Autoimmune Hepatitis

Epidemiology and Etiology

Epidemiology

• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 0.9 to 2.0 per 100,000/year in Europe (no data available for the United States)
• More prevalent in females than males (4:1)
• Bimodal distribution Bimodal distribution Measures of Central Tendency and Dispersion: 1 peak at 10–20 years of age and another at 45–70 years

Etiology

Associated with other autoimmune conditions (e.g., Hashimoto’s thyroiditis Thyroiditis Thyroiditis is a catchall term used to describe a variety of conditions that have inflammation of the thyroid gland in common. It includes pathologies that cause an acute illness with severe thyroid pain (e.g., subacute thyroiditis and infectious thyroiditis) as well as conditions in which there is no clinically evident inflammation and the manifestations primarily reflect thyroid dysfunction or a goiter (e.g., painless thyroiditis and fibrous Riedel’s thyroiditis). Thyroiditis, Graves’ disease, diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis, celiac disease Celiac disease Celiac disease (also known as celiac sprue or gluten enteropathy) is an autoimmune reaction to gliadin, which is a component of gluten. Celiac disease is closely associated with HLA-DQ2 and HLA-DQ8. The immune response is localized to the proximal small intestine and causes the characteristic histologic findings of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. Celiac Disease, Sjogren’s syndrome)

Clinical Presentation

• Heterogeneous presentation that ranges from asymptomatic to acute liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy failure and/or cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
• Early signs:
  • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, general malaise Malaise Tick-borne Encephalitis Virus, and lethargy Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia
  • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics
  • Abdominal pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
  • Hepatomegaly 
  • Weight loss Weight loss Decrease in existing body weight. Bariatric Surgery
  • Itching
  • Transient erythematous rash Rash Rocky Mountain Spotted Fever
• Signs of acute liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy failure: 
  • Jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice
  • Right upper quadrant Right upper quadrant Anterior Abdominal Wall: Anatomy (RUQ) pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
  • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Decreased platelet count

Diagnosis and Management

Diagnosis

Autoimmune hepatitis (AIH) is a differential diagnosis for any patient presenting with at least one of the following:

• Abnormal liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy biochemical tests
• Acute hepatitis
• Cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis
• Acute liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy failure

Autoimmune hepatitis is a diagnosis of exclusion, so the first step is to rule out viral infection, drugs, metabolic, or genetic causes.

• Elevated transaminases (mild to > 1,000 U/L)
• Hypergammaglobulinemia ( IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis is elevated): AIH is classified into type 1 Type 1 Spinal Muscular Atrophy and type 2 Type 2 Spinal Muscular Atrophy based on the autoantibodies Autoantibodies Antibodies that react with self-antigens (autoantigens) of the organism that produced them. Blotting Techniques present:
  • Type 1 Type 1 Spinal Muscular Atrophy AIH:
    • More common
    • Typically seen in adults
    • Characterized by positive anti-smooth muscle antibody (ASMA) and antinuclear antibody (ANA) elevation
    • Anti–soluble liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination/liver-pancreas (SLA/LP) and atypical peripheral anti-neutrophil cytoplasmic antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions ( p-ANCA p-ANCA Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis) also seen.
    • In about 12%, antimitochondrial antibody ( AMA AMA Primary Biliary Cholangitis) is positive (seen more in primary biliary cholangitis Primary Biliary Cholangitis Primary biliary cholangitis (PBC) is a chronic disease resulting in autoimmune destruction of the intrahepatic bile ducts. The typical presentation is that of a middle-aged woman with pruritus, fatigue, and right upper quadrant abdominal pain. Elevated liver enzymes and antimitochondrial antibodies (AMAs) establish the diagnosis. Primary Biliary Cholangitis).
  • Type 2 Type 2 Spinal Muscular Atrophy AIH:
    • Seen in children
    • May be more severe than type 1 Type 1 Spinal Muscular Atrophy
    • Anti-liver kidney microsome 1 (LKM1) elevation
    • Anti-liver cytosol Cytosol A cell’s cytoskeleton is a network of intracellular protein fibers that provides structural support, anchors organelles, and aids intra- and extracellular movement. The Cell: Cytosol and Cytoskeleton antibody-1 (ALC-1) elevation
  • Some individuals with AIH do not have circulating autoantibodies Autoantibodies Antibodies that react with self-antigens (autoantigens) of the organism that produced them. Blotting Techniques (autoantibody negative AIH).
• Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma is the gold standard for diagnosis. Showing:
  • Inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and necrosis Necrosis The death of cells in an organ or tissue due to disease, injury or failure of the blood supply. Ischemic Cell Damage in the periportal (zone 1) and interface areas (interface hepatitis)
  • Mostly lymphoplasmacytic infiltration in the portal tracts
  • Emperipolesis ( lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes: Histology and plasma cells Plasma cells Specialized forms of antibody-producing B-lymphocytes. They synthesize and secrete immunoglobulin. They are found only in lymphoid organs and at sites of immune responses and normally do not circulate in the blood or lymph. Humoral Adaptive Immunity penetrating hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy)
  • Hepatic rosette formation ( hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy arranged in a circular form around a dilated canaliculus)
  • Varying degrees of fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans

Management

• 40% mortality Mortality All deaths reported in a given population. Measures of Health Status in 6 months without treatment
• Management primarily consists of immunosuppressive drugs Immunosuppressive drugs Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-cells or by inhibiting the activation of helper cells. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of interleukins and other cytokines are emerging. Organ Transplantation:
  • Corticosteroids Corticosteroids Chorioretinitis: to achieve remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches (80% response rate) 
  • Steroid-sparing agent: Azathioprine Azathioprine An immunosuppressive agent used in combination with cyclophosphamide and hydroxychloroquine in the treatment of rheumatoid arthritis. According to the fourth annual report on carcinogens, this substance has been listed as a known carcinogen. Immunosuppressants is used as maintenance therapy as most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship relapse Relapse Relapsing Fever when corticosteroids Corticosteroids Chorioretinitis are withdrawn.
  • Remission Remission A spontaneous diminution or abatement of a disease over time, without formal treatment. Cluster Headaches with optimal treatment is achieved in up to 80% of cases after 18 to 24 months of therapy.
  • Liver transplantation Liver transplantation The transference of a part of or an entire liver from one human or animal to another. Hepatocellular Carcinoma (HCC) and Liver Metastases is indicated in cases of decompensated liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis, acute liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy failure, and hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases.
  • Follow-ups are recommended since these patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship have an increased risk of developing hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases ( HCC HCC Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases).

Differential Diagnosis

The following conditions are differential diagnoses of autoimmune hepatitis:

• Primary biliary cholangitis Primary Biliary Cholangitis Primary biliary cholangitis (PBC) is a chronic disease resulting in autoimmune destruction of the intrahepatic bile ducts. The typical presentation is that of a middle-aged woman with pruritus, fatigue, and right upper quadrant abdominal pain. Elevated liver enzymes and antimitochondrial antibodies (AMAs) establish the diagnosis. Primary Biliary Cholangitis ( PBC PBC Primary biliary cholangitis (PBC) is a chronic disease resulting in autoimmune destruction of the intrahepatic bile ducts. The typical presentation is that of a middle-aged woman with pruritus, fatigue, and right upper quadrant abdominal pain. Elevated liver enzymes and antimitochondrial antibodies (AMAs) establish the diagnosis. Primary Biliary Cholangitis): also presents with fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, hepatomegaly, and biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma results similar to AIH. The characteristic presence of anti-mitochondrial antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions ( AMA AMA Primary Biliary Cholangitis) helps differentiate PBC PBC Primary biliary cholangitis (PBC) is a chronic disease resulting in autoimmune destruction of the intrahepatic bile ducts. The typical presentation is that of a middle-aged woman with pruritus, fatigue, and right upper quadrant abdominal pain. Elevated liver enzymes and antimitochondrial antibodies (AMAs) establish the diagnosis. Primary Biliary Cholangitis from autoimmune hepatitis for which anti-smooth muscle antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions (ASMA) are characteristic.
• Primary sclerosing cholangitis Primary Sclerosing Cholangitis Primary sclerosing cholangitis (PSC) is an inflammatory disease that causes fibrosis and strictures of the bile ducts. The exact etiology is unknown, but there is a strong association with IBD. Patients typically present with an insidious onset of fatigue, pruritus, and jaundice, which can progress to cirrhosis and complications related to biliary obstruction. Primary Sclerosing Cholangitis ( PSC PSC Primary sclerosing cholangitis (PSC) is an inflammatory disease that causes fibrosis and strictures of the bile ducts. The exact etiology is unknown, but there is a strong association with IBD. Patients typically present with an insidious onset of fatigue, pruritus, and jaundice, which can progress to cirrhosis and complications related to biliary obstruction. Primary Sclerosing Cholangitis): also presents with fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, hepatomegaly. One of the best ways to differentiate PSC PSC Primary sclerosing cholangitis (PSC) is an inflammatory disease that causes fibrosis and strictures of the bile ducts. The exact etiology is unknown, but there is a strong association with IBD. Patients typically present with an insidious onset of fatigue, pruritus, and jaundice, which can progress to cirrhosis and complications related to biliary obstruction. Primary Sclerosing Cholangitis from AIH is via imaging modalities such as MRCP MRCP Non-invasive diagnostic technique for visualizing the pancreatic ducts and bile ducts without the use of injected contrast media or x-ray. Mri scans provide excellent sensitivity for duct dilatation, biliary stricture, and intraductal abnormalities. Primary Sclerosing Cholangitis ( magnetic resonance cholangiopancreatography Magnetic resonance cholangiopancreatography Non-invasive diagnostic technique for visualizing the pancreatic ducts and bile ducts without the use of injected contrast media or x-ray. Mri scans provide excellent sensitivity for duct dilatation, biliary stricture, and intraductal abnormalities. Primary Sclerosing Cholangitis), which shows characteristic multifocal Multifocal Retinoblastoma structuring and dilation of intrahepatic and/or extrahepatic bile ducts Extrahepatic bile ducts Passages external to the liver for the conveyance of bile. These include the common bile duct and the common hepatic duct. Gallbladder and Biliary Tract: Anatomy and seals the diagnosis of PSC PSC Primary sclerosing cholangitis (PSC) is an inflammatory disease that causes fibrosis and strictures of the bile ducts. The exact etiology is unknown, but there is a strong association with IBD. Patients typically present with an insidious onset of fatigue, pruritus, and jaundice, which can progress to cirrhosis and complications related to biliary obstruction. Primary Sclerosing Cholangitis.
• Viral hepatitis: The most commonly used method is the antibody/ antigen Antigen Substances that are recognized by the immune system and induce an immune reaction. Vaccination detection in the serum. However, some patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with AIH may test false-positive for hepatitis C Hepatitis C Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C virus can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C Virus antibody; this can be confirmed by obtaining a hepatitis C virus Hepatitis C Virus Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). Hepatitis C virus is an RNA virus and a member of the genus Hepacivirus and the family Flaviviridae. The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C Virus RNA RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. RNA Types and Structure level in these patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship. 
• Other causes of hepatitis (drug-induced, non-alcoholic steatohepatitis Steatohepatitis Drug-induced Liver Injury): also present with fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, hepatomegaly, and RUQ tenderness. These causes must be ruled out using history and laboratory evaluation. The presence of ASMA is a strong indicator Indicator Methods for assessing flow through a system by injection of a known quantity of an indicator, such as a dye, radionuclide, or chilled liquid, into the system and monitoring its concentration over time at a specific point in the system. Body Fluid Compartments of AIH as the cause.