In 1950, the Swedish physician Waldenström first described a group of young women with chronic hepatitis presenting with jaundice, hyperglobulinemia, and amenorrhea that eventually progressed to cirrhosis. Several studies in the 1960s and 1970s confirmed the association of this group of chronic hepatitis with other extrahepatic autoimmune syndromes, once called “lupus hepatitis” due to the presence of autoantibodies, and in 1965 Mackay et al. The association of autoimmune hepatitis with HLA alleles was published in 1972. multiple autoantibodies to autoimmune hepatitis were identified in the 1970s and 1980s, and subsequently their target molecules were identified. in 1992 an international working group (later the International Autoimmune Hepatitis Group, IAIHG) officially named the syndrome “autoimmune hepatitis” (AIH), and established diagnostic criteria for AIH. Over the past 20 years other autoantibodies and genes associated with AIH have been recognized and new therapeutic agents have emerged. The IAIHG is also committed to collaborative multicenter research to further characterize AIH disease presentation, prognostic predictors, and appropriate treatment strategies.
AIH is a chronic inflammatory disease of the liver characterized by the destruction of liver parenchyma due to the breakdown of immune tolerance against hepatocytes. In 1999, the IAIHG revised the descriptive diagnostic criteria and diagnostic point system for AIH.
I. Natural history of AIH
Information on the natural history of untreated AIH is scarce. The most recent placebo-controlled studies, published in the 1970s, screened only for viral hepatitis as an epidemiologic risk factor but did not include screening for HCV infection and lacked standardized diagnostic criteria. However, these data showed a poor prognosis for untreated AIH, with 5- and 10-year survival rates of 50% and 10%, respectively. Studies have confirmed that immunosuppressive therapy significantly improves the prognosis of patients with chronic active hepatitis. Current estimates of overall 10-year survival for AIH patients range from 80% to 93%.
Histological changes of cirrhosis are present in more than 30% of adult patients at the time of AIH diagnosis. Recent data suggest that only a small proportion of patients progress to cirrhosis during immunosuppressive therapy and that liver fibrosis scores are stable or improving in more than 75% of patients. The odds of treatment remission and treatment failure were similar for both patients with and without cirrhosis at diagnosis. Notably, however, the presence of cirrhosis at diagnosis significantly increased the risk of death and liver transplantation.
About 50% of pediatric patients have cirrhosis at diagnosis. Long-term follow-up suggests that only a small proportion of patients can stop treatment altogether, with approximately 70% of pediatric patients receiving long-term treatment into adulthood and approximately 15% developing chronic liver failure requiring liver transplantation by age 18.
A heavier liver histologic grading at the time of AIH diagnosis has been reported in older patients, but there is no difference in the incidence of determined cirrhosis between the two compared to younger patients. Older patients respond to immunosuppressive therapy similarly to younger patients, with more than 90% of older patients achieving remission. Whether geriatric patients require higher or lower doses of glucocorticoid therapy remains to be discussed. A study from the United Kingdom showed that 42% of untreated elderly patients had a prognosis no worse than younger patients, and glucocorticoid therapy needs to be individualized.
II. Diagnosis of AIH
1. Descriptive diagnostic criteria
Patients with AIH are mainly women, but men can be affected as well, and they can be affected at any age and by different races. The clinical manifestations are highly variable, ranging from asymptomatic transaminase elevation detected by incidental physical examination to severe or fulminant manifestations. Most patients have an unspecific presentation at the onset, such as malaise, fluctuating jaundice, right upper rib pain, and arthralgia. A subset of patients also present with extrahepatic autoimmune diseases such as rheumatoid arthritis, autoimmune thyroiditis, ulcerative colitis, and diabetes mellitus.
Biochemical tests are more pronounced in most cases with elevated serum transaminases than with elevated bilirubin and alkaline phosphatase (ALP). To differentiate cholestatic disease, the diagnostic score system uses an elevation of serum ALP with a ratio of AST or ALT above 3.0 as a weighting factor for negativity. Another biochemical feature is the elevation of serum globulins, especially gamma-globulins. Serum α1-antitrypsin, copper, and copper orchid protein levels need to be normal, but serum copper and copper orchid protein can be abnormal if Wilson’s disease is excluded.
Autoantibodies are diagnostic indicators specific for AIH. Anti-smooth muscle antibodies (SMA) over 1:40 in adults and 1:20 in children have diagnostic significance. Anti-liver and kidney microsomal antibodies (anti-LKM) greater than 1:10 have diagnostic value. Other autoantibodies include anti-nuclear antibodies (ANA), anti-soluble liver/pancreatic antigen antibodies (anti-SLA/LP,) anti-hepatocyte cytoplasmic antibodies (anti-LC-1), anti-desalic acid glycoprotein receptor antibodies (anti-ASGPR), and perinuclear staining anti-neutrophil cytoplasmic antibodies (pANCA). Anti-mitochondrial antibodies (AMA) should be tested at the same time to exclude primary biliary cirrhosis.
The histology of AIH is characteristic but not specific for diagnosis. Histologic features include interface hepatitis with lymphoplasmacytic infiltration and debris-like necrosis. Mild bile duct changes may be seen.
Genetic factors are involved in the pathogenesis of AIH. HLA DRB1*0301 and DRB*0401 are associated with genetic susceptibility and/or disease severity in Caucasian populations.
The diagnosis of AIH requires the exclusion of viral hepatitis, such as viral hepatitis A, B, C and E. A history of moderate to heavy alcohol intake or recent use of potentially hepatotoxic medications should be considered for AIH in patients with liver injury that persists after abstinence from alcohol and medication discontinuation. The point system excludes alcohol and drug histories as negative weighting indicators of possible AIH in these patients.
The diagnosis of AIH does not require 6 months to establish a chronic course.
2. Use of scoring systems
Several studies have confirmed the validity of the scoring system. The modified scoring system has a high sensitivity (97%-100%) for the diagnosis of AIH and is also effective in excluding patients with PSC and biliary anomalies combined with AIH (the accuracy of excluding confirmed AIH is 96%-100%). However, by including suspected AIH, the overall specificity decreases. The overall diagnostic accuracy of the system is approximately 90%. The scoring system is mainly used for the diagnosis of disease and the application of immunosuppressive therapy and does not provide information on disease severity and prognosis.
The system has good specificity in excluding AIH in patients with chronic liver disease, but its use is limited in cases of AIH overlap syndrome or AIH with other liver diseases. Histological examination of the liver biopsy is particularly important in this case.
3. Autoantibodies
ANA, SMA and anti-LKM1 are the key autoantibodies for the diagnosis of AIH and should be tested first in patients with suspected AIH. For patients lacking these autoantibodies, testing for anti-LC-1, pANCA, anti-SLA/LP and anti-ASGPR is helpful in the diagnosis of AIH.
4.Typing of AIH
Currently, AIH is classified into 3 types according to serum autoantibody profile, but the clinical use of this classification is uncertain because the etiology of AIH is not yet clear.
Type I AIH is characterized by the presence of ANA and/or SMA; type II AIH is characterized by the presence of anti-LKM1 with low frequency of anti-LKM3 (with or without ANA and SMA); type III AIH is characterized by the presence of anti-SLA/LP (with or without ANA and SMA). Type I AIH is the most common form of AIH, while type III AIH and type II AIH are rare in adults. Type II AIH is seen mainly in children, accounting for 30% of AIH cases. Type III AIH is not easily distinguished from type I AIH clinically.
5.Difficulties in diagnosis
(1) Autoantibody-negative AIH
About 10% to 20% of AIH patients are negative for traditional autoantibodies, such as ANA, SMA, anti-LKM, in the initial serum examination, which appear only after starting immunosuppressive therapy. Testing for pANCA is necessary in this group of patients, and testing for other autoantibodies that have not been widely performed, such as anti-SLA/LP, anti-LC-1, and anti-ASGPR, also has important diagnostic value.
(2) Overlap syndrome or variant syndrome
Overlap syndrome refers to the presence of clinical, serological and histological features of two or more autoimmune liver diseases in the same patient, which can manifest as concurrent, sequential or alternating occurrences. Standardized diagnostic criteria for overlap syndrome have not been published, and the IAIHG scoring system has limitations in its use in patients with overlap syndrome.
The clinical diagnosis of AIH-PBC overlap syndrome is made in 10-15% of AIH patients with positive AMA and histology suggestive of cholangitis. 6% of AIH patients with cholangiography suggestive of typical lesions of PSC are diagnosed with AIH-PSC overlap syndrome; 10% of AIH patients with positive ANA and SMA and negative AMA and histology suggestive of cholangitis can be considered as autoimmune cholangitis ( AIC).
When diagnosing a patient with AIH or during the disease process, features of other autoimmune diseases or autoantibody markers should be identified to distinguish whether it is AIH alone or an overlap syndrome. This is important. Because the treatment and prognosis of the two may be very different, liver biopsy is very important at this time.
(3) Viral hepatitis
About 20% to 40% of patients with chronic hepatitis B or C have persistent positive serum levels of multiple autoantibodies, but the titers are usually low (1:20 or 1:40). Conversely, patients with AIH sometimes present with anti-HCV positivity but undetectable HCV RNA. These patients are divided into 3 categories: true AIH patients with false anti-HCV positivity (undetectable HCV RNA); true hepatitis C patients with low titers of autoantibodies but no signs of AIH; and true hepatitis C patients with features of AIH: young women, high titers of autoantibodies (>1 ∶:320), high gamma-globulinemia and a history of extrahepatic autoimmune abnormalities.
Hepatitis B and C need to be excluded before starting treatment. It is important to differentiate chronic viral hepatitis from AIH because interferon antiviral therapy can lead to worsening of AIH and glucocorticoids can promote viral replication.
There is considerable debate about the diagnosis and treatment of chronic viral hepatitis with autoantibodies. Especially in southern Europe, a high percentage of HCV-infected patients are positive for anti-LKM. Recent studies have shown cross-reactivity of anti-LKM1 against CYP2D6 with HCV proteins, possibly as a result of molecular mimicry at the B-cell level. There is more consensus that interferon therapy is safe in patients with anti-LKM1-positive HCV infection.
Patients with chronic viral hepatitis should be screened for autoantibodies before starting interferon therapy and monitored during treatment. pANCA testing appears to be of greater significance for differential diagnosis as it is rarely seen in patients with chronic viral liver disease and is relatively common in patients with AIH.
(4) Alcohol consumption
The diagnosis of AIH is more difficult in alcohol drinkers. Patients who drink alcohol are divided into 2 categories: those without AIH, where alcohol is the causative factor of liver disease, and those with AIH, where alcohol may be a synergistic factor. Abnormalities in serum biochemistry, such as GGT, are generally of little value for differential diagnosis; interface hepatitis is also seen in alcoholic steatohepatitis. However, immunological tests can be helpful in the differential diagnosis. Hyperglobulinemia is common to both, but patients with alcoholic liver disease have predominantly elevated IgA, whereas patients with AIH have predominantly elevated IgG and normal or low IgA. Although 25% to 40% of patients with alcoholic liver disease are positive for ANA or SMA, the titer is relatively low, while anti-LKM1 and pANCA are rarely positive.
III. Treatment of AIH
1.Indications for AIH treatment
AIH usually responds to immunosuppressive therapy and has been shown to improve prognosis. The indication for treatment is inflammatory activity, which reflects the risk factors for disease progression (Table 2). Severe abnormalities in laboratory tests (serum AST ≥ 10 × ULN (grade I), or AST ≥ 5 × ULN with γ-globulin ≥ 2 × ULN (grade I)); incompetent (incapatating) manifestations, acute clinical deterioration, fulminant manifestations; and histological changes such as moderate to severe interface hepatitis, bridging necrosis, and multilobular collapse (grade I) are absolute indications for treatment.
The need for treatment in patients who do not have absolute indications should be judged on a patient-by-patient basis. Since AIH responds better to immunosuppressants, treatment should be actively given to those with a clear diagnosis, but the choice of drugs and dose need to be adjusted according to symptoms, the degree of elevated serum transaminases and γ-globulin, histological findings, and possible side effects of the chosen drugs to achieve individualized treatment.
Patients with asymptomatic and mild inflammation may be left untreated, but need to be closely monitored for changes in their condition. Liver transplantation should be considered for patients with liver failure or fulminant manifestations that have failed to respond to immunosuppressive therapy.
2.Treatment goals
The primary goal of AIH treatment is complete remission of symptoms, complete biochemical improvement and complete improvement of liver histology; the ultimate goal is to maintain sustained remission without drug therapy. Treatment goals include several stages: (1) normalization of transaminases; (2) normalization of gamma-globulin and IgG; (3) normalization of histologic activity; (4) improvement of fibrosis; and (5) maintenance of sustained remission even after drug discontinuation. Clinical, biochemical and histological improvement is achieved in approximately 70% to 80% of patients during the first 3 years of treatment. If the diagnosis is correct, clinical and biochemical normalization can be achieved within 3-6 months of treatment, while histological improvement takes longer.
3.Traditional treatment plan
Prednisone alone or in combination with azathioprine remains the standard of care for AIH (Table 3), and both are equally effective. The choice of which regimen to use is mainly a trade-off between hormonal side effects. Considering the long-term nature of treatment, even lifelong in some patients, it may be wise to add azathioprine and reduce the dose of hormone.
(1) Induction and maintenance of remission
In adult and pediatric patients, conventional therapy should be continued until remission or treatment failure or partial response or drug toxicity occurs.
Maintenance doses of prednisone (Long) are less than 10 mg/day, 5 to 10 mg/day or 10 mg/dose, every other day. Maintenance with azathioprine alone is recommended in combination therapy patients, with glucocorticoid dose reduction of 2.5 mg per month until discontinuation after induction of remission with conventional therapy and concomitant increase in azathioprine to 2 mg/kg/day with long-term maintenance. Prednisone (Lon) alone may be followed by azathioprine 2 mg/kg/day and a 2.5 mg monthly reduction of prednisone (Lon) during the maintenance phase. uDCA may be tried during the prednisone (Lon) reduction or even withdrawal phase.
The recommended maintenance therapy after histological improvement should be at least 6 months, but there is no consensus on how long maintenance therapy should be because of the high relapse rate after discontinuation, but the general trend is to extend the course of therapy to achieve long-term disease stabilization and control disease progression. Krawitt recommends long-term treatment for most patients and lifelong treatment for adult and pediatric patients with cirrhosis present at the time of initiation of therapy, especially for pediatric patients with type II AIH. Our experience supports the idea of long-term treatment.
(2) Treatment endpoints
The ideal treatment endpoint is resolution of all clinical, laboratory, and histological manifestations reflecting disease activity. the resumption of AST, gamma globulin, and IgG, combined with histological improvement reduces the relative risk of relapse after drug discontinuation by a factor of 3 to 10. However, recovery of laboratory tests and histology does not ensure that relapse will not occur. In 60% of patients, relapses occur despite discontinuation of the drug despite normalization of indicators reflecting inflammation. If possible, treatment should be continued until the gamma globulin and IgG are normalized. Extending the duration of consolidation therapy is also an important factor in reducing AIH relapse.
(3) Treatment response
Glucocorticoids alone or in combination with azathioprine for type I AIH for 18 months achieve remission in 65% of patients and within 3 years, 80% of patients achieve remission. 85% of treated patients have a life expectancy of more than 10 years and 74% 20 years, a survival status comparable to the age- and sex-matched general population in the same region. Patients with cirrhosis had a similar, very good response as patients without cirrhosis, and both should be treated similarly. Long-term remission was maintained in 21% of patients after discontinuation (median 76 months of discontinuation follow-up).
Glucocorticoids may reduce or prevent liver fibrosis. In one study followed for 55±9 months, 56% of patients had decreased liver fibrosis scores and 33% had stable fibrosis during the 62±14 month observation period. Glucocorticoids improved liver fibrosis by reducing liver inflammation.
Predictors of poor treatment outcome included youth at diagnosis, anti-LKM1 positivity, prolonged international normalized ratio (INR), hyperbilirubinemia, and high histological activity index score.
Treatment outcomes can be classified into four categories: remission, treatment failure, incomplete response, and relapse.
IV. Other empirical treatments
The new drugs currently available for experimental treatment of AIH are mainly from the transplantation field (Table 4) and have been found to be useful in preliminary studies, but none are formally recommended at this time. For refractory patients or patients intolerant to first-line therapy, these drugs increase treatment options. However, their application lacks sufficient evidence, and there are uncertain risks, as well as uncertainty in dosing, uncertainty in the population treated, and increased costs of empiric therapy, which should be tried on a case-by-case basis weighing the pros and cons.
V. Liver transplantation
Liver transplantation is the only option for patients with end-stage AIH. Between 1998 and 2004, 31,169 liver transplants were performed in Europe, of which 4% were for patients with AIH. The majority of patients requiring liver transplantation were those who did not respond at 6 months of treatment and those who did not remit after 3 years of continuous treatment.
The long-term prognosis of liver transplantation is excellent, with patient and graft survival rates of 80% to 90% at 5 years and 75% at 10 years after liver transplantation. Manns and Bahr suggest that the criteria for the diagnosis of recurrent AIH are: persistently elevated transaminases, significantly elevated autoantibody titers, elevated immunoglobulins, glucocorticoid dependence, liver histology supporting the diagnosis of AIH and the exclusion of other causes of AIH such as HCV infection. transplant organ dysfunction.