Department of Gastroenterology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Institute of Digestive Diseases 200001, China
Autoimmune liver diseases (ALD) are a group of hepatobiliary injuries mediated by abnormal autoimmunity. In addition, there are any of these three diseases, namely primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). In addition, there are overlap syndromes between any two of these three diseases, mainly AIH-PBC overlap syndrome. All of these diseases can manifest as severe liver lesions and can progress to cirrhosis. Ma Xiong, Department of Gastroenterology, Shanghai Renji Hospital
I. Diagnosis of autoimmune liver disease
In the early stage of the disease process, the clinical symptoms of autoimmune liver disease are not obvious, and the comprehensive diagnosis is mainly based on biochemical, immunological, imaging and histopathological features and exclusion of other possible causes.
AIH is more common in women, with two preferred ages in Europe and the United States, children and middle-aged and elderly, and in China, middle-aged and elderly women. The clinical features are hypergammaglobulinemia, serum autoantibodies and response to immunosuppressive therapy. AIH has no specific signs and symptoms, but often presents with fatigue, loss of appetite, nausea, abdominal pain, pruritus and small joint pain. Physical examination is often unremarkable, but hepatomegaly, splenomegaly, jaundice and signs and symptoms of chronic hepatitis may also be present. About 10% of patients may present with acute hepatitis or even fulminant hepatitis and may progress rapidly to cirrhosis [1]. patients with AIH are often associated with other extrahepatic autoimmune diseases such as thyroiditis, ulcerative colitis, type I diabetes, rheumatoid arthritis, and celiac disease.
AIH is classified into 2 serological subtypes according to the serum autoantibody profile [2]. type I AIH is the most common, accounting for about 60%-80% of all AIH. Type II AIH occurs mainly in children and is characterized by positive anti-liver and kidney microsomal type I (LKM-1) or anti-hepatocyte cytoplasmic type I (LC-1) antibodies.
The characteristic histological change of AIH is interfacial hepatitis with infiltration of dense lymphocytes, mainly lymphoplasmacytes, in and around the confluent area or next to the interface and hepatocyte debris-like necrosis. There is also the presence of eosinophils. Damage to the portal system often does not involve the biliary system. Liver fibrosis is present throughout the course of AIH, but progresses more slowly. Occasionally, central lobular hepatocyte injury and inflammation are present.
Elevated serum transaminase levels, interfacial hepatitis with or without lobular hepatitis or bridging-like necrosis of the central-confluent area and the presence of autoantibodies (ANA, SMA, LKM-1 and SLA, etc.) are the main diagnostic bases of AIH [3]. However, these are not sufficient to exclude other causes of liver lesions, such as drug-related hepatitis and viral infections, as these diseases can also produce corresponding autoantibodies. In addition, if AIH is combined with chronic hepatitis C, the pathological histological changes in each of the two diseases can become atypical, so a differential diagnosis needs to be made in conjunction with the history, biochemical and virological test results. Therefore, the diagnosis of definitive AIH needs to exclude these conditions. The International Autoimmune Hepatitis Group has developed a point system based on multiple characteristics, but it is not very practical in clinical work and needs to be further revised and simplified [4]. Recently, Hennes et al. proposed a simplified diagnostic criteria for AIH (Table 1), with the initial aim of developing a point system more suitable for daily clinical work, thus distinguishing it from the former AIH diagnostic point system, which was mainly used for scientific research [5]. ANA or SMA potency ≥ 1:40 and IgG levels above the upper limit of normal were each scored 1 point; ANA or SMA potency ≥ 1:80, or LKM-1 potency ≥ 1:40, or SLA/LP positivity and IgG levels above 1.1 times the upper limit of normal were each scored 2 points. Two points were awarded for each of these. It is important to note that a maximum of 2 points is awarded for the simultaneous presence of multiple autoantibodies, for a total score of 8 points on the simplified diagnostic point system. The investigators defined a total score of ≥6 as “probable” AIH and a score of ≥7 as “confirmed” AIH.
Table 1 Simplified diagnostic criteria for autoimmune hepatitis
Variable
Criteria
Score
Remark
ANA or SMA
³1:40
1 point
ANA or SMA
or LKM-1
or SLA
³1：80
³1:40
Positive
2 points*
A maximum of 2 points when multiple items are present together
IgG
> upper limit of normal
>1.10 times the upper limit of normal
1 point
2 points
Liver histology
Consistent with AIH
Typical AIH presentation
1 point
2 points
Interface hepatitis, lymphoplasmacytic infiltration in the confluent area and lobules, and hepatocellular rosette nodules are considered characteristic AIH histologic changes, and the presence of all 3 together is a typical AIH manifestation
Exclusion of viral hepatitis
Yes
2 points
³ 6 points: AIH possible
³ 7 points: confirmed AIH
PBC is a chronic nonsuppurative granulomatous cholangitis affecting mainly medium-sized intrahepatic bile ducts, especially the intrahepatic interlobular bile ducts.PBC is prevalent in women (more than 90%), with a median age of onset of 50 y. The typical symptoms of PBC are fatigue and pruritus. Signs such as skin scratching, jaundice, and enlarged liver and spleen are specific but more common. Other symptoms are right upper abdominal pain and anorexia. Pruritus may appear at any time during the course of the disease and may occasionally resolve as the disease progresses. In contrast, jaundice is usually persistent and is also the most important indicator of prognosis. other clinical manifestations of PBC include skin pigmentation and macular tumors. Patients with advanced disease may present with manifestations of cirrhotic complications such as ascites, bleeding from ruptured esophagogastric fundic varices, and hepatic encephalopathy. Steatorrhea is common due to lack of bile salts in the intestinal lumen, and steatorrhea may also be associated with pancreatic pancreatic enzyme deficiency or celiac disease that sometimes accompanies patients with PBC. Spontaneous fractures may occur due to severe osteoporosis in patients.
Anti-mitochondrial antibody (AMA) positivity is a serologic feature of PBC and is seen in 90% to 95% of patients and may precede the onset of clinical symptoms and liver function abnormalities by several years. Serum biochemistry shows cholestatic changes, and serum alkaline phosphatase (ALP) with g-glutamyl transpeptidase (g-GT) elevation (3-5 fold) is the most common biochemical abnormality in PBC. AST and ALT are mildly elevated, and significant elevation is rare. Histopathology shows inflammation in the confluent area with lymphocytes surrounding the damaged bile duct and infiltrating into the bile duct basement membrane and between the bile duct epithelial cells, which are vacuolated and degenerated. The damaged bile ducts are surrounded by granulomas composed of epithelioid histiocytes and multinucleated giant cells. Granulomas are characterized by numerous foamy cells within the cytoplasm of the histiocytes and are therefore also called lipid (yellow tumor-like) granulomas. The lesion enlarges the confluent area and diffuses lymphocytes into the lobules of the liver, resulting in a debris-like necrosis. This debris-like necrosis containing proliferating bile ducts and granulomas formed by lymphocytes destroying the basement membrane of bile ducts is called cholestatic debris-like necrosis, which is different from lymphocytic debris-like necrosis in autoimmune hepatitis. A “definitive” diagnosis of PBC is made when the presence of cholestatic liver function changes, anti-mitochondrial antibody (AMA) and/or AMA-M2 titers greater than 1:40, and corresponding histopathologic features are present, while the presence of any two of these is a “probable” diagnosis. “IgM levels may be elevated in 95% of patients with PBC, but may be normal in a small number of patients [6].
PSC is also a progressive cholestatic liver disease with a prevalence of 130/1,000,000. unlike AIH and PBC, PSC predominantly affects men and is associated with inflammatory bowel disease in 70% (40-98%) of patients. psc can lead to destruction of intrahepatic and extrahepatic bold ducts, causing cholestasis, liver fibrosis and cirrhosis. The risk of bile duct cancer is elevated at all stages of the disease. The autoantibody most associated with PSC is pANCA, which is present in more than 85% of PSC cases, but may also be present in more than 5% of patients with PBC and in most patients with AIH. the diagnosis of PSC relies primarily on unique bile duct imaging changes that demonstrate intra- and extrahepatic bile duct involvement. However, imaging cannot differentiate between primary and secondary sclerosing cholangitis. Moreover, only small intrahepatic bile ducts are affected in 5% of PSC cases. Fibrous occlusive cholangitis is a histological feature of PSC. However, evidence from hepatectomy specimens suggests that the lesion is mostly limited to moderately sized bile ducts and is often absent from liver biopsy puncture specimens [7].
Eighteen percent of patients with autoimmune liver disease have features that differ from typical AIH, PBC, and PSC syndromes. Overlapping syndromes are more frequently reported as PBC-AIH and PBC-PSC overlap. It is currently believed that there are three possible states of autoimmune liver disease overlap syndrome, namely, the coexistence of both diseases; the presence of one major disease with some features of the other; and the sequential development of both diseases with changes in diagnosis and treatment. So far, there is no agreement on the criteria for determining the overlap syndrome and the variant syndrome.
II. Treatment of autoimmune liver disease
The lack of ideal animal models in autoimmune liver disease has made the exploration of drug therapy very difficult. Most of the drugs for the treatment of autoimmune liver disease are based on human studies and progress has been slow [8]. The development of novel immunosuppressive agents in the field of organ transplantation in recent years has given great hope for the treatment of AIH, and the research with metabolic nuclear receptors (e.g., FXR, PPARs, LXR, PXR, etc.) will lead to new drugs for the treatment of cholestatic liver disease.
Indications for the treatment of AIH include: ① those with serum transaminase levels 10 times higher than the upper limit of normal; ② those with serum transaminase levels 5 times higher than the upper limit of normal along with serum gammaglobulin levels at least 2 times higher than the upper limit of normal; ③ those with liver histology showing bridging necrosis or multilobular necrosis; ④ patients who do not meet the above three criteria should be treated individually according to their clinical judgment. ⑤ Those with interface hepatitis and no bridging necrosis or multifollicular necrosis on histological examination do not require treatment. (6) Patients with symptomatic AIH also need to be considered for immunosuppressive therapy in conjunction with biochemical and histologic features. The selection of drugs and their doses should be individualized based on clinical symptoms, the degree of elevation of serum transaminases and serum gammaglobulin/IgG and the severity and activity of the disease as determined by histological findings, as well as the possible side effects of the drugs [9].
According to AASLD recommendations, azathioprine can usually be added to prednisone (LON) to reduce the dosage of the former in order to reduce its side effects. A combination regimen (prednisolone 30 mg/d and azathioprine 50 mg/d) is generally used as initial treatment for AIH. Adequate doses of prednisolone (0.5-1.0 mg/kg) alone can also improve clinical symptoms, laboratory and histological indices, leading to remission of AIH. The efficacy of the two treatment regimens is similar. Of course, considering the need for long-term treatment, even lifelong in some patients, the combination of azathioprine seems more sensible. “Remission” is defined as the resolution of symptoms, return to normal serum transaminases, bilirubin and serum gammaglobulin/IgG levels, and improvement in liver histology (return to normal or only mild confluent hepatitis). It should be noted that normal serum aminotransferase levels do not necessarily mean that liver histology returns to normal. The toxic effects of prednisolone and azathioprine need to be closely monitored, especially the myelosuppressive effects of the latter that require urgent management. Recently, budesonide and motilmicronel (MMF) have received increasing clinical attention as alternative treatments to prednisolone and azathioprine, respectively. Available data suggest that comparisons between budesonide and prednisolone, MMF and azathioprine have similar efficacy in AIH, but budesonide and MMF avoid the side effects of the corresponding drugs and can be used as alternative therapy for intolerant patients [8]. The tapering of corticosteroids is a long-term gradual process. Higher doses of prednisone (Lon) can be reduced by 5-10 mg every 1-2 weeks. doses up to 15 mg/d can be reduced by 2.5 mg every 1-2 weeks until the maintenance dose. For patients on combination therapy, maintenance therapy with azathioprine alone is also feasible, in which case prednisone can be reduced by 2.5 mg per month until it is completely withdrawn. It is recommended that maintenance therapy should be continued for at least 6 months after hepatic histological improvement and for a total duration of at least 2 years [9].
Immunosuppressive therapy has no significant efficacy in the treatment of PBC or PSC. Moreover, glucocorticoids aggravate the degree of osteoporosis in patients when treating cholestatic liver disease. UDCA (13-15 mg/Kg body weight) has been shown to significantly improve hepatic biochemical parameters in patients with PBC and has a significant benefit on the long-term survival of patients with PBC, making it the drug of choice for the treatment of PBC and the only drug approved by the US Food and Drug Administration (FDA). The efficacy of UDCA in the treatment of PSC, especially its effect on long-term survival, is controversial. Whether high doses (20 mg/Kg body weight or even higher) of UDCA, which are well tolerated by patients with cholestasis, can further improve the efficacy of PBC and PSC warrants a multicenter prospective controlled study [7].
The management of cholestatic complications (e.g. pruritus, osteoporosis and fat-soluble vitamin deficiency) should also be given high priority, as this aspect of treatment can improve the quality of life and even prolong the survival time of patients in cases where the primary disease cannot be effectively removed. The following is a description of the treatment of the complications of cholestasis. (1) Pruritus: Disulfiram is the drug of choice. For those who cannot tolerate the side effects of cholestyramine or who fail cholestyramine treatment, rifampin should be used as a second-line drug, but the hepatotoxicity of rifampin limits the widespread use of this drug. Opiate antagonists may be considered in tolerated cases. Uncontrollable pruritus is an indication for liver transplantation. ② Osteoporosis: at the first diagnosis of cholestatic liver disease and every two years thereafter, bone mineral density measurement should be performed. Emphasis should be placed on lifestyle health promotion (e.g., regular exercise, smoking cessation) as well as vitamin D and calcium supplementation. Recommend hormone replacement therapy when appropriate, preferably administered via the dermal route. If osteoporosis is confirmed, treatment with diphosphonates is recommended. (iii) Fat-soluble vitamin deficiency: in patients with hyperbilirubinemia, fat-soluble vitamin replacement therapy is best administered as a water-soluble form of fat-soluble vitamins [6].
The choice of treatment for patients with autoimmune liver disease and its overlapping syndromes needs to take into account what predominates in the disease, hepatitis or cholestasis, and immunosuppressive therapy for those with significant hepatitis component, while UDCA is given for those with predominant cholestasis, and combination therapy is considered when both are present [10]. In our opinion, both immunosuppressive therapy and UDCA therapy are more effective in the early stages of the disease. By the stage of cirrhosis, not only the efficacy is not obvious, but also the side effects of glucocorticoids are significantly aggravated. Therefore, the early diagnosis and treatment of autoimmune liver disease is an important topic for us.
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