Beyond the Liver: A Systematic Symptom-Based Approach to Extrahepatic Manifestations in Autoimmune Hepatitis

Abstract

Autoimmune hepatitis (AIH) has long been regarded as an organ-specific disorder. However, increasing evidence supports its systemic nature, with extrahepatic manifestations representing key aspects of clinical management. These manifestations can affect musculoskeletal, gastrointestinal, haematologic, and other systems. They also reflect the complex interplay between systemic inflammation, concomitant autoimmune diseases, and drug-related toxicity. A careful evaluation is therefore essential to distinguish between these scenarios, especially for symptoms like fatigue and cytopenias. This narrative review provides a comprehensive, symptom-based overview of extrahepatic clinical and laboratory findings in AIH. By integrating current evidence with practical diagnostic considerations, it aims to offer clinicians a patient-centred and clinically relevant framework for navigating the multifaceted systemic landscape of AIH.

1. Introduction

Autoimmune hepatitis is often considered a subtle and asymptomatic disease, with only a minority of patients developing liver decompensation in case of acute severe presentation or of delayed diagnosis with already developed liver cirrhosis [1]. However, the presence of extrahepatic symptoms is not uncommon in AIH patients [2]. Systemic and organ-specific extrahepatic manifestation can occur in both untreated and compensated AIH patients due to several factors. These factors include systemic inflammation secondary to hepatitis, autoimmune comorbidities, and toxicity of drugs used for the management of AIH [3,4]. While a recent meta-analysis from Slooter et al. did not demonstrate a significant impact of autoimmune comorbidities on survival and AIH progression, extrahepatic manifestation may still significantly impact patient health and quality of life [5]. This review aims to discuss the most reported extrahepatic clinical and laboratory findings in patient with AIH, analyze their possible causal mechanisms, and provide guidance for the differential diagnosis between those possible causes.

2. Methods

This narrative review summarizes current evidence regarding extrahepatic manifestations in patients with AIH. A literature search was conducted using the PubMed/MEDLINE database up to January 2026. The search strategies employed a combination of the following keywords: “autoimmune hepatitis”, “extrahepatic manifestations”, “comorbidities”, “arthritis”, “arthralgia”, “joint pain”, “myalgia”, “gastrointestinal manifestations”, “diarrhoea”, “malabsorption”, “fatigue”, “depression”, “anxiety”, “quality of life”, “health-related quality of life”, “shortness of breath”, “dyspnoea”, “cytopenia”, “anaemia”, “leukopenia”, “thrombocytopenia”, “aplastic anaemia”, “drug toxicity”, “diabetes mellitus”, “hyperglycaemia”, “hypoglycaemia”, “hypothyroidism”, “hyperthyroidism”, “thyroid disease”, “bone mass density”, “osteopenia”, “osteoporosis”, “sarcopenia”, “weight loss”, “neurologic comorbidities”, “neurologic disease”, “neuropathy”, and “peripheral neuropathy”. Articles in English were considered. We prioritized systematic reviews, meta-analyses, high-quality observational studies over small retrospective studies and case series; however, in most context, evidence was limited to small and retrospective studies. For each section, we provide a subsection summarizing the grade of evidence and whether current EASL guidelines (2025) provided specific recommendations.

3. Arthralgia, Arthritis and Myalgia

Arthralgia (non-specific joint pain) and myalgia (muscle pain) are relatively common in patients with AIH [2,6,7]. In this scenario, arthralgia usually reflects systemic inflammation, determined by the production of pro-inflammatory cytokines (IL 10, IL 17, etc…) by T-cells [8,9]. While these symptoms may occasionally correlate with hepatic disease activity, neither their presence nor their severity is considered as a reliable marker of activity, and treatment tapering should be based on the more accurate biochemical markers of activity (ALT, IgG) [8,10]. On the other hand, the persistence or appearance of arthralgia despite good biochemical control should raise suspicion of an associated autoimmune or inflammatory disorder [11].

The pattern of joint involvement often provides important diagnostic clues. Monoarthritis is typically the result of a localized pathological process (e.g., gout), while polyarthritis is more indicative of a systemic inflammatory disease [12,13]. Rheumatoid arthritis is among the most frequent comorbidities, with a prevalence between 1.8% and 5.7% [3,11,14]. Less commonly, arthritis may present as a feature of connective tissue disease, most often Sjogren’s syndrome [14]. Although historically linked to AIH, systemic lupus erythematosus appears be a rare co-occurrence [15,16,17]. The diagnosis of these systemic autoimmune diseases relies on a combination of clinical features (e.g., arthritis, dermatologic manifestation, serositis) and serological markers (e.g., anti-citrullinated peptide and antinuclear and anti-double-stranded DNA antibodies) [18]. Importantly, many AIH patients may exhibit these autoantibodies in the absence of systemic autoimmune disease [19]. Therefore, isolated serological positivity—particularly for ANA or anti-dsDNA—should be interpreted as part of the typical AIH immunological spectrum rather than as evidence of an additional systemic disorder.

Considerations and proposed approach: For patients presenting with articular symptoms, the first diagnostic step is to distinguish arthralgia from arthritis, based on the presence of clinical signs of inflammation (warmth, swelling, redness) [20]. Isolated arthralgia may occasionally accompany AIH activity, representing a consequence of ongoing systemic inflammation; however, its persistence despite AIH control should prompt further evaluations [2,6,21].

Arthralgia may be observed in several other situations, including osteoarthritis, viral infections, or connective tissue disease. Consequently, a detailed history and review of associated symptoms are essential [22].

In cases of overt arthritis, the number of joints involved could help distinguish between local processes and systemic diseases. Acute monoarthritis may result from traumas, infections (septic arthritis), crystal deposition, or, less commonly, from primary or secondary neoplasms involving the synovia. The differential diagnosis relies on history (traumas, fever, previous similar episodes) and physical examination (identification of specific joint involved, presence of extra-articular manifestations), and laboratory tests comprehensive of blood cell count, c-reactive protein, erythrocyte sedimentation rate and uric acid could help in this differential diagnosis [23]. Imaging studies, such as X-ray studies for chondrocalcinosis and ultrasound for synovial inflammation, are also valuable [24]. In patients with unexplained monoarthritis, arthrocentesis with synovial fluid analysis is crucial to rule out septic arthritis [25].

In patients with involvement of multiple joints, the number and type (small rather than large) of joints involved should be evaluated, and the presence of morning stiffness and relief from pain and stiffness after physical activity should lead to the suspicion of an inflammatory process [26]. Acute polyarthritis (less than 6 weeks) is often reactive to other pathological processes, like infections (rheumatic fever, viral infections), but it may also represent an early presentation of a chronic rheumatologic disease. Polyarthritis, or, more commonly, oligo-arthritis (more than one joint but less than ten joints involved) may also be observed in septic arthritis or in deposition of crystals [27]. In patients with chronic polyarthritis, a careful evaluation of clinical history (previous infections, previous episodes of arthritis, comorbidities like psoriasis), physical examination (pattern of arthritis, evaluation of extraarticular manifestations) and serological markers is essential [22]. The possible differential diagnosis of arthritis is summarized in

Table 1. Main etiologies of mono- and polyarthritis. Oligo-arthritis may develop due to both etiologies of monoarthritis and etiologies of polyarthritis.

Monoarthritis	Polyarthritis
Trauma	Reactive arthritis (post-infectious, paraneoplastic)
Septic arthritis	Rheumatoid arthritis
Deposit of crystals (e.g., gout)	Seronegative spondyloarthritis (ankylosing spondylitis)
Primary or secondary neoplasms of synovia	Psoriatic arthritis

.

The management of articular manifestations in AIH requires coordination between hepatologists and rheumatologists. Treatment should aim to control both hepatic and extrahepatic inflammation while maintaining caution in the use of hepatotoxic drugs such as methotrexate or leflunomide (especially in patients with severe liver fibrosis). Non-steroidal anti-inflammatory drugs can be used cautiously for symptomatic relief, and corticosteroid adjustments may be considered, especially if joint symptoms coincide with a hepatic flare.

Grade of evidence: Evidence regarding the prevalence of arthralgia, myalgia, arthritis (including rheumatoid arthritis), and connective tissue diseases is derived mostly from relatively small retrospective studies. Recommendations for differential diagnosis derive mostly from expert opinion and guidance not specifically designed for patients with AIH or liver disease, as evidence-based or expert-opinion-based diagnostic algorithms specific for AIH are lacking. EASL 2025 guidelines acknowledge rheumatoid arthritis, systemic lupus erythematosus and Sjogren’s syndrome as common extrahepatic manifestations of AIH, yet no specific recommendation is provided regarding screening for these diseases.

4. Gastrointestinal Manifestations

4.1. Chronic Diarrhoea

Chronic diarrhoea, defined as symptoms lasting at least four weeks, may occur in patients with autoimmune hepatitis (AIH). While functional disorders such as irritable bowel syndrome (IBS) are common, gastrointestinal symptoms in AIH warrant careful assessment, as specific autoimmune comorbidities remain more frequent than in the general population [28,29].

Celiac disease (CeD) is the most prevalent associated condition. CeD is an autoimmune enteropathy triggered by gluten, leading to villous atrophy and malabsorption. Beyond its classical presentation with diarrhoea, weight loss and anaemia, CeD may manifest with subtle or extraintestinal features such as osteoporosis or infertility [30,31,32]. The association between CeD and AIH reflects a shared HLA background (DR3, DQ2/DQ8) [32,33]. A meta-analysis by Haggård et al. found a pooled prevalence of biopsy-confirmed CD of 3.5% (95% CI: 1.6–5.3%) in a cohort of 567 individuals with AIH from eight studies [34]. This figure is higher than the prevalence of CeD in the general population (1%). Despite the recognized association, the clinical impact of routine screening and the optimal follow-up strategy for these comorbidities remain uncertain. Instead, a diagnostic work-up for CeD is warranted in patients with AIH and gastrointestinal symptoms [34]. This screening is particularly relevant, as undiagnosed CeD can be the cause of persistent or recurrent abnormal liver function tests despite a proper treatment for AIH [35,36]. Management follows standard gluten-free diet protocols, which can normalize intestinal symptoms and liver enzymes and help restore a proper intestinal absorption of steroid-sparing drugs for AIH.

Inflammatory bowel diseases (IBDs), particularly ulcerative colitis, may also coexist with AIH, although less frequently than with primary sclerosing cholangitis (PSC) [37,38]. The risk of IBDs (especially ulcerative colitis) is particularly high in patients with co-existent features of AIH and PSC, as observed in the PSC/AIH variant syndrome or in autoimmune sclerosing cholangitis, a mixed form of autoimmune liver disease typical of paediatric patients [39,40]. The occurrence of IBDs in AIH patients may suggest an AIH-PSC overlap syndrome rather than isolated AIH [41]. The link between IBD and liver autoimmunity resides probably in the abnormal immune response to antigens of microbiota and the cross-reaction between those antigens and host components, as documented by the common finding of atypical p-ANCAs (perinuclear anti-neutrophil cytoplasmic antibodies) in both UC and AIH [42,43]. Notably, those p-ANCAs differ from those found in small-vessel vasculitis like eosinophilic granulomatosis with polyangiitis, which are directed against the antigen myeloperoxidase (MPO) and whose positivity has been described in patients with the association of AIH and vasculitis but not UC [44]. Atypical p-ANCAs found in UC and AIH are, instead, usually directed against non-MPO antigens and are recognized with indirect immunofluorescence [45].

Considerations and proposed approach: While evaluating patients with chronic diarrhoea, the primary goal is to distinguish organic disease, such as IBDs or CeD, from functional disorders like IBS. Clinical features suggestive of IBD or CeD include weight loss, nocturnal symptoms, bloody stool, unexplained fever, increase in of inflammatory markers and/or anaemia [46]. While chronic diarrhoea, weight loss and anaemia are commonly reported in both CeD and IBDs, the presence of bloody stool and peri-anal fistula should strongly prompt towards the suspicion of IBDs [47].

Conversely, CeD can present in milder forms, mimicking IBS. Given the strong association between CeD and AIH, it appears reasonable to test all AIH patients with new-onset gastrointestinal symptoms for CeD [36]. Notably, a minority of CeD patients have associated IgA deficiency, a condition also described in AIH, especially in paediatric patients [48]. Patients with IgA deficiency are at increased risk of infection (including gastrointestinal and respiratory) but are also commonly affected by autoimmune diseases due to the immune-dysregulatory nature of the defect [49]. Due to its high frequency in patients with CeD and because standard screening relies on anti-tTG IgA-class antibodies, patients screened for CeD should also be tested for total IgA deficiency. If confirmed, IgG-class CeD-related antibodies should be used for the diagnosis [50].

A definitive diagnosis of organic enteropathies often requires endoscopic studies of the gastrointestinal tracts. All patients with positive CeD serology should undergo upper gastrointestinal endoscopy with histological sampling of duodenal mucosa. Additionally, selected patients with negative CeD but strong clinical suspicion (e.g., suspected seronegative CeD, suspected drug-induced enteropathy like that induced by Olmesartan) may also warrant an upper gastrointestinal endoscopy [51]. Colonoscopy should be reserved for patients with suspected IBDs; in these cases, even in the absence of macroscopic lesions, mucosal mapping with biopsies should be performed to identify microscopic colitis [52].

In conclusion, chronic diarrhoea in AIH should not be easily dismissed as functional: identifying associated autoimmune enteropathies may directly influence both hepatic and intestinal management, improving long-term outcomes. A summary of possible causes of diarrhoea in AIH patients is reported in

Table 2. Summary of main gastrointestinal manifestation associated with autoimmune hepatitis, with possible diagnostic tools and causes. IBS: irritable bowel syndrome. CeD: celiac disease. IBD: inflammatory bowel disease. AIG: autoimmune gastritis. GI: gastrointestinal. MRI: magnetic resonance imaging.

Syndrome	Possible Diagnosis	Suggested Tests
Chronic diarrhoea without risk features	Probably IBS, reasonable to exclude CeD due to its association with AIH	Serological test for CeD.
Chronic diarrhoea with weight loss, malabsorption and/or nocturnal symptoms	Probably organic bowel disease, including CeD, other small bowel enteropathies, IBDs	Serological test for CeD. Upper and/or lower GI endoscopy according to the specific clinical suspicion.
Malabsorption with unexplained weight loss	Mandatory to exclude organic disorders, including neoplasms	Serological test for CeD, upper and lower GI endoscopy according to clinical suspicion.
Recurrent abdominal pain, with or without diarrhoea and/or malabsorption, with risk features (e.g., nocturnal symptoms)	Possible IBD	Lower GI endoscopy and intestinal ultrasound, MRI in selected cases.
Persistent or recurrent bloody stool	Possible IBD	Lower GI endoscopy and intestinal ultrasound, MRI in selected cases.
Unexplained malabsorption of iron and B12 vitamin	Possible AIG, possible CeD	Serological test for CeD and AIG. Upper GI endoscopy also in case of negative serology if strong suspicion of AIG or CeD.

.

4.2. Malabsorption

Malabsorption in patients with AIH is uncommon but clinically relevant, as it often signals an associated autoimmune gastrointestinal disorder. It should be suspected in patients with unexplained weight loss, anaemia, or deficiencies of iron, folate, or vitamin B12, regardless of the presence of diarrhoea [53]. CeD represents one of the most common causes of malabsorption in AIH; thus, screening for CeD should be extended to patients with unexplained signs of malabsorption even in the absence of diarrhoea [36].

Historically considered rare in AIH, AIG is now increasingly recognized as a possible cause of malabsorption, with recent studies reporting a high prevalence of anti-parietal-cell antibodies and mild histological gastritis in AIH cohorts [54]. This apparent discrepancy likely reflects the improved sensitivity of modern serological assays and earlier detection of subclinical disease [55]. AIG is associated with iron and B12 malabsorption, leading to cytopenia (up to pancytopenia) if supplementation is not started [56].

Considerations and proposed approach: The initial evaluation of patients with AIH and weight loss should include a thorough history, nutritional assessment, and laboratory tests for micronutrient deficiencies (iron, folate, vitamin B12). When deficiency is confirmed, targeted testing for autoimmune causes is warranted: anti-tissue transglutaminase (anti-TTG) for CeD and anti-parietal-cell or anti-intrinsic-factor antibodies for AIG [36,57]. Upper endoscopy with duodenal and gastric biopsies remains the gold standard for diagnosis. Other causes, such as chronic infection or malignancy, should also be considered and ruled out (especially in patients receiving high-dose steroids or immune-modulating agents) [58]. It should be noted that despite the increasing diagnostic accuracy, serological diagnosis of AIG presents, to this date, some pitfalls due to the limited sensitivity of anti-intrinsic-factor antibodies and the suboptimal accuracy and specificity of anti-parietal-cell antibodies; thus, in cases of strong suspicion, upper GI endoscopy with gastric sampling should be performed also in case of negative AIG serology [59].

Treatment focuses on correcting nutritional deficits and addressing the underlying autoimmune process. A gluten-free diet is indicated for CeD, while AIG management includes vitamin B12 replacement and surveillance for gastric neoplasia. An early identification and management of these conditions may favourably influence outcomes. A summary of possible causes of malabsorption in AIH patients is reported in Table 2.

Grade of evidence: Evidence regarding the prevalence of specific gastrointestinal comorbidities in patients with AIH (and vice versa) derives mostly from retrospective studies. Recommendations for differential diagnosis are derived from guidelines evaluating gastrointestinal syndromes not specifically in the context of AIH and from expert opinion reinforcing the potential relevance of screening AIH patients for specific diseases (e.g., CeD). EASL 2025 guidelines recommend screening for CeD in all AIH patients at diagnosis, while no specific indication is provided for AIG and IBDs (the latter recognized as common comorbidity of AIH).

5. Fatigue Syndrome

Fatigue is one of the most frequent and disabling extrahepatic manifestations of AIH, affecting up to 40–60% of patients at diagnosis and affecting both patients with acute and chronic presentation of AIH [60,61,62]. Despite being frequently overlooked, fatigue may significantly impact quality of life.

Its pathogenesis is multifactorial. Liver and systemic inflammation plays a key role, with pro-inflammatory mediators (IL-6, IL-17) negatively impacting serotonergic and dopaminergic transmission [63,64]. The same pro-inflammatory cytokines also influence the hypothalamus–hypophysis–adrenergic axis, leading to reduced cortisol response to physical and psychological stress [65,66]. This strict relation between inflammation and liver inflammation was also observed by Liu et al., who identified active liver inflammation as an independent risk factor for fatigue in patients with biopsy-proven chronic liver disease; notably, the authors also reported autoimmune liver disease as a risk factor for fatigue, further suggesting its connection with liver autoimmunity [67]. However, concurrent factors, including sleep disturbances, psychological comorbidities, and hypothyroidism, should not be overlooked when investigating fatigue [68,69]. In fact, fatigue in AIH does not reliably correlate with disease activity. Many patients experience persistent symptoms even after complete normalization of liver tests, and some turn to complementary or self-prescribed treatments (including caffeine, cannabidiol, acupuncture) to achieve partial relief [61,70].

Fatigue may also overlap with anxiety and depression, which may alter the perception of disease and reduce adherence to therapy [68,71]. While the association between autoimmunity and psychiatric disorder has been widely reported, with a key role of inflammatory mechanisms such as interleukin production and inflammasome activation, more recent evidence hints towards a genetic correlation between AIH and psychiatric comorbidities, depicting a complex scenario of interconnection between liver autoimmunity and psychiatric disease [72,73,74]. Often overlooked, psychiatric comorbidities negatively impact both quality of life and liver-related outcomes in AIH patients [75,76]. Current guidelines reinforce the importance of early identification of depression and anxiety disorders in AIH patients, with the use of validated tools such as PHQ-2, alone or in combination with PHQ-9, or GAD-7 [10,77,78].

Shortness of breath, frequently described alongside fatigue, requires separate evaluation [68,79]. Common causes include asthma—which is more prevalent in AIH patients—and, more rarely, interstitial lung disease or pulmonary manifestations of connective tissue disease [3,33,60,80,81].

Considerations and proposed approach: Evaluation should first focus on excluding reversible organic contributors. A comprehensive assessment includes history, physical examination, and baseline laboratory tests (cell blood count, kidney and liver function, CRP/ESR, thyroid function), along with targeted imaging such as chest X-ray or abdominal ultrasound when indicated [52]. Screening for sleep disorders, mood disturbances, and adverse effects of medications is recommended, as these frequently coexist in AIH patients and are often under-recognized.

When no organic cause is identified, fatigue should still be pro-actively addressed. Non-pharmacological interventions (including sleep hygiene, psychological support, management of mood disorders, and pacing strategies) represent the core of management. Collaboration with psychology, psychiatry, and primary care specialists can significantly improve outcomes. In case of shortness of breath, the work-up should follow standard algorithms (pulse oximetry, ECG, echocardiography, chest radiography, and 6 min walking test, spirometry or HRCT in selected cases).

In conclusion, fatigue in AIH remains an area of substantial unmet need, given its high prevalence and the absence of targeted pharmacological therapy. Dedicated studies focused on its mechanisms and management are required.

Grade of evidence: Evidence regarding fatigue and associated conditions derive mostly from retrospective studies. While several expert opinions, as well as EASL 2025 guidelines, recommend the use of standardized tools in the evaluation of quality of life in AIH patients, studies investigating and comparing the available tools in the specific setting of AIH are lacking.

6. Neurological Alterations

Neurological manifestations in patients with AIH are uncommon but clinically important, as they often reflect associated autoimmune diseases [82]. Despite the clinical relevance of neurologic comorbidities, data regarding the prevalence of concurrent neurologic autoimmune diseases in AIH remain scarce. Current evidence is primarily derived from small, descriptive studies, largely due to the rarity of these conditions. This limitation highlights the critical need for collaboration between hepatologists and neurologists to ensure timely and accurate recognition and treatment, thereby preventing disease progression and the onset of disability.

The most reported associations are multiple sclerosis and myasthenia gravis. The prevalence of multiple sclerosis was about 1% in various AIH cohorts [83,84,85,86]. The association with myasthenia gravis remains a rare but documented occurrence [87].

Historically, peripheral nervous system disorders were thought to be rare [88], but recent evidence has challenged this assumption. A prospective study demonstrated a higher prevalence of sensory neuronopathy in patients with AIH than in controls, with symptoms persisting despite adequate immunosuppression and biochemical remission [82]. These findings highlight that neuromuscular symptoms (such as weakness, sensory deficits, gait disturbance or fatigability) should not be dismissed as nonspecific manifestations of chronic illness. Instead, they may represent an independent autoimmune neurological process requiring targeted evaluation.

Considerations and proposed approach: the initial assessment should focus on distinguishing central from peripheral neurological symptoms. A detailed history (pattern and progression of symptoms, visual or bulbar manifestations, fluctuating weakness), neurological examination, and baseline laboratory testing are essential. Red-flag features include rapidly progressive weakness, asymmetrical deficits, sphincter involvement, or signs of neuromuscular junction dysfunction. Given the complexity of these conditions, early referral to neurology is recommended.

Management depends entirely on the underlying neurological diagnosis, A careful coordination between hepatologists and neurologists is essential to balance efficacy and hepatic safety. Treatment decisions should, in fact, consider the potential hepatotoxicity of some neurological medications.

Grade of evidence: Evidence regarding central nervous system autoimmunity derives mostly from small retrospective cohort or case series. The topic of peripheral neuropathy has recently been enriched by a prospective controlled study on 70 AIH patients (control group of 52 HBV patients. EASL 2025 guidelines do not provide specific recommendation for neurological manifestations in AIH patients.

7. Alterations in Blood Cell Counts

Cytopenia, affecting one or multiple blood lines, may occur in AIH patients due to several factors, including nutritional deficiency, autoimmune disruption of blood cells or precursors, cirrhosis and portal-hypertension-induced hypersplenism, reduced hepatic production of haematopoietic growth factors, and drug toxicity [89,90]. Less commonly, cytopenia may be a feature of associated non-haematologic autoimmune disease like systemic lupus erythematosus [91,92]. Due to the wide variety of conditions leading to cytopenia, the differential diagnosis should be based on clinical and laboratory findings and further examinations (e.g., bone marrow aspirate) in selected patients; Figure 1 summarizes the key points in the differential diagnosis of cytopenia.

7.1. Thrombocytopenia

Thrombocytopenia is a common finding in chronic liver disease, including AIH, and often reflects portal hypertension with splenic sequestration [93]. Reduced hepatic synthesis of thrombopoietin may further contribute to low platelet counts [94].

In the setting of AIH, immune thrombocytopenia (ITP) represents a well-documented cause of thrombocytopenia. Its diagnosis is clinical, based primarily on the exclusion of secondary causes [95,96,97,98].

Considerations and proposed approach: The first step is to confirm a true reduction in platelet count. Laboratory artefacts, especially EDTA-related pseudo-thrombocytopenia, should be excluded through smear review or by repeating the test in citrate or heparinized samples [99]. Reviewing prior blood counts helps determine whether thrombocytopenia is chronic or newly developed. Other relevant clinical information to collect includes evidence of portal hypertension (splenomegaly, varices), recent infections, medication exposure, bleeding symptoms, and coexisting cytopenia.

When thrombocytopenia is persistent and not clearly attributable to liver-related mechanisms, the diagnostic framework proposed in the updated international ITP consensus report (

Table 3. Synthesis of the 2019 “Updated international consensus report on the investigation and management of primary immune thrombocytopenia”, adapted from Provan et al., 2019 [100]. ¹ Consider tests for anti-phospholipid antibodies only in patients with features of anti-phospholipid syndrome.

Basic Evaluation in All Patients	Test of Potential Utility in the Management of an ITP Patients	Test of Unproven or Uncertain Benefit
Patient and family history	Glycoprotein-specific antibody (not a primary test)	Thrombopoietin level
Physical examination	Anti-phospholipid antibodies (including Lac) 1	Reticulated platelets/immature platelet
CBC counts and reticulocyte count	Thyroid function and antibodies	Bleeding time
Peripheral blood film	Pregnancy test	Serum complement
Quantitative Ig level measurement	Antinuclear antibodies
Blood group (including Rh)	Viral PCR for EBV, CMV, PVB19
Test for HIV, HBV, HCV	Bone marrow examination in selected patients
	Direct antiglobulin test
	Test for H. pylori

) can be useful [100]. Bone marrow examination should be reserved for selected cases, including as patients with unexplained additional cytopenias, atypical features, or inadequate response to initial management.

The management of thrombocytopenia depends on its cause. Portal-hypertension-related thrombocytopenia generally requires no specific treatment. ITP is treated according to standard guidelines: corticosteroids are often first-line and may overlap with AIH therapy, although the overall immunosuppressive regimen should be individualized. Coordination between the hepatology and haematology teams is important when establishing the timing of steroid tapering.

7.2. Anaemia

Anaemia in AIH may arise from several mechanisms, including nutritional deficiencies, chronic disease, autoimmune haemolysis, bone marrow suppression, and, more rarely, marrow failure syndromes. Correct classification of anaemia is essential, as management varies considerably according to the underlying cause.

The most common form of anaemia in liver disease is iron deficiency anaemia, which can result from malabsorption due to associated conditions like CeD and AIG, blood loss from occult or overt bleeding or nutritional deficiency [101,102,103,104].

Less frequently, anaemia can be caused by a deficiency in cobalamin (vitamin B12) and/or folic acid (vitamin B9), often linked to poor dietary intake or the association with AIG [105,106]. Severe deficiencies of those vitamins may even lead to pancytopenia [107].

Autoimmune haemolytic anaemia (AIHA) is an uncommon but well-recognized extrahepatic autoimmune manifestation associated with AIH. Typical features include symptomatic anaemia, jaundice with preserved liver function, elevated reticulocyte count, increased LDH, low haptoglobin, and a positive direct antiglobulin test [108,109]. The coexistence of AIHA and immune thrombocytopenia (Evans’ syndrome) has also been reported, though rarely [110,111].

Anaemia of chronic disease can occur, especially in patients with advanced liver disease, presenting with a characteristically low reticulocyte count, normal or reduced mean corpuscular volume and high ferritin values [112,113].

Hepatitis-associated aplastic anaemia (HAAA) is a rare but life-threatening complication of AIH. It is a syndrome characterized by pancytopenia, marked reticulocytopenia, and a hypocellular bone marrow on biopsy [114,115]. It has been reported after episodes of acute hepatitis, including seronegative or paediatric presentations of AIH [116]. Evidence about HAAA in AIH is scarce but indicates a limited response to corticosteroids and azathioprine, with a need for second-line treatment (including anti-thymocyte globulin plus cyclosporine, up to bone marrow transplantation) [116,117].

Considerations and proposed approach: Given the wide range of potential mechanisms, a systematic diagnostic work-up is usually needed to determine the underlying cause of anaemia [79]. The initial evaluation of anaemia in AIH should include complete blood count with reticulocyte count, blood smear, iron metabolism studies, vitamin B12 and folate levels, and haemolysis work-up (LDH, haptoglobin, bilirubin).

Table 4. Evaluation of anaemia in patients with AIH.

	Iron Deficiency Anaemia	Anaemia of Chronic Disease	Anaemia Due to B12 and/or Folate Deficiency	Haemolytic Anaemia
Mean corpuscular volume (MCV)	Usually decreased	Usually normal, may be decreased	Usually increased	Usually preserved
Iron status	Low ferritin, usually low iron and reduced transferrin saturation	High ferritin, iron may be low, transferrin may be low with increased saturation	Sometimes may associate with iron deficiency features	Usually normal
Other lines	Thrombocytes may be increased	Usually normal	Up to pancytopenia	Other line may be decreased (e.g., Evans’ syndrome)
Haemolytic markers	Usually normal	Usually normal	May be increased due to erythroblastolysis	Present; Coombs’ tests used to identify immune-mediated haemolysis

summarizes the characteristic laboratory profiles of the main forms of anaemia encountered in patients with AIH. When iron, B12, or folate deficiency is identified, evaluation for CeD and AIG is recommended. Suspected haemolysis or unexplained cytopenias should prompt early haematology referral.

Severe or progressive pancytopenia requires rapid investigation to exclude HAAA or drug-induced marrow suppression.

7.3. Leukopenia

Leukopenia, despite being less common than thrombocytopenia and anaemia, should not be overlooked in AIH patients due to its possible association with clinically relevant phenomena such as infections and drug toxicity. Infections related to immune suppression and antimicrobial treatments needed for them can trigger a transitory drop in leukocyte counts [118]. Rarely, leukopenia may result from the immune-mediated destruction of leukocytes or their precursors, as seen in autoimmune neutropenia [118,119]. Compared with thrombocytopenia or anaemia, leukopenia is less common but often more clinically significant, as it may imply an increased risk of infections or an evolving bone marrow dysfunction.

Considerations and proposed approach: In patients with leukopenia, the first questions are (1) whether the alteration is acute (onset in days or week) or chronic (developed over months or more) and (2) whether or not it is accompanied by other manifestations (e.g., fever) [119]. Evaluation of previous blood cell counts may be helpful in enhancing progressive trends towards leukopenia. In all patients receiving azathioprine and/or mycophenolate, suspicion for drug-induced leukopenia should be raised [4]. Azathioprine-induced bone marrow suppression is strongly influenced by TPMT and NUDT15 polymorphisms [120]. Genotyping or phenotyping of these enzymes, now widely available, allows for the identification of patients at increased risk of severe cytopenia and may inform safer therapeutic strategies. Patients with unexplained and persisting neutropenia, especially if associated with other blood cell count alterations, should be referred to a haematology specialist for further investigations [121].

7.4. Drug-Induced Cytopenia

Cytopenias are a well-known side effect of several immunosuppressive drugs, including mofetil mycophenolate and azathioprine, the first-line treatments for AIH [10]. Both drugs can lead to bone marrow failure by interfering with purine metabolism [122]. Genetic variants affecting thiopurine methyltransferase activity have been identified as a risk factor for AZA-induced myelotoxicity [120,123,124]. Due to this risk, current guidelines recommend regular monitoring of CBC in both patients receiving AZA and MMF, especially during the first eight weeks of treatment [10].

Grade of evidence: Evidence regarding ITP and thrombocytopenia in the scenario of AIH are limited mostly to case reports and series. Similarly, evidence concerning anaemia, leukopenia (especially immune leukopenia) and HAAA derive mostly to series and descriptive retrospective studies. EASL 2025 guidelines address the topic of cytopenia mostly in the context of drug toxicity; both AIHA and ITP are cited as common comorbidities of AIH; however, no specific recommendations are provided.

8. Endocrine and Metabolic Comorbidities

Endocrine comorbidities are frequent and clinically relevant manifestations in AIH patients. They could develop as an expression of a concurrent autoimmune disease or of drug toxicity or because of disease activity. A periodic assessment of clinical manifestations and laboratory or instrumental tests suggestive of endocrine and metabolic comorbidities is thus necessary to recognize this condition early, which can develop subtly and become clinically manifested only in severe or complicated forms.

Table 5. Main endocrine and metabolic manifestations in patients with AIH. OGTT: oral glucose tolerance test; T1DM: type 1 diabetes mellitus.

Condition	Main Cause(s)	Suggested Evaluations
Hyperglycaemia	Diabetes mellitus (type 1 and type 2)	Repeat fast glycaemia, evaluate OGTT, plasma insulin, C-peptide, and HbA1c. T1DM antibodies if suspected.
Hypoglycaemia	Antidiabetic medications, rare causes of primary hypoglycaemia	Exclude drug-related hypoglycaemia. If spontaneous hypoglycaemia is suspected, refer to endocrinologist.
Hypothyroidism (elevated TSH)	Autoimmune thyroiditis	Evaluate complete thyroid function tests. Anti-TPO antibodies.
Hyperthyroidism (supressed TSH)	Graves’ disease	Evaluate the clinical symptoms of hyperthyroidism (tachycardia, agitation, poor sleep). Anti-TSHR antibodies.
Low bone mass density	Steroid treatment Advanced liver disease	Evaluate bone mass density at the start of treatment. Optimize vitamin D status. Evaluate prophylactic bisphosphonates in patients expecting long-term treatment with steroids. Refer patients with confirmed osteoporosis. In patients with unexpected low bone mass density, exclude other concurring factors (e.g., celiac disease).
Sarcopenia	Prolonged steroid treatment Disease activity Advanced liver disease	Use of standardized tools (e.g., SARC-F) in routine evaluation, especially in patients at risk for sarcopenia. Multidisciplinary approach to modulate modifiable determinants (e.g., active systemic inflammatory disease) and provide nutritional support.

summarizes the main endocrine and metabolic manifestations that are discussed in the following subsections.

8.1. Glycaemic Abnormalities

Disorders of glucose metabolism are relatively common in patients with AIH, with an increased risk of both type 1 and type 2 diabetes mellitus (T1DM and T2DM). These associations reflect a combination of shared autoimmune predisposition, corticosteroid exposure, liver dysfunction, and the metabolic consequences of chronic inflammation. Thus, current guidelines recommending regular blood glucose monitoring in patients with AIH [10,125].

The association between AIH and T1DM is supported by shared genetic and immunological pathways [126,127]. Conversely, the risk of T2DM in AIH is increased by prolonged corticosteroid therapy, which can induce insulin resistance and hyperglycaemia. Concomitant liver cirrhosis and metabolic-associated steatotic liver disease can further contribute [128,129,130].

Although less common, hypoglycaemia may also occur in patients with AIH. In most cases, recurrent episodes are related to excessive doses of antidiabetic medications, particularly insulin or insulin secretagogues [131]. A relative excess of these medications may occur when steroids are tapered or discontinued. A minority of patients may present with spontaneous hypoglycaemia, which requires careful evaluation for rare causes, such as insulinoma or autoimmune insulin antibody syndrome (Hirata’s disease) [132,133].

Considerations and proposed approach: The finding of hyperglycaemia should prompt evaluations, including repeated fasting plasma glucose, oral glucose tolerance test (when appropriate), C-peptide and insulin levels, and HbA1c. If T1DM is suspected, serological tests for T1DM-associated autoantibodies are indicated [134]. In patients with recurring hypoglycaemia, history evaluation should exclude overdosing or inappropriate use (including self-prescription) of anti-diabetic drugs. Spontaneous or unexplained episodes require endocrinology referral and may need supervised fasting tests or imaging to exclude insulin-producing tumours or autoimmune hypoglycaemia [132].

8.2. Thyroid Disorders

Thyroid dysfunction is one of the most common extrahepatic autoimmune conditions associated with AIH, with a reported prevalence significantly higher than in the general population [135]. Both hypothyroidism, usually due to chronic autoimmune thyroiditis (Hashimoto’s disease), and hyperthyroidism, typically resulting from Graves’ disease, occur more frequently in AIH than in the general population [84,136]. AIH guidelines recommend screening thyroid function at diagnosis and at least annually to identify dysthyroidisms before its clinical presentation [10]. If not recognized and treated, thyroid disorders may lead to a worsening in quality of life, having been linked with fatigue, depression, anxiety and poorer quality of sleep [69,137,138].

Considerations and proposed approach: Initial testing should include TSH and free T4; additional markers (free T3, anti-TPO, anti-TSHR antibodies) are reserved in case of dysfunction [10]. As previously stated, thyroid function tests should be performed periodically in asymptomatic AIH patients. However, assessment becomes imperative in the presence of symptoms suggestive of hypothyroidism (e.g., fatigue, unexplained weight gain) or hyperthyroidism (e.g., sleep disturbance, tachycardia) [137,138].

In newly diagnosed thyroid abnormalities, clinicians should consider the potential impact on fatigue and metabolic control and the possibility of overlap with other autoimmune conditions. Management follows standard endocrine practice [138,139]. Attention is needed when prescribing thyreostatic drugs (methimazole or carbimazole), as they can rarely induce agranulocytosis, a complication that may be confused with AIH-related cytopenias [115].

8.3. Bone Metabolism

Low bone mass density occurs in AIH patients more commonly than in the general population, with retrospective series reporting a prevalence of 15% and 43% for osteoporosis and osteopenia respectively [134]. A large study from Lim et al. reported a significantly increased risk of pathological fractures in AIH patients when compared with healthy controls [135]. The risk of low bone mass density is particularly increased in patients with prolonged disease activity, prolonged steroid treatment and liver cirrhosis [140]. Autoimmune comorbidities like autoimmune thyroiditis and CeD may further increase the risk of mineral bone alterations and pathological fractures [141,142]. Often asymptomatic, if not recognized and treated, low bone mass density may lead to reduced autonomy, disability and increased risk of mortality; in this scenario, screening for low bone mass density is paramount [143,144].

Consideration and proposed approach: The actual EASL guidelines do not specifically address the topic of bone health in AIH, limiting their recommendation to an evaluation of bone mass density at the start of steroid treatment, reserving further evaluation to patients with non-specified features of risk for osteoporosis [10]. The topic is more strictly addressed by AASLD guidelines, where follow-up bone mass density evaluation is suggested every 2–3 years in patients with risk features for osteoporosis and pathologic fractures [145].

A reasonable approach should include a periodic (e.g., yearly) evaluation of risk factors for low bone mineral density (BMD), such as lifestyle factors (e.g., smoking), disease activity, and comorbidities. This strategy aims to maximize accuracy in identifying patients warranting longitudinal BMD assessment. Multidimensional fracture risk assessment tools should be employed to determine the need for anti-resorptive treatment (bisphosphonates, denosumab), while optimization of vitamin D levels should be ensured in all AIH patients [144].

In patients with prolonged steroid treatment (e.g., at least 7.5 mg of prednisone daily for at least 3 months), treatment with bisphosphonates, associated with vitamin D and calcium supplementation, is indicated to prevent steroid-induced osteoporosis and pathological fractures [146,147].

Lastly, in patients with low bone mass density in the absence of known risk factors, it could be reasonable to exclude comorbidities associated with elevated bone reabsorption or intestinal malabsorption, such as hyperthyroidism or CeD [30,141].

8.4. Sarcopenia

Sarcopenia is not uncommon in AIH patients of any age, with a significantly higher prevalence in elderly patients [148,149]. Risk factors for sarcopenia include disease activity, prolonged steroid treatment, age, malnutrition and vitamin D deficiency [149,150,151]. In patients with systemic autoimmune comorbidities like rheumatoid arthritis, ongoing systemic inflammation further increases the risk of sarcopenia [152]. The presence of sarcopenia is associated with increased mortality and morbidity as well as poorer quality of life [151].

Considerations and proposed approach: The use of a standardized questionnaire (SARC-F), functional evaluation (handgrip strength, chair-stand test, etc.) or composite tools like the Liver Frailty Index should be included in the standard periodic evaluation of AIH patients, especially where risk factors for sarcopenia are identified [153,154,155]. Instrumental evaluation of body composition could then help in quantifying the muscle mass [153].

When sarcopenia is diagnosed, multidisciplinary evaluation of potential modifiable determinants (e.g., smoking, undiagnosed systemic immune comorbidities) and nutritional support represent the keys in its management [152,156].

Grade of evidence: Evidence regarding the association between AIH and diabetes (both type 1 and type 2), thyroid disorders and low bone mass density is based on various reports and studies, and previous authors described the pathogenetic mechanisms of those associations. Evidence regarding the association with sarcopenia, on the other hand, is based mostly on studies on chronic liver disease, where patients with AIH were only part of the population. EASL 2025 guidelines clearly recommend screening for autoimmune thyroiditis and low bone mass density in all AIH patients; T1DM is cited as a common comorbidity in AIH, with no further specific recommendation, while T2DM is discussed mostly in the context of drug (steroid) toxicity; sarcopenia is not cited.

9. Impact of Extrahepatic Manifestations

The relationship between the course of AIH and extrahepatic manifestations appears unclear, with most studies focusing on autoimmune comorbidities and giving conflicting results [16,157,158]. Slooter et al. published a meta-analysis of 35 studies in 2025, where they did not demonstrate a significant impact of concurrent autoimmune disease on AIH prognosis [158]. Similarly, the impact of fatigue and anxious–depressive symptoms on survival appears to be limited [75,159]. This de-correlation between comorbidity and course of the hepatic disease can lead the physician to underestimate the relevance of extrahepatic manifestations, focusing the management of AIH only on “objective” data like aminotransferases or liver stiffness that are “silent” for the patient.

Extrahepatic comorbidities, however, significantly impact health-related quality of life (HRQoL). In this context, fatigue and anxiety interplay with disease-related parameters, such as duration of steroid treatment (independently from disease course) or perceived “limitation” due to disease, leading to a poor HRQoF [75,159]. The presence of comorbidities further decreases the HRQoF of AIH patients, highlighting how a careful recognition and management of those could represent a key point in improving the quality of life of people living with AIH [160].

10. Perspective

Far from being restricted to the hepatic compartment, AIH unfolds within a broad immunological, metabolic, and systemic context (Figure 2). Several layers contribute to this complexity, including susceptibility to other autoimmune conditions, complications related to a possible evolution toward liver cirrhosis, and drug-related adverse events. Moreover, clinicians increasingly follow AIH patients into ages at which cardiovascular, metabolic, and frailty-related comorbidities become prevalent.

Consequently, extrahepatic symptoms are not ancillary findings. In fact, while their impact on prognosis, especially when considering liver- and AIH-related outcomes (e.g., development of cirrhosis), appears to be minor, they are central determinants of quality of life [5]. Fatigue, arthralgias, anxiety, and gastrointestinal symptoms are among the most impactful and frequently reported complaints, yet they often remain under-investigated or attributed generically to chronic illness. One of the recurring themes across several manifestations is the poor correlation between hepatic activity and symptom burden. Many patients achieve biochemical remission yet continue to experience symptoms that impair daily functioning, social participation, sleep, and mental health.

This gap between laboratory remission and patient-reported outcomes highlights the need to reassess how success is defined in AIH management. While hepatic control remains essential, quality of life, functional status, and symptom relief should be integrated as therapeutic objectives. At present, few structured instruments exist to systematically capture patient-reported outcomes specific to AIH. As a result, extrahepatic symptoms often emerge only when they become severe enough to trigger additional consultations. This situation leads to a difficult patient journey, possibly leading to a fragmented management.

In perspective, priorities emerge for tackling these problems and improving the care of patients with AIH.

First, multidisciplinary models of care should be developed for AIH, similar to those already in place for other autoimmune diseases. Regular collaboration between hepatology, rheumatology, endocrinology, gastroenterology, and haematology would not only streamline diagnostic evaluation but also avoid redundant testing and accelerate targeted treatment.

Second, the systematic assessment of symptom burden should become routine. This may include the use of general quality-of-life tools but ideally should involve instruments specifically adapted to AIH. Developing and validating such patient-reported outcome measures would be welcome.

Third, clinicians should adopt a proactive approach to monitoring and prevention. Early testing for CeD or autoimmune thyroiditis, attention to bone health, and regular screening for diabetes and cytopenia can reduce delays in care.

Finally, research efforts must continue to elucidate the pathophysiology of extrahepatic manifestations and identify potential therapeutic strategies. Key priorities include validating standardized tools to screen for subtle or overlooked manifestations and evaluating how AIH medications influence the natural history of concurrent diseases. Furthermore, a more nuanced understanding of the impact of specific comorbidities—rather than the mere presence of an unspecified autoimmune condition—is required. Ultimately, this will aid in defining optimal management strategies that account for the potential hepatotoxicity of medications used to treat these comorbidities.

11. Limitations

This review acknowledges several limitations. Firstly, as a narrative review, it provides a comprehensive overview but does not adhere to systematic review protocols (e.g., PRISMA), preventing a statistical evaluation of bias. Secondly, the available evidence regarding extrahepatic manifestations in AIH is largely derived from retrospective, small-cohort studies. These study designs are inherently subject to selection bias and often lack adequate control groups. Finally, due to the scarcity of high-quality prospective data, specific recommendations often rely on expert opinion or are extrapolated from guidelines designed for other diseases, highlighting the urgent need for prospective, multicenter studies dedicated specifically to the AIH population.

12. Conclusions

AIH should be considered a systemic, rather than merely a liver, disease given the significant prevalence of extrahepatic manifestations. Those manifestations may reflect associated autoimmune conditions but also arise as adverse effects of treatment.

Often overlooked due to their limited impact on natural history of AIH, extrahepatic manifestations are key determinants of health-related quality of life. Symptoms like fatigue and depression may also lead to reduced adherence to AIH treatment due to the fear of medications (especially steroids) negatively affecting autonomy and quality of life.

The approach to the patients should not be limited to controlling hepatic inflammation and normalizing liver function tests but should extend to the evaluation of global health to recognize extrahepatic manifestations early. In this context, standardized tools to evaluate fatigue, depression, and the risk of sarcopenia should be implemented in the standard evaluation of people living with AIH.

The systemic nature of AIH requires a multidisciplinary strategy for the diagnosis and long-term care of people living with AIH, with the goal of improving patient outcomes, health and quality of life.