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Last updated: August 20, 2019
Years published: 2016, 2019
NORD gratefully acknowledges Danielle Eagan, DO, RD, Endocrinology Fellow at the University of Florida and patient with AIH, and Craig Lammert, MD, Assistant Professor of Medicine, Department of Gastroenterology, Indiana University Health University Hospital, for the preparation of this report.
Summary
Autoimmune hepatitis (AIH) is a non-contagious, chronic, inflammatory, autoimmune disease in which oneโs own immune system attacks healthy, normal liver cells. The cause of liver cell destruction in this disease is unclear, but may be related to an imbalance in some of the immune system cells (effector and regulatory). The persistent inflammation within the liver observed in AIH can result in scarring, ultimately leading to cirrhosis, liver failure requiring a liver transplant, and even death. AIH is about 4 times more common in females than males and is commonly associated with other autoimmune conditions including type 1 diabetes, Hashimotoโs thyroiditis, and celiac disease. In fact, 25-50% of AIH patients will develop another concurrent autoimmune disease in their lifetime.
There are two clinically relevant types of AIH, including type 1and type 2. Type 1 AIH, also referred to as the classic type, is typically diagnosed in adulthood, whereas type 2 is diagnosed during childhood. Both types are treated similarly; however, type 2 AIH can be more severe and more difficult to control. Symptoms associated with AIH include fatigue, itching (pruritus), yellowing of the skin and whites of the eyes (jaundice), nausea, vomiting, abdominal pain, weight loss, light colored stools, dark colored urine, joint pain, rashes, and loss of menstruation in women. AIH is commonly diagnosed via a combination of the patientโs symptoms, blood work, and a liver biopsy. Although there is no cure for AIH, it can often be controlled with medication including steroids and other agents which suppress the immune system. Those with AIH often follow with either a gastroenterologist or hepatologist to manage their condition.
Introduction
In the 1950โs, an internal medicine doctor named Dr. Waldenstrรถm, first described this condition after observing a cohort of young women with elevated liver tests and an elevated component of the immune system called gamma globulin. This was eventually termed โlupoid hepatitisโ by Dr. Mackay until the 1960s when the name was changed to autoimmune hepatitis. AIH was the first chronic liver disease to have a dedicated treatment. In the 1960s-1970s, therapy with glucocorticoids and azathioprine revealed successful disease control for many. Since these sentinel observations, there has been limited advancement in novel drug therapies. Early detection of AIH is key, as early and effective treatment is associated with better patient outcomes.
Symptoms can vary from person to person with AIH; some may not even have any symptoms. Common initial symptoms can include fatigue, nausea, vomiting, abdominal pain, weight loss, light colored stools, dark colored urine, joint pain, rashes, and loss of menstruation in women. Some may develop an enlarged liver (hepatomegaly) and/or spleen (splenomegaly).
Without adequate therapy, there is risk of disease progression in the form of liver fibrosis. With time, one may develop liver scaring (cirrhosis) that can increase risk of liver failure, development of fluid in the abdomen (ascites), gastrointestinal bleeding from abnormal blood flow in the esophagus and stomach, confusion associated with a poorly functioning liver, and even liver cancer.
At this time, the exact cause of autoimmune hepatitis is unknown. It is believed to be due to a combination of environmental, genetic, and immunologic factors. A few environmental triggers, such as prescribed medications and infections, have been associated with the development of AIH. Some of the medications thought to play a role in those with drug-induced AIH include nitrofurantoin, minocycline, and hydralazine. Infections such as viral hepatitis (hepatitis A, B, C, and D), herpes simplex virus, and cytomegalovirus have also been linked to disease onset.
AIH is considered an โautoimmuneโ disease which means something (whether environmental, genetic, and/or immunologic factors) somehow triggers the immune system to think the cells in your liver are dangerous. This causes the cells in your body that usually attack foreign invaders (like viruses and bacteria) to start attacking the liver. This leads to inflammation and liver damage.
Autoimmune hepatitis is a rare disorder that affects females 4 times as often as males. Type 1 is more common and is usually diagnosed in adults. Type 2 is more common in children and often involves a more severe disease process. There are also variant types of AIH; these include individuals with AIH and one of the other autoimmune liver diseases (primary sclerosing cholangitis or primary biliary cholangitis).Those with other autoimmune conditions have a 25-50% chance of developing another one and thus a higher risk for developing AIH. The new cases per year (incidence) are estimated at 1-2 per 100,000 and total cases (prevalence) are approximately 24 per 100,000. Studies suggest that the incidence of AIH is increasing and the reason is unknown.
Diagnosis of AIH can be complex, and is frequently completed after going through several steps. This includes meeting with your doctor to discuss your past medical problems, your current symptoms, a complete physical exam, blood work, and a liver biopsy.
Clinical Testing and Work-Up
Initial bloodwork will include checking for signs of liver inflammation, liver function, autoimmune markers, and other blood tests to rule out other causes of liver disease.
The inflammation tests will include checking the liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyltranspeptidase (GGT).
Liver function is accessed by checking prothrombin time (PT) and international normalized ratio (INR). These tests can show if you are likely to bleed too much which can happen if the liver is damaged and is not working very well. Albumin is also checked. This is a protein that the liver makes and if it is low it can indicate you may have cirrhosis. Total bilirubin also is completed along with other liver tests. Increased bilirubin may indicate severe inflammation associated with the disease, but may also indicate decreased liver function.
Autoimmune markers that will be checked to include the antinuclear antibody (ANA), smooth muscle antibody (ASMA), liver kidney microsomal antibody (LKM), and immunoglobulin G (IgG). Many autoimmune diseases will cause an elevated ANA and IgG so if those are elevated it does not mean you have AIH, just that you may be more likely to have an autoimmune condition. ASMA and LKM are more specific to AIH when they are elevated alongside elevated liver tests.
Other bloodwork to help make sure that you do not have any other liver disease that could be presenting with similar symptoms to AIH include checking for viral hepatitis (hepatitis, A, B, C, D, E), Wilsons disease (ceruloplasmin levels), hemochromatosis (complete blood count panel (CBC) and anemia panel), alpha1-antitrypsin deficiency (measure alpha 1-antitryspin levels), and alcohol levels in the blood.
A liver biopsy is done to help confirm autoimmune hepatitis and also to stage the amount of fibrosis present. This procedure involves you lying on a table and having part of the right abdomen numbed. The doctor then passes a needle into to the liver. The liver tissue is sent to a pathologist who looks at the sample under a microscope and does special staining to further examine it. A liver biopsy may not completely exclude or confirm AIH. This procedure is typically done as a same day procedure and usually you get to go home 4-5 hours after the test.
A fibroscan is sometimes done between liver biopsies to help quantify the amount of liver fibrosis and fat in the liver or to get an initial idea of how healthy the liver is, but the liver biopsy is the best current test.
Treatment
Those with AIH are usually started on corticosteroids and then placed on other immunosuppressive agents. Most physicians target a goal either to completely stop the steroids or taper them down to the lowest dose possible as the disease gets into remission. Most people will stay on an immunosuppressant for life because without one the disease relapse rate is >80%. If you have a relapse or flare (liver tests increase while on therapy) then steroids are either restarted or the dose is increased if you are already taking them. Everyone does not necessarily tolerate or respond to the same treatment, so your doctor will have to determine what works best for you. With these medications, your risk of infection is higher because the immune system is being suppressed. The current medication options will be reviewed below.
Corticosteroids such as prednisone, prednisolone, or budesonide are usually used to help suppress the immune system (so the liver is not attacked) and calm down the inflammation in the liver. Prednisone is a common first treatment. It has been used for many years and tends to work for many. Unfortunately, there are several side effects of these medications including bone loss (osteoporosis), high blood sugar, increased appetite, insomnia, mood changes, muscle pain, depression, and anxiety. Budesonide tends to have fewer of the side effects, but has been less studied.
Azathioprine (Imuran) is commonly started during the tapering of prednisone. This medication tends to have less severe side effects compared to the prednisone so it is usually the drug of choice for long-term use. Nausea and vomiting occur in 10-15% of people taking azathioprine; therefore, an alternative treatment is used if it is too severe. There is an increased risk of lymphoma with this medication. Some people are unable to metabolize this medication which can be determined with some additional blood tests. While on this medication, white blood cell counts need to be monitored.
Mycophenolate mofetil (Cellcept) is another option if one cannot tolerate azathioprine. It can also cause a significant amount of GI symptoms including abdominal pain, nausea, vomiting, diarrhea, constipation, and anorexia. Some may also have their kidney function affected by this medication so that must be monitored by bloodwork. Females of childbearing age must take a pregnancy test prior to starting this medication and use two forms of birth control while on the medication because it is associated with birth defects. Breastfeeding must be avoided until 6 months after this medication has been stopped because it is unknown if it is excreted in the breast milk.
Cyclosporine, sirolimus (Rapamune), and tacrolimus (Prograf) are other alternative treatments to azathioprine and mycophenolate mofetil. These medications can also lead to nausea, diarrhea, constipation, abdominal pain, high blood pressure, elevated cholesterol, joint pain, diabetes, and gingivitis.
It is important for patients to adopt a healthy diet and exercise routine to obtain an ideal body weight. The best diet to follow is one with a minimal amount of processed food and high in lean protein, vegetables, and fruits. Those that are overweight can have an increased risk of fatty liver disease and worse outcomes.
Methotrexate, rapamycin, rituximab, and infliximab have been used in a small subset of patients with AIH who did not respond well to the drugs discussed above. Currently no specific dosing guidelines, monitoring strategies, or safety profiles of these AIH investigational drugs exist.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
BOOKS
Sabatine MS., ed. Pocket Medicine, 4th ed. Lippincott Williams & Wilkins. Philadelphia, PA; 2010;chapter 3:15-24.
JOURNAL ARTICLES
Czaja, AJ. Diagnosis and management of autoimmune hepatitis: current status and future directions. Gut and Liver. 2016;10(2):117-203. doi:10.5009/gnl15352
European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Autoimmune hepatitis. Journal of Hepatology. 2015;63:971-1004. doi:10.1016/j.jhep.2015.06.030.
Cojocaru, M, Cojocaru, IM and Silosi, I. Multiple autoimmune syndrome. Maedica (Buchar). 2010;5(2):132-134.
Washington, MK. Autoimmune Liver Disease: overlap and outliers. Modern Pathology. 2007;20:S15-S30. doi:10.1038/modpathol.3800684
Manns MP and Vogel A. Autoimmune Hepatitis, from Mechanisms to Therapy. Hepatology. 2006;43(S1)S132-144. doi:10.1002/hep.21059
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The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
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