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Autoimmune Markers for Liver Diseases

                            

       Autoimmune markers are autoantibodies associated with diseases and are therefore used for the diagnosis of the diseases. Four major categories of autoantibody are routinely used for the diagnosis of liver diseases. They are anti-nuclear antibodies, anti-smooth muscle antibodies, anti-mitochondrial antibodies, and anti-liver-kidney microsomal-1 antibodies.

Anti-nuclear Antibodies: Anti-nuclear antibodies (ANA) are serologic hallmarks for systemic or organ-specific autoimmune disease. ANA are the most common circulating autoantibodies in autoimmune hepatitis. They are seen in type 1 autoimmune hepatitis and rarely in type 2 autoimmune hepatitis. While ANA are commonly present in patients with autoimmune hepatitis, they are not specific for autoimmune hepatitis and can be detected in other autoimmune disorders such as systemic lupus erythematosus. They are less specific than anti-smooth muscle antibodies or antimitochondrial antibodies. In addition, absence of circulating ANA does not entirely exclude autoimmune hepatitis.  Occasionally an elevated serum globulin level is the only biomarker detectable in a small number of patients with autoimmune hepatitis, so-called autoantibody negative autoimmune hepatitis. Titers considered positive are dependent in part upon the methodology used and the age of the patient. In most laboratories, a titer of 1:180 or greater is considered positive in adults.  However, the titer does not correlate with disease course, activity, progression, prognosis or recurrence after liver transplantation.

Anti-smooth muscle antibodies: Anti-smooth muscle antibodies (anti-SMA) are directed against cytoskeletal proteins such as actin and troponin. They are the second major class of autoantibodies for the diagnosis of autoimmune hepatitis. Although less prevalent than ANA, anti-SMAs frequently occur in high titers along with ANA. Anti-SMA are more specific than ANA for the diagnosis of autoimmune hepatitis, particularly when present in titers of 1:180 or more, but they can also be detected in infectious diseases and advanced liver diseases of other etiologies. In pediatric patients, anti-SMA may be the only biomarker of typ-1 autoimmune hepatitis. In children, titers of 1:20 or greater are considered positive. Approximately 80% pediatric patients with type 1 autoimmune hepatitis was fund to have Anti-SMAs titers ranging from 1:10 to 1:2560.

Antimitochondrial Antibodies: Antimitochondrial antibodies (AMA) bind to protein antigens that are contained in multienzyme complexes within the inner lining of the mitochondria.  They are considered a serological hallmark of primary biliary cirrhosis (PBC), detectable in approximately 95% of patients with PBC. In PBC, AMA preferentially reacts with the E2 component of one of the multienzymes that is called the pyruvate dehydrogenase complex (PDC). Accordingly, the antigen is designated as PDC-E2, also referred to as M2. Antimitochondrial antibodies bind to PDC-E2 within the epithelial cells of the biliary tree in the liver of patients with PBC.  Therefore, they are considered specific and sensitive serologic markers for primary biliary cirrhosis, although they can occur in type 1 autoimmune hepatitis in a frequency ranging from 5 to 20%. A long-term follow-up study of AMA-positive autoimmune hepatitis reported that no patients progressed to primary biliary cirrhosis. In addition, immunization of animals with PDC-E2 antigen results in production of AMA without any liver or bile duct damage. These findings indicate that AMA itself cannot cause the damage of biliary tree. Neither the presence nor the amount (titer) of AMA in the blood appears to be related to the inflammatory destruction of the bile ducts.

Anti-Liver-Kidney Microsomal-1 and Anti-Liver Cytosol-1 Antibodies: Anti-liver-kidney microsomal-1 (ALKM-1) and anti-liver-cytosol (ALC-1) antibodies are the major autoantibodies in type 2 autoimmune hepatitis, a disease which occurs predominantly in girls and young women. ALKM-1 antibodies, which are directed at the cytochrome P450 enzyme CYP2D6, are also found in approximately 5 percent of patients with chronic HCV and 25 percent of those with halothane-induced hepatitis and graft-versus-host disease. They differ from ALKM-2 and ALKM-3 antibodies.  ALC-1 antibodies are detected in up to 50% of LKM-positive sera. In contrast to LKM autoantibodies, ALC-1 autoantibodies appear to correlate with disease activity.

Reference:

  M.P. Manns et al: Diagnosis and management of autoimmune hepatitis. Hepatology 2010; 51:2193.

  V. Mehendiratta et al: Serologic markers do not predict histologic severity or response to treatment in patients with autoimmune hepatitis. Clin Gastroenterol Hepatol 2009; 7:98.

  K.M. Pollard, ed: Autoantibodies and autoimmunity: molecular mechanisms in health and disease. Edited by K. Michael Pollard. Copyright 2006 WILEY-VCH Verlag gmbh & Co.




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