Autoimmune hepatitis:Appraisal of current treatment guidelines

Autoimmune hepatitis affects patients of all ages and gender, across all geographic regions. Although still rare, its incidence and prevalence are increasing. Genetic predisposition conveyed by human leucocyte antigen is a strong risk factor for the disease and may be responsible in part for the wide variation in presentation in different geographic regions. Our understanding of the underlying pathogenic mechanisms is evolving and may lead to development of more targeted immunotherapies. Diagnosis is based on elevated levels of serum aminotransferases, gamma globulins, autoantibodies and characteristic findings on histology. Exclusion of other causes of chronic hepatitis is important.Although undiagnosed disease is associated with poor outcomes, it is readily treatable with timely immunosuppressive therapy in the majority of patients.International guidelines are available to guide management but there exists a disparity in the standard treatment regimens. This minireview aims to review the available guidelines and summarize the key recommendations involved in management of this complex autoimmune disease.     

Low-dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis

AIM: To determine the eff icacy of tacrolimus on clinical status, histopathological status and biochemical markers in patients with steroid refractory autoimmune hepatitis (AIH). METHODS: Retrospectively, clinical parameters, biochemistry and histology were obtained from patient records. RESULTS: Nine patients [8 females/1 male, median age 32 (range 16-64) years] were identified to have received tacrolimus for a median duration of 18 (12-37) mo. Before initiation of tacrolimus treatment the patients were maintained on a prednisolone dose of 20 mg daily (range 20-80 mg/d), which was tapered to 7.5 (5-12.5) mg/d (P = 0.004). Alanine aminotransferase and immunoglobulin-G concentrations decreased from 154 (100-475) to 47(22-61) U/L (P = 0.007), and from 16 (10-30.2) to 14.5 (8.4-20) g/L (P = 0.032), respectively. All patients showed improvement of the liver inflammatory activity, as determined by the Ishak score (P = 0.016), while the degree of f ibrosis tended to decrease (P = 0.049). CONCLUSION: The use of low dose tacrolimus can lead to biochemical and histologic improvement of inflammation with no progression of the stage of f ibrosis in patients with steroid refractory AIH. Low dose tacrolimus therapy also allows substantial reduction of prednisone dose.     

Mycophenolate mofetil treatment in patients with autoimmune hepatitis failing standard therapy with prednisolone and azathioprine

Background

Data on rescue treatment of autoimmune hepatitis in patients that fail standard treatment are sparse.

Autoimmune hepatitis: new paradigms in the pathogenesis,diagnosis, and management

Autoimmune hepatitis (AIH), primary biliary cirrhosis, and primary sclerosing cholangitis are the three major autoimmune diseases affecting the liver, and of these three, AIH is the most typical autoimmune disease being characterized by a T-cell-rich infiltrate, raised circulating γ-globulins, autoantibodies, HLA associations, and links with other autoimmune diseases. It is the only one, of the three diseases, that responds well to immunosuppressive therapy. AIH is caused by dysregulation of immunoregulatory networks and the consequent emergence of autoreactive T cells that orchestrate a progressive destruction of hepatocytes leading untreated to liver failure. T cells play a major role in the immunopathogenesis, and both CD4⁺ and CD8⁺ T cells are involved together with effector responses mediated by NK cells, γδ T cells, and macrophages. A number of triggering factors have been proposed including viruses, xenobiotics, and drugs, but none have been conclusively shown to be involved in pathogenesis.     

Update on autoimmune hepatitis

Autoimmune hepatitis （AIH） is a necroinflammatory liver disease of unknown etiology that occurs in children and adults of all ages. Characteristics are its autoimmune features, hyperglobulinemia （IgG）, and the presence of circulating autoantibodies, as well as a response to immunosuppressant drugs. Current treatment consists of prednisone and azathioprine and in most patients this disease has become very treatable. Over the past 2 years, a couple of new insights into the genetic aspects, clinical course and treatment of AIH have been reported, which will be the focus of this review. In particular, we concentrate on genome-wide microsatellite analysis, a novel mouse model of AIH, the evaluation of a large AIH cohort for overlap syndromes, suggested novel criteria for the diagnosis of AIH, and the latest studies on treatment of AIH with budenoside and mycophenolate mofetil.     

Autoimmune hepatitis triggered by acute hepatitis A

The patient was a 57-year-old woman presenting with jaundice as the chief complaint. She began vomiting on July 10, 2003. Jaundice was noted and admitted to our hospital for thorough testing. Tests on admission indicated severe hepatitis, based on: aspartate aminotransferase (AST), 1 076 IU/L; alanine aminotransferase (ALT), 1 400 IU/L; total bilirubin (TB), 20.9 mg/dL; and prothrombin time rate (PT%), 46.9%. Acute hepatitis A (HA) was diagnosed based on negative hepatitis B surface antigen and hepatitis C virus RNA and positive immunoglobulin (Ig) M HA antibody, but elevation of anti-nuclear antigen (x320) and IgG (3 112 mg/dL) led to suspicion of autoimmune hepatitis (AIH). Plasma exchange was performed for 3 d from July 17, and steroid pulse therapy was performed for 3 d starting on July 18, followed by oral steroid therapy. Liver biopsy was performed on August 5, and the results confirmed acute hepatitis and mild chronic inflammation. Levels of AST and ALT normalized, so dose of oral steroid was markedly reduced. Steroid therapy was terminated after 4 mo, as the patient had glaucoma. Starting 3 mo after cessation of steroid therapy, levels of AST and ALT began to increase again. Another liver biopsy was performed and AIH was diagnosed based on serum data and biopsy specimen. Oral steroid therapy was reinitiated. Levels of AST and ALT again normalized. The present case was thus considered to represent AIH triggered by acute HA.     

儿童自身免疫性肝炎1例

<正>自身免疫性肝炎(autoimmune hepatitis,AIH)可出现高丙种球蛋白血症和自身抗体阳性,临床表现缺乏特异性。多见于女性,且40岁以后发病率高~([1]),最小发病年龄为6个月~([2-4])。目前,儿童AIH的治疗仍以泼尼松联合或不联合硫唑嘌呤为一线用药~([5-7])。如不治疗,其5 a和10 a生存率分别为50%和10%~([8])。1病例摘要患儿女,5岁5个月,藏族。因"皮肤黄、眼黄、尿黄10     

Management of autoimmune hepatitis:Focus on pharmacologic treatments beyond corticosteroids

In autoimmune hepatitis, patients who are intolerant or with toxicity experience, non-responders, relapsers or refractory are challenging. Non-standard drugs are being tried to preemptively avoid corticosteroid-related side effects. Prognosis and quality of life of life rely on treatment optimization. Recently, emergence of powerful immunosuppressive agents, mainly from liver transplantation, challenged the supremacy of the corticosteroid regime and promise greater immunosuppression than conventional medications, offer site-specific actions and satisfactory patient tolerance. Successes in experimental models of related diseases have primed these molecular interventions. We performed a literature review on alternative treatments. Azatioprine intolerance is the principal indication for mycophenolate use butit can be used as a front-line therapy. Cyclosporine A and tacrolimus have been tested for non-responders or relapsers. Rituximab may be used as salvage therapy. Anti-tumor necrosis factor-alpha agents may be used for incomplete responses or non-responders. Methotrexate is possibly an alternative for induction of remission and maintenance in refractory patients. Cyclophosphamide has been included in the induction regimen with corticosteroids. Ursodeoxycholic acid action is mainly immunomodulatory. Non-standard treatments are coming slowly to the attention, but its use should be cautious performed by experienced centers.     

Hepatocellular carcinoma in the elderly:Meta-analysis and systematic literature review

AIM: To conduct a meta-analysis to investigate theclinical outcomes of surgical resection and locoregional treatments for hepatocellular carcinoma(HCC) in elderly patients defined as aged 70 years or more. METHODS: Literature documenting a comparison of clinical outcomes for elderly and non elderly patients with hepatocellular carcinoma was identified by searching Pub Med, Ovid, Cochrane Library, and Web of Science databases, for those from inception to March 2015 with no limits. Dichotomous outcomes and standard meta-analysis techniques were used. Heterogeneity was tested by the Cochrane Q statistic. Pooled estimates were measured using the fixed or random effect model.RESULTS: Twenty three studies were included with a total of 12482 patients. Of these patients, 6341 were treated with surgical resection, 3138 were treated with radiofrequency ablation(RFA), and 3003 were treated with transarterial chemoembolization(TACE). Of the patients who underwent surgical resection, the elderly had significantly more respiratory co-morbidities than the younger group, with both groups having a similar proportion of cardiovascular co-morbidities and diabetes. After 1 year, the elderly group had significantly increased survival rates after surgical resection compared to the younger group(OR = 0.762, 95%CI: 0.583-0.994, P = 0.045). However, the 3-year and 5-year survival outcomes with surgical resection between the two groups were similar(OR = 0.947, 95%CI: 0.777-1.154, P = 0.67 for the third year; and OR = 1.131, 95%CI: 0.895-1.430, P = 0.304 for the fifth year). Postoperative treatment complications were similar between the elderly and younger group. The elderly group and younger group had similar survival outcomes for the first and third year after RFA(OR = 1.5, 95%CI: 0.788-2.885, P = 0.217 and OR = 1.352, 95%CI: 0.940-1.944, P = 0.104). For the fifth year, the elderly group had significantly worse survival rates compared to the younger group after RFA(OR = 1.379, 95%CI: 1.079-1.763, P = 0.01). For patients who underwent TACE, the elderly group had significantlyincreased survival compared to the younger group for the first and third year(OR = 0.664, 95%CI: 0.548-0.805, P = 0.00 and OR = 0.795, 95%CI: 0.663-0.953, P = 0.013). At the fifth year, there were no significant differences in overall survival between the elderly group and younger group(OR = 1.256, 95%CI: 0.806-1.957, P = 0.313). CONCLUSION: The optimal management strategy for elderly patients with HCC is dependent on patient and tumor characteristics. Compared to patients less than 70, elderly patients have similar three year survival after resection and ablation and an improved three year survival after TACE. At five years, elderly patients had a lower survival after ablation but similar survival with resection and TACE as compared to younger patients. Heterogeneity of patient populations and selection bias can explain some of these findings. Overall, elderly patients have similar success, if not better, with these treatments and should be considered for all treatments after assessment of their clinical status and cancer burden.     

Autoimmune hepatitis in patients with multiple sclerosis: The role of immunomodulatory treatment

BackgroundDevelopment of autoimmune hepatitis (AIH) has been sporadically reported in patients with multiple sclerosis (MS) either concurrently or after treatment with immunomodulatory drugs, including interferon-beta (IFN-β) and steroids.AimTo report a large cohort of 14 patients with MS diagnosed with AIH during an assessment of deranged liver function tests (LFTs).Patients and methodsFrom 2005 to 2017, we prospectively identified 14 (13 women) patients with MS who suffered also from AIH after investigation in our department for the presence of deranged LFTs. Age at diagnosis of MS was 36.7 ± 9.3 years while at diagnosis of AIH 43.1 ± 12 years.ResultsAIH diagnosis was based on elevation of aminotransferases in all patients [alanine aminotransferase: 520 IU/L (range: 115–1219)], elevation of IgG in 6, compatible autoantibody profile in all, including 5 patients with liver-specific autoantibodies and typical or compatible histological features in 11 patients. 5 patients were under treatment with IFN-β plus methylprednisolone pulses, 3 with IFN-β plus oral steroids, 1 with IFN-β, 4 with methylprednisolone pulses whereas 1 patient was free of treatment. The median time from IFN-β initiation to the development of hepatitis was 12 months (range:1–120). Treatment for AIH was initiated in 13 patients with prednisolone (0.5–1 mg/kg/day) plus mycophenolate myfetil (2 g/day) in 10 and prednisolone plus azathioprine in 3 with complete and partial response in 11 and 2 patients, respectively.ConclusionsThe differential diagnosis of hepatitis in MS patients should include AIH and in particular when immunomodulatory treatment has been preceded. Autoantibody testing and liver histology play fundamental role in establishing a prompt diagnosis of AIH in these patients. Treatment of AIH in patients with MS seems safe and efficient as complete or partial response was recorded in all of our patients.     

Azathioprine-induced fever in autoimmune hepatitis

Underdiagnosis of drug-induced fever leads to extensive investigation and prolongation of hospitalization, and may lead to multiple unnecessary invasive procedures and a wrong diagnosis. Azathioprine is a widely used immunosuppressive drug. We report a case of a 53-year-old female patient diagnosed with autoimmune hepatitis treated with azathioprine, who presented to the emergency room with a 6-wk history of fever and chills without other associated symptoms. Since the patient’s fever was of unknown origin, she was hospitalized. All treatment was stopped and an extensive workup to explore the source of fever and chills was performed. Results of chest X-ray, viral, urine, and blood cultures, autoimmune serology, transthoracic and transesophageal echocardiography, and abdominal ultrasound revealed no source of infection. A rechallenge test of azathioprine was performed and the fever and chills returned within a few hours. Azathioprine was established as the definite cause following rechallenge. Fever as an adverse drug reaction is often unrecognized. Azathioprine has been reported to cause druginduced fever in patients with inflammatory bowel disease, rheumatoid arthritis, and sarcoidosis. To the bestof our knowledge there have been no previous reports documenting azathioprine-induced fever in patients with autoimmune hepatitis. The occurrence of fever following the readministration of azathioprine suggests the diagnosis of drug-induced fever, particularly after the exclusion of other causes. A careful rechallenge is recommended to confirm the diagnosis.     

布地奈德与泼尼松分别联合硫唑嘌呤治疗自身免疫性肝炎

目的比较布地奈德联合硫唑嘌呤与泼尼松联合硫唑嘌呤治疗自身免疫性肝炎(AIH)的疗效。方法选择宝鸡市中心医院2015年1月至2018年1月收治的90例AIH患者,随机分为布地奈德组联合硫唑嘌呤与泼尼松组联合硫唑嘌呤,各45例。2组均连续治疗2年。比较2组临床总缓解率、治疗前后的血清ALT、AST、ALP、γ-GT水平与不良反应总发生率。结果布地奈德组临床总缓解率88.89%(40/45),显著高于泼尼松组71.11%(32/45)(P<0.05)。2组治疗2年后的血清ALT、AST、ALP、γ-GT水平均较治疗前显著下降(P<0.05)。布地奈德组治疗后的血清ALT、AST、ALP、γ-GT水平分别为(27.42±5.36)U/L、(29.97±4.52)U/L、(88.11±14.32)U/L、(49.52±7.62)U/L显著低于泼尼松组(P<0.05)。布地奈德组治疗期间不良反应总发生率15.56%(7/45),显著低于泼尼松组35.56%(16/45)(P<0.05)。结论布地奈德联合硫唑嘌呤治疗AIH可获得更高的缓解率,更明显的生物化学指标改善,且不良反应更少,效果优于泼尼松联合硫唑嘌呤。     

Autoimmune hepatitis in human immunodeficiency virus-infected patients: A case series and review of the literature

BACKGROUND Abnormal liver chemistry is a common problem in human immunodeficiency virus(HIV)-infected patients. Common causes of abnormal liver enzymes in this population include viral hepatitis B/C or opportunistic infection, drug toxicity,and neoplasm. Autoimmune hepatitis is a rare cause of hepatitis in HIV-infected individuals; however, this condition has been increasingly reported over the past few years.CASE SUMMARY We present 13 HIV-infected patients(5 males and 8 females) who developed autoimmune hepatitis(AIH) after their immune status was restored, i.e. all patients had stable viral suppression with undetectable HIV viral loads, and median CD4+ counts of 557 cells/× 10~6 L. Eleven patients presented with chronic persistent elevation of aminotransferase enzyme levels. One patient presented with acute hepatitis and the other patient presented with jaundice. The median levels of aspartate aminotransferase and alanine aminotransferase enzymes were178 and 177 U/m L, respectively. Elevation of immunoglobulin G levels was present in 11(85%) patients. Antinuclear antibody and anti-smooth muscle antibody were positive in 11(85%) and 5(38%) patients. Liver biopsy was performed in all patients. They had histopathological findings compatible withAIH. The patients were started on prednisolone for remission induction, with good response. After improvement of the liver chemistry, the dose of prednisolone was tapered, and azathioprine was added as life-long maintenance therapy. At the last follow-up visit, all were doing well, without HIV viral rebound or infectious complications.CONCLUSION This report underscores the emergence of autoimmune hepatitis in the context of HIV infection.     

雷公藤多甙、硫唑嘌呤联合甘草酸二铵治疗自身免疫性肝炎患者初步临床研究

目的 探讨雷公藤多甙片、硫唑嘌呤片联合甘草酸二铵治疗自身免疫性肝炎（AIH）患者的疗效。方法 将2015年1月~2016年1月我院收治的68例AIH患者随机分为对照组和观察组,每组34例。给予对照组患者硫唑嘌呤片联合甘草酸二铵治疗,观察组在对照组治疗的基础上接受雷公藤多甙片治疗3个月,观察两组治疗前后血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、碱性磷酸酶（ALP）和总胆红素（TBIL）、血清免疫球蛋白IgG、IgA和IgM以及肝纤维化指标透明质酸（HA）和层粘蛋白（LN）的变化,观察两组治疗期间不良反应事件发生情况。结果 在治疗3个月末,观察组患者血清ALT、AST、ALP和TBIL水平分别为（51.7±7.2） U/L、（45.6±8.1） U/L、（67.4±3.2） U/L和（11.4±1.2） μmol/L,显著低于对照组[分别为（79.7±11.9） U/L、（77.1±9.2） U/L、（87.1±4.0） U/L和（15.3±1.4） μmol/L,P<0.05];观察组血IgG、IgA和IgM水平分别为（11.29±2.24） mg/ml、（2171.4±100.3） mg/L和（2218.8±98.2） mg/L,均显著低于对照组[分别为（14.80±2.75） mg/ml、（2839.9±107.0） mg/L和（2912.0±113.1） mg/L,P<0.05];观察组血清HA、LN和PCⅢ水平分别为（112.4±6.8）μg/L、（61.3±4.6）μg/L和（52.4±3.3）μg/L,均较对照组显著降低[（164.2±7.3）μg/L、（82.6±5.7）μg/L和（79.2±4.4）μg/L,P<0.05];在治疗期间两组均未出现严重不良反应。结论 雷公藤多甙片、硫唑嘌呤片联合甘草酸二铵治疗AIH患者临床疗效优于硫唑嘌呤片联合甘草酸二铵治疗者。     

Silymarin treatment of viral hepatitis: a systematic review

Silymarin from the milk thistle herb (Silybum marianum) is used by many patients with chronic viral hepatitis, but its efficacy remains unknown. We performed a systematic review of silymarin for the treatment of chronic viral hepatitis B and C. An exhaustive search strategy identified 148 papers that studied silymarin compounds in liver disease. Of these, four trials included patients with hepatitis C, one included hepatitis B patients, and two, unspecified chronic viral hepatitis. However, only one trial exclusively studied patients with hepatitis C, and none involved patients with only hepatitis B. Silymarin treatment resulted in a decrease in serum transaminases compared with baseline in four studies, and compared with placebo in only one study. There is no evidence that silymarin affects viral load or improves liver histology in hepatitis B or C. No studies were found that investigated the use of silymarin concomitantly with interferon, nucleoside analogues, or other conventional treatments for hepatitis B or C. In conclusion, silymarin compounds likely decrease serum transaminases in patients with chronic viral hepatitis, but do not appear to affect viral load or liver histology. Nevertheless it may be worthwhile to determine its effects in conjunction with standard antiviral treatment.     

自身免疫性肝炎合并淋巴结肿大14例分析

目的分析自身免疫性肝炎（autoimmunehe patitis，AIH）合并淋巴结肿大的临床特点及探讨可能形成原因。方法回顾性分析2000年1月～2008年1月在天津医科大学总医院确诊的114例AIH患者的临床资料。结果114例A1H患者分为两组，其中A组无淋巴结肿大100例，B组合并淋巴结肿大14例，二者对比分析。A、B两组比较，B组易出现肝硬化（57／100vs12／14，P〈0．05），两组白细胞、血小板差异有统计学意义（P〈0．05）。结论AIH可合并淋巴结肿大，且合并淋巴结肿大者较易出现肝硬化，表现脾功能亢进，可能是AIH预后不良的一个指标。     

Cryoglobulinemia in elderly patients with HCV-related chronic hepatitis

Hepatitis C virus (HCV) infection affects about 3% of the world's population and often leads to chronic liver disease. In some industrialized countries, HCV prevalence increases with age, but the optimal management of older patients has not been accurately defined. HCV infection can also lead to lymphoproliferative disorders, the most common being mixed cryoglobulinemia (MC), and also for this condition that frequently affects elderly patients, the optimal therapeutic strategy is still debated. We report the case of a 77-year-old Caucasian woman with HCV-related chronic hepatitis and cutaneous manifestations consisting of urticaria and pruritus related to MC resistant to antihistamines. The patient underwent a treatment with interferon and ribavirin. Such a treatment led to early biochemical and virological response associated with the resolution of cryoglobulinemia and cutaneous symptoms. After the end of treatment, HCV replication relapsed, but cryoglobulinemia and cutaneous symptoms did not recur. In the absence of definite treatment guidelines in this particular context, our experience suggests that the presence of symptoms related to HCV-infection that deeply affect patient quality of life warrants antiviral therapy even beyond the age limits that currently exclude patients from treatment.     

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.