Autoimmunity and the Liver: mechanistic insights

Instituto de Investigación Biomédica de Malaga, IBIMA Malaga Biomedical Research Institute 26 Jjanuary 2016 Diego Vergani Institute of Liver Studies, King’s College Hospital, London, UK Autoimmunity and the Liver: Mechanistic insights  Positive AAB and high IgG  Progressive inflammatory disorder  Exclusion of other pathology (Wilson, HCV, HBV, NASH NASH) Autoimmune Hepatitis Interface hepatitis Autoimmune Hepatitis Autoimmune Hepatitis Autoimmune Hepatitis Anti-smooth muscle (SMA) & Anti-nuclear (ANA) autoantibodies  Anti Anti- -smooth muscle (SMA) & smooth muscle (SMA) &  Anti Anti- -nuclear (ANA) nuclear (ANA) autoantibodies autoantibodies Autoimmune Hepatitis - Type 1 Autoimmune Hepatitis Autoimmune Hepatitis - -Type 1 Type 1 Liver Kidney Liver Kidney Microsomal Microsomal antibody antibody Autoimmune Hepatitis - Type 2 Autoimmune Hepatitis Autoimmune Hepatitis - -Type 2 Type 2 Liver Liver Cytosol Cytosol Type 1 antibody Type 1 antibody LC LC- -1 1LKM LKM- -1 1 Homogenous anti-nuclear pattern on HEp2 cells Homogenous a Homogenous anti nti- -nuclear nuclear pattern on pattern on HEp2 cells HEp2 cells Anti-nuclear (ANA) antibodies No No signle signle AIH AIH- -1 specific ANA 1 specific ANA antigen antigen Targets: Targets: Centromere Centromere Histones Histones Chromatin Chromatin dsDNA dsDNA Ribonucleoproteins Ribonucleoproteins  Elevated ALT  histology: interface and lobular hepatitis, multilobular collapse  Anti-mitochondrial Ab positive at 1/800  Hep B, Hep C and other viral infections excluded  King’s testing: anti-LKM-1 positive, Titre >1:10.240  Repeat test confirms: anti-mitochondrial Ab positive at a titre of 1/800  Elisa: anti-cytochrome P450 2D6, positive out of scale Misdiagnosis Misdiagnosis LKM-1 LKM-1 AMA AMA Antimitochondrial Antimitochondrial antibody (AMA) antibody (AMA) Commercial kits available Commercial kits available Commercial kits available Molecular target: Molecular target: PDC PDC- -E2 E2 AMA AMA Commercial kits available Commercial kits available Commercial kits available Molecular target: Molecular target: CYP2D6 CYP2D6 LKM-1 LKM-1 LKM-1 LKM-1 20 yrs old female, Caucasian, Nurse, from Southern California, Non specific symptoms Hepatomegaly-Splenomegaly Unexplained increase of IgG 5x upper NV transaminases ANA, SMA, AMA negative Liver biopsy: cirrhosis Clinical Case Clinical Case - -1 1 DIAGNOSIS: Cryptogenic hepatitis ReTest: anti-LKM1 (1/640) Diagnosis: Autoimmune Hepatitis type 2 Outcome: Liver Transplantation -Alive 16 yrs old female, Hispanic, Student, from Southern California, Unexplained increase of IgG 21X UNV transaminases Jaundiced (14X UNV bilirubin) ANA, SMA, AMA negative Liver biopsy: cirrhosis Clinical Case Clinical Case - -2 2 ReTest: anti-LKM1 (1/320) Diagnosis: Autoimmune Hepatitis type 2 Outcome: Liver Transplantation -Dead DIAGNOSIS: Cryptogenic hepatitis They They conclude conclude that that ‘ ‘The diagnosis of type 2 AIH can be The diagnosis of type 2 AIH can be overlooked if anti overlooked if anti- -LKM antibody is not tested LKM antibody is not tested’ ’ (they) (they) recommend recommend testing anti testing anti- -LKM antibodies in all patients LKM antibodies in all patients with a chronic liver disorder that is otherwise without with a chronic liver disorder that is otherwise without apparent cause, especially if they are young and female. apparent cause, especially if they are young and female. Am J Gastroenterol 2000 Nov;95(11):3238-41 LKM-positive autoimmune hepatitis in the western United States: a case series. Duchini A, McHutchison JG, Pockros PJ They They also conclude also conclude that: that: ‘ ‘Early referral to a tertiary liver Early referral to a tertiary liver transplant transplant center center is is appropriate appropriate in light of the complexity and in light of the complexity and difficulty of management of in these patients difficulty of management of in these patients’ ’. . Division of Gastroenterology and Hepatology, Scripps Clinic, La Jolla, California 92037, USA. Am J Gastroenterol 2000 Nov;95(11):3238-41 LKM-positive autoimmune hepatitis in the western United States: a case series. Duchini A, McHutchison JG, Pockros PJ   Laboratory is familiar with different Laboratory is familiar with different aab aab patterns patterns   Physicians request appropriate tests and Physicians request appropriate tests and interpret results correctly interpret results correctly   Physician and laboratory talk to each other Physician and laboratory talk to each other Autoantibodies are useful if: