Clinical significance and pathogenic mechanisms of fatigue in metabolic dysfunction-associated steatotic liver disease

Abstract

Fatigue is among the most common, albeit underestimated, symptoms in patients with metabolic dysfunction-associated steatotic liver disease. It affects quality of life and reduces the effectiveness of non-pharmacological interventions, thereby negatively affecting the prognosis. This review discusses the clinical problems associated with increased fatigue, explores diagnostic methods, considers key pathogenetic mechanisms of this symptom development (including neuroinflammation, hyperammonemia, mitochondrial and muscle dysfunction, sleep disorders, changes in the composition of gut microbiota), and describes the role of interorgan communication (the liver-brain and gut-brain axes) in the formation of the central link of fatigue. The presented data emphasize the need for an integrated approach to the diagnosis and correction of fatigue, which would include not only the impact on metabolic disorders, but also on neurophysiological and behavioral factors. Early assessment of fatigue and targeted interventions on key pathogenetic links can increase the effectiveness of non-pharmacological intervention (which currently form the basis of metabolic dysfunction-associated steatotic liver disease therapy) and improve the prognosis of patients with this chronic liver disease.

Key Words: Metabolic dysfunction-associated steatotic liver disease; Fatigue; Depression; Inflammation; Neuroinflammation; Neurotoxicity; Mitochondrial dysfunction; Hyperammoniemia; Muscle dysfunction

Core Tip: Fatigue is a frequent but underrecognized symptom in metabolic dysfunction-associated steatotic liver disease (MASLD). This review presents an integrative perspective on fatigue as a systemic manifestation of MASLD, distinct from but overlapping with depression. Central (e.g., neuroinflammation, brain-liver axis dysfunction) and peripheral (e.g., sarcopenia, mitochondrial dysfunction) mechanisms are discussed. Current evidence on exercise, pharmacologic, and behavioral interventions is summarized. Recognizing fatigue as an active factor influencing lifestyle and outcomes may guide new therapeutic strategies and clinical trial designs in MASLD.

INTRODUCTION

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, is currently the leading cause of chronic liver disease (CLD) worldwide[1]. The main treatment method for MASLD is lifestyle modification such as weight loss and increased physical activity. These can slow down the progression of the disease and improve liver function. However, most patients with MASLD experience substantial difficulties not only in starting physical activity but also in maintaining regular physical activity in the long term, which significantly limits the use of exercise as a standard treatment. Numerous studies show that patients with MASLD are, on average, less active than healthy individuals since they lead sedentary lifestyle, taking fewer steps per day. As a result, they exhibit a reduced total daily energy expenditure. Besides that, they seldom change activity, specifically, the transition from sedentary behavior to active behavior, which confirms their sedentary lifestyle[2]. Against the background of a steady increase in the prevalence of MASLD and the lack of effective pharmacotherapy for this CLD, the scientific community continues to actively study the factors hindering lifestyle changes as a method of treating MASLD with a proven favorable effect on the prognosis of patients. One of these factors attracting increasing attention is extreme fatigue.

THE DEFINITION AND CLASSIFICATION OF FATIGUE

Fatigue is a common and debilitating symptom reported by patients with CLD[3], including those with MASLD[4]. Nevertheless, fatigue remains a challenging concept to define due to its multifactorial origins and subjective nature. Several working definitions have been proposed in the literature: Younossi[5] defined fatigue in CLD as “a subjective sensation of physical and/or mental exhaustion that is disproportionate to the level of activity and interferes with usual functioning, not fully explained by comorbid conditions”. According to Wessely and Powell[6], fatigue is “a persistent, overwhelming sense of tiredness, weakness, or exhaustion that results in a reduced capacity for physical and mental work and is not relieved by rest”. In the context of CLD, Swain[7] proposes that fatigue is “a complex and poorly understood symptom involving central mechanisms such as impaired neurotransmission, dysregulated sleep-wake cycles, and altered motivation”. Markowitz and Rabow[8] suggest using the term “fatigue” to describe “a subjective sense of weakness characterized by difficulty initiating any activity, becoming easily fatigued during activities, or mental tiredness involving difficulties with concentration, memory, and emotional stability”. The European Association for the Study of the Liver[9], in the context of cholestatic liver diseases, describes fatigue as “a dominant and often disabling symptom, independent of liver disease severity, believed to result from central rather than peripheral mechanisms”. Finally, Davies et al[10] propose that “fatigue might reflect the body’s resource management strategy in response to chronic stressors, favoring rationing and storage over expenditure”. As one of the manifestations of sickness behavior[7,11], fatigue encompasses a range of symptoms, including lethargy, malaise, lassitude, and exhaustion[7,12,13]. From the perspective of health-related outcomes, fatigue is defined as a feeling of exhaustion or lack of energy accompanied by a reduced capacity to function, specifically, a decreased ability to perform daily activities, including effective work and participation in usual family or social roles[14]. According to Adams and Victor’s Principles of Neurology, fatigue also includes a third component: A subjective sense of tiredness and the mental discomfort experienced by the individual in this abnormal state[15].

Clinicians distinguish two types of fatigue: Physical and pathological. The former is an ordinary adaptive response to physical exertion accompanied by a temporary reduction in muscle performance. As a rule, it is completely reversible after rest and replenishment of energy resources. The latter, on the contrary, is characterized by ongoing exhaustion and energy deficiency, which persists even after adequate sleep or rest, and is often accompanied by cognitive and emotional disorders[16]. From a pathophysiological standpoint, fatigue is categorized into central and peripheral[17]. Central fatigue is associated with disorders of neurotransmitter regulation in such structures of the central nervous system (CNS) as the limbic system and prefrontal cortex, and is manifested by a reduction in the ability to initiate and maintain motivation-dependent activity, as well as by sleep disorders, cognitive dysfunction, anxiety-depressive disorder and social isolation[7,18]. Central fatigue may arise due to an imbalance between the subjective assessment of energy costs and the expected reward from the action[19]. Indeed, MASLD patients frequently experience decreased motivation to change their lifestyle, especially in cases where efforts do not lead to a rapid or apparent improvement in well-being. Consequently, motivational counseling aimed at increasing awareness and forming a steady connection between behavioral changes and improved prognosis is an important non-pharmacological intervention constituent[20].

On the contrary, peripheral fatigue is caused by disorders of neuromuscular transmission, as well as functional changes in skeletal muscles and/or cardiorespiratory system. It is manifested by a decrease in muscle strength and endurance, and reduced ability to maintain repeated or prolonged muscle contractions, often accompanied by metabolic disorders in muscles (including increased lactate formation in muscles with the development of acidosis)[21]. Such changes can be caused by organic lesions and/or functional failure of muscle tissue. Skeletal muscles play an important role in maintaining energy homeostasis; hence, disorders of their structure and function are closely associated with the pathogenesis of MASLD. When discussing fatigue in CLD, the term specifically refers to pathological fatigue, fatigue associated with a serious somatic illness, namely CLD, also known as somatogenic asthenia. Unlike asthenia caused by psychological factors, somatogenic asthenia is directly attributable to an identifiable physical condition or disease[22]. This type of fatigue often exhibits poor responsiveness to treatments targeting somatic causes, such as anemia, hypothyroidism, or infectious diseases[16].

IS FATIGUE A DISTINCT PATHOLOGIC ENTITY OR MERELY A SYMPTOM OF DEPRESSION?

It is crucial to distinguish pathological fatigue from depressive disorders, despite their close association and overlapping pathogenic mechanisms and clinical features, including apathy, reduced physical and mental activity, and disturbances in sleep, concentration, and motivation[23,24]. Fatigue and depression are separate constructs with distinct diagnostic criteria and treatment strategies. Fatigue is a complex, multidimensional symptom encompassing: (1) Physical manifestations, such as reduced activity, low energy, diminished physical endurance, tiredness, generalized weakness, sleepiness, and increased exertion required for physical tasks; (2) Cognitive impairments, including reduced concentration, attentional deficits, decreased mental stamina, and slowed processing speed; and (3) Emotional aspects, such as diminished motivation or initiative, loss of interest, feelings of being overwhelmed, boredom, effort aversion, and a sense of lowness[25]. In CLD, fatigue predominantly manifests as physical symptoms, with patients frequently reporting persistent energy depletion or exhaustion unalleviated by rest. Unlike depressive disorders, CLD-related fatigue typically lacks core affective or cognitive symptoms, such as persistent sadness, excessive guilt or feelings of worthlessness, hopelessness, or suicidal ideation. Furthermore, while patients with CLD-related fatigue may retain interest in activities, their engagement is limited by physical exhaustion. In contrast, depression is characterized by more pervasive anhedonia, defined as a pronounced loss of interest or pleasure.

According to the diagnostic criteria of the International Classification of Diseases, Tenth Revision, symptoms of depressive disorders are categorized into: (1) Main symptoms; (2) Additional symptoms; and (3) Symptoms of the “somatic” syndrome. Fatigue or loss of energy is considered one of the main symptoms of depressive disorder; however, the presence of fatigue in a patient with CLD does not necessarily indicate depression. Indeed, the specificity of fatigue for diagnosing depression does not exceed 50%[26]. According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria, diagnosing depression requires: (1) The presence of at least five depressive symptoms persisting for most of the day, nearly every day, for a minimum of two weeks; and (2) At least one of these symptoms must be either a depressed mood or a markedly diminished interest or pleasure in nearly all activities[27]. Thus, these diagnostic criteria serve as a key distinguishing feature of depression, enabling differentiation from fatigue (Figure 1).

Figure 1 Differentiating fatigue from depression: Major symptoms, commonly used diagnostic tools, and key pathogenic mechanisms. EQ-5D: European Quality of Life 5-Dimension 5-Level Questionnaire; HPA: Hypothalamic-pituitary-adrenal; CLD: Chronic liver disease; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; CRP: C-reactive protein.

Ultimately, a thorough clinical interview, combined with validated questionnaires and consideration of the patient’s broader psychosocial context, is essential for distinguishing fatigue related to CLD from depressive disorders and for guiding appropriate management strategies. Moreover, fatigue may be triggered or exacerbated by several classes of antidepressants, particularly tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors[25]. In contrast, bupropion use is associated with significantly lower levels of fatigue compared to selective serotonin reuptake inhibitors[28]. Nevertheless, timely identification and treatment of depressive symptoms can reduce the subjective severity of fatigue and enhance patients’ motivation to adopt lifestyle modifications[15,29]. The potential association between fatigue and depression during the natural course of chronic diseases, including MASLD, is illustrated in Figure 2. It is important to note that some publications cited in the following sections report findings from studies involving patients diagnosed with both fatigue and depression. However, each condition was identified using validated tools, scales, and questionnaires, thereby enabling confirmation of clinically significant fatigue and/or depression in individual patients. Detailed information on the original studies cited in this review is provided in Table 1[3,23,24,30-36].

Figure 2 The relationship between fatigue and depression. In the context of chronic liver disease, fatigue and depression are generally regarded as distinct pathological entities. However, the persistent feelings of tiredness, general weakness, and sleepiness characteristic of fatigue can precipitate the development of depression. In such cases, a patient experiencing fatigue should also exhibit either a depressed mood or markedly diminished interest or pleasure in most activities for a minimum duration of two weeks. Conversely, certain medications, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors, can independently induce fatigue. Therefore, in patients with metabolic dysfunction-associated steatotic liver disease and depression, fatigue may be caused or exacerbated by these treatments. Under these circumstances, fatigue often manifests as a complex, multidimensional condition involving not only physical but also cognitive and emotional components. TCAs: Tricyclic antidepressants; SSRIs: Selective serotonin reuptake inhibitors; SNRIs: Serotonin-norepinephrine reuptake inhibitors.

Table 1 Original studies on fatigue in metabolic dysfunction-associated steatotic liver disease cited in the present review.

Ref.	Study population	Objective	Assessed symptoms	Assessment tool	Key findings
Sheptulina et al[23]	Patients with MASLD [n = 108; median age 49.5 years (IQR: 41.3-58.8); 63% female]	To analyze the prevalence of sarcopenia in patients with MASLD and identify potential influencing factors	Fatigue	FAS	Depression (OR = 1.25; 95%CI: 1.02-1.53; P = 0.035) and clinically significant fatigue (OR = 1.14; 95%CI: 1.04-1.26; P = 0.008) were independently associated with sarcopenia in patients with MASLD
			Depression, anxiety	HADS
Golubeva et al[24]	Patients with MASLD [n = 95; median age 50 years (IQR: 43-58); 62.1% female] and controls [n = 37; median age 45.5 years (IQR: 36-51); 78.4% female]	To evaluate quality of life in MASLD patients compared to controls by assessing the prevalence of fatigue, depression, and anxiety	Fatigue	FAS	Impaired quality of life was significantly associated with fatigue (FAS score ≥ 22; P < 0.001) and depression (HADS-depression ≥ 8; P < 0.001)
			Depression, anxiety	HADS
Younossi et al[30]	Patients with MASLD from the global NAFLD/NASH registry encompassing 18 countries (n = 5691; age: 50.9 ± 13 years; 54.2% female)	To assess clinical presentation and PROs among MASLD patients across different countries	PROs	CLDQ-NASH (six domains: Abdominal symptoms, activity/energy, emotional health, fatigue, systemic symptoms, and worry)	CLDQ-NASH and FACIT-F PRO scores were significantly lower in patients with MASLD compared to the general population (all P < 0.001). Multivariate analysis adjusted for enrollment region identified younger age, female sex, and nonhepatic comorbidities including fatigue (P < 0.01) as independent predictors of lower PRO scores. Improvement in fatigue scores over time was associated with substantial PRO improvement. Worsening fatigue during follow-up was associated with higher baseline fatigue score, female sex (OR = 1.8; 95%CI: 1.1-2.9), history of depression (OR = 2.5; 95%CI: 1.3-5.0), congestive heart failure (OR = 9.4; 95%CI: 2.2-40.5), and an increase in BMI (OR = 1.17; 95%CI: 1.04-1.31) per 1 kg/m² from baseline (all P < 0.05)
			Fatigue	FACIT-F
			Work productivity	Work Productivity and Activity Impairment Specific Health Problem
Glass et al[31]	Patients with MASLD (n = 94; age: 58 ± 11 years; 43% female)	To characterize baseline physical activity and sedentary behavior, self-perceived fitness, exercise limitations, potential strategies to increase physical activity, and perceptions of exercise as a foundational treatment for MASLD	Limitations to exercise, including pain, reduced physical ability, fatigue, discomfort, lack of energy, and/or shortness of breath	A four-page survey comprising four sections: (1) Weekly physical activity and sedentary behavior; (2) Barriers, limitations, and potential solutions to exercise; (3) Perception of fitness; and (4) Perception of exercise as a foundational treatment for MASLD	Overall, 72% of patients with MASLD reported exercise limitations, with the most common reasons being lack of energy (62%), fatigue (61%), prior or current injury (50%), and shortness of breath (49%)
Funuyet-Salas et al[32]	Patients with MASLD (n = 737): (1) Participants from Spain (HEPAmet registry; n = 513; age: 55.04 ± 11.83 years; 41.1% female); and (2) Participants from the United Kingdom (European NAFLD registry; n = 224; age: 55.31 ± 12.34 years; 35.3% female)	Three primary objectives: (1) To compare HRQoL in MASLD patients by geographic region (Spain vs United Kingdom) and liver disease severity (absence or presence of MASH and fibrosis stage); (2) To identify histological and biopsychosocial predictors of HRQoL in Spanish and United Kingdom cohorts; and (3) To analyze biopsychosocial variables that mediate or moderate HRQoL predictive models	HRQoL, including fatigue	Chronic Liver Disease Questionnaire (CLDQ; six domains: Abdominal symptoms, activity, emotional function, fatigue, systemic symptoms, and worry)	Participants with severe fibrosis reported greater fatigue, systemic symptoms, and worry, as well as lower HRQoL compared to those with none or mild fibrosis, regardless of geographic origin. Female sex was associated with worse emotional function, higher BMI, and more severe fatigue, which predicted lower HRQoL
Younossi et al[33]	Patients with MASH and bridging fibrosis or compensated cirrhosis (n = 1679; age: 58 ± 9 years; 60% were females)	To investigate the association of fatigue with the risk of liver-related events in patients with MASH and bridging fibrosis or compensated cirrhosis	Fatigue	CLDQ-NASH, fatigue score	The presence of significant fatigue was associated with a higher risk of adverse clinical events in patients with MASH and advanced fibrosis or compensated cirrhosis. This suggests that in addition to clinical parameters, the presence of clinically significant fatigue can identify MASH patients at risk for adverse events. The improvement in fatigue may be used as a surrogate endpoint for the assessment of treatment efficacy in this category of patients
Younossi et al[34]	NHANES 2005-2010 cohort (n = 5429; 37.6% with MASLD; mean age 47.1 years; 50.3% female); NHANES 2017-2018 cohort (n = 3830; mean age 48.3 years; 51.4% female)	To determine the prevalence of fatigue and its association with all-cause mortality among patients with MASLD	Fatigue	Patient Health Questionnaire-9	MASLD patients with fatigue experienced a 2.3-fold higher mortality risk than those without fatigue (hazard ratio = 2.31; 95%CI: 1.37-3.89; P = 0.002). Depression (OR = 11.52; 95%CI: 4.45-29.80; P < 0.0001), cardiovascular disease (OR = 3.41; 95%CI: 1.02-11.34; P = 0.0462), and sleep disturbance (OR = 2.00; 95%CI: 1.00-3.98; P = 0.0491) were independently associated with fatigue
			Depression	Patient Health Questionnaire-2
Golabi et al[35]	NHANES 2001-2011 cohort (n = 9661; patients with MASLD: n = 3333; age: 51 ± 0.36 years; 42.2% female)	To assess the impact of MASLD on HRQoL compared to patients with chronic hepatitis C and those without liver disease	Quality of life	HRQoL-4	MASLD impairs HRQoL. After adjustment for age, sex, race, and BMI, patients with MASLD were 18%-20% more likely to report days of poor physical health or inability to perform daily activities (P < 0.0001)
Newton et al[3]	Patients with MASLD (n = 36; age: 55 ± 11 years; 50% female)	To quantify fatigue in MASLD, determine whether perceived fatigue reflects impaired physical function, and explore potential causes	Fatigue	Fatigue Impact Scale	Fatigue was markedly higher in patients with MASLD than in controls and was associated with impaired physical function and significant daytime sleepiness
Du et al[36]	Patients with MASLD (n = 36; age: 55 ± 11 years; 50% female)	To determine the prevalence of fatigue and evaluate factors associated with fatigue in patients with MASLD	Fatigue	Fatigue Severity Scale	The authors found that 51.1% of patients with MASLD experienced fatigue. Logistic regression analysis identified anxiety, habitual sleep efficiency, and sleep disorders as significant predictors of fatigue
			Depression, anxiety	HADS
			Sleep quality	Pittsburgh Sleep Quality Index

MASLD: Metabolic dysfunction-associated steatotic liver disease; IQR: Interquartile range; FAS: Fatigue Assessment Scale; HADS: Hospital Anxiety and Depression Scale; OR: Odds ratio; CI: Confidence interval; NAFLD/NASH: Non-alcoholic fatty liver disease/non-alcoholic steatohepatitis; PROs: Patient-reported outcomes; CLDQ-NASH: Chronic liver disease questionnaire for nonalcoholic steatohepatitis; FACIT-F: Functional Assessment of Chronic Illness Therapy-Fatigue; BMI: Body mass index; HRQoL: Health-related quality of life; MASH: Metabolic dysfunction-associated steatohepatitis; CLDQ: Chronic liver disease questionnaire; NHANES: National Health and Nutrition Examination Survey.

PREVALENCE AND CLINICAL SIGNIFICANCE OF FATIGUE IN MASLD

The prevalence of fatigue among patients with CLD varies widely, ranging from 45% to 85%, depending on research methodology, disease etiology, and stage[37,38]. Specifically, fatigue in MASLD represents one of the most common and clinically significant symptoms, with severity classified as severe in 36%-49% of patients[23,24,30]. An international study analyzing data from 18 countries demonstrated that fatigue levels in 5691 patients with MASLD were statistically significantly higher than those observed in the general population. In this global registry, fatigue was associated with a broad spectrum of metabolic and psychological comorbidities, including type 2 diabetes, hyperlipidemia, anxiety, and depression[30].

Recent studies further corroborate a close association between fatigue in MASLD and systemic comorbidities, particularly type 2 diabetes, cardiovascular disease, and renal disorders. In a prospective study by Mostafa et al[39], fatigue was reported in 67.8% of patients with MASLD compared to 21% of controls (P < 0.001). Fatigue was significantly associated with diabetes, hypertension, steatosis, fibrosis, and Fibrosis-4 scores and remained an independent predictor in multivariate analysis.

Similarly, Hashida et al[40] demonstrated that higher FibroScan-aspartate aminotransferase scores, a noninvasive marker of liver fibrosis, were directly associated with fatigue severity, as measured by the CLD Questionnaire-Non-Alcoholic Fatty Liver Disease version. Importantly, estimated glomerular filtration rate also emerged as a factor interacting with the fatigue domain, implicating renal dysfunction in symptom exacerbation.

In the study by Newton et al[41], patients with histologically confirmed MASLD exhibited a significantly higher autonomic symptom burden and orthostatic intolerance, both strongly correlated with fatigue severity (P = 0.008), indicating that autonomic cardiovascular dysregulation contributes to the fatigue phenotype. Furthermore, Sandireddy et al[42], in a systematic review, emphasized that MASLD contributes to multi-organ dysfunction, particularly affecting the heart, skeletal muscle, and kidneys, via inflammatory and lipotoxic mechanisms, explicitly recognizing fatigue as a key systemic symptom arising from these interorgan interactions. Lastly, focusing on pediatric MASLD, Mouzaki et al[43] highlighted that renal impairment is prevalent in this population and is linked to fibrosis severity, suggesting that early multisystem involvement may contribute to clinical fatigue even in younger patients. Collectively, these studies confirm that fatigue in MASLD is strongly associated with metabolic, renal, and cardiovascular comorbidities and should be recognized as a clinical marker of systemic dysfunction.

Fatigue substantially limits daily routine activities, including physical, professional, family, and social spheres of life[44]. For instance, in the study by Glass et al[31], 72% of patients with a histologically confirmed diagnosis of MASLD reported limited physical activity due to lack of energy (62%) or increased fatigue (61%). It is worth noting that these limitations were pronounced in advanced stages (F3-F4) of metabolic dysfunction-associated steatohepatitis (MASH).

The term fatigue applies to a wide range of subjective sensations, including declined energy, difficulty initiating and maintaining activity, as well as cognitive exhaustion associated with impaired concentration, memory, and emotional stability[17]. Its severity is affected by numerous individual factors, such as age, gender, level of physical fitness, presence of concomitant pathology, motivational and volitional features, as well as the effectiveness of recovery processes[17]. According to the study by Funuyet-Salas et al[32], conducted on the population of British and Spanish patients with MASLD, female gender and higher body mass index (BMI) are predictors of more severe fatigue. The data obtained by Funuyet-Salas et al[32] matched the results of a one-year follow-up study by Younossi et al[5] on patients with MASLD: An increase in BMI was associated with extreme fatigue, while a reduction in BMI was accompanied by decreased fatigue[30].

Despite the high prevalence of fatigue, there are serious misconceptions about effective strategies to cope with it. For example, many patients mistakenly believe that physical activity can aggravate fatigue; consequently, they prefer passive rest, including prolonged sleep time as the main form of self-care. This behavior reveals poor understanding of the physical activity role as a proven method for reducing fatigue[45]. The importance of fatigue in CLD is also recognized at the international level. At the annual congress of the European Association for the Study of the Liver, experts pointed out the importance of timely detection of fatigue in patients with MASLD, given its impact on both quality of life (QoL) and clinical outcomes of the disease[46]. In patients with advanced stages of MASH (F3-F4), high levels of fatigue are associated with an increased risk of disease progression to cirrhosis and the development of liver decompensation[33]. Furthermore, Cox regression analysis demonstrated that the presence of fatigue resulted in a 2.3-fold risk of death in MASLD patients vs those who did not have this symptom (relative risk = 2.31; 95% confidence interval: 1.37-3.89; P = 0.002)[34].

FATIGUE VS QOL IN MASLD

QoL is considered an important indicator of the CLD patient’s condition. Validated scales and questionnaires are employed to assess it, and many of those include a section measuring fatigue. According to numerous studies, patients with MASLD exhibit a substantial reduction in QoL as compared with healthy controls, as well as with patients suffering from other CLDs. Furthermore, fatigue contributes much to this reduction[30,47,48]. A study involving 9661 participants compared QoL in patients with MASLD with a control group and patients with chronic hepatitis C. After adjusting for age, gender, and BMI, it was discovered that patients with MASLD were 18%-20% more likely to report days with poor physical well-being that interfered with a proper performance of daily tasks[35]. A 2018 systematic review focusing on QoL assessment in MASLD patients and including data from nearly 5000 patients showed that the QoL decline in this population was primarily due to deterioration in the physical component of health. At the same time, the severity of fatigue was negatively associated with all QoL components[47]. It is noteworthy that a decrease in fatigue leads to a substantial improvement in patients’ QoL[30]. A larger systematic review including 25 studies assessing QoL in patients with MASH showed a progressive deterioration in both the physical and mental components of health as the disease progresses. The most common symptoms were extreme fatigue and weakness, sleep disorders including obstructive sleep apnea (OSA) syndrome, daytime sleepiness, anxiety, and depressive disorders[23].

METHODS FOR DIAGNOSING INCREASED FATIGUE

Assessing fatigue presents a complex clinical challenge, compounded by the subjective nature of the symptom and the lack of a direct, objective measurement method. To date, more than 250 measurement scales have been described for use in clinical practice and scientific research; however, none offers optimal specificity, sensitivity, and a comprehensive evaluation of fatigue[46]. When selecting a fatigue measurement tool, the primary consideration should be the specific fatigue characteristics requiring assessment. Different instruments emphasize various dimensions, including severity, duration, and impact on daily functioning. For screening purposes, a brief scale may suffice, whereas comprehensive evaluation necessitates a multidimensional assessment addressing affective, cognitive, somatic, and mental components. The choice of instrument should balance the depth of information obtained with respondent burden and practical constraints.

Table 2 summarizes key instruments used to diagnose and evaluate fatigue severity, including those applicable to patients with CLD. All aforementioned instruments vary in terms of practicality and psychometric robustness[49-62]. The Fatigue Assessment Scale (FAS) and fatigue severity scale are the most commonly employed in CLD settings due to their favorable balance of brevity and sensitivity. Notably, none of these instruments has been specifically validated in cohorts with MASLD. Furthermore, to date, no studies have directly compared the diagnostic accuracy of these tools across different fibrosis stages in patients with CLD.

Table 2 Key instruments used to diagnose and evaluate fatigue severity, including those applicable to patients with chronic liver disease.

Ref.	Scale	Domains assessed	Type of assessment	Time lag	Reliability (Cronbach's α)	Strengths and limitations	Most commonly used in	Use for fatigue assessment in chronic liver disease
[49,50]	Fatigue Assessment Scale	Severity, physical and mental fatigue	10 items (5 physical fatigue, 5 mental fatigue); 5-point Likert scale; total score 10-50; ≥ 22 indicates clinically significant fatigue	How a person usually feels	0.90	Differentiates between depression and fatigue; available in 20 languages	General population; used in 26 diseases/conditions including stroke, neurologic disorders, rheumatoid arthritis, idiopathic pulmonary fibrosis; frequently used in sarcoidosis	MASLD
[51]	Fatigue Impact Scale	Cognitive, physical, emotional components of fatigue	40 items; 5-point Likert scale; higher scores indicate more severe fatigue	Past month	0.87; test–retest reliability r = 0.71-0.83	Adapted and validated in 30 languages and many patient groups	General population; wide range of conditions including infectious diseases; target populations: Neurological disorders	PBC; chronic hepatitis B and C
[52-54]	Fatigue Severity Scale	Severity and impact of fatigue on activities and lifestyle	9 items; 7-point Likert scale; total score is mean of items; Fatigue Severity Scale ≥ 4 indicates clinically significant fatigue	Past week	0.93-0.95; high test-retest reliability	Good psychometric performance; cannot differentiate central vs peripheral fatigue; difficulty identifying peripheral fatigue especially muscle dysfunction	General population; wide range of conditions; target populations: Neurological and rheumatological disorders	Chronic hepatitis C; liver cirrhosis
[55-57]	Functional Assessment of Chronic Illness Therapy-Fatigue	Physical, social/family, emotional, functional well-being, fatigue	13 items; 5-point Likert scale; higher scores mean less fatigue	Past week	0.95; good internal consistency and convergent validity	Validated internationally; scores comparable to population norms; requires permission for use	General population; target populations: Cancer patients	Chronic hepatitis C, chronic hepatitis B, MASLD
[58-60]	Multidimensional fatigue inventory	Five subscales: General fatigue, physical fatigue, decreased activity, reduced motivation, mental fatigue	20 items; 5-point Likert scale; total score sum of subscales (20-100); higher scores indicate more severe fatigue	Previous days	0.83-0.94; test-retest reliability r = 0.76	Focuses on cognitive appraisal rather than objective fatigue impact; classification of fatigue subscales is debatable	General population; wide range of conditions	MASLD
[61,62]	Visual analogue scale of fatigue	Energy, fatigue	10 cm line from zero (no fatigue) to extreme fatigue; patient marks current fatigue level	Current level	0.94-0.96; strongly correlated with PHQ-9 total score (r = 0.61) and individual items (r = 0.19-0.67)	Validated in adults 18-55 years; poor differentiation between fatigue and drowsiness; patients may hesitate to use extreme scale values	General population	Chronic hepatitis C, chronic hepatitis B, MASLD, PBC, autoimmune hepatitis, nodular regenerative hyperplasia, liver cirrhosis

MASLD: Metabolic dysfunction-associated steatotic liver disease; PBC: Primary biliary cholangitis; PHQ-9: Patient Health Questionnaire-9.

However, patients with MASLD-related cirrhosis report significantly lower fatigue scores, as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue total score and the emotional, functional, and fatigue domains of the CLD Questionnaire-Non-Alcoholic Fatty Liver Disease version, compared to patients with MASLD without cirrhosis (45% vs 38%; all P < 0.05)[30]. Conversely, effective treatment of CLD, such as chronic hepatitis C, MASH, autoimmune hepatitis, and primary biliary cholangitis (PBC), may improve patient-reported outcomes, including health-related QoL and fatigue[63].

Importantly, when applying these fatigue assessment tools, changes in scores should be interpreted not only for statistical significance but also for clinical relevance. This consideration is addressed through the concept of the minimally clinically important difference, the smallest change in score perceived by patients as beneficial or meaningful. Although minimally clinically important difference values vary by instrument and disease context, a general benchmark suggests that a 4%-5% change in patient-reported outcome scores can be considered clinically meaningful in CLD, including MASLD[64].

PATHOPHYSIOLOGICAL MECHANISMS OF FATIGUE IN MASLD

The pathogenesis of fatigue in MASLD is a complex multilevel process. The key pathophysiological links involved in the development of fatigue are presented in Figure 3 and discussed in more details below.

Figure 3 Pathophysiological mechanisms of fatigue in metabolic dysfunction-associated steatotic liver disease. The pathogenesis of fatigue in metabolic dysfunction-associated steatotic liver disease is complex and may involve the following factors: (1) Dysfunction of the liver-brain axis and neuroinflammation; (2) Sleep disorders, particularly obstructive sleep apnea and daytime somnolence; (3) Skeletal muscle disorders, such as sarcopenia and myosteatosis; and (4) Hyperammonemia and urea cycle dysregulation, which may be at least partially attributed to mitochondrial dysfunction and disturbances in gut microbiota composition and function. These mechanisms contribute to systemic and neuroinflammation, alter neurotransmitter synthesis and balance, induce neurotoxicity, and impair systemic energy metabolism. All the aforementioned pathological processes may be interrelated, for example, sarcopenia may contribute to or exacerbate hyperammonemia, thus highlighting the multifactorial nature of fatigue in metabolic dysfunction-associated steatotic liver disease. NF-κB: Nuclear factor-κB; JAK/STAT: Janus kinase/signal transducers and activators of transcription; MyD88: Myeloid differentiation primary response protein 88; TLR-4: Toll-like receptor 4; ROS: Reactive oxygen species; 4-HNE: 4-hydroxynonenal; FGF-21: Fibroblast growth factor-21; MASLD: Metabolic dysfunction-associated steatotic liver disease; LPS: Lipopolysaccharide; SCFA: Short-chain fatty acid.

Liver-brain axis dysfunction and neuroinflammation

One of the key pathogenetic mechanisms for the development of central fatigue in MASLD is a disorder of the liver-brain axis, which affects intersystem communication between peripheral organs and the CNS. Damage to hepatocytes accompanied by systemic inflammation and metabolic disorders initiates a cascade of neuroinflammatory processes including activation of microglia and disruption of neurotransmitter regulation (i.e., the process of transmitting signals between cells of the nervous system, primarily neurons). These changes affect major brain structures involved in the regulation of motivation and reward (the mesolimbic system, basal ganglia, and prefrontal cortex), which leads to impaired motivational and volitional actions and a decline in cognitive functions[18]. Specific molecular mediators and signaling pathways underlying liver-brain axis dysfunction in MASLD include nuclear factor-κB and the Janus kinase/signal transducers and activators of transcription pathways, both of which play pivotal roles in mediating systemic and neuroinflammation[65,66]. Another critical molecular cascade implicated is the kynurenine pathway. Systemic inflammation upregulates indoleamine 2,3-dioxygenase activity, shifting tryptophan metabolism away from serotonin synthesis toward kynurenine production. This metabolic shift results in the accumulation of neurotoxic metabolites, including quinolinic acid and 3-hydroxykynurenine, which promote neuroinflammation and contribute to fatigue and depression[67,68]. Additionally, activation of toll-like receptor 4 on hepatic Kupffer cells by bacterial endotoxins, arising from gut dysbiosis and increased intestinal permeability, initiates myeloid differentiation primary response protein 88-dependent signaling. This cascade leads to the production of proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, which signal to the brain via both humoral and neural pathways[69,70].

The neuronal pathway is implemented through the activation of vagal afferent fibers, which transmit inflammatory signals from peripheral organs to the brain. The humoral pathway involves the transport of cytokines through the systemic bloodstream with their subsequent penetration through the blood-brain barrier (BBB) into brain tissue. In both cases, activated microglia triggers local neuroinflammation accompanied by the secretion of proinflammatory cytokines, chemokines, and reactive oxygen species (ROS), which disrupts synaptic transmission and aggravates behavioral changes, including fatigue[19,71]. For instance, Zou et al[72] demonstrated that ROS and lipid peroxidation products, including 4-hydroxynonenal, generated during hepatic lipotoxicity, can cross the BBB, impair mitochondrial respiration, and activate glial cells. Once within the CNS, 4-hydroxynonenal disrupts mitochondrial electron transport chains, decreases ATP production, and promotes further ROS generation, thereby establishing a vicious cycle of neurotoxicity and energy failure[73,74]. These reactive species also activate microglia and astrocytes, triggering the release of proinflammatory cytokines and perpetuating chronic neuroinflammation[75].

Neuroinflammation affects primarily the dopaminergic and serotonergic systems by reducing the bioavailability of these neurotransmitters through inhibiting their synthesis and increasing the activity of transporters, as well as modulating the activity of enzymes responsible for their metabolism. Besides that, inflammation activates the hypothalamic-pituitary-adrenal axis, which leads to an increase in the levels of cortisol. The latter is a hormone that can intensify the feeling of fatigue and anxiety. These neurobiological changes are manifested by a decline in motivation, energy, and cognitive impairment, which are the key components of central fatigue[16,17,19].

Immune cells activated in response to inflammation in liver tissue (in particular, monocytes and macrophages) can penetrate the CNS, thereby enhancing local production of proinflammatory factors and contributing to further impairment of neuronal function. This is confirmed by morphofunctional changes in brain structures participating in the regulation of mood, activity, and motivation, including reduced synaptic density, neurodegeneration, and severe oxidative stress[76].

An additional contribution to the development of central fatigue is made by impaired energy metabolism. The liver plays a key role in the regulation of glucose metabolism and the synthesis of neurotransmitter precursors (such as glucose, amino acids, and B vitamins). When the liver is dysfunctional, there is a deficiency of the essential substrates for the synthesis of neurotransmitters, which disrupts neurotransmission and energy supply to neurons, thereby aggravating the clinical manifestations of fatigue. Additionally, hepatokines such as fibroblast growth factor 21, released from stressed hepatocytes, modulate hypothalamic circuits that regulate satiety, energy expenditure, and arousal. Chronic overproduction of fibroblast growth factor 21 in MASLD may induce hypothalamic desensitization, thereby contributing to central fatigue and diminished motivation[77]. These oxidative and inflammatory insults impair synaptic plasticity and neuronal viability, further contributing to cognitive decline and central fatigue in MASLD.

Sleep disorders and OSA

Sleep disorders are an important link in the pathogenesis of fatigue in MASLD. They affect neurophysiological processes both directly and indirectly, via metabolic and behavioral consequences. Some authors believe that the subjective sensation of fatigue in patients with MASLD is more associated with daytime sleepiness and reduced physical activity than with the histological activity of the disease[3,78]. Indeed, some FASs measure daytime sleepiness, and cognitive fatigue often correlates with sleep disorders. The latter (including its fragmentation, reduced duration, and quality) and OSA are common in MASLD. In addition to mutual metabolic risk factors such as obesity and insulin resistance, there is emerging evidence indicating a possible direct pathophysiological link between sleep-disordered breathing and liver damage, e.g., the severity of OSA directly correlates with the severity of inflammation, the degree of ballooning degeneration and fibrosis, which is confirmed by the results of histological, biochemical, and imaging studies[78-80].

According to a large population study (n = 10541), the frequency of OSA in patients with MASLD reaches 64.7%, which is much higher than its occurrence in the general population[81]. A 2015 study by Bernsmeier et al[82] demonstrated a significant reduction in sleep quality in MASLD patients compared with healthy individuals: The mean score of the Pittsburgh Sleep Quality Index was 8.2 vs 4.7, respectively (P = 0.0074). At the same time, daytime sleepiness assessed using the Epworth scale directly correlated with transaminase levels and the stage of fibrosis. According to the study by Du et al[36], sleep disorders are meaningful predictors of fatigue in MASLD.

The key manifestations of OSA (intermittent hypoxia, sleep fragmentation and poor sleep quality) trigger a cascade of pathological responses, including activation of the sympathetic nervous system, along with increased oxidative stress, inflammation, and lipogenesis. Under conditions of intermittent hypoxia, hypoxia-inducible factor is activated, which promotes the production of proinflammatory cytokines, endothelial dysfunction and impaired energy metabolism[83]. These changes launch systemic inflammation and metabolic disorders underlying MASLD and may also contribute to the development of fatigue.

Sarcopenia may be an additional factor that aggravates sleep disorders. A study using Pittsburgh Sleep Quality Index among patients with CLD revealed that a reduction in muscle strength was associated with a poor sleep quality[84]. This finding confirms the close relationship between the structural and functional state of skeletal muscles, sleep disorders, and the development of fatigue. Hence, sleep disorders and daytime sleepiness can negatively affect key aspects of lifestyle: Diminish the ability to perform physical exercise, disrupt eating behavior, worsen mood, and reduce motivation for lifestyle modification[3,85].

Sarcopenia and myosteatosis

Sarcopenia characterized by reduced muscle mass and strength is common among patients with MASLD[21]. Results of regression analysis showed that clinically significant fatigue is an independent factor associated with the presence of sarcopenia: Odds ratio 1.14; 95% confidence interval: 1.035-1.259; P = 0.008[23]. In this case, the qualitative composition of muscle tissue is affected rather than its quantitative composition alone. It was shown that patients with MASLD demonstrate increased echogenicity of the rectus femoris muscle during ultrasound examination, which may indicate the presence of myosteatosis (excess intramuscular fat reducing the functional activity of muscles)[86]. Thus, structural and functional changes in skeletal muscles in MASLD, including sarcopenia and myosteatosis, may contribute to limited physical activity, progression of peripheral fatigue, and increased subjective sensation of fatigue.

Physical discomfort during and after exercise is the most common barrier limiting participation in regular physical activity in MASLD patients. Fatigue that occurs during and after exercise is often perceived as an undefeatable obstacle, reducing motivation to continue physical exercise. This is likely due to the low level of cardiorespiratory fitness and a higher subjectively perceived exertion typical for this population[87]. In their study, Weinstein et al[88] showed that patients with MASLD consider physical activity more tiresome than do the patients with chronic hepatitis C when performing exercises of similar intensity. Increased perceived exertion combined with severe post-workout fatigue may interfere with the achievement of therapeutic goals in terms of lifestyle modification.

Hyperammonemia and impaired ureagenesis

One of the characteristic metabolic disorders at the precirrhotic stage of MASLD is the failure of ureagenesis, the main mechanism for the elimination of ammonia. It is believed that the associated hyperammonemia may contribute to the development of central fatigue. Both in experimental in vivo models and in some clinical studies, it has been noted that already at the stage of simple steatosis, the ability to produce urea declines, along with the suppressed expression and activity of enzymes of the ornithine cycle. These disorders lead to the accumulation of ammonia and the development of hyperammonemia even before the formation of pronounced fibrosis, which emphasizes the importance of this metabolic defect in the early stages of the disease[89]. An additional factor that increases hyperammonemia is sarcopenia. It is widespread in MASLD. A reduction in the mass and functional activity of skeletal muscles leads to a weakening of the alternative pathway for ammonia detoxification via glutamine synthetase localized in myocytes[90].

Some studies indicate that even subclinical hyperammonemia negatively affects cognitive functions and contributes to the formation of a subjective sensation of mental fatigue. This is manifested by a diminished concentration, memory loss, and declined cognitive productivity, which corresponds to the symptom complex of central fatigue[90]. It is hypothesized that chronic low-grade systemic inflammation, characteristic of MASLD, can boost the neurotoxic effect of ammonia by acting synergistically with it. Such a combination of metabolic and inflammatory factors can trigger a cascade of disorders in the nervous system even at the preclinical stage of the disease, thereby contributing to cognitive dysfunction formation[91].

Mitochondrial dysfunction

Mitochondrial disorders represent a critical link between energy metabolism abnormalities and the development of fatigue in MASLD. Beyond these disorders, mitochondrial dysfunction plays a pivotal role in the pathogenesis of fatigue in liver diseases more broadly. It is characterized by impaired oxidative phosphorylation, diminished synthesis of ATP, the universal cellular energy currency, increased production of ROS, and systemic energy deficits. Collectively, these features suggest a plausible biological connection between MASLD and fatigue[92]. In MASLD, mitochondrial damage is accompanied by disorders of fatty acid metabolism, which is demonstrated, in particular, by changes in the levels of carnitine and its derivatives required for the transport of fatty acids into the mitochondria[93]. The accumulation of toxic lipid metabolites, such as acylcarnitines, aggravates oxidative stress and damage to mitochondrial membranes, thereby disrupting their structural and functional integrity. Additionally, reduced levels of coenzyme Q10, an important component of the mitochondrial respiratory chain and antioxidant system, exacerbate energy deficit and increase cellular vulnerability to free radical damage[92]. In conditions of chronic inflammation and impaired liver detoxification function, mitochondrial disorders are aggravated.

Notably, specific polymorphisms associated with high-risk MASLD phenotypes have been shown to result in severe mitochondrial impairment and disease progression. Paolini et al[94] demonstrated that patients carrying high-risk variants in phospholipase domain-containing protein 3 (GG genotype), transmembrane 6 superfamily member 2 (TT), and membrane-bound O-acyltransferase 7 (TT), either individually or in combination, exhibit significant mitochondrial dysfunction in both hepatic tissue and peripheral blood mononuclear cells (PBMCs). Individuals harboring all three variants [defined as nutrient reference values (NRV) = 3] exhibited markedly elevated levels of mitochondrial hydrogen peroxide and ROS, indicating increased oxidative stress. Enzymatic assays revealed reduced activity of mitochondrial complexes I and III, as well as citrate synthase and ATP synthase, in liver biopsies and PBMCs from these patients compared to those without risk variants (NRV = 0).

Furthermore, Seahorse analysis demonstrated a significant reduction in oxygen consumption rate (OCR), a direct measure of oxidative phosphorylation, particularly in complex I/IV and II/IV coupling activities in both tissue types (P < 0.0001 vs NRV = 0). Multivariate regression analysis confirmed that the NRV = 3 genotype independently predicted OCR reduction in both hepatic and circulating cells, even after adjustment for age, sex, BMI, diabetes, and MASLD severity (β = -21.24 in liver, β = -20.08 in PBMCs; P < 0.0001). Importantly, logistic regression analyses indicated that reduced OCR in PBMCs and liver tissue predicted the presence of MASH and fibrosis with high accuracy, with areas under the curve of 0.81 and 0.86, respectively. These findings support the concept that mitochondrial dysfunction, manifested as impaired respiratory chain activity and oxidative phosphorylation, is not only a hepatic hallmark of genetically driven MASLD but also reflects systemic bioenergetic failure, which may underlie clinical fatigue.

This connection is further substantiated by evidence from PBC, another CLD in which mitochondrial dysfunction in skeletal muscle has been directly associated with fatigue. In a magnetic resonance spectroscopy study, fatigued PBC patients exhibited significantly delayed phosphocreatine and pH recovery following exercise, indicating impaired mitochondrial ATP generation and acid-handling capacity in skeletal muscle[95]. A subsequent study confirmed that the inability to shorten pH recovery time across repeated exercise bouts strongly correlated with fatigue severity, highlighting defective muscle bioenergetics as a key mechanism underlying fatigue in PBC[96].

The hypothesis that fatigue in liver disease is predominantly driven by mitochondrial bioenergetic failure was further supported by a randomized trial evaluating B-cell depletion with rituximab in patients with PBC. According to the results of this study, rituximab treatment failed to reduce fatigue symptoms despite demonstrating significant biochemical improvements[97]. Although these findings derive from cholestatic liver disease, they underscore the role of extrahepatic mitochondrial dysfunction, particularly in skeletal muscle, as a contributor to systemic fatigue in chronic liver conditions, including MASLD.

This is especially relevant considering that physical exercise has been shown to improve mitochondrial function in MASLD by upregulating peroxisome proliferator-activated receptor gamma coactivator-1α) expression, thereby enhancing oxidative capacity in both liver and skeletal muscle[98]. Consequently, energy deficit, oxidative stress, and accumulation of metabolites mutually potentiate each other, which leads to systemic insufficiency of energy metabolism primarily in high-energy tissues such as skeletal muscles and the CNS. These processes can clinically manifest as extreme fatigue, decreased endurance, and cognitive dysfunction.

The role of gut microbiota

Changes in the composition and function of the gut microbiota play an important role in the pathogenesis of MASLD and, potentially, in the development of fatigue. Recent evidence suggests a role of the gut microbiota in the changes of mood and behavior, including fatigue, via activation of neuroinflammation, disruption of neurotransmitter metabolism, and destabilization of the gut-brain axis in CLD[99]. Alterations in gut dysbiosis in MASLD, characterized by reduced microbial diversity, predominance of proinflammatory species (e.g., Firmicutes), and depletion of beneficial bacteria (e.g., Bacteroidetes), contribute to disruption of the gut barrier and increased intestinal permeability. It is hypothesized that gut-derived bacterial products, including lipopolysaccharides, ammonia, and bacterial DNA, can initiate and sustain neuroinflammation beyond systemic inflammation alone[91].

Indeed, lipopolysaccharides and other pathogen-associated molecular patterns interact with Toll-like receptors, particularly toll-like receptor 4, expressed on immune and neuronal cells. This interaction activates the nuclear factor-κB signaling pathway, promoting the production of proinflammatory cytokines such as IL-6 and tumor necrosis factor-α[100]. These mediators can access the CNS either directly through a compromised BBB or indirectly via vagal afferent pathways, thereby contributing to neuroinflammation, microglial activation, and dysregulation of the hypothalamic-pituitary-adrenal axis. This hypothesis supports the concept of fatigue as a form of “sickness behavior” mediated by inflammatory signaling within brain regions responsible for motivation and energy regulation, particularly the anterior cingulate cortex and basal ganglia[101].

Other microbial metabolites, such as short-chain fatty acids (SCFAs) including butyrate, acetate, and propionate, regulate microglial activation and synaptic plasticity, thereby modulating neuroinflammatory processes and cognitive function. Under physiological conditions, SCFAs promote microglial homeostasis, maintain BBB integrity, and regulate histone deacetylases, which in turn influence neuronal plasticity. In pathological conditions, SCFAs may affect psychological functioning through interactions with G-protein-coupled receptors or histone deacetylases, exerting their effects on the brain via direct humoral mechanisms, as well as indirect hormonal, immune, and neural pathways[102]. However, it is important to note that the aforementioned effects of SCFAs on neuropsychiatric disorders and psychological functioning have primarily been described in animal models, whereas human studies remain limited and yield inconsistent results.

Via the gut-brain axis, the gut microbiota modulates the synthesis and homeostatic balance of key neurotransmitters such as serotonin and dopamine, which play critical roles in motivation, mood regulation, and fatigue perception[99]. In addition, altered microbiota can impair tryptophan metabolism by shifting the balance away from serotonin synthesis toward the kynurenine pathway. Consequently, neurotoxic metabolites, particularly quinolinic acid, are generated, which further impair CNS function and mood regulation[103]. These complex mechanisms are comprehensively reviewed by Nguyen and Swain[99], who highlight that gut dysbiosis and microbial metabolite imbalances, via both direct immune activation and indirect neuroendocrine disruption, contribute to neurobehavioral manifestations including fatigue, apathy, and cognitive dysfunction in CLD, including MASLD[99].

EFFECTS OF FATIGUE INTERVENTIONS IN MASLD

Despite the high prevalence and clinical significance of fatigue in MASLD, systematic evaluations of therapeutic interventions specifically targeting this symptom remain limited. Currently, treatment of MASLD primarily focuses on lifestyle modifications, particularly dietary changes and regular physical activity, with the objective of achieving a 5%-10% weight loss. However, fatigue itself may constitute a major barrier to achieving these goals. Indeed, Glass et al[31] reported that fatigue significantly hindered exercise participation among adults with MASLD, although most patients expressed a preference for physical activity over pharmacological treatment. This highlights a paradox: While lifestyle interventions are essential, their success may be compromised by the very symptom they aim to improve. Conversely, physical exercise appears to exert a beneficial effect on fatigue.

For example, Sirisunhirun et al[104], in a study involving 40 patients with compensated cirrhosis, demonstrated that a 12-week moderate-intensity home-based exercise training program significantly improved the fatigue domain of the CLD Questionnaire without increasing adverse events. Similar findings were reported by Freer et al[105] in patients with PBC (n = 31). The authors showed that a 12-week home-based exercise program is safe and may exert a beneficial effect on fatigue in this patient population. Notably, PBC patients who completed this exercise program also reported a reduction in daytime somnolence.

While the reasons fatigue may impede increased physical activity are relatively well understood, the mechanisms by which physical activity alleviates fatigue severity require further elucidation. One possible explanation is that physical exercise enhances the muscles’ capacity to clear lactic acid, thereby increasing tolerance to prolonged exercise sessions. Moreover, repetitive exercise may mitigate pyruvate dehydrogenase complex dysfunction by activating alternative metabolic pathways[96], which may help provide sufficient energy to working muscles. It has also been demonstrated that moderate-intensity exercise beneficially affects communication pathways between the CNS and peripheral tissues involved in energy homeostasis. This may positively influence cognition and has been linked to improved cellular energy metabolism accompanied by reduced oxidative stress[106]. A similar effect may occur in patients with MASLD. Available evidence suggests that although exercise capacity is generally preserved in patients with MASLD, their aerobic threshold is frequently reduced, likely due to obesity or deconditioning[107]. Therefore, progressive, low-intensity training programs in patients with MASLD, as well as in patients with PBC, may help reduce fatigue and improve metabolic status[108].

Direct clinical trials evaluating the impact of fatigue-specific interventions in MASLD populations remain limited. Although some studies investigating vitamin D, omega-3 fatty acids, and flavonoids suggest potential benefits in broader populations with CLD, fatigue outcomes are frequently not primary endpoints, and validated fatigue measures to assess changes in fatigue perception are seldom employed. Importantly, one pharmacological option demonstrating promising results in fatigue amelioration is ademetionine (S-adenosylmethionine). A prospective study by Onuchina et al[109], involving patients with MASLD and cognitive dysfunction, reported a significant reduction in fatigue levels, as measured by the FAS, following a six-month course of ademetionine treatment combined with lifestyle interventions. Fatigue scores decreased from a median of 34 to 19 (P = 0.000002), indicating a clinically meaningful improvement. These findings are supported by a recent systematic review[110] and an opinion paper[111] emphasizing the potential role of S-adenosylmethionine in managing fatigue and mood disturbances in liver disease, including MASLD. Although promising, these results underscore the need for larger randomized controlled trials of pharmacological treatments for fatigue in MASLD employing validated fatigue assessment tools.

Glucagon-like peptide-1 (GLP-1) receptor agonists, such as semaglutide and liraglutide, represent another effective class of medications for the treatment of MASLD. These agents have demonstrated the ability to reduce liver fat, improve histological features of MASH, and promote weight loss. However, their direct effects on fatigue in MASLD remain poorly characterized. To date, no randomized controlled trials have evaluated fatigue as a primary or systematically measured secondary endpoint in patients with MASLD receiving GLP-1 receptor agonist therapy. Notably, several studies have reported that weight loss induced by GLP-1 receptor agonists is frequently accompanied by a decrease in fat-free mass, which may exacerbate physical fatigue and sarcopenia if not counteracted by resistance training or adequate protein intake[112,113]. This potential loss of muscle mass may be particularly relevant in individuals with existing metabolic dysfunction, sedentary lifestyles, or suboptimal nutritional status, such as patients with MASLD, especially those of advanced age. Thus, while GLP-1 receptor agonists remain promising agents in MASLD management, their long-term impact on fatigue requires further investigation incorporating validated fatigue measures and assessment of body composition changes during treatment.

Regarding psychological approaches to the treatment of fatigue in MASLD, no published studies specifically addressing this issue have been identified. However, cognitive behavioral therapy has demonstrated efficacy in supporting patients with PBC[114], particularly by empowering them to take ownership of their condition and implement lifestyle changes aimed at improving fatigue management[115]. Overall, a more systematic approach to evaluating fatigue in MASLD, utilizing validated instruments and incorporating fatigue-specific outcomes into clinical trials, is essential for the development of effective, patient-centered management strategies.

CONCLUSION

Fatigue in MASLD is a common and under-recognized symptom that significantly impairs patients’ QoL, adherence to treatment, and long-term outcomes. This review presents, for the first time, an integrative perspective on the multifactorial pathogenesis of fatigue in MASLD, incorporating data on central and peripheral mechanisms, including neuroinflammation, hyperammonemia, mitochondrial dysfunction, sarcopenia, sleep disorders, and gut dysbiosis, and highlighting the complex interplay among these factors. Future studies should prioritize clinical trials that: (1) Assess fatigue as a primary endpoint employing validated measurement tools; (2) Evaluate the impact of interventions targeting the gut microbiota on fatigue perception; and (3) Examine individualized exercise and nutritional programs aimed at enhancing muscle energetics and reversing systemic fatigue.

Despite the expanding body of literature on fatigue in MASLD, several contradictions persist. One notable area of inconsistency concerns the relationship between BMI and fatigue severity. While some studies identify higher BMI as an independent predictor of more severe fatigue and reduced health-related QoL in MASLD patients[30,32], other studies fail to confirm a clear or direct association between BMI and fatigue[3]. These discrepancies may arise from differences in study design, population characteristics (e.g., age, sex, comorbidities), or the use of various fatigue assessment tools (e.g., FAS, fatigue severity scale, CLD Questionnaire, functional assessment of chronic illness therapy-fatigue), thereby limiting comparability.

Similar inconsistencies are evident in the assessment of sarcopenia and its contribution to fatigue. While some studies report a strong association between decreased muscle mass or quality and fatigue symptoms, others indicate a more modest or indirect relationship. These discrepancies may stem from methodological limitations, including variable definitions of sarcopenia, reliance on indirect imaging markers, or the absence of functional muscle assessments. All aforementioned contradictions underscore the necessity for harmonized diagnostic criteria, standardized fatigue assessment methods, and large-scale controlled studies to elucidate the roles of BMI, sarcopenia, and other metabolic variables in the pathogenesis and clinical manifestation of fatigue in MASLD. Recognizing fatigue as a systemic, multisystem manifestation of MASLD may facilitate earlier detection and promote the development of more effective, personalized treatment strategies.