Autoimmune Acute Liver Failure Research Articles

Treatment of rheumatoid arthritis with conventional, targeted and biological disease-modifying antirheumatic drugs in the setting of liver injury and non-alcoholic fatty liver disease.

Increased incidence of liver diseases emphasizes greater caution in prescribing antirheumatic drugs due to their hepatotoxicity. A transient elevation of transaminases to autoimmune hepatitis and acute liver failure has been described. For every 10 cases of alanine aminotransferase (ALT) elevation in a clinical trial, it is estimated that one case of more severe liver injury will develop once the investigated drug is widely available. Biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic (tsDMARDs) are less likely to cause liver damage. However, various manifestations, from a transient elevation of transaminases to autoimmune hepatitis and acute liver failure, have been described. Research on non-alcoholic fatty liver disease (NAFLD) has provided insight into a pre-existing liver disease that may be worsen by medication. Diabetes and obesity could be an additional burden in drug-induced liver injury (DILI). In the intertwining of the inflammatory and metabolic pathways, the most important cytokines are IL-6 and TNF alpha, which are also the cornerstone of biological treatment for rheumatoid arthritis. This narrative review evaluates the complexity and prevention of DILI in RA and treatment options involving biological therapy and tsDMARDs.

Infectious complications and timing for liver transplantation in autoimmune acute liver failure in Japan: a subanalysis based on nationwide surveys between 2010 and 2015.

The prognosis of autoimmune acute liver failure (ALF) without liver transplantation (LT) is poor worldwide. We subanalyzed infectious complications of autoimmune ALF using data of nationwide surveys between 2010 and 2015 retrospectively and tried to determine when to evaluate the efficacy of corticosteroid (CS) treatment or abandon it for LT based on objective data. One hundred and forty-four patients with autoimmune ALF, comprising 79 ALF with coma ≤ I, 52 ALF with coma ≥ II and 13 late onset hepatic failure (LOHF), were analyzed. CS was administered to 140 (97%) patients. Thirty-seven (26%) patients had infectious complications. Patients with infection revealed more advanced disease type (p < 0.001) and poorer spontaneous survival (p < 0.001) than those without infection. Median (interquartile range) duration between diagnosis of ALF and onset of infection was 18.5 (11-36) days, and that between introduction of CS and onset of infection was 17 (10.5-36) days. Seventy-nine (55%) recovered without LT, 14 (10%) received LT and 51 (35%) died without LT. Dead or transplanted patients were older (p = 0.0057), and revealed more advanced liver failure (p < 0.001) and more occurrence of infection (p < 0.001). A critical point for evaluating the efficacy of CS treatment and switching to LT is at most 2-week after diagnosis of ALF and introduction of CS. More important, we should accelerate the point and prepare for LT in cases of ALF with coma ≥ II and LOHF, and we should have performed LT by then at the latest in case of failure to improve.

Treatment of Acute Liver Failure in Resource-Constrained Settings without Transplantation Facilities Can Be Improved.

Treatment of Acute Liver Failure in Resource-Constrained Settings without Transplantation Facilities Can Be Improved.

Analysis of infectious complications and timing for emergency liver transplantation in autoimmune acute liver failure.

Autoimmune hepatitis (AIH) is one of major etiologies of acute liver failure (ALF), and the survival rate without liver transplantation (LT) of patients with fulminant AIH is especially poor worldwide. We investigated the clinicopathological features of infectious complications in autoimmune ALF retrospectively and tried to determine when to continue corticosteroid (CS) treatment or abandon it for LT. Twenty patients with autoimmune ALF, comprising five severe hepatitis, 13 fulminant hepatitis and two late onset hepatic failure, were analyzed. Corticosteroids were administered to 19 patients. Seventeen infectious complications were observed in 12 patients. The median (range) duration between the introduction of CS and onset of infection was 15 (10–41) days. There were no significant differences in clinicobiochemical features between patients with and without infection. Of 20 patients, eight (40%) recovered without LT, four (20%) received LT and eight (40%) died without LT. Dead or transplanted patients had more advanced liver failure on admission than recovered ones (P < 0.01). Two-week after the introduction of CS is a critical point for avoiding infectious complications. Therefore, we should have evaluated efficacy of CS and performed LT by then at the latest in case of failure to improve.

Update on acute liver failure.

Although advances in critical care management and liver transplantation have improved survival in acute liver failure (ALF), mortality remains significant. An evidence base to support management has been lacking, due to the condition's rarity, severity and heterogeneity. The purpose of this review is to critically appraise the latest evidence, updating clinicians on the current understanding of the best management. Transplant-free survival in acetaminophen-related ALF has improved considerably, such that reconsidering thresholds for transplant is required, perhaps utilizing biomarkers of liver regeneration. Autoimmune hepatitis-related ALF may be too advanced to permit rescue with corticosteroids, which could be deleterious in the sickest patients. Acute kidney injury is commoner in ALF than previously suspected. Intracranial pressure monitoring does not appear to alter mortality. Despite altered traditional indices of coagulation, new thrombin generation assays suggest a rebalanced coagulation in liver failure. Antimicrobial prophylaxis may not be required in all patients. Liver support systems remain controversial and require further evaluation. Traditional dogma in ALF management is questioned: transplant thresholds for acetaminophen overdose, steroid use in autoimmune ALF, routine antimicrobial prophylaxis, the coagulopathy of liver disease, the value of intracranial pressure monitoring and extracorporeal liver support.

Pregnant woman with non-comatose autoimmune acute liver failure in the second trimester rescued using medical therapy: A case report.

We present the case of a 25-year-old woman at 16 weeks of gestation who presented with non-comatose autoimmune acute liver failure and was at high risk of developing fulminant hepatitis. Predictive formulas indicated a high probability of developing fulminant hepatitis. Unenhanced computed tomography showed marked hepatic atrophy and broadly heterogeneous hypoattenuating areas. The course of her illness was subacute, and the etiology of liver injury was unclear. Considering all of the above, we predicted a poor prognosis. Plasma exchange (PE) and continuous hemodiafiltration (CHDF) therapy were initiated just after admission. A few days after admission, a high titer (×80) of antinuclear antibody was noted. Because autoimmune hepatitis (AIH) was considered a cause of liver failure, treatment with moderate prednisolone (30 mg/day) doses was administrated, with careful consideration of her pregnancy. Thereafter, her laboratory findings and clinical course gradually improved without the need for liver transplantation. A liver biopsy at 18 days after admission indicated a diagnosis of AIH. She continued the pregnancy and delivered a healthy baby without any complications. Eventually, prednisolone doses were decreased to 10 mg, after which her liver function worsened. The second liver biopsy also indicated a diagnosis of AIH. Accordingly, low-dose prednisolone and azathioprine doses (50 mg/day) were administrated to recover her liver function, after which her liver function regained normalcy. This case illustrates that a pregnant woman with non-comatose autoimmune acute liver failure in the first or second trimester of pregnancy and her fetus can be rescued by PE/CHDF therapy and safe moderate doses of prednisolone.

Steroid use in acute liver failure.

Drug-induced and indeterminate acute liver failure (ALF) might be due to an autoimmune-like hepatitis that is responsive to corticosteroid therapy. The aim of this study was to evaluate whether corticosteroids improve survival in fulminant autoimmune hepatitis, drug-induced, or indeterminate ALF, and whether this benefit varies according to the severity of illness. We conducted a retrospective analysis of autoimmune, indeterminate, and drug-induced ALF patients in the Acute Liver Failure Study Group from 1998-2007. The primary endpoints were overall and spontaneous survival (SS, survival without transplant). In all, 361 ALF patients were studied, 66 with autoimmune (25 steroids, 41 no steroids), 164 with indeterminate (21 steroids, 143 no steroids), and 131 with drug-induced (16 steroids, 115 no steroids) ALF. Steroid use was not associated with improved overall survival (61% versus 66%, P = 0.41), nor with improved survival in any diagnosis category. Steroid use was associated with diminished survival in certain subgroups of patients, including those with the highest quartile of the Model for Endstage Liver Disease (MELD) (>40, survival 30% versus 57%, P = 0.03). In multivariate analysis controlling for steroid use and diagnosis, age (odds ratio [OR] 1.37 per decade), coma grade (OR 2.02 grade 2, 2.65 grade 3, 5.29 grade 4), MELD (OR 1.07), and pH < 7.4 (OR 3.09) were significantly associated with mortality. Although steroid use was associated with a marginal benefit in SS overall (35% versus 23%, P = 0.047), this benefit did not persistent in multivariate analysis; mechanical ventilation (OR 0.24), MELD (OR 0.93), and alanine aminotransferase (1.02) were the only significant predictors of SS. Corticosteroids did not improve overall survival or SS in drug-induced, indeterminate, or autoimmune ALF and were associated with lower survival in patients with the highest MELD scores.

Letter: treatment of autoimmune acute liver failure - beyond consensus guidelines; author's reply

AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Sirs, Dr Fujiwara and colleagues emphasise three key concepts in the diagnosis and management of acute severe (fulminant) autoimmune hepatitis.1 First, its occurrence is underestimated in most experiences. The abrupt onset of the disease may not allow the classical phenotype to emerge, and patients may lack hypergammaglobulinemia, high titres of autoantibodies and classical histological patterns.2 Furthermore, the concept that an archetypal form of chronic hepatitis can present de novo as acute liver failure may not be uniformly entrenched in clinical practice. Second, the diagnosis can be difficult. Classical features may be absent or altered; diagnostic scores by the comprehensive international scoring system may be low; and liver tissue examination may be avoided.3 Doctor Fujiwara and colleagues have already emphasised the importance of liver tissue assessment in the evaluation of these patients,4 and they have indicated that the presence of heterogeneous hypoattenuated areas within the liver by unenhanced computerised tomography is another means of supporting the diagnosis.5 Third, corticosteroid therapy can be life-saving, but it cannot be indefinite. Septic complications can occur and jeopardise the opportunity for successful liver transplantation.6 Patients with multilobular necrosis at presentation who fail to improve at least one liver test within 2 weeks of treatment7 and icteric patients who do not improve mathematical models of end-stage liver disease by at least 2 points within 7 days of therapy have dismal outcomes,8 and they must be considered for liver transplantation. Worsening of any feature during treatment also compels this intervention. A decision regarding the appropriate strategy must be made within 7–14 days.9 The Japanese experience has taught us much about the nature and behaviour of autoimmune hepatitis, and we are indebted to Dr Fujiwara and colleagues for their insights. Acknowledgement The author's declarations of personal and financial interests are unchanged from those in the original article.10 References 1Fujiwara K, Yasui S, Yokosuka O. Letter: treatment of autoimmune acute liver failure – beyond consensus guidelines. Aliment Pharmacol Ther 2013; 38: 1143– 4. 2Yasui S, Fujiwara K, Yonemitsu Y, Oda S, Nakano M, Yokosuka O. Clinicopathological features of severe and fulminant forms of autoimmune hepatitis. J Gastroenterol 2011; 46: 378– 90. 3Abe M, Hiasa Y, Masumoto T, et al. Clinical characteristics of autoimmune hepatitis with histological features of acute hepatitis. Hepatol Res 2001; 21: 213– 9. 4Fujiwara K, Fukuda Y, Yokosuka O. Precise histological evaluation of liver biopsy specimen is indispensable for diagnosis and treatment of acute-onset autoimmune hepatitis. J Gastroenterol 2008; 43: 951– 8. 5Yasui S, Fujiwara K, Okitsu K, Yonemitsu Y, Ito H, Yokosuka O. Importance of computed tomography imaging features for the diagnosis of autoimmune acute liver failure. Hepatol Res 2012; 42: 42– 50. 6Ichai P, Duclos-Vallee JC, Guettier C, et al. Usefulness of corticosteroids for the treatment of severe and fulminant forms of autoimmune hepatitis. Liver Transpl 2007; 13: 996– 1003. 7Czaja AJ, Rakela J, Ludwig J. Features reflective of early prognosis in corticosteroid-treated severe autoimmune chronic active hepatitis. Gastroenterology 1988; 95: 448– 53. 8Yeoman AD, Westbrook RH, Zen Y, et al. Early predictors of corticosteroid treatment failure in icteric presentations of autoimmune hepatitis. Hepatology 2011; 53: 926– 34. 9Czaja AJ. Corticosteroids or not in severe acute or fulminant autoimmune hepatitis: therapeutic brinksmanship and the point beyond salvation. Liver Transpl 2007; 13: 953– 5. 10Czaja AJ. Review article: the management of autoimmune hepatitis beyond consensus guidelines. Aliment Pharmacol Ther 2013; 38: 343– 64. Volume38, Issue9November 2013Pages 1144-1144 ReferencesRelatedInformation

Letter: treatment of autoimmune acute liver failure - beyond consensus guidelines

Letter: treatment of autoimmune acute liver failure - beyond consensus guidelines

Autoimmune acute liver failure: an emerging etiology for intractable acute liver failure.

Diagnosis of acute onset autoimmune hepatitis (AIH) is the most challenging task because of atypical clinicopathological features. We examined the nature of acute onset AIH consisting of nonsevere, severe, and fulminant AIH based on our published data and other published papers, and propose how to diagnose and treat this intractable hepatitis. We analyzed clinical, biochemical, immunological, radiological, and histological features of acute onset AIH. Thirty percent of fulminant hepatitis was due to AIH and autoimmune acute liver failure (ALF) was not rare. The important characteristic of acute onset AIH is its histological, radiological, and clinical heterogeneity. Sometimes acute onset AIH develops into ALF in a sub-acute clinical course without appropriate diagnosis and treatment, and becomes resistant to immunosuppressive therapy and has poor prognosis. Unenhanced computed tomography (CT) often shows heterogeneous hypoattenuation in autoimmune ALF. The revised original scoring system (1999) performed better in patients with acute onset AIH than the simplified scoring system (2008). Liver regeneration from periportal progenitor cells to mature hepatocytes was impaired in ALF, resulting in resistance to immunosuppressive therapy. Precise histological evaluation (the presence of centrilobular necrosis/collapse) along with the revised original scoring system and CT findings of heterogeneous hypoattenuation after systematic exclusion of other causes 36 plays an important role in the diagnosis. The most important strategy for autoimmune ALF is to diagnose and treat acute onset AIH before its development into ALF. Liver transplantation should be considered before the occurrence of infectious complications in the case of fulminant liver failure.

Importance of computed tomography imaging features for the diagnosis of autoimmune acute liver failure

The diagnosis of acute liver failure due to autoimmune hepatitis is often difficult because of atypical clinicopathological features. Patients with autoimmune acute liver failure are sometimes resistant to immunosuppressive therapy and have poor prognosis. Although their survival rates are especially poor (5-20%) without liver transplantation in Japan, their clinicopathological features have remained uncertain. A major problem is that there is no gold standard for making the diagnosis of acute onset autoimmune hepatitis. If there are diagnosing tools supporting clinicopathological features, they are of benefit to the patients. We examined computed tomography (CT) imaging features of autoimmune acute liver failure to clarify the usefulness of imaging for the diagnosis. A retrospective analysis of 129 unenhanced CT scans of 68 patients with acute hepatitis, consisting of 23 with autoimmune acute liver failure (ALF) (group 1), 25 with early admission-viral ALF (group 2) and 20 with late admission-viral ALF (group 3), was performed. Autoimmune acute liver failure showed heterogeneous hypoattenuating areas and viral ALF diffuse ones (P < 0.001). The diffuse hypoattenuating areas were present in none of group 1, 15 (60%) of group 2, and 7 (30%) of group 3. The heterogeneous hypoattenuating areas were present in 15 (65%) of group 1, none of group 2 and 1 (5%) of group 3. Heterogeneous hypoattenuation on unenhanced CT was a characteristic CT imaging feature of autoimmune acute liver failure compared with viral ALF. This finding could be one of the tools for diagnosing autoimmune acute liver failure in combination with clinicopathological features.

Acute Liver Failure, Autoimmune Hepatitis, and Leptospirosis

The etiology of acute liver failure varies widely in children, but the most common causes are viral hepatitis, drugs, and toxins. We report herein a case of autoimmune hepatitis and acute liver failure caused by leptospirosis, which is involved rarely in etiology.

Reply:

We appreciate the comments of Drs. Fujiwara and Duclos-Vallée regarding our article, “Autoimmune acute liver failure: proposed clinical and histological criteria.”1 Dr. Fujiwara reports that approximately 50% of their patient population with acute liver failure (ALF) of unclear etiology was ultimately diagnosed with autoimmune ALF (AI-ALF) on the basis of liver histology and clinical parameters, similar to findings in our series (58%). The investigators advise caution in interpreting our work regarding the heterogeneity of histological findings in liver specimens from patients with ALF. Dr. Fujiwara presents data that demonstrate no difference between the time of onset of hepatitis to time of admission or liver biopsy between patients with autoimmune hepatitis presenting as acute-onset hepatitis, chronic hepatitis, or ALF, with a large degree of overlap, supporting the clinical heterogeneity of the disease. Dr. Duclos-Vallée also raises concern about the fact that two-thirds of our liver specimens were sections from explants, whereas the remainder were transjugular needle biopsies. The lack of uniform biopsy technique, they suggest, may have influenced our results by increasing the probability of finding specific features of autoimmunity in the larger specimens obtained from an explant. We did not, however, find statistically significant differences in the prevalence of the four features of autoimmunity between specimens obtained from explanted livers and those obtained by transjugular biopsy. Dr. Duclos-Vallée also requested further correlation between patients with centrilobular necrosis and their clinical phenotype and outcomes. Patients with central perivenulitis were characterized by a longer jaundice-to-encephalopathy interval, and a poorer prognosis (higher incidence of liver transplantation). These attributes can be ascribed to a more subacute liver injury in patients with AI-ALF compared to those with other indeterminate etiologies. Perhaps due to small numbers (13 of 72 patients; 18%), those patients with exclusive centrilobular necrosis were not clinically different than those without this feature. Finally, Dr. Duclos-Vallée and colleagues raise concern about administering corticosteroids to patients with suspected AI-ALF, a major rationale for performing our study. We strongly agree with their contention that corticosteroid administration may introduce a significant risk of infection, and that no convincing evidence of efficacy exists.2 It should be noted, however, that no randomized, placebo-controlled studies have explored the efficacy of corticosteroids in patients with rigorously defined AI-ALF. In the absence of such information, we would reserve the administration of corticosteroids to patients with recent-onset AI-ALF and low-grade hepatic encephalopathy. Certainly, corticosteroids are unlikely to improve the transplant-free survival of a patient with AI-ALF late in the clinical course of the syndrome or with clinical attributes of poor outcome. R. Todd Stravitz M.D.*, Jay H. Lefkowitch M.D. , * Section of Hepatology, Virginia Commonwealth University, Richmond, VA, Department of Pathology, Columbia University, New York, NY.

Autoimmune acute liver failure

We read with great interest the article entitled “Autoimmune Acute Liver Failure: Proposed Clinical and Histological Criteria” by Stravitz et al.1 Our reading of this article has given rise to several comments. It is necessary to be very cautious when one is ranking histological features first in the diagnosis and management of severe forms of autoimmune disease; during their study, Stravitz et al.1 examined liver biopsy samples from 72 of 204 patients (i.e., 35% of the total cohort). However, the use of different liver biopsy techniques, such as transjugular liver biopsy, native liver biopsy, and postmortem biopsy, may have induced variations in the histological patterns. Centrilobular necrosis (CN), which corresponds to massive hepatic necrosis type 1 in this study, is an important but infrequent histopathological pattern of autoimmune hepatitis; centrilobular necrosis with sparing of the portal tracts was present in 3.5% of the cases reported by Hofer et al.2 This particular pattern is of crucial importance because it may be indicative of an early stage of the disease. For the series described by Stravitz et al., it would be interesting to have a description of the phenotype and, more specifically, the prognosis of the patients with isolated centrilobular necrosis. The fact that the centrilobular zone is damaged during an early stage by the immune process is intriguing and suggests that specific autoantigens in this area could be presented to the immune system early during the course of liver disease. Clearly, the identification of these potential targets during an initial phase of the disease would be of considerable interest. In addition, it is unfortunate that the identification of a pattern typical of severe autoimmune hepatitis (AIH) is based only on this experience; in several reports, researchers have attempted to describe this entity, and experiences besides those of the US Acute Liver Failure Study Group should be cited.3-6 In particular, the characteristics of the patients may differ between the studies. In our cohort, 8 of 16 patients (50%) suffered from grade 3/4 encephalopathy,3 whereas 26 of 72 patients (39%) in Stravitz et al.'s study did. The most important and problematic issue in the management of severe autoimmune liver disease is corticosteroid therapy. Of course, if a response to corticosteroid therapy is an important argument in favor of an autoimmune process, it is important that any decision to administer this therapy be balanced against the high potential risk of sepsis; infections occurred in 5 of 12 patients (42%) during steroid therapy in our study.3 If treatment failure seems to be predicted by changes in the Model for End-Stage Liver Disease–Sodium score and the UK Model for End-Stage Liver Disease score on day 7,7 specific scores on entry must be defined for making decisions about the administration of steroid therapy. Jean-Charles Duclos-Vallée M.D., Ph.D.* , Philippe Ichai M.D.* , Didier Samuel M.D., Ph.D.* , * Centre Hépato-Biliaire, Hôpital Paul Brousse, Assistance Publique–Hôpitaux de Paris, Villejuif, France, Unités Mixtes de Recherche en Santé 785, Université Paris-Sud, Villejuif, France, Unité 785, Institut National de la Santé et de la Recherche Médicale, Villejuif, France.

Autoimmune acute liver failure: Proposed clinical and histological criteria

Identifying autoimmune hepatitis as the etiology of acute liver failure (ALF) is potentially important, because administering corticosteroids might avoid the need for liver transplantation. However, clinical and histological criteria of autoimmune ALF (AI-ALF) have not been defined. Liver sections (biopsies and explants) from a 72-patient subset of the ALF Study Group Registry with indeterminate ALF were reviewed by a pathologist blinded to all clinical data and were diagnosed with probable AI-ALF based on four features suggestive of an autoimmune pathogenesis: distinctive patterns of massive hepatic necrosis (present in 42% of sections), presence of lymphoid follicles (32%), a plasma cell-enriched inflammatory infiltrate (63%), and central perivenulitis (65%). Forty-two sections (58%) were considered probable for AI-ALF; this group demonstrated higher serum globulins (3.7 ± 0.2 g/dL versus 3.0 ± 0.2 g/dL; P = 0.037) and a higher prevalence of antinuclear and/or anti-smooth muscle antibodies (73% versus 48%; P = 0.034) compared to those without histology suggestive of probable AI-ALF. Thirty patients concordant for autoantibodies and probable AI-ALF upon histological analysis were more likely to have the classical autoimmune hepatitis phenotype (female predominance [72% versus 48%; P < 0.05], higher globulins [3.9 ± 0.2 g/dL versus 3.0 ± 0.2 g/dL; P < 0.005], and higher incidence of chronic hepatitis in long-term follow-up [67% versus 17%, P = 0.019]) compared to the population without concordant AI-ALF histology and autoantibodies. Patients with indeterminate ALF often have features of autoimmune disease by histological analysis, serological testing, and clinical recurrence during follow-up. In contrast to classical autoimmune hepatitis, histological features of AI-ALF predominate in the centrilobular zone.