Clinical features of type 1 autoimmune hepatitis in adolescence and early adulthood

Aim:  The peak age of the presentation of autoimmune hepatitis (AIH) is between 40 years and 50 years. Elderly patients have been reported to have higher frequencies of concurrent thyroid or rheumatic diseases and histological cirrhosis and a lower occurrence of treatment failure. In this study, we assessed the clinical features of Japanese type 1 AIH in adolescence and early adulthood.
Methods:  Fifteen patients aged ≤ 30 years (group 1) were compared with 79 patients aged between 40 years and 50 years (group 2).
Results:  At presentation, patients aged ≤ 30 years accounted for 9% of the study population. Although frequencies of extrahepatic concurrent autoimmune diseases were similar between groups 1 and 2, a tendency toward a lower frequency of concurrent autoimmune thyroiditis was shown in group 1 (0 vs. 18%, P  = 0.08). Group 1 had a lower frequency of human leukocyte antigen DR4 (27 vs. 78%, P  = 0.002), and histological acute hepatitis was shown more frequently in group 1 (27 vs. 4%, P  = 0.002). However, there were no differences in frequencies of the normalization of serum transaminase levels after the introduction of corticosteroid treatment or relapse after the normalization of serum transaminase levels between the two groups.
Conclusions:  Japanese type 1 AIH patients in adolescence and early adulthood respond well to corticosteroid treatment. However, they may frequently show atypical features, and the diagnosis of type 1 AIH in adolescence and early adulthood may be difficult and should be made carefully.     

Clinical features of Japanese type 1 autoimmune hepatitis patients with zone III necrosis

Aim: In Caucasians in northern Europe and North America, type 1 autoimmune hepatitis is characterized by susceptibility to human leukocyte antigens DR3 and DR4, and patients with zone III necrosis more frequently have an acute onset of the disease and a lower frequency of cirrhosis than those without. In Japanese patients, however, type 1 autoimmune hepatitis is primarily associated with DR4, and there are almost no DR3-positive patients. Thus, the clinical features of Japanese patients with type 1 autoimmune hepatitis and zone III necrosis may be different from those reported previously for Caucasians. Methods: We investigated 160 consecutive patients with type 1 autoimmune hepatitis (20 males and 140 females; median age, 55 years; range, 16-79 years). Results: Forty-seven patients (29%) had zone III necrosis, and these patients had lower serum levels of albumin and higher serum levels of total bilirubin, aspartate aminotransferaseand alanine aminotransferase. Histologically, zone III necrosis was found more frequently in patients with acute hepatitis than in those with chronic hepatitis. However, there was no difference in the frequency of cirrhosis between patients with and without zone III necrosis. In addition, normalization of serum alanine aminotransferase levels within six months after the introduction of corticosteroid treatment was slightly more frequent in patients with zone III necrosis (95% vs. 88%). Conclusion: In Japanese patients, zone III necrosis may reflect not only acute autoimmune hepatitis, but also acute exacerbation of pre-existing chronic disease. Furthermore, patients with zone III necrosis may respond better to corticosteroid treatment than those without.     

Human leukocyte antigen DR status and clinical features in Japanese patients with type 1 autoimmune hepatitis.

Aim: Human leukocyte antigen (HLA) DR status affects the clinical features of autoimmune hepatitis. In Caucasians, patients with DR3 have poorer outcomes. In Japan, the relationship between HLA DR status and clinical features has yet to be fully examined. Methods: We investigated 79 patients with type 1 autoimmune hepatitis who underwent liver biopsy and were screened for HLA DR status by the polymerase chain reaction sequence specific oligonucleotide hybridization method. Results: Fifty-five patients had DR4 and 23 had DR2. Thirteen patients had both DR2 and DR4. None had DR3. Of patients aged <30 years, 70% did not have DR4. A tendency toward higher serum levels of immunoglobulin G was seen in patients with DR4 compared to those without, while patients with neither DR2 nor DR4 had lower serum levels of immunoglobulin G than those with only DR2 and those with only DR4. Patients with DR2 had a lower frequency of concurrentautoimmune disease. Concurrence of thyroid disease was seen only in patients with DR4. The cumulative incidental rate of the normalization of serum alanine aminotransferase levels within six months after the introduction of corticosteroid treatment was not associated with HLA DR status. Conclusion: HLA DR status is considered to affect the clinical features of Japanese patients with type 1 autoimmune hepatitis. Japanese patients with DR2 may have different clinical features from others. In addition, diagnoses of type 1 autoimmune hepatitis should be made carefully in Japanese patients with neither DR2 nor DR4 and in those aged <30 years.     

Impact of pretransplant antinuclear antibody and antismooth muscle antibody titers on disease recurrence and graft survival following liver transplantation in autoimmune hepatitis patients

Background and Aims: Disease recurrence following transplantation occurs in 20–45% of patients with autoimmune hepatitis (AIH). Factors associated with an increased risk of recurrence include human leukocyte antigen (HLA) DR3 and HLA DR4 positivity, inadequate immunosuppression, and severity of inflammation in the native liver. Titers of several autoantibodies can be elevated in patients with AIH, including antinuclear antibody (ANA) and antismooth muscle antibody (SMA); however, it is unclear whether or not the degree of elevation influences the risk of disease recurrence following transplantation. Methods: We conducted a retrospective study to evaluate the potential impact of pretransplant titers on post‐transplant outcomes for patients with AIH. Sixty‐three patients with AIH who underwent 72 liver transplants between 1 January 1989 and 1 January 2009 were included, with a median follow up of 10 months. Patients were divided into group A (ANA or SMA ≥ 1 : 160) and group B (titers ≤ 1 : 160). Results: There was no significant difference in the recurrence rates or death between patients in groups A and B, respectively. Only race appeared to impact outcomes, with African American patients having a higher incidence of death and recurrent disease post‐transplant compared to other ethnicities. Conclusions: Based on our findings, pretransplant ANA and SMA levels do not appear to impact recurrence rates or outcomes following liver transplantation for AIH.     

Clinical characteristics of patients with autoimmune hepatitis seropositive for anticentromere antibody

Aim: Recent studies have revealed that primary biliary cirrhosis patients with anticentromere antibody (ACA) commonly develop portal hypertension. However, the clinical characteristics of autoimmune hepatitis (AIH) remain uncertain. We investigated the clinical features of patients with AIH seropositive for ACA (ACA‐AIH), comparing them with those of patients with AIH seropositive for other immunofluorescent patterns of antinuclear antibodies (ANA) (other‐AIH). Methods: AIH was diagnosed on the basis of the scoring system proposed by the International Autoimmune Hepatitis Group. Seropositivity for ACA was determined by a discrete speckled pattern on HEp‐2 cells by an immunofluorescent technique. The severity of histological grading and staging was evaluated by the histological activity index (HAI) score. Results: Eight (17%) of 47 patients with AIH had ACA. No significant differences in age, sex, onset pattern of the disease, progression to hepatic failure and relapse rate were present between the ACA‐AIH and other‐AIH groups. The frequency of concurrent autoimmune diseases in ACA‐AIH was significantly higher than that in other‐AIH (75% vs 36%, P = 0.0406). Biochemical analysis revealed a significantly lower mean immunoglobulin G (IgG) level than that in other‐AIH (2176 ± 641 vs 3013 ± 923 mg/dL, P = 0.0150). However, there were no differences in serum alanine aminotransferase levels, titers of ANA, HAI scores or the positive rate of human leukocyte antigen (HLA)‐DR4 between the groups. Conclusion: These results suggest that the emergence of ACA is not a distinct entity of AIH, despite its clinical characteristics of a significantly higher frequency of concurrent autoimmune diseases and lower serum IgG levels.     

Frequency and significance of antibodies to chromatin in autoimmune hepatitis type I

AIMS AND METHODS: To assess the frequency and clinical significance of antibodies to chromatin (ACA) in autoimmune hepatitis (AIH), 36 Japanese patients with AIH type I were studied for serum reactivity with chromatin by using an ELISA. RESULTS: Antibodies to chromatin were detected in 19 of 36 patients with AIH type I. There was a significantly higher frequency of ACA in patients with AIH type I than in patients with primary biliary cirrhosis, chronic hepatitis C and B (52.8 vs 13.2, 5.4 and 6.7%, respectively; P<0.01). None of the 19 healthy subjects had positive reactions. Sixteen of 19 patients with seropositive sera (44.4%) had reactivities with other nuclear antigens (recombinant nucleoproteins U1RNP-A, U1RNP-70; recombinant ribonucleoprotein complexes SSA/Ro 52K, SSA/Ro 60K; recombinant centromere Cenp-B; dsDNA and histones). Adsorption with double-stranded DNA (dsDNA) and histones could not remove the majority of antichromatin reactivity as 81.9% of the antibody reactivity still remained. In five sera samples from AIH type I patients positive for anti-dsDNA and antihistones, the antibody activities for dsDNA and histones were inhibited after the absorbtion of sera with chromatin. The patterns of antinuclear antibodies (ANA) detected by using indirect immunofluorescence were similar between patients with and without ACA. Patients with ACA had significantly high serum levels of gamma-globulin and immunoglobulin G. The ACA titers dropped significantly after corticosteroid treatment (P< 0.01). CONCLUSIONS: Antibodies to chromatin are frequently present in patients with AIH type I and they are one of the dominant autoantibodies associated with ANA reactivity in AIH type I. Antibodies to chromatin cannot be used to characterize distinct clinical subgroups of AIH type I.     

儿童IgG4相关自身免疫性肝炎临床与病理特征分析*

目的 探讨儿童免疫球蛋白G4相关自身免疫性肝炎(IgG4-AIH)患者临床和肝组织病理学特征。方法 2014年6月～2019年6月我科收治的AIH儿童38例,符合2008年国际AIH小组(IAIHG)制定的简化诊断积分系统或1999年IAIHG制定的AIH诊断评分系统。根据肝组织IgG4阳性浆细胞浸润≥10个/高倍镜视野(HPF)诊断IgG4-AIH。采用ELISA法检测血清IgG和IgG4。常规行肝穿刺,采用免疫组织化学染色检测肝组织IgG4阳性浆细胞。结果 在38例AIH患者中,诊断IgG4-AIH患者4例,AIH患者34例;IgG4-AIH患者血清IgG和IgG4水平分别为22.6(13.2, 29.8)mg/dL和226.5(105.8,424.6)mg/dL,与AIH患者的18.9(10.4,25.3)mg/dL和209.4(96.1,401.6)mg/dL比,差异无统计学意义(P>0.05);IgG4-AIH组肝组织IgG4阳性浆细胞计数/HPF为40.2(25.4,55.7),显著高于AIH组患者;IgG4-AIH组肝组织IgG4阳性浆细胞计数与炎性反应活动分级(r=0.48)和肝纤维化分期(r=0.37)呈正相关(P<0.05);IgG4-AIH患者血清ALT恢复正常所需要的时间为(3.5±0.8)w,显著短于AIH组,血清AST恢复时间为(3.6±0.6)w,显著短于AIH组,血清碱性磷酸酶恢复时间为(4.0±1.1)w,显著短于AIH组,血清谷氨酰转肽酶恢复时间为(4.2±1.5)w,显著短于AIH组,血清IgG水平恢复正常的时间为(7.6±2.8)w,显著短于AIH组。结论 IgG4-AIH儿童具有AIH的基本特征,血清IgG4水平并不比AIH患者更高,但肝组织IgG4阳性浆细胞浸润显著多于AIH患者。另外,IgG4-AIH儿童对皮质激素治疗具有良好的应答反应,血清学指标的恢复时间也相对较短,这些特征有助于临床诊断。本组IgG4-AIH儿童例数太少,其结论有待于验证。     

A case of autoimmune hepatitis with a high titer of antimitochondrial antibody and normal γ-globulinemia

We report here a patient with chronic active hepatitis who had no markers for hepatitis viruses and no hyper-gamma-globulinemia, but had high titers of antimitochondrial antibody. Serum levels of alkaline phosphatase were normal, and antinuclear antibody, antismooth muscle antibody, and antiliver kidney microsome antibody tested negative. The titers of antimitochondrial antibody exceeded 1:640, and the positivity for anti-M2 was ascertained by using both ELISA and immunoblot with beef-heart mitochondria and a recombinant pyruvate dehydrogenase E2 subunit as antigens. This patient responded to ursodeoxycholic acid (UDCA) therapy in the beginning, but her hepatitis flared up during UDCA therapy. In contrast, she responded completely to corticosteroid therapy. The clinical course and histological findings of this patient strongly suggest that this patient has autoimmune hepatitis.     

1型自身免疫性胰腺炎13例临床分析

目的总结1型自身免疫性胰腺炎(AIP)的临床特征,进一步认识该病,减少误诊率,加深人们对该病的认识。方法回顾性分析2012年1月-2016年12月吉林大学第一医院收治的13例1型AIP患者的临床资料,包括一般情况、临床表现、实验室血清学检查、影像学、组织病理学、治疗及预后等。结果 13例患者中男9例,女4例,平均(60.08±9.47)岁。主要临床表现为黄疸(69.2%)、腹痛(61.5%)、体质量减轻(61.5%);最常见合并累及器官为胆管受累(46.2%)、硬化性胆管炎(30.8%);23.1%患者合并糖尿病;血清学指标中92.30%患者Ig G4升高2倍以上,7.69%升高1~2倍,53.85%患者CA19-9升高,69.23%患者TBil升高,三分之二以上患者转氨酶或GGT升高;影像学表现上53.8%患者CT示胰腺弥漫性肿大,46.2%为局灶性肿大,46.2%胰腺病变区低密度包囊样边缘影;病理检查显示胰腺导管周围纤维结缔组织增生,伴大量淋巴细胞、浆细胞浸润。所有患者均接受正规的糖皮质激素治疗(起始剂量泼尼松30~40 mg/d),激素治疗缓解率100%。随访时间12个月,1例患者病程中多次复发。结论1型AIP是Ig G4相关性疾病在胰腺的局部表现,好发于中老年男性,常伴有胰腺外病变,激素治疗有效,预后良好,在不规范或不能长期激素治疗的情况下常有复发。     

A model for estimating cirrhosis in patients with type 1 autoimmune hepatitis

Aim:  Longstanding cirrhosis has been recognized as a risk factor for the development of hepatocellular carcinoma in patients with autoimmune hepatitis (AIH). Thus, the accurate determination of cirrhosis is important for prognostication, decisions regarding treatment and monitoring of disease progression. The aim of this study was to identify independent predictors of cirrhosis and to develop a model for estimating cirrhosis in patients with type 1 AIH.
Methods:  Using the training sample, consisting of 121 patients with type 1 AIH, we retrospectively examined independent predictors of cirrhosis and constructed a model for estimating cirrhosis. Validation was prospectively performed in the validation sample, consisting of 35 patients.
Results:  Using a stepwise multiple linear regression analysis, three predictors of serum immunoglobulin A level, ratio of aspartate aminotransferase to alanine aminotransferase, and platelet count were elicited, and a model for estimating cirrhosis was determined as follows: risk score = −0.113 + 0.0006056 × immunoglobulin A (mg/dL) + 0.155 × ratio of aspartate aminotransferase to alanine aminotransferase − 0.007079 × platelet (×10⁴/mm³). In the training sample, the sensitivity and specificity were 90% and 83%, respectively, when patients presenting a risk score ≥0.20 were estimated to be cirrhotic. When this model was applied to the validation sample, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy were 83%, 97%, 83%, 97% and 94%, respectively.
Conclusion:  It is suggested that this model could be useful for the estimation of cirrhosis in patients with type 1 autoimmune hepatitis.     

自身免疫性肝炎的病理特点

本文简要介绍了自身免疫性肝炎（AIH）发病机制的进展,阐述了AIH活动期和缓解期的病理形态特点及缓解的病理诊断标准。AIH的病理组织学特点为淋巴浆细胞性界面炎。急性加重或急性发病可呈现明显的小叶中心带坏死,这些病变中浆细胞成簇是诊断AIH的重要依据。肝穿病理形态有助于澄清其他自身抗体阳性的慢性肝病。并介绍了IgG4相关性自身免疫性肝炎和原位自身免疫性肝炎的病理特点     

IgG4相关自身免疫性肝炎诊治的研究进展

自身免疫性肝炎(AIH)是一种累及肝脏实质的慢性进展性炎症性疾病。近年来,对IgG4相关性疾病的研究日益增多,外国学者研究发现,AIH患者的肝脏亦有IgG4阳性浆细胞浸润,表明IgG4可能参与AIH的发病机制,进而认为这是AIH的特殊类型,称之为IgG4相关性AIH(IgG4-AIH)。对AIH与IgG4-AIH的诊治研究进展进行简要综述,从而加强临床医生对此类疾病的认知。     

Profiles of antinuclear antibodies in chronic active hepatitis,primary biliary cirrhosis and alcoholic liver disease

ABSTRACT— The profiles of specific antinuclear antibodies were determined in sera from 23 patients with the idiopathic type of chronic active hepatitis (CAH), 15 patients with primary biliary cirrhosis (PBC) and 25 patients with alcoholic liver disease (ALD). The indirect immunofluorescence test for antinuclear antibodies using cultured human embryonic fibroblasts as substrate was positive in 78% in CAH, in 73% in PBC and in 24% in ALD. Seventeen percent of CAH sera and 33% of PBC sera stained small speckles in interphase nuclei. This staining pattern probably represents a new subset of ANA as the centromeres (kinetochores) were not stained. Antibodies to native DNA by the Crithidia luciliae test were found in only one serum from a patient with CAH. In addition, 17 percent of the CAH sera reacted with the saline extract of rabbit thymus by double immunodiffusion. Antibodies to the Sm- or RNP-antigens were not found. SS-B antibodies could be demonstrated in 39% of the CAH sera by a sensitive immunoenzymatic technique. Patients with CAH also had significantly higher levels of antibodies against denatured, single-stranded DNA (ss-DNA) and a synthetic RNA molecule, poly(A) as compared to other groups. Patients with an atypical cholestatic CAH had an antinuclear-antibody profile resembling that of the other CAH patients, but different from that of PBC patients. Patients with alcoholic cirrhosis had significantly higher levels of ss-DNA- and poly(A)-antibodies than other patients with ALD. It is concluded that the determination of an antinuclear-antibody profile using the ELISA seems to be clinically useful in the classification of chronic liver diseases.     

Comparison of clinical features and liver histology in acute and chronic autoimmune hepatitis.

Aim: We investigated the clinical and morphological features between acute and chronic autoimmune hepatitis (AIH) with or without acute exacerbation. Methods & Results: Serum total bilirubin on average was elevated to 12 mg/dL in acute AIH, alanine aminotransferase and aspartate aminotransferase peaked to more than 1000 U/L, and serum gamma-glutamyl transpeptidase was higher in the acute type compared with the chronic type without exacerbation. Serum immunoglobulin G was lowest in all other types of AIH. A liver biopsy showed interface or lobular hepatitis with lympho-plasmacytic infiltration, and rosette formations were frequently seen in acute AIH. There were morphological changes of central necrosis with plasmacytic infiltration and giant cell hepatitis. CK19-positive cholangiolar cells had proliferated in the periportal area with massive necrosis, and bile duct injuries were seen in acute AIH more frequently than in the chronic type. Conclusion: Laboratory data and liver histology in acute AIH differed from those of chronic AIH and were clarified for the diagnosis of acute AIH.     

Features and consequences of untreated type 1 autoimmune hepatitis

Background/Aim: The existence of a mild form of autoimmune hepatitis that does not require treatment remains controversial. The aim of this study was to determine the existence, characteristics and outcome of this form. Methods: Untreated patients with type 1 autoimmune hepatitis who did not satisfy pre‐established criteria for severe disease were identified retrospectively and compared with treated patients. Results: Twenty‐one of 282 patients (7%) who were evaluated during a 32‐year period did not receive corticosteroid treatment. These asymptomatic patients constituted 15% of 137 patients who satisfied similar criteria for mild disease. Untreated patients with mild disease were indistinguishable from 116 treated patients with mild disease, and they differed from 145 treated patients with severe disease only by the pre‐established features that defined disease severity. The eight untreated patients with follow‐up assessments satisfied remission criteria less commonly than treated patients with mild or severe disease during 77±31 months of observation (12 vs 63%, P=0.006), and they had a lower 10‐year survival (67 vs 98%, P=0.01). Four patients did improve spontaneously albeit short of remission criteria and remained well for 28±15 months (range, 5–73 months). Four patients worsened during 125±51 months of observation (range, 32–239 months), including two of three patients with cirrhosis who died of liver failure. Conclusions: Mild type 1 autoimmune hepatitis does exist, and it may be as frequent as severe disease. Untreated patients with mild disease can improve spontaneously, but there are no confident indices by which to identify this subgroup and justify withholding treatment.     

Psychological stress is associated with relapse in type 1 autoimmune hepatitis

Background/aim: The pathophysiological basis of relapse and recrudescence in type 1 autoimmune hepatitis (AIH) is poorly understood. This study examined factors associated with biochemical relapse in type 1 AIH, and specifically addressed whether psychological stress was associated with a relapsing‐remitting disease course. Methods: A case–control study design was used to analyse 33 patients with AIH followed at the Yale Liver Clinic during a 4‐year period. Twenty‐two patients with 46 episodes of relapse or recrudescence (cases) and 11 controls in long‐term remission were identified during this period. Clinical variables were collected to establish factors associated with relapse. All patients were administered the Social Readjustment Rating Scale (SRRS), a psychological stress questionnaire consisting of 43 weighted life events. Stress is judged to be low when the score is 0–150; mild, 151–200; moderate, 201–300 and major >300. Results: AST, ALT, prednisone dose and SRRS score were all significantly different between cases and controls. The mean SRRS score for cases with relapse/recrudescence was 239 vs 152 for the control group, P=0.048 and remained significant on ancova analysis which accounted for covariables, P=0.05. Cases also identified additional stressors not represented in the SRRS at a significantly higher rate than controls. Conversely, the controls spontaneously identified coping strategies that may have allowed them to manage stress more effectively. Conclusion: Psychological stress is a significant factor that is associated with relapse in type 1 autoimmune hepatitis. Management of AIH may benefit from strategies to reduce stress and promote psychological well being.     

36例儿童自身免疫性肝炎的临床特征、肝脏病理及治疗转归分析

目的探讨儿童自身免疫性肝炎（autoimmunehepatitis,AIH）的临床特征、肝脏病理及治疗转归。方法回顾性分析2007年6月一2012年6月在我中心住院的36例儿童AIH的临床、肝脏病理、治疗及随访资料,进行统计学分析。结果①患者年龄中位数11岁（1．3～18．0岁）,女性占69．44％。②8．33％的患者急性起病,16．67％亚急性起病,75．00％慢性起病,30．56％就诊时已发展为肝硬化。36例ALT、AST、TBIL、球蛋白（GLO）和免疫球蛋白（IgG）分别为（223．88±218．11）u／L、（352．92_＋247．19）Ix／L、（90．20_＋79．09）Ixmol／L、（34．51±11．06）g／L和（31．43±15．07）g／Lc77．78％的患者IgG高于正常,41．67％血沉快。32例行肝脏病理检查,其中65．63％肝脏炎症≥3级,68．75％肝纤维化≥3期。③分组：I型占77．78％,Ⅱ型占19．44％,2．78％自身抗体全阴性。I型患者GLO和IgG平均值明显高于Ⅱ型（P=0．003、0．000）。④32例接受治疗,其中75．00％激素单药或联合免疫抑制剂治疗有效,12．50％疗效不佳。治疗有效患者中11例治疗中出现转氨酶波动,5例停药后转氨酶波动需再次治疗,1例停药6个月后肝功能维持正常。⑤7例治疗前后行2次肝脏穿刺均提示肝脏炎症明显减轻,纤维化程度改善。结论①儿童AIH发病以慢性起病多见,I型为主;@2／3的儿童AIH患者肝脏炎症和纤维化分期较重,均≥3级／3期;③75．00％的AIH患者激素单药或联合硫唑嘌呤治疗有效,激素治疗可明显改善炎症和纤维化程度,但需较长期治疗。