Autoimmune liver disease (AILD) is a group of inflammatory diseases of the hepatobiliary system mediated by abnormal autoimmunity, including autoimmune hepatitis (AIH), which is mainly hepatocellular damage, and primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and IgG4-related sclerosing cholangitis (IBC), which are mainly biliary damage and cholestasis. primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and IgG4 related sclerosing cholangitis (IgG4-SC). The diagnosis of these diseases often requires a combination of clinical manifestations, serum autoantibodies and liver histology, especially in patients with non-specific clinical manifestations and negative autoantibodies, histological manifestations often play a crucial role in the diagnosis. In this paper, we review the pathological histological manifestations of several autoimmune liver diseases mentioned above.
I. AIH
AIH is an inflammatory lesion of the liver parenchyma mediated by an abnormal autoimmune response, mostly in women, characterized by hypergammaglobulinemia, positive serum autoantibodies and response to immunosuppressive agents (1).
1. Histologic manifestations: AIH pathologic histologic manifestations are diverse and can be acute or chronic, with varying degrees of fibrosis, but in general, hepatocellular injury is predominant. There are no histological morphological changes that confirm the diagnosis, but have the following pathological features.
(1) Interfacial hepatitis: necrosis of hepatocytes adjacent to the portal area or fibrous septum is called interfacial hepatitis (interface hepatitis) or piecemeal hepatitis (piecemeal hepatitis). It manifests as single or small clusters of hepatocytes at the interface, resulting in a “wormy” appearance at the lobular interface, with inflammatory cells extending into the lobules along the damaged interface and encircling the necrotic hepatocytes. Depending on the severity of the lesion, bridging necrosis, sub-massive necrosis or even massive necrosis may form in adjacent areas. If the lesion progresses further, the reticular fibrous scaffold of the necrotic area collapses, the mesenchymal cells (e.g., stellate cells) proliferate, the fibrous septa widen, and eventually pseudobullets form, leading to cirrhosis. It should be emphasized that interfacial hepatitis is characteristic rather than specific for the diagnosis of AIH, and it is also present in other chronic liver diseases, such as viral or drug-induced chronic hepatitis, and even in cholestatic liver disease PBC (2). Therefore, the diagnosis of AIH needs to be combined with clinical information.
(2) Lymphoplasmacytic infiltration is predominant: Inflammatory cells infiltrating in and around the portal duct area are mainly lymphocytes and plasma cells. Plasma cells are mainly found in the hilar region, but sometimes also in the lobules. However, nearly one third of patients with confirmed AIH can show a scarcity or even absence of plasma cells (3). It is worth mentioning that plasma cell aggregates confined to the border plate are often indicative of AIH rather than viral hepatitis (4). plasma cells in AIH are predominantly IgG-positive, with a small number of IgM-positive cells, whereas plasma cells in PBC are predominantly IgM, a phenomenon that may be used to help differentiate AIH from PBC (5). CD4+ T cells are predominant in the hilar region of AIH, whereas CD8+ T cells are more often seen in interface hepatitis. Plasma cells containing IgG4-positive cells are seen in liver tissue with combined autoimmune pancreatitis, but this is not a typical manifestation of AIH (6).
(3) Hepatocytes arranged in a rosette formation: a pseudoglandular structure formed by 2-3 aqueous degenerated hepatocytes with dilated capillary bile ducts visible in the center, so named because of its resemblance to a rosette.
4) Penetration phenomenon: i.e. histological manifestation of lymphocytes entering hepatocytes, mostly seen in active interfaceitis, another typical manifestation of AIH (7).
In addition, non-specific histological manifestations such as hepatocyte hydropic degeneration, ballooning, eosinophilic necrosis and apoptotic vesicles are also seen.
2. Rare histological manifestations of AIH
(1) Central lobular necrosis
Necrosis in the central lobe of the liver (zone III) is mostly seen in drug-induced or viral hepatitis. Recent studies have shown that central lobular necrosis is present in 17.5% of AIH liver biopsy tissues, suggesting that it may be one of the manifestations of the acute phase of AIH and can be used for early diagnosis of AIH (8). It can occur alone or with interfacial hepatitis. AIH patients presenting with this pathology are characterized by high bilirubin levels, high histological activity (8) and high recurrence rate (9).
2) Presence of multinucleated or meganucleated hepatocytes
Multinucleated or meganucleated hepatocytes may be a feature of AIH; however, they are also seen in pharmacologic or viral hepatitis, especially associated with paramyxovirus (10), so other causes need to be excluded before considering them as suggestive of autoimmune pathology. It has also been suggested that multinucleated giant cell hepatitis may be a subtype of AIH, which is more severe and prone to progression to cirrhosis (11).
3) Bile duct injury
In AIH, damage to the bile ducts is uncommon but still present. Studies have shown that bile duct damage is seen in 12% of AIH liver biopsy specimens (12), which shows that the presence of bile duct damage alone cannot completely exclude AIH.
3. Different point systems
In 1993, the International Autoimmune Hepatitis Group (IAIHG) developed descriptive diagnostic criteria and a point system for autoimmune hepatitis (13), which was updated in 1999 (14).Alvarez F et al. summarized data from 6 studies with 983 patients and showed that the point system had a sensitivity of 97-100% and an accuracy of 89.9% for the diagnosis of AIH. accuracy of 89.9% (14). Its main components include 7 points for clinical features, 14 points for laboratory tests, 5 points for histopathology, >1 5 points required for a definite diagnosis, and 10-15 points for a possible diagnosis. Liver histology was specified as follows: interfacial hepatitis +3, lymphoplasmacytic infiltration in the portal area and lobules +1, hepatocytes with roseola-like changes +1, no such manifestations -5, bile duct changes -3, and other atypical changes -3.
Although the above point system has good sensitivity and specificity for the diagnosis of AIH, it is too complex to be fully generalized in clinical practice. 2008 Hennes et al. proposed simplified diagnostic criteria for AIH, with the initial intention of developing a point system more suitable for daily clinical work, thus distinguishing it from the A1H diagnostic point system, which is mainly used for scientific research (7). The total score for the diagnostic criteria is 8, and a score greater than or equal to 7 is required for a confirmed diagnosis. The point system classifies the histological changes in the liver into three categories: typical, conforming and atypical. “The “typical” AIH presentation includes interfacial hepatitis, lymphoplasmacytic infiltration in the portal area/lobules, hepatocellular “rosette”-like changes, and penetration, with a score of 2 if all 3 are present. AIH” refers to chronic hepatitis with lymphocytic infiltration, but lacking the three features of typical AIH, scoring 1 point; “atypical” has a histological basis to support other diagnoses, scoring 0 points. In contrast, in the previous point system, points were subtracted for the presence of steatosis, iron deposits, or bile duct changes in liver histology, whereas in the simplified system, there were no subtractions and the maximum score was 2. In the new point system, the proportion of liver histology has increased compared with the previous system. Recently, Ma Xiong et al. used the simplified diagnostic criteria to validate AIH in Chinese, suggesting that the new simplified criteria have better sensitivity and specificity compared with the previous ones, and emphasizing that liver biopsy is indispensable in the diagnosis of AIH using the simplified criteria (15).
4. Pathological and clinical: It is important to perform liver histology before discontinuing immunosuppressive therapy in AIH patients. Histologic regression of inflammation in the liver is often later than biochemical, so liver biopsy should also be considered in patients with normal biochemistry prior to discontinuation (16). Histologic intralobular inflammatory necrosis and remission or disappearance of interfacial hepatitis can be defined as disease remission, and discontinuation of immunosuppression in the presence of interfacial hepatitis with plasma cells can lead to disease relapse (17). The histological manifestations of AIH recurrence are similar to those of pretreatment AIH in some patients, even if fibrosis is found on first liver biopsy.
5. Differential diagnosis.
Acute episodes of AIH with intrafollicular inflammation as the main manifestation need to be differentiated from acute viral hepatitis and drug-induced liver damage. In addition to the common HAV, HBV, and HCV, systemic viral infections such as Epstein-Barr infection may also present with histologic manifestations similar to AIH. the differentiation between AIH and DILI is difficult because the drugs themselves can induce persistent AIH. careful history of drug use may help in the diagnosis. An in-depth study by Suzuki A et al (18) in recent years suggests that histological differences between the two still exist. They randomized liver biopsies of 35 cases of clinically definite diagnosis of DILI (19 hepatocellular; 16 biliary or mixed) and 28 cases of AIH to four liver pathologists in a double-blind fashion. Scores were based on Ishak score, type of inflammatory cells in the portal area and lobules, presence of penetration, rosette ring and cholestasis. The results showed that interface hepatitis, focal necrosis and inflammation in the portal ductal area were both present, but more severe in AIH than in DILI. histological manifestations specific to AIH included plasma cell infiltration, rosette ring and penetration, whereas infiltration of neutrophils in the confluent ductal area and intrahepatic cholestasis were more common in DILI. in addition, there were seven cases of immune-mediated DILI in the study, compared with AIH, in which there was no significant fibrosis. However, some scholars are skeptical about this (19). The reasons for this are the low concordance rate (46%) among the four pathologists, the low percentage of DILI patients who underwent liver biopsy themselves, and the fact that the acute phase had passed by the time of biopsy, which led to a poor understanding of the histological features by the pathologists. For example, eosinophil infiltration is generally seen in DILI, whereas in the study by Suzuki A (18) it was suggested that eosinophil infiltration could not be used to differentiate AIH from DILI.
AIH presenting as chronic liver damage often needs to be distinguished from chronic viral hepatitis and other autoimmune liver diseases (e.g., PBC and PSC). In general, serum virologic markers can identify patients with viral hepatitis, and histologically, initial untreated AIH is more inflamed than HCV within the lobules and at the interface. It is important to note that some HBV and to a lesser extent HCV are seen as plasma cells and can be easily confused with AIH. Wilson’s disease can also present as chronic liver damage, but it is more common in young adults and can be differentiated by 24h-urine copper, copper cyanide and copper deposits in liver tissue. The differentiation of AIH from typical PBC and PSC is not difficult. Some PBC portal areas may present with plasma cells as well as interfacial hepatitis, but exuberant cholangitis and bile duct agenesis are not usually seen in AIH. Early PSC and AIH are difficult to differentiate, especially in pediatric patients. Fibrous occlusive bile ducts are seen in some PSCs, and cholangiography is useful for differential diagnosis.
AIH is often associated with other diseases, such as nonalcoholic steatohepatitis, which can often present with fatty liver pathology such as large vesicular predominant steatosis, hepatocellular edema, and zone 3 fibrosis combined with interfacial hepatitis. Since steatohepatitis can also have inflammatory cell infiltration in the portal area, other clinical indicators (e.g., elevated serum IgG, positive autoantibodies) need to be combined before diagnosing steatohepatitis combined with AIH.
6.AIH and liver transplantation
About 1/3 of adult patients with AIH will have a relapse after liver transplantation, and this is more common in children (20). Some patients who were not diagnosed with AIH prior to transplantation develop histological manifestations of AIH with predominantly plasma cell infiltration after transplantation, and these patients are referred to as “de-nove” AIH. The etiology remains unknown. Both post-transplant AIH relapse and de-novo AIH need to be histologically differentiated from chronic graft rejection. In general, a greater variety of inflammatory cells in the hilar region and cholangitis clearly suggest graft rejection, whereas a lymphocyte-plasma cell infiltrate predominates in the hilar region and the presence of a rosette ring in the lobules often suggests AIH recurrence or de-novo AIH (21).