Autoimmune liver disease (ALD) is a group of immune-mediated liver injuries that can be briefly classified, based on their clinical manifestations, biochemical, immunological, imaging and histopathological features, into a predominantly hepatitis-based type, namely autoimmune hepatitis (AIH), and a predominantly biliary system damage and cholestasis-based type, namely primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). In addition, there are overlap syndromes between any two of these three diseases, mainly AIH-PBC overlap syndrome. Since hepatitis and cirrhosis in China are mostly caused by hepatitis viruses, especially hepatitis B virus, ALD was thought to be less common in the past. However, in recent years, due to the accumulation of clinical experience and the development of laboratory diagnostic techniques, the detection rate of ALD has increased. Since the etiology and pathogenesis of this group of diseases have not been fully elucidated and there are no curative drugs available, it is an important cause of liver failure. In the early stage of the disease, the clinical symptoms of ALD are not obvious and the diagnosis is based on biochemical, immunological, imaging and histopathological features. In this paper, we review the progress of autoantibody detection in autoimmune liver disease and its diagnostic value. I. Autoimmune hepatitis AIH is a chronic disease that produces immune-mediated damage to hepatocytes over a long period of time due to loss of immune tolerance to hepatocytes. It is characterized clinically by fluctuating xanthogranuloma, hypergammaglobulinemia, presence of circulating autoantibodies and female susceptibility. Persistent parenchymal liver damage is prone to progression to cirrhosis and has a high mortality rate. However, immunosuppressive therapy for AIH is effective, so early diagnosis is important. AIH is classified into three serological subtypes according to the serum autoantibody profile. type I AIH, the classic type, is the most common and accounts for about 60% to 80% of all AIH. It is characterized by positive anti-nuclear antibody (ANA), anti-smooth muscle antibody (SMA), anti-hepatocyte membrane antibody (LMA) or perinuclear anti-neutrophil cytoplasmic antibody (pANCA). type II AIH occurs mainly in children and is characterized by positive anti-hepatic and renal microsomal type I antibody (LKM-1) or anti-hepatocyte cytoplasmic type I antibody (LC-1). type III AIH is the most indeterminate type III AIH is the most indeterminate type and is characterized by positive anti-soluble liver antigen/hepatopancreatic antigen antibody (SLA/LP). (i) Anti-nuclear antibody (ANA) ANA was the first autoantibody identified in the sera of AIH patients and remains the most sensitive landmark antibody for the diagnosis of AIH. It is a general term for autoantibodies to all nuclear antigen components in cells, and its target antigens include the nucleus, cytoplasm, cytoskeleton and cytokinesis cycle proteins. Although ANA is a serologic marker for type I AIH (about 75% of patients with type I AIH are positive) it is not disease-specific. It can also be positive in chronic viral hepatitis, other autoimmune diseases and even in healthy elderly people. However, the potency of ANA in AIH is generally high, usually exceeding 1:160 by indirect immunofluorescence). The fluorescence pattern of ANA is not directly related to the AIH typing and is not sufficient to indicate the development and prognosis of the disease. Some ANA target antigens are extracted by molecular biology, i.e. anti extractable nuclear antigens (ENA). The conventional ENA profile includes: anti-double-stranded DNA antibodies (dsDNA), anti-dry syndrome antigen A antibodies (SSA), anti-dry syndrome antigen B antibodies (SSB), anti-nuclear ribonucleoprotein antibodies (nRNP), anti-histones antibodies (Histones), anti-Jo-1 antibodies, anti-Sm antibodies and anti-scleroderma 70 antibodies (Scl-70). These antibodies are useful for the diagnosis and differential diagnosis of ALD and whether it is combined with other autoimmune diseases. （The target antigens are cytoskeletal proteins, including microfilaments (F-actin and G-actin), intermediate filaments (wave proteins, cytokeratin and junctional proteins) and microtubules. The most diagnostic target antigen is F-actin, which is closely related to the plasma membrane of hepatocytes and has better diagnostic specificity than ANA for type I AIH. However, like ANA, SMA is not organ and species specific and can be positive in the sera of patients with chronic hepatitis C and infectious mononucleosis. However, SMA titers exceed 1:80 in type I AIH (indirect immunofluorescence assay). After immunosuppressive treatment, most patients with type I AIH can have negative serum ANA and SMA, but antibody levels do not indicate disease prognosis. SMA can be divided into three fluorescence patterns by indirect immunofluorescence: staining for cords (SMAv), bulbous cords (SMAvg), and tubular bulbous cords (SMAvgt). Among them, SMAvgt combined with anti-microfilament (MF)-reactive positive SMA or anti-F actin-type SMA is a highly sensitive and specific antibody for the diagnosis of type I AIH.8o0o Patients with type I AIH may present with both SMAvgt and anti-MF-type SMA, which are highly correlated. Compared with the conventional indirect immunofluorescence method, the ELISA method using purified antigen to detect F actin can improve the sensitivity of type I AIH diagnosis with similar specificity of both trapped. It has been found that patients with type I AIH who are positive for anti-F-actin antibodies tend to have a younger age of onset and poor treatment outcome. (iii) Anti-liver and kidney microsomal antibodies (LKM) were first discovered in 1973 by applying indirect immunofluorescence, and LKM can be detected in some immune-mediated liver diseases, such as type II AIH, hepatitis C and D, as well as in patients with drug-induced hepatitis.LKM includes three isoforms, of which the target antigens of LKM-1 and LKM-3 are cytochrome monooxygenase P4502D6 ( CYP2D6), which constitutes the determinant cluster for the recognition of linear antigens in patients with AIH. Recently, it was found that human leukocyte antigen class I gene (HLA-A2)-restricted CYP2D6-specific CD8+ T cells have immune responsiveness that varies depending on the severity of AIH and is associated with hepatocyte damage. the major antigenic epitope on CYP2D6 recognized by CD8+ T cells is located at amino acid residues 245-254, and studies suggest that this sequence is expected to The study suggests that this sequence is expected to be a new hot spot for immune intervention therapy in type II AIH. In conclusion, LKM-1 is the main serological feature of type II AIH, and the antibody positivity rate can reach 90%, mostly in patients with progressive liver disease, who usually need further immunosuppressive therapy. (iv) Anti-hepatocyte cytoplasmic type I antibody (LC-1) LC-1 is also the hallmark autoantibody of type II AIH and is found to be positive in 50% of patients with type II AIH but much lower in patients with type I AIH or chronic hepatitis C. The target antigen recognized by LC-1 is iminomethyltransferase a cyclized deaminase, which performs iminomethyltransfer between glutamate and tetrahydrofolate and deamination. LC-1 is the only detectable autoantibody in 10% of type II AIH patients, and LC-1 is associated with disease activity and progression in AIH. (v) Anti-soluble liver antigen/hepatopancreatic antigen antibodies (SLA/LP) were discovered in 1987 and 1983, respectively, and were initially thought to be different from each other until Wies successfully cloned the full-length DNA sequence of SLA from human liver tissue and tested 2,000 patients with various chronic liver diseases and found that SLA is an unknown soluble protein in the plasma of hepatocytes that is identical to IT. Today the two are collectively referred to as SLA/LP antibody, a serum marker for type III AIH. Although it is less frequent, it has a high specificity and is almost exclusively seen in AIH, making it of diagnostic significance. In addition, there is a correlation between SLA/LP positivity and the severity of AIH. (vi) Anti-hepatocyte membrane antibody (LMA) and anti-liver-specific protein antibody (LSP) are both liver-specific autoantibodies, but not disease-specific; LMA is positive in the active phase of type I AIH, while LSP occurs most frequently in AIH. (vii) Perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) Anti-neutrophil cytoplasmic antibodies (ANCA) are a group of heterologous autoantibodies that react with neutrophils. Since its first discovery in 1985, ANCA has become an extremely valuable serological marker for the diagnosis and observational treatment of systemic vasculitis (e.g., Wegner’s granulomatosis, polyarteritis, etc.). Based on immunofluorescence it can be divided into cytoplasmic ANCA (cANCA) and perinuclear ANCA (pANCA). In recent years, ANCA similar to pANCA but with cytoplasmic fluorescence has been found in ALD, which is called atypical pANCA. o It has a positive rate of 40%-96% in type I AIH and almost negative in type II AIH. The antibody is also detected in 60% to 92% of PSC, compared to 0-39% of PBC patients. In addition pANCA is also seen in 60%-87% of ulcerative colitis, 5%-25% of Crohn’s disease and other diseases. (viii) Anti-desalic acid glycoprotein receptor antibody (ASGPR) ASGPR is a liver-specific endocytic receptor located on the hepatocyte membrane and is one of the components of liver-specific membrane lipoproteins that are closely related to AIH. It has good disease specificity and is found in all types of AIH and rarely in other liver diseases or extrahepatic autoimmune diseases. The potency of this antibody varies with the activity of AIH, and a positive ASGPR or high potency indicates that the disease is active. (ix) Anti-glutathione sulfotransferase antibody (GSTA1-1) Kato et al. found that anti-GSTA1-I antibody is also an autoantibody in AIH, with a positivity rate of 16% in AIH. Although the positivity rate is low, positive patients tend to have a more severe clinical presentation. (J) Anti-heterogeneous ribonucleoprotein A2/B1 (hnRNPA2/B1) antibody Hugnet et al. applied proteomics technology to discover a new antigen for type I AIH, namely hnRNPA2/B1. Its antibody positivity may provide more basis for the diagnosis of type I AIH. II. Primary biliary cirrhosis (PBC) PBC is a chronic progressive cholestatic liver disease of unknown etiology. It is most commonly seen in middle-aged women and presents clinically with an itchy rash with or without xanthogranuloma. Routine application of serologic screening may detect it before the onset of symptoms. The diagnosis is confirmed in most cases by elevated alkaline phosphatase (ALP) and a positive serum anti-mitochondrial antibody (AMA). The natural history of PBC is a slow progressive cholestasis process with liver damage, liver fibrosis, cirrhosis and its complications. (i) Anti-mitochondrial antibody (AMA) and anti-mitochondrial type 2 antibody (AMA-M2) High-valence AMA, especially AMA-M2, is an important basis for the diagnosis of PBC, with a sensitivity of more than 90% and specificity of 98%. There are multiple antigen components on mitochondria, and AMA is classified into 9 types (M1-M9) according to the location of target antigen on inner or outer mitochondrial membrane and its sensitivity to trypsin and electrophoretic characteristics. While AMA in PBC patients mainly recognizes the M2 antigen component of mitochondria. the M2 antigen determinant clusters are some components of the 2-oxoglutarate dehydrogenase complex on mitochondria, including pyruvate dehydrogenase complex E2 subunit (PDC-E2), branched chain diketonate dehydrogenase complex E2 subunit (BCOADC-E2), 2-ketoglutarate dehydrogenase complex E2 subunit (OGDC- E2), and dihydrothioinophthalamide dehydrogenase binding protein (E3BP), of which PDC-E2 is its predominant autoantigen. Although AMA can be detected in most PBC patients before clinical manifestations, abnormal liver function and hepatic histological changes, its potency and typing do not correlate with the severity of PBC and disease progression. The AMA potency can be 200-fold different between PBC patients, but for the same patient alone, the AMA potency should be stable. their AMA potency should be stable. The specific typing of AMA can be detected by Western blotting, but its typing is not directly related to the stage of liver disease, clinical manifestations, biochemical indicators, histology, immunological features or Mayo risk score. Although unconfirmed, it has been suggested that IgA antibodies against BCOADC-E2 may be a predictor of liver histological deterioration. In contrast, serum levels of IgA antibodies against pyruvate dehydrogenase decreased after treatment with ursodeoxycholic acid. Recently, it was found that patients with PBC may be more susceptible to cirrhosis than other patients if their AMA is 1gG3, and AMAIgG3 potency is closely associated with Mayo risk score. Although the typing and positive rate of AMA in PBC are not related to the gender of patients, usually male patients are found later and the disease is already in the progressive stage when diagnosed. (ii) Anti-nuclear antibody (ANA) is also an important antibody in addition to AMA, with a positive rate of 50% in PBC patients, especially when AMA is negative. The common fluorescence patterns of ANA in PBC are multinuclear dot type, perinuclear type and anti-mitochondrial type. The target antigens include SP100, promyelocytic leukemia antigen (PMI), and micro-ubiquitin-related modifier (SUMO). Anti-SP100 antibodies are specific for PBC as they are present in only 3% of patients with other autoimmune or rheumatic diseases. However, many recent studies have found a higher rate of positive anti-SP100 antibodies in non-PBC patients than previously reported, especially in patients with SLE, thus casting doubt on its high specificity in the diagnosis of PBC. However, these studies also found that those positive for anti-SP100 antibodies were more likely to develop cirrhosis and hyperbilirubinemia than those who were negative, and that their disease progressed rapidly. PML proteins are inhibitory proteins of cell transformation and growth and are aberrantly expressed in promyelocytic leukemia cells. Anti-PMI antibodies were first identified in patients with PBC, but are also seen in other autoimmune diseases, but are significantly less likely to be positive than in PBC, and are negative in the normal population. SUMO is a new antigenic component recently identified in PBC that covalently binds SP100 and PMI. anti-SUMO-1 and anti-SUMO-2 antibodies are found in patients with PBC. SUMO-2 antibodies can be found in PBC patients with positive anti-nuclear punctiform ANA antibodies, and the detection rates of both are 15% and 42%, respectively, while they are not detected in negative PBC patients. 2. Perinuclear ANA: Perinuclear ANA is also a specific serological marker of PBC, and its target antigens are nuclear pore complex and nuclear membrane. Among them, the nuclear pore complex mainly includes gp210 and p62. The nuclear pore membrane glycoprotein (gp210) is involved in the adhesion of the core complex components. Anti-gp210 antibodies are highly specific for the diagnosis of PBC, and although the sensitivity is only 10%-53%, it is closely related to disease activity, and the incidence of liver failure is significantly higher in positive than in negative PBC patients. p62 is a glycoprotein present in the nuclear pore complex and is an autoantigen of PBC. Anti-p62 antibodies are positive in 140% to 32% of patients with PBC and 13% of patients with dry syndrome, in addition to a few patients with mixed connective tissue disease. Studies suggest that anti-p62 antibodies are more sensitive and specific in patients with PBC than in other autoimmune diseases, and may be associated with advanced or progressive PBC. Anti-LBR antibodies can be detected in a minority of PBC patients (about 1%). Anti-LBR antibodies are also specific for PBC. 3. Anti-synuclein ANA: The target antigen in PBC patients is synuclein B (CENP-B), a protein with a relative molecular mass of 80,000 that is associated with human chromosomal synuclein heterochromatin. It was found that in addition to anti-gp210 antibodies being a significant risk factor for liver failure in Japanese PBC patients, anti-synuclein ANA positivity also suggested a poor prognosis, and it was closely associated with the development of portal hypertension. 4. Other target antigens: SOX13 (ICA12) is a transcription factor, and anti-SOX13 antibodies have recently been found to be positive in 18% of patients with PBC, 13% in AIH, and 14% in autoimmune cholangitis, and can also be detected in 18% of patients with type 1 diabetes. However, the diagnostic and clinical significance of anti-SOX13 antibodies in PBC needs to be further investigated. Primary sclerosing cholangitis PSC is a chronic cholestatic liver disease of unknown cause, commonly seen in young and middle-aged men. Patients often present with progressive stenosis of intrahepatic and/or extrahepatic bile ducts, eventually leading to cirrhosis and portal hypertension. Approximately 75% of patients with PSC develop an associated inflammatory bowel disease, most frequently ulcerative colitis and less frequently Crohn’s disease. The diagnosis of the disease is supported by positive atypical perinuclear anti-neutrophil cytoplasmic antibodies (pANCA), which recognize target antigens such as lactoferrin and histone G. However, since atypical pANCA can also be found in patients with other chronic liver diseases, such as PBC and AIH, it is only a non-specific indicator and has no confirmatory significance for PSC. The atypical pANCA found in PSC, AIH and ulcerative colitis specifically identifies nuclear membrane proteins with a relative molecular mass of 50,000, with a positivity rate of 92%, and is present only on the nuclear membrane of neutrophils and their precursor myeloid cells, so the antibody is called perinuclear anti-neutrophil nuclear antibody (pANNA). However, there is no close relationship between its potency level and the clinical manifestations, biochemical indices, disease progression and efficacy observations of PSC. In contrast, histological examination of the liver and retrograde cholangiography are more helpful in confirming the diagnosis of PSC, with typical cholangiography showing irregular hyperplasia of the bile duct wall and diffusely distributed multilocus stenosis. anguloP et al. detected ANCA in 84% of 73 patients with untreated PSC and anticardiolipin antibodies in 66%, compared with 53% for ANA, while finding that the potency of anticardiolipin antibodies seemed The potency of anticardiolipin antibodies was also found to be related to histological changes in PSC and disease severity. Recently, autoantibodies against bile duct epithelial cells, which mediate the expression and production of CD44 and IL-6, an adhesion molecule widely involved in pathophysiological processes, have been found to be present in 63% of patients with PSC, and inhibition of CD44 expression and function may be a new therapeutic approach for PSC. In summary, serum autoantibody testing plays an important role in the diagnosis of autoimmune liver diseases, especially AIH and PBC. However, most autoantibodies are neither organ-specific nor disease-specific, and although potency levels fluctuate during the natural evolution of the disease and its treatment, most scholars believe that the absolute levels of autoantibodies and their changes should not be used as an indicator of disease severity or efficacy. It is hoped that with the continuous development of laboratory testing technology, more new autoantibodies with disease and organ specificity and prognosis can be discovered to improve the clinical diagnosis and treatment of autoimmune liver disease.