Autoimmune hepatitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

Autoimmune hepatitis was first to describe under the name of lupoid hepatitis in young females in early 1950. In 1950, Waldenstrom described a form of chronic hepatitis in young women. The term autoimmune hepatitis was first used by the international panel. Gene mutations implicated in the pathogenesis of autoimmune hepatitis is C4 gene.

• Autoimmune hepatitis was the first to describe early in the 1950s, under the name lupoid hepatitis, which mainly affects young women.^[1]
• In 1950, Waldenstrom described a form of chronic hepatitis in young women.^[2]
• In 1950, Kunkel, and in 1956, Bearn, described features of the disease, including hepatosplenomegaly, jaundice, acne, hirsutism, cushingoid facies, pigmented abdominal striae, obesity, arthritis, and amenorrhea.
• In 1992, an international panel described the diagnostic criteria for autoimmune hepatitis.
• The term autoimmune hepatitis was used to replace terms such as autoimmune liver disease and autoimmune chronic active hepatitis by an international panel.
• C4 gene mutations were first implicated in the pathogenesis of autoimmune hepatitis.^[3]

• The IAIHG scoring system, published in 1993 and revised in 1999 to diagnose autoimmune hepatitis.^[4]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

According to European Association for the Study of the Liver, There are three types of autoimmune hepatitis based on the types of antibodies present- AIH type 1, AIH type 2, AIH type 3. Overlap syndrome is a type of syndrome found in a patient who presents with the features of AIH, PBC-AIH or PSC-AIH.

According to European Association for the Study of the Liver, there are three types of autoimmune hepatitis based upon the types of antibodies present:^{[1][2][3][4][5]}

Autoimmune hepatitis Type-1:

• Common type of AIH (accounts almost for 90% of AIH cases) is type one.
• Presents at any age and prevalent worldwide.
• Antibodies like ANA (antinuclear antibodies), SMA (smooth muscle antibodies) or anti-SLA/LP (soluble liver antigen/liver pancreas antibodies) are characteristics.
• Antiactin antibodies are more specific.
• Association with HLA (human leukocyte antigens) DR3, DR4, and DR13 is present.
• Treatment failure is rare but if relapse occurs after withdrawal of treatment and long-term maintenance therapy is given occasionally.

Autoimmune hepatitis Type 2:

• Accounts for 10% of AIH cases.
• Presents usually in childhood and young adulthood and prevalent worldwide but rare in North America.
• Antibodies like anti-LKM1(liver/kidney microsomal antibody type 1), anti-LC1(antibodies against liver cytosol type 1 antigen) and rarely anti-LKM3(liver/kidney microsomal antibody type 3) are characteristics.
• Anti–LKM-1 and anti–LC-1 are more specific.
• Association with HLA DR3 and DR7.
• Treatment failure is common and frequent relapse rates after withdrawal of treatment, and long-term maintenance therapy commonly is given.

Autoimmune hepatitis Type 3:

• AIH type 3 is similar to AIH type 1 but presents more severe.
• SLA/LP (soluble liver antigen/liver pancreas antibodies) is characteristics.
• Ro52-antibody positive

Overlap syndrome:

Patients who present with the features of primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) along with the features of AIH, PBC-AIH or PSC-AIH.^[6][7]

Classification of overlap syndrome
Name of syndrome	Dominant disease	Recessive disease
PBC-AIH overlap	PBC	AIH
PSC-AIH overlap	PSC	AIH
AIH-PBC overlap	AIH	PBC
AIH-PSC overlap	AIH	PSC
AIH, autoimmune hepatitis; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

Autoimmune hepatitis is a chronic disease characterized by inflammation of the liver which results from the combination of genetic predisposition and environmental triggers. The genetic predisposition is related to the defect in HLA haplotypes B8, B14, DR3, DR4, and Dw3, complement system, and T-cell level. The environmental factors involved are viruses like Rubella, Epstein-Barr, Hepatitis A, B, and C have molecular mimicry of viral sequences to host proteins and drugs like oxyphenisatin, methyldopa, nitrofurantoin, diclofenac, interferon, minocycline, and atorvastatin causes autoimmune hepatitis.

Autoimmune hepatitis is a chronic disease characterized by inflammation of the liver which results from the combination of genetic predisposition and environmental triggers

Normal physiology of liver:^{[1][2][3][4][5]}

• Liver is known to be an organ with special innate immune features.
• Liver has distinct cellular composition with predominance of Kupffer cells (KCs), natural killer (NK) cells and natural killer T (NKT).
• Liver is constantly exposed to microbial products,(toxic) environmental substances and food antigens from the portal stream draining the intestine, the liver plays an important role in the induction and maintenance of immune tolerance.
• Liver is a target of adverse immune reactions in chronic inflammatory liver diseases like autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC).

Autoimmune hepatitis is a chronic idiopathic disease that occurs as a result of an environmental factor that triggers a series of T-cell–mediated events directed at liver antigens in a genetically predisposed host.

• The genetic predisposition is related to the defect in HLA haplotypes B8, B14, DR3, DR4, and Dw3, complement system, and T-cell level.
  • HLA-DR3 positive patients are usually younger and less responsive to medical therapy.
  • HLA-DR4 patients usually develop extrahepatic manifestations of their disease.
  • There is a partial deficiency of complement component C4 which results in failure to remove viruses.
  • There are low levels of T lymphocytes that express the CD8 marker and a specific defect in a subpopulation of T cells that controls the immune response to specific liver cell membrane antigens.^[6]

Various environmental factors involved are:

• Viruses like rubella, Epstein-Barr, hepatitis A, B, and C have molecular mimicry of viral sequences to host proteins.
• Drugs like oxyphenisatin, methyldopa, nitrofurantoin, diclofenac, interferon, minocycline, and atorvastatin causes autoimmune hepatitis.
• An environmental agents triggered the autoimmune response against liver antigens leads to necroinflammatory liver damage, fibrosis, and cirrhosis.

Mechanism of Autoreactivity:^{[7][8][9][10]}

• Autoimmune hepatitis is caused by a cell-mediated immunologic attack.
• There is abnormal position of human leukocyte antigen (HLA) class II on the surface of liver cells which is caused by genetic and environmental triggers.
• This further leads to the exposure of normal liver cell membrane constituents to antigen-presenting cells(APC).
• APC further interacts with helper T-cell at the ligand-ligand levels leads to activation helper T-cells.
• Helper T-cells activation is followed by differentiation of helper T-cells into helper T cell 1 (TH 1) or helper T cell 2 (TH 2).
  • TH 1 secretes interleukin 2 (IL-2) and interferon gamma, which activate macrophages.
  • TH 2 cells produce interleukins 4, 5, and 10, which activate autoantibody production by B cells.
  • Normally TH 1 and TH 2 cells antagonize each other.
  • Failure of autoantigen recognition leads to autoimmune attack.
• The action of cytotoxic lymphocytes that are stimulated by IL-2, complement activation, natural killer lymphocytes, or reaction of autoantibodies with liver-specific antigens causes injury to liver.

• Genes deletion involved in the pathogenesis of autoimmune hepatitis include C4A gene.
• Autoimmune hepatitis have an abnormality in the MHC locus on chromosome 6.

Associated conditions due to the AH:

• Chronic autoimmune thyroiditis
• Hyperthyroidism (Graves’ disease)
• Ulcerative colitis
• Hemolytic anemia
• Idiopathic thrombocytopenia
• Diabetes mellitus
• Diabetes insipidus
• Celiac disease
• Polymyositis
• Myasthenia gravis
• Pulmonary fibrosis
• Pericarditis
• Glomerulonephritis
• Acute lichenoid pityriasis
• Febrile panniculitis
• Hypereosinophilic syndrome
• Sjogren’s syndrome
• Mixed connective tissue disease

• On gross pathology, diffuse whitish-gray plaque without nodularity are demonstrated in autoimmune hepatitis.

Microscopic histopathologic features are:^[11][12]

• A portal and periportal infiltrate of mononuclear cells.
• The infiltrate crosses the limiting plate that forms the portal triad and invades the surrounding lobule.
• The periportal infiltrate is occasionally referred to as piecemeal necrosis and generally spares the biliary tree.
• Emperipolesis: apparent engulfment of lymphocytes by hepatocytes.
• Hepatocyte rosette formation.
• Variable fibrosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2], Aditya Govindavarjhulla, M.B.B.S. [3]

Autoimmune hepatitis may be caused by the Drugs like minocycline, nitrofurantoin, hydralazine, methyldopa, statins, fenofibrate, interferon, infliximab, etanercept, viral infections e.g measles virus, EB virus, CMV and hepatitis A, B, C, D, E and if there is the history of other autoimmune diseases e.g graves disease, inflammatory bowel disease, rheumatoid arthritis, scleroderma, Sjogren syndrome, systemic lupus erythematosus, thyroiditis, type 1 diabetes, ulcerative colitis.

• Drugs ^[1]
  • Minocycline
  • Nitrofurantoin
  • Hydralazine
  • Methyldopa
  • Statins
  • Fenofibrate
  • Interferon
  • Infliximab
  • Etanercept
• History of viral infections:
  • Measles viruse
  • Cytomegalovirus
  • Epstein–Barr virus
  • Hepatitis A, B, C, D, E.
• History of autoimmune disease:^[2]
  • Graves disease
  • Inflammatory bowel disease
  • Rheumatoid arthritis
  • Scleroderma
  • Sjogren syndrome
  • Systemic lupus erythematosus
  • Thyroiditis
  • Type 1 diabetes
  • Ulcerative colitis

Cardiovascular	No underlying causes
Chemical / poisoning	Morinda citrifolia (Noni juice), Dai-saiko-to [3], Germander, Herbal compounds, Toxic mushrooms (cyclopeptides)
Dermatologic	Scleroderma, Systemic lupus erythematosus
Drug Side Effect	3,4-methylenedioxymetamphetamine, Alpha interferon, Beta interferon, Methyldopa, Minocycline , Ecstasy, Artorvastatin, Atomexitine , Carboxymethyl cellulose , Clometacine [4], Diclofenac , Dioctyl sodium sulfosuccinate, Doxycycline, Etanercept, Fenofibrate, Hydralazine, Infliximab, Interferon , Nitrofurantoin, Oxyphenisatin, Papaverine,Peginterferon Beta-1a,Pemoline,Phenprocoumon, Pyrazinamide, Rifampin, Rosuvastatin, Simvastatin , Twinrix
Ear Nose Throat	No underlying causes
Endocrine	Graves disease, Polyendocrine deficiency syndrome type 1, Thyroiditis, Type 1 diabetes
Environmental	No underlying causes
Gastroenterologic	Inflammatory bowel disease, Ulcerative colitis
Genetic	No underlying causes
Hematologic	No underlying causes
Iatrogenic	No underlying causes
Infectious Disease	Measles viruse, Cytomegalovirus, and Epstein–Barr virus
Musculoskeletal / Ortho	Rheumatoid arthritis,
Neurologic	No underlying causes
Nutritional / Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	No underlying causes
Opthalmologic	Grave’s disease, Sjogren syndrome
Overdose / Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal / Electrolyte	No underlying causes
Rheum / Immune / Allergy	Rheumatoid arthritis, Graves disease, Inflammatory bowel disease, Polyendocrine deficiency syndrome type 1, Scleroderma, Sjogren syndrome, Systemic lupus erythematosus, Thyroiditis, Type 1 diabetes, Ulcerative colitis
Sexual	No underlying causes
Trauma	No underlying causes
Urologic	No underlying causes
Miscellaneous	No underlying causes

• 3,4-methylenedioxymetamphetamine^[5]

• Alpha interferon ^[6]

• Atorvastatin

• Atomexitine

• Beta interferon ^[7]

• Carboxymethyl cellulose

• Clometacine

• Dai-saiko-to

• Diclofenac

• Dioctyl sodium sulfosuccinate

• Doxycycline

• Ecstasy^[5]

• Etanercept

• Fenofibrate

• Germander ^[8]

• Graves disease

• Herbal compounds

• Hydralazine

• Inflammatory bowel disease

• Infliximab

• Interferon

• Methyldopa

• Minocycline

• Minocycline

• Morinda citrifolia (Noni juice)

• Nitrofurantoin

• Oxyphenisatin ^[9]

• Peginterferon Beta-1a

• Papaverine

• Pemoline

• Phenprocoumon ^[10]

• Polyendocrine deficiency syndrome type 1

• Pyrazinamide

• Rheumatoid arthritis

• Rifampin

• Rosuvastatin

• Scleroderma

• Simvastatin

• Sjogren syndrome

• Systemic lupus erythematosus

• Thyroiditis

• Toxic mushrooms (cyclopeptides)

• Twinrix ^[11]

• Type 1 diabetes

• Ulcerative colitis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ;Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

Autoimmune hepatitis must be differentiated from other diseases that cause jaundice, nausea and vomiting, abdominal pain, arthragia, and hepatomegaly such as hepatitis A, B, C, E, drug-induced hepatitis, CMV hepatitis, EBV hepatitis, alcoholic hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis.

Autoimmune hepatitis must be differentiated from other diseases that cause jaundice, nausea and vomiting, abdominal pain, arthragia, and hepatomegaly such as Hepatitis A,B,C, E, drug induced hepatitis, CMV hepatitis, EBV hepatitis, alcoholic hepatitis, Primary biliary cirrhosis and Primary sclerosing cholangitis.^{[1][2][3][4][5][6][7][8][9]}

Classification of jaundice based on etiology Disease History and clinical manifestations Diagnosis Lab Findings Other blood tests Other diagnostic Family history Fever RUQ Pain Pruritis AST ALT ALP BLR Indirect BLR Direct Viral serology Jaundice Hepatocellular Jaundice Infiltrative liver disorders: Hemochromatosis, amyloidosis + – -/+ – ↑ ↑ ↑/N ↑/N N – Ferritin ↑ (hemochromatosis) Liver biopsy Wilson’s disease + – -/+ – ↑ ↑ N ↑/N N – ↑ Serum ceruloplasmin Liver biopsy Viral hepatitis – -/+ – – ↑ ↑ N ↑/N N + Specific viral antibody for each type – Alcoholic hepatitis – -/+ -/+ – ↑↑ ↑ N ↑/N N – – – Drug induced hepatitis – -/+ – – ↑ ↑ N ↑/N N – – – Autoimmune hepatitis -/+ – – -/+ ↑ ↑ N ↑/N N – Anti-LKM antibody Liver biopsy Cirrhosis -/+ -/+ -/+ – ↑ ↑ ↑/N ↑/N ↑/N -/+ Low platate Small liver on ultrasond Nonalcoholic steatohepatitis -/+ – – – ↑ ↑ N ↑/N N – Dyslipidemia liver biopsy Ischemic hepatopathy -/+ – -/+ – ↑ ↑ N ↑/N N – Cardiovascular risk factors – Cholestatic Jaundice Common bile duct stone -/+ – + + N N ↑ N ↑ – Dilated ducts on ultrasound CT/ERCP Hepatitis A (cholestatic type) – -/+ + + N/↑ N/↑ ↑ N ↑ + HAV- Ab Abdominal ultrasound EBV / CMV hepatitis – -/+ + + N N ↑ N ↑ + Positive serology – Primary biliary cirrhosis -/+ – -/+ + N/↑ N/↑ ↑ N ↑ – AMA positive Liver biopsy Primary sclerosing cholangitis -/+ – -/+ + N/↑ N/↑ ↑ N ↑ – ↑Autoantibodies (P-ANCA), hypergammaglobulinemia MRCP, Liver biopsy Sickle cell disease + – – +/- N/↑ N/↑ ↑ N ↑ – Genetic testing Pancreatic carcinoma + – -/+ -/+ N/↑ N/↑ ↑ N ↑ – – CT scan for diagnosis AIDS cholangiopathy – – -/+ -/+ N/↑ N/↑ ↑ N ↑ – HIV Ab Ultrasound or ERCP Parasites induces cholestasis – – -/+ -/+ N/↑ N/↑ ↑ N ↑ – Serology Ultrasound or ERCP Intrahepatic cholestasis of pregnancy -/+ – -/+ + ↑ ↑ ↑ N ↑ – Thrombocytopenia Diagnosed clinically Isolated Jaundice Crigler-Najjar type 2 + – – – N N N ↑ ↑ – Genetic testing Gilbert + – – – N N N ↑ ↑ – Genetic testing Rotor syndrome + – – – N N N N ↑ – Genetic testing Liver biopsy Dubin-Johnson syndrome + – – – N N N N ↑ – Genetic testing Liver biopsy Hereditary spherocytosis + – -/+ – N N N ↑ N – Genetic testing Osmotic fragility G6PD deficiency + – – – N N N ↑ N – Genetic testing Thalassemia + – – – N N N ↑ N – Genetic testing Paroxysmal nocturnal hemoglobinuria – – – – N N N ↑ N – Flocytometery Immune hemolysis – -/+ – – N N N ↑ N – Autoantibodies Hematoma – -/+ – – N N N ↑ N – Anemia Truma or surgery in history

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

The incidence and prevalence of autoimmune hepatitis are generally higher among individuals of the whites of northern European ancestry with a high frequency of HLA-DR3 and HLA-DR4 markers.The incidence of autoimmune hepatitis approximately 1 to 2 per 100,000 individuals worldwide. Autoimmune hepatitis has bimodal distribution usually presents around puberty and between 4th and 6th decade, although a significant proportion presents in older people usually above 65 years of age. Young women are more commonly affected by autoimmune hepatitis than men.

• The incidence of autoimmune hepatitis is approximately 1 to 2 per 100,000 individuals worldwide.
• The incidence of autoimmune hepatitis is estimated to be 0.9 to 2 cases per 100,000 population annually in Europe.^{[1][2][3][4][5]}

• The prevalence of autoimmune hepatitis is approximately 11 to 25 per 100,000 individuals worldwide.
• In Europe, the prevalence of autoimmune hepatitis ranges from 10 to 17 per 100 000.^[6][7]
• In Japan, the prevalence of autoimmune hepatitis ranges from 0.08-0.015 cases per 100,000 persons.

• Patients of all age groups may develop autoimmune hepatitis.
• Autoimmune hepatitis has bimodal distribution usually presents around puberty and between 4th and 6th decade, although a significant proportion older people is usually above 65 years of age.

• Autoimmune hepatitis usually affects individuals of the whites of northern European ancestry with a high frequency of HLA-DR3 and HLA-DR4 markers.

• Young women are more commonly affected by autoimmune hepatitis than men.
• The women to men ratio is approximately 3:1.^[8][9]

• Autoimmune hepatitis is more common in North American First Nations populations compared with predominantly Caucasian, Non-first Nations populations.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

Common risk factors in the development of autoimmune hepatitis include female gender, Genetic predisposition associated with HLA-DR3 and HLA-DR4, and history of other autoimmune hepatitis eg thyroiditis, type 1 diabetes, ulcerative colitis, celiac disease, and rheumatoid arthritis.

Common risk factors in the development of autoimmune hepatitis include:

• Females:
  • Autoimmune hepatitis is more common in young females.
• Genetic predisposition:^[1]
  • Autoimmune hepatitis type 1 has the association with HLA-DR3 and HLA-DR4.
  • Type 2 AIH has an association with the HLA-DQB1 and HLA-DRB1 alleles.
• History of another autoimmune disease:^[2]
  • Autoimmune diseases, including thyroiditis, type 1 diabetes, ulcerative colitis, celiac disease, and rheumatoid arthritis.

Less common risk factors in the development of Autoimmune hepatitis include:

• A history of viral infections:^[3][4]
  • Autoimmune hepatitis is common who are infected with the measles, herpes simplex or epstein-Barr virus and hepatitis A, B or C infection in the past.
• History of drug intake:^[5]
  • minocycline, nitrofurantoin, hydralazine, methyldopa statins, fenofibrate, interferon, infliximab, etanercept increases the risk of autoimmune hepatitis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Manpreet Kaur, MD [2]

According to the American Association for the Study of Liver Diseases, screening for autoimmune hepatitis is not recommended.

According to the American Association for the Study of Liver Diseases, screening for autoimmune hepatitis is not recommended.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: :Manpreet Kaur, MD [2]

Autoimmune hepatitis has a bimodal age distribution, with the first peak of incidence at age 10-20 years and a second at age 45-70 years. Patients presents initially with no symptom but can progress to acute liver failure If not treated, patients can develop complications like cirrhosis, portal hypertension, esophageal varices, metabolic bone disease, hyperlipidaemia, hypovitaminosis, cholestasis. Prognosis is generally excellent, and the 10-year survival rate of patients with autoimmune hepatitis treated with immunosuppressive therapy is approximately 80%. The presence of young age at presentation, AIH-2, coagulopathy, severe histologic activity is associated with a poor prognosis among patients with autoimmune hepatitis.

• The symptoms of autoimmune hepatitis usually has a bimodal age distribution, with a first peak of incidence at age 10-20 years and a second at age 45-70 years of life, and starts with asymptomatic progresses to acute liver failure.^[1]
• If left untreated, patients with autoimmune hepatitis may progress to develop cirrhosis, and portal hypertension.

Common complications of Autoimmune hepatitis include:^[2][3]

• Cirrhosis and complications of cirrhosis:
  • Ascites
  • Coagulopathy
  • Liver failure
  • Hepatocellular carcinoma
  • Hepatic encephalopathy
• Portal hypertension
• Esophageal varices
• Metabolic bone disease
• Hyperlipidaemia
• Hypovitaminosis
• Cholestasis

• Prognosis is generally excellent, and the 10-year survival rate of patients with autoimmune hepatitis treated with immunosuppressive therapy is approximately 80%.^[4][5]
• Prognosis is poor without treatment, 50% of patients with severe autoimmune hepatitis will die in a 5 years.
• The presence of young age at presentation, AIH-2, coagulopathy, severe histologic activity is associated with a poor prognosis among patients with autoimmune hepatitis.

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