Autoimmune diseases are a group of rheumatic immune diseases with liver damage as the main cause, and are classified into Autoimmune hepatitis (AIH), Primary Biliary Cirrhosis (PBC), Primary Sclerosing Cholangitis (PSC) and Autoimmune Hepatitis (AIH) according to their immunological characteristics, clinical features and pathological features. Primary sclerosing cholangitis (PSC). In recent years, autoimmune liver disease has been explored at home and abroad, both in terms of etiology, pathogenesis and diagnosis and treatment, and some of the recent advances are described below.
Section I. Progress in autoimmune hepatitis research.
AIH was described in detail in the 1950s and has undergone various nomenclature since then, such as “hepatitis of unknown cause” and “lupus hepatitis”, but there has been little progress in its research. “AIH is a chronic hepatitis of unknown etiology that can occur at any age in children and adults, often with continuous progression or fluctuating changes in disease. AIH can be classified into 3 different subtypes based on the different types of antibodies in the serum. If left untreated, it can gradually progress to cirrhosis or even hepatocellular carcinoma. Treatment is mainly based on the application of glucocorticoids alone or in combination with azathioprine. In recent years, the international research on AIH is very active, and with the improvement of the understanding of AIH, it is found that this disease is not uncommon in China, but many clinicians lack sufficient knowledge about it, so that many AIH patients do not receive timely diagnosis and treatment.
I. Epidemiology.
AIH is mostly seen in women and can develop at any age. There is a lack of worldwide epidemiological data. The incidence of AIH in Western Europe and North American whites is 0.1-1.2/100,000; the annual incidence of AIH in Northern Europe is 1.9/100,000 and the prevalence is about 16.9/100,000; the prevalence of AIH in the American Alagas population is the highest, 42.9/100,000; the prevalence of AIH in the Japanese population is the lowest, 42.9/100,000. The Japanese have the lowest prevalence of 0.08-0.15/100,000; worldwide, because viral hepatitis, such as HCV, HBV infection is more common, AIH can be missed due to the presence of combined chronic hepatitis B and C. Therefore, it is estimated that its actual incidence is higher than the reported prevalence, and the exact incidence and prevalence of AIH in China is not yet known.
II. Pathogenesis.
1, genetic susceptibility.
The etiology of AIH is still unclear, genetic factors are related to the occurrence of AHI, and research on its genetic susceptibility is mostly focused on the study of the human leukocyte antigen (HLA) gene, which is a component of the histocompatibility antigen (MHC) gene system and is located on the broken arm of chromosome 6. Recent studies have shown that type I AIH has a strong genetic susceptibility and is strongly associated with HLA-DR3 serotype, especially in Caucasians. most of the HLA-DR3 negative type I AIH is associated with HLA-DR4. HLA-DR3-related type I AIH has an early onset and occurs more frequently in female children or young women, with more severe disease; HLA-DR4-related type I AIH occurs more frequently in adults, with relatively mild disease, more frequent extrahepatic manifestations, and good response to cortisol treatment. In Japan, type I AIH related to HLA-DR3 is rare, and more often related to HLA-DR4.
The high frequency of HLA-DRB1*0301, DRB3*0101, DQAl*0501, and DQB1*0201 haplogroups was associated with type I AIH, which was associated with HLA-DRB1*1301 alleles in the South American population and with DRB1*0405 and DQB1*0401 in Japan, and type I AIH in children was associated with HLA- DRB1*03 and HLA-DRB1*13 alleles. RB1*1501 is a protective gene for Caucasian populations, which is isoleucine and alanine at DRb and 67 and 71 positions, respectively, replacing leucine and lysine of DRB1*0301, thus changing the nature of antigen binding. Black AIH patients have an aggressive onset and are less effective and have a worse prognosis than non-black AIH patients with conventional immunosuppression.
DRB1*0301 or (and) DRB1*0401 also have a significant impact on the clinical presentation of AIH. Compared to DRB1*0401-positive patients, DRB1*0301-positive patients are often younger and less responsive to hormonal therapy, maintain remission for a shorter period of time, are prone to relapse, and die more often from liver failure. On the contrary, DRB1*0401 positive patients are usually older women, often with other autoimmune diseases, hormone therapy is easy to maintain remission.
The genetic susceptibility gene for type II AIH is not well defined, and there are reports of a possible association with HLA-DRB1, HLA-DQB. HLA-DR2 is protective for Northern European Caucasians, and HLA-DRB1*1302 is protective for Argentines.
Genetic susceptibility to AIH is also shown to be associated with tumor necrosis factor (TNF) gene polymorphisms, which are located in the class 3 region of the MHC gene, and polymorphisms at locus 308 of the TNF-α gene are thought to be associated with type I AIH in North Americans and Europeans, but this association was not found for Japanese and Brazilians. Recently, polymorphisms of the Fas gene have also been reported to be associated with susceptibility to AIH, but the opposite has also been reported to be unrelated to susceptibility to AIH, but associated with earlier onset of cirrhosis in AIH.
2. Environmental factors.
Molecular mimicry suggests that peptides of certain viruses can form cross-immune reactions with antigens of hepatocytes, but it is very difficult to find exact evidence of these viruses, mainly because of the “lag effect” of immunity, i.e., the cross-immune reaction is manifested long after the virus infection, so that it is difficult to find evidence of virus infection again. The most common viruses considered are measles virus, hepatitis virus, cytomegalovirus, and EBV, with the most evidence associated with hepatitis viruses, such as HCV and HAV.
Certain drugs such as methyldopa, furantoin, diclofenac, interferon, minomycin, and avastatin can induce AIH, and some herbal components, such as Da Chai Hu Tang, are thought to be associated with the development of AIH.
3. Auto-target antigens.
Auto-target antigen is the primary link to initiate autoimmune cascade reaction, both CTL cells and immunoglobulins need to bind with auto-target antigen for immune damage to occur. It is currently believed that the unique sialic acid glycoprotein receptor on the surface of hepatocytes in AIH patients may be the specific target antigen, and immunohistochemistry found it highly expressed in hepatocytes around the portal vein. Most of the specific auto-target antigens of type II AIH are thought to be CYP2D6. It has been newly reported that CD8 T-cell immune response against CYP2D6 (245-254) target may be the immune response mode of type 2 AIH.
4. Mechanisms of immune loss in hepatocytes.
The mechanism of immunopathological damage in AIH involves two main aspects: (1) cell-mediated cytotoxicity: CD4+ T cells are activated and differentiate into cytotoxic T lymphocytes, and cytotoxic T lymphocytes directly destroy hepatocytes by releasing lymphokines, or directly lyse hepatocytes by perforin. The presence of antigen-sensitized disease-specific cytotoxic T lymphocytes in the hepatocyte tissue of AIH patients has been demonstrated. (2) Cell-mediated, antibody-dependent cytotoxicity: Under the synergistic action of T cells, AIH plasma cells secrete and produce large amounts of autoantibodies against hepatocyte antigenic components, which react with protein components on the hepatocyte membrane to form immune complexes, and natural killer cells recognize such immune complexes through FC receptors, causing lysis and destruction of hepatocytes.
5. Role of regulatory T cells in the pathogenesis of AIH.
CD4+CD25+ regulatory T cells (CD4+CD25+ regulatory T cells, TReg) play an important role in maintaining immune stability. sakaguchi et al. in 1995 found that 5% to 10% of CD4+ T cells in the peripheral circulation of unimmunized (naive) mice expressed CD25 (IL 2α chain) surface molecules that would Passing CD4+ T cells with CD25+ T cells removed to T cell-deficient mice can lead to autoimmune diseases in various organs of the host, such as autoimmune thyroiditis, gastritis, type I diabetes, etc., whereas co-transfer of CD4+CD25+ T cells together with CD4 single-positive cells was found to avoid autoimmune diseases. This process suggests that CD4+CD25+ T cells are one of the main factors in the maintenance of autoimmune tolerance.
The autoimmune response is primarily an immune response of the immune system to its own antigens. If this response reaches high levels, it can lead to damage of self tissues and organs, causing autoimmune diseases. Immunological theory suggests that the mechanisms by which autoimmune tolerance is achieved are clonal clearance, immune incompetence and immune neglect. All three of these mechanisms achieve autoimmune tolerance in a passive manner. TReg, on the other hand, achieves tolerance in an active manner and plays an important role in peripheral tolerance. Autoantigens induce TReg to suppress auto-invasive T cells and thus suppress autoimmune diseases.
Recent studies suggest that TReg dysfunction is also present in AIH, as evidenced by a decrease in the number of CD4+CD25+ T cells and a downregulation of FoxP3 gene expression. Further studies have shown that CD4+CD25+ T cells are required to come into direct contact with CD8+ cells and secrete IL-4, IL-10, TGF-1, and other components of the CD4+CD25+ T cells. -The secretion of B-cell activator (a tumor necrosis factor family protein) may be related to AIH disease, and the higher the serum level, the higher the patient’s ALT, AST, and TBil levels. It has been recently reported that dysregulation of immunomodulatory molecules PD-1/PD-L1 may be related to the onset and evolution of AIH.
III. Clinical manifestations.
1. Clinical features.
AIH can occur at any age, about 70% to 80% of patients are female, the mode of onset is varied, more than half of patients have an insidious onset, can be asymptomatic, only detected during physical examination, or mild discomfort, followed by acute hepatitis mode of onset, or even fulminant hepatitis, but these “acute hepatitis” patients liver tissue The symptoms of AIH patients are not specific compared to other types of hepatitis, mainly weakness, sleepiness, discomfort in the liver, poor appetite, nausea, abdominal pain, pruritus, arthralgia, intermittent low-grade fever in some patients, and scanty menstruation in women. Some patients may have jaundice, rash, liver palms or spider nevus, etc. Heavy hepatitis is often accompanied by severe jaundice and prolonged PT; it is worth noting that some AIH patients often develop during pregnancy or after delivery, and some patients may have a stable disease during pregnancy and a sharp increase after delivery. About 17-48% of AIH patients are often combined with other autoimmune diseases, mainly thyroiditis, synovitis, duodenal ulcer, type 1 diabetes mellitus, rheumatoid arthritis, dry syndrome, inflammatory bowel disease, etc. The first three are the most common. Among them, the first three are the most common.
2.Biochemical examination.
Biochemical changes are mainly manifested as elevated serum transaminases and bilirubin, alkaline phosphatase and transpeptidase can be mildly elevated, elevated gammaglobulin is common, mainly elevated IgG, IgM is not significantly elevated or is mildly elevated, but the elevated level is lower than that of PBC, blood sedimentation can be mildly elevated or normal, recently a case was reported in which CA199, an indicator of response to pancreatic malignancy, was significantly elevated in AIH Recently, a case was reported in which CA199, an indicator of pancreatic malignancy, was significantly elevated in AIH and returned to normal after hormone therapy.
3. Autoantibodies and subtypes.
According to the difference of serum immunological indexes, AIH is often clinically divided into three different subtypes, with their own characteristics of clinical manifestations and treatment responses, ANA is the most common type of type I AIH, 67% of AIH patients are positive for ANA alone (13%) and/or positive for SMA (54%), ANA is not a specific antibody for AIH, many diseases, such as systemic systemic lupus erythematosus, dry syndrome The main target antigen of SMA is F-actin, and 87% of AIH patients are positive for SMA alone (33%) and combined. More than 70% of these patients are women younger than 40 years of age. About 40% of these patients develop as acute hepatitis, a few may present as fulminant, and 25% may present as cirrhosis, suggesting that some type I AIH has an asymptomatic, progressive subclinical stage.
The auto-target antigen of type I AIH in liver tissue is uncertain. Because anti-sialoglycoprotein receptor antibodies are often also present, it has been speculated that the sialoglycoprotein receptor may be one of the auto-target antigens of type I AIH, which is located on the surface of hepatocytes, but recent studies have found that anti-sialoglycoprotein receptor antibodies are also present in other types of AIH, are specific immunologic indicators for all AIH, and that positivity of this antibody is associated with disease activity. Anti-actin antibodies are currently considered to be relatively specific autoantibodies, and a multicenter clinical study in France found higher titers of anti-actin antibodies in AIH patients and elevations in non-AIH disease and normal controls, but at lower titers. However, this antibody has received increasing attention in the last two years, especially in SMA-positive patients, and it is believed that as the titer of SMA positivity increases, the rate of anti-actin antibody positivity also increases. All patients with SMA antibody titers greater than 1:160 were positive for anti-actin antibody, and some scholars have compared this antibody (examined by ELISA) with SMA (detected by indirect immunofluorescence). The specificity and accuracy of the two were found to be the same, but the sensitivity of the anti-actin antibody was significantly greater than that of SMA, and the detection method was simple.
Type II AIH is less common, accounting for about 20% of AIH in Europe and 4% of AIH in the United States; it is mainly characterized by positive anti-liver/kidney microsomal antibody I (anti-LKM-1). This type is mainly seen in women and children, but also in adults, accounting for about 20% of cases. The fulminant manifestations of this type are more common and are prone to progression to cirrhosis. Only the auto-target antigen of this type has been identified, namely cytochrome monooxygenase P450IID6 (CYP2D6). In vitro studies have shown that anti-LKM-1 antibodies can inhibit the activity of this enzyme, and the use of P450IID6 as an antigen can induce the establishment of an animal model of AIH. Another autoantibody, antibodies to liver cytosol type1 (anti-LC1), is often present in type II AIH. Patients who are positive for anti-LC1 are generally relatively older and have relatively severe lesions. The serum concentration of anti-LC1 often parallels the level of aspartate aminotransferase and is a sensitive indicator of disease activity. 15% of patients with type II AIH may also have autoimmune polyglandular syndrome type 1 (autoimmune polyglandular syndrome typel , APS1): ASP1 is mainly characterized by ectodermal ASP1 is characterized by ectodermal dysplasia, mucocutaneous Candida infection and multiple endocrine organ failure (parathyroid, ovarian and adrenal glands). The auto-target antigens of APS1 are P450IA2 and P450-IA6. Patients with APS1 respond poorly to hormonal therapy.
The signature autoantibody of type III AIH is the anti-soluble liver antigen/liver pancreas (anti-SLA/LP). The autoantigen it recognizes is a soluble 50KD protein molecule in the hepatocyte plasma, probably a transporter nucleoprotein complex. Because it is extremely similar to traditional type I AIH in terms of immunogenetic characteristics, clinical features and response to immunosuppressive therapy, many scholars advocate that it need not be classified as a special type, but only as a special type of type I AIH. This antibody is highly specific for AIH, but its positivity rate is only about 10-30%. Patients with AIH who are positive for this antibody often have severe and rapidly progressing liver lesions and are more likely to relapse when the drug is withdrawn.
Other antibodies include perinuclear anti-neutrophil cytoplasmic antibodies, which have a positivity rate of 50% to 90% in type I AIH and are extremely rare in type II AIH and are mainly IgG1. In AIH, the titer of perinuclear-type anti-neutrophil cytoplasmic antibodies is generally higher, but it has no guiding significance for the prognosis. One study found that the rate of positive anti-cardiolipin antibodies was significantly higher in AIH patients than in HCV, HBV, non-autoimmune liver disease and healthy controls, and was related to the degree of AIH progression, but not to the clinical characteristics of the patient.
4. AIH characteristics in children.
In a clinical analysis of 142 Caucasian pediatric patients, the common clinical symptoms were jaundice (58%), malaise (57%), poor appetite (47%), abdominal pain (38%), pallor (26%), type 1 in 73% of children, type 2 in 25% of patients, acute hepatitis in 52%, mild inflammatory manifestations in 10%, and cirrhosis in 38%. The percentage of children with acute hepatitis was 52% and 10% with mild inflammatory manifestations, while 38% showed cirrhotic changes. It is concluded that there is no gender difference in the incidence of AIH in children, and 90% show a strong inflammatory response or cirrhosis, which is more common than in adults.
IV. Pathology.
The pathological changes of AIH are mainly those of chronic hepatitis, with some typical changes but lacking specificity. Typical pathological changes of AIH are mainly manifested as interfaceitis, mostly moderate to severe, and in severe cases, there can be lobular hepatitis, as well as bridging necrosis between the confluence and confluence, and between the confluence and septum; the lobular interface, lobular necrotic area and the area around the confluence have a large number of inflammatory cells, mainly lymph The presence of eosinophils can be detected; in general, the inflammation is limited to the confluent area, but there is also a predominance in the central area of the lobule, and it is believed that this may be an early pathological change of AIH, or it may be another kind of AIH different from the common AIH. at the lobular interface, hepatocytes arranged in rose petals can be seen in the lobular necrotic area, often in the area with heavy inflammatory reaction and necrosis, suggesting that it may be a manifestation of post-necrosis hepatocyte regeneration. manifestation of hepatocyte regeneration after necrosis. Bile duct injury and hyperplasia are rare, but mild reversible changes of the bile ducts may be involved in more severe inflammation of the portal veins. Hepatic fibrosis is often seen around the confluent area and the hepatic sinusoidal area in the form of mild to moderate hyperplasia and less frequently in the form of severe manifestations, but when it enters cirrhosis, fibrous septa are seen.
V. Diagnosis and differential diagnosis.
There are no specific clinical or laboratory indicators to confirm the diagnosis of AIH. the diagnosis of AIH requires a combination of clinical features, laboratory tests and liver pathology to make the diagnosis. The International Autoimmune Hepatitis Group (IAIHG) revised the diagnostic criteria for AIH in 1999. The new diagnostic criteria have significantly improved the sensitivity and specificity of AIH diagnosis, but they are not necessarily accurate for a particular case, especially for children. The diagnosis of AIH in children is slightly different from that in adults. Since the level of autoantibodies in children is lower than that in adults, a positive autoantibody at any level, together with other necessary conditions, can diagnose AIH, but it should be emphasized that autoantibodies alone, regardless of level, cannot be the only condition for the diagnosis of AIH in either adults or children.
The diagnosis of AIH should first exclude lesions caused by liver-related viral infections, mainly hepatitis A, B, C, D or E virus infections; liver damage caused by EBV, herpes simplex virus, cytomegalovirus and herpes zoster virus infections; and drug-related liver disease, alcoholic liver damage, etc. should also be excluded. Also need to be associated with primary biliary cirrhosis, primary sclerosing cholangitis, Wilson’s disease, pigmentary disease and alpha-antitrypsin deficiency syndrome.
VI. Overlapping syndromes.
The overlapping syndrome of autoimmune liver disease refers to a patient having the clinical manifestations, serologic and histologic features of two autoimmune liver diseases in the same time period or course of disease. The most common include the overlapping syndromes of AIH/PBC and AIH/PSC.
The diagnosis of AIH/PBC overlap syndrome requires two or three clinical features from each of the following two diseases: (1) ALP > 2ULN or GGT > 5ULN in AIH; (2) positive AMA; (3) pathological damage with “red tubule sign” on histology. 5ULN; (2) IgG > 2ULN or SMA positive; (3) histology showing moderate or severe periportal fragmentation necrosis.
It is believed that AIH/PBC overlap syndrome is actually a manifestation of AIH, or PBC disease progressing to a certain stage, where the liver histological changes show AIH, but the immunological changes (positive anti-mitochondrial antibody M2 type) are consistent with PBC changes, which is a typical AIH/PBC overlap syndrome. The clinical course and response to treatment in this overlap syndrome is similar to that of typical AIH.
The term “autoimmune cholangitis” for anti-mitochondrial negative PBC is controversial, and the application of immunospot and ELISA methods to detect anti-mitochondrial and other antinuclear antibodies relatively specific for PBC (e.g., anti-SP100 and anti-GP210) yields a range of different autoantibodies, suggesting the complexity of this overlap syndrome. The complexity of this overlap syndrome.
The differentiation and classification of AIH/PSC is more difficult, as it has been suggested that the term “autoimmune sclerosing cholangitis” can be used for pediatric patients, but has not been standardized for adult patients. In patients with AIH, the presence of histological bile duct damage, elevated bile duct enzymes such as ALP and GGT, or clinical manifestations such as pruritus and inflammatory bowel disease, and non-response to immunosuppressive therapy should be suspected for the presence of AIH/PSC overlap syndrome.
VII. Treatment.
Since the 1970s, several foreign randomized controlled studies with large samples have shown that treatment of more severe AIH with glucocorticoids alone or in combination with azathioprine can significantly improve the clinical symptoms, biochemical tests and liver pathology of patients and prolong their survival. Many studies have shown that patients with AIH have a survival rate of 50% at 3 years and 10% at 10 years without treatment. 60% to 80% of patients can be successfully treated with hormonal therapy, with a survival rate of 90% at 10 years, 80% at 20 years in patients without cirrhosis, and 40% at 20 years after the development of cirrhosis, and once a complete response is achieved, maintenance therapy with azathioprine alone is successful in more than 90% of patients. Once complete response is achieved, maintenance therapy with azathioprine alone is successful in more than 90% of patients. The slow progress of new drugs and regimens for the treatment of AIH in recent years poses a great challenge for the selection of initial and maintenance regimens, relapse treatment, side effects and tolerability of drugs, patient compliance, and treatment during pregnancy.
The American Academy of Liver Diseases (AASLD) provides detailed descriptions of its indications, treatment regimens, treatment endpoints, treatment of relapse after drug discontinuation, and treatment of poor efficacy, which have important clinical value. Currently, there is a lack of recommendations for the treatment of AIH in China, and domestic experts suggest that the recommendations of AASLD can be referred to, but they should not be blindly copied and should be individually adjusted according to the patient’s specific situation.
First of all, it is necessary to clarify which patients need treatment. The condition of liver histology is the key factor to decide the treatment, as long as there is interfaceitis, regardless of ALT and GLO high or low, cortisol or cortisol combined with azathioprine should be applied, because sometimes ALT and GLO high or low do not correlate well with the extent of liver injury. In the presence of inflammation in the portal area only, treatment depends on ALT and GLO levels and clinical symptoms. In asymptomatic patients with only mild portal zone inflammation without fibrosis, treatment may be withheld, but should be reviewed at any time, as various clinical features, including pathological changes, may be exacerbated and the decision to treat may be adjusted at any time.
Next, the question of which treatment option to choose should be considered. The current induction therapy for AIH mainly includes two regimens: hormone therapy alone and low-dose hormone plus azathioprine combination therapy. Hormone therapy alone consists of starting with prednisone 60 mg/d orally, changing to 40 mg/d after one week, and then gradually decreasing to 10 mg/d for maintenance; adding azathioprine 50 mg/d orally while treating with prednisone 30 mg, gradually decreasing to 10 mg for maintenance after 2 weeks, and continuing with azathioprine 50 mg/d. Controlled clinical studies have shown that prednisone alone or low-dose prednisone plus azathioprine combination therapy is effective in all cases of AIH. Several factors influence the efficacy of hormones, such as patients with early age of onset, acute onset, deep jaundice, and poor response to hormones in type 1 AIH with HLADRB1*03 genotype.
Generally, if the diagnosis is correct, the transaminases may drop to normal within 3-6 months after treatment. However, liver pathology changes 3-6 months later than clinical and biochemical parameters, and clinical remission does not imply improvement in liver histology. Although some patients are in sustained remission after discontinuation, most patients require long-term drug therapy, especially into cirrhosis, and children with type II AIH rarely do not recur after discontinuation. Some patients are stable for months or even years after their disease has been controlled. These patients do not need to take anti-inflammatory drugs for a long time, and regular review every 3-6 months is essential. One source on how to avoid relapse concluded that normal liver histology, including the absence of specific interfaceitis or active cirrhosis, must be achieved before consideration can be given to phasing out the drug.
The use of other drugs has been reported less frequently. Cyclocytin A has been used successfully in adult patients with hormone-resistant AIH, and a regimen of cyclocytin A followed by glucocorticoids and azathioprine has been considered effective in children with AIH, as well as alone, with cyclocytin A alone being 94.5% effective in treating children with AIH. Tacrolimus may improve the degree of intrahepatic inflammation and fibrosis in patients with AIH and may be considered in patients who have failed hormone therapy or are intolerant to hormones.
No particular efficacy has been reported for the treatment of overlap syndrome, and reports of the efficacy of hormone therapy for AIH/PBC are conflicting, with treatment of anti-mitochondrial antibody-positive AIH generally considered to be relatively ideal. Although UCDA is effective in the treatment of PBC, it is uncertain whether it improves the degree of liver inflammation in the overlap syndrome. Although ursodeoxycholic acid (UDCA) has been shown to improve AIH biochemical parameters in some clinical trials, some randomized controlled studies have shown that it is a failure in the treatment of AIH. Therefore, it has been reported that the efficiency of hormone and UCDA alone is only about 50%, while the combination therapy is more efficient in the overlapping syndrome of AIH/PBC.
Liver transplantation is the only option for patients with immunosuppressive therapy that is ineffective or intolerant and for patients with end-stage liver disease, with a 5-year survival rate of about 80-90% and a 10-year survival rate of about 75%, and a better long-term prognosis for living liver transplantation than for dead liver transplantation has been reported. recurrence after AIH transplantation is not uncommon, reported to be about 20-42 The recurrence of liver histology is earlier than the recurrence of clinical and biochemical indicators, and the recurrence is related to the post-transplantation immunosuppressive application scheme. Recurrent AIH is generally mild, rarely leads to cirrhosis and graft failure, and is more easily controlled by immunosuppression.
Section 2: Advances in primary biliary cirrhosis research.
PBC is is a chronic inflammatory liver disease associated with autoimmunity. It eventually leads to cirrhosis and even hepatocellular carcinoma. It is more common in women, with a male to female ratio of 1:8-10, and its peak incidence is around 50 years of age, and it is rare below 25 years of age. The pathogenesis is unknown and may be related to genetic, environmental, immune and other factors, often accompanied by other autoimmune diseases, such as dry syndrome, autoimmune thyroiditis, etc. The pathological changes are mainly in the liver and, to a lesser extent, in the salivary glands. Chronic nonsuppurative cholangitis of the interlobular bile ducts, epithelioid granulomatous nodules in the peripheral bile ducts and high titers of anti-mitochondrial antibodies (AMA) in the serum are the main features.
I. Epidemiology.
The disease is distributed all over the world with regional aggregation. The prevalence is higher in western countries, about 1.9-15.1/100,000, and the annual incidence is about 0.39-1.5/100,000, and the trend is increasing year by year.
II. Pathogenesis.
1, genetic factors.
The incidence rate is significantly higher in those with family history (the incidence rate of the first offspring of patients is 570 times higher than that of the general population). It is not uncommon for 1-6% of patients to have at least one member of the family with the same disease, and it is not uncommon for mothers and daughters and sisters to have the disease at the same time. The incidence of PBC in monozygotic twins is 63%, which confirms that the development of PBC is inseparable from genetic factors, but unlike other autoimmune diseases, no association with MHC alleles has been found so far.
2. Environmental factors.
The molecular mimicry theory is believed to explain the pathogenesis of PBC. Molecular mimicry means that microorganisms have antigenic epitopes with the same or similar amino acid sequence or some local conformations as human autoantigens, and lymphocytes targeting this epitope may recognize the corresponding autoantigens after being activated due to microbial infection, causing autoimmune response and thus tissue and organ damage. It is believed that Escherichia coli is the most studied microorganism related to the pathogenesis of PBC, and experiments have shown that anti-human mitochondrial PDCE can also react with mitochondrial PDCE of Escherichia coli, but the titer is relatively low.
Other chemicals may also play a role in molecular mimicry. Autoantibodies isolated from patients’ peripheral blood can react with many environmental compounds, and their binding power is much greater than the immune binding power of the patient’s antigenic antibodies, which are mostly halogenated compounds, mainly found in pesticides and detergents. Mitochondrial antibodies can be produced at high titers when these chemicals bind to calf serum proteins, but no loss of liver was found after 18 months, so it is uncertain whether these chemicals can induce PBC.
3. Immunoreactivity of anti-Mitochondria antibody (AMA) with antigen.
The target antigens of AMA are members of the family of acid dioxide dehydrogenases, including four dehydrogenases: pyruvate dehydrogenase complex E2 subunit (PDCE2) side chain acid dioxide dehydrogenase, ketoglutarate dehydrogenase and dihydrothioctamidine dehydrogenase, all four dehydrogenases are involved in the oxidative phosphorylation process, and most patients AMA reacts with PDCE2 immunologically, and AMA reacts with the other three dehydrogenases in a small number of patients.
PDCE2 is located in the inner side of the cell mitochondrial matrix and catalyzes the oxidative dehydrogenation of ketoacid substrate, which is actually a huge complex including more than 60 subunits, PBC is the only disease in which autoimmune B cells and T cells are found to react with PDCE2. The proliferating B-cell clones in PBC patients are mainly directed against this linear sequence of amino acid residues, especially the 5 or 6 amino acid residues that are directly associated with antigen-antibody binding. However, the mechanism by which the PDCE2 212-226 amino acid residue sequence becomes immunoreactive with PBC-specific anti-mitochondrial antibodies remains poorly understood. This antigenic determinant is located in the N-terminal lipid region, and synthetic oligopeptides or proteins can be immunoreactive with this segment of amino acids. The application of synthetic proteins can be used as diagnostic reagents to detect anti-AMA, and if positive, it supports the diagnosis of PBC or predicts the possibility of PBC in 5-10 years.
4. T cell-mediated mitochondrial damage.
Immunohistochemical study of liver tissue biopsy specimens from PBC patients revealed that infiltrating cells in the liver of PBC patients included NKT cells, B cells, CD4 + T cells, CD8 + T cells, monocytes, dendritic cells, eosinophils, etc. Infiltrating auto-invasive CD3+ CD57+ T cells were significantly increased around the damaged bile ducts compared to other diseases and normal liver, CD8+ T cells, eosinophils were more abundant in the initial stage of the disease, aggregation of eosinophils in the bile duct area and increase of peripheral blood eosinophils were characteristic of PBC patients in the early stage, while a significant increase of CD4+ T cells was observed in the progressive stage of the disease. These T cells are self-reactive cells specific for PDCE2, yet they are present in the peripheral blood only infrequently.
T cells that infiltrate the liver specifically target PDCE2, and there are two types of T cell clones that primarily target the PDCE2 1632176 amino acid residue sequence: a co-stimulation-dependent and a co-stimulation-independent type. Both types of T-cell clones present in PBC patients have the same toxic effect in lysing bile duct epithelial cells. The formation of cytotoxic T-cell clones targeting the sequence PDC2E2 1592167 has also been shown in PBC patients. This sequence is very similar to the antigenic determinants recognized by MHC II-restricted CD4+ cells. Although the function of CTLs targeting this sequence is less clear, PDC2E2 1592167-specific CTLs were found to be 10-fold higher in the livers of PBC patients than in peripheral blood, and there was also a significant increase of such CTLs pre-T cells in the peripheral blood of PBC patients in the early stages of the disease.
The activation of T cells in PBC patients was followed by an increase in cytokine expression by Th1 and Th2 in the liver, an increase in serum IL-28 levels in progressive PBC, a decrease in the number of IL-24-producing CD4+ cells in peripheral blood, and an abnormal expression of CK27: normal hepatic CK27 was almost exclusively expressed The expression level of CK27 correlated with serum bilirubin, but not with liver enzymology.
5. Bile duct epithelial cell injury.
A large number of apoptotic cells were present in the damaged bile duct area in PBC patients. It was found that the apoptotic cells in PBC patients were mainly bile duct epithelial cells, while in other autoimmune liver disease patients, it was mainly hepatocytes that were apoptotic. Further study of the damaged bile duct area in PBC patients showed that the expression of Bcl22 and Mcl21 proteins in the damaged area was decreased, while the expression of WAF1 (wild-type P53 activating factor 1) was significantly increased, Bcl22 and Mcl21 proteins are inhibitors of apoptosis, and their decrease directly led to the decrease of apoptosis threshold and increased the apoptosis of bile duct cells. As the reversible cell cycle (G1, G2) inhibition is due to the upregulation of WAF1, a large number of cholangiocytes are in G1 and G2 phases, the differentiated cholangiocytes are reduced, and the apoptotic cells are significantly increased, which shows the destruction and disappearance of cholangiocytes.
It is puzzling that mitochondrial proteins are present in all cells, so why the damage only targets the cholangiocytes of PBC? This is because the metabolic process of PDCE2 in cholangiocyte apoptosis is different from other cells, and the redox state of the cells, especially whether the lysine-esteryl part of PDCE2 can be modified by glutathione, is crucial. Thus, the antigenic determinant cluster is not degraded during apoptosis, but is presented as antigen to immune cells and autoimmune reaction occurs. iii.
50-60% of patients have no obvious discomfort at the time of PBC diagnosis, but 1/3 of them start to have symptoms after 2-4 years. Weakness and skin scratching are the first and most important symptoms in most patients. The itching can be localized or generalized and is often worse at night, during sweating, etc. The exact mechanism is unknown and the jaundice often deepens slowly as the disease progresses. Other symptoms include hyperlipidemia, osteoporosis, nutritional deficiencies, fat-soluble vitamin deficiencies, and other autoimmune diseases such as Sjögren “s syndrome and scleroderma. In severe cases, steatorrhea may develop, and in cases of cirrhosis, ascites, upper gastrointestinal bleeding, and hepatic encephalopathy may develop. Patients with histologic lesions that have progressed over time have an increased risk of developing primary hepatocellular carcinoma. Other common diseases associated with PBC include interstitial pneumonia and renal tubular acidosis.
Most patients have no positive signs on physical examination, but in patients with persistent progression, signs such as patient desquamation, dullness, hyperpigmentation, hepatic palms, spider nevi, and yellow tumors may be found. Liver accounts for approximately 70% of patients, splenomegaly is relatively uncommon, and persistent deepening jaundice is often indicative of a more advanced stage of disease.
Elevated ALP is the most common biochemical abnormality in PBC. Elevated serum bilirubin is dominated by direct bilirubin, and elevated hyperbilirubinemia is a manifestation of advanced PBC and a good indicator of the prognosis of PBC.
IV. Pathological changes.
The typical pathological manifestation is non-purulent injurious cholangitis or granulomatous cholangitis, with destruction of small bile ducts as the main cause, and microscopically mainly chronic non-purulent destructive changes of the intermediate bile ducts, and reduction of interlobular bile ducts. According to the evolution of the lesions in the confluent area, there are 4 stages, each of which may appear one after another or overlap. Stage I: Non-purulent destructive cholangitis stage, with inflammatory damage and necrosis of bile ducts, crumbling of bile duct cells with vacuole-like changes, and granuloma-like lesions, the latter mainly composed of lymphocytes, plasma cells, histiocytes, eosinophils and giant cells. Serum IgG and IgM are elevated, and there are immune complexes and C3 deposits around the bile duct injury area. Stage II: Small bile duct hyperplasia, with inflammation spreading from the portal lobules to the periphery, and biliary debris-like necrosis, manifested by vacuolation of periportal hepatocytes and infiltration of foamy macrophages, as well as increased fibroblasts and collagen, and proliferating hepatic fibrous tissue. Stage III: scar formation, with fibrosis and scar tissue, and adjacent portal veins connected by fibrous septa. Stage IV: cirrhosis, the fibrous septum between the confluence area extends and interconnects, the fibrous tissue extends into the lobules and divides the lobules, local hepatocyte necrosis and nodules appear, often manifested as small nodular cirrhosis.
V. Immunological features.
The elevation of immunoglobulin in PBC patients is mainly IgM, and positive serum AMA is the characteristic immunological marker for PBC diagnosis. The specificity and sensitivity of AMA positive test in PBC cases are more than 95%, and it is often positive before the appearance of clinical symptoms. About 50% of PBC cases are positive for ANA and SMA. Positive ANA of perinuclear and nuclear dot type is important for the diagnosis of PBC. Many other autoantibodies can also be found, including anti-platelet antibodies, anti-thyroid antibodies, anti-adherent antibodies, anti-SSA (Ro) antibodies, anti-SSB (L a) antibodies, anti-2A enolase, lymphocytotoxic antibodies, etc.
VI. Treatment.
1. Ursodeoxycholic acid (UDCA).
UDCA is currently the most effective drug for the treatment of PBC, and the recommended dose is 13-15 mg/kg/day, divided into 2-3 doses. The mechanism of UDCA for the treatment of PBC is currently considered to have three main aspects: promotion of bile secretion, anti-apoptosis of hepatocytes and bile duct epithelial cells, and immunomodulatory effects. The results of a large randomized controlled study showed that UDCA was effective in reducing biochemical parameters in patients, delaying liver transplantation and reducing mortality, and that long-term administration of UDCA was safe, with only a few minor adverse effects such as weight gain, hair loss, bloating, and diarrhea. Two meta-analyses including many clinical studies in the last two years have shown that UDCA can delay the progression of the disease and is effective in 25-30% of patients, and the life expectancy of PBC patients taking UDCA is similar to that of controls of the same age and sex over 20 years. However, there are still many patients whose disease continues to progress despite taking UDCA, so it is necessary to switch to or combine other drugs.
2. Immunosuppressants.
Colchicine is also effective in improving the biochemical parameters of patients, but less effective than UDCA. If the effect of taking UDCA for one year is not good, colchicine can be added. A recent clinical meta-analysis showed that colchicine can effectively reduce the occurrence of complications of cirrhosis, thus delaying the time to liver transplantation. Methotrexate has been used as an immunosuppressant to treat PBC, but its efficacy has yet to be further evaluated and should only be used for patients who have not been treated with the above two types of drugs for one year, and its own course should not exceed one year. budesonide has been shown to be effective in improving the histological and biochemical indices of PBC, but its side effect of aggravating osteoporosis limits its application, and silymarin has been shown to be ineffective.
3. Symptomatic management.
Skin scratching can be treated with abciximide, 8-24g/day, which is effective for most patients; those who are ineffective can consider applying rifampin 15mg twice daily; histamine inhibitors taken at bedtime are useful for mild scratching, and opiate receptor antagonists such as naloxone are indicated for those who are ineffective to the above treatments. Plasma consideration may be considered when all medications are ineffective. Osteoporosis is more common in PBC and there is no specific treatment available. For menopausal women estrogen replacement therapy can improve osteoporosis. Pregnancy in patients with PBC has been rarely reported. In most cases, pregnancy leads to pruritus or worsens pruritus, mainly due to the cholestatic effect of high estrogen levels, for which there is no better treatment. The safety of all treatments for PBC in the first trimester is unknown and should be discontinued in the first trimester. uDCA is safe in the second trimester and is effective in improving the cholestatic symptoms of the mother.
4. Liver transplantation.
Liver transplantation is the only treatment effective option for late stage liver failure in PBC. The survival rates at 1 and 5 years are 92% and 85%. The symptoms of PBC completely disappear after transplantation, but AMA is still positive. The relapse rate of PBC at 3 and 10 years after transplantation is 15% and 30%.
Section III Progress in primary sclerosing cholangitis research.
PSC is a chronic cholestatic hepatobiliary disease characterized by diffuse inflammation and fibrotic destruction of intra- and extrahepatic bile ducts, deformation and segmental narrowing of bile ducts, with progressive progression of the disease, which may eventually lead to liver failure and bile duct cancer. The cause of this disease is not yet clear, but may be related to genetics, immunity, infection, intestinal toxin absorption, bile duct ischemia, toxic bile acids and other pathogenic factors. The recent research progress on the etiology, diagnosis and treatment of primary sclerosing cholangitis is introduced.
I. Epidemiology of primary sclerosing cholangitis.
The worldwide prevalence of PSC is unknown, and the annual incidence and prevalence of PSC in the United States are estimated to be 0.9/100,000 and 1-6/100,000, respectively. In Canada, a survey of Calgary’s healthy community residents from 2000 to 2005 showed an incidence of 0.92/100,000, including 0.15/100,000 for those with small bile duct lesions, 0.23/100,000 for children, and 1.11/100,000 for adults, and the incidence of PSC in Crohn’s disease and ulcerative colitis are similar. A few have comorbidities: 6.1% with bile duct cancer, 4.1% with pancreatitis, and 4.1% with Crohn’s disease. Spain reported an incidence of 0. 07 per 100,000 P-years and a prevalence of 0. 22 per 100,000, which are much lower than in the United States, United Kingdom and Canada, suggesting possible geographical differences. Of the 53 cases of PSC described by Kingham et al, 33 (62%) were combined with inflammatory bowel disease (30 ulcerative colitis and 3 Crohn’s disease), with an incidence of 0. 91/100,000 P-year and a prevalence of 12. 7/100,000.
II. Etiology and pathogenesis.
The etiology and pathogenesis of the disease is not fully understood, there are a variety of theories to explain the occurrence and development of the disease, but can not yet make a final conclusion, is divided into the following.
1, genetic factors.
The concentration of family members and the fact that PSC is closely related to human leukocyte antigens (HLA) suggest an important role for genetic factors in the development of PSC. Wiencke K et al. reported that the extended HLA DRB3 haplogroup may be associated with PSC, and found that individuals carrying HLA DR6 were more likely to develop PSC with the presence of a D6S265 in the chain imbalance region, and they also found that individuals carrying HLA DR11 individuals were found to be protective against progression of PSC. PSC has also been reported to be associated with polymorphisms in the TNF2α receptor gene, with a significant correlation between the base G substitution A at position 308 of the TNF2α gene and susceptibility to PSC. Polymorphisms of matrix metalloproteinases may affect both susceptibility and disease progression. The above facts suggest an intrinsic genetic basis for the occurrence and development of PSC.
2. Immune factors.
There is more support for autoimmune abnormalities leading to pathogenesis, as with most autoimmune diseases, and although there is a theoretical basis for immune-mediated injury, there is no direct evidence yet that it can lead to PSC. available data suggest the presence of multiple autoimmune abnormalities in PSC patients, including humoral and cellular immune abnormalities. The former manifests as increased blood γ2 globulin, increased immunoglobulin 2M (IgM) ratio, increased circulating immune complexes, accelerated complement C3 metabolism, and the presence of multiple anti-autoantibodies in peripheral blood. The abnormalities in cellular immunity are characterized by a significant increase in the number and percentage of B cells, a decrease in the total number of T cells and a significant increase in the Leu23α/Leu22α ratio. Immunologic studies have revealed enhanced expression of adhesion molecule 21 (ICAM21) and intrahepatic lymphocyte function-associated antigen (LFA21) in bile duct epithelial cells of PSC patients, both of which contribute to the attachment of T lymphocytes to antigen-expressing cells, thereby mediating bile duct cell injury. Although PSC patients show expression of the HLA2 class II antigen HLA2DR/HLA2DP in bile duct endothelial cells, this abnormal expression is nonspecific, seen in cholestatic diseases of multiple etiologies, and is considered to be a secondary phenomenon.
The immunopathogenesis of PSC, as with most autoimmune diseases, is unclear, and although there is a theoretical basis for immune-mediated injury, there is no direct evidence that it leads to PSC. immunological studies have found that the inflammatory cells infiltrating the hepatic hilar and peribiliary areas are predominantly T-lymphocytes, with the majority of the hilar area being T-lymphocyte subtypes with immune helper induction CD4, and another subtype of CD8 cells, which suppress immunity and cytotoxicity, were mainly clustered around the bile ducts [11,12].
Recently, Karrar A reported that anti-biliary epithelial cell antibodies (BEC-Ab) could be detected in PSC, and that BEC-Ab induces Toll-like receptor (TLR) expression after binding to biliary epithelial cells and initiates extracellular signal-regulated kinases, thus inducing biliary epithelial cells to produce and secrete a large number of cytokines and inflammatory chemokines, including IL-1β, IL-8, IFN γ, TNF-α, granulocyte-macrophage colony-stimulating factor, etc. These cytokines can recruit a large number of inflammatory cells to reach the bile duct tissue, and therefore it is believed that bile duct epithelial cells are not only the target tissue for immune attack, but also active participants and regulators of this response.
Certain cytokines may be involved in the progression of the disease. Mendes FD reported that peripheral blood levels of IL-4 were higher in PSC patients than in controls, and those with high IL-4 were also characterized by high bilirubin, high ALP, and a short time from onset to liver transplantation.
3. Infection and intestinal toxin absorption.
PSC and inflammatory bowel disease (IBD) are closely correlated, and IBD as a potential pathogenic factor has long attracted the attention of a large number of researchers. It has been hypothesized that the increased permeability of the mucosal barrier in the inflamed intestine, the increased absorption of bacterial endotoxins and toxic bile acids, and the increased production of tumor necrosis factor (TNF) due to the activation of Kupffer cells in the liver, and the excessive production of TNF can lead to bile duct destruction and hyperplasia similar to the pathological changes of PSC [12-13 ]. However, there is also unsupportive evidence, such as that the colon is normal in 25% of PSC patients, that PSC can occur before colon disease, and that resection of the colon has no effect on the course of PSC. Although cytomegalovirus has been reported to cause PSC in patients with acquired immunodeficiency, there is no evidence that it can cause PSC in immunocompetent patients. Recently, it has been reported that Helicobacter pylori may be involved in the pathogenesis of PSC, 9/56 cases of PSC bile can be detected in the DNA of Helicobacter pylori, there are also reports of Candida can be cultured in patients with PSC, and therefore speculate whether it is related to the pathogenesis of PSC, but of course these reports need a lot of clinical confirmation, can not be excluded from these viruses and bacteria may also play a role only in secondary damage.
4. Other.
The onset of PSC in children may be related to cystic fibrosis, especially in patients with cystic fibrosis complicated by dysfunctional intra- and extracellular transduction of chloride ions are more likely to develop PSC; recently Fickert P et al. argued that in view of the sclerosis of the small bile ducts in patients with PSC and arteriosclerosis similar to the “bile duct arteriosclerosis” theory, that may be when The toxic components of the bile duct wall destruction leads to bile duct inflammation and sclerosis, just like arteriosclerosis because of the large accumulation of lipids and lipoproteins in the blood to harden the blood vessels, but this theory needs more evidence to support.
III. Clinical and diagnostic.
PSC patients are mostly male (the ratio of male to female is about 2:1), and the median age of onset is less than 40 years, although it can be seen in children, but it is rare.
1. Clinical manifestations: Typical symptoms include jaundice and pruritus, as well as non-specific symptoms such as fatigue, poor appetite, nausea and weight loss. Because many patients have no specific symptoms, misdiagnosis of PSC is more common, with a mean misdiagnosis time of 8.4 months and advanced manifestations of cirrhosis, liver failure, and portal hypertension. Most patients are accompanied by IBD, with ulcerative colitis being the most common.
Notably, with the development of endoscopic techniques enabling the diagnosis of more and more asymptomatic cases, the strong correlation between PSC and IBD has prompted physicians to screen for patients with IBD with abnormal liver function, resulting in an increasing number of patients being diagnosed early. The latest reported percentage of patients with asymptomatic PSC is 45%, which differs from the 10-25% reported earlier. Overall, there was no difference in the incidence of IBD, mean age at onset, or male-to-female ratio between symptomatic and asymptomatic PSC patients. However, in a comparison of 134 asymptomatic patients with 171 symptomatic patients, Broome et al. found that the former were younger, more often male, more closely associated with IBD, and had less extrahepatic bile duct involvement.
The ratio of ALT to AST is of greater significance in determining the prognosis of PSC, as the ALT/AST ratio is greater than 1, often suggesting that the time to cirrhosis and liver failure is shorter in PSC. With the progression of the disease can appear higher bilirubin, the appearance of cirrhosis.
3, immunological tests: hyperglobulinemia, in which IgM is elevated, autoantibody titers can also be increased, such as ANA, but no specific antibodies, previously considered perinuclear anti-neutrophil cytoplasmic antibodies have some value in the diagnosis of PSC, but currently found that other liver diseases, such as autoimmune hepatitis, primary biliary cirrhosis and other patients whose positivity rate is higher, its diagnostic value is not significant.
4, histological changes: due to non-specific histological changes in the liver of patients with PSC, so liver biopsy is of little value for the diagnosis of PSC. Histological changes in this disease include: peribiliary fibrosis, inflammation in the confluent area, peribiliary hepatitis and parenchymal changes. As the disease progresses, fibrosis in the confluent area increases. Interlobular bile ducts decrease, and interlobular septa form and eventually manifest as biliary cirrhosis. Depending on the degree of abnormality, the disease can be histologically classified into stages I-IV. Stage IV is biliary stasis cirrhosis.
5.Imaging: ERCP is currently the best method to diagnose PSC. Retrograde cholangiography (ERCP) is the most common examination method, and percutaneous hepatic puncture cholangiography (PTC) is generally used for those who fail endoscopy. Magnetic resonance cholangiography (MRCP) is an increasingly popular test, which is less painful and more acceptable to patients than ERCP, but most scholars believe that it is inferior to ERCP, and the new Berstad AE, which compared the difference between the two in the diagnosis of PSC, found no significant difference in sensitivity, specificity and accuracy, but the images of ERCP were clearer.
The characteristic radiological features of PSC are irregular, multiple localized stenoses and dilatations of the bile ducts, and diffuse stenoses of the bile ducts with normal dilated segments forming typical “bead-like” or “dead branch”-like changes. In a recent study of 394 patients in five European medical centers, 73% of them involved intrahepatic and extrahepatic bile ducts, less than 1% had intrahepatic bile duct changes only, and 20% had extrahepatic bile duct changes only. One type of PSC, called “small bile duct”, is very difficult to diagnose because the affected bile ducts are so small that ERCP cannot reveal the abnormality. This patient has IBD, liver function tests show biliary stasis, and a liver biopsy resembles the usual PSC. The diagnosis of PSC in children is difficult because many of the manifestations are more like autoimmune hepatitis, and in differentiating it from the latter, ERCP should be performed more frequently. Prytz H applied positron tomography to dynamically observe changes in bile duct strictures, which can also lead to earlier detection of bile duct cancer. Other scholars applied cholangioscopy or applied bile duct brush under ERCP for exfoliative cytological examination can also significantly improve the diagnosis rate of bile duct cancer.
IV. Treatment.
1. Symptomatic treatment.
(1) Skin pruritus: The treatment of skin pruritus can be based on the degree of pruritus and the condition of the selected drugs, such as local skin medication for localized skin, such as systemic skin pruritus can choose to apply bile acid binding resin, cauleenamine, biliary amine, etc. These drugs can reduce the reabsorption of bile salts, pruritus is very effective, rifampin mediates the enzymes of microsomal drug oxidation system, promoting the metabolism of endogenous itch-causing substances; its in The antiallergic drugs, such as paracetamol and loratadine, can also relieve pruritus, but are less effective in heavier patients; opioid antagonists can block the effect of excessive endogenous opioid agonists in biliary sludge, and are effective in biliary sludge-related pruritus. It is effective for biliary-associated pruritus. However, withdrawal reactions should be noted.
(2) malaise: because the cause of malaise is still unclear, so there are no drugs for this symptom, early scholars believe that the malaise of PSC is not as serious as imagined, may be related to post-PSC depression, but new research shows that although the combined depressive manifestations of PSC up to 42%, but only 3.7% of those who really reach depression, and the general population prevalence is similar.
(3) Osteoporosis: Strictly speaking, osteoporosis is not a complication specific to PSC. Many chronic liver diseases, especially at the stage of cirrhosis, have varying degrees of osteoporosis, and osteoporosis is particularly pronounced in PBC patients, with various risk factors for osteoporosis: cirrhosis, degree of cholestasis, and corticosteroid use. There is no specific drug treatment. Patients should pay attention to their lifestyle habits, such as limiting alcohol consumption, regular weight-bearing exercises, quitting smoking, eating a reasonable diet to avoid low body mass index, and taking calcium and vitamin D supplements.
2.Ursodeoxycholic acid (UCDA).
Under normal physiological conditions, UDCA accounts for about 3% of the bile acid component, and the content increases with the dose of the drug, reaching a plateau at a dose of 22-25 mg/kg/d. The increased bile flow and excretion of bile acids in bile and urine can protect cells, stabilize cell membranes, reduce abnormal HLA expression in bile ducts, improve T-cell responses, reduce immunoglobulin and cytokine production, and replace more toxic hydrophobic endogenous bile acids. Various guidelines recommend a dose of 13-15 mg/kg/d for the treatment of PBC, but there is no unified standard for the dose of PSC, which is divided into two dose groups, one for the standard dose, 8-15 mg/kg/d, and one for the high dose, 20-30 mg/kg/d. The high dose group is better than the standard dose group in improving the biochemical indexes and liver pathology of patients, but it is more effective in stopping and delaying the development of cirrhosis, portal sclerosis, and hepatopathy. However, it has no effect on stopping and delaying the time of cirrhosis, portal hypertension and liver transplantation in patients, and there is still disagreement on whether it can reduce the incidence of bile duct cancer.
3.Immunosuppressants.
The more commonly used immunosuppressants include glucocorticoids, azathioprine, cyclosporine, aminopterin, etc. However, whether these drugs are applied alone or in combination, although there are reports that they can improve the biochemical indexes of patients, there is no clear evidence-based medical evidence to confirm their efficacy. Recently, it has been reported that the application of tacrolimus for the treatment of PSC, 0.05 mg/Kg, twice daily, for one year, AST, ALP, and TBil were significantly decreased, unfortunately, 31% of patients had different degrees of side effects.
4.Endoscopic treatment.
Treatment includes transduodenoscopic incision of Oddi’s sphincter, probe bar or balloon tube to dilate the biliary stricture, placement of internal stent stricture expansion placement of stenting, bile duct lithotomy, endoscopic nasobiliary drainage and lavage and other measures. The aim is to relieve biliary obstruction and alleviate secondary damage, which has proved to be an effective method to relieve jaundice and infection caused by major biliary strictures, but it has little effect on high biliary strictures, and only dilation, irrigation or drainage, which has more chances to cause restenosis and is less effective. The literature reports that endoscopic treatment can improve clinical, biochemical and biliary imaging abnormalities, but has no significant impact on patient survival.
5. Palliative surgical treatment.
Palliative surgery is often used for bile duct dissection and lithotomy, dilation and T- or U-tube drainage, resection of strictures or unresected bile-intestinal anastomosis, and various procedures to relieve portal hypertension. The purpose is to relieve biliary obstruction and treat other complications. However, there are two major disadvantages of surgical treatment: firstly, surgery itself increases the risk of patients, especially postoperative biliary infection, and is basically ineffective for patients with high obstruction; secondly, surgery sets obstacles to later liver transplantation, which increases the difficulty and risk of liver transplantation. Therefore, endoscopic treatment of bile duct obstruction and infection is currently advocated to avoid surgery as much as possible and to create favorable conditions for liver transplantation.
6.Liver transplantation treatment.
Liver transplantation has been recognized as the only and best treatment option for advanced PSC. Due to the high success rate and satisfactory outcome, many transplant centers have listed PSC as one of the best transplant recipients. The 5-year survival rate after liver transplantation can reach about 80%, but there is no definite conclusion when is the best time for liver transplantation for patients with recurrent cholangitis due to decompensated hepatic sclerosis, portal hypertension and high bile duct extensive stenosis. However, it is also believed that patients with intractable pruritus, severe wasting, and persistent bilirubin elevation may be recommended for liver transplantation, although liver biopsy confirms that cirrhosis has not yet developed.
Bile duct cancer is the key to the success of liver transplantation, once the cancer of PSC occurs, the efficacy of liver transplantation is greatly reduced, the 5-year survival rate is only 26.7%, bile duct cancer is a serious complication of PSC, some reports found that patients with bile duct cancer accompanied by PSC accounted for 20-30%, up to 50% within a year, many patients with PSC and bile duct cancer did not occur cirrhosis, but bile duct stenosis exists, if single or cancerous disease The survival rate of liver transplantation for 3-5 years is 35% for smaller patients, and the administration of 5-FU or slow-release iridium 192 radiotherapy before transplantation can significantly improve the efficacy. The survival rate with this regimen is 79% at year 1, 61% at 3 years, and 58% at 5 years, which is significantly better than resection, and the new combination of chemotherapy and liver transplantation is expected to be a treatment for cholangiocarcinoma confined to the portal vein. Cytomegalovirus hepatitis, male, uninvolved colon, recipient, donor sex mismatch, use of murine monoclonal antibodies2CD3, and hormone-resistant rejection are positively associated with recurrence. Practically all advanced autoimmune liver diseases face the same problem after liver transplantation regardless of the type of autoimmune liver disease, and relapse rates of 22%, 18%, and 11% have been reported for all three after advanced liver transplantation for AIH, PBC, and PSC, respectively, but not much has been reported for the treatment of PSC after relapse.