Autoimmune hepatitis can be defined as a chronic inflammatory liver disease of unknown etiology, occurring at any age. If untreated, this inflammation can give rise to necrosis, fibrosis and cirrhosis. Autoimmune hepatitis is almost always associated with immune abnormalities in the form of auto-antibodies or an elevation of serum gamma globulins. A final characteristic is the susceptibility of liver inflammation to immunosuppressant medications, and particularly to corticosteroids.
Cause and pathogenesis of the disease
The etiology of the disease is unknown. In other words, in order to make a diagnosis, the usual causes of liver inflammation must be eliminated. It is currently considered that the mechanism underlying the onset of autoimmune hepatitis requires trigger factors and a particular genetic susceptibility.
The trigger factors are most probably viruses. The following arguments are put forward:
- many viruses, and particularly hepatotrophic viruses (that multiply in the liver) often trigger autoimmune phenomena which resemble those observed in autoimmune hepatitis;
- some cases of autoimmune hepatitis are preceded by viral infections such as measles, cytomegalovirus or Epstein Barr infections, as well as hepatitis A or C
- other classic trigger factors are medicinal products. Indeed, some drugs have been incriminated in liver damage which closely mimics autoimmune hepatitis. This was particularly the case with oxyphenisatine, a drug used to treat constipation, and some antihypertensive drugs (the best known being tienilic acid, a product withdrawn from the market several years ago for this reason). More recently, some statins, antibiotics and anti-inflammatories have been held responsible for liver damage resembling autoimmune hepatitis. However, in all these situations, withdrawal of the medication has always been accompanied by a regression of the signs of autoimmune hepatitis.
The second major factor triggering the disease is genetic susceptibility. One of the systems controlling immunity is the HLA (Human Leukocyte Antigen) system. This comprises a series of genes present on chromosome 6 in the major histocompatibility complex. This system presents with considerable genetic variability. It includes a very large number of genes coding for proteins, the role of which is to present molecules from viruses, bacteria or xenobiotics to the immune system (lymphocytes, macrophages). In other words, if the protein or an HLA peptide characteristic of an individual is unable to correctly present a peptide of microbial origin to the immune system, the immune reaction will not occur, and inflammation will not take place. On the other hand, a reverse situation can be imagined, where some individuals have strongly performing HLA molecules which are able to present microbial peptides to the immune system. In this case, the immune system will respond in an optimum way and allow definitive elimination of the microbial peptide. In intermediate situations, it can be imagined that the microbial antigen will be presented in such a way that the immune system reaction will be triggered but will not be strong enough to eliminate the antigen definitively. In this case, it comes to a chronic inflammatory reaction, i.e. chronic autoimmune hepatitis.
Some HLA molecules (HLA-DR3 or DR4) are typically associated with autoimmune hepatitis. The HLA-DR3 group is frequently associated with severe hepatitis, and HLA-DR4 with less severe hepatitis. As seen above, it is the immune system itself (independently of HLA molecules) which has a crucial role to play. A paralysed immune system, as seen in some types of primary or acquired immune deficiency (acquired meaning that it results from the administration of chemotherapy or immunosuppressant drugs), provides protection against the triggering of autoimmunity. Recent arguments have been put forward by in vitro and in vivo studies which showed that some populations of regulatory lymphocytes (CD4+ CD25+) could be involved in the onset of autoimmunity. This was demonstrated in an autoimmune disease such as disseminated lupus erythematosus, but also in autoimmune hepatitis.
Clinical characteristics and diagnosis of autoimmune hepatitis
Autoimmune hepatitis is more common in women than in men. However, it can affect both sexes and all ethnic groups and occurs equally in children and adults.
Autoimmune hepatitis can be diagnosed in several situations. Schematically, a diagnosis can be made in the event of fluctuating and chronic elevations of serum transaminase activity. Serum transaminase elevations may have been revealed in the context of routine blood tests or because certain symptoms such as fatigue have aroused suspicion. In 10% to 15% of cases, patients present with severe liver damage, characterised by jaundice, a marked elevation of serum transaminase activity and low prothrombin levels, suggestive of fulminant hepatitis. In a patient with a moderate but chronic elevation of transaminase levels, diagnosis is based on the following three elements:
- there is no other normal reason for these elevated levels: no use of medications, no intake of toxic substances, no known viral disease (in particular), markers for B and C viral hepatitis are absent, and there is no genetically-linked metabolic disease (alpha 1 antitrypsin deficiency, Wilson’s disease, hemochromatosis, etc.).
- gamma globulin levels are elevated: in particular, IgG levels are more than 1.2 times the upper normal laboratory limit. However, in 10% of cases, this elevation is not observed.
- most patients present with auto-antibodies. Two important facts must be remembered. These auto-antibodies are detected using immunofluorescence tests performed by specialised laboratories. The auto-antibodies detected in this way are antinuclear antibodies, smooth muscle antibodies or anti-LKM (anti-liver kidney microsome) antibodies. Immunofluorescence techniques can also detect anti-mitochondrial antibodies. Some antibodies are not detected by these techniques, so that certain specific techniques need to be employed. These are the so-called anti-SLA (Soluble Liver Antigen) antibodies. They are detected using Elisa or Western Blot methods. In 10% of cases, these are the only antibodies detected in a setting of autoimmune hepatitis. In other words, negative immunofluorescence results do not necessarily indicate an absence of autoimmune hepatitis.
Depending on the type of antibody and the age at the onset, it is possible to distinguish two major types of autoimmune hepatitis: type 1 is characterised by the presence of anti-actin, anti-SLA antibodies. This type of autoimmune hepatitis occurs at any age, although it is mainly seen in adults. It often responds well to corticosteroid therapy. Type 2 autoimmune hepatitis is characterised by the presence of antibodies directed against the endoplasmic reticulum (anti-liver microsome or LKM antibodies and anti-liver cytosol antibodies). This type of hepatitis occurs almost exclusively in children, exceptionally after puberty. The disease is generally more severe and responds less well to corticosteroids and immunosuppressant drugs.
If a diagnosis of autoimmune hepatitis is not made rapidly or is delayed, cirrhosis may develop (this being an irreversible disorder of the liver characterised by severe liver fibrosis and disorganisation of its architecture rendering the organ incapable of functioning normally), or severe hepatitis which may be life-threatening. In both situations, liver transplantation becomes the only option available in the short or long term.
A liver biopsy is essential for the initial diagnosis of autoimmune hepatitis, as the lesions are indeed characteristic: they are sited in the portal tract, creating the so-called interface hepatitis, also referred to as piecemeal necrosis. The persistence of inflammation in portal tracts and in the periportal region is the only element upon which the duration of treatment can be based (for life or not).
A related syndrome is also called variant syndrome or overlap syndrome. Ten to 15% of primary biliary cirrhosis cases are associated with clear signs of autoimmune hepatitis. Recognition of these forms is essential as their treatment is based both on that of the primary biliary cirrhosis with ursodeoxycholic acid and on treatment of the autoimmune hepatitis with corticosteroids or immunosuppressant drugs.
The diagnostic criteria for this variant are as follows: in the first instance, they are the main criteria for autoimmune hepatitis, i.e.
- elevation of transaminase activity by more than five times the upper normal limit, despite continuous treatment with ursodeoxycholic acid;
- elevated immune globulin levels of more than 20 g/l, or the presence of smooth muscle antibodies in the form of anti-actin or anti-SLA antibodies; 3
- the existence of interface hepatitis characteristic of autoimmune hepatitis.
All the criteria for primary biliary cirrhosis must also be present, i.e.:
- a biochemical syndrome of cholestasis (elevation of alkaline phosphatase levels at more than twice the upper normal limit);
- the presence of anti-mitochondrial antibodies;
- he existence of lymphocytic destructive cholangitis on histopathological examination of the liver. In most cases, the two diseases are expressed simultaneously. More rarely, autoimmune hepatitis occurs several months to several years after the diagnosis of primary biliary cirrhosis. In this case, the diagnosis of autoimmune hepatitis is often unrecognised, as this development is considered as a worsening of the primary biliary cirrhosis, justifying liver transplantation.
In 10% to 20% of cases, autoimmune hepatitis is associated with primary sclerosing cholangitis. This situation is more common in children than in adults. A diagnosis can only be made if, during cholangiography or an MRI scan of the bile ducts, visible fibrous obliterating lesions are present. This implies that the initial assessment and follow-up of any case of autoimmune hepatitis must include an MRI scan of the bile ducts. This is a recent notion, but the approach is justified because an MRI scan of the bile ducts is a simple, non-invasive procedure, unlike endoscopic cholangiography which was the only option available a few years ago.
The treatment of autoimmune hepatitis is based on intake of prednisolone alone or in combination with azathioprine or mycophenolate mofetil. The two latter drugs enable a rapid tapering and withdrawal of corticosteroid therapy. Azathioprine and mycophenolate mofetil represent the long-term treatment for this condition. This treatment can avoid the complications of long-term corticosteroid therapy, and particularly osteoporosis. The mean initial doses of prednisone are 20 to 50 mg per day, and 1 to 2 mg per kilo body weight in children. When a combination of corticosteroids and azathioprine is used for long-term therapy, the daily doses are 10 mg and 50 mg to 200 mg.
Once transaminase and immune globulin levels have returned to normal, corticosteroid therapy can be discontinued (usually after two years of treatment) and azathioprine and mycophenolate mofetil should be pursued at respective doses of 50 to 200 mg per day and 1 to 2 g per day. In patients exhibiting resistance to corticosteroid therapy, the administration of cyclosporine can be attempted; it has been shown to achieve complete remission.
Overlap syndrome needs the administration of both ursodeoxycholic acid and corticosteroids in combination with azathioprine or mycophenolate mofetil.
Key points and summary of the article
- Autoimmune hepatitis is an inflammatory liver disease which can occur at any age.
Its diagnosis should be considered in the event of any chronic elevation of transaminase activity which is not due to usual causes, particularly of a viral nature.
- Apart from elevated liver transaminases, diagnosis is based on elevated immune globulin levels, the presence of auto-antibodies and liver biopsy findings demonstrating a so-called lymphoplasmocytic interface.
- The antibodies detected by immunofluorescence techniques are present in 85% to 90% of cases. Additional testing for anti-SLA antibodies should always be specified if no anti-tissue antibodies are present.
- 10% to 15% of patients with either primary biliary cirrhosis or primary sclerosing cholangitis present with autoimmune hepatitis.
- And a final important element: autoimmune hepatitis is a disease which can be cured by the administration of corticosteroids and immunosuppressant drugs. However, these treatments generally need to be pursued for lifetime in order to prevent any recurrence.
- Autoimmune hepatitis is an inflammatory liver disease which can occur at any age.
The principal references may be found in the following articles:
- Krawitt EL. Autoimmune hepatitis. N Engl J Med 2006; 354:54-66.
- Gregorio GV, Portmann B, Karani J, et al. Autoimmune hepatitis / sclerosing cholangitis overlap syndrome in childhood : a 16-year prospective study. Hepatology 2001; 33:544-53.
- Mieli-Vergani G, Vergani D. De novo autoimmune hepatitis after liver transplantation. J Hepatol 2004; 40:3-7.
- Chazouillères O, Wendum D, Serfaty L, Montembault S, Rosmorduc O, Poupon R. Primary biliary cirrhosis / autoimmune hepatitis overlap syndrome: clinical features and response to therapy. Hepatolog 1998; 28:296-301.
Professeur R. Poupon 02.03.06