Authors: Rita Baron-Faust,Jill Buyon
The Autoimmune Connection: Essential Information for Women on Diagnosis, Treatment, and Getting On With Your Life (49 page)
Assault on the Liver—Autoimmune Hepatitis and Primary Biliary Cirrhosis
I turned yellow when I was a senior in college. Having jaundice was the first sign that there was something really wrong with me. I had been under a lot of stress, was feeling tired and lethargic, and had no appetite. But I hadn’t been sleeping or eating that well, and I had just gotten over the flu. So nothing really rang alarm bells until a friend of mine said to me, “You don’t look so well—you look yellow.” I looked in the mirror, and sure enough, I was. I went to the college health center and they tested me for everything possible: mono, hepatitis A, hepatitis C, Epstein-Barr virus. My tests did show I’d been exposed to Epstein- Barr virus, but there were no viruses in my blood. The only thing they found was that my liver enzymes were off the charts. But I tested negative for primary biliary cirrhosis and gallstones. So no one knew what was wrong with me. The college sent me to a couple of local doctors; one of them was even a liver doctor. And he said it was probably mono, that 4 percent of people with mono had jaundice. He told me I’d been working too hard, and to take it easy. It took two and a half months and four doctors to find out what I really had.
H
ANNAH
, 27
T
he liver is the body’s main chemical processing plant. Autoimmune diseases can cause it to seriously malfunction, spilling chemicals into areas where they shouldn’t be and damaging the processing equipment.
The liver’s amazing processing system makes bile to help digest food; stores iron (along with vitamins and minerals); and stockpiles carbohydrates, glucose, and fat until the body needs them for energy. The liver manufactures components of blood, including clotting factors to stop bleeding and help wound healing, and detoxifies the various chemicals we ingest, including alcohol and drugs (both legal and illegal). In fact, much of what we eat, drink, breathe, and even absorb through the skin passes through the liver to be detoxified and excreted in bile. The liver also makes cholesterol, a fat needed by all the cells in our body, and proteins that help carry fats in the bloodstream (having too much of certain types of cholesterol and other blood fats contributes to heart disease). It also produces complement, which plays a role in many autoimmune diseases.
Autoimmune hepatitis (AIH)
and
primary biliary cirrhosis (PBC)
affect the small bile ducts in the liver.
Sclerosing cholangitis
affects the larger bile ducts and is primarily seen in men. These diseases are caused by an immune attack on specific cells in the liver and bile ducts, producing inflammation and scarring (
cirrhosis
), eventually compromising the liver’s ability to function. Autoimmune hepatitis occurs four times more often in women than men; PBC strikes women 6 to 10 times more often than men, mostly in middle age and later life.
“I often use an analogy to describe the liver as a tree. The
hepatocytes
, the cells of the liver, are the leaves; the bile ductules are the twigs and small branches, and the bile duct is the trunk. In autoimmune hepatitis, the immune system attacks the hepatocytes, the leaves of the tree; in PBC, it attacks the bile ductules, the twigs. And in sclerosing cholangitis, it attacks the bile duct, the trunk of the tree and the major branches,” explains hepatologist Henry C. Bodenheimer, Jr., MD, professor of medicine at the Hofstra North Shore-LIJ School of Medicine.
“Think of these diseases as arthritis of the liver or bile ducts. Just as in arthritis, where there’s inflammation in the joints and destruction of the joints, there is inflammation and scarring in the liver,” says Dr. Bodenheimer, who also serves as medical director of the Medicine Service Line for the North Shore Health System in Manhasset, New York.
In some women, the scarring becomes so extensive that the liver begins to fail and a transplant is needed. Although some women can experience a remission, autoimmune hepatitis is a disease that may require lifelong treatment.
The Liver and Bile Ducts
When you think of hepatitis, you probably think about the infectious kind—hepatitis A, B, or C—but autoimmune hepatitis is not like infectious hepatitis. It’s a distinct condition, caused by an immune system assault on the liver. Why this happens is still unknown; a number of genes have been linked to vulnerability to the disease, and there are some suspect environmental factors. AIH typically hits women during their twenties, and there’s another peak during the sixties. Between 10 and 20 percent of cases of chronic hepatitis are due to AIH.
The disease does not often make its presence known early. The most pronounced outward sign, yellowing of the whites of the eyes and the skin (
jaundice
), appears only after the liver has sustained severe damage. Only in 25 percent of cases does AIH begin with an acute episode of hepatitis.
1
While there’s no link between autoimmune hepatitis and any of the infectious hepatitis viruses, some women with AIH may have had a past infection with
hepatitis C and gotten over it without ever knowing they had it. Between 15 and 40 percent of people infected with hepatitis C completely clear it from their system.
1
As many as 5 percent of people with AIH may have false-positive antibody tests to the hepatitis C virus (10 percent of people with viral hepatitis may also have autoantibodies). “We can test for the presence of hepatitis C virus, and do a sensitive test,” says Dr. Bodenheimer.
Instead of a viral attack on liver cells, in autoimmune hepatitis the damage is done by T cells and liver-specific autoantibodies, including
antinuclear antibodies (ANAs), smooth muscle cell antibodies (SMA)
, and
anti-liver microsomal antibody type 1 (anti-LKM-1)
also known as
liver kidney microsomal type 1 antibodies
.
1
But the trigger of this attack is not known.
A liver biopsy will reveal T cells and plasma cells (activated B cells), which manufacture autoantibodies (see
pages 4
to
5
). As inflammation and damage progress, liver tissues become hardened (
fibrotic
) and scarred. Progressive scarring called
fibrosis
spreads throughout the liver, leading to extensive damage termed
cirrhosis
. Eventually liver blood flow is impaired, choking off vital nutrients, and cells begin to die (
necrosis
). As more and more liver cells die,
the liver begins to fail. Although immunosuppressant drugs can slow this process, some women eventually require a liver transplant.
Among the genes associated with autoimmune hepatitis are genes linked to rheumatoid arthritis, in particular genes called
DR3 and DR4
.
1
Patients with DR3 often have a faster progression of the disease and fewer remissions, and require a transplant more often. Women may also have other immune abnormalities or a family history of autoimmune diseases, such as thyroid disease or ulcerative colitis.
Autoimmune hepatitis may be triggered by environmental factors, such as a virus, bacteria, chemicals, or drugs.
2
Drugs linked to AIH include the antibiotic
minocycline
, cholesterol-lowering drugs called
statins
, and, possibly, the tumor necrosis factor-alpha (TNFα) blockers
adalimumab (Humira)
and
infliximab (Remicade)
.
1
Drug-induced autoimmune hepatitis can be reversed when the medication is stopped.
2
Some studies have suggested—but not proven—that AIH can develop after infection with hepatitis A, B, or C. Other suspect viruses include Epstein-Barr virus (EBV), measles virus, and herpes simplex type 1 (HSV-1).
Molecular mimicry
, in which liver cells resemble invading pathogens, may be another mechanism involved in AIH.
1
However, no single trigger has yet been linked to AIH. Other cofactors may be needed, such as genes, female hormones, alcohol, and nicotine that upregulate or downregulate the immune system or liver enzymes that metabolize drugs, which, by being unusually elevated, may provoke an immune reaction.
Hannah’s story continues:
I was getting ready to go home for Christmas when I saw the first liver doctor, who had said I had mono. I even asked him if it was OK to drink alcohol. He told me it was fine to have a beer or two. That amazes me now. By then, the jaundice had gone away, I started feeling better. I got my appetite back. I figured he must be right; it was mono. But while I was visiting my mother that January, the jaundice came back. I lost my appetite, and had this gurgling in my stomach, which I realized later were other symptoms of autoimmune hepatitis. My stools had also been white
and my urine bright yellow, but I hadn’t paid it much attention the first time. My mother said my eyes were the color of electric daffodils—that’s how yellow I was when the jaundice came back. My mother made me promise I’d see a doctor.When I got back to college, I did go back to the local hepatologist, who realized it wasn’t mono. He tested me for antinuclear antibodies and smooth muscle antibodies and said, “You have this rare disease, autoimmune hepatitis.” I had a liver biopsy, and fortunately my liver wasn’t damaged—there was no cirrhosis. The most uncomfortable thing about the biopsy is that even though the needle goes into your right side, you feel a pain in your left shoulder. But I was very lucky. Some people only have symptoms when their liver is so damaged that their only hope is a liver transplant.
AIH can be present for some time before producing any symptoms at all. Typically, the disease has been present for at least six months (or longer) before a woman is diagnosed.
“Often a woman will come in after having abnormal liver test results. She may be taking medications that require liver monitoring, or maybe she’s just not feeling well. Fatigue is a very common symptom,” remarks Dr. Bodenheimer.
Up to 40 percent of people with AIH present with apparent acute liver injury, but others can have a subclinical disease with very small elevations of liver enzymes.
There can be ethnic and racial differences in the way AIH presents, as well. For example, African Americans have cirrhosis more frequently than do white women. Asian Americans may have milder, later onset AIH, while Native American women may have more advanced disease and other immune disorders.
3
Liver Enzyme Tests
are often part of routine blood work and include
bilirubin
, various liver proteins, biliary associated
liver enzymes
like
alkaline phosphatase
(indicating inflammation or blockage of bile ducts), and
aminotransferases
, which are elevated when there’s inflammation or injury to liver cells. These enzymes can be elevated in a number of conditions, viral hepatitis, alcoholic liver disease, medication-induced liver disease, nonalcoholic “fatty” liver (excess fat deposits), and liver tumors. So when liver enzymes are elevated, these other problems must be ruled out.
4
Gamma globulins/immunoglobulins
components of blood plasma that respond to bacteria or viruses, especially
immunoglobulin G (IgG)
, are considered a hallmark of the disease.
Liver biopsy
is the usual way of diagnosing AIH to see whether there is inflammation and/or scarring.
Your liver is located on the right side of your body underneath the diaphragm. Under local anesthesia and ultrasound guidance, a hollow needle is gently inserted between the right lower ribs to take a small tissue sample the size of a pencil lead that’s analyzed by a pathologist. If autoimmune hepatitis is present, the tissue sample will show an infiltration of T cells and plasma cells, as well as scarring and tissue death. Even though the tissue sample is small, a liver biopsy usually indicates what’s going on in the rest of the liver, as well as how severe the disease is, says Dr. Bodenheimer.
Autoantibody Tests.
Almost all AIH patients have autoantibodies. In North America, an estimated 96 percent have
antinuclear antibodies (ANAs)
or
anti-smooth muscle antibodies (SMAs)
or both. These are detected in liver cells by using a staining process that makes them fluorescent when seen under a special microscope (a technique called
immunofluorescence
).
There are two subcategories of AIH, depending on which antibodies are found.
The most common is type 1, or classic AIH, in which there are elevated ANAs and SMAs. In the less common type 2 AIH, levels of
LKM-1 antibodies
and/or
anti-liver cytosol type 1 antibody (anti-LC-1)
are elevated and the disease seems to have a more rapidly progressing course.
3
However, the subcategory of AIH you have will
not
determine your treatment. LKM-1 is mostly found in young women and children.
1
Around 80 percent of AIH patients have type 1, with the majority women ages 16 to 30.
3
The International Autoimmune Hepatitis Group (IAIHG) has a 17-point scoring system to help diagnose AIH.
5
In the scoring system, being a woman is two points; having elevated aminotransferases is another two points.
Included in the list: levels (
titers
) of autoantibodies (ANAs, SMAs) are one to three points each, depending on the level detected; increased gamma globulin (two times the normal level is three points); and having another autoimmune disease is one point. If your score is 10 to 15 points, the diagnosis is “probable” AIH; a total score of 15 or greater is “definite AIH.”
5
This scoring system can also be used to determine if asymptomatic patients need treatment. The IAIHG is studying a simpler system for routine clinical use.
6