Highlights
-
•
Systematic review of acute-onset autoimmune hepatitis.
-
•
Identifies key predictors of severity: bilirubin, INR, and extrahepatic autoimmunity.
-
•
Acute vs. chronic AIH differ in symptoms, lab findings, and outcomes.
-
•
Anorexia and jaundice are key symptoms distinguishing acute AIH.
Keywords: Autoimmune hepatitis, Acute-onset autoimmune hepatitis, Auto-immune disease, Clinical feature, Meta-analysis
Abstract
Background and aims
Autoimmune Hepatitis (AIH), a rare chronic progressive inflammatory disease of the liver, and acute-onset AIH usually lack typical manifestations and have a poor prognosis. Hence, we have systematically examined all accessible data on the clinical features of acute-onset AIH to aid clinicians in deepening their understanding of the disease.
Methods
Eligible studies were gathered from a computer search of literature published from the inception of the database to June 2024 in PubMed and CNKI. Data on basic features, clinical manifestations, laboratory examinations, clinical outcomes, and pathological results were collected as relevant outcomes.
Results
Thirty-two retrospective studies encompassing 2,561 patients, and four cohort studies involving 419 patients were ultimately included. Approximately 31% of AIH patients present with acute disease onset, with 58% being acute non-severe, 25% acute severe, and 17% commencing with fulminant liver failure. Patients with acute-onset AIH tend to be younger (OR = 0.25, 95% CI: -0.449 to -0.057) and exhibit a diminishing female predilection that increases with severity compared to the more chronic classic AIH (OR = 0.65, 95% CI: 0.569‒0.727). The presence of comorbid extrahepatic autoimmune disease showed a potential protective effect when compared with C-AIH (OR = 0.63, 95% CI: 0.455‒0.874).
Conclusions
About 30% of patients with AIH exhibit an acute disease onset, understanding its proportion and clinical features aids clinicians in making timely diagnoses to prevent severe consequences. However, in existing studies, the results of laboratory tests and histologic examinations of A-AIH are influenced by AC-AIH to varying degrees, which somewhat restricts the clinicians' understanding.
Introduction
Autoimmune Hepatitis (AIH) is a chronic liver disease, driven by abnormal autoimmunity, likely precipitated by the interplay of genetic susceptibility, environmental factors, and triggering events.1 The clinical presentation of AIH varies greatly, it typically has a chronic onset, and most of its symptoms are nonspecific, making physical examinations rather uninformative.
To address the need for reliable, user-friendly diagnostic tools in clinical practice, the International Autoimmune Hepatitis Group (IAIHG) introduced diagnostic criteria in 1993, which were later revised in 1999 The comprehensive diagnostic scoring system,2 though highly sensitive and specific in AIH diagnosis, is complicated and challenging to widely implement. Hence, the IAIHG proposed a simplified scoring system in 2008.2 Despite the absence of specific biomarkers, the current diagnostic scoring system is quite effective and clinically applicable.3
However, approximately 20% of patients exhibit acute symptoms,4 presenting clinical features that are more elusive. These individuals could be experiencing true acute AIH or Acute on Chronic AIH (AC-AIH), typically manifesting as acute jaundice and/or coagulation dysfunction. Based on INR and encephalopathy, these cases can be further classified as Acute AIH (A-AIH), Acute Severe AIH (AS-AIH), or fulminant AIH (ALF-AIH).5 Notably, patients with an acute AIH presentation differ significantly from those with classic, Chronic Autoimmune Hepatitis (C-AIH) in terms of histomorphology, serology, and laboratory characteristics.6
Due to these variable clinical features, scoring systems often fall short in diagnosing acute AIH, making early diagnosis and differential diagnosis quite challenging.4,5 Acute-onset AIH's complexity, diagnostic difficulty, rapid progression, and poor prognosis warrant thorough examination and summarization. Our study is the first to systematically review the clinical features of acute AIH, encompassing clinical manifestations, outcomes, serologic and laboratory tests, and histologic examinations. The aim is to enhance clinicians' understanding of acute AIH and thereby improve their diagnostic and therapeutic capabilities.
Method
Literature search strategy
We conducted a comprehensive search on both PubMed and CNKI (China National Knowledge Infrastructure), covering the time frame from the establishment of these databases up to May 30, 2024. We utilized the search terms 'acute autoimmune hepatitis', along with the combinations of 'Autoimmune hepatitis' AND 'acute', 'acute onset', 'severe', and 'fulminant hepatic failure'. Furthermore, we combed through the reference lists of relevant articles to identify any additional suitable studies.
Study selection and data extraction
Our study selection encompassed articles that specifically explored acute-onset AIH. We also included studies pertaining to AIH, if they separately grouped clinical features of acute AIH and had a sample size of 10 or more patients. Our systematic reviews and meta-analyses conform to the protocols developed by authors XTD, JHZ, and YFG and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies available despite searching all literature in relevant databases were retrospective studies.
Two independent researchers, Xiaotian Dong & Jinhua Zhang, undertook the data extraction process. The extracted data included the first author's name, year of publication, study design, study region, diagnostic criteria, basic features, clinical manifestations, laboratory examinations, clinical outcomes, and pathological results. In instances of discrepancy, the two researchers would re-examine the data and negotiate to reach an agreement. If necessary, expert Jiaze An was consulted to ensure a consensus among all investigators.
Assessment of the study quality and risk of bias
The quality of each study was assessed independently by two reviewers. To determine the potential occurrence of publication bias in randomized studies, assessment tools from the Cochrane Collaboration were utilized. Evaluations were performed in various domains, with studies classified as possessing either ‘low risk”, “unclear risk”, or “high risk” of bias. For observational studies, the evaluation of bias was conducted using the modified Newcastle-Ottawa Scale (NOS). This scale considers three aspects: participant selection (up to a maximum of 4-points), comparability (up to a maximum of 2-points), and the exposure or outcomes of study participants (up to a maximum of 3-points). Based on the overall scores obtained, studies were categorized as either high quality (≥ 7), fair quality (4–6), or low quality (≤ 4).
Statistical analysis
Review Manager Version 5.3 software was employed for statistical data analysis. We computed pooled proportion, pooled mean, mean difference, odds ratios and 95% Confidence Intervals to examine various aspects of acute-onset autoimmune hepatitis patients, using a random-effects model. Heterogeneity was assessed via the χ2 test (α = 0.1) and was quantitatively measured by I2. High heterogeneity was considered if (p < 0.1, I2 > 50%). We assessed potential publication bias using the Egger's regression model.
Result
In summary, our database search yielded 3,920 articles. After eliminating duplicates, 149 records were assessed at the title/abstract stage, and 126 were evaluated at the full-text stage. Our PRISMA flowchart (Supplementary Fig. 1) provides detailed explanations for the exclusion of 90 studies at the full-text stage. Eventually, 36 studies4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 were included in this systematic review and quantitative synthesis (Supplementary Table 1).
Supplementary Table 1 encapsulates our findings. The majority of the studies (24 out of 36) were conducted in Asia, with Japan leading with 16 studies,6,8, 9, 10, 11,13,16, 17, 18,20,23,24,26,29,30,38 followed by six studies31, 32, 33, 34,37,39 from China, and one study each from Saudi Arabia5 and India.36 The vast majority of the research (33 out of 36 studies) diagnosed AIH using the 1999 original criteria40 and/or the 2008 simplified criteria,2 two studies15,28 conducted prior to 1999 utilized published criteria,41 and one study25 focused on children used the classical criteria for diagnosing AIH in children.42
Acute onset was defined as the clinical presentation of acute hepatitis with acute-onset liver injury, with onset ranging from less than one month to less than a year. All studies excluded other diseases affecting the liver, such as hepatitis B and overlap syndrome. The definition of AS-AIH fell into two main groups, 1) INR ≥1.5 without encephalopathy; 2) Prothrombin Time (PT) activity < 50% of control or total bilirubin level more than 20 mg/dL. ALF-AIH was primarily defined by the presence of hepatic encephalopathy, accompanied by abnormalities in INR or PT. As the definitions of acute non-severe AIH and ALF-AIH were relatively consistent, we did not further classify AS-AIH.
Characteristic
Of all patients diagnosed with AIH, 31.4% presented with an acute onset. Among those experiencing acute manifestations of AIH, 58.4% were acutely non-severe, 25.3% were acutely severe, and 16.9% initiated with fulminant liver failure (Table 1).
Table 1.
Number of cases of acute-onset AIH among all AIH cases and percentage of each severity level in acute-onset AIH.
| Studies (n) | Participants (n) | Heterogeneity |
Model | Meta analysis |
Egger | |||
|---|---|---|---|---|---|---|---|---|
| p | I2 | Pooled proportion | 95% CI | |||||
| Acute-onset AIH/ AIH | 5 | 527 | 0.050 | 57.786 | Random | 0.314 | 0.255‒0.380 | 0.94 |
| A-AIH / Acute onset AIH | 3 | 208 | 0.341 | 7.065 | Random | 0.584 | 0.511‒0.653 | 0.29 |
| AS-AIH / Acute onset AIH | 4 | 309 | 0.980 | 0.000 | Random | 0.253 | 0.207‒0.304 | 0.96 |
| ALF-AIH / Acute onset AIH | 3 | 208 | 0.114 | 53.934 | Random | 0.169 | 0.102‒0.268 | 0.51 |
Within the A-AIH, AS-AIH, and ALF-AIH groups, the mean age was 49.9 (95% CI: 44.578‒55.204), 46.2 (95% CI: 42.934‒49.400), and 50.3 (95% CI: 42.453‒58.203), respectively, and these differences were not statistically significant (Table 2).
Table 2.
Basic characteristics of patients with acute-onset AIH.
| Studies (n) | Participants (n) | Heterogeneity |
Model | Meta analysis |
Egger | |||
|---|---|---|---|---|---|---|---|---|
| p | I2 | Pooled mean/ Proportion | 95% CI | |||||
| A-AIH | ||||||||
| Age | 19 | 612 | 0.000 | 98.816 | Random | 49.891 | 44.578‒55.204 | 0.00 |
| Sex (females) | 24 | 1070 | 0.007 | 46.644 | Random | 0.810 | 0.770‒0.845 | 0.06 |
| AS-AIH | ||||||||
| Age | 7 | 357 | 0.057 | 50.940 | Random | 46.167 | 42.934‒49.400 | 0.06 |
| Sex (females) | 9 | 415 | 0.921 | 0.000 | Random | 0.743 | 0.698‒0.783 | 0.43 |
| ALF-AIH | ||||||||
| Age | 6 | 134 | 0.000 | 91.888 | Random | 50.328 | 42.453‒58.203 | 0.03 |
| Sex (females) | 6 | 134 | 0.227 | 25.332 | Random | 0.169 | 0.569‒0.727 | 0.10 |
In terms of gender distribution, the female proportion in the A-AIH, AS-AIH, and ALF-AIH groups was 81% (95% CI: 0.770‒0.845), 74% (95% CI: 0.698‒0.783), and 65% (95% CI: 0.569‒0.727), respectively. Unlike age, the female to male ratio tended to decrease with the severity of the condition, and a significant difference in the female ratio was observed between the A-AIH and ALF-AIH groups (Table 2).
Symptoms
In the 36 papers we reviewed, 21 symptoms were reported. A meta-analysis was conducted on the 13 symptoms with two or more reports, namely jaundice, fatigue, abdominal pain, anorexia, bloating, ascites, oil aversion, nausea, weight loss, urine discoloration, lower limb swelling, fever, and arthralgia. The most commonly reported were jaundice 79% (95% CI: 0.656‒0.879), fatigue 65% (95% CI: 0.462‒0.794), anorexia 64% (95% CI: 0.514‒0.756), urine discoloration 44% (95% CI: 0.348‒0.544), and oil aversion 40% (95% CI: 0.312‒0.491). The least common were lower limb swelling 16% (95% CI: 0.061‒0.356) and arthralgia 6% (95% CI: 0.030‒0.105) (Table 3).
Table 3.
Symptoms associated with acute-onset AIH.
| Studies (n) | Participants (n) | Heterogeneity |
Model | Meta analysis |
Egger | |||
|---|---|---|---|---|---|---|---|---|
| p | I2 | Pooled proportion | 95% CI | |||||
| ALL | ||||||||
| Jaundice | 9 | 265 | 0.001 | 69.993 | Random | 0.788 | 0.656‒0.879 | 0.08 |
| Fatigue | 7 | 231 | 0.000 | 79.143 | Random | 0.646 | 0.462‒0.794 | 0.01 |
| Abdominal pain | 4 | 167 | 0.084 | 54.958 | Random | 0.171 | 0.097‒0.285 | 0.01 |
| Anorexia | 5 | 149 | 0.087 | 50.719 | Random | 0.644 | 0.514‒0.756 | 0.14 |
| Ventosity | 3 | 105 | 0.904 | 0.000 | Random | 0.334 | 0.250‒0.429 | 0.45 |
| Ascites | 8 | 420 | 0.000 | 73.769 | Random | 0.287 | 0.189‒0.411 | 0.57 |
| Detesting oil | 4 | 113 | 0.952 | 0.000 | Random | 0.399 | 0.312‒0.491 | 0.25 |
| Nausea | 3 | 85 | 0.123 | 52.291 | Random | 0.251 | 0.137‒0.415 | 0.28 |
| Weight loss | 3 | 97 | 0.867 | 0.000 | Random | 0.176 | 0.112‒0.266 | 0.17 |
| Yellow urine | 3 | 97 | 0.628 | 0.000 | Random | 0.444 | 0.348‒0.544 | 0.67 |
| Lower limb swelling | 5 | 149 | 0.001 | 79.929 | Random | 0.159 | 0.061‒0.356 | 0.02 |
| Fever | 3 | 130 | 0.012 | 77.353 | Random | 0.301 | 0.155‒0.503 | 0.77 |
| Arthralgia | 4 | 167 | 0.828 | 0.000 | Random | 0.057 | 0.030‒0.105 | 0.01 |
| Extrahepatic autoimmune disease | 9 | 912 | 0.785 | 0.000 | Random | 0.216 | 0.191‒0.245 | 0.15 |
| Thyroid disease | 5 | 300 | 0.084 | 51.381 | Random | 0.163 | 0.104‒0.245 | 0.49 |
| A-AIH | ||||||||
| Jaundice | 7 | 225 | 0.003 | 69.390 | Random | 0.745 | 0.608‒0.846 | 0.38 |
| Fatigue | 6 | 215 | 0.000 | 78.287 | Random | 0.599 | 0.423‒0.752 | 0.04 |
| Abdominal pain | 4 | 167 | 0.084 | 54.958 | Random | 0.171 | 0.097‒0.285 | 0.02 |
| Anorexia | 4 | 133 | 0.285 | 20.777 | Random | 0.620 | 0.522‒0.709 | 0.68 |
| Ventosity | 3 | 105 | 0.904 | 0.000 | Random | 0.334 | 0.250‒0.429 | 0.45 |
| Ascites | 5 | 128 | 0.612 | 0.000 | Random | 0.282 | 0.210‒0.368 | 0.18 |
| Detesting oil | 3 | 97 | 0.894 | 0.000 | Random | 0.392 | 0.300‒0.492 | 0.46 |
| Weight loss | 3 | 97 | 0.867 | 0.000 | Random | 0.176 | 0.112‒0.266 | 0.17 |
| Yellow urine | 3 | 97 | 0.628 | 0.000 | Random | 0.444 | 0.348‒0.544 | 0.67 |
| Lower limb swelling | 4 | 133 | 0.000 | 83.617 | Random | 0.127 | 0.035‒0.370 | 0.02 |
| Fever | 2 | 106 | 0.003 | 88.350 | Random | 0.288 | 0.097‒0.604 | ‒ |
| Arthralgia | 4 | 167 | 0.828 | 0.000 | Random | 0.057 | 0.030‒0.105 | 0.01 |
| Extrahepatic autoimmune disease | 8 | 623 | 0.792 | 0.000 | Random | 0.225 | 0.194‒0.260 | 0.08 |
| Thyroid disease | 5 | 300 | 0.084 | 51.381 | Random | 0.163 | 0.104‒0.245 | 0.42 |
| AS-AIH | ||||||||
| Ascites | 3 | 292 | 0.000 | 91.478 | Random | 0.311 | 0.090‒0.672 | 0.73 |
| Extrahepatic autoimmune disease | 2 | 275 | 0.296 | 8.292 | Random | 0.207 | 0.158‒0.266 | - |
Between 19%‒24% of acute onset autoimmune hepatitis cases also presented with other autoimmune diseases, with no significant differences in prevalence among various severity levels. The most frequently reported comorbid condition was thyroid disease, occurring in 16.3% (95% CI: 0.104‒0.245) of A-AIH cases (Table 3).
Laboratory examination
White Blood Cell (WBC) and Platelet (PLT) counts were most often included in the studies of A-AIH, reports of these counts in AS-AIH and ALF-AIH were not sufficient, and although the heterogeneity was high (I2 > 90), the combined results all fell within the normal range (Table 4).
Table 4.
Laboratory examination results pertaining to acute-onset AIH.
| Studies (n) | Participants (n) | Heterogeneity |
Meta analysis |
Egger | ||||
|---|---|---|---|---|---|---|---|---|
| p | I2 | Model | Pooled mean | 95% CI | ||||
| ALL | ||||||||
| WBC (109/L) | 3 | 148 | 0.000 | 95.945 | Random | 5.466 | 3.809‒7.124 | 0.18 |
| PLT (109/L) | 4 | 390 | 0.000 | 99.035 | Random | 164.482 | 86.501‒242.462 | 0.83 |
| TB (mg/dL) | 21 | 737 | 0.000 | 99.600 | Random | 12.109 | 7.424‒16.794 | 0.02 |
| ALB (g/L) | 10 | 274 | 0.000 | 92.818 | Random | 32.862 | 30.973‒34.750 | 0.53 |
| GLB (g/L) | 10 | 503 | 0.000 | 96.962 | Random | 30.667 | 27.952‒33.382 | 0.22 |
| AST (IU/L) | 15 | 734 | 0.000 | 99.702 | Random | 694.471 | 455.147‒933.796 | 0.01 |
| ALT (IU/L) | 23 | 952 | 0.000 | 99.397 | Random | 693.336 | 480.741‒905.932 | 0.19 |
| ALP (IU/L) | 12 | 444 | 0.000 | 97.548 | Random | 345.002 | 277.342‒412.661 | 0.00 |
| GGT (IU/L) | 5 | 150 | 0.000 | 80.384 | Random | 194.924 | 150.817‒239.031 | 0.86 |
| PT (%) | 8 | 340 | 0.000 | 97.943 | Random | 67.114 | 52.245‒81.982 | 0.73 |
| INR | 9 | 526 | 0.000 | 99.733 | Random | 2.168 | 1.527‒2.809 | 0.54 |
| A-AIH | ||||||||
| WBC (109/L) | 3 | 119 | 0.000 | 93.748 | Random | 5.527 | 3.920‒7.135 | 0.96 |
| PLT (109/L) | 3 | 119 | 0.000 | 98.759 | Random | 156.845 | 46.586‒267.103 | 0.24 |
| TB (mg/dL) | 15 | 223 | 0.000 | 93.180 | Random | 7.579 | 5.897‒9.261 | 0.49 |
| ALB (g/L) | 9 | 229 | 0.000 | 91.649 | Random | 33.432 | 31.469‒35.395 | 0.39 |
| GLB (g/L) | 7 | 144 | 0.000 | 96.136 | Random | 29.938 | 25.443‒34.433 | 0.43 |
| AST (IU/L) | 11 | 351 | 0.000 | 92.388 | Random | 682.292 | 584.030‒780.554 | 0.72 |
| ALT (IU/L) | 15 | 458 | 0.000 | 94.256 | Random | 724.323 | 563.935‒884.710 | 0.71 |
| ALP (IU/L) | 8 | 321 | 0.000 | 93.874 | Random | 403.649 | 315.836‒491.462 | 0.62 |
| GGT (IU/L) | 4 | 134 | 0.000 | 84.642 | Random | 192.798 | 134.610‒250.985 | 0.92 |
| PT (%) | 7 | 231 | 0.000 | 91.614 | Random | 81.945 | 74.585‒89.304 | 0.78 |
| INR | 4 | 138 | 0.000 | 96.154 | Random | 1.552 | 1.296‒1.809 | -0.40 |
| IgG (g/L) | 17 | 496 | 0.000 | 97.431 | Random | 23.717 | 20.669‒26.765 | 0.70 |
| AS-AIH | ||||||||
| TB (mg/dL) | 5 | 300 | 0.090 | 50.278 | Random | 15.461 | 13.017‒17.905 | 0.73 |
| AST (IU/L) | 2 | 266 | 0.000 | 99.648 | Random | 795.622 | ‒334.580‒1925.825 | - |
| ALT (IU/L) | 6 | 324 | 0.000 | 98.567 | Random | 589.840 | 135.136‒1044.543 | 0.22 |
| ALP (IU/L) | 2 | 38 | 0.000 | 92.820 | Random | 307.908 | 120.073‒495.743 | - |
| PT (%) | 4 | 77 | 0.000 | 90.661 | Random | 43.416 | 38.367‒48.465 | 0.52 |
| INR | 2 | 266 | 0.127 | 57.116 | Random | 2.04 | 1.895‒2.184 | - |
| IgG (g/L) | 5 | 82 | 0.093 | 49.681 | Random | 22.101 | 19.282‒24.920 | 0.03 |
| ALF-AIH | ||||||||
| TB (mg/dL) | 6 | 125 | 0.003 | 72.519 | Random | 22.555 | 19.686‒25.425 | 0.19 |
| GLB (g/L) | 2 | 88 | 0.118 | 59.165 | Random | 34.727 | 32.578‒36.876 | - |
| ALT (IU/L) | 6 | 125 | 0.000 | 97.227 | Random | 726.800 | 299.574‒1154.026 | 0.20 |
| ALP (IU/L) | 4 | 113 | 0.000 | 95.715 | Random | 282.466 | 207.558‒357.374 | 0.20 |
| PT (%) | 3 | 32 | 0.314 | 13.748 | Random | 27.509 | 23.952‒31.065 | 0.07 |
| INR | 3 | 93 | 0.171 | 43.346 | Random | 3.263 | 2.935‒3.591 | 0.88 |
| IgG (g/L) | 5 | 58 | 0.000 | 88.465 | Random | 24.570 | 20.895‒28.246 | 0.13 |
From the combined results, aminotransferase levels offered minimal utility in gauging disease severity. Despite high heterogeneity (I2 > 90), these levels showed no statistical differences between A-AIH, AS-AIH, and ALF-AIH (Table 4).
Total Bilirubin (TB), International Normalized Ratio (INR), and Prothrombin Time (PT) served as significant indicators for diagnosing acute AIH and differentiating AIH severity. These measures varied significantly among groups, with TB mg/dL: A-AIH 7.6 (95% CI: 5.897‒9.261), AS-AIH 15.5 (95% CI: 13.017‒17.905), ALF-AIH 22.6 (95% CI: 19.686‒25.425); INR: A-AIH 1.6 (95% CI: 1.296‒1.809), AS-AIH 2.0 (95% CI: 1.895‒2.184), ALF-AIH 3.3 (95% CI: 2.935‒3.591); and PT(%): A-AIH 81.9 (95% CI: 74.585‒89.304), AS-AIH 43.4 (95% CI: 38.367‒48.465), ALF-AIH 27.5 (95% CI: 23.952‒31.065) (Table 4).
The combined results of Globulin (GLB) levels were 29.9 (g/L) for A-AIH and 34.7 (g/L) for ALF-AIH, but the difference between the two groups was not statistically significant. The combined Immunoglobulin G (IgG) levels for each AIH subtype were approximately 22‒24 (g/L), and the differences among the three groups were not statistically significant (Table 4).
The rates of autoantibody positivity were as follows: ANA 77.3% (95% CI: 0.729‒0.811), ASMA 41.1% (95% CI: 0.331‒0.495), AMA 10.5% (95% CI: 0.062‒0.171), and LKM-1 5.2% (95% CI: 0.038‒0.072). Moreover, there were no significant differences among the various severity levels (Table 5).
Table 5.
Autoantibodies detected in acute-onset AIH.
| Studies (n) | Participants (n) | Heterogeneity |
Meta analysis |
Egger | ||||
|---|---|---|---|---|---|---|---|---|
| p | I2 | Model | Pooled proportion | 95% CI | ||||
| ALL | ||||||||
| ANA+ | 32 | 1541 | 0.000 | 63.668 | Random | 0.773 | 0.729‒0.811 | 0.00 |
| SMA+ | 23 | 1260 | 0.000 | 84.481 | Random | 0.411 | 0.331‒0.495 | 0.48 |
| AMA+ | 9 | 593 | 0.001 | 69.498 | Random | 0.105 | 0.062‒0.171 | 0.61 |
| LKM1 | 16 | 1016 | 0.325 | 11.197 | Random | 0.052 | 0.038‒0.072 | 0.01 |
| A-AIH | ||||||||
| ANA+ | 25 | 1010 | 0.107 | 27.013 | Random | 0.759 | 0.722‒0.792 | 0.00 |
| SMA+ | 16 | 720 | 0.000 | 84.593 | Random | 0.476 | 0.365‒0.589 | 0.46 |
| AMA+ | 5 | 405 | 0.000 | 80.700 | Random | 0.105 | 0.048‒0.214 | 0.92 |
| LKM1 | 11 | 547 | 0.408 | 3.595 | Random | 0.070 | 0.049‒0.100 | 0.04 |
| AS-AIH | ||||||||
| ANA+ | 7 | 358 | 0.028 | 57.609 | Random | 0.720 | 0.604‒0.812 | 0.76 |
| SMA+ | 4 | 313 | 0.714 | 0.000 | Random | 0.374 | 0.322‒0.429 | 0.49 |
| AMA+ | 2 | 56 | 0.780 | 0.000 | Random | 0.054 | 0.018‒0.155 | - |
| LKM1 | 3 | 80 | 0.812 | 0.000 | Random | 0.027 | 0.007‒0.102 | 0.18 |
| ALF-AIH | ||||||||
| ANA | 7 | 145 | 0.001 | 73.781 | Random | 0.857 | 0.642‒0.953 | 0.00 |
| SMA | 4 | 116 | 0.096 | 52.797 | Random | 0.302 | 0.162‒0.493 | 0.44 |
| AMA | 3 | 102 | 0.324 | 11.265 | Random | 0.106 | 0.046‒0.226 | 0.03 |
| LKM1 | 3 | 102 | 0.993 | 0.000 | Random | 0.029 | 0.009‒0.086 | 0.36 |
Outcomes
The overall mortality rate was 12.7% (95% CI: 0.088‒0.178), with an overall transplantation rate of 15.4% (95% CI: 0.079‒0.279), a relapse rate of 24.4% (95% CI: 0.114‒0.449), and a graft-free survival rate of 45.8% (95% CI: 0.215‒0.722) (Table 6).
Table 6.
Outcomes related to acute-onset AIH.
| Studies (n) | Participants (n) | Heterogeneity |
Meta analysis |
Egger | ||||
|---|---|---|---|---|---|---|---|---|
| p | I2 | Model | Pooled proportion | 95% CI | ||||
| ALL | ||||||||
| Mortality | 17 | 877 | 0.001 | 59.859 | Random | 0.127 | 0.088‒0.178 | 0.42 |
| Liver transplantation | 13 | 784 | 0.000 | 89.821 | Random | 0.154 | 0.079‒0.279 | 0.13 |
| Recurrence | 5 | 170 | 0.004 | 73.646 | Random | 0.244 | 0.114‒0.449 | 0.82 |
| Survived without liver transplantation | 4 | 353 | 0.000 | 92.311 | Random | 0.458 | 0.215‒0.722 | 0.52 |
| A-AIH | ||||||||
| Mortality | 10 | 415 | 0.237 | 22.351 | Random | 0.089 | 0.057‒0.137 | 0.43 |
| Liver transplantation | 7 | 327 | 0.026 | 58.098 | Random | 0.045 | 0.017‒0.116 | 0.36 |
| Recurrence | 4 | 137 | 0.015 | 71.154 | Random | 0.302 | 0.139‒0.538 | 0.91 |
| Treat with corticosteroid | 8 | 337 | 0.193 | 29.420 | Random | 0.930 | 0.872‒0.963 | 0.08 |
| Clinical remission | 5 | 174 | 0.002 | 76.372 | Random | 0.814 | 0.583‒0.932 | 0.047 |
| AS-AIH | ||||||||
| Mortality | 5 | 340 | 0.305 | 17.151 | Random | 0.138 | 0.090‒0.205 | 0.14 |
| Liver transplantation | 4 | 333 | 0.000 | 85.488 | Random | 0.257 | 0.107‒0.501 | 0.89 |
| Clinical remission | 3 | 253 | 0.141 | 48.869 | Random | 0.659 | 0.538‒0.762 | 0.067 |
| ALF-AIH | ||||||||
| Mortality | 4 | 41 | 0.047 | 62.285 | Random | 0.412 | 0.165‒0.712 | 0.93 |
| Liver transplantation | 3 | 96 | 0.778 | 0.000 | Random | 0.593 | 0.492‒0.687 | 0.80 |
Mortality rates gradually increased with disease severity: 8.9% (95% CI: 0.057‒0.137) for A-AIH, 13.8% (95% CI: 0.090‒0.205) for AS-AIH, and 41.2% (95% CI: 0.165‒0.712) for ALF-AIH. There was a statistically significant difference between the A-AIH and ALF-AIH groups. The transplantation rate similarly escalated with severity, ranging from 4.5% in A-AIH, 25.7% in AS-AIH, to 59.3% in ALF-AIH. Once again, the statistical difference was only significant between the A-AIH and ALF-AIH groups (Table 6).
The relapse rate in the A-AIH group stood at 30.2%. However, the number of studies in the remaining two groups was fewer than two, precluding any combination of results. Steroid use was the primary treatment, implemented in 93% of cases (95% CI: 0.872‒0.963). The clinical remission rate was 81.4% (95% CI: 0.583‒0.932) in the A-AIH group and 65.9% (95% CI: 0.538‒0.762) in the AS-AIH group. Yet, no statistically significant difference emerged between the two groups (Table 6).
Histological examination
Owing to the insufficient number of AS-AIH and ALF-AIH studies, the pathology was primarily derived from the A-AIH group. The most prevalent pathological findings included lobulitis in 91.2% of cases, plasma cell infiltration in 88.2%, and interface hepatitis in 85.3%. Rosettes, a feature typical of AIH, were present in 52.4% of A-AIH cases (95% CI: 0.353‒0.689), and in 28.9% of AS-AIH cases (95% CI: 0.150‒0.485), which was not statistically different between the two groups. Uncommon in classical AIH, bile duct injury was observed in biopsy samples of about 43% of acute AIH cases (Table 7).
Table 7.
Histological Examination of acute-onset AIH.
| Studies (n) | Participants (n) | Heterogeneity |
Meta analysis |
Egger | ||||
|---|---|---|---|---|---|---|---|---|
| p | I2 | Model | Pooled proportion | 95% CI | ||||
| ALL | ||||||||
| Interface hepatitis | 10 | 554 | 0.000 | 76.790 | Random | 0.798 | 0.703‒0.869 | 0.18 |
| Plasma cells | 5 | 372 | 0.261 | 24.119 | Random | 0.871 | 0.822‒0.908 | 0.07 |
| Rosettes | 10 | 548 | 0.000 | 76.622 | Random | 0.440 | 0.338‒0.547 | 0.28 |
| Bile duct injury | 6 | 314 | 0.000 | 81.582 | Random | 0.426 | 0.280‒0.586 | 0.72 |
| Lobulitis | 5 | 271 | 0.000 | 87.064 | Random | 0.806 | 0.545‒0.935 | 0.37 |
| Centrilobular necrosis | 9 | 472 | 0.000 | 80.881 | Random | 0.514 | 0.376‒0.650 | 0.43 |
| Inflammation grade 0 | 4 | 155 | 0.982 | 0.000 | Random | 0.013 | 0.003‒0.051 | 0.00 |
| Inflammation grade 1 | 4 | 155 | 0.794 | 0.000 | Random | 0.048 | 0.023‒0.098 | 0.02 |
| Inflammation grade 2 | 4 | 155 | 0.063 | 58.854 | Random | 0.114 | 0.052‒0.234 | 0.00 |
| Inflammation grade 3 | 4 | 155 | 0.989 | 0.000 | Random | 0.697 | 0.620‒0.764 | 0.78 |
| Inflammation grade 4 | 4 | 155 | 0.125 | 47.667 | Random | 0.167 | 0.087‒0.296 | 0.00 |
| Fibrosis stage 0-1 | 8 | 350 | 0.000 | 88.952 | Random | 0.511 | 0.326‒0.693 | 0.99 |
| Fibrosis stage 2 | 8 | 350 | 0.229 | 25.027 | Random | 0.205 | 0.156‒0.265 | 0.01 |
| Fibrosis stage 3 | 8 | 350 | 0.004 | 66.267 | Random | 0.121 | 0.063‒0.222 | 0.00 |
| Fibrosis stage 4 | 8 | 350 | 0.001 | 71.760 | Random | 0.166 | 0.085‒0.300 | 0.08 |
| A-AIH | ||||||||
| Interface hepatitis | 6 | 215 | 0.035 | 58.218 | Random | 0.853 | 0.740‒0.922 | 0.19 |
| Plasma cells | 4 | 246 | 0.153 | 43.029 | Random | 0.882 | 0.805‒0.931 | 0.13 |
| Rosettes | 7 | 223 | 0.000 | 71.154 | Random | 0.524 | 0.353‒0.689 | 0.79 |
| Bile duct injury | 4 | 144 | 0.002 | 77.950 | Random | 0.468 | 0.249‒0.700 | 0.72 |
| Lobulitis | 4 | 116 | 0.000 | 80.404 | Random | 0.912 | 0.381‒0.994 | 0.00 |
| Centrilobular necrosis | 7 | 300 | 0.027 | 77.950 | Random | 0.470 | 0.373‒0.569 | 0.68 |
| Inflammation grade 0 | 4 | 155 | 0.982 | 0.000 | Random | 0.013 | 0.003‒0.051 | 0.00 |
| Inflammation grade 1 | 4 | 155 | 0.794 | 0.000 | Random | 0.048 | 0.023‒0.098 | 0.02 |
| Inflammation grade 2 | 4 | 155 | 0.063 | 58.854 | Random | 0.114 | 0.052‒0.234 | 0.00 |
| Inflammation grade 3 | 4 | 155 | 0.989 | 0.000 | Random | 0.697 | 0.620‒0.764 | 0.78 |
| Inflammation grade 4 | 4 | 155 | 0.125 | 47.667 | Random | 0.167 | 0.087‒0.296 | 0.00 |
| Fibrosis stage 0-1 | 8 | 350 | 0.000 | 88.952 | Random | 0.511 | 0.326‒0.693 | 0.99 |
| Fibrosis stage 2 | 8 | 350 | 0.229 | 25.027 | Random | 0.205 | 0.156‒0.265 | 0.01 |
| Fibrosis stage 3 | 8 | 350 | 0.004 | 66.267 | Random | 0.121 | 0.063‒0.222 | 0.00 |
| Fibrosis stage 4 | 8 | 350 | 0.001 | 71.760 | Random | 0.166 | 0.085‒0.300 | 0.08 |
| AS-AIH | ||||||||
| Interface hepatitis | 2 | 177 | 0.059 | 71.981 | Random | 0.803 | 0.509‒0.941 | ‒ |
| Rosettes | 2 | 177 | 0.117 | 59.363 | Random | 0.289 | 0.150‒0.485 | ‒ |
Compared to the inflammatory grade of A-AIH, which primarily clustered in Grade 3 (69.7%) and Grade 4 (16.7%), fibrosis was predominantly found in F0-1 (51.1% with 95% CI: 0.326‒0.693). This was significantly higher than in F2 (20.5% with 95% CI: 0.156‒0.265), F3 (12.1% with 95% CI: 0.063‒0.222), and F4 (16.6% with 95% CI: 0.085‒0.300) (Table 7).
Acute-onset Autoimmune Hepatitis (A-AIH) and Chronic Autoimmune Hepatitis (C-AIH)
Characteristics
Compared to typical Chronic AIH (C-AIH), patients with acute-onset AIH (A-AIH) tended to be younger (MD = -0.253, 95% CI: -0.449 to -0.057). However, there was no significant difference in the ratio of female patients between the two groups (Table 8).
Table 8.
Clinical features of A-AIH compared with C-AIH.
| Studies (n) | Participants (n) | Heterogeneity |
Meta analysis |
Egger | ||||
|---|---|---|---|---|---|---|---|---|
| p | I2 | Model | Mean difference/ Odds ratio | 95% CI | ||||
| Characteristics | ||||||||
| Age | 8 | 438 | 0.720 | 0.000 | Random | -0.253 | -0.449‒-0.057 | 0.35 |
| Sex (females) | 11 | 1133 | 0.983 | 0.000 | Random | 1.215 | 0.888‒1.663 | 0.88 |
| Symptom | ||||||||
| Jaundice | 5 | 300 | 0.443 | 0.000 | Random | 5.841 | 3.446‒9.899 | 0.85 |
| Fatigue | 3 | 244 | 0.998 | 0.000 | Random | 1.320 | 0.786‒2.216 | 0.73 |
| Abdominal pain | 3 | 244 | 0.837 | 0.000 | Random | 0.698 | 0.331‒1.474 | 0.07 |
| Anorexia | 3 | 244 | 0.851 | 0.000 | Random | 7.323 | 4.014‒13.359 | 0.47 |
| Ascites | 4 | 270 | 0.891 | 0.000 | Random | 1.153 | 0.652‒2.039 | 0.12 |
| Weight loss | 3 | 244 | 0.449 | 0.000 | Random | 1.543 | 0.739‒3.221 | 0.98 |
| Yellow urine | 3 | 244 | 0.815 | 0.000 | Random | 4.290 | 2.325‒7.826 | 0.68 |
| Lower limb swelling | 3 | 244 | 0.988 | 0.000 | Random | 0.464 | 0.189‒1.138 | 0.32 |
| Extrahepatic autoimmune disease | 4 | 825 | 0.503 | 0.000 | Random | 0.630 | 0.455‒0.874 | 0.41 |
| Laboratory examination | ||||||||
| ALB (g/L) | 6 | 289 | 0.000 | 87.778 | Random | -0.479 | -1.231‒0.272 | 0.79 |
| GLB (g/L) | 4 | 225 | 0.189 | 37.200 | Random | -0.457 | -0.831‒‒0.084 | 0.83 |
| TB (mg/dL) | 7 | 271 | 0.000 | 80.790 | Random | 1.607 | 0.932‒2.281 | 0.03 |
| AST (IU/L) | 6 | 306 | 0.003 | 72.162 | Random | 1.920 | 1.368‒2.472 | 0.04 |
| ALT (IU/L) | 6 | 305 | 0.000 | 89.885 | Random | 2.032 | 1.081‒2.983 | 0.12 |
| Autoantibody | ||||||||
| ANA+ | 12 | 1222 | 0.001 | 64.025 | Random | 1.706 | 0.960‒3.033 | 0.23 |
| SMA+ | 8 | 962 | 0.652 | 0.000 | Random | 1.243 | 0.939‒1.647 | 0.61 |
| LKM1 | 6 | 889 | 0.943 | 0.000 | Random | 0.854 | 0.505‒1.445 | 0.90 |
| Outcomes | ||||||||
| Mortality | 4 | 174 | 0.550 | 0.000 | Random | 7.141 | 1.569‒32.506 | 0.21 |
| Liver transplantation | 3 | 148 | 0.927 | 0.000 | Random | 4.994 | 1.108‒22.504 | 0.05 |
| Histological examination | ||||||||
| Rosettes | 4 | 331 | 0.140 | 45.199 | Random | 3.629 | 1.500‒8.780 | 0.10 |
| Interface hepatitis | 3 | 135 | 0.743 | 0.000 | Random | 1.775 | 0.691‒4.563 | 0.35 |
| Bile duct injury | 2 | 110 | 0.001 | 91.516 | Random | 2.918 | 1.161‒7.331 | ‒ |
| Centrilobular necrosis | 3 | 140 | 0.019 | 74.708 | Random | 1.691 | 0.326‒8.771 | 0.75 |
| Inflammation grade 0 | 3 | 242 | 0.946 | 0.000 | Random | 0.417 | 0.067‒2.605 | 0.01 |
| Inflammation grade 1 | 3 | 242 | 0.977 | 0.000 | Random | 0.101 | 0.030‒0.340 | 0.00 |
| Inflammation grade 2 | 3 | 242 | 0.993 | 0.000 | Random | 0.141 | 0.061‒0.326 | 0.60 |
| Inflammation grade 3 | 3 | 242 | 0.940 | 0.000 | Random | 3.594 | 2.076‒6.224 | 0.16 |
| Inflammation grade 4 | 3 | 242 | 0.986 | 0.000 | Random | 25.900 | 4.816‒139.276 | 0.06 |
| Fibrosis stage 0‒1 | 4 | 272 | 0.650 | 0.000 | Random | 0.746 | 0.446‒1.248 | 0.55 |
| Fibrosis stage 2 | 4 | 272 | 0.722 | 0.000 | Random | 0.630 | 0.315‒1.258 | 0.58 |
| Fibrosis stage 3 | 4 | 272 | 0.163 | 41.456 | Random | 1.553 | 0.595‒4.055 | 0.64 |
| Fibrosis stage 4 | 4 | 272 | 0.944 | 0.000 | Random | 1.438 | 0.832‒2.486 | 0.00 |
Symptoms
When compared to C-AIH, anorexia (OR = 7.323, 95% CI: 4.014‒13.359) was the most prominent symptom in A-AIH patients. Jaundice and yellow urine followed, with no significant difference noted among the remaining symptoms. Moreover, the incidence of A-AIH combined with autoimmune disease (OR = 0.63, 95% CI: 0.455‒0.874) was significantly lower than in C-AIH. Notably, unlike the high heterogeneity of symptoms across severity levels, these studies exhibited very low heterogeneity (I2 = 0) (Table 8).
Laboratory examination
Patients with A-AIH demonstrated significantly lower Globulin (GLB) levels (MD = -0.457, 95% CI: -0.831 to -0.084) compared to those with C-AIH. In contrast, Total Bilirubin (TB) (MD = 1.607, 95% CI: 0.932‒2.281), Aspartate Aminotransferase (AST) (MD = 1.920, 95% CI: 1.368‒2.472), and Alanine Aminotransferase (ALT) (MD = 2.032, 95% CI: 1.081‒2.983) levels were significantly higher than in patients with C-AIH. There was, however, no statistically significant difference in ANA, SMA, and LKM1 positivity between the two groups (Table 8).
Outcomes
The mortality (OR = 7.141, 95% CI: 1.569‒32.506) and transplantation rates (OR = 4.994, 95% CI: 1.108‒22.504) were significantly higher in patients with A-AIH than in those with C-AIH (Table 8).
Histological examination
Although A-AIH patients often lacked rosettes, combined results showed the presence of rosettes in A-AIH (OR = 3.629, 95% CI: 1.500‒8.780) was significantly higher than in C-AIH patients (Table 8). Consistent with the previous results, A-AIH showed significantly more bile duct injuries than C-AIH (OR = 2.918, 95% CI: 1.161‒7.331) (Table 8).
By comparison, patients with A-AIH had higher inflammation grades of 3 (OR = 3.594, 95% CI: 2.076‒6.224) and 4 (OR = 25.900, 95% CI: 4.816‒139.276), while C-AIH patients typically had milder inflammation grades of 1 (OR = 0.101, 95% CI: 0.030‒0.340) and 2 (OR = 0.141, 95% CI: 0.061‒0.326) (Table 8).
The degree of fibrosis in A-AIH and C-AIH patients showed slight variation, though these differences were not statistically significant.
Publication bias
Egger's test was used for each outcome, and the results are presented in the last column of each table, and the majority of significant results were free of publication bias.
Discussion
The notion of acute Autoimmune Hepatitis (AIH) was first introduced by Lefkowitch et al. in 1984, who detailed two instances of AIH displaying histological indications of acute hepatitis.43 Acute-onset AIH is characterized by its swift progression and potential for misdiagnosis due to its resemblance to other illnesses causing liver dysfunction. Therefore, comprehending the clinical features of Acute-onset AIH is crucial for its accurate diagnosis and effective treatment.
Our study showed that patients with A-AIH were younger compared to patients with C-AIH. Although no continuous statistical differences were found in demographic characteristics between different severities of acute-AIH, there was indeed a tendency for the female sex ratio to gradually decrease as the severity of acute AIH worsened, eventually showing a significant difference between A-AIH and C-AIH. It is well-documented that females have a considerably higher incidence of certain autoimmune diseases, such as Graves' disease or scleroderma, possibly due to differences in immune function between sexes.44 Genetic factors, sex hormones, and other influences could enhance women's immune response, yet simultaneously increase their susceptibility to autoimmune diseases. Historically, women spent most of their lives in states of pregnancy and lactation, providing long-term regulation of the immune system.44 However, modern contraception and fewer pregnancies have potentially disrupted this immune regulation. One study indicated that women with autoimmune hepatitis initiated oral contraception at an earlier age and more frequently, with fewer lifetime pregnancies compared to the control group.45 Our findings indicate a decrease from 81% to 65% in female prevalence from acute non-severe exacerbation to fulminant hepatic failure in AIH. If patients with an acute onset of chronic AIH could be further excluded, there is a possibility that the male-to-female ratio may even out to 1:1. This suggests that severe A-AIH differs substantially from typical Chronic AIH (C-AIH), and that the fulminant progression may bypass the influence of gender, notably the predominant female impact. Considering the female predominance in autoimmune hepatitis patients, it is imperative to further investigate the role of hormones in both acute and chronic AIH, which may reveal the underlying causes of variation in the course and progression of AIH.
AIH has been demonstrated to be strongly correlated with extra-hepatic autoimmune diseases.46 As specified in the 1999 International Autoimmune Hepatitis Group (IAIHG) criteria,40 two points are added to the diagnosis score for coexisting immune disorders. This correlation is primarily due to shared genetic backgrounds, susceptibility genes, and other contributing factors. However, the mechanisms underlying this intricate association are still not extensively understood. Shen et al.37 discovered that about 22% of acute AIH cases were accompanied by an extrahepatic autoimmune disease, a figure slightly higher than the 19% seen in classical AIH. Notably, the difference between these two was not statistically significant. Conversely, our study revealed a notably lower co-occurrence of extrahepatic autoimmune diseases in acute AIH (A-AIH) compared to Chronic AIH (C-AIH).
The clinical implications and prognostic influence of extrahepatic autoimmune diseases on AIH remain a contentious subject. Some researchers suggest that AIH patients with concurrent extrahepatic autoimmune diseases are mostly asymptomatic at presentation and exhibit less severe disease progression.46 It's also been suggested that the co-occurrence of extrahepatic autoimmune liver diseases does not significantly impact AIH's progression, prognosis, or survival.47 However, this contrasts with findings by Birn-Rydder et al., who reported increased mortality in AIH patients with extrahepatic autoimmune diseases.48
Our results show that A-AIH is significantly less likely to be associated with other autoimmune diseases than C-AIH. We observed a trend of declining comorbidity as the severity increased, i.e., 23% of A-AIH, 21% of Acute-Severe AIH (AS-AIH), and 7% of Acute Liver Failure AIH (ALF-AIH) cases4 were accompanied by extrahepatic autoimmune diseases, though the differences were not statistically significant. This pattern seems to bolster the notion that the presence of other autoimmune diseases may serve as a protective factor for AIH patients.46
The co-occurrence of other autoimmune diseases with AIH suggests a potential linkage between these diseases and the prognosis of A-AIH, given the significantly different outcomes of AIH with acute manifestations of varying severity. We postulate that this could be due to the influence of extrahepatic autoimmune diseases on immune homeostasis, although the mechanism warrants further exploration. It's important to note that although AIH often coexists with certain immune disorders, this relationship isn't always bidirectional. While 0.7%‒18.8% of AIH cases may be associated with Systemic Lupus Erythematosus (SLE), up to 60% of patients with SLE may develop hepatic insufficiency, yet rarely coexist with autoimmune hepatitis.49
Recent advancements in molecular genetics, including Genome-Wide Association Studies (GWAS) and risk-associated Single Nucleotide Polymorphism (SNP) research, have greatly improved our understanding of autoimmune diseases' coexistence. These findings suggest that a shared genetic background contributes to the concurrent presence of autoimmune liver disease and other extrahepatic autoimmune diseases.50
The primary challenge in managing acute-onset AIH is timely and accurate diagnosis, as untreated cases can swiftly progress to liver failure or even result in death. We found that over half of patients might exhibit symptoms like jaundice (74.5%), anorexia (62.0%), and fatigue (59.9%), all of which could stem from elevated bilirubin levels. Subgroup analysis revealed that while fatigue and anorexia are common nonspecific symptoms of chronic autoimmune hepatitis, anorexia was the most prominent symptom in patients with Acute AIH (A-AIH) compared to those with Chronic AIH (C-AIH). This suggests that patients with gastrointestinal symptoms such as anorexia warrant closer monitoring.
Acute-onset AIH typically lacks the clinical features characteristic of chronic autoimmune hepatitis, making the identification of serological features even more crucial. Our results indicated that White Blood Cell (WBC) and Platelet (PLT) counts were within the normal range. However, it's important to note that these factors can serve as predictors for complications like infections and treatment outcomes, and thus require dynamic observation for meaningful interpretation. A study by Shen et al.37 reported lower Albumin (ALB) levels in the acute group, suggesting that a deteriorating liver condition in A-AIH affects ALB production. In line with this, Kessler et al.5 proposed that ALB might play a role in the acute phase response, hence hypoalbuminemia is a suitable indicator of A-AIH. Yet, our results showed no significant difference in ALB levels between A-AIH and C-AIH, possibly due to the high heterogeneity of the included studies (I2 = 87.778). Unfortunately, the Acute-Severe AIH (AS-AIH) and Acute Liver Failure AIH (ALF-AIH) groups lacked sufficient studies to further examine the role of ALB.
Acute-onset AIH is primarily defined as acute exacerbation symptoms accompanied by elevated serum bilirubin and/or serum alanine aminotransferase.38 Our results affirmed that this accurately reflects the characteristics of acute exacerbation of autoimmune hepatitis. Although it is reliable as an indicator of acute onset of disease, but it's the bilirubin and coagulation indices that can further differentiate the degree of severity. Aminotransferases do not serve such a role. Despite many unresolved questions in diagnosing acute manifestations of AIH, current indicators of response severity perform adequately.
Autoantibodies are a crucial diagnostic criterion in all autoimmune hepatitis scoring systems, serving significant roles in diagnosis and subtype determination.2 A distinguishing feature of A-AIH is often the absence of typical ANA, ASMA, and LKM-1. However, this feature was not significant in our meta-analysis and was found to be independent of severity. This might be due to a significant proportion of Acute-onset Chronic AIH patients mixed into this group. The value of autoantibodies in acute-onset AIH remains uncertain, but with current results, autoantibodies still remain key diagnostic indicators for both true A-AIH and acute onset of C-AIH.
In Furthermore, Globulin (GLB) levels were significantly lower in A-AIH than in C-AIH, and also some researchers have suggested that globulin may be an important indicator for differentiating between A-AIH and AC-AIH.37 An Italian study7 revealed that histologically identified acute onset AIH (between true A-AIH and AC-AIH) had lower GLB (19 vs. 24, p = 0.005) and IgG (1.12 vs. 1.4, p = 0.03) levels, which might explain why we didn't find a difference across different degrees of severity.
Pathologically, acute AIH is predominantly characterized by acute lobulitis with centrilobular necrosis, although the intrinsic significance of this still requires further verification. Our findings in the A-AIH group align with this, with lobulitis accounting for 91.2% and centrilobular necrosis 47%. Notably, acute AIH, often thought to lack typical pathology such as interface hepatitis and rosettes, was still present in half or even over 80% of cases. The presence of rosettes was significantly higher in A-AIH than in C-AIH. This may be because, along with true A-AIH, there is also some acute onset of C-AIH in a sub-clinical stage. A recent study39 showed that 16.7% of A-AIH patients and 37.5% of AC-AIH patients presented with rosettes, along with a similar profile in interface hepatitis, suggesting that many previous studies have confused A-AIH and AC-AIH.
Regarding the degree of fibrosis, nearly half of the patients were in stages F2-F4, indicating that at least half of the patients in the current study were experiencing an acute exacerbation of C-AIH. Future studies should more effectively differentiate between A-AIH and AC-AIH. More accurate subgroup analyses may yield different results.37
Bile duct injuries, although uncommon in classical AIH, have shown that Acute-Severe AIH (AS-AIH) slightly less frequently present with bile duct injuries than C-AIH.36 Our results, however, found that bile duct injuries were more common in A-AIH, significantly differing from C-AIH. Bile duct injury appears to be one of the histologic criteria to distinguish between acute and chronic stages. Yet, due to the small number of included studies and the high heterogeneity (I2 = 91.516), more research is needed to understand the significance of bile duct injury on the diagnosis and prognosis of A-AIH.
Our meta-analysis comes with certain limitations. Parts of the data types and formats were not compatible for results integration, leading us to discard some significant findings. Moreover, only a few studies provided a comprehensive documentation of the disease's full course, and incomplete data made further analysis challenging. Acute-onset AIH, being a manifestation of rare diseases, made it difficult for us to gather sufficient data to classify by ethnicity, region, and age, thereby increasing the heterogeneity of our data. Most importantly, not all studies have been able to discern AC-AIH due to diagnostic complexities and difficulties in differential diagnosis of A-AIH. While it has been posited37 that initial differentiation between acute manifestations and chronic autoimmune hepatitis, based solely on serologic markers without using acute and chronic histologic features, is reliable, a more granular classification might reveal different results or even alter the current understanding of acute-onset AIH.
Conclusion
In conclusion, this is the first systematic summary of acute-onset AIH. Our study found that patients with acute-onset AIH were younger and that the gender difference narrowed with increasing disease severity. Among numerous nonspecific symptoms, apart from jaundice, anorexia was the symptom that differed most from C-AIH. The presence of comorbid extrahepatic autoimmune diseases correlated with less severe disease in acute-onset AIH, implying a potential protective role. Current laboratory tests for identifying acute-onset AIH and differentiating its severity demonstrated moderately acceptable performance. Both autoantibody and histologic manifestations of A-AIH seem to be affected by AC-AIH, rendering some of the typically rare manifestations of A-AIH statistically indistinguishable from those of standard AIH. The current evidence supports only our initial conclusions, and future studies need to underscore the importance of comprehensive documentation and follow-up.
Ethics approval and consent to participate
Since this is a meta-analysis, which involves the synthesis of data from previously published studies, no new data were collected directly from human participants. Therefore, formal ethics approval from an Institutional Review Board (IRB) was not required. All the studies included in this meta-analysis had already obtained appropriate ethics approvals from their respective institutions at the time of original data collection. We have carefully reviewed the ethics statements in each of the included studies to ensure that the data used in our analysis were collected in accordance with ethical principles. As no new participants were involved in this study, the issue of consent to participate did not arise. However, we respect the privacy and rights of all individuals whose data are included in the original studies. We have made every effort to ensure that the data extraction and analysis were conducted in a way that maintains the confidentiality and integrity of the original data sources.
Consent for publication
Not applicable.
Availability of data and material
The data for this meta-analysis were retrieved from well-known databases like PubMed and Embase. All data are available within the text. The search strategies are detailed in the Methods section. All data are from published studies and can be accessed via the original journals' websites. For paywalled articles, institutional subscriptions or requests to authors may help. We've compiled an analyzed dataset. Upon request, the corresponding author can provide this dataset and relevant analysis code (if any), subject to the original data source terms. Also, the data extraction form and study metadata are available to ensure transparency and reproducibility.
Clinical trial number
Not applicable.
Funding
This work was supported by Sponsored Programs: Xijing Discipline Boosting Project of Xijing Hospital (no. XJZT21CZ02).
Declaration of competing interest
The authors declare no conflicts of interest.
Acknowledgement
Not applicable.
Edited by José Maria Soares Junior
Footnotes
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.clinsp.2026.101118.
Appendix. Supplementary materials
References
- 1.Sahebjam F., Vierling J.M. Autoimmune hepatitis. Front Med. 2015;9(2):187–219. doi: 10.1007/s11684-015-0386-y. [DOI] [PubMed] [Google Scholar]
- 2.Hennes E.M., Zeniya M., Czaja A.J., Pares A., Dalekos G.N., Krawitt E.L., et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology. 2008;48(1):169–176. doi: 10.1002/hep.22322. [DOI] [PubMed] [Google Scholar]
- 3.Gatselis N.K., Zachou K., Papamichalis P., Koukoulis G.K., Gabeta S., Dalekos G.N., et al. Comparison of simplified score with the revised original score for the diagnosis of autoimmune hepatitis: a new or a complementary diagnostic score? Dig Liver Dis. 2010;42(11):807–812. doi: 10.1016/j.dld.2010.03.005. [DOI] [PubMed] [Google Scholar]
- 4.Urzua A., Pizarro C., Gajardo A., Poniachik R., Pavez C., Cattaneo M., et al. Autoimmune Hepatitis with Acute Presentation: Clinical, Biochemical, and Histological Features of 126 Patients. Can J Gastroenterol Hepatol. 2022;2022:1–9. doi: 10.1155/2022/6470847. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Aljumah A.A., Al-Ashgar H., Fallatah H., Albenmousa A. Acute onset autoimmune hepatitis: clinical presentation and treatment outcomes. Ann Hepatol. 2019;18(3):439–444. doi: 10.1016/j.aohep.2018.09.001. [DOI] [PubMed] [Google Scholar]
- 6.Joshita S., Yoshizawa K., Umemura T., Ohira H., Takahashi A., Harada K., et al. Clinical features of autoimmune hepatitis with acute presentation: a Japanese nationwide survey. J Gastroenterol. 2018;53(9):1079–1088. doi: 10.1007/s00535-018-1444-4. [DOI] [PubMed] [Google Scholar]
- 7.Muratori P., Carbone M., Stangos G., Perini L., Lalanne C., Ronca V., et al. Clinical and prognostic implications of acute onset of Autoimmune Hepatitis: An Italian multicentre study. Dig Liver Dis. 2018;50(7):698–702. doi: 10.1016/j.dld.2018.02.015. [DOI] [PubMed] [Google Scholar]
- 8.Fujiwara K., Fukuda Y., Seza K., Saito M., Yasui S., Nakano M., et al. Long-term observation of acute-onset autoimmune hepatitis presenting clinically and radiologically as acute hepatitis. Hepatol Int. 2018;12(2):191–199. doi: 10.1007/s12072-018-9848-z. [DOI] [PubMed] [Google Scholar]
- 9.Yamamoto K., Miyake Y., Ohira H., Suzuki Y., Zeniya M., Onji M., et al. Prognosis of autoimmune hepatitis showing acute presentation. Hepatol Res. 2013;43(6):630–638. doi: 10.1111/j.1872-034X.2012.01109.x. [DOI] [PubMed] [Google Scholar]
- 10.Miyake Y., Iwasaki Y., Kobashi H., Yasunaka T., Ikeda F., Takaki A., et al. Autoimmune hepatitis with acute presentation in Japan. Dig Liver Dis. 2010;42(1):51–54. doi: 10.1016/j.dld.2009.04.009. [DOI] [PubMed] [Google Scholar]
- 11.Fujiwara K., Fukuda Y., Seza K., Saito M., Yasui S., Nakano M., et al. High level of persistent liver injury is one of clinical characteristics in treatment-naive acute onset autoimmune hepatitis: experience in a community hospital. J Hepatobiliary Pancreat Sci. 2016;23(3):174–180. doi: 10.1002/jhbp.319. [DOI] [PubMed] [Google Scholar]
- 12.Ferrari R., Pappas G., Agostinelli D., Muratori P., Muratori L., Lenzi M., et al. Type 1 autoimmune hepatitis: patterns of clinical presentation and differential diagnosis of the 'acute' type. QJM. 2004;97(7):407–412. doi: 10.1093/qjmed/hch072. [DOI] [PubMed] [Google Scholar]
- 13.Iwai M., Jo M., Ishii M., Mori T., Harada Y. Comparison of clinical features and liver histology in acute and chronic autoimmune hepatitis. Hepatol Res. 2008;38(8):784–789. doi: 10.1111/j.1872-034X.2008.00347.x. [DOI] [PubMed] [Google Scholar]
- 14.Smolka V., Tkachyk O., Ehrmann J., Karaskova E., Zapalka M., Volejnikova J. Acute onset of autoimmune hepatitis in children and adolescents. Hepatobiliary Pancreat Dis Int. 2020;19(1):17–21. doi: 10.1016/j.hbpd.2019.08.004. [DOI] [PubMed] [Google Scholar]
- 15.Nikias G.A., Batts K.P., Czaja A.J. The nature and prognostic implications of autoimmune hepatitis with an acute presentation. J Hepatol. 1994;21(5):866–871. doi: 10.1016/s0168-8278(94)80251-3. [DOI] [PubMed] [Google Scholar]
- 16.Fujiwara K., Yasui S., Tawada A., Fukuda Y., Nakano M., Yokosuka O. Diagnostic value and utility of the simplified International Autoimmune Hepatitis Group criteria in acute-onset autoimmune hepatitis. Liver Int. 2011;31(7):1013–1020. doi: 10.1111/j.1478-3231.2011.02524.x. [DOI] [PubMed] [Google Scholar]
- 17.Tellez L., Sanchez Rodriguez E., Rodriguez de Santiago E., Llovet L., Gomez-Outomuro A., Diaz-Fontenla F., et al. Early predictors of corticosteroid response in acute severe autoimmune hepatitis: a nationwide multicenter study. Aliment Pharmacol Ther. 2022;56(1):131–143. doi: 10.1111/apt.16926. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Yasui 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(3):378–390. doi: 10.1007/s00535-010-0316-3. [DOI] [PubMed] [Google Scholar]
- 19.Chavez-Tapia N.C., Martinez-Salgado J., Granados J., Uribe M., Tellez-Avila F.I. Clinical heterogeneity in autoimmune acute liver failure. World J Gastroenterol. 2007;13(12):1824. doi: 10.3748/wjg.v13.i12.1824. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Dohmen K., Tanaka H., Haruno M., Aishima S. Immunoserological and histological differences between autoimmune hepatitis with acute presentation and chronic autoimmune hepatitis. Hepatol Res. 2017;47(13):1375–1382. doi: 10.1111/hepr.12875. [DOI] [PubMed] [Google Scholar]
- 21.Yeoman A.D., Westbrook R.H., Zen Y., Bernal W., Al-Chalabi T., Wendon J.A., et al. Prognosis of acute severe autoimmune hepatitis (AS-AIH): the role of corticosteroids in modifying outcome. J Hepatol. 2014;61(4):876–882. doi: 10.1016/j.jhep.2014.05.021. [DOI] [PubMed] [Google Scholar]
- 22.Joao M., Carvalhana S., Moura M., Freitas L.C., Silva A., Figueiredo P., et al. Severe acute autoimmune hepatitis: how to early predict who will not respond to corticosteroids and needs urgent liver transplantation? Dig Liver Dis. 2022;54(12):1681–1685. doi: 10.1016/j.dld.2022.08.035. [DOI] [PubMed] [Google Scholar]
- 23.Fujiwara K., Yasui S., Yokosuka O., Oda S., Kato N. Diagnostic utility of radiological heterogeneity in acute severe (fulminant) autoimmune hepatitis. J Hepatobiliary Pancreat Sci. 2017;24(8):485–491. doi: 10.1002/jhbp.487. [DOI] [PubMed] [Google Scholar]
- 24.Fujiwara K., Nakano M., Yasui S., Okitsu K., Yonemitsu Y., Yokosuka O. Advanced histology and impaired liver regeneration are associated with disease severity in acute-onset autoimmune hepatitis. Histopathology. 2011;58(5):693–704. doi: 10.1111/j.1365-2559.2011.03790.x. [DOI] [PubMed] [Google Scholar]
- 25.Di Giorgio A., Bravi M., Bonanomi E., Alessio G., Sonzogni A., Zen Y., et al. Fulminant hepatic failure of autoimmune aetiology in children. J Pediatr Gastroenterol Nutr. 2015;60(2):159–164. doi: 10.1097/MPG.0000000000000593. [DOI] [PubMed] [Google Scholar]
- 26.Yasui S., Fujiwara K., Tawada A., Fukuda Y., Nakano M., Yokosuka O. Efficacy of intravenous glycyrrhizin in the early stage of acute onset autoimmune hepatitis. Dig Dis Sci. 2011;56(12):3638–3647. doi: 10.1007/s10620-011-1789-5. [DOI] [PubMed] [Google Scholar]
- 27.Stravitz R.T., Lefkowitch J.H., Fontana R.J., Gershwin M.E., Leung P.S., Sterling R.K., et al. Autoimmune acute liver failure: proposed clinical and histological criteria. Hepatology. 2011;53(2):517–526. doi: 10.1002/hep.24080. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Burgart L.J., Batts K.P., Ludwig J., Nikias G.A., Czaja A.J. Recent-onset autoimmune hepatitis. Biopsy findings and clinical correlations. Am J Surg Pathol. 1995;19(6):699–708. doi: 10.1097/00000478-199506000-00010. [DOI] [PubMed] [Google Scholar]
- 29.Abe M., Onji M., Kawai-Ninomiya K., Michitaka K., Matsuura B., Hiasa Y., et al. Clinicopathologic features of the severe form of acute type 1 autoimmune hepatitis. Clin Gastroenterol Hepatol. 2007;5(2):255–258. doi: 10.1016/j.cgh.2006.10.011. [DOI] [PubMed] [Google Scholar]
- 30.Abe M., Hiasa Y., Masumoto T., Kumagi T., Akbar S.M., Ninomiya T., et al. Clinical characteristics of autoimmune hepatitis with histological features of acute hepatitis. Hepatol Res. 2001;21(3):213–219. doi: 10.1016/s1386-6346(01)00109-7. [DOI] [PubMed] [Google Scholar]
- 31.Fu X., Yang Y., Jin J. Analysis of 36 cases of autoimmune hepatitis misdiagnosed as acute jaundiced viral hepatitis. Zhejiang Medicine. 2008;(07):759–760. [Google Scholar]
- 32.Huanrong H., Jia S., Yi K., Yukui L., Chongshan M., Yanli Z., et al. Clinical analysis of acute liver failure as the first symptom of autoimmune hepatitis. Chin J Gastroenterol Hepatol. 2016;25(04):426–427. [Google Scholar]
- 33.Xia J., Gao S., Zhang F., Wang L., Li J., Yang X. Observations on the clinical and pathological features of acute autoimmune hepatitis. Mod Dig Interv. 2021;26(7):904–907. [Google Scholar]
- 34.Nie H., Song J., Shi N. Clinical and pathological features of acute autoimmune hepatitis. Chinese Hepatol. 2021;26(6):664–666. [Google Scholar]
- 35.Kessler W.R., Cummings O.W., Eckert G., Chalasani N., Lumeng L., Kwo P.Y. Fulminant hepatic failure as the initial presentation of acute autoimmune hepatitis. Clin Gastroenterol Hepatol. 2004;2(7):625–631. doi: 10.1016/s1542-3565(04)00246-0. [DOI] [PubMed] [Google Scholar]
- 36.Sonthalia N., Rathi P.M., Jain S.S., Surude R.G., Mohite A.R., Pawar S.V., et al. Natural history and treatment outcomes of severe autoimmune hepatitis. J Clin Gastroenterol. 2017;51(6):548–556. doi: 10.1097/MCG.0000000000000805. [DOI] [PubMed] [Google Scholar]
- 37.Shen Y., Lu C., Men R., Liu J., Ye T., Yang L. Clinical and pathological characteristics of autoimmune hepatitis with acute presentation. Can J Gastroenterol Hepatol. 2018;2018:1–10. doi: 10.1155/2018/3513206. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Nguyen Canh H., Harada K., Ouchi H., Sato Y., Tsuneyama K., Kage M., et al. Acute presentation of autoimmune hepatitis: a multicentre study with detailed histological evaluation in a large cohort of patients. J Clin Pathol. 2017;70(11):961–969. doi: 10.1136/jclinpath-2016-204271. [DOI] [PubMed] [Google Scholar]
- 39.Zheng L.H., Shang Y.L., Han Z.Y., Han Y. [Analysis of clinical features and prognosis of acute severe autoimmune hepatitis] Zhonghua Gan Zang Bing Za Zhi. 2022;30(1):69–73. doi: 10.3760/cma.j.cn501113-20201106-00603. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Alvarez F., Berg P.A., Bianchi F.B., Bianchi L., Burroughs A.K., Cancado E.L., et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31(5):929–938. doi: 10.1016/s0168-8278(99)80297-9. [DOI] [PubMed] [Google Scholar]
- 41.Czaja A.J. Natural history, clinical features, and treatment of autoimmune hepatitis. Semin Liver Dis. 1984;4(1):1–12. doi: 10.1055/s-2008-1040641. [DOI] [PubMed] [Google Scholar]
- 42.Mieli-Vergani G., Vergani D. Autoimmune liver diseases in children ‒ what is different from adulthood? Best Pract Res Clin Gastroenterol. 2011;25(6):783–795. doi: 10.1016/j.bpg.2011.10.007. [DOI] [PubMed] [Google Scholar]
- 43.Lefkowitch J.H., Apfelbaum T.F., Weinberg L., Forester G. Acute liver biopsy lesions in early autoimmune ("lupoid") chronic active hepatitis. Liver. 1984;4(6):379–386. doi: 10.1111/j.1600-0676.1984.tb00954.x. [DOI] [PubMed] [Google Scholar]
- 44.Fairweather D., Rose N.R. Women and autoimmune diseases. Emerg Infect Dis. 2004;10(11):2005–2011. doi: 10.3201/eid1011.040367. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45.Lammert C., Chalasani S.N., Atkinson E.J., McCauley B.M., Lazaridis K.N. Environmental risk factors are associated with autoimmune hepatitis. Liver Int. 2021;41(10):2396–2403. doi: 10.1111/liv.14944. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Muhling T., Rohrbach H., Schepp W., Gundling F. Overlap of concurrent extrahepatic autoimmune diseases is associated with milder disease severity of newly diagnosed autoimmune hepatitis. Hepatobiliary Pancreat Dis Int. 2021;20(1):21–27. doi: 10.1016/j.hbpd.2020.06.019. [DOI] [PubMed] [Google Scholar]
- 47.Wong G.W., Yeong T., Lawrence D., Yeoman A.D., Verma S., Heneghan M.A. Concurrent extrahepatic autoimmunity in autoimmune hepatitis: implications for diagnosis, clinical course and long-term outcomes. Liver Int. 2017;37(3):449–457. doi: 10.1111/liv.13236. [DOI] [PubMed] [Google Scholar]
- 48.Birn-Rydder R., Jensen M.D., Jepsen P., Gronbaek L. Extrahepatic autoimmune diseases in autoimmune hepatitis: effect on mortality. Liver Int. 2022;42(11):2466–2472. doi: 10.1111/liv.15382. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Floreani A., De Martin S., Secchi M.F., Cazzagon N. Extrahepatic autoimmunity in autoimmune liver disease. Eur J Intern Med. 2019;59:1–7. doi: 10.1016/j.ejim.2018.10.014. [DOI] [PubMed] [Google Scholar]
- 50.Guo L., Zhou L., Zhang N., Deng B., Wang B. Extrahepatic autoimmune diseases in patients with autoimmune liver diseases: a phenomenon neglected by gastroenterologists. Gastroenterol Res Pract. 2017;2017 doi: 10.1155/2017/2376231. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data for this meta-analysis were retrieved from well-known databases like PubMed and Embase. All data are available within the text. The search strategies are detailed in the Methods section. All data are from published studies and can be accessed via the original journals' websites. For paywalled articles, institutional subscriptions or requests to authors may help. We've compiled an analyzed dataset. Upon request, the corresponding author can provide this dataset and relevant analysis code (if any), subject to the original data source terms. Also, the data extraction form and study metadata are available to ensure transparency and reproducibility.