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Review

Pathophysiological Differences and Differential Diagnosis of Autoimmune and Drug-Induced Hepatitis

by
Nicola Zeni
1,
Alessandro Cristofani
1,
Salvatore Silvio Piano
1,
Massimo Bolognesi
1 and
Antonietta Romano
1,2,*
1
Unit of Internal Medicine and Hepatology, Department of Medicine, University of Padova, 35128 Padova, Italy
2
Department of Medicine, University of Padova, Via Giustiniani 2, 35128 Padova, Italy
*
Author to whom correspondence should be addressed.
Livers 2025, 5(2), 22; https://doi.org/10.3390/livers5020022
Submission received: 23 March 2025 / Revised: 25 April 2025 / Accepted: 30 April 2025 / Published: 13 May 2025
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Abstract

:
Autoimmune hepatitis (AIH) and drug-induced liver injury (DILI) are major causes of liver inflammation with distinct pathophysiology but overlapping clinical features. Among acute cases, DILI is a key differential diagnosis for AIH, especially when drug history is unclear or the injury is non-dose-dependent. Mechanisms of DILI include direct toxicity, metabolic idiosyncrasies, and immune-mediated responses that can mimic AIH. Moreover, certain drugs can induce AIH-like syndromes, further complicating the diagnosis. While causality assessment tools aid initial evaluations, liver biopsy remains valuable for distinguishing AIH from DILI; given these complexities, hepatologist consultation is often essential to ensure appropriate diagnosis and treatment management.

1. Introduction

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease characterized by an immune-mediated attack on hepatic tissue, is often associated with autoantibodies and specific genetic predispositions, and if not treated properly may progress to liver cirrhosis and ultimately lead to hepatic failure. One of the main pathologies that enters into the differential diagnosis of autoimmune hepatitis, especially in acute forms, is drug-induced liver injury (DILI) [1].
DILI constitutes hepatic damage attributed to drug exposure and a challenging liver disorder, considering the vast array of potentially hepatotoxic drugs, the heterogeneity of clinical and histopathological manifestations, and the current absence of specific diagnostic biomarkers.
Despite sharing common features, such as elevated liver enzymes and histological evidence of inflammation, AIH and DIH differ in their immunological mechanisms, triggering factors, and treatment strategies [2].
The pathophysiological mechanisms underlying drug-induced damage are varied, and the damage may also be non-dose-dependent; sometimes, the pharmacological medical history is not clear.
Additionally, various drugs have been implicated in the onset of clinical syndromes that closely mimic autoimmune hepatitis. Differential diagnosis can be particularly difficult in non-dose-dependent forms of damage and in cases where the drug triggers an immune response that mimics a form of autoimmune hepatitis. While AIH requires long-term immunosuppressive therapy, DILI management is primarily based on the cessation of the drug suspected to be responsible, making accurate differentiation crucial for appropriate treatment [3].
In this article, starting from pathogenic mechanisms, we will try to highlight the crucial points of the differential diagnosis of DILI/AIH and the diagnostic gaps. Additionally, we will examine diagnostic approaches, including serological markers, liver biopsy findings, and clinical history, to facilitate accurate differentiation between these conditions.

2. Autoimmune Hepatitis

Autoimmune hepatitis (AIH) is a persistent, acute, subacute, or chronic liver disorder that is characterized by hypergammaglobulinemia even without cirrhosis and, in most cases, the presence of circulating autoantibodies. Additionally, the condition typically demonstrates a beneficial response to immunosuppressive therapy, but if not treated, AIH frequently progresses to fibrosis, liver failure, and, ultimately, death [4]. The incidence of the disease is 1.28 cases per 100,000 individuals world-wide, and recent findings indicate a rising trend in both the occurrence and overall burden of the condition [5].
Clinically, AIH can present itself as anything from an asymptomatic or very-little-symptomatic sub-clinical and intermittent hypertransaminasemia to fulminant hepatitis with acute hepatic failure. Even if the clinical presentation may vary significantly among patients, the pathogenesis of these presentations is shared.

Pathophysiology of AIH

As with other autoimmune disorders, the specific patterns underlying AIH’s pathogenesis are unidentified.
The liver is constantly exposed, and thus highly tolerant, to environmental stimuli, and promotes immune tolerance by priming CD8+ T cells through mechanisms like stunning and exhaustion, which prevent excessive inflammation [6]. In AIH, tolerance mechanisms are known to fail; usually, tolerance loss occurs due to genetic factors, environmental triggers, and immune dysregulation, resulting in T-cell-mediated liver injury involving both T cell subsets and B cells. External factors are thought to be essential for triggering the autoimmune response against liver structures. Common viral infections, including major and minor hepatitis viruses and measles, are known triggers. Additionally, various drugs have been linked to the development of an autoimmune-hepatitis-like condition [6,7,8].
AIH represents a clinical syndrome with diverse underlying mechanisms of liver damage. Liver damage in AIH occurs primarily through self-antigen presentation to naive T cells, which can lead to the activation of the T helper1 (Th1), T helper2 (Th2), and T helper17 (Th17) pathways, in the presence of costimuli and external factors. When driven by specific cytokines, those pathways can direct adapting immune responses toward autoantigens, most of which are not yet fully identified. Among cytokines, interleukin (IL)-12 induces Th1 cells, promoting cytotoxic T-cell-mediated liver damage, and the activation of Natural Killer (NK), IL-6, and transforming growth factor-β (TGF-β) together drives Th17 differentiation cells, causing an imbalance between increased pro-inflammatory Th17 and decreased Treg immunomodulatory cells, leading to liver damage and inflammation. Finally, IL-4 promotes Th2 cells, aiding B cell differentiation and complement activation [9] (Figure 1). Even though AIH remains predominantly T-cell-mediated, B cells and the role of the production of their autoantibodies in liver damage has been studied. In in vivo models of AIH, B cells, per se, do not appear to be directly linked to liver damage, but instead play a more modulatory role [10]. Nonetheless, emerging data from patients with AIH suggest that B-cell-depleting therapies may offer a promising therapeutic approach, thus confirming the potential pathophysiological role of B cells in AIH [11]. Consequently, a double-blind randomized clinical trial is currently underway to evaluate the efficacy and safety of lanalumab in patients where standard therapies are ineffective or must be discontinued due to side effects [12].
The autoantibody profile observed in AIH has often been explored in relation to liver damage. Autoantibodies and a selective increase in IgG are characteristic features of AIH. Although at least two target antigens of autoantibodies with mapped epitopes (Liver Kidney Microsome-1 (LKM-1) and soluble liver antigen/liver–pancreas (SLA/LP)) have been identified and proven to be pathophysiologically linked directly to liver damage development, the antigens involved in type 1 AIH, which is more prevalent, remain unidentified [13]. One speculation is that liver immune-mediated damage might include a variety of heterogeneous antigens that produce diverse immunological responses over time instead of a fixed one. The hypothesis is that unknown enzymatic substrates could be metabolized, presented, and later recognized by T cells, but this remains highly speculative [1,8]. Finally, the role of IgG4 in AIH liver damage has been investigated, but significant findings on the matter are yet to be proven [14,15].
Even after the first external triggers and antigen/T cell contact cease, inflammation may persist due to molecular mimicry and ongoing cytokine-driven damage. A murine study demonstrated that T cell activation was strongest in response to antigens with low to moderate homology to CYP2D6, implying that molecular mimicry could enhance immune response. This also suggests the potential for drug breakdown molecules and haptens to trigger autoimmune reactions [16].
Compelling evidence and experimental models of AIH strongly support the notion that AIH is predominantly a T-cell-dependent process, with the dysregulated immune response targeting specific antigens. Some intrinsic predispositions or alterations of physiological immune response in the liver, most of which are yet to be determined, seem to play a key role in AIH development [17,18,19].
A strong correlation between AIH occurrence and specific human leukocyte antigen (HLA) variants underscores the influence of genetic predisposition. This association predominantly involves HLA class II alleles (HLA-DRB1*0301), which play an important role in presenting peptide antigens to CD4+ T cells via antigen-presenting cells [19,20]. While the involvement of co-stimulatory signaling has also been highlighted in a genome-wide association study, in vivo studies identified a significant association between AIH and genetic loci related to T cell activation (CD28/CTLA4/ICOS) [10].
Regarding T-cell-mediated damage, both peripheral and intrahepatic T cells are involved, several hypo-methylated genes have been identified in CD4+ and CD19+ T lymphocytes of autoimmune hepatitis patients, and the circulating microRNAs miR-21 and miR-122 correlate with liver inflammation markers both clinically and histologically [18,21,22]; a persistent TRBV-J-biased signaling pathway alteration was identified in T cells in AIH, even following successful immunosuppressive therapy. These findings are of absolute interest not only for the study of the mechanism of AIH, per se, but also for suggesting that treatment might modulate T cell function without fundamentally altering the T cell architecture, potentially contributing to the high relapse rate observed in AIH at withdrawal [18]. Accordingly, one study found that patients with AIH who achieved biochemical remission did not restore the imbalanced CD4+ subset cells and MAIT cells, indicating that, while standard immunosuppressive treatment may effectively resolve hepatitis, it does not fully impact on the pathogenesis of AIH to properly restore liver immune tolerance [23].
While a significant expansion of TCR clonotypes has been observed in CD8+ T cells in AIH, single-nucleotide polymorphisms (SNPs) have also been linked to pro-inflammatory and regulatory pathways and implicated in autoimmune hepatitis, including genes like tumor necrosis factor (TNF), Cytotoxic T-Lymphocyte Antigen 4 CTLA-4/Cluster of Differentiation 28 (CD28), Fatty Acid Synthase (FAS), Tumor Growth Factor-β 1 (TGFβ1), and IL-4 [24].
In summary, in predisposed patients, after liver immune tolerance is lost, different T and B cell immune dysfunctions occur and lead to liver damage (Figure 1). Even though this process is usually located at the portal–parenchymal interface within the liver (interface hepatitis), the autoimmune process arises from no pathognomonic morphologic feature [25,26]. Cholangiocytes may be sometimes the target of the dysregulated autoimmune response, with slightly different pathophysiological mechanisms that resemble those of primary biliary cholangitis (PBC) or primary biliary sclerosis (PBS). When this occurs in the context of AIH, the clinical entity goes under the name of “overlap syndrome” or variants forms of AIH and cholestatic liver disease [27]. The pathogenesis, diagnostic criteria, and nomenclature of these entities remain subjects of ongoing debate and are not addressed in this review, which is instead focused on the pathophysiological mechanisms and differential diagnosis of AIH and DILI.
Antigen-presenting cells—APCs; interleukin—IL; Natural Killer—NK; T helper1—Th1; T helper2—Th2; T helper17—Th17; Treg—regulatory T cell; transforming growth factor-β—TGF-beta.

3. Diagnostic Criteria of AIH

Diagnosing autoimmune hepatitis can be difficult, as no single clinical sign, biochemical, or histological finding is pathognomonic. Moreover, concomitant liver injury factors may be present and should not delay the diagnosis or treatment of autoimmune hepatitis. Diagnostic workup should be always sought in patients with unexplained elevated liver enzymes or cirrhosis; all known causes of liver injury must be excluded, namely alcoholic (ASH) and non-alcoholic steatohepatitis (NASH), infection with hepatitis A, B, C, or E viruses, the intake of hepatotoxic drugs, HSV, EBV, or CMV infection (Figure 2) [28].
A comprehensive scoring system was introduced in 1999 to aid clinicians in diagnosing AIH once other causes of hypertransaminasemia are ruled out. The AIH score grades the clinical, laboratory, and histological features of autoimmune hepatitis (AIH), including response to corticosteroid treatment (criteria of definite AIH according to AIH score: normal α-1AT phenotype, normal ceruloplasmin, normal iron and ferritin levels, no active hepatitis A, B, C infection, daily alcohol < 25 g/day, no recent hepatotoxic drugs, predominant AST/ALT abnormality, γ-globulins or IgG level > 1.5 times the upper normal limit, ANA, SMA anti-LKM1 > 1:80 in adults and >1:20 in children, liver histology of moderate to severe interface hepatitis, and no biliary lesions, granulomas, or prominent changes suggestive of another disease) [29]. Subsequently, a revised and simplified AIH scoring system has been developed. Compared to the original, which offers higher sensitivity (100% vs. 95%), the simplified system has greater specificity (90% vs. 73%) and accuracy (92% vs. 82%). The typical diagnostic features used in the simplified AIH scoring system are summarized in Table 1. The simplified system helps exclude AIH in patients with other conditions but may miss atypical and complicated cases, and consequently it is important to apply it with experience and clinical judgment [29,30,31,32,33,34,35]. The original scoring system still plays an important role in equivocal cases. Typical HLA or known polymorphism associated with AIH are not routinely investigated in clinical practice.

3.1. Biochemical Features

The classical presentation of autoimmune hepatitis includes a hepatitic liver damage pattern, with bilirubin and aminotransferase levels ranging from slightly elevated to more than 50 times normal, while cholestatic enzyme levels remain normal or only moderately elevated [30,36]. However, ALT elevation does not consistently correlate with disease severity at the histological level. The variability in biochemical findings can lead to delays or underestimation in diagnosis, as clinical symptoms may reappear months or years later or remain asymptomatic. This behavior may explain why up to one-third of patients already have established cirrhosis at the time of diagnosis [37,38].
Increased serum c-globulin or IgG levels are found in about 85% of AIH patients, even without cirrhosis. This prevalence is lower in those with acute disease onset, where 25% to 39% of patients may have normal IgG levels. IgG levels are also a useful marker for monitoring treatment response and remission, as normal levels typically correlate with reduced inflammatory activity. However, mild inflammatory activity (HAI 5–6) may still coexist with normal IgG levels [39].

3.2. Sierology

The serologic classification of AIH is based on autoantibody profiles: type 1 AIH is associated with antinuclear antibodies and SMA, while type 2 AIH, primarily seen in children, is marked by anti-LKM1 and anti-antibody to liver cytosol 1 (LC1) [40]. Approximately 15–20% of AIH patients test positive for anti-SLA/LP antibodies, which have a high specificity but low sensitivity (99% and 19%, respectively). These antibodies often coexist with other autoantibodies and are the hallmark of type 3 AIH [41,42]. While initially linked to a severe disease phenotype, their prognostic significance remains uncertain. However, anti-SLA/LP positivity is associated with a higher risk of relapse, often necessitating long-term immunosuppression [43]. The autoantibody-based subclassification of autoimmune hepatitis has limited clinical relevance, despite its association with epidemiologic and genetic differences. This is because the disease presentation, treatment approach, response, and outcomes are largely similar in both adults and children [44]. Further autoantibody testing, such as Antineutrophil Cytoplasmic Antibody (ANCA) detection, is useful for initially seronegative patients. Atypical pANCA, linked to PSC and inflammatory bowel disease, is also common in type 1 AIH [45,46].
Autoantibody titers and specificity can change over time, and initially seronegative patients may later develop detectable autoantibodies. Repeat testing can aid in diagnosis and classification [47,48]. In adults, autoantibody titers are not associated with disease activity and/or treatment outcome, so routine monitoring is unnecessary unless there is a significant clinical change.
Autoantibody detection is crucial for AIH diagnosis, requiring expertise in disease presentation and serology interpretation. Tests should be ordered based on reliable clinical data and interpreted within the clinical context to ensure accurate, evidence-based decisions are made for the patients’ benefit.

3.3. Liver Biopsy

Liver histology is essential for diagnosing autoimmune hepatitis, assessing inflammation and fibrosis, and ruling out other liver diseases. However, no single histological feature is specific to AIH [40]. According to the International Autoimmune Hepatitis Group (IAIHG) simplified criteria, a typical AIH histology requires at least two of three features: interface hepatitis, emperipolesis, and hepatocellular rosettes. Interface hepatitis, the hallmark of AIH, appears in up to 98% of cases and is typically more severe than in viral hepatitis. Emperipolesis and rosettes, though common, are not specific to AIH, as they reflect inflammation and regeneration rather than disease etiology [49].
Interpreting liver histology is challenging in the first three months of acute-onset autoimmune hepatitis, as early liver damage primarily affects the centrilobular region [50,51]. The transition to portal–periportal hepatitis occurs later. Centrilobular injury, present in 29% of AIH patients and the sole finding in 1–2%, likely represents the disease’s initial histological manifestation [52,53,54,55]. Pathologists should use the Histological Activity Index (HAI) to assess the degree of inflammatory activity, providing a quantitative evaluation of the inflammation to guide treatment and follow-up monitoring [56].
In many cases, diagnosing AIH can be difficult, and consultation with more expert hepatologists may be necessary. For patients with subacute onset and slow progression without noticeable symptoms, diagnosis primarily depends on biochemical findings. The key diagnostic elements include autoantibodies, polyclonal hypergammaglobulinemia, and typical or compatible histology in the absence of viral hepatitis markers. Histology remains essential for confirming the diagnosis.

4. Drug-Induced Liver Injury (DILI)

Drug-induced liver injury (DILI) refers to an adverse reaction to medications, herbal supplements, or other xenobiotics that results in liver dysfunction, manifesting across a broad clinical spectrum, from the asymptomatic elevation of liver enzymes to acute liver failure. The prevalence and presentation of DILI varies by region, the specific class of drugs involved, and the demographics of the patient population, shaped by differences in prescribing practices, genetic backgrounds, and healthcare infrastructure. Research from France and Iceland indicates that the annual incidence of DILI is approximately 13.9 to 19.1 cases per 100,000 individuals [54,55]. Studies have shown that the incidence of DILI is lower in the United States compared to Europe, while data from China suggest a significantly higher incidence [56,57]. These variations may be due to several factors, such as differences in study design and population characteristics, inconsistent diagnostic criteria for DILI, and variations in prescribing practices among physicians.

4.1. Physiopathology

DILI was originally classified in two main types, intrinsic and idiosyncratic, but indirect injury has recently emerged as a third type of DILI [58]. Drugs that are associated with intrinsic and idiosyncratic DILI are shown in Table 2 [59].
Intrinsic DILI is dose-related, occurs in most individuals exposed to a predictable dose of a drug and, its onset is typically rapid, within hours to days. As the principal organ responsible for the biotransformation and clearance of foreign chemical substances, the intrinsic damage of the liver is characterized by direct hepatotoxicity caused by a drug or its metabolites. The main processes involved in intrinsic DILI include the production of toxic metabolites; drugs metabolized in the liver can generate toxic intermediates that bind to cellular structures, deplete protective antioxidants, and cause oxidative stress [60], increasing reactive oxygen species (ROS) [61]. An overload of ROS can damage cellular components including lipids, proteins, and DNA, leading to the activation of signaling pathways that promote cell death [62]. Furthermore, drugs can also trigger an immune response that exacerbates liver damage. When hepatocytes die, they release damage-associated molecular patterns (DAMPs). These DAMPs activate Kupffer cells (KCs), the liver’s resident macrophages, Natural Killer T (NKT) cells, γδ T cells, and dendritic cells (DCs), leading to the release of pro-inflammatory cytokines. This activation initiates an inflammatory cascade characterized by the recruitment of neutrophils and circulating monocytes. Inflammatory cell infiltrates are frequently detected by immunohistochemical analysis in liver biopsy specimens from patients with acute DILI [63,64]. KCs activated by DAMPs determine the production and release of interleukin-1 beta (IL-1β) and interleukin 18 (IL-18) [65]. IL-1β and pro-inflammatory chemokines mediate the recruitment of neutrophils and monocytes [66]. IL-18 enhances the expression of Interferon-gamma (IFN-γ) and the Fas Ligand (FasL), thereby contributing to the perpetuation of hepatocellular death [67]. Furthermore, KCs can produce tumor necrosis factor alpha (TNF-α), contributing to cell death in hepatocytes and the recruitment of inflammatory leukocytes [68,69]. Activated hepatic NKT cells and γδ T cells are able to produce two key cytokines attracting neutrophils, osteopontin, and IL-17. Multiple chemokines with affinity for the CXCR2 receptor mediate the recruitment of neutrophils to hepatic tissue [70,71,72]. Neutrophil/hepatocyte contact, facilitated by β2 integrins, induces the neutrophil-derived production of reactive oxygen species (ROS) and hepatocyte injury and death [73,74]. Monocytes are recruited to sites of hepatic injury in response to the chemokine CCL2 and, together with resident liver macrophages, contribute to the amplification of the inflammatory response by releasing pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1 [75,76,77]. One of the most well-studied examples of intrinsic DILI is injury via paracetamol, the most common cause of acute liver failure (ALF) in the US and parts of Europe [78,79].
Otherwise, idiosyncratic DILI occurs unpredictably in a small subset of individuals exposed to a drug, without a clear relationship to the dose or duration of therapy and often with a delayed onset. Even if idiosyncratic DILI does not exhibit a clear dose-dependent relationship, recent research indicates that a minimum daily dose of 50–100 mg of the causative drug is typically necessary to trigger the condition [59,80]. In recent years, the role of the immune system in the development of idiosyncratic DILI has gained significant recognition, supported by numerous studies that associate specific HLA genotypes with an elevated risk of DILI.
Liver dendritic cells (DCs) internalize drugs and/or their metabolites, presenting them as drug-modified peptide–HLA complexes on their membranes, thereby functioning as antigen-presenting cells (APCs) and initiating drug-specific T cell responses. This process activates naïve CD4+ and CD8+ T cells against drug-modified peptide–HLA molecules, which migrate to liver lymph nodes via lymphatic vessels. After significant proliferation and differentiation, drug-specific effector CD4+ and CD8+ T cells are released into the peripheral circulation. They can be recruited to the liver by elevated chemokine levels [81] or activated upon recognizing drug-modified peptide–HLA complexes displayed on the surface of various hepatic cell types [82].
The recruitment and activation of effector T cells in the liver result in hepatic damage through the secretion of pro-inflammatory cytokines (such as IFN-γ, IL-17, etc.) and pro-allergic cytokines (including IL-4, IL-5, IL-13, etc.) by CD4+ T cells, as well as through direct cytotoxic effects. IL-17 produced by T cells can recruit high numbers of neutrophils into the liver, causing tissue damage [83,84]. The pathophysiology of idiosyncratic drug-induced liver injury (DILI) elucidates why individuals with specific HLA alleles are at an elevated risk of developing DILI upon exposure to certain medications. This is supported by the preferential molecular binding of a drug to particular peptide–HLA complexes [85,86]. However, only a subset of individuals with the risk-associated HLA allele who are exposed to a drug develop DILI, indicating that additional factors are necessary for the onset of the disease. Recently, information on risk alleles derived from Genome-Wide Association Studies (GWASs) has revealed an increased incidence of gene inactivation in pathways related to mitochondrial function and protein translation in individuals predisposed to DILI [87]. Finally, hypergammaglobulinemia, circulating autoantibodies, and liver-infiltrating plasma cells are found in DILI with autoimmune features, actually named drug-induced autoimmune-like hepatitis (DI-ALH) [88,89] (Table 3). Different mechanisms can explain DI-ALH, including the loss of immune tolerance due to drug-induced liver injury with the release of damage-associated molecular patterns (DAMPs) or the formation of drug–protein complexes that activate innate immunity, subsequently triggering adaptive immune responses against self-antigens [90]. In individuals with a genetic predisposition, environmental factors such as infections are believed to act as initiators of the self-sustaining disease process, although a definitive trigger remains unidentified [80,91,92]. The autoimmune response is typically self-limiting, with resolution occurring upon discontinuation of the offending drug. However, progression to overt autoimmune hepatitis may occur in the presence of additional susceptibility factors [80,89].
Indirect DILI occurs as a secondary effect of a drug’s systemic or pharmacological effects rather than through direct hepatotoxicity or idiosyncratic reaction to the implicated medication, and it is associated with the pharmacodynamic characteristics of the compound [90]. In most patients, these AEs are mild and reversible, while serious AEs occur in around 6–8% of patients.
For example, increasing evidence suggests indirect DILI to be induced by immune checkpoint inhibitors or rituximab in patients with chronic hepatitis B; in these instances, the hepatic injury is predominantly mediated by immune activity, resulting in an imbalance between pro-inflammatory and anti-inflammatory signals in the liver [28].
The exact mechanisms responsible for liver toxicity induced by immune checkpoint inhibitors (ICIs) are not yet fully elucidated, and the presence of this third variant is still a matter of debate in the scientific community [93].
Table 3. Drugs associated with DI-ALH.
Table 3. Drugs associated with DI-ALH.
Drug NameMechanism of DI-ALHReferences
NitrofurantoinInduces autoimmune-like reaction[94,95]
MinocyclineInduces autoimmune-like reaction[94,95]
MethyldopaInduces autoimmune-like reaction[96,97]
HydralazineInduces autoimmune-like reaction[95,96]
IsoniazidHepatotoxicity with potential autoimmune features[94,95,98]
Amoxicillin–clavulanateCan cause idiosyncratic liver injury with autoimmune features[96,98]
PhenytoinCan cause immune-mediated liver injury[95,96]
CarbamazepineCan trigger autoimmune-like response in predisposed individuals[95,97]
StatinsCan trigger immune-mediated liver damage[96,98]
HalothaneCan induce hepatotoxic reaction with autoimmune features[94,95]

4.2. Diagnosis

The diagnosis of drug-induced liver injury is challenging due to the lack of specific biomarkers and the need to exclude other causes of liver injury. It requires a thorough clinical evaluation, including a detailed drug history (with a specific timeline surrounding the drug usage), laboratory tests, imaging studies, and sometimes liver biopsy. The case definitions for DILI are based on one of the following criteria: (1) ALT levels elevated to ≥5 times the upper limit of normal (ULN); (2) ALP levels elevated to ≥2 times the ULN (especially if accompanied by increased gamma-glutamyltransferase (GGT) levels and no known bone conditions contributing to the ALP rise); (3) ALT levels elevated to ≥3 times the ULN along with a total bilirubin (TBL) concentration exceeding 2 times the ULN [59]. AST values can be effectively used as a substitute for ALT in determining the injury pattern when ALT is not available at the time of DILI diagnosis, while GGT is not as reliable a substitute for ALP [61]. DILI assessments should include coagulation tests as well, since an elevated prothrombin time ratio could indicate a risk of acute liver failure (ALF), necessitating evaluation at a liver transplantation center [59].
DILI is commonly categorized based on the prevailing pattern of liver enzyme abnormalities, which can be hepatocellular, cholestatic, or mixed. Serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), and bilirubin serve as principal biomarkers for assessing hepatic injury and dysfunction in DILI. The ratio (R) helps identify the type of liver injury by dividing multiples of ALT’s upper limit of normal (ULN) by multiples of ALP’s ULN. If the ratio is above 5, it indicates hepatocellular injury; below 2 suggests cholestatic injury; and between 2 and 5 is categorized as mixed (Figure 2). Because the diagnosis of DILI mainly depends on excluding other possible causes of liver damage, patients should be tested for hepatotropic viruses, including hepatitis A-E. It is also important to perform an autoantibody panel, including substances such as antinuclear antibody, anti-smooth muscle antibody (ASMA), M2-anti-mitochondrial antibody (AMA), liver microsomal antibody, and immunoglobulins. Alcoholic hepatitis should be ruled out based on a history of alcohol abuse, a pattern of AST elevation typically exceeding ALT levels (with ALT usually remaining below 300 IU/L), and other biochemical indicators of chronic alcohol use, such as elevated GGT levels and an increased mean corpuscular volume (MCV) of erythrocytes. In younger patients (<40 years), it is important to exclude Wilson’s disease by testing ceruloplasmin levels. An abdominal ultrasound is recommended for all patients suspected of DILI to rule out biliary, parenchymal, or vascular disorder, but liver imaging is generally normal. Additional imaging may be needed depending on the clinical context, so, in some cases, computerized tomography (CT) and magnetic resonance cholangiography (MRC) may be needed to exclude gallstone disease and other alternative diagnoses. Several methods for the preliminary assessing of the causality of DILI have been developed [99,100]. One of the best known and validated is the Roussel Uclaf causality assessment method (RUCAM scale). The RUCAM comprises seven distinct domains: the temporal association between drug exposure and liver injury onset; clinical course following drug withdrawal; exclusion of alternative causes of hepatic injury; concomitant use of other medications; presence of risk factors such as sex, pregnancy, or alcohol use; prior documentation of hepatotoxicity linked to the suspected agent; and the response upon re-exposure. The applicability of the RUCAM has been limited by the complexity of its instructions, subjectivity in the weighting of criteria, a lack of evidence-based validation for certain risk factors, and its omission of liver histopathological data [62,101]. Liver biopsy, although not required as part of the evaluation, is especially helpful when autoimmune hepatitis is suspected or when DILI persists after stopping the suspected drug. Furthermore, it provides information on the severity and pattern of liver injury, guiding clinical decisions. The pathologist’s evaluation can help to narrow the differential diagnosis and establish a causal link between the drug and liver injury [102].
Recent studies have tried to better define the role of liver biopsy, and some aspects of differential diagnosis, especially with AIH, have been studied [103]. Agents such as nitrofurantoin, minocycline, methyldopa, and hydralazine have been linked to clinical presentations that resemble autoimmune hepatitis (AIH). In a study by de Boer et al., 18 out of 65 cases lacked typical clinical features of AIH, and among the 13 cases exhibiting clinical signs of AIH and undergoing liver biopsy, 4 did not display the full spectrum of histological features expected in AIH [94]. Additionally, several cases exhibited histological findings such as cholestasis or necrosis, which are considered atypical for AIH. In a separate analysis, Suzuki et al. compared the histopathological profiles of DILI and AIH, revealing that DILI is more frequently characterized by parenchymal inflammation or canalicular cholestasis, whereas portal plasma cell infiltration—a hallmark of AIH—was not commonly observed in DILI cases [104]. Differences in lymphocytic infiltrates have also been noted between AIH and DILI. In a comparative analysis of idiopathic AIH and DILI cases exhibiting an autoimmune phenotype, portal B cell infiltration was found to be more prominent in AIH [95]. Intrinsic DILI related to an imbalance of immune checkpoint inhibitors (ICI) has been studied [66,95,105,106]. A comprehensive comparison between ICI-induced DILI and AIH has shown that liver biopsies from AIH cases more frequently exhibit portal infiltration by plasma cells, B lymphocytes, and CD4+ T cells compared to DILI, thereby facilitating histopathological differentiation in most instances [96,107]. DI-ALH is a liver injury with laboratory and/or histological features that may be indistinguishable from those of autoimmune hepatitis (AIH) and with laboratory and/or histological evidence of autoimmunity. This type of liver injury could be associated with high IgG levels, and positive results for anti-nuclear antibody (ANA), anti-smooth muscle antibody (ASMA), and anti-liver-kidney microsomal antibody. The detection of ANA and ASMA may, in some individuals, represent an epiphenomenon secondary to the acute phase of DILI. Drug-induced autoimmune-like hepatitis (DI-ALH) typically presents clinically within three months of drug exposure, though in certain cases it may have a delayed onset [94,97,108,109,110]. Following the discontinuation of the offending agent, hepatic injury resolves in the vast majority of patients [94,110]. Distinguishing DI-ALH from idiopathic autoimmune hepatitis (AIH) is clinically relevant, as DI-ALH generally does not require prolonged immunosuppressive therapy and tends to resolve spontaneously after drug withdrawal [111]. Corticosteroid responsiveness appears comparable between DI-ALH and AIH, but in DI-ALH, immunosuppression can be successfully discontinued in all reported cases [94,110].
DI-ALH mimics the morphological pattern of AIH, including the prominent lympho-plasmocytic infiltrates in portal spaces and interface hepatitis. The discriminating criteria between the two conditions are largely unknown, except for advanced fibrosis being much more frequent in AIH [97,104,112].
Although histological findings in liver biopsy may at times be indistinguishable from those of AIH, biopsy remains a valuable tool for detecting features atypical of AIH and for supporting the diagnosis of AIH-like pathology. Communication between pathologists and hepatologists is critical in the clinicopathological assessment of liver injury.
In specific cases, human leukocyte antigen (HLA) genotyping may also be employed, as genetic testing can support diagnosis and management, particularly in patients with autoimmune-hepatitis-like features.
GWASs have identified specific HLA alleles that modulate susceptibility to DILI induced by various drugs. To date, over 15 pharmacological agents have been linked to increased DILI risk based on HLA genotype or haplotype, with some associations exhibiting high relative risk ratios. However, due to the low incidence of DILI with individual drugs, many of these HLA alleles demonstrate a negative predictive value exceeding 95% [98].
Likewise, when differential diagnoses include drug-induced AIH, evaluation with genetic markers and liver biopsy is justified. The presence of DILI-associated HLA risk alleles may support the diagnosis of drug-induced AIH, although further validation is necessary before this check is incorporated into routine clinical practice [98].
Given the limited specificity of conventional liver enzyme assays, there is increasing interest in the identification of novel serum biomarkers to refine the diagnostic accuracy of DILI and improve prognostic assessment. However, none are currently used in routine clinical practice, though they represent promising areas for future research [62].

5. Conclusions

The diagnosis of AIH and DILI remains a significant challenge due to the overlap of some presenting features. The complexity of distinguishing between these conditions is particularly true in patients with AIH who present with a slow, insidious progression and in those with DILI where the timing and drug-related causality are unclear. The lack of a specific biomarker for DILI and its reliance on clinical history and exclusion criteria make it difficult to differentiate from AIH [1,2,40,62].
Histology remains a cornerstone in diagnosing AIH, with its key features including non-organ-specific autoantibodies, polyclonal hypergammaglobulinemia, and characteristic liver biopsy findings. However, biopsy interpretation itself is subject to variability, as some patients with AIH may have atypical histological presentations, and certain drugs can induce a liver injury pattern mimicking AIH. The literature suggests that drug-induced AIH-like syndromes account for approximately 9–12% of AIH cases, further complicating differential diagnosis [1,2,40,62].
Liver biopsy plays a crucial role in the evaluation of unexplained liver injury, and although not required as part of the evaluation of DILI, is especially helpful when autoimmune hepatitis is suspected or when DILI persists after stopping the suspected drug.
While no single test definitively distinguishes AIH from DILI, biopsy findings provide critical information in cases where clinical and serological results are inconclusive. Previous studies have emphasized that AIH diagnosis is typically supported by a combination of serological markers and histology, while DILI diagnosis is often an exclusion-based process [113,114]. The presence of granulomas, cholestasis, bile duct loss, or microvesicular steatosis in a biopsy may favor a diagnosis of DILI over AIH, although these findings are not always definitive [115].
The current data support previous findings that liver biopsy should be considered a last-resort tool when distinguishing between AIH and DILI, particularly in complex cases where clinical presentation does not align with typical serological and clinical patterns [1,2,40,62]. Some patients with clinical AIH features may exhibit biopsy findings inconsistent with the disease, while others with suspected DILI may demonstrate histological features suggestive of AIH. In the context of pre-existing chronic liver disease, the differential diagnosis between DILI and AIH is even more challenging. In such cases, overlapping clinical, biochemical, and histological features can complicate the diagnostic process and delay appropriate treatment. In these cases, distinguishing between a flare of underlying liver disease and an acute-on-chronic presentation due to DILI or AIH requires the careful consideration of the patient’s medication and clinical history, immune profile, response to the withdrawal of the drug suspected to cause DILI, and liver biopsy findings.
These considerations and the previous ones further highlight the limitations of the current diagnostic tools and the need for additional biomarkers.
Recent advances in immunogenetics suggest that HLA genotyping could aid in differentiating DILI from AIH, particularly in cases where genetic predisposition plays a role. Studies have associated specific HLA genotypes with an increased risk of DILI, suggesting that genetic testing may offer additional diagnostic value in selected cases. While HLA genotyping has been proposed as a supportive tool, further validation is needed before it can be routinely implemented in clinical practice [40,62,98]. These findings emphasize the need for continued research into genetic markers that could improve diagnostic accuracy and facilitate early differentiation between AIH and DILI.
Although this accumulating evidence is promising, genetic screening panels are not yet commercially available. Moreover, genotyping is costly and requires expert interpretation, as its results do not always directly correlate with phenotype. These practical limitations may undermine the clinical utility of emerging biomarkers.
A key gap to being able to distinguish AIH from DILI is the absence of reliable biomarkers. AIH is typically diagnosed based on serological markers, but some patients may exhibit normal IgG levels and negative autoantibodies despite biopsy findings suggestive of AIH. Conversely, DILI diagnosis is often retrospective and based on exclusion criteria rather than a definitive test. Future research should prioritize the discovery and validation of biomarkers that can predict which patients with liver enzyme elevation are at risk of developing clinically significant DILI versus those with an alternative diagnosis [40,62]. Moreover, in the era of personalized medicine, DILI prevention should be a key focus of research. Although we are not yet able to identify individuals at risk of developing DILI following drug exposure, a deeper understanding of its pathophysiology and the genetic alleles involved could speculatively reduce its incidence.
These data reinforce the need for a multidisciplinary approach in diagnosing AIH and DILI. Clinicians should integrate clinical history, serological markers, liver biopsy findings, and genetic testing where applicable. Additionally, the development of novel biomarkers could revolutionize the diagnostic process, reducing reliance on invasive procedures such as biopsy. The urgent need for reliable biomarkers could mark a major breakthrough in clinical practice, allowing DILI to shift from a diagnosis of exclusion to one supported by serological or biochemical evidence. Similarly, identifying robust biomarkers for AIH would enhance differential diagnosis, reduce the reliance on invasive procedures such as biopsy, and accelerate the diagnostic process. Future studies should focus on validating these biomarkers and refining diagnostic algorithms to improve patient management and treatment outcomes.
In conclusion, the diagnosis of AIH and DILI remains challenging. Liver biopsy remains an important diagnostic tool, though its interpretation requires expertise. HLA genotyping and novel biomarkers hold promise for improving diagnostic accuracy, but further validation is necessary before their routine implementation.

Author Contributions

Conceptualization, N.Z., A.R. and M.B.; methodology, N.Z., S.S.P. and A.R.; writing—review and editing, N.Z., A.C. and A.R.; supervision, A.R. and M.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflict of interest.

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Livers 05 00022 g001
Figure 1. The physiopathological mechanisms of AIH. After external factors trigger liver damage due to a loss of liver tolerance mechanisms, hepatocellular self-antigens are presented to T cells. Naive CD4+ differentiates through a variety of cytokines in Th1, Th2, and Th17. Those patterns lead to CD8+, NK, and complement activation, as well as autoantibody production, that further contributes to liver damage, as well as decreasing Tregs, which cannot effectively perform their immune modulation activity.
Figure 1. The physiopathological mechanisms of AIH. After external factors trigger liver damage due to a loss of liver tolerance mechanisms, hepatocellular self-antigens are presented to T cells. Naive CD4+ differentiates through a variety of cytokines in Th1, Th2, and Th17. Those patterns lead to CD8+, NK, and complement activation, as well as autoantibody production, that further contributes to liver damage, as well as decreasing Tregs, which cannot effectively perform their immune modulation activity.
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Figure 2. Stepwise approach to AIH/DILI diagnosis: First of all, the liver damage pattern must be assessed; while DILI can be suspected in all patterns if the patient is taking hepatotoxic drug(s), a hepatic pattern is more suggestive for AIH. The diagnosis of DILI and AIH must include ruling out other liver damage causes via histology, biochemical, and serological features, as well as response to drug withdrawal/steroid administration. ALP, alkaline phosphatase; ALT, alanine aminotransferase; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis E virus.
Figure 2. Stepwise approach to AIH/DILI diagnosis: First of all, the liver damage pattern must be assessed; while DILI can be suspected in all patterns if the patient is taking hepatotoxic drug(s), a hepatic pattern is more suggestive for AIH. The diagnosis of DILI and AIH must include ruling out other liver damage causes via histology, biochemical, and serological features, as well as response to drug withdrawal/steroid administration. ALP, alkaline phosphatase; ALT, alanine aminotransferase; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HEV, hepatitis E virus.
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Table 1. Simplified AIH scoring system.
Table 1. Simplified AIH scoring system.
FeatureCriteriaPoints
AutoantibodiesAnti-nuclear antibodies (ANA): titer ≥ 1:801 point
Anti-smooth muscle antibodies (SMA): titer ≥ 1:401 point
Anti-liver kidney microsomal antibodies (LKM-1): titer ≥ 1:20 (associated with type 2 AIH)2 points
Anti-soluble liver antigen/liver pancreas (SLA/LP): titer ≥ 1:402 points
Serum IgGIgG level greater than 1.1 times upper limit of normal1 point
HistologyCharacteristic features of interface hepatitis (necrosis and inflammation at liver portal tract), emperipolesis, and/or rosettes3 points
Exclusion of Other Liver DiseasesExclusion of viral hepatitis:
No0 point
Yes2 points
Legend: Score ≥ 7 points: strongly suggestive of AIH; score 6–7 points: probable AIH; score < 6 points: less likely to be AIH, further investigation needed.
Table 2. Drugs associated with intrinsic and idiosyncratic DILI.
Table 2. Drugs associated with intrinsic and idiosyncratic DILI.
IntrinsicIdiosyncratic
AcetaminophenAllopurinolLapatinib
AmiodaroneAmiodaroneMethyldopa
Anabolic steroidsAmoxicillin-clavulanateMinocycline
AntimetabolitesBosentanNitrofurantoin
CholestyramineDantrolenePazopanib
CyclosporineDiclofenacPhenytoin
Valproic acidDisulfiramPyrazinamide
HAART drugsFelbamatePropylthiouracil
HeparinsFenofibrateStatins
Nicotinic acidFlucloxacillinSulfonamides
StatinsFlutamideTerbinafine
TacrineHalothaneTiclopidine
IsoniazidTolvaptan
KetoconazoleLolcapone
LeflunomideTrovafloxacin
Lisinopril
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Zeni, N.; Cristofani, A.; Piano, S.S.; Bolognesi, M.; Romano, A. Pathophysiological Differences and Differential Diagnosis of Autoimmune and Drug-Induced Hepatitis. Livers 2025, 5, 22. https://doi.org/10.3390/livers5020022

AMA Style

Zeni N, Cristofani A, Piano SS, Bolognesi M, Romano A. Pathophysiological Differences and Differential Diagnosis of Autoimmune and Drug-Induced Hepatitis. Livers. 2025; 5(2):22. https://doi.org/10.3390/livers5020022

Chicago/Turabian Style

Zeni, Nicola, Alessandro Cristofani, Salvatore Silvio Piano, Massimo Bolognesi, and Antonietta Romano. 2025. "Pathophysiological Differences and Differential Diagnosis of Autoimmune and Drug-Induced Hepatitis" Livers 5, no. 2: 22. https://doi.org/10.3390/livers5020022

APA Style

Zeni, N., Cristofani, A., Piano, S. S., Bolognesi, M., & Romano, A. (2025). Pathophysiological Differences and Differential Diagnosis of Autoimmune and Drug-Induced Hepatitis. Livers, 5(2), 22. https://doi.org/10.3390/livers5020022

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