Question

    Autoimmune Hepatitis

    Autoimmune hepatitis - cropped - very high mag[1]

    This disorder originates from the following process: auto-immune.

    Presentation

    Oettinger et al. published a series of 142 children with autoimmune hepatitis [8]. Findings included:

    Other symptoms and signs may include:

    Liver, Gall & Pancreas
    Hepatomegaly
    • CT Nonspecific, ranging from normal to hepatomegaly and cirrhosis.[radiopaedia.org]
    • Figure 1: CT of abdomen showing hepatomegaly.[hindawi.com]
    • Findings included: Jaundice 58% Non specific weakness 57% Anorexia 47% Abdominal pain 38%  Paleness 26% Other symptoms and signs may include: General discomfort or uneasiness  Abdominal distension Pruritis Diarrhea Edema Weight loss Spider angiomata Hepatomegaly[symptoma.com]
    • AIH symptoms include: enlarged liver (hepatomegaly) abnormal blood vessels on the skin (spider angiomas) abdominal distention (swelling) dark urine pale-colored stools Additional symptoms that may occur include: yellowing of the skin and eyes (jaundice[healthline.com]
    Jaundice
    • Common initial symptoms include fatigue or muscle aches or signs of acute liver inflammation including fever, jaundice, and right upper quadrant abdominal pain.[en.wikipedia.org]
    • This leads to decreased liver function, which may cause jaundice.[iuhealth.org]
    • On physical exam, there was right upper-quadrant tenderness and notable jaundice but no hepato-splenomegaly.[bloodjournal.org]
    • Symptoms include jaundice, dark urine, fever and flu­like symptoms.[bshr.com]
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  • Entire body system
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  • Skin
    Hirsutism
    • Compared to prednisone, it has a relatively safe adverse-effect profile with headache and respiratory infection seen most commonly. 9 Cosmetic changes such as moon face, acne, and hirsutism have been noted. 8 Budesonide is primarily metabolized through[uspharmacist.com]
    • Common symptoms include the following: Fatigue Upper abdominal discomfort Mild pruritus Anorexia Myalgia Diarrhea Cushingoid features Arthralgias Skin rashes (including acne) Edema Hirsutism Amenorrhea Chest pain from pleuritis Weight loss and intense[emedicine.medscape.com]
    • Skin rashes (including acne), hirsutism.[patient.info]
    • Liver toxicity Myelosuppression Pancreatitis Malignancy (most often lymphoma) Rash Pregnancy Malignancy Leukopenia 2.5 x 10 9 /L Thrombocytopenia 50 x 10 9 Known complete TPMT deficiency Budesonide Usually none Cosmetic changes (moon faces, acne and hirsutism[clevelandclinicmeded.com]
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  • musculoskeletal
    Arthralgia
    • Although patients may present with acute symptoms (eg, arthralgia), about 34% to 45% are asymptomatic and are identified subsequent to abnormal liver function tests such as increased alanine and/or aspartate aminotransferase (generally 500 U/L but occasionally[questdiagnostics.com]
    • People usually present with one or more nonspecific symptoms, sometimes of long lasting duration, as fatigue, general ill health, lethargy, weight loss, mild right upper quadrant pain, malaise, anorexia, nausea, jaundice or arthralgia affecting the small[en.wikipedia.org]
    • The patient will sometimes present with jaundice, fever and right upperquadrant pain and occasionally systemic symptoms such as arthralgias (arthritis), myalgias (muscle aches), polyserositits and thrombocytopenia.[texasliver.com]
    • The next most common symptoms are abdominal pain, jaundice, arthralgia, and epistaxis.[clinicaladvisor.com]
    • About 1% of patients develop symptomatic cryoglobulinemia with fatigue, myalgias, arthralgias, neuropathy, glomerulonephritis, and rashes (urticaria, purpura, leukocytoclastic vasculitis); asymptomatic cryoglobulinemia is more common.[merckmanuals.com]
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  • urogenital
    Amenorrhea
    • Symptoms Symptoms may include: Abdominal distention Dark urine Fatigue General discomfort, uneasiness, or ill feeling ( malaise ) Itching Loss of appetite Nausea or vomiting Pale or clay-colored stools Absence of menstruation (amenorrhea) may also be[scripps.org]
    • Genetic predisposition: North America / Europe: HLA-DR3 (DRB1*0301) and HLA-DR4 (DRB1*0401) China / Japan: HLA-DR4 (DRB1*0405) Clinical features Most patients have nonspecific symptoms: fatigue, anorexia, nausea, weight loss, jaundice, pruritus and amenorrhea[pathologyoutlines.com]
    • Common symptoms include the following: Fatigue Upper abdominal discomfort Mild pruritus Anorexia Myalgia Diarrhea Cushingoid features Arthralgias Skin rashes (including acne) Edema Hirsutism Amenorrhea Chest pain from pleuritis Weight loss and intense[emedicine.medscape.com]
    • In autoimmune hepatitis, especially in young women, manifestations may involve virtually any body system and can include acne, amenorrhea, arthralgia, ulcerative colitis, pulmonary fibrosis, thyroiditis, nephritis, and hemolytic anemia.[merckmanuals.com]
    • […] one or more of the following nonspecific symptoms of varying severity: fatigue, general ill health, mild pain in the right upper quadrant, lethargy, malaise, anorexia, weight loss, nausea, pruritus, jaundice, and arthralgia involving the small joints; amenorrhea[uspharmacist.com]
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  • Workup

    Work up consists of a detailed history and physical examination.

    Laboratory Tests

    • Complete blood count
    • Liver function tests
    • Serology for ANAs, SMAs, LKM1, anti-LC1
    • Immunoglobulins and albumen levels
    • Blood profile

    Imaging Studies

    Test Results

    Test results will indicate eosinophilia, raised ANA, ASMA and other increased antibody titres. Blood profile will show increased blood count and a prolonged prothrombin time. Biopsy will show Ag-Ab aggregates in the liver. CT scan will show extrahepatic involvement, if any.

    Pathology

    Biopsy
    Liver Biopsy
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  • Laboratory

    Serum
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  • HLA Type
    HLA-B8
    • […] have prominent features of immune-mediated hepatocellular injury (autoimmune hepatitis), including the following: The presence of serologic immune markers An association with histocompatibility haplotypes common in autoimmune disorders (eg, HLA-B1, HLA-B8[merckmanuals.com]
    • B8, DR3 haplotype has been associated with a number of autoimmune diseases such as AIH, thyroiditis, celiac disease, and myasthenia gravis.[nature.com]
    HLA-DR3
    • For example, HLA DR3 positivity only contributes when other antibodies are negative.[napervillegi.com]
    • The Japanese population has a low frequency of HLA-DR3 markers.[emedicine.medscape.com]
    • It also usually signifies a decreased response to corticosteroids; however extra-hepatic manifestations are less common in HLA-DR3 serotype associated AIH.[jpma.org.pk]
    • For AIH-2, the primary association is HLA DR3 in Europe and HLA DQ2 and HLA DR7 in Canada.[journal.frontiersin.org]
    • […] depends on subtype: Type 1: bimodal (10-25 years and 45-70 years) Type 2: 15 years Etiology Etiology unknown; genetic and environmental factors may play roles in pathogenesis ( J Hepatol 2015;62:S100 ) Genetic predisposition: North America / Europe: HLA-DR3[pathologyoutlines.com]
    HLA-DR4
    • (DRB1*0401) China / Japan: HLA-DR4 (DRB1*0405) Clinical features Most patients have nonspecific symptoms: fatigue, anorexia, nausea, weight loss, jaundice, pruritus and amenorrhea Up to 25% of patients are asymptomatic, whereas 25-30% have episodes of[pathologyoutlines.com]
    • Race-, sex-, and age-related differences in incidence The disease is most common in whites of northern European ancestry with a high frequency of HLA-DR3 and HLA-DR4 markers.[emedicine.medscape.com]
    • HLA-DR3 serotype also occurs more commonly in caucasians. 10,11 HLA-DR4 serotype associated disease occurs more commonly in older adults and usually responds well to immunosuppressive therapy and exhibits more extra-hepatic manifestations. 10,11 HLA-DR4[jpma.org.pk]
    • In contrast, HLA DR4 is the primary association in Japan and Mexico.[journal.frontiersin.org]
    • […] features of immune-mediated hepatocellular injury (autoimmune hepatitis), including the following: The presence of serologic immune markers An association with histocompatibility haplotypes common in autoimmune disorders (eg, HLA-B1, HLA-B8, HLA-DR3, HLA-DR4[merckmanuals.com]
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  • Treatment

    Medications

    Corticosteroids are the mainstay of treatment. Budesonide has been shown to be more effective in inducing remission than prednisone, and results in fewer adverse effects [9].

    Transplantation

    Liver transplantation may be required if patients do not respond to drug therapy or when patients present with fulminant liver failure.

    Prognosis

    Autoimmune hepatitis may advance to cirrhosis [3]. Without treatment, almost 50% of patients will die within five years. Mild liver disease generally has a good prognosis with treatment, however, the more severe the disease, the worst the prognosis. In severe and/or complicated disease, life expectancy is greatly reduced.

    Complications

    Untreated and uncontrolled autoimmune hepatitis may progress to chronic hepatitis that will then show widely systemic manifestations. Complications include the following:

    Complications

    Arthritis
    • Some other symptoms, such as glomerulonephritis and arthritis , are due to deposits of antibodies that accumulate in the kidney or joints, leading to damage in those tissues.[webmd.com]
    • ENBREL was first approved in 1998 for moderate-to-severe rheumatoid arthritis.[phx.corporate-ir.net]
    • About half the people with type 1 autoimmune hepatitis have other autoimmune disorders, such as celiac disease, rheumatoid arthritis or ulcerative colitis.[mayoclinic.org]
    • This is the most common form of autoimmune hepatitis, and about half of patients have another form of autoimmune disease such as celiac disease, rheumatoid arthritis, Crohn’s disease, or other.[columbiasurgery.org]
    Autoimmune Disease
    Autoimmune Hemolytic Anemia
    • hemolytic anemia, proliferative glomerulonephritis) A response to therapy with corticosteroids or immunosuppressants Less common causes Sometimes chronic hepatitis has features of both autoimmune hepatitis and another chronic liver disorder (eg, primary[merckmanuals.com]
    • Autoimmune hemolytic anemia with giant cell hepatitis: case report and review of the literature. .[nature.com]
    Chronic Active Hepatitis
    • Liver biopsy may show mild chronic active hepatitis, more advanced chronic active hepatitis with scarring (fibrosis), or a fully developed cirrhosis.[hepatitiscentral.com]
    • Antigen specific suppressor cell function in autoimmune chronic active hepatitis.[link.springer.com]
    • The prognosis of chronic active hepatitis without cirrhosis in relation to bridging necrosis.[healio.com]
    • Applicable To Lupoid hepatitis NEC Approximate Synonyms Autoimmune hepatitis, chronic Chronic active hepatitis Chronic autoimmune hepatitis Lupus hepatitis ICD-10-CM K75.4 is grouped within Diagnostic Related Group(s) (MS-DRG v34.0): 441 Disorders of[icd10data.com]
    • This process is similar to any other chronic active hepatitis.[meddean.luc.edu]
    Hashimoto's Thyroiditis
    • People who already have an autoimmune disease, such as celiac disease, rheumatoid arthritis or hyperthyroidism (Graves’ disease or Hashimoto’s thyroiditis), may be more likely to develop autoimmune hepatitis.[mayoclinic.org]
    Primary Biliary Cirrhosis
    • In 1997 Heathcote coined the phrase “autoimmune cholangitis” to describe AMA negative primary biliary cirrhosis [ 4 ].[hindawi.com]
    • MRI T2: nonspecific, increased periportal oedema 4 MRCP: primary sclerosing cholangitis (PSC) should be excluded Treatment and prognosis Treatment is similar to other autoimmune conditions, and often uses immunomodulating medications. primary biliary[radiopaedia.org]
    • Overlapping presentation with primary biliary cirrhosis and primary sclerosing cholangitis has been observed.[en.wikipedia.org]
    Primary Sclerosing Cholangitis
    • […] cirrhosis (PBC) primary sclerosing cholangitis (PSC) acute hepatitis from other etiologies Wilson disease (mostly paediatric patients)[radiopaedia.org]
    • Diagnosis and management of primary sclerosing cholangitis.[arupconsult.com]
    • Overlapping presentation with primary biliary cirrhosis and primary sclerosing cholangitis has been observed.[en.wikipedia.org]
    • Autoimmune hepatitis and primary sclerosing cholangitis.[journals.lww.com]
    Sjogren's Syndrome
    • The more common form is type I, which most often affects young women and may be found in association with other autoimmune disorders , such as type 1 diabetes , ulcerative colitis, and Sjogren syndrome .[labtestsonline.org]
    • Many people with this disease also have other autoimmune diseases, including type 1 diabetes, thyroiditis (inflammation of the thyroid gland), ulcerative colitis (inflammation of the colon), vitiligo (patchy loss of skin pigmentation), or Sjogren’s syndrome[liverfoundation.org]
    • Some patients have other autoimmune disorders such as thyroiditis, ulcerative colitis, diabetes mellitus, vitiligo (patchy loss of skin pigmentation), or Sjogren’s syndrome (a syndrome that causes dry eyes and dry mouth).[hepatitiscentral.com]
    • For example, patients with other autoimmune diseases — thyroiditis, ulcerative colitis, diabetes mellitus, vitiligo (a patchy loss of pigment in the skin), Sjogren’s syndrome (a condition causing dry eyes and mouth) — are more likely to have autoimmune[gicare.com]
    Ulcerative Colitis
    • Disease Ulcerative colitis Ulcerative colitis is a condition in which the lining of the large intestine (colon) and rectum become inflamed.[scripps.org]
    • These symptoms can include absence of a menstrual period, bloody diarrhea (due to ulcerative colitis ), abdominal pain , arthritis , rashes , anemia , kidney disease , dry eyes , and dry mouth .[webmd.com]
    • ., thyroiditis, diabetes, ulcerative colitis, Coombs-positive haemolytic anaemia, proliferative glomerulonephritis, Sjögren syndrome.[medical-dictionary.thefreedictionary.com]
    • Also, other autoimmune disorders can be associated with type 1 such as thyroiditis, Grave's disease, and ulcerative colitis.[beaumont.edu]
    • Almost half of individuals with type 1 disease also have other autoimmune disorders, including: Type 1 diabetes Graves' disease Sjögren's syndrome Ulcerative colitis Thyroiditis (inflammation of the thyroid gland) Autoimmune hepatitis is a chronic disorder[virginiamason.org]
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  • Etiology

    Autoimmune hepatitis is an inflammation of the liver that occurs when immune cells mistake the liver's normal cells for harmful invaders and attack them [3]. The exact cause of the disease is unknown, but a number of factors have been implicated in its development. It may be initiated or triggered by genetic factors, viral infections (eg acute hepatitis A and B, Epstein-Barr virus infection) [4], etc. Some chemical factors such as interferons, etc may also play a role.

    Genetic factors are proposed to be the main culprit behind this disease. DR3, DR4, B8, B15 and C4A gene deletions and mutations may lead to the production of autoantibodies. To some point, the body will be able to combat these autoantibodies but when an environmental trigger, such as infection by a virus, etc may cause the threshold of tolerance to be breached, then the disease becomes symptomatic.

    Epidemiology

    Incidence

    0.1-1.2 cases per 100,000 people are estimated to suffer from autoimmune hepatitis in the United States. 6% of all liver transplantations conducted in the US are due to this disease.

    Age

    It may occur at any age, ranging from infants to old people. Some studies reveal a bimodal age prevalence, with peak incidence first in the mid-second to early-third decade of life and second peak incidence between the late-fourth to seventh decade of life.

    Sex

    Women are affected more often than men (70% to 80% of patients are women) [2].

    Sex distribution
    Age distribution

    Pathophysiology

    Microscopically, clusters of plasma cells in the interface of portal tracts and hepatic lobules are fairly characteristic for autoimmune hepatitis [5]. The salient features [6] include the absence of serologic markers of viral infection, elevated serum IgG and gamma-globulin levels (1-2-3x normal), and high serum titres of autoantibodies.

    Subtypes

    Type I

    It is characterised by presence of positive ANA and ASMA [7] antibodies. Anti-actin antibodies may also be present. Gamma globulin levels are greatly elevated. This type occurs predominantly in elderly patients. HLA associations include DR3, DR4 and B8.

    Type II

    It is characterised by presence of Anti-LKM (anti-liver kidney microsomal antibody) and P450 IID6 antibodies. It occurs most commonly in young girls , and is very rare in adults. HLA associations include DR3, B14 and C4AQO.

    Type III

    This subtype occurs most commonly in middle-aged adults and is characterised by elevated levels of cytokeratin 8 and 18. Soluble liver-kidney antigens are also present. HLA association is unclear.

    Prevention

    Since the exact etiology is unknown, this disease can not be prevented. However, by taking appropriate treatment of other autoimmune disease such as autoimmune thyroiditis, Grave's disease, proliferative glomerulonephritis, rheumatoid arthritis, etc the autoimmune factors leading to this disease may be controlled.

    Summary

    Autoimmune hepatitis is a chronic and progressive hepatitis of unknown etiology [1]. It is a type of inflammation of the liver which occurs due to production of autoantibodies that target the normal cells of the liver and destroy them, leading to an inflammatory cascade that further damages the liver and symptoms of liver disease appear. These symptoms may vary from those of mild liver disease to those of liver failure in severe cases.

    Patient Information

    Autoimmune hepatitis is a disease resulting in inflammation of the liver due to autoantibodies produced by the body itself. This type of hepatitis is different from viral hepatitis, in terms of mode of transmission, pathophysiology and prognosis. If you are suffering from other autoimmune disease, you may be more at risk for developing this form of hepatitis. It is therefore, recommended to regularly visit your physician for routine tests and work up.

    Self-assessment

    References

    1. Krawitt EL: Autoimmune Hepatiti. N Engl J Med 354:54, 2006
    2. McFarlane IG, Heneghan MA. Autoimmunity and the Female Liver. Hepatol Res. April 2004;28(4):171-176. [Medline]
    3. Czaia AJ. Autoimmune Hepatitis. In: Feldman M, Friedman LS, Brandt LJ, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease. 9th edition. Philadelphia. Pa: Saunders Elsevier;2010: Chap 88
    4. Vento S, Cainelli F. Is there a role for viruses in triggering autoimmune hepatitis? Autoimmune Rev. Jan 2004;3(1):61-9
    5. Czaja AJ:Autoimmune Liver Disease. Curr Opin Gastroenterol 23:255, 2007
    6. Robbins and Cotran, Pathologic Basis of Disease. 8th ed. Pa: Saunders Elsevier. Chap 17. pg 855-56
    7. Bogdanos DP, Invernizzi P, Mackay IR, Vergani D (June 2008). Autoimmune Liver Serology:Current Diagnostic and Clinical challenges. World J Gastroenterol. 14(21):3374-3387 doi 10.3748/wjg.14.3374 PMC 2716592 
    8. Oettinger R, Brunnberg A, Gerner P, Wintermeyer P, Jenke A, Wirthe S. Clinical features and biochemical data of Caucasian children at diagnosis of autoimmune hepatitis. J Autoimmune. Feb 2005;24(1):79-84 
    9. Mann MP, Strassburg, CP (2011). Therapeutic Strategies for Autoimmune Hepatitis. Digestive Strategies. Basel, Switzerland. 29(4):411-5. 
    10. Stephen J McPhee, Maxine A Papadakis. Current Medical Diagnosis and Treatment 2009. Pg 596

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    • A 10 year follow up study of patients transplanted for autoimmune hepatitis: histological recurrence precedes clinical and biochemical recurrence - JC Duclos-Vallee, M Sebagh, K Rifai, C Johanet - Gut, 2003 - gut.bmj.com
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    Media References

    1. Autoimmune hepatitis - cropped - very high mag, CC BY-SA 3.0

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