Liver International ISSN 1478-3223
Editorial DOI:10.1111/liv.12784 Liver Int. 2015; 35: 1489–1491
Fatigue in chronic liver disease: exploring the role of the autonomic nervous system See Article on Page 1633 This issue of Liver International has published an article by Dyson et al., which presents data implicating the sympathetic nervous system as a potentially significant contributor and pathogenetic factor for fatigue (1). Given the prevalence and importance of this line of research, we propose to discuss some general aspects of fatigue, its taxonomy and place the findings reported by Dyson et al. in this context. What is meant by ‘fatigue’? The Oxford English Dictionary defines fatigue as ‘lassitude or weariness resulting from either bodily or mental exertion’ or . . . ‘as a condition of muscles, organs, or cells characterized by a temporary reduction in power or sensitivity following a period of prolonged activity or stimulation’. (2) This definition, commonly held, helps confirm the view that there may be both physical and mental contributors to fatigue, but it implies that fatigue ‘results’ from exertion, prolonged activity or stimulation, a view not held by those who study fatigue. (3). Fatigue is a symptom that certainly may result from exercise, work and activities of daily living. However, it can also be associated with a variety of illnesses and their treatments. In fact, several illnesses and syndromes use fatigue as a diagnostic criterion (rheumatic diseases, multiple sclerosis et al.) and as a key measure of disease activity and severity or successful treatment. (4) Well-defined chronic illnesses and cancer have fatigue as a prevalent and prominent associated condition. (5) These kinds of fatigue have specific criteria that must be met. Additionally, fatigue can be idiopathic, having no obvious ‘objective’ basis or identifiable ‘cause’. Examples of idiopathic fatigue include multisystem disease or chronic fatigue syndrome (CFS). The evaluation and treatment of fatigue present at least two significant challenges to clinicians. The first is diagnostic and requires assessments of symptoms, performance measures, laboratory and other physiological measures. The second pertains to taxonomy and depends on using standard evaluations, namely patient self-reports, to assess the pattern, severity and quality of fatigue. It requires one to interpret patient self-reports. Self-reports often use generic phrases (e.g. ‘I lack energy’ or ‘It is difficult to get going in the Liver International (2015) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
morning’) or more specific phrases (e.g. I tire walking up stairs). A useful construct, although still not universally accepted, is to divide fatigue into two separate entities. One is peripheral, or physical, fatigue and the other central, or mental, fatigue. Peripheral fatigue results from a decline in muscle function originating from non-central nervous system mechanisms. (6) Fatigue is worsened by low physical fitness and chronic illnesses. These conditions may intensify fatigue to levels that limit physical and social functioning and severely diminish health-related quality of life. The other is central fatigue, defined as ‘the failure to initiate and/or sustain attentional tasks and physical activities requiring self-motivation’, thus emphasizing a cognitive component. (7) Fig. 1 illustrates the overlap and distinctions of central and peripheral fatigue with regards to both measurement and symptomatic presentation. The value gained using specific constructs would enable a treatment plan to be targeted towards a particular organ system(s), making treatment more effective. Researchers have struggled to better assess and understand the aetiology and classification of fatigue within different illness groups. The largest area of difficulty is criterion variance, the inability to classify patients into the two diagnostic categories (peripheral and central fatigue). This is in part dependent upon measurement and the sensitivity and specificity of the instruments. Dyson et al. have contributed to the understanding of fatigue in chronic liver disease by demonstrating an association between sympathetic over-activity, increased cardiac output and primary sclerosing cholangitis. The association between autonomic dysfunction and fatigue has been identified in people with primary biliary cirrhosis (PBC) (8), nonalcoholic fatty liver disease and chronic hepatitis C (9) and CFS (10), suggesting this is a multidomain phenomenon, one of which may be autonomic dysfunction. Activated immune cells secrete cytokines that influence central nervous system activity, which, in turn, activates output through the peripheral nervous system to regulate the magnitude of an immune response. (11) It is possible that dysregulation of this line of communication between the nervous and immune systems might contribute to disease development and progression. The sympathetic nervous sys-
1489
Austin et al.
Editorial
Peripheral fatigue Symptoms • •
Decreased muscle exertion Reduced exercise/ activity tolerance
• • • • •
Measurement • •
Functional/Exercise testing Muscle ultrasonography
Central fatigue
Fatigue (Generalized)
• •
Symptoms
Symptoms
Weakness/weariness Lack of energy Malaise Loss of motivation Prolonged rest following exertion
• •
Measurement
• •
Paent self-report Serum biomarkers
Loss of focus Impaired memory, reaction-time
Measurement Cognitive testing Functional Neuroimaging
Fig. 1. The complexity of fatigue.
tem regulation of immune system functioning is a critical link to the development and exacerbation of chronic immune-mediated diseases. Primary sclerosing cholangitis shares a number of features of autoimmune diseases, such as PBC and inflammatory bowel disease (IBD). The genetic susceptibility (HLA region), inflammatory markers (liver infiltrating T cells, cytokine milieu) and autoantibodies (ANNA, ANCA, ASMAb) are shared with these other diagnostic groups that may also contribute to fatigue. (12) Primary sclerosing cholangitis is distinct in its gender distribution and response to immunotherapy. (13, 14) Therefore, it is important to pursue findings such as the contribution of sympathetic over-activity to fatigue in an effort to establish pathways that may be specific for primary sclerosing cholangitis. Measuring fatigue presents a significant challenge to clinicians and investigators. A necessary condition is that the instrument is valid, sensitive and specific to the variable of interest, a goal that is particularly challenging as fatigue is complex and multifactorial. Fatigue assessments may either be subjective, evaluated through patient-reported outcomes, or objective, through performance and functional tests. While data integrity in research is generally maximized through objective measures, the patient-centred nature of the fatigue makes self-reports essential. Questionnaires may be unidimensional (e.g. visual analogue scale) or multidimensional [e.g. Chronic Liver Disease Questionnaire (CLDQ), Fatigue Impact Scale (FIS)]. One difficulty is that measures often do not discriminate between types of fatigue, although they provide reliable information about severity. Second, investigators often
1490
use different measures, making comparisons between studies difficult. Both instances lead to the challenge of construct contamination, in which components of fatigue are falsely classified as fatigue itself, or an instrument fails to distinguish fatigue from related conditions such as depression and sleepiness. In a recent review of patient-reported assessments of fatigue, Whitehead outlined criteria for evaluation of an ideal measurement. These criteria include ease of use for the patient or respondent, effectiveness as a research measure that can discriminate cases from non-cases and display sensitivity to change, and robust psychometric properties with demonstrated validity and reliability. (15) The use of the FIS in the present study appears to meet a majority of these guidelines. The FIS assesses three separate domains: physical, cognitive and psychosocial functioning; and displays a Cronbach’s a > 0.87 and has been validated in multiple patient groups, including those with primary biliary cirrhosis. (16) The scale’s ease of use is suspect, however, as severely fatigued individuals may require considerably more time for completion. (16). Objective measurements are required to assess physiological and performance based data. Dyson et al.’s use of orthostatic tilt tests and measures of heart rate variability and cardiac output was effective in establishing a potential link between autonomic nervous system abnormalities and fatigue experienced by patients with primary sclerosing cholangitis. Objective means of identifying central fatigue include cognitive assessments of sustained attention or working memory, such as the Stroop effect test (17) or Psychomotor vigilance test (18), while peripheral fatigue is assessed Liver International (2015) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Austin et al.
through tests of sustained muscular performance. While assessing components of central fatigue, cognitive tests do not appear to correlate well with selfreported measures of fatigue. (19) Dyson et al. chose not to use objective measures of cognitive and physical performance. These kinds of tests would have provided objective data about fatigue and possibly helped distinguish physical from central fatigue. The authors note that subjective fatigue has been associated with decreased physical activity. Caution should be taken not to conflate measures of physical activity, including self-reports or accelerometry, with tests of physical performance, such as a six-minute walk test, graded exercise test or repeated functional tasks. The former are assessments of a lifestyle factor that may not accurately reflect physical fitness and muscular performance due to confounders such as accessibility, time and motivation. The latter are performed under more controlled circumstances and, when properly supplemented with physiological and biological measures, provide a direct indication of muscular performance, aerobic capacity and fitness and fatigability. Dyson et al. have contributed to a better understanding of fatigue in primary sclerosing cholangitis. (1) Additional research in primary sclerosing cholangitis is needed to explore mechanisms of fatigue that have been reported in other diseases, including dysfunction of the hypothalamic–pituitary–adrenal axis, cytokine-mediated immune alterations and physiological brain dysfunction. (7, 20) The prevalence of fatigue, its impact on function and well-being and life satisfaction require continued research towards a fuller understanding of potential causes to provide effective treatment. Acknowledgements
Financial support: None. Conflict of interest: The authors do not have any disclosures to report.
Patrick W. Austin, Lynn Gerber and, Azza K. Karrar Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA
References 1. Dyson JK, Elsharkawy AM, Lamb CA, et al. Fatigue in primary sclerosing cholangitis is associated with sympathetic over-activity and increased cardiac output. Liver Int 2015; 35: 1633–41. 2. Fatigue [Def. 1, 2]. (n.d.) In Oxford English Dictionary, Available at: http://public.oed.com/ (Accessed 16 November 2014)
Liver International (2015) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Editorial
3. DeLuca J. Fatigue as a Window to the Brain. Cambridge, MA: The MIT Press, 2005. 4. Jacobson DL, Gange SJ, Rose NR, Graham NMH. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997; 84: 223–43. 5. Smets EMA, Garssen B, Schuster-Uitterhove ALJ, de Haes JCJM. Fatigue in cancer patients. Br J Cancer 1993; 68: 220–4. 6. Fitts RH. The muscular system: fatigue processes. In: Tipton CM, ed. ACSM’s Advanced Exercise Physiology. Philadelphia: Lippincott Williams and Wilkins, 2006; 178–96. 7. Chaudhuri A, Behan PO. Fatigue and basal ganglia. J Neurol Sci 2000; 2: 34–42. 8. Newton JL, Okonkwo O, Sutcliffe K, et al. Symptoms of autonomic dysfunction in chronic fatigue syndrome. QJM 2007; 100: 519–26. 9. Price JK, Escheik C, Weinstein AA, et al. Medications affecting the autonomic nervous system (ANS) do not explain abnormal diastolic blood pressure in patients with chronic hepatitis C (Ch-C) or non-alcoholic fatty liver disease (NAFLD). Gastroenterology 2013; 144: S– 969. 10. Rowe PC, Bou-Holaigh I, Kan JS, Calkins H. Is neurally mediated hypotension an unrecognized cause of chronic fatigue? Lancet 1995; 345: 623–4. 11. del Ray A, Besedovsky HO. Sympathetic nervous systemimmune interactions in autoimmune lymphoproliferative diseases. Neuroimmunomodulation 2008; 15: 29–36. 12. Trivedi PJ, Hirschfield GM. Overlap syndromes and autoimmune liver disease. Aliment Pharmacol Ther 2012; 36: 517–33. 13. Cullen SN, Chapman RW. The medical management of primary sclerosing cholangitis. Semin Liver Dis 2006; 26: 52–61. 14. Worthington J, Cullen S, Chapman R. Immunopathogenesis of primary sclerosing cholangitis. Clin Rev Allergy Immunol 2005; 28: 93–103. 15. Whitehead L. The measurement of fatigue in chronic illness: a systematic review of unidimensional and multidimensional fatigue measures. J Pain and Symp Man 2009; 37: 107–28. 16. Firth J, Newton J. Fatigue impact scale. Occ Med 2010; 60: 159. 17. Barwick F, Arnett P. Slobounov S. EEG correlates of fatigue during administration of a neuropsychological test battery. Clin Neurophysiol 2012; 123: 278–84. 18. Dinges DF, Powell JW. Microcomputer analysis of performance on a portable, simple visual RT task during sustained operations. Behav Res Meth Instrum Comp 1985; 1986: 652–5. 19. Ackerman PL, Kanfer R. Test length and cognitive fatigue: an empirical examination of effects on performance and test-taker reactions. J Exp Psychol Appl 2009; 15: 163–81. 20. Thomas CA, Newton J, Wilson S. A review of hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. International Scholarly Research Notices(ISRN) Neuroscience 2013; 2013: 1–8.
1491
Copyright of Liver International is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Editorial DOI:10.1111/liv.12784 Liver Int. 2015; 35: 1489–1491
Fatigue in chronic liver disease: exploring the role of the autonomic nervous system See Article on Page 1633 This issue of Liver International has published an article by Dyson et al., which presents data implicating the sympathetic nervous system as a potentially significant contributor and pathogenetic factor for fatigue (1). Given the prevalence and importance of this line of research, we propose to discuss some general aspects of fatigue, its taxonomy and place the findings reported by Dyson et al. in this context. What is meant by ‘fatigue’? The Oxford English Dictionary defines fatigue as ‘lassitude or weariness resulting from either bodily or mental exertion’ or . . . ‘as a condition of muscles, organs, or cells characterized by a temporary reduction in power or sensitivity following a period of prolonged activity or stimulation’. (2) This definition, commonly held, helps confirm the view that there may be both physical and mental contributors to fatigue, but it implies that fatigue ‘results’ from exertion, prolonged activity or stimulation, a view not held by those who study fatigue. (3). Fatigue is a symptom that certainly may result from exercise, work and activities of daily living. However, it can also be associated with a variety of illnesses and their treatments. In fact, several illnesses and syndromes use fatigue as a diagnostic criterion (rheumatic diseases, multiple sclerosis et al.) and as a key measure of disease activity and severity or successful treatment. (4) Well-defined chronic illnesses and cancer have fatigue as a prevalent and prominent associated condition. (5) These kinds of fatigue have specific criteria that must be met. Additionally, fatigue can be idiopathic, having no obvious ‘objective’ basis or identifiable ‘cause’. Examples of idiopathic fatigue include multisystem disease or chronic fatigue syndrome (CFS). The evaluation and treatment of fatigue present at least two significant challenges to clinicians. The first is diagnostic and requires assessments of symptoms, performance measures, laboratory and other physiological measures. The second pertains to taxonomy and depends on using standard evaluations, namely patient self-reports, to assess the pattern, severity and quality of fatigue. It requires one to interpret patient self-reports. Self-reports often use generic phrases (e.g. ‘I lack energy’ or ‘It is difficult to get going in the Liver International (2015) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
morning’) or more specific phrases (e.g. I tire walking up stairs). A useful construct, although still not universally accepted, is to divide fatigue into two separate entities. One is peripheral, or physical, fatigue and the other central, or mental, fatigue. Peripheral fatigue results from a decline in muscle function originating from non-central nervous system mechanisms. (6) Fatigue is worsened by low physical fitness and chronic illnesses. These conditions may intensify fatigue to levels that limit physical and social functioning and severely diminish health-related quality of life. The other is central fatigue, defined as ‘the failure to initiate and/or sustain attentional tasks and physical activities requiring self-motivation’, thus emphasizing a cognitive component. (7) Fig. 1 illustrates the overlap and distinctions of central and peripheral fatigue with regards to both measurement and symptomatic presentation. The value gained using specific constructs would enable a treatment plan to be targeted towards a particular organ system(s), making treatment more effective. Researchers have struggled to better assess and understand the aetiology and classification of fatigue within different illness groups. The largest area of difficulty is criterion variance, the inability to classify patients into the two diagnostic categories (peripheral and central fatigue). This is in part dependent upon measurement and the sensitivity and specificity of the instruments. Dyson et al. have contributed to the understanding of fatigue in chronic liver disease by demonstrating an association between sympathetic over-activity, increased cardiac output and primary sclerosing cholangitis. The association between autonomic dysfunction and fatigue has been identified in people with primary biliary cirrhosis (PBC) (8), nonalcoholic fatty liver disease and chronic hepatitis C (9) and CFS (10), suggesting this is a multidomain phenomenon, one of which may be autonomic dysfunction. Activated immune cells secrete cytokines that influence central nervous system activity, which, in turn, activates output through the peripheral nervous system to regulate the magnitude of an immune response. (11) It is possible that dysregulation of this line of communication between the nervous and immune systems might contribute to disease development and progression. The sympathetic nervous sys-
1489
Austin et al.
Editorial
Peripheral fatigue Symptoms • •
Decreased muscle exertion Reduced exercise/ activity tolerance
• • • • •
Measurement • •
Functional/Exercise testing Muscle ultrasonography
Central fatigue
Fatigue (Generalized)
• •
Symptoms
Symptoms
Weakness/weariness Lack of energy Malaise Loss of motivation Prolonged rest following exertion
• •
Measurement
• •
Paent self-report Serum biomarkers
Loss of focus Impaired memory, reaction-time
Measurement Cognitive testing Functional Neuroimaging
Fig. 1. The complexity of fatigue.
tem regulation of immune system functioning is a critical link to the development and exacerbation of chronic immune-mediated diseases. Primary sclerosing cholangitis shares a number of features of autoimmune diseases, such as PBC and inflammatory bowel disease (IBD). The genetic susceptibility (HLA region), inflammatory markers (liver infiltrating T cells, cytokine milieu) and autoantibodies (ANNA, ANCA, ASMAb) are shared with these other diagnostic groups that may also contribute to fatigue. (12) Primary sclerosing cholangitis is distinct in its gender distribution and response to immunotherapy. (13, 14) Therefore, it is important to pursue findings such as the contribution of sympathetic over-activity to fatigue in an effort to establish pathways that may be specific for primary sclerosing cholangitis. Measuring fatigue presents a significant challenge to clinicians and investigators. A necessary condition is that the instrument is valid, sensitive and specific to the variable of interest, a goal that is particularly challenging as fatigue is complex and multifactorial. Fatigue assessments may either be subjective, evaluated through patient-reported outcomes, or objective, through performance and functional tests. While data integrity in research is generally maximized through objective measures, the patient-centred nature of the fatigue makes self-reports essential. Questionnaires may be unidimensional (e.g. visual analogue scale) or multidimensional [e.g. Chronic Liver Disease Questionnaire (CLDQ), Fatigue Impact Scale (FIS)]. One difficulty is that measures often do not discriminate between types of fatigue, although they provide reliable information about severity. Second, investigators often
1490
use different measures, making comparisons between studies difficult. Both instances lead to the challenge of construct contamination, in which components of fatigue are falsely classified as fatigue itself, or an instrument fails to distinguish fatigue from related conditions such as depression and sleepiness. In a recent review of patient-reported assessments of fatigue, Whitehead outlined criteria for evaluation of an ideal measurement. These criteria include ease of use for the patient or respondent, effectiveness as a research measure that can discriminate cases from non-cases and display sensitivity to change, and robust psychometric properties with demonstrated validity and reliability. (15) The use of the FIS in the present study appears to meet a majority of these guidelines. The FIS assesses three separate domains: physical, cognitive and psychosocial functioning; and displays a Cronbach’s a > 0.87 and has been validated in multiple patient groups, including those with primary biliary cirrhosis. (16) The scale’s ease of use is suspect, however, as severely fatigued individuals may require considerably more time for completion. (16). Objective measurements are required to assess physiological and performance based data. Dyson et al.’s use of orthostatic tilt tests and measures of heart rate variability and cardiac output was effective in establishing a potential link between autonomic nervous system abnormalities and fatigue experienced by patients with primary sclerosing cholangitis. Objective means of identifying central fatigue include cognitive assessments of sustained attention or working memory, such as the Stroop effect test (17) or Psychomotor vigilance test (18), while peripheral fatigue is assessed Liver International (2015) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Austin et al.
through tests of sustained muscular performance. While assessing components of central fatigue, cognitive tests do not appear to correlate well with selfreported measures of fatigue. (19) Dyson et al. chose not to use objective measures of cognitive and physical performance. These kinds of tests would have provided objective data about fatigue and possibly helped distinguish physical from central fatigue. The authors note that subjective fatigue has been associated with decreased physical activity. Caution should be taken not to conflate measures of physical activity, including self-reports or accelerometry, with tests of physical performance, such as a six-minute walk test, graded exercise test or repeated functional tasks. The former are assessments of a lifestyle factor that may not accurately reflect physical fitness and muscular performance due to confounders such as accessibility, time and motivation. The latter are performed under more controlled circumstances and, when properly supplemented with physiological and biological measures, provide a direct indication of muscular performance, aerobic capacity and fitness and fatigability. Dyson et al. have contributed to a better understanding of fatigue in primary sclerosing cholangitis. (1) Additional research in primary sclerosing cholangitis is needed to explore mechanisms of fatigue that have been reported in other diseases, including dysfunction of the hypothalamic–pituitary–adrenal axis, cytokine-mediated immune alterations and physiological brain dysfunction. (7, 20) The prevalence of fatigue, its impact on function and well-being and life satisfaction require continued research towards a fuller understanding of potential causes to provide effective treatment. Acknowledgements
Financial support: None. Conflict of interest: The authors do not have any disclosures to report.
Patrick W. Austin, Lynn Gerber and, Azza K. Karrar Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA
References 1. Dyson JK, Elsharkawy AM, Lamb CA, et al. Fatigue in primary sclerosing cholangitis is associated with sympathetic over-activity and increased cardiac output. Liver Int 2015; 35: 1633–41. 2. Fatigue [Def. 1, 2]. (n.d.) In Oxford English Dictionary, Available at: http://public.oed.com/ (Accessed 16 November 2014)
Liver International (2015) © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Editorial
3. DeLuca J. Fatigue as a Window to the Brain. Cambridge, MA: The MIT Press, 2005. 4. Jacobson DL, Gange SJ, Rose NR, Graham NMH. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997; 84: 223–43. 5. Smets EMA, Garssen B, Schuster-Uitterhove ALJ, de Haes JCJM. Fatigue in cancer patients. Br J Cancer 1993; 68: 220–4. 6. Fitts RH. The muscular system: fatigue processes. In: Tipton CM, ed. ACSM’s Advanced Exercise Physiology. Philadelphia: Lippincott Williams and Wilkins, 2006; 178–96. 7. Chaudhuri A, Behan PO. Fatigue and basal ganglia. J Neurol Sci 2000; 2: 34–42. 8. Newton JL, Okonkwo O, Sutcliffe K, et al. Symptoms of autonomic dysfunction in chronic fatigue syndrome. QJM 2007; 100: 519–26. 9. Price JK, Escheik C, Weinstein AA, et al. Medications affecting the autonomic nervous system (ANS) do not explain abnormal diastolic blood pressure in patients with chronic hepatitis C (Ch-C) or non-alcoholic fatty liver disease (NAFLD). Gastroenterology 2013; 144: S– 969. 10. Rowe PC, Bou-Holaigh I, Kan JS, Calkins H. Is neurally mediated hypotension an unrecognized cause of chronic fatigue? Lancet 1995; 345: 623–4. 11. del Ray A, Besedovsky HO. Sympathetic nervous systemimmune interactions in autoimmune lymphoproliferative diseases. Neuroimmunomodulation 2008; 15: 29–36. 12. Trivedi PJ, Hirschfield GM. Overlap syndromes and autoimmune liver disease. Aliment Pharmacol Ther 2012; 36: 517–33. 13. Cullen SN, Chapman RW. The medical management of primary sclerosing cholangitis. Semin Liver Dis 2006; 26: 52–61. 14. Worthington J, Cullen S, Chapman R. Immunopathogenesis of primary sclerosing cholangitis. Clin Rev Allergy Immunol 2005; 28: 93–103. 15. Whitehead L. The measurement of fatigue in chronic illness: a systematic review of unidimensional and multidimensional fatigue measures. J Pain and Symp Man 2009; 37: 107–28. 16. Firth J, Newton J. Fatigue impact scale. Occ Med 2010; 60: 159. 17. Barwick F, Arnett P. Slobounov S. EEG correlates of fatigue during administration of a neuropsychological test battery. Clin Neurophysiol 2012; 123: 278–84. 18. Dinges DF, Powell JW. Microcomputer analysis of performance on a portable, simple visual RT task during sustained operations. Behav Res Meth Instrum Comp 1985; 1986: 652–5. 19. Ackerman PL, Kanfer R. Test length and cognitive fatigue: an empirical examination of effects on performance and test-taker reactions. J Exp Psychol Appl 2009; 15: 163–81. 20. Thomas CA, Newton J, Wilson S. A review of hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. International Scholarly Research Notices(ISRN) Neuroscience 2013; 2013: 1–8.
1491
Copyright of Liver International is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
