OVERVIEW: What every practitioner needs to know

Are you sure your patient has autoimmune hepatitis? What are the typical findings for this disease?

Autoimmune hepatitis (AIH) often presents with nonspecific symptoms of fatigue, anorexia, and nausea.  The next most common symptoms are abdominal pain, jaundice, arthralgia, and epistaxis.

AIH is a chronic progressive inflammatory disease that mainly affects the liver and is characterized by autoimmune injury to hepatocytes, resulting in liver fibrosis and cirrhosis.  AIH is described biochemically by an elevation of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, serologically by elevated immunoglobulin G (IgG) levels and the presence of autoantibodies, and histologically by the presence of interface hepatitis and lymphoplasmacytic infiltrates in the liver in the absence of other known conditions.

Classifications of Autoimmune Hepatitis

Three forms of AIH have been traditionally defined, each of which was categorized by the presence of different types of autoantibodies. The presence of smooth muscle antibody (SMA) with specificity to F-actin, so-called antiactin antibody (AAA), and/or antinuclear antibody (ANA) defines type 1 AIH (AIH-1). The presence of liver kidney microsomal type 1 antibody (anti-LKM-1) or liver cytosol type 1 antibody (anti-LC1) defines type 2 AIH (AIH-2). The presence of anti-soluble liver antigen (SLA) was formerly used to define AIH-3, but this is now included in AIH-1. Antibodies to SLA and liver pancreas (LP) are highly specific for AIH-1 and are not associated with the presence of anti-LKM-1 or anti-LC-1. Antibodies to SLA/LP can be present in overlap syndrome with cholestatic disease, but are rarely found in individuals with drug-induced hepatitis or hepatitis C infection.

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Clinical Manifestations of Autoimmune Hepatitis

The majority of patients with AIH present with insidious and nonspecific symptoms. Seventy-five percent of patients with AIH are girls/women. AIH-1 affects all age groups with a bimodal presentation: one peak occurs in children and adolescents and the other in occurs adults older than 40 years of age. AIH-2 predominantly affects children and young adults.

AIH-1 presents mostly with nonspecific indolent symptoms of fatigue, malaise, nausea, abdominal pain, and arthralgia. Some patients with AIH-1 are coincidentally diagnosed when biochemistry laboratory tests are obtained for other reasons and liver enzyme levels are found to be elevated. Approximately one third of patients with AIH-1 have acute illness, with jaundice, fatigue, anorexia, and arthralgia. These features are more common in children and are indistinguishable from the clinical presentation of other causes of acute hepatitis. Recurrent acute hepatitis or chronic liver disease with portal hypertension can be the initial presentation.

Physicians must have a high index of suspicion for AIH. An early clue to the diagnosis of AIH is female sex, negative serologic test results for the various causes of viral hepatitis, and high serum globulin or IgG.

Interestingly one third of pediatric patients with AIH have cirrhosis at diagnosis, as reported by Gregorio et al.

Certain medications such as minocycline and nitrofurantoin can lead to immune-mediated hepatitis or drug-induced autoimmune-like hepatitis (AIH-DILI). This condition is probably underreported. It is unknown if the natural history in all patients with AIH-DILI would be similar to that of AIH.

Family history of autoimmune diseases and other associated autoimmune disorders

Forty percent of patients with AIH have a positive family history of autoimmune disorders. Up to 20% of patients have other autoimmune  disorders, including autoimmune thyroiditis, type 1 diabetes mellitus, arthritis, celiac disease, vitiligo, and inflammatory bowel disease.

What other disease/condition shares some of these symptoms?

Typical symptoms of AIH can also be seen in patients with viral hepatitis, metabolic liver disease such as Wilson disease, nonalcoholic steatohepatitis, and drug-induced liver injury (DILI).

What caused this disease to develop at this time?

Predisposing factors include previous or concomitant infection, possession of certain HLA DRB1 variants, medications, and  known autoimmune diseases; however, more studies are needed to understand the role of these factors in the development of AIH . 

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Serum aminotransferase levels are usually elevated, as is the IgG level. Test results for one or more autoantibodies are usually positive. These include ANA (titer ≥20), SMA (titer ≥20), anti-LKM-1 (≥20),  and/or  seropositivity for SLA.  In AIH-1, serum aminotransferase levels could be mildly to markedly elevated (1-2 times to 10-50 times the upper limit of normal). 

Histologic examination of the liver confirms the diagnosis in most cases. Interface hepatitis is characterized by the presence of lymphoplasmacytic infiltrate that invades the limiting plate into the liver parenchyma. Others features include hepatocyte swelling with pyknotic necrosis and panlobular hepatitis with bridging fibrosis.

Would imaging studies be helpful? If so, which ones?

Imaging studies are not necessary for the diagnosis of AIH; however abdominal ultrasonography aids in detecting complications of AIH such as liver fibrosis/cirrhosis, evidence of portal hypertension, liver masses, and other conditions resulting in liver dysfunction, such as liver abscess, complicated choledochal cyst, or common bile duct obstruction.

Confirming the diagnosis

The usual algorithm to be followed is to suspect the diagnosis when a patient presents with the symptoms described above and to obtain a liver enzyme panel. If abnormalities are noted, a screen for the common causes of liver enzyme elevation should be performed. This would include tests for serum immunoglobulins and the autoantibodies described above; serologic tests for hepatitis secondary to hepatitis viruses A, B, and C; alpha-1-antitrypsin phenotyping; and serum ceruloplasmin and 24-hour urine copper determination to rule out Wilson disease. If other conditions are excluded and autoantibody results are positive, the definitive test for AIH is a liver biopsy.

If you are able to confirm that the patient has autoimmune hepatitis, what treatment should be initiated?

The treatment goal is to obtain early complete remission to prevent disease progression and further liver damage. Without treatment, the mortality rate in patients with AIH can be as high as 75% at 5 years.

If the patient is taking a hepatotoxic drug, the offending drug should be discontinued, if possible.

The standard treatment for AIH is prednisone. Based on small clinical trials and a lack of a randomized controlled study, azathioprine has been added in the early phase of therapy to avoid using high-dose prednisone over a long period. Azathioprine is not recommended as a single drug in induction phase because it takes about 2 months to attain therapeutic drug levels. 

For children, 1 – 2 mg/kg/d of prednisone (maximum dose 60 mg/d) is recommended as initial therapy. Azathioprine at 1 – 2 mg/kg/d could be added later when  the disease activity is improved. Thiopurine methyltransferase enzyme activity could be performed to classify how well a patient is able to metabolize azathioprine. Thereafter erythrocyte 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-MMP) metabolites are helpful in assessing treatment efficiency and side effects of azathioprine.

The absence of clinical presenting symptoms, the presence of normalized aminotransferases and IgG levels, and disappearance or lower titers of autoantibodies indicate complete remission. There is as yet no consensus on the duration of treatment or whether a liver biopsy is always necessary before treatment withdrawal.

The treatment is usually long-term to obtain and maintain remission, since relapse commonly occurs when early withdrawal of immunosuppression is attempted.  Azathioprine monotherapy can sometimes be used to maintain remission. In some patients azathioprine combined with low-dose prednisone is necessary for maintenance of remission.

In patients with AIH who are refractory to conventional treatment, mycophenolate mofetil (20 mg/kg twice daily) in conjunction with prednisone has been reported as an alternative treatment.

Other steroid-sparing agents in the treatment of AIH include cyclosporine and tacrolimus, which have more severe side effects and are expensive. Budesonide (3 mg three times daily) with azathioprine as a combination regimen was reported as a valid alternative in a large European trial in adults. Currently there are no data on this combination regimen in children.

Liver transplantation is indicated in patients with AIH with fulminant liver failure or with end-stage liver disease; however, AIH may recur after liver transplantation.  

What are the adverse effects associated with each treatment option?

The common adverse effects of prednisone are gastrointestinal disturbances, mood changes, increased appetite, acne, salt retention, osteopenia, frequent infection, and hypertension. Uncommon side effects include diabetes mellitus, pancreatitis, steroid psychosis, and avascular necrosis of the hip joints. Azathioprine is known to cause nausea, vomiting, rash, pancreatitis, bone marrow suppression, liver dysfunction, cholestatic hepatitis, and frequent infection. Individuals with extremely low TPMT enzyme activity or elevated 6-TG metabolites are at risk for bone marrow suppression. An elevation of the 6-MMP metabolite is associated with liver dysfunction. In an individual who has extremely high TPMT enzymes or has low 6-TG metabolites and very high 6-MMP metabolites, hepatotoxicity often occurs. To avoid hepatotoxicity, Al-Shamma et al. used allopurinol, which is a xanthine oxidase inhibitor in an AIH patient who went into remission rapidly. Xanthine oxidase inhibitors promote the metabolism of azathioprine to 6-TU and 6-TG metabolites, therefore resulting in less substrate for the TPMT enzyme to metabolize azathioprine into 6-MMP metabolites, therefore resulting in less hepatotoxicity.

What are the possible outcomes of autoimmune hepatitis?

Treatment with immunosuppression generally induces remission in up to 80% of AIH cases, even in cases manifesting with acute liver failure. However, relapse is common and requires an increase in prednisone or azathioprine dose. Relapse is usually associated with nonadherence to treatment or an attempt to withdraw immunosuppression after treatment for 2 – 3 years. Couto et al. reported the presence of persistently elevated titers of SMA and AAA could indirectly be an indicator of histological and biochemical activity in AIH patients after immunosuppressive therapy. Although adverse effects of immunosuppressive drugs are abundant, the regimen to avoid long-term use of high-dose prednisone by using low-dose prednisone in combination with azathioprine reduces the steroid side effects. In a recent report of a population-based study (56 children with AIH) from Deneau et al., discontinuation of all immunosuppressive medications was successful at a median duration of 2 years after the treatment was started. This was particularly in type 1 AIH children who had a stable biochemical remission. Czaja et al. proposed that elevated serum IgG values are a good marker for relapse after discontinuing immunosuppression.

Safety measures are available for the administration of azathioprine by using TPMT and 6-TG and 6-MMP metabolites. Azathioprine has no reported teratogenic effects in humans. Long-term immunosuppressive therapy is reported to be associated with the development of malignancies, including skin cancer and non-Hodgkin lymphoma. Nevertheless, AIH without appropriate treatment can lead to cirrhosis, which carries a risk for chronic liver disease, liver failure, and hepatocellular carcinoma.

For individuals who have milder degrees of AIH and are asymptomatic, the risks and benefits should be clearly discussed with patients and their families.

What causes this disease and how frequent is it?

In general AIH-1 is the most common form. The prevalence is 1/200,000 in the US population; however this could have been underreported, since AIH is an insidious disease and some cases could be asymptomatic. The prevalence of AIH-2 is unknown.

Previous hepatitis A virus (HAV) infection has been proposed as a factor that results in molecular mimicry between the infectious particle and the liver parenchyma in AIH-1. Hepatitis C (HCV) infection is frequently associated with AIH-2.

Individuals who are susceptible to AIH likely have allelic variants of DRB1 on their human leucocyte antigen (HLA) region, suggesting a pathogenic role for HLA class II antigen presentation and T-cell activation.  HLA DRB1*0301 and DRB1*0401 increase susceptibility for AIH-1 in North American and European populations, and DRB1*0405 and DRB1*0404 play that role in Japanese, Argentinean, and Mexican populations. In South America, individuals with DRB1*1301 likely have frequent exposure to HAV and are predisposed to AIH-1. Possession of HLA DRB1*701 and DRB1*0301 increases susceptibility to AIH-2, with the former carrying a more severe form of AIH.

How do these pathogens/genes/exposures cause the disease?

A defect in immunoregulatory mechanisms results in autoimmune phenomena. The self-antigenic peptide is processed through HLA class II molecules and presented to CD4 T-helper cells (Th0) by antigen-presenting cells within the liver or lymph nodes. Immune activation occurs. Th0 cells differentiate to Th1 cells promoted by interleukin-12 (IL-12) from macrophages. Th1 cells secrete IL-12 and interferon gamma, which further activate macrophages and enhance HLA class I expression. This phenomenon makes the liver susceptible to cytotoxic CD8 T cells.

Th0 can differentiate to Th2 in an IL-4 milieu and will then produce more IL-4, IL-10, and IL-13, cytokines that promote autoantibody production by B lymphocytes.

It is unknown what leads the immune system to react to a self-antigen, but some studies suggest that molecular mimicry is a trigger for anti-LKM-1 in HCV infection.

Other clinical manifestations that might help with diagnosis and management

AIH can present with other autoimmune disorders, such as autoimmune thyroiditis, celiac disease, type 1 diabetes mellitus, pernicious anemia, inflammatory bowel disease, common variable immune deficiency, vitiligo, Addison disease, and rheumatoid arthritis.

What complications might you expect from the disease or treatment of the disease?

AIH is a chronic inflammatory disease of the liver. A significant degree of hepatic necrosis can lead to marked fibrosis, even with appropriate treatment. Despite normal serum aminotransferase levels, it is possible that the liver still has low-grade inflammation (subclinical relapse). Eventually, some  patients  with this type of inflammation will experience cirrhosis and manifest signs and symptoms of portal hypertension.

It is almost an art to titrate immunosuppressive drugs to achieve an early complete remission. Patient education is essential to the success and safety of the treatment in AIH. Susceptibility to frequent viral and bacterial infections may require discontinuation or a decrease in immunosuppressant drug doses as treatment, with an appropriate antibiotic.

The use of high-dose prednisone and azathioprine at the beginning of therapy requires vigilant monitoring with biochemistry panels. Persistent hyperglycemia or the development of diabetes mellitus from high-dose prednisone should be avoided, as this may lead to severe opportunistic infections such as fungal diseases. 

Are additional laboratory studies available; even some that are not widely available?

Antibodies against cytochrome P450 2E1 have been described as playing a role in the form of AIH triggered by inhalant anesthetics, but the test for these antibodies is available on a research basis only.

How can autoimmune hepatitis be prevented?

There is no commercial testing to delineate which individual would be at risk for acquiring AIH. Immunization with hepatitis A vaccine is encouraged by the American Academy of Pediatrics for all children older than 12 months of age and with three doses of hepatitis B vaccine from birth. This may help prevent the development of AIH in genetically predisposed individuals. More studies are needed to understand the role of viral infection in AIH. Perhaps individuals who have a strong family history of autoimmune disease should be aware of certain medications that can cause AIH-DILI.

What is the evidence?

The evidence for treatment presented above is expert opinion only. There are no randomized controlled treatment trials in children with AIH.

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Ongoing controversies regarding etiology, diagnosis, treatment

The major thrust of AIH research is to identify the autoantigens so as to enable the development of more specific immunotherapy as opposed to the management described above, which is more general immunosuppressive therapy with well-recognized side effects.