Liver transplant and autoimmune liver diseases: An up-to-date review

Abstract

Autoimmune liver diseases, encompassing autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis, are chronic immune-mediated disorders that are uncommon but clinically significant due to their progressive nature, diagnostic complexity, and limited treatment options. These conditions may evolve into advanced fibrosis, cirrhosis, or liver failure, and liver transplantation, while life-saving, does not eliminate the underlying immune dysregulation and introduces risks of disease recurrence and complications from chronic immunosuppressive therapy, such as osteoporosis, infections, and metabolic disorders. Autoimmune hepatitis is characterized by hepatocellular inflammation and fibrosis associated with autoantibodies, including antinuclear antibodies, smooth muscle antibodies, anti–liver kidney microsomal type 1 antibodies, and anti–soluble liver antigen/liver pancreas antibodies, as well as aberrant B and T lymphocyte activity. Standard therapy relies on corticosteroids combined with azathioprine, but novel approaches are under investigation, including rituximab, zetomipzomib, and toll-like receptor 4 antagonists. Primary biliary cholangitis is marked by autoimmune-mediated destruction of small bile ducts, commonly associated with antimitochondrial antibodies, gp210, and sp100 antibodies. Ursodeoxycholic acid (UDCA) is the cornerstone of therapy, although up to 40% of patients show incomplete response, prompting interest in obeticholic acid, bezafibrate, peroxisome proliferator-activated receptor agonists, and setanaxib. Primary sclerosing cholangitis involves progressive intra- and extrahepatic duct fibrosis, associated with IgG4, perinuclear anti-neutrophil cytoplasmic antibodies, and an increased cancer risk, with emerging therapies such as norUDCA, farnesoid X receptor agonists, anti-tumor necrosis factor, anti-integrin agents, and autologous stem cell transplantation.

Key Words: Autoimmune liver diseases; Autoimmune hepatitis; Primary biliary cholangitis; Primary sclerosing cholangitis; Liver transplantation

Core Tip: Autoimmune liver diseases, including autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis, are chronic immune-mediated disorders that may progress to cirrhosis, liver failure and death. Although liver transplantation mostly ensures favorable survival rates, recurrence and complications remain significant challenges. Therefore, the understanding of immune mechanisms, the gut-liver axis, and novel targeted therapies offer new perspectives to improve long-term outcomes and optimize patient management.

INTRODUCTION

Autoimmune liver diseases (AILD) comprise a group of chronic immune-mediated conditions, including autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC). Although considered rare diseases, they hold great clinical relevance due to their potential to progress to advanced fibrosis, cirrhosis, and end-stage liver failure[1-3]. The diagnosis of these conditions is challenging, given their heterogeneous clinical presentation and the need for careful interpretation of serological, histological, and imaging findings[4,5]. This complexity stems from a central point: Although less prevalent than other liver diseases, AILD imposes a substantial burden on patients and healthcare systems, frequently culminating in the need for liver transplantation, a complex therapeutic intervention[6].

Despite condition-specific differences, the clinical management of AILD shares a common trajectory toward transplantation in refractory or advanced cases. In AIH, treatment is based on generalized immunosuppression with corticosteroids and azathioprine, an approach capable of inducing remission in most patients but associated with significant long-term toxicity, documented adverse events, and a high risk of comorbidities[7,8]. For PBC, ursodeoxycholic acid (UDCA) is the first-line therapy; however, up to 40% of patients exhibit an insufficient response and remain at high risk of disease progression[9]. Moreover, debilitating symptoms such as pruritus and fatigue may persist even among treatment responders, negatively affecting quality of life[10,11]. The scenario is even more challenging in PSC, for which, to date, no pharmacological therapy has proven effective in altering disease course or improving transplant-free survival, leaving management focused on complication control and surveillance of associated malignancies[12,13].

The therapeutic limitations - arising from toxicity, partial efficacy, or the absence of effective options - constitute the main reason why patients with AILD are considered for liver transplantation (LT). When pharmacological therapy fails, LT emerges as the only curative option, offering favorable survival for patients with end-stage liver disease[1], an integrated evaluation and referral algorithm for LT in AILD is presented in Figure 1. Outcomes of transplantation in patients with AILD are generally comparable to or even better than those observed in other etiologies, with 5-year patient survival rates of approximately 79% for AIH, 86% for PBC, and 80% for PSC[14,15]. However, the procedure does not represent an absolute cure but rather a transition to a new state of chronicity. The autoimmune predisposition of the patient is not eradicated, which manifests as recurrence of the primary disease in the graft - a significant clinical challenge, with reported recurrence rates of approximately 20% in PBC and at least 25% in PSC[16,17].

Figure 1 Integrated algorithm outlining the evaluation and referral process for liver transplantation in autoimmune liver diseases. The flowchart summarizes the stepwise decision process for transplant referral after confirming the diagnosis of autoimmune hepatitis, primary biliary cholangitis, or primary sclerosing cholangitis. AIH: Autoimmune hepatitis; PBC: Primary biliary cholangitis; PSC: Primary sclerosing cholangitis; AILD: Autoimmune liver diseases; UDCA: Ursodeoxycholic acid; OCA: Obeticholic acid.

In addition, the requirement for chronic immunosuppression to prevent graft rejection imposes a substantial burden of morbidity, including cumulative adverse effects such as osteoporosis, hypertension, dyslipidemia, diabetes mellitus, and increased susceptibility to infections[18,19]. Thus, transplantation replaces liver failure with a new set of chronic challenges, centered on immunosuppression management and the risk of disease recurrence.

In this complex scenario, advances in understanding the underlying immune mechanisms and the gut-liver axis interaction are opening perspectives for new, more targeted and effective therapeutic strategies[20]. The investigation of novel molecules and biological approaches aims not only to improve disease control in the pre-transplant phase but also to reduce the need for transplantation and lower the risk of post-transplant recurrence[21].

The purpose of this narrative review is to synthesize the most up-to-date evidence on AILD and LT. It will address diagnostic approaches, established and experimental treatments, clinical indications and criteria for transplantation, as well as post-procedure outcomes and challenges. The goal is to provide an integrated reference to support healthcare professionals in decision-making, aiming to optimize clinical outcomes and quality of life for patients with autoimmune liver conditions.

GENERAL INDICATIONS FOR LIVER TRANSPLANTATION

LT has been established as treatment in cases of fulminant hepatitis, end-stage liver disease, or liver cancer, but it is also considered in specific conditions where there is no effective alternative treatment, for example Wilson’s disease or Hereditary hemochromatosis[1].

To assess severity and determine the indication for transplantation, several scores and criteria are used. The Milan criteria select patients with hepatocellular carcinoma (HCC) who are suitable candidates for transplantation by assessing the size and quantity of the tumor mass, but there are currently controversies and expansions regarding its applicability[21,22]. The Model for End-Stage Liver Disease (MELD) score is used to prioritize patients on transplant waiting lists and to define disease severity. It considers sex - according to MELD 3.0, 1.33 extra points are assigned to female patients, since conventional MELD disadvantaged women tend to have lower serum creatinine levels - and laboratory parameters such as total bilirubin, international normalized ratio (INR), serum creatinine, serum sodium, and albumin[23].

Another important system is the Child-Pugh score, which assesses post-operative mortality in cirrhotic patients. It classifies prognosis into three profiles (A, B, and C) based on clinical features such as hepatic encephalopathy and ascites, and on laboratory measures such as total bilirubin, albumin, and INR. This approach allows for better risk stratification in the preoperative setting[24].

There are general contraindications for LT, which are divided into absolute and relative contraindications. Absolute contraindications include extrahepatic malignancy, uncontrolled inflammation or infection, substance use disorders without adherence to a structured rehabilitation program and conditions associated with low adherence to treatment or drug abuse. Among the relative contraindications, the most notable are anatomical abnormalities for transplantation, cholangiocarcinoma - unresectable perihilar cholangiocarcinoma can be treated with combined neoadjuvant and transplant protocols in specialized centers[25], but outside of these strict protocols, cholangiocarcinoma remains associated with high recurrence rates and is generally contraindicated for transplantation, human immunodeficiency virus infection (depends on the immune status and well-controlled antiretroviral therapy) and portal vein thrombosis - only complete thrombosis of the entire portal system remains a contraindication, as it is not possible to reconnect the liver to the portal circulation[26]. Age is no longer widely considered a relative contraindication, as there is no longer a fixed age limit for recipients, since patients over 65 years only need careful multidisciplinary evaluation, and transplants in octogenarians have been performed successfully, although there is a higher cardiovascular risk[27].

Currently, eligibility assessment is more individualized, as it incorporates psychosocial factors, recovery support, and institutional criteria[27,28]. Therefore, some historically absolute contraindications are now considered relative or conditional, reflecting clinical advances and the diversity of protocols among transplant centers. However, it is worth noting that systematization of indications and contraindications associated with the improvement of surgical techniques, scoring systems, donor selection systems, immunosuppression regimens, and prognosis assessment in light of risk factors are still factors that improve the current results of liver transplants[29].

AIH

AIH is a chronic liver disease in which an immune response is directed against hepatocytes, leading to progressive inflammation, fibrosis, cirrhosis, and liver failure[2]. Clinically, AIH generally responds well to pharmacological therapy involving immunosuppressants, for instance prednisone, and LT is reserved for cases of end-stage cirrhosis and acute liver failure[30].

The incidence of AIH is approximately 1.37 cases per 100000 individuals. However, although the epidemiology of AIH is not yet fully defined, it is well established that the risk increases with advancing age and is higher among female patients[31].

AIH is classified into two types: Type 1, which is more common and associated with antinuclear antibodies (ANA) and anti-smooth muscle antibodies (SMA)[32].

In contrast, type 2 is linked to anti-liver kidney microsomal type 1 antibodies and anti-soluble liver antigen/Liver pancreas antibodies, and is known for its aggressive nature and its higher incidence among younger individuals[33]. However, the 2025 European Association for the Study of the Liver (EASL) guidelines no longer recommend using AIH subtypes (type 1/type 2) for diagnostic or therapeutic decisions, as this classification has no practical clinical utility.

The pathophysiological process of AIH is defined by the loss of tolerance to hepatocytes, leading to an attack mediated by CD4+ and CD8+ T lymphocytes, B cells, and plasma cells[34]. Inflammatory cytokines such as Th1, Th2, and Th17 participate as well, as does the dysregulation of regulatory T cells, which normally suppress autoimmune attacks[35]. In addition, more recently, the gut microbiome is also considered a contributing factor in modulation of the immune dysregulation present in the disease[3].

Diagnosis can be supported by serologic detection of antibodies, especially ANA, smooth muscle antibodies, anti-liver kidney microsomal type 1, and anti-soluble liver antigen/Liver pancreas, along with hypergammaglobulinemia marked by elevated serum IgG, and liver histology, which may show periportal necrosis, inflammatory infiltrate, and hepatocyte destruction[36,37].

However, it is important to highlight that although the presence of antibodies is essential, no laboratory finding alone can confirm or exclude AIH. Clinical history, along with histological tests is mandatory to exclude other causes of liver injury, such as viral hepatitis, drug-induced liver injury, or metabolic disorders, as no single test can diagnose AIH[4].

The clinical presentation of AIH varies according to disease progression. For instance, in mild and early cases, it may be asymptomatic. As the disease advances, it can manifest with fatigue, jaundice, and abdominal pain, mainly in the right upper quadrant. In acute flare-ups, nausea, vomiting, loss of appetite, dark urine, and acholic stools may occur[38,39].

In cases of fulminant and acute AIH, therapy should be initiated with corticosteroids as soon as possible, as this treatment improves or does not compromise survival[40,41]. Importantly, even if grade 1 hepatic encephalopathy is present, characterized by subtle neuropsychological impairments, altered sleep pattern, mild cognitive changes, and possible mood disturbances such as euphoria or anxiety[42], it is still recommended to start therapy with prednisone 1 mg/kg/day[43,44].

Treatment of the chronic form also consists of immunosuppression with steroids, preferably prednisone, followed by maintenance with non-steroidal immunosuppressants, with azathioprine being the first-line drug[5,45].

Nevertheless, corticosteroid therapy should be discontinued and LT should be considered when the patient is refractory; however, there is controversy regarding the exact point at which to determine whether there has been a response or not[1]. Accordingly, the American Association for the Study of Liver Diseases (AASLD) recommends discontinuing therapy within two weeks if there is no biochemical improvement[5]. Studies have shown that increased bilirubin and/or INR are predictive markers for discontinuing therapy and considering LT[1,43,46].

CURRENT LIMITATIONS IN THE MANAGEMENT OF AIH

Corticosteroids remain an essential part of therapy in AIH. However, the identification of other steroid-free treatments is important, as the medications currently available for AIH are not specific. Consequently, they cause generalized immunosuppression and lead to severe side effects[6,7]. Monitoring for adverse therapeutic effects should focus on metabolic effects (hyperglycemia, weight gain, dyslipidemia), bone health (risk of osteoporosis), hypertension, and neuropsychiatric changes[47]. Overall, there is no consensus on the management of patients with AIH[48]. For first-line therapy, the AASLD recommends prednisone or budesonide, with or without immunosuppressants such as azathioprine or mycophenolate mofetil[49]. Research has shown that the combination of budesonide and azathioprine was more effective in inducing and maintaining remission, in addition to causing fewer side effects than the prednisone and azathioprine combination[5]. However, this idea is controversial, as a Spanish study indicated that, as a first-line treatment for AIH, budesonide shows inferior results compared to prednisone[48]. Methodological differences (e.g., patient profile, presence of cirrhosis, duration of follow-up) may also contribute to the discrepancies between studies[50]. An American study reported corticosteroid-related adverse events in 25% of patients on long-term maintenance therapy for AIH. Furthermore, azathioprine can present side effects such as cholestatic hepatitis, pancreatitis, nausea and vomiting, skin rash, bone marrow suppression, and opportunistic infections, which are the most common, but it can also cause more severe, albeit rarer, ones, such as veno-occlusive disease and malignancy[36,51]. Before initiating treatment with azathioprine, it is crucial to assess the activity of the thiopurine methyltransferase enzyme. Individuals with low or absent activity of this enzyme have an elevated risk of severe myelosuppression due to the accumulation of cytotoxic metabolites[8]. Routine laboratory monitoring includes a complete blood count for early detection of cytopenias (leukopenia, thrombocytopenia) and liver function tests to identify hepatotoxicity, which can manifest as acute cholestasis or hepatocellular injury[52]. Additionally, the use of budesonide in cirrhotic patients has been associated with portal vein thrombosis events, constituting an absolute safety contraindication[9]. Therefore, assessment for the presence of cirrhosis is a non-negotiable step before prescribing budesonide[47]. The persistence of biochemical or histological inflammation, or the worsening of parameters despite optimized therapy, defines treatment failure and indicates the need for second-line therapies or, in cases of progression to end-stage liver disease, evaluation for transplantation[53].

EMERGING THERAPIES FOR AIH

Recently, the treatment for various autoimmune diseases has been transitioning from generalized immunosuppression to targeting specific inflammatory mediators involved in the pathology (Table 1)[54], one of these approaches for AIH is rituximab, a monoclonal antibody that targets CD20 to deplete B-cells and has shown positive results in difficult-to-treat cases of AIH, In clinical practice, it functions as an off-label, third-line or rescue therapy, to be considered after the failure of first-line regimens, including corticosteroids, azathioprine, and mycophenolate mofetil[55]. Kezar Life Sciences, Inc., a clinical-stage biotechnology company, announced positive preliminary data from its phase 2a clinical study, known as PORTOLAD. This study suggests that zetomipzomib, a selective immunoproteasome inhibitor, has shown efficacy in the treatment of AIH. Approximately 36% of the patients who received the medication achieved a complete biochemical response, indicating significant improvement in the disease, while simultaneously managing to reduce steroid use. However, it is not yet used outside the context of a clinical trial. Its importance lies in its potential to become a future targeted therapeutic option.

Table 1 Emerging therapies for autoimmune hepatitis.

Disease	Emerging therapies	Mechanism/target	Current evidence	Ref.
Autoimmune hepatitis	Rituximab	anti-CD20 monoclonal antibody → B-cell depletion	Positive results in refractory cases; clinical and biochemical improvement	Than et al[56], 2019
				Multicenter retrospective series, n = 22
	Zetomipzomib	Selective immunoproteasome inhibitor	Approximately 36% complete biochemical response in phase 2a trial	PORTOLA Trial (Kezar Life Sciences), 2025
				Phase 2a, n = 24
	JKB-122	TLR4 antagonist	Biochemical and histological improvement in animal model; potentiates corticosteroid effect	Hsu et al[57], 2017
				Preclinical study (murine model)

TLR4: Toll-like receptor 4.

JKB-122, a toll-like receptor 4 antagonist with hepatoprotective and anti-inflammatory properties, was evaluated in an animal model of AIH. The results indicated biochemical and histological improvement. Moreover, there was an inhibition of pro-inflammatory cytokines in the serum and liver. Therapy with JKB-122 was effective on its own and potentiated the effect of steroid doses. However, success in animals does not guarantee success in humans[56].

PBC

PBC is a rare autoimmune disease that affects the small bile ducts in the liver. Destruction of these ducts leads to bile accumulation, fibrosis, and eventually cirrhosis[8].

The disease affects 1.6 per 100000 people, mainly in North America, and predominantly affects non-Hispanic women. It has been suggested there is a link to urban pollution and the use of certain cosmetic products such as nail polish and hair dye, due to 2-octynoic acid, which mimics part of the PBC-E2 antigen and activates the immune system[57]. The female-to-male ratio can reach 10:1. This disparity is thought to be due to the interaction of several factors, such as estrogen levels, infections, epigenetic factors, and intestinal and vaginal microbiota[58].

The immune response is both humoral and cellular, targeting cholangiocytes (bile duct epithelial cells), primarily through CD4+ and CD8+ T cells[59]. When cholangiocytes are destroyed, the resulting fibrosis blocks bile flow, leading to a condition called cholestasis. The accumulation of acidic bile upregulates inflammation and promotes further liver injury[60].

Once cholangiocytes are destroyed, the mitochondrial PBC-E2 antigen is released and binds to antimitochondrial antibodies (AMA), forming immune complexes and perpetuating the immune response. Moreover, damaged cholangiocytes are not replaced by normal cells but instead enter a pro-inflammatory state known as the senescence-associated secretory phenotype, further contributing to cytokine and chemokine release[61].

AMA is the most important biomarker in suspected PBC, being present in 90%-95% of cases. When suspicion remains high and AMA is negative, investigation of ANA-specific antibodies (sp100 and gp210) should be pursued. Anti-kelch-like 12 and anti-hexokinase 1 antibodies are also potential biomarkers that may aid in diagnosis[62].

Clinically, the most commonly reported symptoms are fatigue and intense generalized pruritus. As liver damage progresses, signs such as hepatomegaly, jaundice, skin hyperpigmentation, xanthelasma, and portal hypertension may appear[63].

UDCA is the first-line treatment for PBC, it must be established immediately after diagnosis and consists of administering a dose of 13 mg/kg/day to 15 mg/kg/day to increase bile flow, cause immunomodulation, and reduce bile salt toxicity[49,64,65]. UDCA exerts anti-inflammatory effects, protecting cholangiocytes from bile toxicity, stimulates bile secretion, reduces bile stasis, and makes the bile more hydrophilic and less harmful[66]. The effectiveness of this medication and other lines of treatment[67] has dramatically reduced the need for LT in cases of PBC since 1980[68].

Although UDCA is the first-line therapy, around 40% of patients do not respond adequately. In these cases, obeticholic acid (OCA) and/or bezafibrate are commonly added. A multicenter study involving 58 patients treated with this combination therapy showed partial immune response; however, even with this regimen, 50% of patients fail to achieve an ideal biochemical response[66].

According to the EASL, transplantation should be considered in certain situations, such as complications of cirrhosis based on severity scores, progressive increase in bilirubin (3-5 mg/dL), patients with treatment-refractory pruritus, hepatic encephalopathy, bleeding from esophageal varices, portal hypertension, and refractory ascites[69-71]. The survival rate for this transplant is better than most other transplant indications, but there is a 20% recurrence rate in transplant patients[9]. Current knowledge on the subject suggests that this recurrence can occur in any transplanted patient, but it has been reported more frequently in young patients, those using tacrolimus, or those with elevated biochemical markers of cholestasis[72]. However, the available studies addressing recurrence are mostly observational, and there is currently no single marker capable of reliably predicting its occurrence. The use of UDCA after transplantation to prevent recurrent PBC appears to be effective in reducing this incidence, but evidence is controversial and there is still no absolute recommendation[70,73].

CURRENT LIMITATIONS IN THE MANAGEMENT OF PBC

Up to 40% of patients do not respond adequately to UDCA[10], the first-line treatment, and are at a higher risk of disease progression and HCC[74]. Pruritus affects up to 70% of patients and negatively impacts their quality of life[49,70]. It can occur in very early stages and may be present even after the normalization of liver biochemical tests with UDCA treatment[11]. Additionally, fatigue is the most common and disabling symptom, occurring in up to 80% of patients[12]. To date, there is no specific medication approved for the treatment of fatigue[67].

EMERGING THERAPIES FOR PBC

OCA is a semi-synthetic farnesoid X receptor agonist that was previously approved as a second-line therapy for patients with an inadequate response to UDCA (Table 2). Clinical trials demonstrated significant improvements in biochemical markers, particularly alkaline phosphatase and bilirubin, but no proven benefit in transplant-free survival[75,76]. Post-marketing reports of severe liver injury, including hepatic decompensation and liver failure in patients with and without cirrhosis, led to the discontinuation of OCA marketing in the European Union in 2024, although it remains available with restrictions in North America and the United Kingdom[77]. Fibrates (bezafibrate and fenofibrate) used off-label have been shown to improve liver biochemistry and transplant-free survival. Studies have demonstrated that patients treated with bezafibrate normalized their liver function within 24 months[78,79]. Peroxisome proliferator-activated receptor agonists are a class of drugs under development that shows promise. This class includes elafibranor and seladelpar, which have been approved for second-line use by the Food and Drug Administration in 2024[80,81]. Furthermore, setanaxib is a nicotinamide adenine dinucleotide phosphate oxidase inhibitor and targets oxidative stress and fibrosis. It is proposed to act directly on the liver's healing process[82].

Table 2 Emerging therapies for primary biliary cholangitis.

Disease	Emerging therapies	Mechanism/target	Current evidence	Ref.
Primary biliary cholangitis	Obeticholic acid	FXR agonist; increases bile flow, has immunomodulatory and anti-inflammatory effects	Improves biochemical markers and is associated with longer transplant-free survival	Hirschfield et al[76], 2015
				Phase 3, n = 217
	Bezafibrate/fenofibrate	PPARα agonists	Off-label use has been shown to improve liver biochemistry and transplant-free survival	Khakoo et al[80], 2023
				Meta-analysis, n = 1107 (8 RCTs)
	Seladelpar, Elafibranor, or Saroglitazar	PPARδ or PPAR pan-agonists	Clinical trials show promising biochemical improvement	Hirschfield et al[76], 2015
				(Seladelpar phase 3, n = 193)
	Setanaxib	NOX inhibitor; reduces oxidative stress and fibrosis	Ongoing studies are promising with anti-fibrotic effect	GS-02 trial, University of Miami, 2025
				Phase 2, n ≈ 111

FXR: Farnesoid X receptor; PPAR: Peroxisome proliferator-activated receptor; RCTs: Randomized controlled trials; NOX: Nicotinamide adenine dinucleotide phosphate oxidase.

PRIMARY SCLEROSING CHOLANGITIS

PSC is an autoimmune disease with increasing prevalence in recent years. It is characterized by progressive fibrosis of both intrahepatic and extrahepatic bile ducts[13].

It predominantly affects men aged 20-40 years and has a strong association with ulcerative colitis (UC); 70%-80% of PSC patients also have UC, whereas 2%-8% of UC patients develop PSC[83].

PSC is associated with human leukocyte antigen genes, a protein system on cell surfaces involved in antigen presentation to the immune system[84]. It is believed that bacterial products cross the intestinal barrier and reach the liver, causing bile duct inflammation. Thus, PSC is not considered purely autoimmune but rather an immune-mediated disease influenced by external factors[14].

Diagnosis is made using magnetic resonance cholangiopancreatography, cholestatic markers (especially alkaline phosphatase and gamma-glutamyl transferase), and liver biopsy. Currently, there is no proven medical cure for PSC, with LT being the only established curative treatment[15]. However, ongoing studies are exploring the use of modified bile acids (24-nor-UDCA), Farnesoid X receptor agonists, and experimental immunotherapies, particularly anti-tumor necrosis factor and anti-integrin agents[16].

The clinical presentation of PSC is similar to that of other AILD, emerging as liver involvement progresses and characterized mainly by acholic stools, jaundice, and dark urine[16]. With regard to treatment, there is no proven method that delays the disease progression or increases patient survival in PSC. Although the use of UDCA improves hepatic biochemical markers, there is no evidence of clinical improvement or increased survival in affected patients[85].

PSC is also associated with an increased risk of colorectal cancer, cholangiocarcinoma, and liver failure. Some prognostic factors linked to worse outcomes include alkaline phosphatase levels three times above the upper limit, platelet count below 150000/mm³, and bilirubin ≥ 23 μmol/L[86].

PSC can lead to complications such as bacterial cholangitis, cirrhosis, and cholangiocarcinoma; however, LT continues to follow indications similar to other liver diseases[16]. A major difference is related to intrahepatic cholangiocarcinoma (ICCA), whose standard treatment is resection with regional lymphadenectomy[87]. Although ICCA has been deemed a formal contraindication for LT[88], in situations of low resectability or high recurrence rates, LT should be considered[1].

ICCA is not a current standard indication for LT, especially if it is locally large, advanced, and metastatic, due to the low survival rate. A study by Pascher et al[89] pointed out that ICCA measuring 2 cm or less in cirrhotic patients has a survival rate of up to 73% in 5 years when transplanted, but also highlighted that confirmation through a larger cohort study is necessary to consider it a consolidated indication for transplantation.

A prospective cohort study evaluated the success of LT in patients with unresectable and advanced ICCA who responded to prior initial treatment with chemoradiotherapy, revealing a survival rate of 100% at 1 year, 71% at 3 years, and 57% at 5 years[90]. The tumor recurrence rate after transplantation was approximately 39%.

In contrast, perihilar cholangiocarcinoma has become an accepted indication in several centers when managed under specific neoadjuvant protocols, such as the Mayo Clinic protocol. This approach combines external-beam radiation, brachytherapy, and systemic chemotherapy before transplantation, followed by careful intraoperative assessment to exclude metastasis[91]. In well-selected cases, 5-year post-transplant survival exceeds 65%-70%, comparable to outcomes for HCC, whereas recurrence rates drop significantly when strict inclusion criteria are followed. This intensive regimen is only applied to carefully selected patients who meet certain strict criteria, such as: Tumor ≤ 3 cm, no previous transperitoneal biopsy, no detectable metastatic foci in preoperative studies. This strict selection process reduces the number of cases eligible for this procedure[92], but it is precisely these rigorous criteria that make it more successful.

CURRENT LIMITATIONS IN THE MANAGEMENT OF PSC

Currently, no medication has been shown to alter the course of the disease or increase transplant-free survival[16,17]. Furthermore, PSC manifests differently among patients, varying in age of onset, sex, association with inflammatory bowel disease, and the type of bile ducts affected (small or large). This heterogeneity suggests that a one-size-fits-all treatment approach may not be suitable for everyone[93]. LT is the only curative treatment for advanced disease, but the procedure has risks, and the disease can recur in the new organ in at least 25% of patients[17].

Emerging therapies for PSC

Studies have indicated that autologous hematopoietic stem cell transplantation in patients who have already received a liver transplant is a potential treatment for recurrent PSC and for preventing graft rejection. However, these studies are highly experimental, with data from small cohorts (Table 3)[94].

Table 3 Emerging therapies for primary sclerosing cholangitis.

Disease	Emerging therapies	Mechanism/target	Current evidence	Ref.
Primary sclerosing cholangitis	NorUDCA	Modified bile acid; anti-fibrotic, anti-inflammatory effect	Clinical trials in progress	Karlsen et al[14], 2017
				Phase 2, n ≈ 161
	FXR agonists	Regulates bile acid metabolism and has anti-inflammatory properties	Preliminary positive results	Hov and Karlsen[14], 2023
				Review and translational data
	anti-TNF anti-integrin agents	Target immune-mediated inflammation	Early experimental and clinical studies	Karlsen et al[16] 2017
				Translational/pilot data
	Autologous hematopoietic stem cell transplantation	Immune reconstitution and graft protection	Pilot study showing promising results for recurrent PSC after transplantation	Chruscinski et al[95], 2022
				Pilot, n = 6

NorUDCA: 24-nor-ursodeoxycholic acid; FXR: Farnesoid X receptor; TNF: Tumor necrosis factor; PSC: Primary sclerosing cholangitis.

OUTCOMES OF LT IN AILD

The clinical outcomes of LT in patients with AILD, including AIH, PBC, and PSC, encompass multiple dimensions such as patient and graft survival, recurrence of the underlying disease, the need for retransplantation, and impact on long-term quality of life[95]. These outcomes are influenced by disease-specific pathophysiology, pre-transplant severity, immunological profile, and post-transplant immunosuppressive management.

In a comprehensive analysis from the European Liver Transplant Registry including patients transplanted for chronic liver diseases between 1988 and 2016, the 5-, 10-, and 15-year survival rates after LT for AIH were 79.4% [95% confidence interval (CI): 77.5%-81.2%], 70.8% (95%CI: 68.4%-73.2%), and 60.3% (95%CI: 56.9%-63.9%), respectively. Corresponding first graft survival without death or retransplantation was 73.2% (95%CI: 71.2%-75.2%), 63.4% (95%CI: 60.9%-66.0%), and 50.9% (95%CI: 47.3%-54.7%) at 5 years, 10 years, and 15 years[96]. These data highlight a relatively stable long-term prognosis for AIH recipients, although recurrence and acute rejection remain important determinants of late graft loss.

For PBC, survival outcomes after LT are generally excellent, reflecting both the indolent nature of the disease and the effectiveness of current post-transplant management. Data from the OPTN/UNOS database (2002-2010) demonstrated 1-, 3-, and 5-year patient survival rates of 92.8%, 90.1%, and 86.4% among living donor recipients, and 89.6%, 87.0%, and 85.1% among deceased donor recipients. Corresponding graft survival rates were 85.6%, 80.9%, and 77.4% (living donor), and 85.2%, 82.5%, and 80.7% (deceased donor)[97]. Factors such as older recipient age and higher pre-transplant MELD scores were independently associated with decreased post-transplant survival, similarly to AIH.

Regarding PSC, data from 138 centers across 23 European countries between 1980 and 2015 showed that patient survival after first LT was 89%, 80%, and 73% at 1, 5, and 10 years, respectively, while graft survival (including retransplantations) was 80%, 70%, and 60% over the same intervals[98]. Despite these favorable results, PSC remains a challenging indication due to its association with inflammatory bowel disease and increased risk of biliary complications and recurrence.

When compared to other etiologies, such as viral hepatitis, alcoholic liver disease (ALD), and non-alcoholic steatohepatitis (NASH), patients transplanted for autoimmune etiologies generally exhibit comparable or superior outcomes[18]. Analyses of large international registries indicate that recipients with PBC and PSC have higher long-term survival rates - both patient and graft - compared to those transplanted for NASH and ALD[99]. For instance, a UNOS analysis (2005-2019) showed that 10-year survival post-LT reached between 67.5% and 73.5% in AIH, PBC, and PSC, compared with approximately 60% in NASH and ALD[98]. These differences are largely attributed to the absence of ongoing metabolic injury and alcohol-related relapse, underscoring the favorable immunological profile of AILD in the post-transplant setting.

Despite these encouraging survival rates, certain disease-specific challenges persist. AIH recipients, for example, have been shown to carry a relatively higher risk of mortality from severe infections and acute rejection compared to those with PBC or PSC. European Liver Transplant Registry data from 1998-2017 revealed that AIH was associated with lower patient survival relative to PBC (hazard ratio = 1.48; P < 0.001) and PSC (hazard ratio = 1.19; P = 0.002), even after adjustment for age and MELD score[100]. Nonetheless, when compared to etiologies such as hepatitis C and NASH, AIH tends to have similar or superior outcomes, provided there is strict control of immunosuppression and adequate post-operative monitoring[95]. Therefore, even with potential challenges related to recurrence and exacerbated immunoreactivity, AILD generally has a favorable prognostic profile in the context of LT, standing out in relation to metabolic and toxic-infectious etiologies.

Recurrence of AILD following LT remains a significant yet variably reported event, typically occurring in 10%-35% of AIH, 15%-25% of PBC, and 20%-30% of PSC recipients, depending on follow-up duration and diagnostic criteria. Key risk factors include younger recipient age, high pre-transplant disease activity, persistent cholestasis, and the choice of calcineurin inhibitor. While tacrolimus has been associated with lower rejection rates, some studies suggest a marginally higher risk of recurrence compared to cyclosporine, although evidence remains inconclusive. In PBC, the prophylactic use of UDCA post-transplant has shown modest biochemical benefit in reducing cholestasis, yet current AASLD and EASL guidelines do not recommend routine administration, reserving its use for centers with historically higher recurrence rates or in patients with early cholestatic patterns[101]. Close post-transplant surveillance combining biochemical monitoring, imaging, and, when indicated, protocol biopsies is essential to detect early recurrence and guide immunosuppression adjustments.

Beyond graft and patient survival, post-transplant quality of life in AILD recipients represents a central dimension of long-term outcomes. Studies employing validated instruments, such as the Short Form-36 and EuroQol 5-Dimensional questionnaire, consistently demonstrate significant improvement in physical function, vitality, and pain control compared with pre-LT baselines, particularly among patients with PBC and PSC[102]. However, younger recipients with AIH frequently report persistent psychosocial distress, including anxiety over recurrence, altered body image, and prolonged dependence on immunosuppression[103].

Furthermore, the long-term use of immunosuppressive agents, particularly corticosteroids, is associated with cumulative adverse effects such as osteoporosis, hypertension, dyslipidemia, diabetes mellitus, and increased susceptibility to opportunistic infections[96,104]. Contemporary strategies emphasize gradual steroid minimization - ideally within 6 to 12 months post-LT - to mitigate metabolic and bone complications, except in high-risk AIH recipients who may benefit from extended low-dose regimens. The choice of primary immunosuppressant also affects outcomes: Tacrolimus is associated with superior rejection control but greater nephrotoxicity, while mechanistic target of rapamycin inhibitors (sirolimus, everolimus) offer renal protection at the cost of dyslipidemia and delayed wound healing[105]. Practical follow-up checkpoints at 3 months, 12 months, and 24 months post-transplant are critical to reassess metabolic control, bone density, infection prophylaxis (including cytomegalovirus, hepatitis B virus, and fungal pathogens), and vaccination status (influenza, pneumococcal, hepatitis B, humanpapillomavirus)[106].

Retransplantation remains a high-impact adverse outcome, generally necessitated by irreversible graft failure due to rejection, aggressive disease recurrence, or vascular and infectious complications[95,96]. Beyond survival metrics, LT outcomes in AILD should thus be viewed through a multidimensional framework encompassing graft functionality, recurrence risk, reintegration into daily and occupational life, and overall well-being[107,108]. Comprehensive follow-up strategies and individualized supportive interventions are essential to optimize both clinical and patient-reported outcomes in this population.

In conclusion, although LT provides excellent long-term outcomes for AILD, residual challenges such as disease recurrence, infection susceptibility, and metabolic complications persist (Table 4). Future strategies should prioritize less toxic immunosuppressive regimens, improved prediction and prevention of disease recurrence, and structured psychosocial follow-up programs to optimize both clinical and patient-centered outcomes.

Table 4 Recurrence after liver transplantation in autoimmune liver diseases.

Disease	Estimated recurrence rate and main risk factors	Post-transplant surveillance and management considerations	Ref.
AIH	Recurrence in 10%-35% of recipients; risk increases with younger age, high pre-LT inflammatory activity, rapid corticosteroid withdrawal, and use of tacrolimus-based regimens (evidence moderate)	Monitor AST, ALT, IgG levels every 3 months in first year; consider protocol biopsy at 12 months in high-risk cases; maintain low-dose corticosteroid or azathioprine in selected patients to reduce recurrence	[97,101]
PBC	Recurrence in 15%-25% of cases; higher risk with female sex, younger age, persistent cholestasis, and shorter duration of UDCA therapy pre-LT (evidence moderate)	Routine monitoring of ALP and GGT; early recognition of cholestasis patterns; UDCA prophylaxis may be considered in centers with historically higher recurrence or in patients with biochemical cholestasis - not mandatory per EASL/AASLD guidelines	[71,73,74]
PSC	Recurrence in 20%-30% of recipients; increased risk with active IBD, male sex, younger age, and biliary anastomotic strictures (evidence moderate-high)	Surveillance with MRCP or ultrasound every 6-12 months and liver biochemistry every 3 months; aggressive management of IBD activity; prompt treatment of biliary strictures or infections to prevent graft injury	[17,95,99]

AIH: Autoimmune hepatitis; PBC: Primary biliary cholangitis; PSC: Primary sclerosing cholangitis; IBD: Inflammatory bowel disease; LT: Liver transplantation; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; UDCA: Ursodeoxycholic acid; ALP: Alkaline phosphatase; GGT: Gamma-glutamyl transferase; EASL: European Association for the Study of the Liver; AASLD: American Association for the Study of Liver Diseases; MRCP: Magnetic resonance cholangiopancreatography.

CONCLUSION

AILD represent an important clinical challenge, characterized by complex pathogenesis, diagnostic difficulties, and limitations in current therapeutic options. Despite encouraging survival rates after transplantation, recurrence and complications still persist. Advances in the understanding of immune mechanisms and host-microbiome interactions may open new avenues for more precise and effective therapies, capable of improving long-term outcomes in these patients.