|
1
|
Ueno M, Takabatake H, Hata A, Kayahara T, Morimoto Y, Notohara K, Mizuno M. Mycophenolate mofetil for immune checkpoint inhibitor‐related hepatotoxicity relapsing during dose reduction of corticosteroid: A report of two cases and literature review. Cancer Rep (Hoboken) 2022; 5:e1624. [PMID: 35575047 PMCID: PMC9458512 DOI: 10.1002/cnr2.1624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 03/27/2022] [Accepted: 04/17/2022] [Indexed: 11/21/2022] Open
Abstract
Background Immune checkpoint inhibitors (ICIs) sometimes cause immune‐related liver injury, which can lead to cessation of treatment, hospitalization, and even mortality. Although high‐dose corticosteroids are usually effective in treatment of ICI‐related liver injury, one fifth of affected patients require additional immunosuppressive therapy. It remains uncertain how best to treat ICI‐related liver injury that relapses under corticosteroid therapy after temporary remission. Case Here we report two cases of ICI‐related liver injury successfully treated with mycophenolate mofetil (MMF). In the first case, a 74‐year‐old man with stage IIIA lung cancer underwent curative chemoradiotherapy. After the second infusion of durvalumab, grade 3 ICI‐related liver injury (mixed pattern) developed. In the second case, a 46‐year‐old man with stage IVB lung cancer received pembrolizumab‐containing chemotherapy. After the first cycle, grade 2 ICI‐related hepatitis developed. In the both cases, liver injury improved with high‐dose prednisolone but relapsed during tapering of the drug. After liver biopsy was performed to confirm the diagnosis of ICI‐related liver injury, MMF (2000 mg/day) was added. MMF was effective for both patients and permitted discontinuation or reduction of prednisolone. Conclusion MMF appears to be an appropriate treatment option for ICI‐related liver injury that respond to high‐dose corticosteroids but relapse during steroid tapering.
Collapse
Affiliation(s)
- Masayuki Ueno
- Department of Gastroenterology and Hepatology Kurashiki Central Hospital Okayama Japan
- Department of Gastroenterology and Hepatology, Graduate School of Medicine Kyoto University Kyoto Japan
| | - Hiroyuki Takabatake
- Department of Gastroenterology and Hepatology Kurashiki Central Hospital Okayama Japan
| | - Ayako Hata
- Department of Gastroenterology and Hepatology Kurashiki Central Hospital Okayama Japan
| | - Takahisa Kayahara
- Department of Gastroenterology and Hepatology Kurashiki Central Hospital Okayama Japan
| | - Youichi Morimoto
- Department of Gastroenterology and Hepatology Kurashiki Central Hospital Okayama Japan
| | - Kenji Notohara
- Department of Anatomic Pathology Kurashiki Central Hospital Okayama Japan
| | - Motowo Mizuno
- Department of Gastroenterology and Hepatology Kurashiki Central Hospital Okayama Japan
| |
Collapse
|
|
2
|
Autoimmune Hepatitis-Immunologically Triggered Liver Pathogenesis-Diagnostic and Therapeutic Strategies. J Immunol Res 2019; 2019:9437043. [PMID: 31886312 PMCID: PMC6899271 DOI: 10.1155/2019/9437043] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 09/15/2019] [Accepted: 09/21/2019] [Indexed: 12/20/2022] Open
Abstract
Autoimmune hepatitis (AIH) is a severe liver disease that arises in genetically predisposed male and female individuals worldwide. Diagnosis of AIH is made clinically applying diagnostic scores; however, the heterotopic disease phenotype often makes a rapid determination of disease challenging. AIH responds favorably to steroids and pharmacologic immunosuppression, and liver transplantation is only necessary in cases with acute liver failure or end-stage liver cirrhosis. Recurrence or development of de novo AIH after transplantation is possible, and treatment is similar to standard AIH therapy. Current experimental investigations of T cell-mediated autoimmune pathways and analysis of changes within the intestinal microbiome might advance our knowledge on the pathogenesis of AIH and trigger a spark of hope for novel therapeutic strategies.
Collapse
|
|
3
|
Terziroli Beretta-Piccoli B, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: Standard treatment and systematic review of alternative treatments. World J Gastroenterol 2017; 23:6030-6048. [PMID: 28970719 PMCID: PMC5597495 DOI: 10.3748/wjg.v23.i33.6030] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2017] [Revised: 07/18/2017] [Accepted: 08/02/2017] [Indexed: 02/06/2023] Open
Abstract
Autoimmune hepatitis is a rare chronic inflammatory liver disease, affecting all ages, characterised by elevated transaminase and immunoglobulin G levels, positive autoantibodies, interface hepatitis at liver histology and good response to immunosuppressive treatment. If untreated, it has a poor prognosis. The aim of this review is to summarize the evidence for standard treatment and to provide a systematic review on alternative treatments for adults and children. Standard treatment is based on steroids and azathioprine, and leads to disease remission in 80%-90% of patients. Alternative first line treatment has been attempted with budesonide or cyclosporine, but their superiority compared to standard treatment remains to be demonstrated. Second-line treatments are needed for patients not responding or intolerant to standard treatment. No randomized controlled trials have been performed for second-line options. Mycophenolate mofetil is the most widely used second-line drug, and has good efficacy particularly for patients intolerant to azathioprine, but has the major disadvantage of being teratogenic. Only few and heterogeneous data on cyclosporine, tacrolimus, everolimus and sirolimus are available. More recently, experience with the anti-tumour necrosis factor-alpha infliximab and the anti-CD20 rituximab has been published, with ambivalent results; these agents may have severe side-effects and their use should be restricted to specialized centres. Clinical trials with new therapeutic options are ongoing.
Collapse
Affiliation(s)
| | - Giorgina Mieli-Vergani
- Paediatric Liver, GI and Nutrition Centre, MowatLabs, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom
| | - Diego Vergani
- Institute of Liver Studies, MowatLabs, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom
| |
Collapse
|
|
4
|
Enomoto H, Nishiguchi S. Similarities and Differences in Autoimmune Hepatitis Epidemiology between East and West: Autoimmune Hepatitis in East Asia, Southeast Asia, and South Asia. Inflamm Intest Dis 2017; 1:150-158. [PMID: 29922671 DOI: 10.1159/000454879] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Background Autoimmune hepatitis (AIH) is a relatively rare disease that can develop regardless of age or ethnicity. However, its clinical features differ between eastern and western populations due to several heterogeneous genetic and environmental factors. We herein report the clinical characteristics of AIH patients in East Asia, Southeast Asia, and South Asia. Summary and Key Messages The prevalence of AIH in eastern countries is considered to be lower than in western countries. Although a few young patients with type 2 AIH have been observed in South Asia, most patients in Asia are middle-aged women with type 1 AIH who respond well to steroid-based immunosuppressive therapy. Human leukocyte antigen DR4 is suggested to be an influential factor in the genetic background of AIH patients in Asia, particularly in East Asia. Notably, AIH may be induced by some societal- or culture-associated medicines, including herbal medicines. The IAIHG (International Autoimmune Hepatitis Group) scoring systems are generally accepted as the standard diagnostic methods for AIH in Asian countries. The results of repeated nationwide surveys in Japan suggest that the clinical features of AIH patients in East Asia are changing, with IgG levels and rates of anti-nuclear antibody positivity decreasing.
Collapse
Affiliation(s)
- Hirayuki Enomoto
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| |
Collapse
|
|
5
|
Abstract
Autoimmune hepatitis (AIH) is a chronic progressive liver disease characterized by high levels of aminotransferases and autoantibodies, hypergammaglobulinemia, and interface hepatitis. AIH affects all races and all ages worldwide, regardless of sex, although a preponderance of females is a constant finding. The etiology of AIH has not been completely elucidated, but immunogenetic background and environmental parameters may contribute to its development. The most important genetic factor is human leukocyte antigens (HLAs), especially HLA-DR, whereas the role of environmental factors is not completely understood. Immunologically, disruption of the immune tolerance to autologous liver antigens may be a trigger of AIH. The diagnosis of classical AIH is fairly easy, though not without pitfalls. In contrast, the diagnosis of atypical AIH poses great challenges. There is confusion as to the definition of the disease entity and its boundaries in the diagnosis of overlap syndrome, drug-induced autoimmune hepatitis, and AIH with concomitant nonalcoholic fatty liver disease (NAFLD) or chronic hepatitis C. Centrilobular zonal necrosis is now included in the histological spectrum of AIH. However, the definition and the significance of AIH presenting with centrilobular zonal necrosis have not been examined extensively. In ~20% of AIH patients who are treated for the first time with standard therapy, remission is not achieved. The development of more effective and better tolerated novel therapies is an urgent need. In this review, we discuss the current challenges and the future prospects in relation to the diagnosis and treatment of AIH, which have been attracting considerable recent attention.
Collapse
Affiliation(s)
- Yoshio Aizawa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University Katsushika Medical Center, Katsushika-ku, Tokyo, Japan
| | - Atsushi Hokari
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University Katsushika Medical Center, Katsushika-ku, Tokyo, Japan
| |
Collapse
|
|
6
|
Torisu Y, Nakano M, Takano K, Nakagawa R, Saeki C, Hokari A, Ishikawa T, Saruta M, Zeniya M. Clinical usefulness of ursodeoxycholic acid for Japanese patients with autoimmune hepatitis. World J Hepatol 2017; 9:57-63. [PMID: 28105259 PMCID: PMC5220272 DOI: 10.4254/wjh.v9.i1.57] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Revised: 09/25/2016] [Accepted: 11/22/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the therapeutic effects of ursodeoxycholic acid (UDCA) on autoimmune hepatitis (AIH).
METHODS A total 136 patients who were diagnosed with AIH were included in our study. All of the patients underwent a liver biopsy, and had at least a probable diagnosis on the basis of either the revised scoring system or the simplified scores. Initial treatment included UDCA monotherapy (Group U, n = 48) and prednisolone (PSL) monotherapy (Group P, n = 88). Group U was further classified into two subgroups according to the effect of UDCA: Patients who had achieved remission induction with UDCA monotherapy and showed no sign of relapse (Subgroup U1, n = 34) and patients who additionally received PSL during follow-up (Subgroup U2, n = 14). We compared the clinical and histological findings between each groups, and investigated factors contributing to the response to UDCA monotherapy.
RESULTS In Group U, 34 patients (71%) achieved and maintained remission over 49 (range: 8-90) mo (Subgroup U1) and 14 patients (29%) additionally received PSL (Subgroup U2) during follow-up. Two patients in Subgroup U2 achieved remission induction once but additionally required PSL administration because of relapse (15 and 35 mo after the start of treatment). The remaining 12 patients in Subgroup U2 failed to achieve remission induction during follow-up, and PSL was added during 7 (range: 2-18) mo. Compared with Subgroup U2, Subgroup U1 had significantly lower alanine aminotransferase (ALT) levels at onset (124 IU/L vs 262 IU/L, P = 0.023) and a significantly higher proportion of patients with mild inflammation (A1) on histological examination (70.6% vs 35.7%, P = 0.025). When multivariate analysis was performed to identify factors contributing to the response to UDCA monotherapy, only a serum ALT level of 200 IU/L or lower was found to be associated with a significant difference (P = 0.013).
CONCLUSION To prevent adverse events related to corticosteroids, UDCA monotherapy for AIH needs to be considered in patients with a serum ALT level of 200 IU/L or lower.
Collapse
|
|
7
|
Reardon J, Hussaini T, Alsahafi M, Azalgara VM, Erb SR, Partovi N, Yoshida EM. Ursodeoxycholic Acid in Treatment of Non-cholestatic Liver Diseases: A Systematic Review. J Clin Transl Hepatol 2016; 4:192-205. [PMID: 27777888 PMCID: PMC5075003 DOI: 10.14218/jcth.2016.00023] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Revised: 06/30/2016] [Accepted: 07/12/2016] [Indexed: 12/11/2022] Open
Abstract
Aims: To systematically evaluate the literature for evidence to support the use of bile acids in non-cholestatic liver conditions. Methods: Searches were conducted on the databases of Medline (1948-March 31, 2015), Embase (1980-March 31, 2015) and the Cochrane Central Register of Controlled Trials, and on Google and Google Scholar to identify articles describing ursodeoxycholic acid (UDCA) and its derivatives for non-cholestatic hepatic indications. Combinations of the following search terms were used: ursodeoxycholic acid, ursodiol, bile acids and/or salts, non alcoholic fatty liver, non alcoholic steatohepatitis, fatty liver, alcoholic hepatitis, alcohol, liver disease, autoimmune, autoimmune hepatitis, liver transplant, liver graft, transplant rejection, graft rejection, ischemic reperfusion injury, reperfusion injury, hepatitis B, hepatitis C, viral hepatitis, chronic hepatitis, acute hepatitis, transaminases, alanine transaminase, liver enzymes, aspartate aminotransferase, gamma-glutamyl transferase, gamma-glutamyl transpeptidase, bilirubin, alkaline phosphatase. No search limits were applied. Additionally, references of the included studies were reviewed to identify additional articles. Results: The literature search yielded articles meeting inclusion criteria for the following indications: non-alcoholic fatty liver disease (n = 5); alcoholic liver disease (n = 2); autoimmune hepatitis (n = 6), liver transplant (n = 2) and viral hepatitis (n = 9). Bile acid use was associated with improved normalization of liver biochemistry in non-alcoholic fatty liver disease, autoimmune hepatitis and hepatitis B and C infections. In contrast, liver biochemistry normalization was inconsistent in alcoholic liver disease and liver transplantation. The majority of studies reviewed showed that normalization of liver biochemistry did not correlate to improvement in histologic disease. In the prospective trials reviewed, adverse effects associated with the bile acids were limited to minor gastrointestinal complaints (most often, diarrhea) and did not occur at increased frequency as compared to controls. As administration of bile acids was often limited to durations of 12 months or less, long-term side effects for non-cholestatic indications cannot be excluded. Conclusions: Based on the available literature, bile acids cannot be widely recommended for non-cholestatic liver diseases at present.
Collapse
Affiliation(s)
- Jillian Reardon
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Trana Hussaini
- Division of Gastroenterology, The University of British Columbia, Diamond Health, Vancouver, British Columbia, Canada
- Pharmaceutical Sciences Clinical Service Unit, Vancouver General Hospital, Vancouver, British Columbia, Canada
| | - Majid Alsahafi
- Division of Gastroenterology, The University of British Columbia, Diamond Health, Vancouver, British Columbia, Canada
| | - Vladimir Marquez Azalgara
- Division of Gastroenterology, The University of British Columbia, Diamond Health, Vancouver, British Columbia, Canada
| | - Siegfried R. Erb
- Division of Gastroenterology, The University of British Columbia, Diamond Health, Vancouver, British Columbia, Canada
| | - Nilufar Partovi
- Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, British Columbia, Canada
- Pharmaceutical Sciences Clinical Service Unit, Vancouver General Hospital, Vancouver, British Columbia, Canada
| | - Eric M. Yoshida
- Division of Gastroenterology, The University of British Columbia, Diamond Health, Vancouver, British Columbia, Canada
| |
Collapse
|
|
8
|
Morii K, Nagano Y, Yamamoto T, Nakamura S, Okushin H. Increasing incidence of elderly-onset autoimmune hepatitis. Geriatr Gerontol Int 2016; 17:1722-1728. [PMID: 27531184 DOI: 10.1111/ggi.12874] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Revised: 06/16/2016] [Accepted: 06/23/2016] [Indexed: 12/24/2022]
Abstract
AIM Autoimmune hepatitis (AIH) commonly shows bimodal distribution of onset age: at young adulthood and at 50-60 years-of-age. However, in recent times, the incidence of elderly-onset AIH seems to be increasing. This study aimed to investigate whether the incidence of elderly-onset AIH is increasing, and whether these patients show any clinical features different from those observed in younger patients. METHODS Data about patients with newly diagnosed AIH visiting the Japanese Red Cross Society Himeji Hospital, Himeji, Hyogo, Japan, were retrospectively collected for the period ranging from January 2010 to May 2016. A total of 71 patients (56 women and 15 men, age 18-88 years) were included in this study. Patients were divided into two cohorts: elderly (≥70 years; n = 28) and adult cohort (15-69 years; n = 43). Demographic and clinical characteristics, biochemical and serological markers, radiological and histological findings, and therapeutic courses were evaluated. RESULTS The median age of the patients was 65 years, the most frequent range being the 70s (37%), followed by the 60s (25%). The elderly cohort had significantly higher levels of serum immunoglobulin G and antinuclear antibody, lesser hepatitis activity scores, and lesser chance of developing other autoimmune diseases. They tended to have higher C-reactive protein levels and lower serum alanine aminotransferase levels. All patients achieved clinical remission after treatment. CONCLUSIONS This study clearly showed an increase in the incidence of elderly-onset AIH. These patients had some unique characteristics, showing that the development of elderly-onset AIH is influenced by age-associated immune dysfunction called immunosenescence. Geriatr Gerontol Int 2017; 17: 1722-1728.
Collapse
Affiliation(s)
- Kazuhiko Morii
- Department of Hepatology, Japanese Red Cross Society Himeji Hospital, Himeji, Hyogo, Japan
| | - Yuh Nagano
- Department of Hepatology, Japanese Red Cross Society Himeji Hospital, Himeji, Hyogo, Japan
| | - Takeharu Yamamoto
- Department of Hepatology, Japanese Red Cross Society Himeji Hospital, Himeji, Hyogo, Japan
| | - Shinichiro Nakamura
- Department of Gastroenterology and Hepatology, Okayama University Hospital, Kitaku, Okayama, Japan
| | - Hiroaki Okushin
- Department of Hepatology, Japanese Red Cross Society Himeji Hospital, Himeji, Hyogo, Japan
| |
Collapse
|
|
9
|
Kawamura T, Hiraoka A, Toshimori A, Ueki H, Kaneto M, Aibiki T, Okudaira T, Yamago H, Nakahara H, Tomida H, Suga Y, Azemoto N, Mori K, Miyata H, Ninomiya T, Hirooka M, Abe M, Matsuura B, Hiasa Y, Kito K, Michitaka K. A Possible Case of Hepatitis due to Hypereosinophilic Syndrome. Intern Med 2016; 55:1453-8. [PMID: 27250051 DOI: 10.2169/internalmedicine.55.5982] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
A 63-year-old Japanese man whose white blood cell count and total-bilirubin and aminotransferase levels were elevated was referred to our hospital. Computed tomography did not reveal any abnormalities, and there was no evidence of gastritis or colitis on esophagogastroduodenoscopy. Although the patient had no history of drug use or allergies, a high concentration of eosinophils (80%) was noted. A liver biopsy revealed hepatitis with eosinophilic infiltration. The patient's alanine aminotransferase and eosinophil levels improved with the administration of steroids. A second biopsy, performed 6 months later, showed the improvement of the eosinophilic infiltration. The patient was diagnosed with eosinophilic hepatitis due to the presence of hypereosinophilic syndrome without the dysfunction of other organs.
Collapse
Affiliation(s)
- Tomoe Kawamura
- Gastroenterology Center, Ehime Prefectural Central Hospital, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
10
|
Casal Moura M, Liberal R, Cardoso H, Horta e Vale AM, Macedo G. Management of autoimmune hepatitis: Focus on pharmacologic treatments beyond corticosteroids. World J Hepatol 2014; 6:410-418. [PMID: 25018851 PMCID: PMC4081615 DOI: 10.4254/wjh.v6.i6.410] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Accepted: 05/08/2014] [Indexed: 02/06/2023] Open
Abstract
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 but it 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.
Collapse
|
|
11
|
Czaja AJ. Hepatic inflammation and progressive liver fibrosis in chronic liver disease. World J Gastroenterol 2014; 20:2515-32. [PMID: 24627588 PMCID: PMC3949261 DOI: 10.3748/wjg.v20.i10.2515] [Citation(s) in RCA: 255] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 10/24/2013] [Accepted: 11/12/2013] [Indexed: 02/06/2023] Open
Abstract
Chronic liver inflammation drives hepatic fibrosis, and current immunosuppressive, anti-inflammatory, and anti-viral therapies can weaken this driver. Hepatic fibrosis is reversed, stabilized, or prevented in 57%-79% of patients by conventional treatment regimens, mainly by their anti-inflammatory actions. Responses, however, are commonly incomplete and inconsistently achieved. The fibrotic mechanisms associated with liver inflammation have been clarified, and anti-fibrotic agents promise to improve outcomes as adjunctive therapies. Hepatitis C virus and immune-mediated responses can activate hepatic stellate cells by increasing oxidative stress within hepatocytes. Angiotensin can be synthesized by activated hepatic stellate cells and promote the production of reactive oxygen species. Anti-oxidants (N-acetylcysteine, S-adenosyl-L-methionine, and vitamin E) and angiotensin inhibitors (losartin) have had anti-fibrotic actions in preliminary human studies, and they may emerge as supplemental therapies. Anti-fibrotic agents presage a new era of supplemental treatment for chronic liver disease.
Collapse
|
|
12
|
Pure red cell aplasia associated with autoimmune hepatitis successfully treated with cyclosporine A. Clin J Gastroenterol 2014; 7:74-8. [PMID: 24523831 PMCID: PMC3915077 DOI: 10.1007/s12328-013-0448-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Accepted: 12/15/2013] [Indexed: 11/03/2022]
Abstract
A 47-year-old female with a 17-year history of autoimmune hepatitis had been treated with prednisolone, azathioprine, and ursodeoxycholic acid. Although her alanine aminotransferase level occasionally showed mild abnormality, the prednisolone dose could not be increased because she had developed cataract during the course of her illness. In May 2012, she developed severe normochromic normocytic anemia without hemorrhage, and azathioprine was discontinued because it was suspected of being the cause. However, anemia recurred frequently even after discontinuation, necessitating repeated blood transfusions. Bone marrow analysis revealed selective erythroblastopenia, thus leading to a diagnosis of pure red cell aplasia. Cyclosporine A was administered, which led to a dramatic recovery from anemia, and stabilized her alanine aminotransferase levels. Furthermore, the prednisolone dose could be gradually tapered. Pure red cell aplasia associated with autoimmune hepatitis is extremely rare. The present case shows that patients with autoimmune hepatitis refractory to the standard treatment regimen and those with concomitant pure red cell aplasia may be treated with cyclosporine A.
Collapse
|
|
13
|
Czaja AJ. Review article: the management of autoimmune hepatitis beyond consensus guidelines. Aliment Pharmacol Ther 2013; 38:343-64. [PMID: 23808490 DOI: 10.1111/apt.12381] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2013] [Revised: 05/30/2013] [Accepted: 06/03/2013] [Indexed: 12/17/2022]
Abstract
BACKGROUND Consensus guidelines aid in the diagnosis and management of autoimmune hepatitis, but they are frequently based on low-quality clinical evidence, conflicting experiences and divergent opinions. Recommendations may be weak, discrepant or non-existent at critical decision points. AIMS To identify the decision points where guidelines are weak or non-existent and review the evidence essential in the decision process. METHODS Full-text articles published in English using the keyword 'autoimmune hepatitis' were identified by PubMed from 1972 to 2013. Personal experience and investigations in autoimmune hepatitis also identified important contributions. RESULTS Seventy per cent of the guidelines developed by the American Association for the Study of Liver Diseases and 48% of those proposed by the British Society of Gastroenterology are based on low-quality evidence, conflicting experiences or divergent opinions. The key uncertainties in diagnosis relate to the timing of liver biopsy, recognising acute severe (fulminant) disease, interpreting coincidental nonclassical histological changes, accommodating atypical or deficient features in non-White patients, differentiating drug-induced from classical disease and identifying overlap syndromes. The key uncertainties in management relate to pre-treatment testing for thiopurine methyltransferase activity, treating asymptomatic mild disease, determining treatment end points, managing suboptimal responses, incorporating nonstandard medications as front-line and salvage agents, using azathioprine in pregnancy and instituting surveillance for hepatocellular carcinoma. CONCLUSIONS Consensus guidelines are fraught with uncertainties in the diagnosis and management of autoimmune hepatitis. Each decision point must counterbalance the current available evidence and tailor the application of this evidence to the individual patient.
Collapse
Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
| |
Collapse
|
|
14
|
Czaja AJ. Autoimmune hepatitis in diverse ethnic populations and geographical regions. Expert Rev Gastroenterol Hepatol 2013; 7:365-85. [PMID: 23639095 DOI: 10.1586/egh.13.21] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Autoimmune hepatitis has diverse clinical phenotypes and outcomes in ethnic groups within a country and between countries, and these differences may reflect genetic predispositions, indigenous etiological agents, pharmacogenomic mechanisms and socioeconomic reasons. In the USA, African-American patients have cirrhosis more commonly, treatment failure more frequently and higher mortality than white American patients. Survival is poorest in Asian-American patients. Autoimmune hepatitis in other countries is frequently associated with genetic predispositions that may favor susceptibility to indigenous etiological agents. Cholestatic features influence treatment response; acute-on-chronic liver disease increases mortality and socioeconomic and cultural factors affect prognosis. Ethnic-based deviations from classical phenotypes and the frequency of late-stage disease can complicate the diagnosis and management of autoimmune hepatitis in non-white populations.
Collapse
Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
| |
Collapse
|
|
15
|
Overlap syndromes of autoimmune hepatitis: an open question. Dig Dis Sci 2013; 58:344-8. [PMID: 23086110 DOI: 10.1007/s10620-012-2378-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2011] [Accepted: 08/20/2012] [Indexed: 01/15/2023]
Abstract
The headword "overlap syndromes" of liver diseases includes the coexistence of autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. These syndromes often represent a diagnostic and therapeutic challenge for hepatologists; it remains unclear whether these overlap syndromes form distinct entities or they are only variants of the major autoimmune liver diseases. The most frequent reported association occurs between autoimmune hepatitis and primary biliary cirrhosis, whereas the overlap between autoimmune hepatitis and primary sclerosing cholangitis is less frequent, typically at young age and often attendant with an inflammatory bowel disease. The choice therapy is based on ursodeoxycholic acid and immunosuppressive drugs, used at the same time or consecutively, according to the course of disease. The diagnostic scores for autoimmune hepatitis can help for diagnosis, even though their definitive soundness is lacking.
Collapse
|
|
16
|
Hino-Arinaga T, Ide T, Kuromatsu R, Miyajima I, Ogata K, Kuwahara R, Hisamochi A, Torimura T, Sata M. Risk factors for hepatocellular carcinoma in Japanese patients with autoimmune hepatitis type 1. J Gastroenterol 2012; 47:569-76. [PMID: 22187167 DOI: 10.1007/s00535-011-0519-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Accepted: 11/23/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is occasionally seen even in patients with autoimmune hepatitis (AIH) without prior infection either with hepatitis C virus (HCV) or hepatitis B virus. The aim of this study was to identify the incidence of and risk factors for HCC with AIH in a large-scale population with a long-term follow-up in Japan. METHODS One hundred and eighty patients diagnosed with AIH were enrolled (F/M = 159/21; mean age, 59.9 years; mean observation period, 80.2 months). Patients with positive HCV antibody/serum HCV RNA and/or positive HBs Ag were excluded. Initial treatment included immunosuppressant therapy (n = 147), other drugs (n = 28), and no drug (n = 5). Patients underwent abdominal ultrasonography at intervals of 3-6 months during observation. Patients' demographic factors, biochemical data, liver histology, medications, response to treatment, and complications were evaluated in relation to HCC. RESULTS During the observation period, six patients (3.3%) developed HCC. Univariate analysis showed that risk factors for HCC were cirrhosis at diagnosis with AIH (p = 0.0002), absence of a treatment response (p = 0.033), abnormal alanine aminotransferase (ALT) at the final observation (p = 0.0002), and diabetes (p = 0.0015). Multivariate analysis showed that risk factors for HCC were cirrhosis at diagnosis of AIH (odds ratio 4.08) and abnormal ALT at final observation (odds ratio 3.66). CONCLUSION This retrospective study showed that cirrhosis at diagnosis of AIH and abnormal ALT at final observation were independently associated with HCC development. It is important to pay attention to the presence of cirrhosis at diagnosis of AIH and to normalize ALT.
Collapse
Affiliation(s)
- Teruko Hino-Arinaga
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
17
|
Abstract
While a certain international consensus has been reached regarding the diagnosis and treatment of autoimmune hepatitis (AIH), there are some unique clinical characteristics of AIH in Japan. For diagnosis of AIH using the new simplified criteria proposed by the International Autoimmune Hepatitis Group, it is necessary to re-evaluate the antibody titer determined by using HEp-2 cells, which are widely used in Japan, and the finding of emperipolesis in liver histology, although the criteria are useful for rapid identification of AIH in routine clinical practice. The use of azathioprine as first-line therapy for AIH is limited in Japan because the drug is not covered by the Japanese national health insurance. Concomitant use of ursodeoxycholic acid (UDCA) to reduce corticosteroids and use of UDCA as monotherapy are therefore considered promising. Moreover, a relatively good survival rate has been reported in patients who developed AIH-induced acute liver failure and underwent living-donor liver transplantation. Current trends in the diagnosis and treatment of AIH in Japan are described in this report with a review of recent findings.
Collapse
Affiliation(s)
- Hiromasa Ohira
- Department of Gastroenterology and Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | | |
Collapse
|
|
18
|
Muratori L, Muratori P, Granito A, Pappas G, Cassani F, Lenzi M. Current topics in autoimmune hepatitis. Dig Liver Dis 2010; 42:757-764. [PMID: 20615766 DOI: 10.1016/j.dld.2010.05.019] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2010] [Revised: 05/23/2010] [Accepted: 05/31/2010] [Indexed: 12/11/2022]
Abstract
Autoimmune hepatitis is a chronic liver disease of unknown aetiology characterized by interface hepatitis, hypergammaglobulinaemia and circulating autoantibodies. In the last decade a number of advancements have been made in the field of clinical and basic research: the simplified diagnostic criteria, the complete response defined as normalization of transaminase levels, the molecular identification of the antigenic targets of anti-liver cytosol antibody type 1 and anti-soluble liver antigen, the detection of anti-actin antibodies, the description of de novo autoimmune hepatitis after liver transplantation for non-autoimmune liver diseases, the characterization of autoimmune hepatitis with overlapping features of primary biliary cirrhosis or primary sclerosing cholangitis, the preliminary experience with novel treatment strategies based on cyclosporine, mycophenolate mofetil and budesonide, the role played by "impaired" regulatory T cells and the development of novel animal models of autoimmune hepatitis.
Collapse
MESH Headings
- Animals
- Autoantibodies/immunology
- Autoantigens/immunology
- Biomarkers/blood
- Budesonide/therapeutic use
- Cholangitis, Sclerosing/complications
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/immunology
- Cholangitis, Sclerosing/therapy
- Cyclosporine/therapeutic use
- Glucocorticoids/therapeutic use
- Hepatitis, Autoimmune/complications
- Hepatitis, Autoimmune/diagnosis
- Hepatitis, Autoimmune/immunology
- Hepatitis, Autoimmune/therapy
- Humans
- Hypergammaglobulinemia
- Immunity, Cellular
- Immunoglobulin G/blood
- Immunosuppressive Agents/therapeutic use
- Liver Cirrhosis, Biliary/complications
- Liver Cirrhosis, Biliary/diagnosis
- Liver Cirrhosis, Biliary/immunology
- Liver Cirrhosis, Biliary/therapy
- Liver Transplantation/adverse effects
- Mice
- Mycophenolic Acid/analogs & derivatives
- Mycophenolic Acid/therapeutic use
- Rats
- Transaminases/blood
Collapse
Affiliation(s)
- Luigi Muratori
- Department of Clinical Medicine, Alma Mater Studiorum - University of Bologna, Policlinico Sant'Orsola-Malpighi, Padiglione 11, Bologna, Italy.
| | | | | | | | | | | |
Collapse
|