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

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.

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.