Introduction

Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic, relapsing immune-mediated condition that primarily affects the gastrointestinal tract. It is estimated that approximately 20-30% of patients with IBD develop hepatobiliary abnormalities, most commonly manifesting as mild elevations in transaminase levels [1]. The high prevalence of concomitant liver abnormalities is probably attributable to shared pathogenic mechanisms. These factors encompass immunological, metabolic, and genetic elements, in addition to disturbances in the gut microbiota, which plays a role in the modulation of the gut-liver axis [2, 3]. The most prevalent etiologies of hepatic injury in patients with IBD include metabolic dysfunction-associated steatotic liver disease (MASLD) and medication-related adverse effects [4]. It is important to note that all medications used in the treatment of IBD have the potential to induce abnormalities in liver function tests (LFTs). These abnormalities may manifest in the form of hypersensitivity reactions or the development of hepatocellular, cholestatic, or mixed patterns of liver injury. However, the concomitant presence of chronic autoimmune hepatobiliary diseases should be considered. The risk of developing immune-mediated hepatobiliary disorders, such as primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH), is estimated to be approximately 5% [5].

Hepatobiliary abnormalities are usually asymptomatic, but may be associated with hepatomegaly, icterus, fatigue, or pruritus. In view of the fact that liver injury frequently remains asymptomatic, European Crohn’s and Colitis Organisation (ECCO) guidelines recommend that alanine aminotransferase, alkaline phosphatase, γ-glutamyltransferase and total serum bilirubin be measured every 6-12 months in all patients diagnosed with IBD [6]. It is considered acceptable to reduce the frequency of monitoring of LFTs for patients who are in long-term remission and being treated with 5-aminosalicylates in monotherapy [6]. In the event of LFT abnormalities being detected, it is imperative to assess the severity of the elevation and the persistence of these changes. For a mild elevation, the initial step is to repeat the measurement in one month. In cases of persistent, recurrent, or moderate to severe elevations in LFTs, it is imperative that a differential diagnostic work-up is initiated. If significantly elevated liver enzyme levels are detected, a differential diagnosis should be conducted, encompassing both IBD-related liver conditions and other liver diseases that may coexist with IBD (Table 1).

The first step following the detection of abnormal LFTs is to determine the biochemical pattern of damage – hepatocellular or cholestatic – which may indicate potential causes of liver damage (Fig. 1). A hepatocellular injury pattern is characterized by elevated levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), whereas a cholestatic pattern is associated with elevated levels of alkaline phosphatase. In the case of hepatocellular injury, the etiology may be multifactorial, including metabolic syndrome, viral hepatitis, and immune-mediated liver diseases. To establish a diagnosis of a cholestatic profile, it is necessary to exclude the presence of PSC and cholelithiasis [4].

However, it has been established that the measurement of transaminase levels alone is an inadequate method for diagnosing MASLD, as values may remain within the normal range even in affected individuals [7]. It is important to emphasize the value of non-invasive methods for assessing chronic liver disease (CLD), such as blood-based tests (e.g., the FIB-4 score and the hepatic steatosis index) and liver stiffness measurement using validated ultrasound elastography techniques, preferably vibration-controlled transient elastography [7]. These diagnostic tools are of particular utility in patients considered to be at risk of developing CLD. Depending on the suspected underlying cause of liver disease, further diagnostic evaluation should include a detailed medication history, viral and immunological markers, imaging studies (ultrasound or magnetic resonance cholangiopancreatography [MRCP]), and, in selected cases, a liver biopsy.

This review provides a comprehensive overview of the causes of abnormal liver test results in patients with IBD and highlights the key challenges in diagnosing liver injury in this population, particularly in the era of contemporary therapeutic strategies.

Metabolic dysfunction-associated steatotic liver disease

MASLD is a CLD characterized by hepatic steatosis in the presence of at least one cardiometabolic risk factor and in the absence of excessive alcohol consumption [8]. Since June 2023, the European Association for the Study of the Liver (EASL) guidelines have recommended the use of the term “MASLD” [8]. However, in this paper, the term non-alcoholic fatty liver disease (NAFLD) is used where appropriate to align with the variety of diagnostic methods employed in earlier studies.

Latest data indicate that MASLD is one of the most common CLDs, affecting approximately 30% of the global population [9, 10]. The cardiometabolic risk factors for MASLD include obesity, diabetes, hypertension, and dyslipidemia [11]. It is noteworthy that the prevalence of MASLD appears to be higher in patients with IBD (34.1%) [12]. There are several reasons for this phenomenon, including shared pathogenic mechanisms such as chronic inflammation, alterations in gut microbiota composition, and impaired bile and lipid metabolism [2, 13]. Another important factor is the global rise in obesity observed in patients with IBD in recent years. Based on a recent systematic review, data indicate that approximately 15-40% of patients with IBD are obese, with an additional 25-40% classified as overweight [14]. Obesity is associated with low-grade chronic inflammation and increased production of pro-inflammatory factors by adipocytes, including cytokines such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β and IL-6, which may trigger intestinal inflammation [15, 16]. A further notable aspect that requires consideration is the role of dysbiosis and the bidirectional impairment of the gut–liver axis in both IBD and MASLD. Alterations in microbial composition, observed in both conditions, result in reduced production of short-chain fatty acids [17, 18]. This in turn disrupts the intestinal barrier and activates pro-inflammatory signaling pathways. Consequently, these changes may exacerbate both intestinal and hepatic inflammation, thereby creating a vicious cycle [17]. Furthermore, bile acids act as key signaling molecules within the enterohepatic circulation contributing to the pathogenesis and progression of both MASLD and IBD. These molecules play an important role in maintaining intestinal homeostasis, regulating lipid metabolism, and modulating the immune response. In particular, disturbances in bile acid metabolism have been observed in patients with CD involving the terminal ileum [19]. Impaired bile acid reabsorption may lead to disruptions in signaling pathways and bile acid synthesis, consequently contributing to dysregulation of the gut-liver axis. Additionally, multiple IBD-related factors, including therapies such as prolonged corticosteroid use, as well as malabsorption and prior surgical procedures, may promote steatosis in the course of MASLD (Table 2) [20]. Current evidence indicates that IBD concomitant with diabetes, particularly in individuals with elevated BMI, is associated with a higher risk of MASLD and liver fibrosis [21].

Recent studies have demonstrated that among patients diagnosed with IBD who have undergone a liver biopsy due to abnormal LFTs, NAFLD was the most prevalent diagnosis, accounting for 32.7% of cases [4]. Furthermore, data on the prevalence of NAFLD in patients stratified by disease type (UC vs. CD) are inconsistent [20]. Accumulating evidence suggests that patients diagnosed with IBD, particularly those with severe disease, are at an increased risk of developing MASLD and progressive liver fibrosis, regardless of conventional metabolic risk factors [21]. Moreover, the meta-analysis revealed that a diagnosis of CD and a history of complications of IBD were also significant risk factors for fibrosis [21]. This phenomenon appears to be primarily driven by chronic systemic inflammation associated with both conditions, which contributes to hepatic fibrosis. However, transaminase levels do not reliably reflect disease activity or fibrosis stage in MASLD and are therefore not suitable for disease monitoring. In contrast, non-invasive methods, including serum biomarkers and liver elastography, are applied for disease follow-up [7]. At present, there are no specific guidelines for the management of patients with both IBD and MASLD. Therefore, it is recommended that clinical practice be informed by existing recommendations for MASLD [7, 8]. Appropriate IBD treatment appears to be of crucial importance, including avoidance of prolonged corticosteroid therapy and consideration of replacing potentially hepatotoxic agents such as thiopurines and methotrexate with novel therapies where appropriate. Current evidence suggests that patients with IBD, particularly those with severe and long-standing disease, are at increased risk of developing MASLD, thereby highlighting the need for regular screening in this population.

Primary sclerosing cholangitis

Primary sclerosing cholangitis is one of the most well-characterized autoimmune liver diseases associated with IBD. It is a rare, chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts and is associated with IBD in approximately 50-80% of patients [22, 23]. It is estimated that this condition affects approximately 2% of patients with IBD, and its prevalence is significantly higher in patients with UC, reaching as high as 8% [6]. Recent studies have indicated that patients diagnosed with CD involving the large intestine exhibit a shared genetic etiology with UC and PSC, which has been linked to MHC variability [24]. However, the genetic component accounts for less than 10% of the etiopathogenesis of PSC, thereby underscoring the multifactorial nature of this condition. A significant pathogenic factor is dysbiosis, which leads to disturbances in short-chain fatty acid production, an altered bile acid signaling pathway, and increased intestinal permeability (‘leaky gut syndrome’), resulting in immune dysfunction [23]. Alterations in the gut microbiota, including an increase in potentially pathogenic bacteria and a decrease in beneficial short-chain fatty acid-producing bacteria, are increasingly recognized as important contributors to PSC progression through gut barrier dysfunction and the translocation of virulent bacteria and toxins [25]. Moreover, it remains unclear whether PSC and IBD are two distinct conditions or whether PSC should be regarded as an extraintestinal manifestation (EIM) of IBD [23].

The most typical initial presentation of PSC is abnormal liver biochemistry with a cholestatic pattern. Most patients remain asymptomatic; therefore, it is important to conduct regular monitoring of serum markers of cholestasis in IBD patients. In the symptomatic form of PSC, the most common clinical manifestations include abdominal pain, fatigue, pruritus and jaundice. The preferred diagnostic imaging method is magnetic resonance cholangiopancreatography (MRCP), which reveals multifocal strictures and dilatations involving the intra- and/or extrahepatic biliary tree [26]. However, if small-duct PSC is suspected (elevated cholestatic markers with a normal appearance of the bile ducts on MRCP), a liver biopsy is mandatory [26]. The same applies in cases where an AIH overlap syndrome is suspected [26]. The standard of care remains the administration of UDCA at a dose of 15-20 mg/kg body weight per day. It should be emphasized that the use of UDCA in this indication remains controversial, and the available data regarding its efficacy are inconsistent and conflicting. There are some data indicating that UDCA may improve biochemical parameters, but it has no proven effect on disease progression, the risk of fibrosis, or prognosis, including cancer development. However, there are reports suggesting an impact of UDCA on quality of life and transplant-free survival in PSC [27, 28]. Interestingly, available studies suggest that low doses of UDCA may decrease the risk of developing colorectal dysplasia or cancer, whereas long-term use of high-dose UDCA may be associated with an increased risk of colorectal neoplasia in patients with UC and PSC [29, 30]. Consequently, no pharmacological therapy has yet been established as standard disease-modifying treatment for PSC. The new pharmaceuticals should be characterized by pleiotropic action, encompassing immunological modulation and fibroblast proliferation, in addition to metabolic process regulation [31]. Ongoing studies are currently investigating therapies with such multidirectional mechanisms of action, including norUDCA, peroxisome proliferator-activated receptor agonists, farnesoid X receptor agonists, and anti-fibrotic agents such as CM-101 [31].
Patients with PSC have an increased risk of developing cholangiocarcinoma (CCA) and gallbladder carcinoma compared with the general population. Additional risk factors for their development include coexisting IBD (especially UC), large duct PSC, long disease duration, and the presence of dominant biliary strictures [32]. Monitoring of patients with PSC involves regular assessment of biochemical parameters, liver elastography, and annual imaging of the liver and bile ducts (ultrasound, MRCP) [26]. Although endoscopic retrograde cholangiopancreatography is not recommended as a routine screening tool, it may be useful in selected cases, combined with biliary sampling with brush cytology and fluorescence in situ hybridization analysis or cholangioscopy. In highly selected patients with early-stage, unresectable cholangiocarcinoma, liver transplantation after neoadjuvant therapy may be considered as a potential treatment option [33].

Although in most cases IBD precedes the diagnosis of PSC, a colonoscopy should be performed if PSC is the initial diagnosis. This is based on the observation that patients with coexisting PSC and IBD have a distinct course of intestinal inflammation: right-sided colonic involvement, spared rectum, and backwash ileitis are observed more frequently [23, 34]. Although IBD often follows a milder clinical course, it is associated with an increased risk of colorectal cancer; therefore, annual surveillance colonoscopy is recommended [26, 35].

Autoimmune hepatitis and overlap syndrome

Autoimmune hepatitis is a chronic, progressive liver disease with a wide spectrum of clinical presentations, ranging from asymptomatic disease to acute liver failure (ALF). It is estimated that the prevalence of AIH and IBD is around 0.5%, and it is more commonly associated with UC [4, 6, 36]. According to EASL guidelines, the diagnosis of autoimmune hepatitis is based on the assessment of IgG levels, autoantibody titers (preferably using HEp-2 cells or ELISA), and liver histology, with the exclusion of viral causes of liver disease [37]. A recent meta-analysis found that, over a 20-year follow-up period, 9.81% of patients with AIH were diagnosed with IBD, and smoking was a significant risk factor that further increased the risk of complications [38]. Furthermore, individuals with IBD-AIH are at an increased risk of developing liver disease at a young age, as well as having a higher risk of progression to cirrhosis [4].

Several distinctive features should be noted in patients with IBD. Firstly, antibodies are relatively frequently present, so their detection is less useful. Secondly, given the high risk of AIH/PSC overlap syndrome, MRCP should be performed as part of the diagnostic work-up [6]. The EASL and ECCO guidelines are largely consistent regarding the recommended treatment of AIH in patients with coexisting IBD, and the long-term therapeutic approach to AIH remains unchanged regardless of the presence of IBD [6, 37]. Induction therapy involves the use of corticosteroids, specifically prednisone or prednisolone, while budesonide may only be used in the absence of cirrhosis. Azathioprine should be introduced approximately 2 weeks after the initiation of corticosteroid therapy as combined therapy. The recommended initial dose is 50 mg/day, which should be gradually increased to a maintenance dose of 1-2 mg/kg/day. Maintenance therapy usually consists of azathioprine monotherapy or, alternatively, azathioprine in combination with low-dose corticosteroids (≤ 5 mg/day). In patients with IBD who have previously been treated with other immunosuppressive agents, switching to azathioprine should be considered. It is worth noting that corticosteroids and azathioprine are effective therapies for both AIH and IBD. Therefore, immunosuppressive treatment initiated for IBD may attenuate the clinical expression of coexisting AIH and thus influence the assessment of disease activity.

Primary biliary cholangitis

Primary biliary cholangitis is a chronic cholestatic liver disease characterized by non-suppurative cholangitis that occurs considerably less frequently in patients with IBD and predominantly affects those with UC [39]. Among patients with both PBC and IBD, the condition is most commonly observed in young men with a mild form of proctitis [4]. PBC is frequently associated with other autoimmune diseases, including Hashimoto’s disease, rheumatoid arthritis, and celiac disease, whereas IBD is relatively uncommon. The coexistence of IBD in patients with PBC is thought to be largely attributable to shared genetic predisposition. Diagnosis is based on detecting cholestasis in the presence of antimitochondrial antibodies, and in selected patients, it may be confirmed by a liver biopsy. Management is primarily based on the use of ursodeoxycholic acid at a dose of 13-15 mg/kg/day [37]. No specific therapy is recommended for patients with IBD-PBC. Another immunologically mediated cholestatic condition, IgG4-related cholangitis, is only rarely observed in patients with IBD [40].

The hepatotoxic potential of drugs used in IBD

Although detailed epidemiological data are limited, available evidence suggests that patients with IBD are at an increased risk of developing drug-induced liver injury (DILI). DILI can be classified as dose-dependent (intrinsic) or non-dose-dependent (idiosyncratic) [41]. Clinically, it may range from a mild presentation with slight elevations in transaminases to severe cases manifesting as ALF. Hy’s law is used to identify patients at increased risk of ALF. It is defined by hepatocellular injury with ALT/AST ≥ 3× upper limit of normal (ULN) and bilirubin ≥ 2× ULN, without evidence of cholestasis or an alternative etiology [42]. Established risk factors for DILI in IBD patients include advanced age, polypharmacy, female sex, genetic predisposition, and alterations in the gut microbiota [43]. Given the chronic and incurable nature of IBD, long-term pharmacological therapy is required. Therefore, identifying drugs associated with a higher risk of hepatotoxicity is essential, as they require closer and more frequent biochemical monitoring (see Table 3) [44]. It should be noted that reliable data on the incidence of hepatotoxicity during different IBD therapies are limited. This is partly due to the absence of validated biomarkers confirming a causal relationship, meaning that reported estimates are often based primarily on clinical observation.

5-aminosalicylic acid

5-aminosalicylic acid, including mesalazine and sulfasalazine, is commonly used in the treatment of UC and is still prescribed in selected patients with CD, although it is not recommended for this indication by current ECCO guidelines [45]. Mesalazine is the most widely used drug and is considered to carry a very low risk of liver injury, regardless of the formulation [46, 47]. In contrast, sulfasalazine, an older 5-aminosalicylic acid compound which is particularly used in patients with concomitant rheumatological conditions, carries a higher risk of hepatotoxicity. This is primarily attributed to its sulfapyridine moiety, which mediates hypersensitivity reactions [43]. Clinically, hepatotoxicity may present with systemic features such as fever, rash, and jaundice, accompanied by eosinophilia and variable patterns of liver injury [46]. Granulomatous hepatitis and cholestatic liver injury have also been reported in patients receiving sulfasalazine [44].

Thiopurines

Thiopurines, in particular azathioprine and 6-mercaptopurine (6-MP), are widely used drugs for maintaining remission in IBD and are associated with a relatively high risk of liver injury. Thiopurine-induced hepatotoxicity occurs in up to 32% of patients and is usually manifested as transient, mild elevation of transaminases [44, 46]. Azathioprine is metabolized in the liver to 6-MP, which is subsequently converted into the active metabolite 6-thioguanine (6-TGN), responsible for its therapeutic effects, as well as methylated metabolites, including 6-methylmercaptopurine (6-MMP), which is an inactive metabolite (Fig. 2). The risk of adverse events, including liver injury, is closely related to thiopurine S-methyltransferase (TPMT) enzyme activity. It has been established that minimal TPMT activity is associated with a risk of myelotoxicity, which is attributable to increased production of 6-TGN. Conversely, excessive TPMT activity leads to overproduction of methylated metabolites (6-MMP), with concomitantly reduced 6-TGN levels, and may be associated with an increased risk of hepatotoxicity [48]. In patients in whom the methylation pathway predominates, dose escalation is generally ineffective. Furthermore, long-term thiopurine therapy has been shown to be associated with an increased risk of endothelial injury, manifesting as nodular regenerative hyperplasia or sinusoidal obstruction syndrome, which may warrant discontinuation of treatment [46].

To minimize the risk of liver complications in patients treated with thiopurines, the following approach is recommended: 1) assessment of TPMT activity in red blood cells (RBCs) prior to treatment initiation; 2) periodic monitoring of LFTs; and 3) monitoring of thiopurine metabolites (6-MMP and 6-TGN) [49, 50]. TPMT testing may involve phenotyping (measurement of enzyme activity) or genotyping. In cases of absent TPMT activity/homozygosity (0.5%), the use of the drug is contraindicated [49]. LFTs should be performed weekly during the first month, every two weeks over the subsequent two months, and thereafter every three to four months [49]. Thiopurine metabolite testing should be performed after at least 4 weeks of therapy and subsequently repeated after 12-14 weeks of treatment. Further measurements should be considered in cases of IBD flare, suspected drug toxicity, dose changes, or non-adherence to therapy [51]. Target 6-TGN levels should be > 235 pmol/8 × 10⁸ RBCs, whereas levels > 450 pmol/8 × 10⁸ RBCs are associated with an increased risk of myelotoxicity. In contrast, hepatotoxicity occurs at 6-MMP levels > 5700 pmol/8 × 10⁸ RBCs [49]. Dose reduction with splitting and the addition of 100 mg of allopurinol may be considered [51]. Treatment with thiopurines should be discontinued in the presence of jaundice or a cholestatic pattern of liver injury, or if LFTs fail to normalize following dose reduction.

Methotrexate

Parenteral methotrexate (MTX) is currently used for the induction and maintenance of remission in moderate-to-severe CD [52]. In light of current evidence, hepatotoxicity is rarely observed and, when present, most commonly manifests as mild elevations in transaminases, whereas more severe liver injury is uncommon [46]. It should be emphasized that MTX is currently considered a relatively safe drug with a low risk of severe hepatotoxicity. Concerns regarding MTX-associated hepatic toxicity, including cirrhosis, appear to have been overestimated. This may be explained by the presence of undiagnosed metabolic liver disease in a subset of patients. Moreover, studies indicate that hepatotoxicity during MTX therapy occurs less frequently in patients with IBD compared with patients with rheumatologic or dermatologic conditions [53].

Previously, MTX therapy was associated with both acute and chronic liver injury, potentially leading to progressive fibrosis. However, current evidence suggests that, as an independent risk factor, it is not associated with chronic liver damage [54]. In most cases of methotrexate-associated liver damage, the presence of pre-existing CLD or additional risk factors, such as diabetes, dyslipidemia, alcohol consumption or obesity, plays a major role [43, 54]. In this context, a baseline assessment should be performed prior to initiating MTX therapy, including evaluation of LFTs, assessment of metabolic risk factors, exclusion of hepatitis B and C, and calculation of the FIB-4 score [54]. If any abnormalities are identified, further hepatological evaluation is recommended before deciding to initiate MTX therapy. In addition, during MTX therapy, liver enzyme levels should be monitored monthly at treatment initiation, followed by assessments every three months, along with periodic evaluation of the FIB-4 score [54]. It seems reasonable to perform non-invasive assessment of liver fibrosis (elastography of FibroScan) in patients at risk of hepatotoxicity. In most cases, mild elevation in transaminases during treatment with MTX is transient, and only if they persist is dose reduction or drug discontinuation required. To reduce the risk of hepatotoxicity during MTX therapy, folic acid supplementation is recommended at a dose of 1 mg daily or 5 mg weekly, ideally administered 1-2 days after MTX intake [43].

Biologic treatment

According to ECCO guidelines, the currently recommended biologic therapies for moderate-to-severe IBD include anti-TNF-α, anti-IL-23, anti-IL-12/23, and anti-integrin agents [55]. Among the therapies listed, anti-TNF-α agents, particularly infliximab (IFX), are associated with the highest risk of hepatotoxicity. The pathogenesis of this phenomenon is complex and not fully understood, but it has been observed that less than 1% of patients develop liver injury during anti-TNF-α therapy [43, 46]. Possible hepatic complications associated with the use of TNF-α inhibitors include transient elevations in transaminases, DILI, drug-induced autoimmune hepatitis (DI-AIH), and AIH.

The most common liver-related complications associated with TNF-α inhibitor use include mild and transient elevations in transaminase levels. In rare cases, treatment discontinuation is required, which leads to normalization of liver enzyme levels. DILI is observed in approximately 0.5% of patients during IFX treatment, most commonly in the form of hepatocellular liver damage occurring after the administration of 3-5 doses [46]. DILI most commonly occurs as a result of idiosyncratic reactions, regardless of the dose administered, and its clinical course is difficult to predict. Studies indicate that the risk of DILI is most strongly associated with infliximab, whereas adalimumab appears to have a more favorable safety profile [46].

Moreover, in patients treated with IFX, cases of drug-induced autoimmune-like hepatitis (DI-ALH), associated with the presence of antinuclear antibodies, elevated IgG levels, and characteristic histopathological findings, have also been reported [56]. Differentiation between DI-ALH and classic AIH is challenging due to the frequent presence of autoantibodies in patients with IBD and the lack of distinct histopathological differences in liver biopsy specimens [56]. The occurrence of DI-ALH is supported by the resolution of abnormalities after drug discontinuation, as well as the absence of recurrence of the changes [37]. Given the difficulty in distinguishing between these conditions, a definitive diagnosis should be made with caution, and steroid therapy may be necessary. It has been shown that the majority of patients with DI-ALH respond well to corticosteroid therapy, and switching to a different biologic agent does not result in recurrence of the condition [46, 56]. Moreover, long-term immunosuppressive treatment used in patients with IBD before initiation of biological therapy may keep a previously unrecognized AIH latent. Subsequently, anti-TNF-α therapy may act as a trigger unmasking AIH, which may represent either classical AIH or de novo disease. While the majority of cases of infliximab-induced liver injury have a favorable prognosis, rare cases of acute liver failure and vanishing bile duct syndrome requiring liver transplantation have also been reported [56]. Overall, liver injury associated with TNF-α inhibitors is most commonly reported following treatment with IFX. Nevertheless, most patients respond well to corticosteroid therapy and subsequently tolerate treatment with other biologics, including alternative TNF-α inhibitors.

Anti-integrin agents (vedolizumab) and anti-IL-12/23 inhibitors (ustekinumab) have a favorable hepatic safety profile, but mild elevations in transaminase levels and cases of DI-ALH have been reported during their use [57-59]. There is currently no evidence of hepatotoxicity associated with anti-IL23 inhibitors (mirikizumab, risankizumab). However, given their recent introduction, periodic monitoring of LFTs is recommended.

With regard to the safety of biological therapies in patients with IBD following liver transplantation, no differences in safety were observed between vedolizumab, which acts more selectively in the gut, and systemic biologic agents such as TNF-α inhibitors and ustekinumab [60]. However, it should be noted that the study included only a limited number of patients.

Small molecules

New small molecules, including Janus kinase (JAK) inhibitors such as tofacitinib, filgotinib, upadacitinib, and sphingosine 1-phosphate (S1PR) modulators like ozanimod and etrasimod, are oral synthetic agents that represent an alternative to conventional biologic therapies. Overall, these medications are regarded as having a good hepatic safety profile.

In a recent meta-analysis evaluating the JAK inhibitors tofacitinib, filgotinib, and upadacitinib in CD patients, only upadacitinib was associated with a significantly increased risk of liver enzyme elevations [61]. Although a single report has suggested a possible link between tofacitinib and DILI and ALF, this association still needs to be confirmed [62, 63]. In addition, JAK inhibitors have been shown to exert a potentially favorable effect on metabolic diseases, including MASLD, obesity, and type 2 diabetes, by regulating insulin secretion and glucose levels [64]. Previous studies have demonstrated that upadacitinib exerts a beneficial effect on endoplasmic reticulum stress, leading to a reduction in lipid accumulation and apoptosis in hyperlipidemic hepatocytes [65]. However, it is important to take into account the potential of JAK inhibitors to elevate low-density lipoprotein cholesterol levels. Nevertheless, this does not currently appear to be associated with an increased risk of cardiovascular events [66]. In addition, the data available to date suggest that tofacitinib has a safe profile when used in liver transplant recipients with UC [64].

Upadacitinib is a selective JAK1 inhibitor primarily metabolized by CYP3A4, with a minor contribution from CYP2D6, and partially eliminated through renal excretion. Administration of strong CYP3A4 inhibitors has been shown to increase upadacitinib exposure, with area under the concentration-time curve and maximum plasma concentration increasing by approximately 75% and 70%, respectively [67]. Mild and moderate hepatic impairment and renal impairment do not appear to have a clinically relevant effect on the pharmacokinetics of upadacitinib [67, 68]. In a similar manner, tofacitinib, a pan-JAK inhibitor, is primarily metabolized in the liver by CYP3A4, with a smaller contribution from CYP2C19 [69]. In contrast, filgotinib is a selective JAK1 inhibitor that is predominantly metabolized by carboxylesterase 2 rather than cytochrome P450 enzymes [69]. Its elimination occurs mainly via the kidneys, predominantly as metabolites. However, further studies are needed to evaluate the influence of concomitant therapies on the safety and pharmacokinetics of these agents.

Ozanimod, the first S1PR approved for the treatment of moderate-to-severe active UC, has been associated with an increased risk of elevated transaminases and γ-glutamyl transferase levels in UC patients [70, 71]. Ozanimod is extensively metabolized in the liver via a series of enzymes, primarily CYP2C8, with contributions from CYP3A4 and other pathways, leading to the formation of active metabolites. It has been demonstrated that the use of CYP2C8 inhibitors and inducers can affect exposure to ozanimod [71]. Studies to date on the use of etrasimod have shown only a mild increase in transaminases [72]. So far, no connection has been identified between S1PR and either DILI or ALF.

Combined therapeutic strategies, referring to the concomitant use of two therapeutic agents with different mechanisms of action, are increasingly being explored in IBD. Available data on combination therapy involving biologic agents and small-molecule drugs have not revealed an increased risk of liver injury [61]. However, given the limited available data, further studies are needed.

Viral hepatitis

A significant clinical concern in patients with IBD receiving immunosuppressive therapy, particularly combination regimens, is the risk of opportunistic infections, especially hepatotropic viruses. The ECCO guidelines recommend screening all newly diagnosed IBD patients for hepatitis A, B, and C, HIV, Epstein-Barr virus, and cytomegalovirus at diagnosis and before initiation of immunosuppressive therapy, with subsequent completion of vaccination where indicated [73]. In the case of hepatitis B vaccination, an anti-HBs IgG level of more than 10 IU/l is generally considered indicative of an adequate serologic response. If a chronic hepatitis B or C is diagnosed, treatment must be administered in accordance with current guidelines [73]. In patients with a history of hepatitis who are scheduled to receive immunosuppressive therapy, the need for antiviral prophylaxis against HBV reactivation should be assessed based on HBsAg, anti-HBc, and HBV DNA status [74]. The risk of infection reactivation also depends on the planned immunosuppressive therapy and the type of HBV serological status, including occult HBV infection, isolated anti-HBc positivity, or possible HBsAg mutant infection (Table 4). However, it should be noted that data on new biologic and small-molecule therapies are limited. The literature describes cases of HBV reactivation following treatment with anti-TNF-α inhibitors, including infliximab and adalimumab. Therefore, this risk is considered to be class-related [75].

Conclusions

Liver injury is a common and often asymptomatic concern in patients with IBD, requiring careful evaluation as it may be easily overlooked. This phenomenon is partly related to the shared pathophysiological mechanisms between IBD and liver diseases, including immunological, metabolic, and genetic factors, as well as alterations in the intestinal microbiota and bile acid metabolism. In the context of CLD and IBD, low-grade systemic inflammation has been identified as a pivotal factor in their shared etiopathogenesis and in the progression of liver disease. A limitation of this review is the insufficient number of studies addressing some of the topics covered, which has been emphasized throughout the manuscript. Liver abnormalities are frequently observed in patients receiving IBD therapy and may reflect either underlying CLD or an increased susceptibility to its development, or drug-induced hepatotoxicity. This highlights the need for proactive screening and risk stratification, particularly before initiating agents with higher hepatotoxic potential. It is imperative to use non-invasive methods for the assessment of liver fibrosis, such as the FIB-4 score and elastography. The frequent coexistence of primary liver diseases and overlapping syndromes further complicates the clinical course and may pose significant diagnostic challenges. A thorough understanding of the distinct features of these conditions is essential for accurate diagnosis and optimal management of liver injury in patients with IBD.

Disclosures

This research received no external funding.

Institutional review board statement: Not applicable.

The authors declare no conflict of interest.

References