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==Microscopic Pathology==
==Microscopic Pathology==
*On microscopic histopathological analysis:
On microscopic histopathological analysis:
*A portal and periportal infiltrate of mononuclear cells  
*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 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.
*The periportal infiltrate is occasionally referred to as piecemeal necrosis, and generally spares the biliary tree.
:* All cases, except the mildest, have some degree of ‘bridging fibrosis’ that connects the portal and central areas.
 
::* Primary biliary cirrhosis (PBC) and Primary sclerosing cholangitis (PSC) tend to have either a paucity of, inflammation of, or damage to the bile ducts (or all three features).
::* .
::* Cholangiography is often required to differentiate PSC from AH.
:* The ‘overlap syndrome’ has the histologic features of AH in conjunction with the serologic features of PBC (anti-mitochondrial antibodies).
:* The ‘overlap syndrome’ has the histologic features of AH in conjunction with the serologic features of PBC (anti-mitochondrial antibodies).
:* Most patients with  
:* Most patients with  

Revision as of 19:33, 26 December 2017


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

Overview

Pathophysiology

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

Genetic factors involved in autoimmune hepatitis are:

  • 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

Environmental factors:

  • An environmental agent triggered the autoimmune response against liver antigens leads to necroinflammatory liver damage, fibrosis, and cirrhosis

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, pemoline, minocycline, and atorvastatin causes autoimmune hepatitis

Pathogenesis

Mechanism of Autoreactivity:[6][7][8]

  • 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 by the autoantibody bound to the hepatocyte surface, or reaction of autoantibodies with liver-specific antigens expressed on hepatocyte surfaces causes injury to liver

Genetics

  • 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

Associated conditions due to the AH:

Gross Pathology

  • On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].

Microscopic Pathology

On microscopic histopathological analysis:

  • 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.
  • .
  • The ‘overlap syndrome’ has the histologic features of AH in conjunction with the serologic features of PBC (anti-mitochondrial antibodies).
  • Most patients with
  • Additionally, there is evidence that loci that encode complement products, immunoglobulins, and T-cell receptors play a role in the genetic predisposition to AH.
  • As far as the environmental stimulus goes, postulated associations include the measles virus, hepatitis viruses as well as Epstein-Barr virus (EBV).
  • Unfortunately, the relevant antigens and the mechanisms underlying the chronicity of inflammation remain undefined.
  • The circulating antinuclear, anti-smooth muscle and anti-actin antibodies are not organ-specific, do not appear to have a role in the direct pathogenesis, and are thought to be just markers of disease.
  • Recent attention has, however, focused on the asialoglycoprotein receptor (a liver-specific membrane protein that may be the target for cellular toxicity).
  • Defects in suppressor T-cell function are also thought to play a role in the pathogenesis of AH, resulting in the unmodulated production of IgG antibodies against normal hepatocyte membranes

References

  1. ↑ Seki S, Habu Y, Kawamura T, Takeda K, Dobashi H, Ohkawa T, Hiraide H (2000). "The liver as a crucial organ in the first line of host defense: the roles of Kupffer cells, natural killer (NK) cells and NK1.1 Ag+ T cells in T helper 1 immune responses". Immunol. Rev. 174: 35–46. PMID 10807505.
  2. ↑ Selmi C, Mackay IR, Gershwin ME (2007). "The immunological milieu of the liver". Semin. Liver Dis. 27 (2): 129–39. doi:10.1055/s-2007-979466. PMID 17520513.
  3. ↑ Gao B, Jeong WI, Tian Z (2008). "Liver: An organ with predominant innate immunity". Hepatology. 47 (2): 729–36. doi:10.1002/hep.22034. PMID 18167066.
  4. ↑ Feld JJ, Heathcote EJ (2003). "Epidemiology of autoimmune liver disease". J. Gastroenterol. Hepatol. 18 (10): 1118–28. PMID 12974897.
  5. ↑ Corless JK, Middleton HM (1983). "Normal liver function. A basis for understanding hepatic disease". Arch. Intern. Med. 143 (12): 2291–4. PMID 6360063.
  6. ↑ Liberal R, Longhi MS, Mieli-Vergani G, Vergani D (2011). "Pathogenesis of autoimmune hepatitis". Best Pract Res Clin Gastroenterol. 25 (6): 653–64. doi:10.1016/j.bpg.2011.09.009. PMID 22117632.
  7. ↑ McFarlane IG (1999). "Pathogenesis of autoimmune hepatitis". Biomed. Pharmacother. 53 (5–6): 255–63. doi:10.1016/S0753-3322(99)80096-1. PMID 10424247.
  8. ↑ Obermayer-Straub P, Strassburg CP, Manns MP (2000). "Autoimmune hepatitis". J. Hepatol. 32 (1 Suppl): 181–97. PMID 10728804.

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