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autoimmune hepatitis has been recognized for more than 40 years, only the
advent of diagnostic tests for infections with hepatitis B and C viruses has
permitted it to be reliably identified. Even so, up to 5 percent of patients
with autoimmune hepatitis have false positive tests for antibodies to
hepatitis C virus, and about 10 percent of patients with viral hepatitis
have autoantibodies. Nonetheless, it is clear that autoimmune hepatitis and
hepatitis C are completely distinct conditions. There is no evidence of a
link between infection with one of the hepatotropic viruses and autoimmune
hepatitis. Like other autoimmune conditions, autoimmune hepatitis is a
disease of unknown cause that occurs in persons with a genetic
predisposition.
Diagnostic uncertainty is
probably the main reason so few trials of the treatment of autoimmune
hepatitis have been performed. The earlier studies probably included some
patients with hepatitis C who had autoimmune markers, since tests for
hepatitis C virus were not available. With a better understanding of the
pathophysiology of autoimmune hepatitis, a better definition of its target
autoantigens, data on its immunoregulatory control, the availability of
experimental models, and more accurate international diagnostic criteria,
there are now firmer grounds for complementary studies of the natural
history and treatment of autoimmune hepatitis.
The short- and long-term
efficacy of immunosuppression in patients with autoimmune hepatitis has been
demonstrated unequivocally. In many cases, however, patients are not treated
or treatment is begun too late because the diagnosis is missed. Autoimmune
hepatitis has been considered a disease occurring predominantly in young
women, but up to one third of the patients are men, and the disease can
develop in all age groups. Although the clinical findings can vary
substantially, a chronic fluctuating course is most common. Up to 40 percent
of patients present with acute hepatitis, but either a fulminant
presentation or a long subclinical course with only minimal elevations of
liver enzymes may be seen. Almost all patients have autoantibodies, but only
about two thirds have one of the classic autoimmune markers: antinuclear or
anti-smooth-muscle antibodies. Tests for autoantibodies to soluble liver
antigen, liver cytosol antigen, and the asialoglycoprotein receptor can help
identify most cases.
Hypergammaglobulinemia with a
selective increase in serum IgG concentrations is a characteristic
laboratory finding. In addition, HLA typing should be performed, since most
patients are positive for HLA-B8, DR3, or DR4. If the findings are
suggestive but not definitive, a prompt and complete response to
immunosuppressive therapy may confirm the diagnosis. It is estimated that in
Western countries 20 percent of patients with chronic hepatitis have
autoimmune hepatitis, but many cases remain undiagnosed and thus untreated.
Considerable progress in therapy could be made by considering the diagnosis
earlier and more often.
Initial therapy usually
includes corticosteroids. Unless the disease is very mild, therapy should be
started at about 1 mg of prednisone per kilogram of body weight daily. When
serum aminotranferasc concentrations start to fall, the dose of prednisone
should be tapered (at a rate of 10 mg per week, down to a dose of 30 mg per
day, and then at a rate of 5 mg per week, down to a dose of 10 to 15 mg per
day). Adding azathioprine can help keep the required dose of corticosteroids
low. Azathioprine takes several weeks to work and should therefore be
initiated as soon as the diagnosis is certain. Reports from King's College
Hospital in London, in particular the report by Johns on et al. [October
1995] Journal, have helped define the role of azathioprine in the treatment
of autoimmune hepatitis. The superiority of azathioprine over
corticosteroids in maintaining remission and its efficacy as long-term
maintenance therapy have been clearly shown by these studies.
The rate of steroid withdrawal
and the increased risk of cancer with long-term and high-dose azathioprine
therapy in the study by Johnson et al. merit discussion. The researchers
used 1 mg of azathioprine per kilogram together with prednisolone to induce
remission and maintain it for one year. The dose of azathioprine was then
doubled, and the prednisolone was withdrawn fairly rapidly in decrements of
2.5 mg per day every two weeks. Why was the dose of azathioprine doubled,
and why was the prednisolone withdrawn over such a short time? More than
half the patients in the study by Johnson et al. has arthralgias -
presumably a symptom of corticosteroid withdrawal - which required the use
of analgesic agents in about 40 percent of the patients. In our experience,
withdrawal symptoms can generally be averted by tapering the prednisolone
much more slowly (usually, 2.5 mg per day every three months).
he relatively high dose of
azathioprine was probably chosen because of concern about frequent relapses
after the withdrawal of corticosteroids. After remission, the goal of
therapy is to prevent relapses, with minimal side effects. The risks of
osteoporosis and obesity, the most serious dose-dependent adverse effects of
corticosteroids, have to be weighed against the risk of cancer due to
relatively high doses of azathioprine. Many patients remain in remission
with a dose of 50 mg of azathioprine per day. If this dose is insufficient,
it may be safer to add 5 to 7.5 mg of prednisone per day than to increase
the dose of azathioprine to 2 mg per kilogram per day. Of the 72 patients
described by Johnson et al., 5, including 4 who died, had tumors. The risk
of cancer is of particular concern in treating young patients, most of whom
require lifelong immunosuppression.
Other questions remain. First,
can this experience in treating patients with the classic type of autoimmune
hepatitis be extended to patients with autoantibodies to soluble liver
antigen or liver-kidney-microsomal antigen or to the few patients with
autoantibody-negative disease? We believe the answer is yes. Second, which
drugs should be given to the minority of patients who cannot tolerate
azathioprine or who do not have a complete remission? We have had favorable
results with cyclophosphamide. Cyclosporine has been used successfully by
other investigators. Third, should the goal always be complete biochemical
remission, and should mild disease be treated? We believe the answer in both
cases is yes, because fibrosis can develop rapidly, even serum
aminotransferase concentrations are not very high. In the early clinical
experience with this disease, many patients already had cirrhosis at the
time of diagnosis. This is still true today.
Finally, how long should
patients be treated? Most patients with autoimmune hepatitis have to be
treated throughout their lives, but 10 to 30 percent remain in remission
without medications after a minimum of four years of maintenance therapy.
Before immunosuppressive therapy is stopped, a liver biopsy should be
performed to confirm that there is no inflammatory activity. After therapy
has been stopped, patients should be monitored closely. Relapses usually
occur during the first year but are still possible after many years.
[Source: Karl-Hermann Meyer, ZUM; Buschenfelde, M.D., Ph.D. Ansgar W.
Lohse, M.D.]
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Questions and Answers
Questions
Go
here to ask your questions, this is a great site !!
1) What does the liver do?
2) What is Auto-Immune Hepatitis exactly?
3) What are the different types of AIH?
4) Who does it effect more, males or females,...?
5) How much is know of the disease?
6) Is it a common illness or is it a rare, much undiscovered
disease?
7) What types of problems are likely to happen with this type
of disease?
8) How is it treated?
9) What do the drugs do and how do they help?
10) Will I ever come off the drugs? Why?
11) What can I do, and what can't I do if I have AIH?
12) Will transplantation be needed?
13) What is the survival rate of transplantation?
14) If a transplantation is needed, will it come back?
15) Why does it come back?
16) What are the chances of it coming back?
17) What happens after transplant, what would the next step
be?
18) What drugs would be needed to stop rejection?
19) If I have AIH, can I have children?
20) Can AIH be inherited?
21) What is a liver biopsy?
22) What are the dangers of liver biopsy?
23) What is cirrhosis?
24) What are the causes of cirrhosis?
25) Can cirrhosis be cured?
26) Is there any treatment for cirrhosis?
Answers:
What does the liver do?
The liver is the body's "engineroom". It plays an important role in
digestion, it manufactures hundreds of components (e.g. most blood proteins)
essential for life, it is a major site of energy production and acts as an
energy storehouse, and it assists in removing toxic substances from the
blood.
The human liver is comprised of two main segments or lobes: a large right
lobe and a smaller left lobe. It nestles against the diaphragm under the rib
cage in the upper right part of the abdomen. In adults, it weighs
approximately 2-3 lbs (1.0-1.5 kg) and maintains its size in relatively
constant proportion to body weight, increasing or decreasing in size as we
gain or lose weight. This represents a large excess capacity over what is
actually required to sustain life, and we can in fact manage fairly well
with only about 20-30% of our livers functioning normally. It is a
remarkably robust organ. When damaged, and if the damage can be stopped, or
when a part is surgically removed, it is the only organ that has the ability
to completely regenerate itself to exactly the right size.
The liver aids digestion by producing bile, a dark orange-brown fluid which
is a mixture of cholesterol, various proteins and so-called bile salts -
which are powerful detergents. Its color is due to the presence of
bilirubin, which is the waste product formed from hemoglobin (the main
oxygen-carrying protein in red blood cells) when old red blood cells are
broken down. The bile is secreted via the bile ducts and stored in the gall
bladder, from where it is then expelled into the duodenum (the first part of
the intestines) when needed. Fatty foods entering the duodenum from the
stomach are made more digestible by being emulsified by the bile salts.
Bilirubin and its breakdown products are the pigments that give feces their
normal brown color. It is also the pigment which makes the skin turn yellow
in people who are jaundiced. This is because, when the liver is damaged,
bile often cannot be secreted properly and the bilirubin tends to accumulate
in the blood.
What is Auto-Immune Hepatitis exactly?
In a sense, it is a disease in which the body is "rejecting" its own liver.
The body's immune system is designed normally to fight infection. When we
are infected by, say, a virus, special white blood cells attack the
infecting organism and either eliminate it directly or produce proteins
known as antibodies that specifically recognise and help to destroy the
organism. Quite often, infections are accompanied by some (usually fairly
minor) "accidental" damage to healthy tissues, either by the white blood
cells themselves or through the production of antibodies (known as auto
antibodies) against the body's own tissues. The same sort of thing can
happen when tissues are damaged by chemical substances (such as some types
of drugs). In other words, we are all in a state of "autoimmunity", but in
most people there is a mechanism which switches off (or controls) autoimmune
reactions by our immune systems against our own tissues. In people with AIH,
it seems that they are born with (or develop) defects in this control system
such that they cannot switch off an autoimmune attack against their own
livers. Similar defects seem to be present in people with autoimmune
diseases of other organs, such as autoimmune thyroid disease, myasthenia
gravis (which affects the nerves and muscles), rheumatoid arthritis
(affecting the joints), and some forms of diabetes.
Why are only some tissues affected, e.g. the liver in AIH, and not others ?
This is because the control mechanism is extremely complex. It seems that it
has several components, some that have a general "dampening down" effect on
the immune system and others that control reactions separately against each
of the different tissues in the body. To develop an autoimmune disease
affecting only (or mainly) one organ, it is likely that the general control
parts are not working properly and that there are additional defects in one
of the parts that control reactions against each tissue separately.
What are the different types of auotimmune hepatitis?
Until a few years ago, investigators doing research on AIH classified the
disease according to the different types of autoantibodies found in the
blood of patients. Patients with antinuclear (ANA) or smooth muscle (SMA)
autoantibodies, or both, were said to have Type 1 AIH and those who lack
these but have so?called liver-kidney microsomal antibodies (LKM1) were said
to have Type 2 disease. About 95% of people with AIH, spanning the whole age
range of both males and females, have Type 1. Type 2 patients comprise a
small group of (usually) young females with severe disease. Later, it was
recognised that some patients have none of these three antibodies but have
other autoantibodies that were being discovered. These were classified as
having Type 3 AIH and other subdivisions were proposed on the basis of other
autoantibodies that were being found. Experience and further research has
shown that severity of the disease is related more to the age at which it
develops (see question 3) rather than to the type of autoantibodies and
that, at least from the clinical standpoint, there is little difference
between the different types or sub-types. All types respond to standard
treatment (see question 7) in most cases and there is not much difference in
the long-term outcome. Nonetheless, the terms Type 1 and Type 2 are still
commonly used because it is felt that the mechanisms of liver damage may be
different in these two types - even though the response to treatment and
outcome are similar.
Who does it affect more, males or females,...?
Like most autoimmune diseases, it mainly affects females (only about 20% of
people with AIH are male). It can develop at any age but the large majority
of people with AIH develop the disease between 50 and 70 years of age (often
around the menopause in women). It tends to be more severe in younger
people. Older people generally have a milder form that is often easier to
control with treatment (see How is it treated
- question 8).
How much is known of the disease?
Quite a lot really - at least with respect to its signs and symptoms and how
to diagnose and treat it. It is known that people with AIH seem to have a
genetic predisposition to the disease (What is AIH
exactly? - question 2) and that there is probably something, such as
a viral infection of the liver (which may go unrecognised), which is
required to trigger off the autoimmune reaction in the first place (which
probably explains why most people do not have the disease from birth, even
though they may be born with the defects). However, the precise nature of
the defects, or how to correct them permanently, or how the liver damage is
actually caused, is still not known.
Is it a common illness or is it a rare, much undiscovered
disease?
It does seem to be quite rare, but we really don't know how common it is.
Rough estimates suggest that there may be somewhere between 6,000 and 10,000
affected people in the U.K. However, it is now known that many people may
have no symptoms for long periods and it is likely that many of those who
have milder disease may never be diagnosed as having AIH. In some countries
where other diseases of the liver (such as chronic viral hepatitis) are very
common, these conditions may mask the AIH and it may go undiscovered.
What types of problems are likely to happen with this
type of disease?
The large majority of people with AIH respond well to treatment (see
question 7) and feel pretty well most of the time. The main problem that
some people complain of is feeling rather tired from time to time. Also, for
reasons that are not understood, in some people the disease progresses to
cirrhosis despite apparently adequate control with treatment. Cirrhosis is
the term used to describe the deposition of scar tissue in the liver
(whatever the cause). This may present its own problems, the main one being
an increase in pressure in the blood vessels going to the liver (portal
hypertension) which, in turn, may lead to the development of varicose veins
(varices) in the stomach and around the lower end of the oesophagus, which
may bleed. On the other hand, it is known that people can have cirrhosis for
20 or 30 years without developing such problems, so they may never arise.
Other problems that can develop may be due to the drugs used to control the
disease (see How is it treated? - question 8),
but in most cases these are not serious. About 50% of people find that they
put on weight when they first start taking the steroids. In about 20% of
these, the excessive weight gain causes an increase in blood pressure (which
may require treatment). Steroids can also lead to development of diabetes or
osteoporosis (thinning of the bones) but, again, at the fairly low doses
that are usually required to maintain remission (see How is
it treated? - question 8), these complications are relatively rare.
About 10% of people cannot tolerate azathioprine, either because they
develop a rash, or it upsets their stomachs, or it affects their white blood
cells. In these cases, slightly higher doses of steroids may be required to
maintain remission.
How is it treated?
AIH is one of the very few chronic liver diseases that can be very
effectively treated by simple drug therapy in the large majority of cases.
Corticosteroids (usually prednisone or prednisolone) are the standard
treatment. Azathioprine is often used as well, since this has an additive
effect which allows for lower doses of steroids to be used, but about 10% of
people cannot tolerate azathioprine for various reasons (see
What types of problems are likely to happen with this type of
disease? - question 7). Initially, moderately high doses of the
steroids are required for a few weeks or months to get the disease under
control quickly. Thereafter, and especially if azathioprine is tolerated,
the steroid dose can often be reduced to quite low levels. Three recent
studies (in the USA, Sweden and Germany) have indicated that, for most
people with AIH whose disease is well controlled, life expectancy is not
significantly different from that in the rest of the population. The
important thing is to take the tablets exactly as prescribed by the doctor.
What do the drugs do and how do they help?
The two main drugs, corticosteroids and azathioprine (see
How is it treated? - question 8), dampen down the
autoimmune reaction. In a sense, they act as "anti-rejection" drugs and
indeed they are also used (among other drugs) to prevent rejection after
transplantation. Other, newer, "anti-rejection" drugs are showing promise
for people who do not respond to this standard treatment.
Will I ever come off the drugs? Why?
This will depend partly on how severe your disease was in the first place
and how well (and how quickly) it responded to the treatment. As noted in
question 7, the large majority of people respond fairly quickly and their
disease begins to come under control within a few months on treatment, but
it seems to take at least one year, sometimes several years, to get it
completely under control (i.e. to enter complete remission). Thereafter, it
may be possible to stop treatment, but the existing evidence indicates that
only about 20-30% of people can remain off the drugs for long periods. There
is always the possibility that the disease may return (relapse), even many
years after stopping treatment. However, if it does return, it can usually
be controlled again by standard treatment.
What can I do, and what can't I do if I have AIH?
If your disease is well controlled on treatment, there is really little that
you cannot do. However, you should generally avoid alcohol. A glass of wine
or half-pint of beer on special occasions will probably do you no harm, but
this should really be only "occasional" (e.g. not more than once a month).
On the other hand, if your AIH is not completely under control, you can do
whatever you feel up to doing but you should avoid alcohol completely. Your
doctor is the best person to advise you on this.
Will transplantation be needed?
This will depend on whether your disease responds satisfactorily to
treatment. As mentioned in questions 8 and 10, the large majority of people
with AIH do respond well and therefore never require a transplant. The small
number who may need a transplant are those with very severe disease that
does not respond quickly enough to drug treatment and the few with long
standing disease that has progressed to the point where there is not enough
liver left to sustain life or who have developed serious complications.
What is the survival rate of transplantation?
Because of improvements in the surgery (and in the drugs used to prevent
rejection) over the past 5-10 years, survival rates are usually calculated
for only 5 years (because doctors don't yet have enough experience with
these new developments over longer periods). Also, because so few people
with AIH require liver transplants, experience is still fairly limited. The
good news is that, among the centres around the world where the most liver
transplants for AIH are performed, 5-year survival is currently about
80-90%.
If a transplant is needed, will it come back?
Unfortunately, yes it can. However, the drugs used to prevent rejection can
also help to control AIH and it is usually only when these drugs are reduced
to low dosages or stopped altogether that the disease recurs. But, if it
does come back, it can often be controlled again with standard therapy.
Why does it come back?
Probably because transplantation does not cure the basic genetic defects
relating to control of the autoimmune reaction (see
question 2).
What are the chances of it coming back?
This is really not known, because the numbers of people with AIH who require
transplants is so small and there is not yet enough long-term experience to
make these calculations.
What happens after transplant, what would the next
step be?
This depends on how well the transplant goes. However, most people
transplanted for AIH do very well and lead virtually normal lives - even to
the extent of sometimes competing in the Transplant Olympics !!!
What drugs would be needed to stop rejection?
Previously, the main drugs used were steroids, azathioprine and
cyclosporine, in various combinations. However, in recent years tacrolimus
is being increasingly used to great effect and other, newer, drugs such as
mycophenolate are also giving promising results.
If I have AIH, can I have children?
If you are a man, there should be no problem. If you are a woman, it will
depend on how well your disease is controlled and what (if any)
complications you have developed (question 9). Your doctor is the best
person to advise you on this. If your disease is active, you may find that
you cannot become pregnant because active disease can affect ovulation.
Recent studies have shown that younger women with AIH whose disease is in
remission quite often do become pregnant. Most have no major problems during
their pregnancies and have normal healthy babies. However, for reasons that
are not understood, some women relapse during their pregnancies and others
relapse within a few months after delivery, even if they have continued
their normal drug treatment throughout. Therefore, it is important to have
very regular check-ups during pregnancy and after delivery, and to recognise
that an increase in your medication may be required at some stage. The
available evidence suggests that, at the doses normally used to maintain AIH
in remission, steroids and azathioprine do not seem to affect the baby.
Can AIH be inherited?
Everything about our bodies is controlled by our genes, which we inherit
from our parents and their ancestors. But the functions of our genes can be
affected by external factors and do change throughout life - which is why we
do not enjoy "eternal youth". Furthermore, we all have defects of one kind
or another in our genes. Whether these defects affect our lives depends on
what they are. In many instances the defects are either not important or
there are other genes that can compensate for them. As discussed under
Question 2, it seems likely that several defects in control of the immune
system are required for AIH to develop, and that these are genetic in nature
and are probably inherited. Thus, there seems to be a genetic predisposition
to the development of AIH. However, AIH is not hereditary in the usual
sense. Rather, it seems that it is more an "accident of nature", in which a
number of different genes that predispose to the disease have come together
in one individual. There are very few reports of AIH occurring in more than
one member of a family, so present knowledge suggests that it is extremely
unlikely that it can be passed on to one's children.
What is a liver biopsy?
This is a diagnostic procedure used to obtain a small amount of liver
tissue, which can be examined under a microscope to help identify the cause
or stage of liver disease.
What are the dangers of liver biopsy?
Bleeding is the primary risk of a liver biopsy, from the side of needle
entry into the liver, although this occurs in less than 1% of patients.
Fortunately, the risk of death from a liver biopsy is extremely low, ranging
from 0.1% to 0.01%.
What is cirrhosis?
The liver has a remarkable capability to repair itself when damaged. But
when the cause of the damage persists, however, as in chronic hepatitis, the
repair process may not be able to keep pace with the continuing cell death.
As a consequence, the reticulin framework which holds the hepatocytes in
place collapses on itself and eventually begins to stick together, forming
scar tissue. This process is known as fibrosis.
If the fibrosis is severe, the scar tissue formed can begin to interfere
with the normal passage of blood through the liver. Some liver cells may
then become starved of oxygen and nutrients, and this can lead to further
cell death and formation of more scar tissue - a sort of self-perpetuating
process that can proceed in parallel with whatever is causing the damage in
the first place. When fibrosis becomes very severe, it is known as cirrhosis
- a term derived from the Greek word kirros, meaning orange or tawny,
which aptly describes the appearance of the cirrhotic liver due to the
decreased amount of blood flowing through and the accumulation of bile
pigments in it.
What are the causes of cirrhosis?
It is often thought that cirrhosis is due to excessive alcohol consumption.
This is NOT correct. In fact, cirrhosis can be caused by any process that
persistently damages the liver. Although heavy drinking of alcohol is the
main cause in Europe or North America, this accounts for only about 60% of
cases of cirrhosis in these countries. In areas of the world where viral
hepatitis and various other microbial infections of the liver are very
common, the large majority of cases of cirrhosis are due to chronic
infections with these agents. Other important causes include the autoimmune
liver diseases and the various genetic disorders that affect the liver.
Can cirrhosis be cured?
Once cirrhosis is established the process is essentially not reversible. The
only cure is liver transplantation, but this may not always be possible or
appropriate. However, the severity can often be reduced by removing or
treating the underlying cause of the cirrhosis. For example, individuals
with cirrhosis due to excessive alcohol consumption often experience a
dramatic improvement when they stop drinking alcohol.
Is there any treatment for cirrhosis?
There is no treatment for cirrhosis itself, but the complications that arise
in the advanced stages can often be successfully treated, with considerable
prolongation of life.
If portal hypertension develops, it is sometimes possible to treat this
with drugs to reduce the blood pressure. Other drugs, known as diuretics,
are often used to reduce the accumulation of fluid in patients with ascites
or other forms of oedema. If these don't work, an operation may be necessary
to reduce the ascites or a liver transplant may be required.
Gastric or esophageal varices can be injected with a substance known as a
sclerosant to block these off to stop bleeding. This is very similar to the
treatment of varicose veins in the legs, except that it has to be done by
endoscopy. A more recent development involves using an endoscope to place
small rubber bands around the varices to 'choke off' the local blood supply.
If there is severe bleeding, an inflatable balloon (known as a Sengstaken
tube) may be passed down the esophagus to apply pressure as an emergency
measure to stop the bleeding until endoscopic injection or the varices can
be performed. In some cases, it may be considered necessary to perform an
operation, known as a shunt procedure (or TIPS), to divert blood from the
portal vein into other vessels that can cope with the pressure.
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