Authors: Rita Baron-Faust,Jill Buyon
The Autoimmune Connection: Essential Information for Women on Diagnosis, Treatment, and Getting On With Your Life (50 page)
Seventy to eighty percent of autoimmune hepatitis occurs in women, usually before age 30 and less often after age 50 (in older age, it’s more common in men), says Melissa Palmer, MD, clinical professor of medicine at New York University School of Medicine and Global Head of Clinical Development in Hepatology at Shire Pharmaceuticals. But research into possible hormonal aspects is scant.
It is known that processing (
metabolism
) of male and female hormones by the liver can be abnormal in people who have cirrhosis. “Both testosterone
and estrogen can be altered in some people with cirrhosis. In women, estrogen metabolism may be inhibited in some way, and that could be a contributing factor in why some women with cirrhosis have abnormal menstrual cycles or, in severe cases, stop menstruating,” explains Dr. Palmer. “In men, it seems to go the opposite way. Men with cirrhosis often get feminization—
gynecomastia
, enlarged breasts—and a change in hair distribution.”
Primary biliary cirrhosis (PBC)
is a disease predominantly of middle age and older women, but there’s no indication of any link to low estrogen in menopause. “Women may be diagnosed later in life, but they may have had the disease for years. If you biopsy the liver years before the disease was diagnosed, it will usually show some microscopic changes,” she remarks.
Hannah’s story continues:
I started on the prednisone and Imuran a week after my diagnosis. At first I didn’t want to take them; I knew they were really powerful drugs and I was afraid of what they might do to my body. But I also knew that they would help get rid of the inflammation and calm down my immune system.
I was put on a big dose of prednisone, 60 milligrams a day, which acted like caffeine for me—it gave me lots of energy. I didn’t gain a lot of weight, but I did get the steroid moon face. On the advice of a naturopathic physician I had been seeing since before I was diagnosed, I also started taking calcium and magnesium to prevent osteoporosis from the steroids. Thanks to her, I was doing that from the beginning.
Treatment for autoimmune hepatitis is generally indicated if you have:
- Any AIH symptoms
- Significantly elevated liver enzymes
- A liver biopsy showing active inflammation
Immunosuppressive drugs
are the standard treatment for autoimmune hepatitis. You may be given “monotherapy” with prednisone or
prednisolone, or a combination therapy with
azathioprine (Imuran)
, with either prednisone or another steroid called
budesonide (Entocort EC)
. Adding azathioprine helps keep the needed dose of corticosteroids low. Budesonide is more rapidly taken up by the liver, so it has fewer systemic side effects than prednisone.
Even with combination therapy, as many as 80 percent of women will have some side effects with corticosteroids, such as bone loss, weight gain, and mood swings (see
pages 42
to
43
).
7
Prednisone is usually started out at a high dose (60 mg a day), tapered over three months to a lower dose (30 mg), and then reduced to a maintenance dose (20 mg or less).
7
Prednisone starts to improve aminotransferase values and IgG within three to four weeks. However, it can take six to eight weeks for the benefits of azathioprine (50 mg to 150 mg a day) to kick in. So if azathioprine is prescribed, it’s usually started as soon as possible after a diagnosis is made.
Remission is currently defined as the complete normalization of aminotransferase liver enzymes and IgG in lab tests, along with no symptoms or
histological signs (cellular evidence)
, such as inflammation, of hepatitis in a liver biopsy. Be aware that histological improvement may lag behind biochemical remission by three to eight months. However, rates of histological remission actually increase the longer therapy is continued, up to approximately 80 percent after 36 months.
7
Up to 65 percent of women with AIH will experience complete remission. After at least two years in remission, some patients can be weaned off immunosuppressant therapy.
“If they have a flare, they go back on medication, usually permanently. There are no clear-cut triggers for a relapse, but factors like viruses or stress may be important,” explains Dr. Palmer. “Infection with one of the hepatitis viruses may cause a flare, or they may have a worse course of hepatitis A or B. So we recommend that all patients be vaccinated against hepatitis A and B.”
There are risks to long-term maintenance therapy. In younger women, who may require lifelong treatment, there’s a slightly increased risk of cancer with long-term, higher-dose azathioprine. Symptoms of steroid withdrawal, such as body and joint aches, can also occur if corticosteroid doses are
reduced too abruptly. Plus, there’s the risk of corticosteroid-induced osteoporosis.
Most women with autoimmune hepatitis will need lifelong treatment. However, 10 to 30 percent of women will stay in remission without medications after a minimum of four years of maintenance therapy.
A liver biopsy is performed to make sure there is no inflammation before maintenance medications are stopped. Relapses occur most often during the first year after stopping medications, but can also arise many years later, so close follow-up is needed.
Also needing surveillance are women diagnosed with AIH before age 18, those with histological cirrhosis when first diagnosed, and soluble liver antigen/liver pancreas antigen (SLA/LP) antibodies, all of which may be risk factors for poorer outcomes.
8
Immunosuppressive drugs used in transplantation medicine, including
cyclosporine
—either regular (
Sandimmune
) or modified (
Neoral
)—
tacrolimus (Prograf)
, and
mycophenolate mofetil, MMF (CellCept)
,
9
offer alternatives for difficult-to-treat AIH patients. MMF seems especially beneficial for women who are azathioprine-intolerant or those who have haven’t responded to treatment, and it has very rapid steroid-sparing effects.
7
Note that regular and modified cyclosporine are absorbed differently and cannot be substituted for each other. It’s important to make sure you received the same cyclosporine drug each time you get a new prescription refill.
10
The B-cell-depletion
drug
rituximab
(
Rituxan
, see
pages 79
to
80
)
11
and the tumor necrosis factor-alpha blocker
infliximab
(Remicade),
12
both used in other autoimmune conditions, have met with some success in treating refractory AIH.
Liver transplants
can replace a damaged liver, but do not correct the underlying problem in autoimmune hepatitis. “If you start out with a liver that’s badly damaged and you put in a new one, it ‘resets’ the clock. You do have the potential for the return of the disease. But you are starting over and recurrence may take years. Immunosuppressants may also slow the process down,” says Dr. Bodenheimer. “It can be a pretty aggressive disease with or without a transplant, however. What we’re doing is fixing the results of the disease, but not the immune system problem that caused it.”
Menstruation and Fertility
The first sign of AIH in young women is often a stoppage of menstruation,
amenorrhea
.
“Because of menstrual cycle irregularities, it’s hard for some women to become pregnant,” remarks Dr. Palmer. However, treatment with prednisone and azathioprine can normalize menstrual cycles and ovulation, so women can have successful pregnancies and deliveries. Women without cirrhosis have normal fertility.
Oral contraceptives containing estrogen may cause the growth of benign tumors (
hemangiomas, hepatic adenoma
, and
focal nodular hyperplasia
), so women with AIH are usually advised to take all-progestin birth control pills (or a long-acting injection of
medroxyprogesterone
,
Depo-Provera
). Women who have fluid in the abdomen (
ascites
) are advised to avoid progesterone because it can cause sodium and fluid retention.
Oral contraceptives do not protect against sexually transmitted diseases, including hepatitis B (and in rare cases, hepatitis C). Again, AIH is
not
infectious.
Women may have a remission of AIH during pregnancy. “That’s because of the immunosuppressive effects of pregnancy, and perhaps higher estrogen levels,” says Dr. Palmer. “Some women may have a disease flare during pregnancy, but that’s rare.”
Although prednisone is considered safe, azathioprine is usually discontinued as soon as a woman becomes pregnant. Guidelines from the American Association for the Study of Liver Disease (AASLD) advise that “patients must be counseled regarding the uncertain risk of azathioprine in pregnancy, and azathioprine should be discontinued, if possible, in patients during pregnancy.”
13
Women with AIH planning to become pregnant are advised to discontinue azathioprine approximately six months before conceiving, says Dr. Palmer.
If a woman’s steroid dose was reduced because she was also taking azathioprine, she may need an increased dose. If a woman has had a flare of AIH or liver-related complications (such as bleeding from varices), pregnancy should be postponed for at least a year, she adds.
[Author’s note from Dr. Buyon: “Azathioprine has been used safely during pregnancy without evident side effects in the baby in lupus, and recent data in other diseases support its use when needed. As always, a balance between the benefits on maternal health and potential fetal effects should be discussed with patients.”]
Potential harm to a fetus can’t be ruled out with oral budesonide, and it has been found in breast milk.
14
MMF carries the risk of first trimester pregnancy loss and certain congenital abnormalities, such as cleft lip.
15
It’s not known whether rituximab will harm an unborn baby, and it can also be excreted in breast milk.
16
Cyclosporine and tacrolimus also pose risks. So use of these medications is generally not recommended during pregnancy, unless the potential benefits of treatment outweigh the risks.
Hannah’s story continues:
The problem with our medical system is that you see specialists. So I have a doctor that focuses on my liver. And I have a gynecologist who focuses on that. And I have an internist I see for everything else. The gynecologist knows that I have autoimmune hepatitis, but he hasn’t discussed any of the gynecologic or reproductive issues with me. My hepatologist knows I’m taking birth control pills, but he never asked which one or what dose. You have to find out so much for yourself. For instance, I noticed that in the three years I’ve been taking the pill, the symptoms of the prednisone have been minimal. I had bad acne when I first started prednisone, and that cleared up. They’re both good doctors, but neither really looks at the whole person. I found out on my own about the other diseases that people can have with autoimmune hepatitis. The first liver doctor I saw didn’t tell me much about the effects of prednisone on bones, maybe because of my age. This year I had a bone density scan that showed that I had lost a lot of bone despite taking calcium. So now I’m taking Fosamax once a week. I was a bit scared of it at first; you can’t lie down for a half hour after taking it or it can harm the esophagus, and you can’t eat anything for two hours after taking it. Really, you do need a doctor who will give you all the information.
Oral estrogens for menopausal symptoms are not recommended for women with AIH.
“I usually shy away from oral estrogens in women with liver disease, since estrogens may elevate liver enzymes. Women experiencing severe hot flashes or other symptoms who wish to use estrogen can use the estrogen patch or estrogen cream with an oral progestin. Transdermal estrogen enters the bloodstream directly, bypassing the liver on the first pass, so it has lesser effects on the liver,” says Dr. Palmer.
There are several types of estrogen patches, which look like large, clear bandages. They are worn on the lower abdomen, upper thigh, or buttocks and are changed once a week (
Climara
,
FemPatch
) or twice a week (
Alora
,
Vivelle
, or
Estraderm
). Estrogen creams (like
Premarin
) are inserted into the vagina with an applicator to prevent atrophy and drying of tissues. Very little is absorbed into the bloodstream.
There’s no physical reason for sexual dysfunction in women with AIH, but, as in any chronic disease, depression and fatigue can affect libido. Note that androgen therapy may be dangerous. “Some androgens, like anabolic steroids, have been shown to lead to liver cancer. They really have not done the studies to see what kinds of effects androgens will have on someone with liver disease,” remarks Dr. Palmer.
As with other autoimmune diseases, chronic use of corticosteroids causes bone loss. “I give alendronate or one of the other antiresorptive drugs, and I usually follow women with bone density tests,” says Dr. Palmer. “I also tell patients they need to do weight-bearing exercises to protect their bones, as well as take calcium and vitamin D.”
Women with AIH (and primary biliary cirrhosis) are advised to avoid iron, vitamin A, and niacin, which can be toxic to the liver in high doses, unless they are found to be deficient in these vitamins.
“Women may not realize they are getting so much iron, for example, if they take a multivitamin. Also, some herbs may be coated with iron, and this information may not be listed on the label. But too much iron can speed any kind of liver disease,” cautions Dr. Palmer. “I advise women to buy a multivitamin without iron, and not to take any over-the-counter products that contain vitamin A or iron. The best thing is to take vitamins separately.
The only supplements I find helpful are calcium and vitamin D.” However, women in advanced stages of PBC may actually have a deficiency in vitamin A, so get vitamin A levels checked, adds Dr. Palmer. “Supplementation is recommended only if a deficiency is found and a woman experiences night blindness, a side effect of vitamin A deficiency.”
Cases of autoimmune hepatitis that arise in later life can also pose a problem. Women may already have osteoporosis or other medical problems, and steroid drugs may make them worse. So the decision to treat aggressively is highly individualized in older age.