 20-25% of patients can be successfully withdrawn from therapy. So this is really more to be felt as more of a chronic liver disease. Even in patients in which we are able to withdraw therapy, these patients do need to continue to be monitored closely, meaning getting liver labs drawn every three to six months.

Falk: Let’s go back to this biopsy. I’m a patient and I’ve just gotten a liver biopsy, and you’re telling me that the biopsy may not actually tell me what’s wrong with me?

Darling: Actually, the biopsy will oftentimes eliminate other possibilities. It wouldn’t look like viral hepatitis, it’s unlikely to look like steatohepatitis or inflammation from fat in the liver. I think it’s difficult sometimes to tell the difference between a drug effect and an autoimmune liver disease, but there are certain classic features that we look for on a liver biopsy that tells us that this is much more likely to be an autoimmune hepatitis. Actually this is where having a good liver pathologist review the biopsy slides is really important. That’s one of the first things we do when we have a new autoimmune patient, even if they’re already biopsied, is look at their slides.

Considerations for pregnancy

Falk: Let’s take the special circumstance of a young woman with autoimmune hepatitis and hopefully under reasonable control. Is it possible for them to become pregnant, and is it safe for them to do so?

Darling: It is safe for a patient with autoimmune hepatitis to become pregnant. It’s one of the most common questions that I get, because it’s a disease that’s often seen in young females of childbearing age. We really like for the patient to be on a stable dose of medication and for them not to have a flare within the last year. We like to keep patients on medications during pregnancy, especially azathioprine in pregnancy and a low dose of prednisone if needed. We obviously don’t recommend mycophenolate mofetil but we do keep our patients on azathioprine. If a patient already has cirrhosis, we’re usually very protective or careful with our patients. Often times I send a patient to preconception counseling if they are interested in becoming pregnant.

Falk: In reality, patients who are on mycophenolate mofetil—the trade name is Cellcept—shouldn’t be getting pregnant to start with because of the real risk of fetal abnormalities with that drug.

Autoimmune hepatitis & lifestyle changes

Falk: What kind of changes in lifestyle do patients with autoimmune hepatitis need to do? Or do they need to try to maintain their normal lifestyle as best as possible?

Darling: I think certainly they should try to maintain their normal lifestyle as best as possible. Most patients do feel better once their autoimmune liver disease is under good control. In general, if you decrease inflammation, you usually feel better. We do remind patients that it’s very important for them to have blood monitoring, so they need to get blood work about every three months, even if they’re on a stable dose of medication. If they already have early cirrhosis, they’re going to need an ultrasound every six months to look for liver cancer which is a risk if you have more advanced scarring in the liver. In general, we want patients to try to maintain a healthy lifestyle and do the things they enjoy doing including working and playing sports.

Falk: What do you tell patients about the fatigue, because that more than likely is the last thing to go away?

Darling: In regards to fatigue, I think I don’t necessarily have a great answer for that one. Our patients that are under a lot of stress and are not sleeping, we try to do things that help with getting a good night’s rest, especially if they’re stressed about their condition, encouraging some sort of physical activity improves that.

Falk: Sometimes the fatigue is just hard to deal with. One of the main causes of hepatitis as you’ve described are viruses—you described them as blood-blood transmission. What about autoimmune hepatitis? Am I worried about giving that to a loved one or friend?

Darling: No, and that’s actually a common question we get. Certainly you can’t pass it on to your co-workers or your friends; this is not a blood-blood transmission hepatitis, this is your own personal hepatitis so to speak, in which your body’s immune system is recognizing something in the liver is foreign.

Falk: If you have autoimmune hepatitis, is it okay to drink alcohol?

Darling: It’s a great question and one we often get. If you already have cirrhosis of the liver or advanced scarring in the liver, we want to be as protective of the liver as we can, and we want you to not drink alcohol. Anyone with chronic liver disease, if they don’t have significant scarring, modest or light alcohol consumption, at most one drink a day for a woman and two drinks a day for a man.

Falk: The only way then that a person knows they have cirrhosis or scarring of the liver is with a liver biopsy. Are there non-invasive ways of figuring this out?

Darling: A liver biopsy is necessary for the diagnosis of hepatitis, gives us some good prognostic information. We can judge how aggressive the hepatitis and how much scarring there is in the liver. That’s one way of showing us liver fibrosis, or liver scarring. As far as non-invasive ways of tracking liver scarring, interestingly, autoimmune hepatitis we can follow patients with non-invasive methods. You can look at lab work.

You can also use something call transient elastography – it measures liver stiffness, or how soft or hard the liver is and it takes about five minutes to do, and it’s painless, it’s non-invasive. Interestingly, autoimmune hepatitis it has not been used as frequently as it has bene with other forms of liver disease such as hepatitis B or hepatitis C.

Falk: Where should patients turn for a trustworthy source for information about autoimmune hepatitis?

Darling: A good resource would be the American Liver Foundation, it has a number of different patient support sites and links as well as patient information.

Falk: Thank you, Dr. Darling for joining me on this podcast, and thanks to our listeners for tuning in. If you enjoy this series, you can subscribe to the Chair’s Corner on iTunes or like us on FaceBook. Stay tuned for our next episode.