Paediatric autoimmune liver diseases: A descriptive study of patients from Saudi Arabia

Background and study aimsAutoimmune liver diseases (ALDs) are a clinico-pathologic spectrum of disorders that share some similarities. They are formally classified as autoimmune hepatitis (AIH), isolated autoimmune sclerosing cholangitis (ASC), and the overlap syndrome of these. We describe the clinical, biochemical, and outcomes data of a cohort of autoimmune ALDs patients in a tertiary care centre.Patients and methodsThis is a cross-sectional study conducted at King Abdulaziz University Hospital, Jeddah, Saudi Arabia. Data were collected in 2007–2018. All cases were 18 years old or younger at the time of diagnosis. The data collection comprised clinical, laboratory, imaging, treatment, and longitudinal follow-up data.ResultsTwenty-five patients were identified; 14 (56%) were females. Twenty-one patients (84%) had AIH-1,1 patient (4%) had AIH-2, and 3 patients (12%) had autoimmune sclerosing cholangitis (ASC). An insidious course was found in 21 (84%) cases. Acute hepatitis and fulminant hepatic failure was found to be very rare. Eight cases (32%) had cirrhosis at diagnosis. A total of 20 cases (80%) had complete remission following therapy. The median follow-up period was 45 months. There was no mortality, and only one patient was referred for transplant. Thus, the transplant-free survival was 96%.ConclusionsOur study showed predominance of AIH-1 over AIH-2. Response to treatment in our cohort was found to be similar to the results found in some other key studies. Prognosis and transplant-free survival is better than many published paediatric studies.     

自身免疫性肝病临床与病理研究

目的分析自身免疫性肝病临床、病理特点,探讨早期诊断、治疗方法。方法１９９６—１９９８年收治６２例自身免疫性肝病,比较原发性胆汁性肝硬化（ＰＢＣ）、自身免疫性肝炎（ＡＩＨ）的临床症状、体征、生物化学指标及病理特征。结果自身免疫性肝病中ＰＢＣ占５９．６８％, ＡＩＨ ４０．３２％。自身免疫性肝病中８３．８％是中老年女性,男女之比１∶１０,而ＡＩＨ　１∶５,发病年龄平均３５岁。ＰＢＣ中血循环自身免疫抗体阳性率８５．２９％,ＡＩＨ　７８．９５％。在阳性病例中 ＡＭＡ, ＡＭＡ－Ｍ２阳性率 １００％, ＡＮＡ阳性率 ８０％,血清免疫球蛋白异常, ＰＢＣ　ＩｇＭ增高占８０％, ＡＩＨＩｇＧ增高占８２．２５％, Ｐ值＜０．０５和Ｐ值＜ ０．０２５。 ＰＢＣ肝脏活组织病理显示,胆管炎和胆管增生、炎症、损伤或三者共存的特征。ＡＩＨ显示门静脉区炎症、淋巴细胞、单核细胞、浆细胞浸润、坏死、纤维化。结论ＰＢＣ和ＡＩＨ是自身免疫性肝病临床上两个常见类型,其中ＡＩＨ以Ⅰ型为主;而血中ＡＭＡ－Ｍ２是ＰＢＣ特征抗体,强的松龙治疗效果ＡＩＨ优于ＰＢＣ。     

Clinical usefulness of serum antibodies as biomarkers of gastrointestinal and liver diseases

The progressively growing knowledge of the pathophysiology of a number of immune-mediated gastrointestinal and liver disorders, including autoimmune atrophic gastritis, coeliac disease, autoimmune enteropathy, inflammatory bowel disease, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis and autoimmune pancreatitis, together with the improvement of their detection methods have increased the diagnostic power of serum antibodies. In some cases – coeliac disease and autoimmune atrophic gastritis – they have radically changed gastroenterologists’ diagnostic ability, while in others – autoimmune hepatitis, inflammatory bowel disease and autoimmune pancreatitis – their diagnostic performance is still inadequate. Of note, serum antibody misuse in clinical practice has raised a number of controversies, which may generate confusion in the diagnostic management of the aforementioned disorders. In this review, we critically re-evaluate the usefulness of serum antibodies as biomarkers of immune-mediated gastrointestinal and liver disorders, and discuss their pitfalls and merits.     

细胞因子与自身免疫性甲状腺疾病

自身免疫性甲状腺疾病(AITD)是最常见的器官特异性自身免疫性疾病,其中辅助性T细胞(Th)1/Th2细胞因子的动态平衡在维持正常的细胞免疫和体液免疫中起重要作用,一旦这种平衡被打破,将导致AITD的发生.这些细胞因子可以直接影响机体免疫细胞的活性,也可以通过影响甲状腺细胞免疫相关因子的表达,影响AITD的发生、发展,因此对细胞因子在AITD中发生机制的深入研究可为临床诊治提供更充分的理论依据.     

Prevalence and Relative Risk of Other Autoimmune Diseases in Subjects with Autoimmune Thyroid Disease

Background

Common autoimmune disorders tend to coexist in the same subjects and to cluster in families.

Methods

We performed a cross-sectional multicenter study of 3286 Caucasian subjects (2791 with Graves' disease; 495 with Hashimoto's thyroiditis) attending UK hospital thyroid clinics to quantify the prevalence of coexisting autoimmune disorders. All subjects completed a structured questionnaire seeking a personal and parental history of common autoimmune disorders, as well as a history of hyperthyroidism or hypothyroidism among parents.

Results

The frequency of another autoimmune disorder was 9.67% in Graves' disease and 14.3% in Hashimoto's thyroiditis index cases (P = .005). Rheumatoid arthritis was the most common coexisting autoimmune disorder (found in 3.15% of Graves' disease and 4.24% of Hashimoto's thyroiditis cases). Relative risks of almost all other autoimmune diseases in Graves' disease or Hashimoto's thyroiditis were significantly increased (>10 for pernicious anemia, systemic lupus erythematosus, Addison's disease, celiac disease, and vitiligo). There was relative “clustering” of Graves' disease in the index case with parental hyperthyroidism and of Hashimoto's thyroiditis in the index case with parental hypothyroidism. Relative risks for most other coexisting autoimmune disorders were markedly increased among parents of index cases.

Conclusion

This is one of the largest studies to date to quantify the risk of diagnosis of coexisting autoimmune diseases in more than 3000 index cases with well-characterized Graves' disease or Hashimoto's thyroiditis. These risks highlight the importance of screening for other autoimmune diagnoses if subjects with autoimmune thyroid disease present with new or nonspecific symptoms.     

自身免疫性胰腺炎

慢性胰腺炎是指由于胰腺实质反复或持续性炎症所导致的胰腺形态改变，伴有不同程度的胰腺内、外分泌功能障碍。既往认为其病因主要与急性胰腺炎或饮酒有关，近年米有研究发现Ⅱ类主要组织相容性复合物缺陷的人鼠可自发地发展为慢性胰腺炎，提示自身免疫可能也是其发病的原因之一并提出了自身免疫性胰腺炎概念。本文拟对此类胰腺炎的研究进展进行综述。     

细胞因子与自身免疫性甲状腺疾病

自身免疫性甲状腺疾病(AITD)是最常见的器官特异性自身免疫性疾病,其中辅助性T细胞(Th)1/Th2细胞因子的动态平衡在维持正常的细胞免疫和体液免疫中起重要作用,一旦这种平衡被打破,将导致AITD的发生.这些细胞因子可以直接影响机体免疫细胞的活性,也可以通过影响甲状腺细胞免疫相关因子的表达,影响AITD的发生、发展,因此对细胞因子在AITD中发生机制的深入研究可为临床诊治提供更充分的理论依据.     

Autoimmune paediatric liver disease

Liver disorders with a likely autoimmune pathogenesis in childhood include autoimmune hepatitis（AIH）,autoimmune sclerosing cholangitis（ASC）,and de novo AIH after liver transplantation.AIH is divided into two subtypes according to seropositivity for smooth muscle and/or antinuclear antibody（SMA/ANA,type 1） or liver kidney microsomal antibody（LKM1,type 2）.There is a female predominance in both.LKM1 positive patients tend to present more acutely,at a younger age,and commonly have partial IgA deficiency,while duration of symptoms before diagnosis,clinical signs,family history of autoimmunity,presence of associated autoimmune disorders,response to treatment,and long-term prognosis are similar in both groups.The most common type of paediatric sclerosing cholangitis is ASC.The clinical,biochemical,immunological,and histological presentation of ASC is often indistinguishable from that of AIH type 1.In both,there are high IgG,non-organ specific autoantibodies,and interface hepatitis.Diagnosis is made by cholangiography.Children with ASC respond to immunosuppression satisfactorily and similarly to AIH in respect to remission and relapse rates,times to normalization of biochemical parameters,and decreased inflammatory activity on follow up liver biopsies.However,the cholangiopathy can progress.There may be evolution from AIH to ASC over the years,despite treatment.De novo AIH after liver transplantation affects patients not transplanted for autoimmune disorders and is strikingly reminiscent of classical AIH,including elevated titres of serum antibodies,hypergammaglobulinaemia,and histological findings of interface hepatitis,bridging fibrosis,and collapse.Like classical AIH,it responds to treatment with prednisolone and azathioprine.De novo AIH postliver transplantation may derive from interference by calcineurin inhibitors with the intrathymic physiological mechanisms of T-cell maturation and selection.Whether this condition is a distinct entity or a form of atypical rejection in individuals susceptible to t     

Pediatric autoimmune liver disease and extra-hepatic immune-mediated comorbidities

Background

Autoimmune liver disease (AILD) includes autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC). AILD is often associated with other extra-hepatic immune-mediated disorders (EDs), but there are few pediatric studies available to date. In this study we evaluated the association between AILD and EDs in our pediatric series.

自身免疫性肝炎和原发性胆汁性肝硬化患者自身免疫性甲状腺疾病流行率调查*

目的 调查自身免疫性肝病(AILD)患者自身免疫性甲状腺疾病(AITD)发病率情况。 方法 2018年6月～2020年12月我院诊治的自身免疫性肝炎(AIH)41例和原发性胆汁性肝硬化(PBC)患者45例,采用间接免疫荧光法或免疫印迹法检测血清抗核抗体(ANA)、抗线粒体抗体(AMA)或AMA-M2)、抗平滑肌抗体(ASMA)、抗双链DNA抗体(抗dsDNA)和抗着丝点抗体(ACA);采用ELISA法检测血清免疫球蛋白,包括IgG、IgM和γ-球蛋白。结果 在本组41例AIH患者中,合并HT患者12例,合并GD患者6例,在45例PBC患者中,合并HT患者8例,合并GD患者7例;AIH患者血清IgG水平为17.5(14.8,19.8)g/L,显著低于AIH合并HT组【21.6(17.5,29.0)g/L,P<0.05】或AIH合并GD组【22.4(20.2,26.4)g/L,P<0.05】,血清γ-球蛋白为22.2(19.3,25.6)%,显著低于合并HT组【26.5(22.2,32.2)%,P<0.05】或合并GD组【27.1(24.3,32.0)%,P<0.05】;PBC患者年龄为(55.2±1.1)岁,显著小于合并HT组【(62.4±1.6)岁,P<0.05】或合并GD组【(62.2±1.5)岁,P<0.05】,血清IgG水平为15.4(12.2,18.0)g/L,显著低于合并HT组【20.3(16.8,24.7)g/L,P<0.05】或合并GD组【21.3(16.8,25.6)g/L,P<0.05】,血清γ-球蛋白水平为21.2(17.8,25.6)%,显著低于合并HT组【26.7(21.7,30.4)%,P<0.05】或合并GD组【25.4(22.2,29.4)%,P<0.05】。结论 AILD合并AITD的发病率较高,合并AITD患者血清IgG和γ-球蛋白水平较高,其原因还有待于进一步研究。     

HIV感染者的自身抗体检测分析

目的分析人免疫缺陷病毒（HIV）感染者中出现的自身抗体和自身免疫现象。方法回顾性分析经间接免疫荧光法检测过自身抗体的HIV感染者的临床和相关实验室指标。结果共有19例HIV感染者检测了自身抗体,明确合并银屑病、溃疡性结肠炎、特发性血小板减少性紫癜（ITP）的患者各1例;8例出现风湿性症状,主要表现为原因不明的皮疹（5例）、关节疼痛（2例）和肌痛（1例）。10例自身抗体检测结果阳性,出现的自身抗体分别为抗核抗体（ANA）、抗平滑肌抗体（SMA）、抗线粒体抗体（AMA）、抗细胞骨架抗体（CS）、抗胃壁细胞抗体（AP—CA）。自身抗体阳性组患者的IgG和IgA水平明显高于自身抗体阴性组（P〈0．05）。结论HIV感染者中可检测出自身抗体,而且可以合并有自身免疫病或免疫亢进的现象。     

Uveitis in autoimmune hepatitis： A case report

In this case report we describe for the first time an association between autoimmune hepatitis (AIH) and uveitis, without any doubts about other possible etiologies, such as HCV, since all the old reports describe the association of AIH with iridocyclitis before tests for HCV-related hepatitis could be available. A 38-year-old businessman with abnormal liver function tests and hyperemia of the bulbar conjunctiva was admitted to the hospital. Six years before admission, the patient presented with persistent fever, arthralgias, conjunctival hyperemia, leukocytosis and increased ESR, referred to acute rheumatic fever. The presence of systemic diseases, most commonly associated with uveitis, was investigated without results and the patient was then treated with topical corticosteroids. His symptoms resolved. A test for anti-nuclear antibodies was positive, at a titre of 1:320, with a speckled and nucleolar staining pattern. Liver ultrasound showed mild hepatomegaly with an increased echostructure of the liver. Percutaneous liver biopsy was performed under ultrasound assistance. Histological examination showed necroinflammation over the portal, periportal and lobular areas, fibrotic portal tracts, with periportal fibrosis and occasional portal-to-portal bridgings, but intact hepatic architecture. Some hepatocytes showed barely discernible granules of hemosiderin in the lobular area. Bile ductules had not any significant morphological alterations. METAVIR score was A2-F3, according to the modified HAI grading/fibrosis staging. The patient was diagnosed to have AIH with mild activity and fibrosis and was discharged on 25 mg prednisone, entering clinical and biochemical remission, further confirming diagnosis. After discharge the patient continued to have treatment with corticosteroids as an outpatient at a dose of 5 mg. On January 2002 the patient was readmitted to the hospital. A test for anti-nuclear antibodies was positive, at a titre of 1:320, with a speckled and nucleolar staining pattern. Anti-smooth muscle antibody test was also positive (1:160), while anti-LKM antibodies were negative. Ophthalmologic examination revealed inflammatory cells and proteinaceous flare in the anterior chamber of the left eye, and a stromal lesion in the cornea. He was maintained on immunosuppressive therapy (5 mg prednisone plus topical antibiotic therapy for two weeks) and then discharged. A complete remission of the symptoms was registered on follow-up. At present (July 2005), the patient is on prednisone (5 mg) and has no symptoms. Liver function tests are also within the normal range.     

A review of the utility of tacrolimus in the management of adults with autoimmune hepatitis

Background: There is paucity of data on alternative drug therapies for patients with autoimmune hepatitis (AIH). Tacrolimus (TAC) is a promising salvage agent. We present a review of TAC therapy in AIH patients.

Methods: A search for studies with keywords ‘autoimmune hepatitis’ and ‘tacrolimus’ was performed. Reviews, studies of AIH post-transplant and AIH in children were excluded. Diagnosis of AIH was based on criteria established by the International Autoimmune Hepatitis Group. Complete biochemical response was defined as normalisation of aspartate aminotransferase (AST <45) and alanine aminotransferase (ALT <50). No biochemical response was defined as failure to return to normalisation at the end of follow-up. Demographic information and details of pre- and post-treatment liver biopsy were collected.

Results: Seven articles achieved the inclusion criteria and reported data for a total of 162 adult patients. The majority of studies reported average ages approximately 35 years old. Treatment duration ranged from 1 to 136 months. Indications for therapy were mostly AIH refractory to steroid treatment or inability to tolerate standard steroid treatment. Eighty-three patients (51.2%) were reported to have pre-therapy liver biopsy. Of 49 patients for whom stage was reported, 6 patients were stage 1, 16 were stage 2, 14 were stage 3 and 13 were stage 4. Of 40 patients for whom grade was reported, 1 patient was grade 0, 3 were grade 1, 9 were grade 2, 14 were grade 3 and 13 were grade 4. Dosing regimens were between 1 and 8?mg/day. Target trough TAC serum concentrations ranged from 0.5 to 10.7?ng/mL TAC was discontinued in 28 (17.3%) patients for various reasons. Renal function remained stable in most patients. One hundred and twenty-one patients (74.7%) demonstrated complete biochemical response to treatment. Post-therapy liver biopsy was obtained for 30 (18.5%) patients, and 25 (15.4%) of these patients were noted to have histological remission according to the grade of inflammation or stage of fibrosis.

Conclusion: TAC is relatively effective in the treatment of AIH refractory to traditional therapy. It appears that liver function can be enhanced at a minimal cost to renal function.

Key Points

• There is a cohort of patients with autoimmune hepatitis (AIH) who do not respond to standard therapy.

• Alternative treatment options for these patients have been explored, but outcomes have not been comprehensively examined.

• We report the use and efficacy of tacrolimus (TAC) in patients with AIH.

• We found that TAC can be safely and effectively used in patients with AIH with minimal side effects.

• TAC can be a potential treatment option for patients with AIH refractory to standard therapy.

     

肝移植术治疗自身免疫性肝炎(附1例报告)

目的探讨肝移植术在自身免疫性肝炎(AIH)中的治疗价值。方法对1例AIH肝硬化患者行肝移植手术。结果患者术后恢复顺利,随访1年未出现排斥反应及复发,抗核抗体(ANA)转阴,肝功能正常。结论肝移植术可作为终末期AIH的有效治疗手段。     

药物性肝损伤与自身免疫性肝炎临床和肝组织病理学特征比较研究

目的 通过对比药物性肝损伤（ DILI）与自身免疫性肝炎（AIH）患者临床和肝组织病理学特点,以分析它们各自的诊断要点。方法 2014年2月~2016年4月在本院接受治疗的41例DILI患者和50例AIH患者,回顾性分析血清学和肝组织学特点。结果 DILI组血清ALT、AST、ALB和TBIL水平分别分306.35±214.84 U/L、311.21±168.24 U/L、39.21±6.89 g/L、276.48±169.20 μmol/L,均显著高于AIH组的223.12±179.26 U/L、245.31±220.62 U/L、26.07±8.39 g/L和139.55±87.27 μmol/L（P<0.05）;AIH组血清ASMA、抗LKM-1、抗SLA阳性率分别为78.00%、86.00%和82.00%,均显著高于DILI组的43.90%、51.22%和29.27%（P<0.05）; AIH组血清Ig G、Ig A和Ig M水平分别为23.12±5.26 g/L、3.86±1.26 g/L、2.38±0.94 g/L,均显著高于DILI组的10.44±6.34 g/L、1.91±0.82 g/L和1.02±0.67 g/L（P<0.05）;AIH患者肝组织浆细胞浸润和肝细胞玫瑰花结样结构检出率分别为92.00%和86.00%,均显著多于DILI组的26.83%和7.32%（P<0.05）,而DILI组患者汇管区中性粒细胞浸润和肝内胆汁淤积阳性率分别为90.24%和78.05%,均显著多于AIH组的38%和26%（P<0.05）。结论 DILI与AIH患者存在一些临床和肝组织病理学特点的不同,认真分析这些差异,有助于临床诊断和给予相应的治疗。     

Progressive multi-organ expression of immunoglobulin G4-related disease: A case report

A 63-year-old Caucasian man presented with a cholestatic syndrome, renal failure and arthralgias. A laboratory examination revealed high immunoglobulin G (IgG) and IgG4 levels (5.95 g/L; normal range: 0.08-1.4 g/L), pointing to a diagnosis of systemic IgG4-related disease, with definite radiological evidence of biliary and pancreatic expression, and plausible renal, articular, salivary and lacrimal glands involvement. Due to the rarity of the condition, there are currently no random control trials to point to the optimal therapeutic approach. The patient has been on steroid therapy with the subsequent introduction of azathioprine, with a complete resolution of all symptoms, a rapid reduction to normalization of all blood tests, and a complete regression of the radiological picture. Our experience underlines the complexity of IgG4-related disease and its variable and sometimes progressive presentation, while pointing out the need for a careful and complete assessment for possible multi-organ involvement.     

儿童1型糖尿病合并自身免疫性甲状腺疾病12例临床分析

目的 分析儿童1型糖尿病(T1DM)合并自身免疫甲状腺疾病(AITD)对T1DM治疗的影响。方法 1993～2002年在我院诊治的T1DM患儿合并甲状腺疾病者12例。对患儿的病史、家族史、体格检查及内分泌相关检查的结果进行分析。抗体检查：GAD-Ab、IAA、ICA、TG-Ab、TPO-Ab、TRAb和肾上腺皮质细胞浆抗体(ACC)。采用t检验将T1DM合并Graves病(GD)与合并桥本甲状腺炎(HT)者进行糖化血红蛋白(HbA1c)和胰岛素用量的分组比较；采用秩和检验对病程进行比较。结果 该组儿童患GD和HT者，分别为4例和8例。T1DM和AITD发病间隔为0～10年；GD的临床表现可不突出。有内分泌家族史者占25％。GD控制前患儿的HbA1c分别为10％、12％和14％，1例结束GD疗程者的HbA1c为7．8％。合并HT者的糖尿病代谢控制相对较好，HbA1c为7．2％～10％，1例新诊断T1DM合并HT且尚未治疗HT的患儿，HbA1c为6．3％。经t检验显示两组患儿的HbA1c差异有显著意义(P=0．011)，而病程和胰岛素用量差异无显著意义。结论该组患儿女性多于男性；HT患儿较GD患儿为多；有较强的内分泌疾病家族史。AITD影响糖尿病控制。T1DM患儿宜定期进行甲状腺自身抗体和甲状腺功能检查。     

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.