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 Autoimmune Hepatitis

  Although 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.]

 

 

Questions and Answers


Questions

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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.

 



 

 

  Background
  Clinical Features of Autoimmune Hepatitis
  The Hepatitis C Connection
  Lab Studies and Treatment
   

 

  Authored by Unnithan V Raghuraman, MD, Honorary Assistant Professor, University of Alabama School of Medicine

Coauthored by David C Wolf, MD, FACP, FACG, Medical Director of Liver Transplantation, Associate Professor, Department of Internal Medicine, Division of Gastroenterology and Hepatobiliary Diseases, New York Medical College and Westchester Medical Center

http://www.emedicine.com/MED/topic366.htm    

Background:

 During the past 30 years, remarkable advances have occurred in our understanding of the epidemiology, natural history, and pathogenesis of chronic hepatitis. The development of viral serologic tests has permitted hepatologists to differentiate chronic viral hepatitis from other types of chronic liver disease, including autoimmune hepatitis. Autoimmune hepatitis is now accepted as a chronic disease of unknown cause, characterized by continuing hepatocellular inflammation and necrosis, which tends to progress to cirrhosis. Immune serum markers are frequently present, and the disease is often associated with other autoimmune diseases. Autoimmune hepatitis cannot be explained on the basis of chronic viral infection, alcohol consumption, or exposure to hepatotoxic medications or chemicals.

In 1950, Waldenstrom first described a form of chronic hepatitis in young women. This condition was characterized by cirrhosis, plasma cell infiltration of the liver, and marked hypergammaglobulinemia. Kunkel, in 1950, and Bearn, in 1956, described other features of the disease, including hepatosplenomegaly, jaundice, acne, hirsutism, cushingoid facies, pigmented abdominal striae, obesity, arthritis, and amenorrhea. In 1955, Joske first reported the association of the lupus erythematosus (LE) cell phenomenon in active chronic viral hepatitis. This association led to the introduction of the term lupoid hepatitis by Mackay and associates in 1956. Researchers currently know that no direct link exists between systemic lupus erythematosus (SLE) syndrome and autoimmune hepatitis; thus, lupoid hepatitis is not associated with SLE.

Autoimmune hepatitis now is recognized as a multisystem disorder that can occur in males and females of all ages. This condition can coexist with other liver diseases (eg, chronic viral hepatitis) and also may be triggered by certain viral infections (eg, hepatitis A) and chemicals (eg, minocycline).

The histopathologic description of autoimmune hepatitis has undergone several revisions over the years. In 1992, an international panel last codified the diagnostic criteria. The term autoimmune hepatitis was selected to replace terms like autoimmune liver disease and autoimmune chronic active hepatitis. The panel waived the requirement of 6 months of disease activity to establish chronicity, expanded the histologic spectrum to include lobular hepatitis, and reaffirmed the nonviral nature of the disease. The panel also designated incompatible histologic features, such as cholestatic histology, the presence of bile duct injury, and ductopenia.

 

Pathophysiology:

Evidence suggests that liver injury in a patient with autoimmune hepatitis is the result of a cell-mediated immunologic attack. This attack is directed against genetically predisposed hepatocytes. Aberrant display of human leukocyte antigen (HLA) class II on the surface of hepatocytes facilitates the presentation of normal liver cell membrane constituents to antigen-processing cells. These activated cells, in turn, stimulate the clonal expansion of autoantigen-sensitized cytotoxic T lymphocytes. Cytotoxic T lymphocytes infiltrate liver tissue, release cytokines, and help to destroy liver cells.

The reasons for the aberrant HLA display are unclear. It may be initiated or triggered by genetic factors, viral infections (eg, acute hepatitis A or B, Epstein-Barr virus infection), and chemical agents (eg, interferon, melatonin, alpha methyldopa, oxyphenisatin, nitrofurantoin, tienilic acid). The asialoglycoprotein receptor and the cytochrome mono-oxygenase P-450 IID6 are proposed as the triggering autoantigens.

Some patients appear to be genetically susceptible to developing autoimmune hepatitis. This condition is associated with the complement allele C4AQO and with the HLA haplotypes B8, B14, DR3, DR4, and Dw3. C4A gene deletions are associated with the development of autoimmune hepatitis in younger patients. HLA DR3-positive patients are more likely than other patients to have aggressive disease, which is less responsive to medical therapy; these patients are younger than other patients at the time of their initial presentation. HLA DR4-positive patients are more likely to develop extrahepatic manifestations of their disease.

Evidence for an autoimmune pathogenesis includes the following:

 

The autoantibodies described in these patients include the following:

 

Frequency:
 

Mortality/Morbidity: Without treatment, nearly 50% of patients with severe autoimmune hepatitis will die in approximately 5 years.

Race: The disease is most common in Caucasians of northern European ancestry, with a high frequency of HLA-DR3 and HLA-DR4 markers. The Japanese have a low frequency of HLA-DR3 markers. In Japan, autoimmune hepatitis is associated with HLA-DR4.

Sex: Women are affected more often than men (70-80% of patients are women).

Age: Autoimmune hepatitis usually is detected in the third to fifth decades of life, but young children and older adults also are affected. Men are affected more commonly than women in older age groups.

 

    bullet Hematologic complications

     

    • Hematologic manifestations of hypersplenism
    • Autoimmune hemolytic anemia
       
    • Coombs-positive hemolytic anemia
       
    • Pernicious anemia
       
    • Idiopathic thrombocytopenic purpura
       
    • Eosinophilia
    bullet Gastrointestinal complications

     

    • Inflammatory bowel disease (6%): The presence of ulcerative colitis in patients with autoimmune hepatitis should prompt cholangiography to exclude primary sclerosing cholangitis.

       

    • Celiac disease
    bullet Proliferative glomerulonephritis

     

    bullet Fibrosing alveolitis

     

    bullet Pericarditis and myocarditis

     

    bullet Endocrinologic complications

     

    • Graves disease (6%) and autoimmune thyroiditis (12%)
    • Juvenile diabetes mellitus
    bullet Rheumatologic complications

     

    • Rheumatoid arthritis and Felty syndrome
    • Sjögren syndrome
       
    • Systemic sclerosis
       
    • Mixed connective tissue disease
       
    • Erythema nodosum
       
    • Leukocytoclastic vasculitis: Patients may present with symptoms of leg ulcers.
    bullet Febrile panniculitis

     

    bullet Lichen planus

     

    bullet Uveitis

 

 
  • Cryptogenic autoimmune hepatitis is characterized by a clinical picture that is indistinguishable from autoimmune hepatitis. ANA, ASMA, and anti–LKM-1 are negative at disease onset and may appear late in the disease course, as might anti-SLA. The disease is usually responsive to steroid therapy.

        Physical:

  • Common findings at physical examination are as follows:
    bullet Hepatomegaly (83%)
    bullet Jaundice (69%)
    bullet Splenomegaly (32%)
    bullet Spider angiomata (58%)
    bullet Ascites (20%)
    bullet Encephalopathy (14%)
  • All of these findings may be observed in patients with disease that has progressed to the point of cirrhosis with ensuing portal hypertension; however, hepatomegaly, jaundice, splenomegaly, and spider angiomata also may be observed in patients who do not have cirrhosis.

         Causes: Autoimmune hepatitis is a chronic disease of unknown etiology

Lab Studies:
 

  • Autoantibodies: Autoimmune hepatitis is characterized by positive autoantibody tests  . Autoimmune hepatitis type 1 is characterized by positive tests for ASMA and ANA. Type 2 disease is infrequently observed in the US but is well characterized in Europe. Type 2 disease is marked by a positive anti–LKM-1 antibody test. Type 3 disease also is infrequently observed in the US. Type 3 is marked by a positive anti-SLA antibody test.
  • Serum protein electrophoresis and quantitative immunoglobulins
    • An immunoglobulin G (IgG)-predominant polyclonal hypergammaglobulinemia is a common finding in patients with untreated autoimmune hepatitis. Gamma globulin values typically range from 3-4 g/dL and frequently are as high as 5-6 g/dL. Cases of hyperviscosity syndrome secondary to high IgG levels are reported. Autoimmune hepatitis is an unlikely diagnosis in patients who have acute hepatitis without hypergammaglobulinemia.
    • The gamma globulin or the IgG level may be followed on a regular basis as a marker of disease responsiveness to therapy.
  • Aminotransferases
    • Serum aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) are elevated in 100% of patients at initial presentation, with average values of 200-300 U/L. Aminotransferase values correlate poorly with the degree of hepatic necrosis; however, values in the thousands may indicate acute hepatitis or a severe flare of preexisting disease.
    • Continued elevation of the aminotransferases in the face of ongoing therapy is a reliable marker for ongoing inflammatory activity in the liver. Normalization of the aminotransferases during therapy is an encouraging sign, but active liver inflammation is present in more than 50% of patients who normalize their liver chemistries. Indeed, biochemical remission may precede true histologic remission by 3-12 months; thus, patients should be treated for at least 1 year after documentation of normal liver chemistries. Liver biopsy may then be employed to determine whether the patient is in histologic remission. Drug withdrawal may be attempted at this time (see Treatment).
    • Worsening of aminotransferases in a patient undergoing treatment or in a patient who is in remission may signal a resurgence of disease activity.
  • Other liver chemistries
    • Serum bilirubin and alkaline phosphatase values are mildly to moderately increased in 80-90% of patients. A sharp increase in the alkaline phosphatase values during the course of autoimmune disease might reflect the development of primary sclerosing cholangitis or the onset of hepatocellular carcinoma as a complication of cirrhosis.
    • Hypoalbuminemia and prolongation of prothrombin time are markers of severe hepatic synthetic dysfunction, which may be observed in active disease or decompensated cirrhosis.
  • Other common laboratory abnormalities
    • Mild leukopenia
    • Normochromic anemia
    • Coombs-positive hemolytic anemia
    • Thrombocytopenia
    • Elevated sedimentation rate
    • Eosinophilia (uncommon but counts ranging from 9-48% are described)
    • Autoimmune hepatitis has even been described as the sole presenting feature of idiopathic hypereosinophilic syndrome.

Imaging Studies:
 

  • Imaging studies, in general, are not helpful in making a definitive diagnosis of autoimmune hepatitis; however, the presence of heterogeneous echotexture on abdominal ultrasound or abnormal contrast enhancement on abdominal CT imaging may suggest the presence of active inflammation or necrosis. The appearance of an irregular nodular liver may confirm the presence of cirrhosis. Furthermore, these imaging studies may be used to rule out the presence of hepatocellular carcinoma, a potential complication of autoimmune hepatitis-induced cirrhosis.

Procedures:
 

  • Liver biopsy
    • Liver biopsy is the most important diagnostic procedure in patients with autoimmune hepatitis. This procedure can be performed percutaneously, with or without ultrasound guidance, or by the transjugular route. The latter is preferred if the patient has coagulopathy or severe thrombocytopenia. A transjugular liver biopsy also may be preferable if ascites is present or if the liver is small, shrunken, and difficult to reach percutaneously. Liver biopsy routinely is performed in the outpatient setting to investigate abnormal liver chemistries. Liver biopsy should be performed as early as possible in patients with acute hepatitis who are thought to have autoimmune hepatitis. Confirmation of the diagnosis enables initiation of treatment at an early stage in the disease process.
    • The role of biopsy in patients presenting with well-established cirrhosis secondary to autoimmune hepatitis is less clear. As an example, the initiation of treatment in a patient with cirrhosis, normal aminotransferases, and a minimally elevated gamma globulin is not expected to influence the disease outcome.
  • Endoscopic retrograde cholangiopancreatography: Occasionally, a patient with autoimmune hepatitis and ulcerative colitis may require endoscopic retrograde cholangiopancreatography (ERCP) to rule out coexisting primary sclerosing cholangitis.

Histologic Findings:

 Autoimmune hepatitis is characterized by a chronic inflammatory cell infiltrate. Plasma cells are the prominent cell type. Biopsies may show evidence for interface hepatitis (piecemeal necrosis), bridging necrosis, and fibrosis. Lobular collapse, best identified by reticulin staining, is a common finding.

Interface hepatitis does not predict a progressive disease course. By contrast, there is a strong likelihood that cirrhosis will develop when bridging necrosis is present. The presence or absence of cirrhosis on liver biopsy is an important determinant of the patient's prognosis.

Liver biopsy can help to differentiate autoimmune hepatitis from chronic HCV infection, alcohol-induced hepatitis, drug-induced liver disease, primary biliary cirrhosis, and primary sclerosing cholangitis.


Treatment

Medical Care:

For more than 3 decades, prednisone and azathioprine have been the mainstays of drug therapy for patients with autoimmune hepatitis. Considerable variation in practice style exists when it comes to answering the following common clinical questions:

How high a dose of prednisone should be used when initiating therapy?

When should azathioprine be added to the patient's treatment regimen? When should a reduction in steroid dosing be considered?

How long should treatment continue beyond a patient's biochemical remission?

Should liver biopsy be performed in order to document histologic remission, prior to attempting to withdraw immunosuppression? Should patients receive life-long low-dose maintenance therapy with azathioprine?

Approximately 65% of patients respond to initial therapy and enter histological remission; however, 80% of these patients relapse after drug withdrawal.

Albert Czaja has recently published his treatment recommendations for autoimmune hepatitis, which are as follows:

bullet Absolute indication for treatment

 

  • Incapacitating symptoms

     

  • Relentless clinical progression

     

  • AST greater than 10 times normal

     

  • AST greater than 5 times normal and IgG greater than 2 times normal

     

  • Bridging necrosis on histology

     

  • Multilobular necrosis on histology

 

bullet Relative indication for treatment

 

  • Mild or no symptoms

     

  • AST 3-9 times normal

     

  • AST greater than 5 times normal and IgG less than 2 times normal

     

  • Periportal hepatitis on histology

 

bullet No indication

 

  • Asymptomatic

     

  • Previous intolerance to prednisone or azathioprine

     

  • AST less than 3 times normal

     

  • Severe cytopenia

     

  • Inactive cirrhosis or mild portal hepatitis on histology

     

  • Decompensated cirrhosis with variceal bleeding

 

bullet Czaja's guidelines for single-drug therapy are as follows:

 

bullet Treatment endpoints: Patients may achieve 1 of 4 treatment endpoints.

 

bullet Treatment results

 

bullet Treatment failures and incomplete responses

 

bullet Relapse

 

bullet Treatment adverse effects

 

The goals of pharmacotherapy are to reduce morbidity and prevent complications. Medications used include prednisone, prednisolone, and azathioprine.
 

Drug Category: Corticosteroids --

Drug Name
 
Prednisone (Deltasone, Orasone, Meticorten) -- Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.
Adult Dose 5-60 mg/d PO qd or divided bid/qid; taper over 2 wk, as symptoms resolve
Pediatric Dose 4-5 mg/m2/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk, as symptoms resolve
Contraindications Documented hypersensitivity; viral, fungal or tubercular infections, peptic ulcer disease, osteoporosis
Interactions Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin, may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy B - Usually safe but benefits must outweigh the risks.
Precautions Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteoporosis and osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use
Drug Name
 
Azathioprine (Imuran) -- Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.
Adult Dose 1 mg/kg/d PO for 6-8 wk; increase by 0.5 mg/kg q4wk until response or dose reaches 2.5 mg/kg/d
Pediatric Dose Initial dose: 2-5 mg/kg/d PO/IV

Maintenance dose: 1-2 mg/kg/d PO/IV
Contraindications Documented hypersensitivity; low levels of serum thiopurine methyl transferase (TPMT)
Interactions Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine
Pregnancy D - Unsafe in pregnancy
Precautions Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; check TPMT level prior to therapy and follow liver, renal, and hematologic function; pancreatitis rarely associated
Drug Name
 
Prednisolone (Delta-Cortef, Econopred, Articulose-50) -- Decreases autoimmune reactions, possibly by suppressing key components of immune system.
Adult Dose 5-60 mg/d PO/IV/IM in divided doses
Pediatric Dose 0.1-2 mg/kg/d PO/IV/IM qd or divided tid/qid
Contraindications Documented hypersensitivity; viral, fungal or tubercular infections, peptic ulcer disease, osteoporosis
Interactions Decreases effects of salicylates and toxoids (for immunizations); phenytoin, carbamazepine, barbiturates, and rifampin decrease the effect of corticosteroids
Pregnancy C - Safety for use during pregnancy has not been established.
Precautions Caution in hyperthyroidism, osteoporosis, cirrhosis, nonspecific ulcerative colitis, peptic ulcer, diabetes, and myasthenia gravis

 

Generic Name

Brand Name(S)

Azathioprine

Imuran

Corticosteroids

-

Chlorphenirahine

Piriton

Cyclosporin

Neoral, Sandimmun, SangCya

Diuretics

-

Mycophenolate

CellCept

Omeprazole

Losec

Phytomenadione (Vit K)

Konakion

Prednisolone

Precortisyl Forte, Prednesol

Ranitidine

Zantac

Spironolactone

Aldactone

Sucralfate

Antepsin

Tacrolimus

Prograf

Ursodeoxycholic Acid

Destolit, Urdox, Ursofalk, Ursogal

   


 


Azathioprine
Explanation: It is a powerful CYTOTOXIC and IMMUNOSUPPRESSANT drug. It is mainly used to reduce tissue rejection in transplant patients, but it can also be used to treat myasthenia gravis, rheumatoid arthritis, ulcerative colitis and several autoimmune diseases.
Possible Side-Effects: Hypersensitivity reactions including dizziness, malaise, vomiting, fever, muscular pains and shivering, joint pain, jaundice, heart arrhythmias, low blood pressure (requiring withdrawal of treatment), symptoms of bone marrow suppression, which should be reported (eg bleeding or bruising), hair loss, increased susceptibility to infections, nausea, pneumonia and pancreatitis.


 

Corticosteroids
Explantion: Steroid hormone secreted by the cortex (outer part) of the adrenal glands, or are synthetic substances that closely resemble the natural forms. There are two main types, glucocorticoids and mineralocorticoids. The latter assist in maintaining the salt-and water balance of the body. Corticosteroids such as the glucocorticoid HYDROCORTISONE and the mineralocorticoid FLUDROCORTISONE ACETATE can be given to patients for replacement therapy where there is a deficiency, or in Addison's disease, or following adrenalectomy or hypopituitarism. The glucocorticoids are potent ANTI-INFLAMMATORY and ANTI-ALLERGIC drugs and are frequently used to treat inflammatory and/or allergic reactions of the skin, airways and elsewhere. COMPOUND PREPARATIONS are available that contain both an ANTIBACTERIAL or ANTIFUNGAL drug with an anti-inflammatory corticosteroid and can be used in conditions where an infection is also present. However, these preparations must be used with caution because the corticosteroid component diminishes the patient's natural immune response to the infective agent. Absorption of a high dose of corticosteroid over a period of time may also cause undesirable, systemic side-effects.
Possible Side-Effects: Mineralocorticoid adverse effects include hypertension, sodium and water retention and potassium loss. Glucocorticoid adverse effects include diabetes, osteoporosis, avascular necrosis, mental disturbances, euphoria, muscle wasting and possibly peptic ulceration. Corticosteroids may also cause Cushing's syndrome, suppressed growth in children and adrenal atrophy. If administered during pregnancy, they may affect adrenal gland development in the child. Suppression of the sympoms of infection may occuR.


 

Chlorphenirahine
Explantion: Is an ANTIHISTAMINE drug. It is used to treat the symptoms of allergic conditions such as hay fever and urticaria (itchy skin rash) and is also occasionally used in emergencies to treat anaphylactic shock. Administration is either oral as tables or a syrup, or by injection.
Side-effects: Because of its sedative side-effects, the performance of skilled tasks such as driving may be impaired. Injections may be irritant and cause short-lasting hypotension and stimulation of the central nervous system.


 

Cyclosporin
Explantion: It is an IMMUNOSUPPRESSANT drug, which is particularly to limit tissue rejection during and following organ transplant surgery. It can also be used to treat severe, active rheumatoid arthritis and some skin conditions such as severe, resistant atopic dermatitis and) under special supervision) psoriasis. It has very little effect on the blood-cell producing capacity of the bone marrow, but does have liver toxicity.
Possible Side-Effects: Include changes in blood enzymes, disturbances in liver, kidney and cardiovascular function, excessive hair growth, gastrointestinal disturbances, tremor, gum growth, oedema (accumulation of fluid in the tissues), fatigue and burning sensations in the hands and feet.


 

Duretics
Explantion: Drugs used to reduce fluid in the body by increasing the excretion of water and mineral salts by the kidney, so increasing urine production.


 

Mycophenolate
Explantion: see Cyclosporin
Possible Side-Effects: Diarrhoea, vomiting, constipation, nausea, dyspepsia, abdominal pain, dizziness, insomnia, headache, tremor.


 

Omeprazole
Explantion: Is an ulcer-healing drug. It works by being a proton-pump inhibitor and so interferes with the secretion of gastric acid from the parietal cells of the stomach lining. It is used for the treatment of benign gastric and duodenal ulcers.
Possible Side-Effects: Diarrhoea or constipation, nausea, flatulence; dizziness, headaches, sleep disorders, disturbances of vision, hair loss, skin and mood disorders (some of these last side-effects occur only in the very ill).


 

Phytomenadione (Vit K)
Explantion: Is a natural form of Vitamin K and is normally obtained from vegetables and dairy products. Phytomenadione can be used to treat Vit K deficiency, but not a deficiency caused by malabsorption states. Administration is either oral in the form of tables or by slow intravenous injection.
Possible Side-effects: there may be liver damage if high doses are taken for a long period.


 

Prednisolone
Explantion: It is a synthetic, glucocorticoid CORTICOSTEROID with ANTI-INFLAMMATORY properties. It is used in the treatment of a number of rheumatic and allergic conditions (particularly those affecting the joints or lungs) and collagen disorders. It is also an effective treatment for ulcerative colitis, inflammatory bowel disease, Crohn's disease, rectal or anal inflammation, haemorrhoids and as an IMMUNOSUPPRESSANT in the treatment of myasthenia gravis. It may also be used for systemic corticosteroid therapy.
Possible Side-Effects: See Corticosteroids
 


 

Ranitidine
Explantion: Is an effective and extensively prescribed H2-antagonist and ulcer-healing drug. It is used to assist in the treatment of benign peptic (gastric and duodenal) ulcers, to relieve heartburn in cases of reflux oesophagitis (caused by regurgitation of acid and enzymes into the oesophagus).
Possible Side-Effects: Tiredness, rash, dizziness, headache or confusion.


 

Spironolactone
Explantion: Is a diuretic drug of the aldosterone-antagonist type. It is also potassium-sparing and so can be used in conjunction with other types of diuretic, such as the thiazides, which cause loss of potassium, to obtain a more beneficisal action. It can be used to treat oedema (accumulation of fluid in the tissues) associated with aldosteronism (abnormal production of aldosterone by the adrenal gland), in congestive heart failure treatment, kidney disease and fluid retention and ascites caused by liver disease.
Possible Side-Effects: Gastrointestinal disturbances, impotence and gynaecomastia (enlargements of breats) in men; irregular periods in women; skin rashes, raised blood potassium and lowered blood sodium levels.


 

Sucralfate
Explantion: Is a drug that is a complex of aluminium hydroxide and sulphated sucrose. It can be used as a long-term treatment of gastric and duodenal ulcers. It has very little antacid action, but is thought to work as a cytoprotectant by forming a barrier over an ulcer, so protecting it from acid and the enzyme pepsin and allowing it to heal.
Possible Side-Effects: Constipation, diarrhoea, nausea, indigestion, gastric discomfort, dry mouth, skin rash and itching.


 

Tacrolimus
Explantion: It is a IMMUNOSUPPRESSANT drug (a MACROLIDE ANTIBIOTIC) that is used particularly to limit tissue rejection during and following organ transplant surgery (particularly of liver or kidney).
Possible Side-Effects: See Cyclosporin


 

Ursodeoxycholic Acid
Explantion: A drug that can dissolve some gallstones in situ. Administration is oral in the form of capsules or tablets.
Possible Side-Effects: Diarrhoea and itching, mid liver dysfunction and changes in blood enzymes.

 

Surgical Care:

Diet:

Activity: Most patients do not need hospitalization, although this may be required for clinically severe illness. Forced and prolonged bed rest is unnecessary, but patients may feel better with restricted physical

 

   
  Also see our Related Conditions for additional information on Autoimmune Hepatitis

Other AIH websites
Autoimmune Liver Disease Support Group http://members.aol.com/_ht_a/pbcers/liverdis.htm 
American Autoimmune Related Diseases Association, Inc. http://www.aarda.org/  
Understanding Autoimmune Diseases http://www.niaid.nih.gov/publications/autoimmune/autoimmune.htm 
Primary Biliary Cirrhosis website http://hometown.aol.com/pbcers/pbcers.htm 
Another AIH website http://www.healthatoz.com/atoz/hepatitis/hepauto.asp 
AutoImmune Diseases on About.com's website http://hepatitis.about.com/ 

 

   
Reviewed Feb 2004
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