Thiopurine Methyltransferase Deficiency and Azathioprine Intolerance in Autoimmune Hepatitis

Thiopurine methyltransferase deficiency has been associated with intolerance to azathioprine. Our goals were to assess the frequency of enzyme deficiency in autoimmune hepatitis and correlate deficiency states with azathioprine intolerance. Eighty-six patients receiving azathioprine (50–150 mg daily) were evaluated for enzyme activity and azathioprine-related complications. Their findings were compared to 89 similarly treated but untested patients. Thirteen patients (15%) had low thiopurine methyltransferase levels (11.4± 0.9 U/ml RBC; range, 3.5–14.9 U/ml RBC). Azathioprine intolerance occurred as commonly in patients with normal or above normal enzyme levels as in patients with below normal levels (12% versus 15%, p = 0.7). Patients treated without enzyme testing had the same frequency of complications (9% versus 13%, p = 0.5) as tested patients. We conclude that routine screening of blood thiopurine methyltransferase levels has a low yield for identifying individual patients at risk for azathioprine toxicity during conventional low dose therapy for autoimmune hepatitis.     

187例自身免疫性肝病的临床特点分析

目的分析自身免疫性肝病（AILD）的临床、生化及免疫学特点。方法分析北京大学人民医院2001年1月～2010年12月187例自身免疫性肝病患者的临床表现、生化及免疫学特点。结果 AILD的发病以40岁以上女性多见,30.5%（57/187）的患者确诊时已进展为肝硬化失代偿期。临床症状无特异性,自身免疫性肝炎（AIH）以ALT、IgG及γ球蛋白升高更为明显（P〈0.05）,而PBC以ALP、GGT、IgM升高更为明显（P〈0.05）。AILD患者常合并一种或多种肝外自身免疫病,AILD合并干燥综合症最为常见,AIH组及PBC组合并干燥综合症的发生率均达30%以上。AILD患者均有一种或多种自身抗体阳性,其中AIH组ANA阳性率为88.3%,AMA阳性率为7.5%（3/40）,AMA-M2阳性3.7%（2/54）;PBC组ANA阳性率为88.2%（97/110）,AMA阳性率为96.4%（81/84）,AMA-M2阳性率为94.4%（85/90）。AIH患者主要应用糖皮质激素治疗,其中共46例（59.7%）患者单用或联用UDCA治疗后肝脏酶学指标改善。结论生化、免疫学、自身抗体等检查对诊断与鉴别诊断具有重要意义。UDCA在AIH的治疗中有一定的作用。     

Occult hepatitis B virus infection in patients with autoimmune liver diseases

Background: Occult hepatitis B virus (HBV) infection is characterized by undetectable serum HBV surface antigen (HBsAg) but detectable HBV‐DNA in serum or liver. Aims: To determine the prevalence and clinical impact of occult HBV in autoimmune liver diseases as similar data are missing. Methods: One hundred and ninety‐six sera samples from HBsAg‐negative patients, including 66 autoimmune hepatitis (AIH), 93 primary biliary cirrhosis (PBC) and 37 primary sclerosing cholangitis (PSC), were investigated for HBV‐DNA using the polymerase chain reaction (PCR) before treatment initiation. One hundred and three serial samples from 38 AIH patients under immunosuppression and 282 selected blood donors (HBsAg negative; antibodies to HBV‐core antigen positive) were also investigated. Fourteen available paraffin‐embedded AIH liver samples were also investigated for HBV‐DNA by nested‐PCR. Results: Hepatitis B virus DNA was detected in the serum of 24/196 patients (12.2%) and 0/282 donors (P=0.0000). Nine patients had AIH (13.6%), eight had PBC (8.6%) and seven had PSC (18.9%) (P=0.0000 vs healthy). HBV‐DNA detection in AIH livers was higher than in serum. HBV‐DNA was associated neither with HBV markers nor with epidemiological, laboratory and clinical data. Serial testing of AIH patients revealed two HBV‐DNA‐negative patients before treatment becoming positive during treatment, while all HBV‐DNA‐positive patients before immunosuppression became negative. Conclusion: Based mainly on serum HBV‐DNA, we found a significant proportion of autoimmune liver disease patients with occult HBV compared with donors. However, taking into account our results in a small number of liver tissues, it should be emphasized that occult HBV could be even higher when both serum and liver specimens are investigated. Occult HBV does not seem to affect the clinical and laboratory features of the diseases, while AIH patients with occult HBV under immunosuppression do not deteriorate during follow‐up.     

Overlap syndromes with autoimmune hepatitis in chronic cholestatic liver diseases

Conditions exhibiting features of two different autoimmune liver diseases are commonly designated overlap syndromes, although there is no current agreement on what constitutes an overlap syndrome or specific diagnostic criteria. As in the classic autoimmune liver diseases, such as autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), the etiology is unknown but presumed to be related to alterations of immune regulation. Distinction of these clinical entities is important for management as outcomes may differ from outcomes of patients with diagnosis of classic autoimmune liver diseases. Due to their presumed rarity, no large therapeutic trials are available and treatment of overlap conditions is empirical and based upon extrapolation of data from the primary autoimmune liver diseases. PBC–AIH overlap is the most frequently described overlap syndrome and may be associated with a poor prognosis. This may represent an important and unrecognized cause of resistance to ursodeoxycholic acid in patients with PBC. PSC–AIH overlap is less commonly reported. Prognosis may be better than in patients with PSC alone; however, worse than in patients with AIH alone. Further studies are needed for determining diagnosis, natural history and optimal therapeutic strategies of overlap syndromes of autoimmune liver disease.     

Spectrum of autoimmune liver diseases in western India

BACKGROUND AND AIM: The prevalence and spectrum of autoimmune liver diseases (AILDs) in India are rarely reported in comparison to the West. METHOD: During a study period of 7 years, all patients with chronic liver diseases (CLDs) were evaluated for the presence of AILDs on the basis of clinical, biochemical, imaging, serological, and histological characteristics. RESULTS: Of a total of 1760 CLD patients (38.1% females), 102 patients (5.7%) had an AILD. A total of 75 (11.2%) female patients had an AILD. Among males, 27 (2.4%) had an AILD. The prevalence of AILDs in women increased from 11.2% to 45.7% and in men from 2.4% to 10.3%, after excluding alcohol, hepatitis B virus, and hepatitis C virus as a cause of CLD. Of the AILDs, autoimmune hepatitis (AIH) was present in 79 patients (77.4%), followed in descending order by primary biliary cirrhosis (PBC) in 10 patients (9.8%), PBC/AIH true overlap syndrome in six patients (5.8%), primary sclerosing cholangitis (PSC) in five patients (4.9%), and PBC/AIH switchover syndrome in two patients (1.9%). None had PSC/AIH or PBC/PSC overlap syndrome. Associated known autoimmune diseases were found in 40 (39.2%) patients. CONCLUSIONS: AILDs are not uncommon in India. They should be suspected in all cases of CLDs, especially in middle-aged women who do not have problems with alcoholism and who are without viral etiology, as well as in all patients with known autoimmune diseases.     

不同类型自身免疫性肝病患者肝组织炎症因子表达的变化

目的 探讨不同类型自身免疫性肝病(AILD)患者肝组织炎症因子表达的变化。方法 2016年12月～2018年12月我院肝病科收治的AILD患者74例,其中自身免疫性肝炎(AIH)患者19例,原发性胆汁性肝硬化(PBC)患者42例,自身免疫性肝炎/原发性胆汁性肝硬化重叠综合症(AIH/PBC OS)患者13例。采用免疫组化法检测肝穿组织白介素-12(IL-12)、IL-17和干扰素-γ(IFN-γ)表达情况。结果 AIH、PBC和AIH-PBC OS患者血清ALT水平分别为(132.5±12.5)U/L、(40.1±8.4)U/L和(166.2±16.3)U/L,AST水平分别为(120.3±11.7)U/L、(52.8±5.6)U/L和(194.7±18.3)U/L,差异显著(P<0.05);血清ALP水平分别为(98.0±9.2)U/L、(323.5±30.9)U/L和(257.1±24.1)U/L,血清GGT水平分别为(49.1±4.7)U/L、(236.8±22.6)U/L和(376.7±35.5)U/L,差异显著(P<0.05);AIH、PBC和AIH-PBC OS组患者肝组织IL-12表达阳性率无统计学差异(分别为15.8%、7.1%和15.4%,P>0.05),肝组织IL-17阳性表达率无统计学差异(分别为73.7%、76.2%和76.9%,P<0.05),肝组织IFN-γ阳性表达率无统计学差异(分别为68.4%、85.7%和76.9%,P<0.05);AIH患者血清抗肝肾微粒体I型抗体(LKM-1)、抗可溶性肝抗原/肝胰抗原抗体(SLA/LP)阳性率分别为21.1%和10.8%,均显著高于PBC组或AIH-PBC OS患者(分别为0.0%和0.0%,和0.0%和0.0%,P<0.05);PBC患者血清抗sp100抗体阳性率为19.0%,显著高于AIH组(0.0%)或AIH-PBC OS患者(7.7%,P<0.05);AIH-PBC OS组血清抗gp210抗体阳性率为38.5%,显著高于AIH组(0.0%,P<0.05),AIH-PBC OS组患者血清抗线粒体M2抗体(AMA-M2)阳性率为100.0%,显著高于AIH组(0.0%)或PBC组(73.8%,P<0.05);AIH患者血清ANA和SMA阳性率分别为94.7%和78.9%,显著高于PBC患者(分别为19.0%和19.0%,P<0.05)。结论 不同类型AILD患者血清自身抗体呈交叉阳性现象,肝组织炎性因子检测对鉴别诊断没有意义,常规肝功能指标仍对诊断起关键作用。     

New insights into autoimmune liver diseases.

Autoinflammatory liver disease represents an important aspect of global hepatological practice. The three principal disease divisions recognized are autoimmune hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis. Largely, but not exclusively, these diseases are considered to be autoimmune in origin. Increased recognition of outlier and overlap syndromes, changes in presentation and natural history, as well as the increased awareness of IgG4-associated sclerosing cholangitis, all highlight the limitations of the classic terminology. New insights continue to improve the care given to patients, and have arisen from carefully conducted clinical studies, therapeutic trials, as well as genetic and laboratory investigations. The challenges remain to treat patients before liver injury becomes permanent and to prevent the development of organ failure.     

自身免疫性肝病诊断与治疗进展

自身免疫性肝病是一组由自身免疫介导的慢性肝胆系统损伤性疾病,主要包括自身免疫性肝炎、原发性胆汁性肝硬化及原发性硬化性胆管炎.本文就自身免疫性肝病的诊断与治疗进展进行综述.     

Celiac disease autoantibodies in severe autoimmune liver disease and the effect of liver transplantation

Background/aims: Celiac disease (CD) is associated with primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis. We investigated the following: (i) the prevalence of tissue transglutaminase antibodies (tTGAs) and endomysial antibodies (EMAs) in end‐stage autoimmune liver disease (ESALD), (ii) the correlation among auto‐antibodies and the human leucocyte antigen (HLA) haplotype, and (iii) the effect of liver transplantation on antibody kinetics. Methods: Pretransplantation sera from 488 patients (310 with ESALD, and 178 with non‐autoimmune disease) were tested for tTGAs. Positive samples were also tested for EMAs, and retested 6–12 and ≥24 months post‐transplantation. Results were correlated with the HLA type of the recipient. Results: Serological evidence of CD was found in 3% (ESALD) vs. 0.6% (non‐autoimmune) of the patients (five‐fold increased risk in ESALD). The prevalence of tTGAs (14.2 vs. 5.4%, P=0.0001) and EMAs (4.3 vs. 0.78%, P=0.01) was significantly higher in patients with the HLA‐DQ2 or HLA‐DQ8 haplotypes. tTGAs and EMAs normalized in 94 and 100%, respectively, without gluten exclusion post‐transplantation. Post‐transplantation, of the five patients with symptoms of ‘classical’ CD, three improved. Intestinal lymphoma was diagnosed in another two cases with clinically ‘silent’ CD. Conclusions: Patients with ESALD, especially those who are HLA‐DQ2 or HLA‐DQ8 positive had a high prevalence of CD‐associated antibodies. Both tTGAs and EMAs decreased post‐transplantation without gluten withdrawal. Immunosuppression may improve symptoms of CD, but might not prevent progression to intestinal lymphoma.     

Intrahepatic status of regulatory T cells in autoimmune liver diseases and chronic viral hepatitis.

Aim: Regulatory T cells (Tregs) maintain immunological tolerance and suppress autoreactive immune responses. We evaluated the intrahepatic status of Tregs in patients with autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), chronic hepatitis C (CH-C), or chronic hepatitis B (CH-B). Methods: We analyzed 85 patients (20 AIH, 22 PBC, 27 CH-C, and 16 CH-B) and 14 controls. Using liver tissue samples obtained by needle biopsy or from marginal parts of resected metastatic liver tumors in the controls, immunohistochemical analyses of forkhead box P3(+), which is a specific marker for Tregs, CD4(+), and CD8(+) cells were performed. Results: Intrahepatic Tregs were significantly more infiltrated in patients with liver diseases than in the controls. There were significantly fewer intrahepatic Tregs in the AIH patients than in the PBC patients (P = 0.037). Patients with alow frequency of intrahepatic Tregs were detected significantly more in the AIH and CH-B groups than in the PBC and CH-C groups (P < 0.05). In addition, the frequency of Tregs decreased in the liver of PBC patients as the pathological stage of the disease advanced. We found significantly less infiltration of CD4(+) T cells in AIH than in other diseases (P < 0.05). Liver-infiltrating CD8(+) T cells were detected more frequently in the CH-B group than in other groups (P < 0.003). Conclusion: Intrahepatic Tregs were increased in both patients with autoimmune liver diseases and those with viral hepatitis. In autoimmune liver diseases, intrahepatic Tregs were fewer in the AIH patients than in the PBC patients.     

Epidemiology of autoimmune liver disease

Primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) are chronic liver diseases that likely have an autoimmune basis to their pathogenesis. Although significant strides have been made in the clinical management of these conditions, their pathogenesis remains obscure. Understanding of various epidemiological factors may shed light on predisposing or causative factors for these diseases. Most is known about the epidemiology of PBC, with only minimal information on that of PSC and AIH. In this review, the current data on the epidemiology of PBC, AIH and PSC are summarized and suggestions are made for future work in this important area.     

Spectrum of liver pathology in immune mediated liver diseases

Abstract   Immune mechanisms are involved in a wide range of parenchymal liver diseases and are of particular importance in conditions where the pathogenesis appears to be related to loss of tolerance to self antigens. In the liver there are two classical 'autoimmune' conditions: primary biliary cirrhosis and autoimmune hepatitis. It is increasingly apparent however that these may represent ends of a spectrum and overlap syndromes are well recognised. Furthermore there is evidence that primary sclerosing cholangitis may be a further example of autoimmune liver disease and overlpa conditions between this and autoimmune hepatitis are described. Histopathological assessment remains an important diagnostic tool in the investigation of autoimmune liver disease, particularly in the context of outlier and overlap conditions.     

Low prevalence of hepatitis B virus infection in patients with autoimmune diseases in a Chinese patient population

Hepatitis B is a very common communicable disease in China but the prevalence of hepatitis B virus (HBV) infection in patients with autoimmune diseases is unknown. We retrospectively investigated the prevalence of autoimmune diseases in patients with HBV infection. The medical records of 4060 patients with autoimmune or nonautoimmune diseases were reviewed. A positive test result for hepatitis B surface antigen (HBsAg) was used to indicate the presence of HBV infection. Autoimmune diseases included autoimmune hepatitis, primary biliary cirrhosis, systemic lupus erythematosus and ulcerative colitis. Nonautoimmune conditions included inguinal hernia, appendicitis and pregnant or postpartum women. The proportion of autoimmune disease patients who were HBsAg positive (2.24%) was significantly lower than that of nonautoimmune disease patients who were HBsAg positive (4.58%; P = 0.0014). Regarding hepatic autoimmune diseases, the positivity rates for HBsAg in autoimmune hepatitis patients (0.83%) and primary biliary cirrhosis patients (1.02%) were both significantly lower than in nonautoimmune patients (4.58%; P = 0.006 and 0.004, respectively). Patients with hepatic autoimmune disease were significantly less likely to be HBsAg positive (0.93%) than patients with non‐hepatic autoimmune disease (3.99%; P = 0.002). Patients with autoimmune diseases, especially those with hepatic autoimmune disease, may more efficiently clear HBV than patients with nonautoimmune diseases.     

+49A/G polymorphism of cytotoxic T‐lymphocyte antigen 4 gene in type 1 autoimmune hepatitis and primary biliary cirrhosis: A meta‐analysis

Aim: Recently, the associations of +49A/G polymorphisms of cytotoxic T‐lymphocyte antigen 4 (CTLA‐4) gene with the susceptibility to type 1 autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) have been reported; however these associations are yet to be fully elucidated. This study aimed to identify the associations of CTLA‐4 gene +49A/G polymorphisms with the susceptibility to type 1 AIH and PBC by using a meta‐analysis. Methods: PubMed was searched by using the following keywords: “autoimmune hepatitis AND (polymorphism OR polymorphisms)” or “primary biliary cirrhosis AND (polymorphism OR polymorphisms)”. Meta‐analyses of five studies including 526 patients with type 1 AIH and 631 controls and seven studies including 1500 patients with PBC and 2345 controls were performed. Results: For type 1 AIH, the odds ratio (OR) of G allele was 1.26 [95% confidence interval (CI) 1.06–1.51] although G/G homozygosity was not associated with the susceptibility to type 1 AIH. On the other hand, the OR of A/A homozygosity for type 1 AIH was 0.66 (95% CI 0.50–0.86). For PBC, the OR of G allele was 1.20 (95% CI 1.06–1.34). Furthermore, G/G homozygosity was significantly associated with the susceptibility to PBC (OR 1.29, 95% CI 1.01–1.66). The OR of A/A homozygosity for PBC was 0.81 (95% CI 0.70–0.94). Conclusions: This study suggests that CTLA‐4 gene +49A/G polymorphisms may be associated with the susceptibility to type 1 AIH and PBC. Especially, while G/G genotype may be associated with the susceptibility to PBC, A/A genotype may be protective against type 1 AIH and PBC.     

2010年自身免疫性肝病临床进展回顾

本文的目的在于回顾2010年原发性硬化性胆管炎、原发性胆汁性肝硬化、自身免疫性肝炎及重叠综合征在诊断、治疗及监测等方面的研究进展     

Recurrence of autoimmune liver diseases after liver transplantation

Liver transplantation(LT) is the most effective treatment modality for end stage liver disease caused by many etiologies including autoimmune processes. That said, the need for transplantation for autoimmune hepatitis(AIH) and primary biliary cirrhosis(PBC), but not for primary sclerosing cholangitis(PSC), has decreased over the years due to the availability of effective medical treatment. Autoimmune liver diseases have superior transplant outcomes than those of other etiologies. While AIH and PBC can recur after LT, recurrence is of limited clinical significance in most, but not all cases. Recurrent PSC, however, often progresses over years to a stage requiring re-transplantation. The exact incidence and the predisposing factors of disease recurrence remain debated. Better understanding of the pathogenesis and the risk factors of recurrent autoimmune liver diseases is required to develop preventive measures. In this review, we discuss the current knowledge of incidence, diagnosis, risk factors, clinical course, and treatment of recurrent autoimmune liver disease(AIH, PBC, PSC) following LT.     

自身免疫性肝病的回顾性研究

目的 提高对自身免疫性肝病的认识,以利于早期诊断、早期治疗.方法 回顾性对81例自身免疫性肝病患者进行诊断,比较自身免疫性肝炎(AIH)、原发性胆汁性肝硬化(PBC)及其重叠综合征(OS)的临床、血液化学及病理特点.结果 81例患者中,女性占91.4%;总体误诊率为45.7%,OS漏诊率为96.7%,初始诊断为肝硬化者60.5%(49/81),其中37%(30/81)为失代偿期肝硬化.AIH组18.2%(6/33)以急性肝功能衰竭发病,明显高于PBC、OS组,3组患者症状、体征基本一致,AIH、OS组患者丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)水平及抗核抗体(ANA)阳性率明显高于PBC组(Z=6.411,P=0.041;Z=7.980,P=0.019;X2=11.951,P=0.003),PBC、OS组患者血清门冬氨酸氨基转移酶(GGT)、碱性磷酸酶(ALP)、总胆固醇、载脂蛋白B水平及抗线粒体抗体(AMA)阳性率明显高于AIH组(Z=37.327,P=0.000;Z=12.929,P=0.002;Z=16.722,P=0.000;Z=6.695,P=0.035;X2=31.219,P=0.000).结论 自身免疫性肝病误诊率高.AIH、OS患者氨基转移酶升高明显,ANA阳性率高,PBC、OS患者GGT、ALP升高明显,血脂代谢障碍,AMA阳性率高.     

肝功能异常患者中自身抗体及自身免疫性肝病的检测

目的 自身免疫性肝病临床流行病学调查,观察在肝功能异常患者中自身抗体检测的阳性率、自身免疫性肝病检出率及临床意义。方法 连续收集就诊病例中肝功能异常患者丙氨酸氨基转移酶(ALT)大于40 U/L血清511份,分别进行相关自身抗体(ANA)检测,并查阅临床资料。结果 511份血清检测出ANA阳性率为14.09％,抗平滑肌抗体(SMA)阳性率0,59％,抗线粒体抗体(AMA)阳性率2.94％,抗线粒体抗体亚型-丙酮酸脱氢酶复合物(AMA-M2)阳性率0.98％;ANA谱中的SS-A阳性率0.59％、SS-B阳性率0.20％、JO-1阳性率0.20％,dsDNA阳性率0.78％;未检出抗肝肾微粒体抗体(LKM-1)、可溶性肝抗原/肝胰抗原(SLA/LP)、抗肝细胞溶质抗原1型抗体(LC-1)及ANA谱中其他抗体。从ALT升高的患者中收集到的511份血清,可查到完整临床资料者共469例。原发性胆汁性肝硬化(PBC)及自身免疫性肝炎(AIH)患者检出率分别为1.06％及0.43％,未检出原发性硬化性胆管炎患者。自身抗体阳性患者77.78％诊断为病毒性肝炎及相关疾病。病毒性肝炎及相关疾病中自身抗体阳性率为18.29％。结论 高滴度(>1:320)自身抗体对自身免疫性肝病诊断有意义。PBC及AIH患者检出率近似丙型及戊型肝炎检出率,临床不能忽视,病毒性肝炎及相关疾病中可检测出自身抗体。