Autoimmune Chronic Active Hepatitis – Symptoms, Treatment

• Antiviral medications (if virus causes)
• Antibiotics, (if bacteria cause)
• Steroids are used to reduce brain swelling
• Sedatives for restlessness
• Acetaminophen for fever
• Occupational and physical therapy (if the brain is affected post-infection)

Medications

autoimmune hepatitis is a rare condition with no randomized controlled trials to guide treatment. Treatments that have been tried include intravenous immunoglobulin, plasmapheresis, corticosteroids, cyclophosphamide, and rituximab.^[rx]

• Corticosteroids – are a class of drug that lowers inflammation in the body. They also reduce immune system activity. Because corticosteroids ease swelling, itching, redness, and allergic reactions, doctors often prescribe them to help treat diseases like autoimmune hepatitis. Because most patients respond to corticosteroids or glucocorticoid immunosuppressant treatment, this condition is now also referred to as steroid-responsive autoimmune hepatitis. Initial treatment is usually with oral prednisone (50–150 mg/day) or high-dose intravenous methylprednisolone (1 g/day) for 3–7 days or prednisone is usually administered orally at 2 mg/kg/day (up to a maximum of 60 mg/day), azathioprine is administered at the initial dose of 1 mg/kg/day, which can be further increased up to 2.5 mg/kg/day until sustained biochemical remission is achieved.[rx]
• Budesonide – has been shown to be more effective in inducing remission than prednisone, and result in fewer adverse effects.^[17]
• Immunoglobulin infusion(IVIG)  – Prompt treatment can be initiated before the final diagnosis in case of a reasonable degree of suspicion after collecting serum and CSF samples for confirmation of autoimmune hepatitis[rx] [rx] Expeditious immunomodulatory/immunosuppressive therapies with corticosteroids, immunoglobulin infusion(IVIG), and plasmapheresis (PLEX) are first-line therapies, as well as tumor removal if applicable, with robust supportive therapies.[rx][rx]
• Plasmapheresis – can remove autoantibodies of the blood. Plasmapheresis is a method for removing unwanted substances (toxins, metabolic substances, autoantibodies) from the blood. During plasmapheresis, blood is removed from the affected individual and blood cells are separated from plasma. The plasma is then replaced with other human plasma and the blood is transfused back into the affected individual. [rx]
• Biological Drugs – Rituximab, cyclophosphamide, azathioprine, mycophenolate mofetil have been used as second-line therapies if clinical improvement does not occur after four weeks of treatment with first-line therapy. Some experts recommended the use of rituximab early in the disease process as first-line therapy. For refractory patients, bortezomib(proteasome inhibitor), alemtuzumab(humanized monoclonal antibody against CD52), intrathecal methotrexate, and tocilizumab(a monoclonal antibody against interleukin-6 receptor) can work in a small number of patients with success.[rx]
• Anti Seizure Drugs – management in the acute phase can be difficult and requires AEDs along with immunotherapy. However, these patients do not develop epilepsy as the seizure improves with the improvement of autoimmune hepatitis. A retrospective series reported that valproate, levetiracetam, and carbamazepine had been similarly effective, but carbamazepine was associated with fewer side effects.[rx] Gradual reduction of autoimmune hepatitis is possible during follow-up and most can be discontinued in 2 years without seizure recurrence. Antipsychotic agents are frequently used to treat behavioral symptoms, but the neuroleptic malignant syndrome can occur.[rx][rx]
• Benzodiazepines and electroconvulsive therapy – have been utilized to treat catatonia. Abnormal movements associated with this autoimmune hepatitis are challenging to control and require a high dose of sedative medications, botulinum toxin, or tetrabenazine. ICU management is essential during the severe phase of the disease for several reasons: airway protection, altered cognition, dyskinesias, seizures, abnormal behavior, temperature instability, heart rate variability, and arrhythmia.[rx][rx]
• Antiviral Medication – Herpes simplex encephalitis is the commonest autoimmune hepatitis. Any patient who presented with clinical features of autoimmune hepatitis should be treated empirically with IV acyclovir, pending the result of autoimmune hepatitis results. Acyclovir will be continued or stopped depending on the outcome of the PCR test. It is essential to recognize the fact that early recurrence of HSV encephalitis within 2 to 3 weeks of autoimmune hepatitis is often due to autoimmune hepatitis triggered by autoimmune hepatitis. The viral infection may lead to a higher likelihood of release of the receptor and subsequent antibody formation and secondary autoimmune hepatitis.[rx]
• Liver transplant – When medications don’t halt the progress of the disease or you develop irreversible scarring (cirrhosis) or liver failure, the remaining option is a liver transplant. During a liver transplant, your diseased liver is removed and replaced with a healthy liver from a donor. Liver transplants most often use livers from deceased organ donors. In some cases, a living donor liver transplant can be used. During a living donor liver transplant, you receive only a portion of a healthy liver from a living donor. Both livers begin regenerating new cells almost immediately.

Most Common Treatment Options for Autoimmune Hepatitis

Induction Phase

In the induction phase, prednisone 30 mg per day plus azathioprine 50 mg per day is started for 1 week. This is followed by a prednisone taper over the course of 4 weeks with a fixed azathioprine dose of 50 mg per day to achieve a dose of prednisone 10 mg per day plus azathioprine 50 mg per day as shown in Table 5.

Should budesonide plus azathioprine be selected, induction is achieved with a combination of budesonide 3 mg three times daily plus azathioprine 50 mg per day for 2 weeks, followed by a budesonide 3 mg twice daily thereafter.

Maintenance Phase

For those receiving prednisone plus azathioprine, the maintenance phase begins typically after 4 weeks, when the dose of prednisone 10 mg per day plus azathioprine 50 mg per day is started. This dose is continued for at least 1 full year. The daily maintenance dose of prednisone should remain fixed, as dose titration according to liver transaminases or alternate day schedules of prednisone are associated with incomplete histological improvement despite laboratory improvement.

After 1 year of controlled disease, consideration can be given to withdrawal of prednisone while continuing azathioprine. Thereafter azathioprine monotherapy is continued for long-term maintenance. Patients can often be maintained on doses of azathioprine monotherapy of 50 mg per day to 100 mg per day with normal liver enzymes. Azathioprine doses of less than 100 mg per day have the advantage of less toxicity, particularly less leukopenia. Table 5 shows the medical regimen for AIH.

If budesonide is used, the maintenance dose is 6 mg twice daily in combination with azathioprine 50 mg per day. One may consider tapering budesonide while maintaining azathioprine 50 mg per day to 100 mg per day (azathioprine monotherapy) after 12 months, but there are currently no studies on the long term effect of azathioprine monotherapy after budesonide plus azathioprine combination.

Current Alternative Treatments

Although conventional treatment with steroids ± azathioprine allows achieving remission in most patients, in cases of initial treatment failure or multiple relapses during tapering or discontinuation attempts, alternative therapies are often proposed.

Cyclosporine (CSA) is a powerful immunosuppressant that has been successfully used in patients with JAIH as a short-term initial treatment alternative to steroid-azathioprine or as a salvage treatment (rx, rx). The main side effects of CSA include nephrotoxicity, arterial hypertension, and gastrointestinal and neurological toxicity. Minor but frequent side effects are Hypertrichosis and gum hypertrophy; although transient they occasionally can influence adherence to treatment. Since 1985, the use of CSA has been documented in 133 adults with autoimmune hepatitis. CSA was used as salvage therapy and showed an overall positive response of any degree in about 93% of patients and a negative response, defined as no response, non-compliance, or drug intolerance in 7% (rx, rx).

Regarding pediatric patients, there are only five major publications in which CSA is mostly administered for short periods, mainly to induce remission, as a bridge to conventional treatment (rx, rx).

Furthermore, the effectiveness of CSA was similar to steroids as salvage therapy in children with JAIH and liver failure (rx). Prolonged CSA treatment for autoimmune pediatric liver disorders was first reported in 2004 with an excellent safety profile (rx), confirmed also in a recent follow-up study (rx).

A recent meta-analysis by Zizzo et al. confirmed that CSA has the highest short-term response rate (86%) in conventional treatment-refractory children with autoimmune hepatitis (rx).

Besides CSA, a wide range of immunosuppressive drugs has been used in small series of children (rx).

Mycophenolate Mofetil (MFM) is the second most effective drug for conventional treatment-refractory children with JAIH after cyclosporine (36% remission rate at 6 months) (rx). The main concern is the use of MMF is the lack of knowledge regarding its therapeutic range and toxic threshold; moreover, MFM is more expensive than azathioprine and is absolutely contraindicated during pregnancy.

Recently, Budesonide, a corticosteroid with potentially fewer side effects than other glucocorticoids, emerged as an alternative first-line treatment in association with azathioprine. When comparing the effects of budesonide vs. prednisone, both in combination with azathioprine, budesonide did cause fewer side effects than prednisone; however, after 12 months, only 46% of the patients treated with budesonide achieved complete remission (rx). The low proportion of remission observed in this study does not support its use as a first-line treatment of AIH (rx, rx).

mTOR inhibitors as sirolimus or everolimus have been used as salvage therapy with good results in few published adult patients (rx, rx).

Liver transplantation represents a therapeutic option for a small proportion of patients under two main circumstances: patients presenting with acute liver failure that does not respond to salvage therapy with rescue immunosuppression, and patients with cirrhosis with end-stage liver disease.

Monitoring

We suggest the following tests to monitor patients with AIH.

Prior to treatment

• Pregnancy test
• Vaccination for hepatitis A and hepatitis B viruses
• Bone density in postmenopausal women
• Bone maintenance regimen of calcium and vitamin D supplementation and exercise for all patients
• Complete blood count to rule out severe cytopenia that would preclude azathioprine

During induction phase

• AST or ALT, total bilirubin concentration, and alkaline phosphatase every 1-2 weeks

During maintenance phase

• AST or ALT, total bilirubin concentration, alkaline phosphatase, and gamma globulin or IgG levels every 3-6 months
• Complete blood count every 6 months while on azathioprine
• Bone mineral density once a year while on prednisone
• Routine eye examination in patients on prednisone at least once a year

During treatment withdrawal

• AST or ALT, total bilirubin concentration, alkaline phosphatase, and gamma globulin or IgG levels every month for 3 months, then every 6 months for 1 year, and then yearly lifelong

When end-stage liver disease ensues

• Hepatic ultrasonography every 6 months or computed tomography of the abdomen with contrast once a year to screen for hepatocellular carcinoma
• Esophagogastroduodenoscopy screening for esophageal varices every 2-3 years for primary prophylaxis of variceal bleeding
• Bone mineral density every 3 years

Next steps

Tips to help you get the most from a visit to your healthcare provider:

• Know the reason for your visit and what you want to happen.
• Before your visit, write down questions you want to be answered.
• Bring someone with you to help you ask questions and remember what your provider tells you.
• At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also write down any new instructions your provider gives you.
• Know why a new medicine or treatment is prescribed, and how it will help you. Also, know what the side effects are.
• Ask if your condition can be treated in other ways.
• Know why a test or procedure is recommended and what the results could mean.
• Know what to expect if you do not take the medicine or have the test or procedure.
• If you have a follow-up appointment, write down the date, time, and purpose for that visit.
• Know how you can contact your provider if you have questions.

References