Anti–Liver–Kidney Microsomal Antibodies (LKM-1)

Autoimmune liver diseases are a group of rare chronic liver disorders caused by immune dysregulation that leads the immune system to attack hepatic structures. Autoimmune hepatitis (AIH) is a chronic inflammatory liver condition characterised by persistent hypertransaminasemia, hypergammaglobulinemia (high levels of IgG) and circulating autoantibodies. AIH may occur in association with or overlap with other liver diseases, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), drug-induced liver injury (DILI) or viral hepatitis, complicating the clinical and diagnostic picture.

Autoimmune hepatitis is classified into three subtypes based on the autoantibody profile:
A. Type 1 AIH: the most common form, can affect both children and adults; defined by the presence of antinuclear antibodies (ANA) and/or anti-smooth muscle antibodies (ASMA);
B. Type 2 AIH: more frequent in paediatric/adolescent patients; characterized by antibodies to LKM1 (liver–kidney microsomal type 1) and/or LC1 (liver cytosol type 1);
C. Type 3 AIH: more recently proposed; defined by anti-SLA/LP (soluble liver antigen/liver–pancreas antigen) antibodies. There is ongoing debate as to whether this should be considered as a separate entity or a variant of type 1 AIH.

Anti–liver–kidney microsomal antibodies (LKM) are a heterogeneous class of autoantibodies against microsomal enzymes involved in hepatic metabolism; anti-LKM1 antibodies are the main serological marker of type 2 autoimmune hepatitis (AIH-2), especially in paediatric patients. The main antigenic target of anti-LKM1 is cytochrome P4502D6 (CYP2D6), an enzyme of the cytochrome P450 family involved in the metabolism of various drugs and endogenous substances. The involvement of the following has also been described: anti-LKM2 antibodies against CYP2C9 associated with cases of drug-induced liver injury (DILI); and anti-LKM3 antibodies against UDP-glucuronosyltransferase (UGT-1), present in about 10–20% of patients with type 2 AIH, often together with LKM.

The gold standard for anti-LKM screening is indirect immunofluorescence (IIFT) on rat kidney sections, to reveal the typical cytoplasmic staining of proximal tubules without glomerular staining. This method does not distinguish among LKM subtypes (LKM1, LKM2, LKM3). Therefore, solid-phase assays (ELISA, immunoblot, ChLIA) are used as confirmation methods, allowing more specific antigenic characterisation, particularly for LKM1, which is relevant for both diagnosis and classification of AIH-2.