Chaïmaâ Zeroual*
*Corresponding Author: Zeroual Chaimaa, CHU Ibn Rochd, department of Internal Medicine, Casablanca, Morocco.
ReceivedFeb 14, 2024 | RevisedFeb 29, 2024 | AcceptedMar 5, 2024 | PublishedMar 27, 2024 |
Most often chronic, autoimmune liver and biliary diseases are rare. Although the etiology is still unclear, several factors including infection, environment, and genetics seem to be involved in the development of those damage. Autoimmune hepatitis AIH is liver inflammation characterized by the presence of antibodies, polyclonal hypergammaglobulinemia, and periportal infiltration are not due to another viral, medicated, or toxic cause. Primary biliary cholangitis PBC previously called primary biliary cirrhosis is a chronic disease in which the bile ducts are infiltrated by lymphocytes, obstructed then slowly destroyed.
Primary sclerosing cholangitis PSB is a chronic cholestatic liver disease characterized by progressive inflammation and fibrosis of the intra-hepatic and extra-hepatic bile ducts. Antibodies are of great help in those diseases. They are more than classificatory and diagnostic markers. Their prognostic contribution predicts severity, allows for monitoring of the therapeutic evolution, and watches for recurrence and complications.
Autoimmune diseases; Hepatitis; Antibodies; Cholangitis; Lymphocytes; Bile ducts; Chronic; Infection; Cirrhosis
The liver, being an organ with the functions of synthesis, storage, and purification, can be subject to changes in its architecture by an autoimmune process. The latter will target the cellular components mainly the hepatocyte and the cholangiocyte. Autoimmune hepatitis AIH is an inflammatory disease of hepatocytes of unknown cause that is generally progressive with fluctuating activity [1]. Most often chronic, it can progress to fibrosis and then cirrhosis. The acute installation, although exceptional, exposes to fulminant hepatitis which is a diagnostic and therapeutic emergency [2].
Autoimmune cholangiopathies include primary biliary cholangitis PBC, primary sclerosing cholangitis PSC, and IgG4 cholangitis. The risk of secondary biliary cirrhosis is present in both PBC and PSC in addition to the predisposition to angiocholitis and cholangiocarcinoma in PSC [3]. In addition to the undeniable role of antibodies in the classification of AIH and the diagnosis of autoimmune hepato-cholangiopathies, their prognostic value allows the assessment of severity and follow-up after treatment [4].
Diagnosis
Occurring at any age in both sexes with a predominance of females, the diagnosis of AIH is established thanks to the very sensitive and specific criteria of the International Autoimmune Hepatitis Group IAIHG [5]. Initially proposed in 1992, the diagnostic criteria were revised in 1999. However, given their difficulty of use in practice and their complexity, the IAIHG proposed in 2008 simplified ones comprising autoantibodies, IgG gamma globulins, histology, and negative viral serology [6]. When the score is equal to 6, the AIH is probable and if it is greater than or equal to 7, the diagnosis becomes certain (Table 1) [7].
Autoantibodies |
||
ANA or SMA |
+1:40 |
+1 |
ANA or SMA |
+1:80 |
+2 |
Antibodies to liver kidney microsome type 1 |
+1:40 |
+2 |
Antibodies to soluble liver antigen |
Positive |
+2 |
Absent autoantibodies |
None |
0 |
Immunoglobulin level |
||
Immunoglobulin G |
+UNL |
+1 |
+1.1ULN |
+2 |
|
Normal |
0 |
|
Histological Findings |
Compatible |
+1 |
Morphological features of AIH |
Typical |
+2 |
Incompatible |
0 |
|
Viral Disease |
||
Absence of viral hepatitis |
No viral markers |
+2 |
Viral markers present |
0 |
|
Score pre-treatment = 7Dg certain |
Score pre-treatment = 6 Dg probable |
Table 1: Simplified Diagnostic Score of AIH according to the IAIHG.
Classification
In the beginning, 2 types were proposed AIH1 and AIH2. However, the discovery of anti-SLA soluble liver antigens (found similar to the anti-LP anti-liver pancreas, hence the name anti-SLA/ LP) has made it possible to define a third AIH3 type. Some authors equate AIH1 to AIH3 given the clinical, histological, and therapeutic similarity, but the latter has a darker prognosis [8].
In AIH1, which is the most frequent (90%), the antibodies found are the antinuclear antibodies ANA and the smooth muscle antibodies SMA. This AIH1 can occur at any age but with a preference for adults. AIH2, found in 5 to 10%, is characterized by the presence of anti-liver kidney microsome LKM1 and anti-liver cytosol LC1. This type affects almost exclusively the child. AIH3 is rare. It is distinguished by the presence of anti-SLA/LP [9].
Autoantibodies
Antibodies are proteins synthesized in response to antigenic aggression by B lymphocytes activated in plasma cells. Autoantibodies, directed against the self's cells, are frequently found in autoimmune diseases but not exclusively. Detected by IFI indirect immunofluorescence, the substrates used are mainly Human Epithelial Cell Line Type 2 (HEp-2). These are cells of the human laryngeal carcinoma [10].
Other organs can be used such as the kidney, liver, and stomach. After detection, other techniques are used to identify the molecular target of antibodies such as immunoprecipitation, enzyme-linked immunosorbent assays, radioimmunology, and immunoblotting [11].
Anti-nuclear antibodies
Discovered in 1943 by the hematologist Malcolm Hargraves, they are non-organ-specific autoantibodies directed against the constituents of the cell nucleus (DNA, chromatin, lamin, histone) and the cytoplasmic elements of the nucleus. Due to their high sensitivity, their interest is major in the detection and diagnosis of HAI1. Anti-chromatins are associated with severe forms of HAI1 and correlate with significant activity and relapse after corticosteroid therapy [12]. Given the poor specificity of ANA, it is necessary to ask for them only in front of a very evocative clinic. In front of a low clinical probability and positive ANA, a dosage of the anti-DFS70 (Dense Fine Speckled 70kD) can be carried out. The positivity is not in favor of an autoimmune disease [13].
Smooth muscle antibodies
Discovered by Johnson in 1965, they are directed against the antigens of the cytoskeleton (desmin, tubulin, vimentin, cytokeratin, actin). SMA is usually searched for by IFI on a rat substrate (liver-kidney-stomach). The fluorescence has a reticulated honeycomb appearance at the hepatic level, fine needles in the renal tubules, and radial filaments at the muscularis mucosae and the gastric mucosa [14]. There are F-actin (filamentous) types as very suggestive of AIH1 at a level greater than or equal to 160 and non-F-actin SMA not specific to AIH [15]. The anti-actin F typing can be done either by IFI on HEp-2 cells treated with colchicine (long straight actin cables) or by immunodot.
Anti-liver kidney microsome 1
Anti-LKM1 are anti-endoplasmic reticulum autoantibodies directed against liver and kidney cells. In IFI, they attach to the entire hepatic lobule. On the substrate, cytoplasmic fluorescence (intense so-called lacquered) and proximal tubules are detected. However, the fluorescence of distal tubules and stomach is negative [4]. Their antigenic target is the isoform 2D6 of the cytochrome P450 superfamily, hence the other name of anti CYP2D6. Their value in diagnosis is not deniable: They are found in 85% of AIH2. They are also prognostic markers. Their rate increases with advanced stages and decreases after a good response to treatment [16].
Anti-liver cytosol 1
They are diagnostic markers of excellent specificity found in 30 to 70% of AIH2. In more than 90% associated with anti-LKM1, their antigenic target is aminotransferase cyclodeaminase. In IFI, anti-LC1 does not attach to the central-lobular areas of the liver. Thus, the anti-LKM1 can mask the presence of the anti-LC1 since it will cover the areas spared by the anti-LC1 [4]. Their prognostic value varies depending on the stage of the disease and the treatment. In the acute phase, the anti-LC1 is absent or present at a low titer, whereas in the case of chronicity, the titer is high. Immunosuppressants and liver transplantation make it possible to reduce the level of anti-LC1 to negate them [17].
Anti-soluble liver antigen /liver pancreas SLA /LP
In 1987, Mann, et al., discovered these antibodies and proposed type 3 of AIH. They are directed against a protein associated with a tRNA for the selenocysteine Trnp (Ser) Sec. Although their specificity is excellent, their sensitivity is mediocre (20 to 30%) dependent on detection techniques [18]. In addition to their diagnostic interest, sometimes their presence is of poor prognosis. When the anti-SLA are positive, there is the risk of AIH de novo after discontinuation of treatment or recurrence of AIH3 after liver transplantation. However, whether the anti-SLA is positive or negative, the therapeutic response remains the same [19].
Anti-receptors of the anti-ASGPR asialoglycoprotein
Rarely used, they are non-specific markers of 50 to 90% of AIH1 or 2. Anti-ASGPR can be present in other liver pathologies (viral hepatitis B or C, PBC, and alcoholic hepatitis). Markers of severity of AIH, their presence is correlated with histological activity, the levels of transaminases and immunoglobulins G. Usually, the positivity of anti-ASGPR is predictive of a good response to corticosteroids and their level decreases under immunosuppressants or even during remission. However, if their level remains high, relapse at the end of immunosuppressive treatment would be very likely [20].
Anti-SSA/Ro52 or TRIM21
Being part of the family of proteins with tripartite motifs, it has been called TRIM21. The "Ro" comes from the name of the patient whose antibodies were extracted and discovered in 1969 by Clark, et al. The anti-SSA autoantibody targets the Ro proteins: Ro52 and Ro60. These are two different proteins encoded by genes on separate chromosomes. However, the Ro52 can be masked by the anti-60 if the 2 are searched simultaneously. Anti-Ro52 is frequently associated with anti-SLA (77% of HAI3). The presence of anti-Ro52 is of poor prognosis, but the interest in researching them remains controversial [21].
Native anti-DNA
Presently, 20 to 30% of AIH1 without there being systemic lupus erythematosus SLE. They can have a poor prognosis [22].
Primary biliary cholangitis
Formerly called “primary biliary cirrhosis”, the term "cirrhosis" has been replaced by “cholangitis” since the diagnosis is now made at earlier stages. It is the main cholestatic disease of adults whose diagnosis is made if at least 2 of the 3 criteria are met. Biological cholestasis (alkaline phosphatases PAL1,5 the upper limit of normal), anti-mitochondrial antibodies AMA ≥ 1/40 or specific anti-nuclear antibodies (anti-gp210 or anti-sp100) or histologically, destructive non-suppurative cholangitis of the interlobular ducts [23].
Anti-mitochondrial 2 or anti-M2 antibodies
Being early markers, AMA anti-mitochondria can be detected by IFI on HEp-2 cells, on tissues (kidney, mouse stomach), or by immunoblot. The typing of these AMAs can be carried out by immunoblot, ELISA, and western blot. There are 10 types of AMAs. In PBC, anti-M2 or anti-pyruvate dehydrogenase, anti-M4 almost always associated with anti-M2, anti-M8, anti-M9, or anti-glycogen phosphorylase, and anti-M10 in the early forms can be found [11].
Presently, in 90% of cases, the anti-M2 has a cytoplasmic fluorescence of the filamento-granular type. They are very sensitive (90 to 95%) and quite specific. Since they can be detected before the onset of the clinical picture, the Anti-M2 titer is not correlated with the severity. After liver transplantation, the anti-Mi2 remains positive but at a reduced rate in IFI [24].
ANA
Anti-glycoproteins 210
Endowed with a specificity of 99%, they correspond to anti-nuclear antibodies with "rim-like" circled membrane fluorescence directed against nuclear pores. Found in 30% of PBC, they are predictive of progression to liver failure with a risk of liver transplantation [25].
Anti-sp100
The sp100 antigen is a 100 kDa protein constituting a specific target during PBC. The anti-sp100s are directed against nuclear bodies, unlike the anti-gp210s targeting the nuclear membrane. In IFI, the fluorescence is in large grains "dot blot". Their prognostic value is not as clear as that of anti-gp210 [26]. However, the combination of anti-gp210 and anti-sp100 significantly increases the risk of portal hypertension and liver transplantation [27].
Anti-centromeres
Frequently found in limited systemic scleroderma, they can also be present in PBC. In the latter, their presence predisposes to renal damage [28]. These anti-centromeres are also predictive of portal hypertension with an increase in its severity in parallel with the increase in their level [4].
Anti-p62
These are antibodies directed against the 62 kD nucleoporin protein. Their presence is frequent in stage 4 PBC, which corresponds to cirrhosis according to Scheuer's histological classification [29].
Anti-kelch-like 12 and anti-hexokinase 1
These two antibodies, recently discovered, are found in PBC. Research is still ongoing on their diagnostic and prognostic interests [30].
Primary sclerosing cholangitis
It is a sensing fibro-inflammatory involvement of the intra and/or extrahepatic bile ducts. Often associated with a chronic inflammatory bowel disease IBD, the diagnosis is based on chronic cholestasis, the typical histological or radiological abnormalities on the bili-MRI with an absence of arguments for secondary infectious, ischemic, lithiasis, and tumor cholangitis [31]. Unlike PBC, there are no specific or constant antibodies.
1. x-anti-neutrophil cytoplasmic antibodies or x-ANCA: They are autoantibodies directed against the antigens present in the azurophilic granules of neutrophil polynuclear cells. The IFI makes it possible to define 3 types of antibodies: c-ANCA (cytoplasmic fluorescence), p-ANCA (perinuclear fluorescence), and x-ANCA or "atypical" p-ANCA (perinuclear fluorescence with a fine border) [32]. The x-ANCA does not have an identified antigenic target. They are observed in 40 to 70% of PSC and even during inflammatory bowel disease IBD (50 to 70% of ulcerative colitis and 2 to 20% of Crohn's disease). Their prognostic value is still poorly known [33].
2. Anti-glycoprotein 2 IgA or anti-gp2 IgA: This IgA-type antibody directed against pancreatic glycoprotein 2 is found in PSC with a distinct and more serious phenotype. It is an immunological marker whose presence during the PSC makes it possible to detect patients at high risk of developing cholangiocarcinoma. Its predictive value is confirmed. However, it remains to be integrated into clinical practice [34].
Overlap syndrome
It corresponds to the simultaneous or consecutive association of AIH with an autoimmune cholangiopathy, either PBC or PSC. The bone between AIH and PBC is more frequent (10% of PBC), while that between AIH and PBC is rare (less than 5% of PBC) [35]. Antibodies alone do not allow the diagnosis of a bone to be made. It is the combination of various clinical, biological, immunological, and histological elements that makes it possible to make the diagnosis. If a PBC is confirmed and in addition, F-actin-type SMA, an overlap AIH-PBC syndrome is uncertain.
Antibodies |
Liver's autoimmune disease associated |
Diagnostic Value for First Time |
Prognostic Value |
ANA
|
AIH1 |
+++ |
Anti-chromatin in the AIH1 |
PBC |
|
Anti-gp210 in the PBC: |
|
|
Progression to failure and transplantation of the liver |
||
|
|
Anti-centromere in the PBC: Predisposition to renal impairment and pulmonary hypertension |
|
Anti-M2 |
PBC |
+++ |
No |
ASMA-type F-actin |
AIH1 |
+++ |
No |
Anti-LKM1 |
AIH2 |
+++ |
In the AIH2, a title very high can be seen in cirrhosis. Their rate decreased after immunosuppressive therapy and liver transplantation |
Anti-LC1 |
AIH2 |
No (in the second intention if the anti LKM1 are negative) |
Similar to anti-LKM1 |
Anti-SLA/LP |
AIH3 (Considered by the authors HAI1) |
+++ |
Their presence is predictive of AIH de novo or recurrence after liver transplantation |
Anti-ASGPR |
AIH |
No (in second intention) |
Correlation between their presence and the activity of histological |
|
|
|
Relapse after immunosuppressive treatment if rates remain high |
Anti-SSA/Ro52 |
AIH3 |
No |
Similar to anti-SLA |
Anti-DNA native |
AIH |
No |
Their presence is a sign of poor prognosis |
|
Overlap syndrome with AIH |
+++ |
Poorly-known |
|
PBC |
|
|
Anti-p62 |
PBC |
No |
Presence at the stage of cirrhosis |
Anti-Kelch-like 12(anti-KLH12), anti-hexokinase1(antiHK1) |
PBC |
No |
Misunderstood |
x-ANCA |
AIH |
No |
Poorly-known |
|
PSC |
|
|
Anti-GP2 IgA |
PSC |
No |
High risk of cholangiocarcinoma |
Table 2: The autoantibodies found in liver autoimmune diseases (diagnostic and prognostic values).
Similarly, a bone is possible in a patient who has a confirmed HAI with negative AMAs. This seronegative AIH-PBC profile has a risk of more severe disease and more extensive fibrosis [36].
Double-stranded or native anti-DNA
Associated with anti-M2, the native anti-DNA seems to be a serological markers of the AIH-PBC overlap syndrome [22]. Research is still underway as to their diagnostic and prognostic interests. Diagnostic and prognostic value of antibodies in autoimmune liver diseases. In autoimmune liver and biliary diseases, the autoantibodies have an important utility in the diagnosis and prognosis that varies from one antibody to another (Table 2). ANA and ASMA of the F-actin type make it possible to diagnose AIH1. On the other hand, the anti-LKM1 and anti-LC1 define AIH2. The AIH3 is a class that is denied by authors and considered a particular form
of the AIH-1. It includes anti-SLA/LP. ANA and ASMA of the F-actin type make it possible to diagnose AIH1.
On the other hand, the anti-LKM1 and anti-LC1 define AIH2. The AIH3 is a class that is denied by authors and considered a particular form of the AIH-1. It includes anti-SLA/LP. In the 3 classes of AIH, the presence of native anti-ASGPR and anti-DNA is correlated with histological activity and relapse after immunosuppressive treatment if the levels remain high. In AIH1, anti-chromatins have a poor prognosis, whereas, in AIH2, it is anti-LKM1 and anti-LC1 that predispose to cirrhosis if the levels remain high. Moreover, in AIH3, anti-SSA/Ro52 are markers of severity, in particular, given their frequent association with anti-SLA/LP. In PBC, anti-M2 are early and specific markers. In case of negativity, the anti-gp210 and anti-sp100 help in the diagnosis.
The combination has a derogatory prognostic value (hepatic insufficiency, portal hypertension, and liver transplantation). Anti-centromeres and anti-p62 are also markers of poor prognosis. PSC, unlike AIH and PBC, does not have specific antibodies. However, the x-ANCA retains their diagnostic contribution and their prognostic value is still poorly known. Anti-gp2 IgA, on the other hand, is associated with a high risk of developing cholangiocarcinoma.
The diagnosis of autoimmune liver diseases is based on a bundle of clinical-biological, immunological, and sometimes histological arguments. Antibodies are a great help to the clinician to label the pathology and predict possible complications. This then allows to process correctly and prepare for subsequent challenges.
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Chaïmaâ Zeroual*
*Corresponding Author: Zeroual Chaimaa, CHU Ibn Rochd, department of Internal Medicine, Casablanca, Morocco.
Copyright© 2024 by Zernoul C. All rights reserved. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Zeroual C. More Than a Classificatory and Diagnostic Marking, a Prognostic Importance of Antibodies in Autoimmune Liver Diseases. J Immuno Allerg. 2024;4(2):63-72. DOI: https://doi.org/10.37191/Mapsci-2582-6549-4(2)-046