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Fatigue is the most commonly encountered symptom in patients with liver disease, and it has a significant impact on their quality of life. However, although some progress has been made with regard to the understanding of the processes which may generate fatigue in general, the underlying cause(s) of liver disease-associated fatigue remain incompletely understood. The present review describes recent advances which have been made in our ability to measure fatigue in patients with liver disease in the clinical setting, as well as in our understanding of potential pathways which are likely important in the pathogenesis of fatigue associated with liver disease. Specifically, experimental findings suggest that fatigue associated with liver disease likely occurs as a result of changes in neurotransmission within the brain. In conclusion, a reasonable approach to help guide in the management of the fatigued patient with liver disease is presented.
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Can J Gastroenterol Vol 20 No 3 March 2006 181
Fatigue in liver disease: Pathophysiology
and clinical management
Mark G Swain MD MSc FRCPC
University of Calgary, Liver Unit, Health Sciences Centre, Calgary, Alberta
Correspondence: Dr Mark G Swain, 3330 Hospital Drive Northwest, Calgary, Alberta T2N 4N1. Telephone 403-220-8457, fax 403-270-0995,
Received for publication August 22, 2005. Accepted October 12, 2005
MG Swain. Fatigue in liver disease: Pathophysiology and clinical
management. Can J Gastroenterol 2006;20(3):181-188.
Fatigue is the most commonly encountered symptom in patients with
liver disease, and it has a significant impact on their quality of life.
However, although some progress has been made with regard to the
understanding of the processes which may generate fatigue in general,
the underlying cause(s) of liver disease-associated fatigue remain
incompletely understood. The present review describes recent
advances which have been made in our ability to measure fatigue in
patients with liver disease in the clinical setting, as well as in our
understanding of potential pathways which are likely important in
the pathogenesis of fatigue associated with liver disease. Specifically,
experimental findings suggest that fatigue associated with liver dis-
ease likely occurs as a result of changes in neurotransmission within
the brain. In conclusion, a reasonable approach to help guide in the
management of the fatigued patient with liver disease is presented.
Key Words: Cholestasis; Fatigue; Hepatitis; Liver disease;
Neurotransmitters; Therapy
La fatigue en cas de maladie hépatique : La
physiopathologie et la prise en charge clinique
La fatigue est le principal symptôme chez les patients atteints d’une mal-
adie hépatique, et elle a des conséquences considérables sur leur qualité de
vie. Cependant, même si certains progrès ont été réalisés quant à notre
compréhension des processus généraux susceptibles de produire de la
fatigue, les causes sous-jacentes de la fatigue associée à la maladie hépa-
tique sont mal comprises. La présente analyse décrit les progrès récents
accomplis dans notre capacité de mesurer la fatigue chez les patients
atteints d’une maladie hépatique en milieu clinique, ainsi que dans notre
compréhension des voies potentielles qui, selon toute probabilité, jouent
un rôle important dans la pathogenèse de la fatigue associée à la maladie
hépatique. Plus précisément, les observations expérimentales laissent sup-
poser que la fatigue associée aux maladies hépatiques découle de modifi-
cations à la neurotransmission dans le cerveau. En conclusion, une
démarche raisonnable pour orienter la prise en charge du patient atteint
d’une maladie hépatique et de fatigue est présentée.
Fatigue is a complex symptom that encompasses a range of
complaints including lethargy, malaise, lassitude and
exhaustion. Chronic fatigue commonly occurs, affecting up to
20% of the population (1). Although the exact prevalence of
fatigue in patients with chronic liver disease is somewhat vari-
able in different studies and with different specific liver dis-
eases, it is readily apparent that fatigue constitutes the most
common complaint among this patient group (2-6). However,
because of difficulties in defining and treating fatigue, this
symptom is often overlooked or minimized by physicians car-
ing for patients with liver disease. The prevalence of fatigue in
patients with different forms of liver disease also appears to be
quite variable. Specifically, cholestatic liver disease caused by
primary biliary cirrhosis (PBC), primary sclerosing cholangitis
or drugs is commonly associated with fatigue (2,3). In fact,
fatigue in cholestatic patients can be the presenting symptom
and occurs in 65% to 85% of patients (2,3,7,8). Moreover,
fatigue in PBC is considered to be the worst symptom in
approximately 50% of patients, and is disabling in approxi-
mately 25% (7). Fatigue also has a significant impact on the
health-related quality of life (HRQOL) of PBC patients (7-9).
The prevalence of fatigue in hepatitic liver diseases is less
clearly defined. Fatigue is an integral component of the clini-
cal presentation of patients with autoimmune hepatitis, often
paralleling hepatic inflammation as determined by serum ala-
nine aminotransferase measurements or liver biopsy findings,
and responding usually quite rapidly to the institution of
immunosuppressive therapy (4,10,11). However, the overall
prevalence of fatigue in patients with viral hepatitis is less
clear. Acute presentations of viral hepatitis are often associated
with feelings of fatigue or malaise, which gradually subside
because the patient recovers clinically (eg, recovers from hep-
atitis A). However, the situation in patients with chronic viral
hepatitis appears to be more controversial. Specifically, a sig-
nificant proportion of patients with chronic hepatitis C who
are followed in tertiary care centres, or who participate in clin-
ical trials, complain of fatigue or decreased vitality, which has
a direct negative impact on their HRQOL (5,6,12). However,
this high prevalence of fatigue does not appear to hold for
patients infected with hepatitis C who are unaware of their
diagnosis (13,14). Moreover, the complaint of fatigue in hepa-
titis C patients does not appear to correlate with whether these
patients are viremic (15). In contrast, patients chronically
infected with hepatitis B appear to have HRQOL scores simi-
lar to those of healthy controls (12).
Recently, patients with hepatitis C have been reported to
have subclinical findings of cognitive impairment and altered
cerebral metabolism as reflected by magnetic resonance spec-
troscopy (16-18). The suggestion from these findings is that
hepatitis C infection of the brain itself may lead to these
changes (17,19). However, it is unclear whether these central
changes observed in hepatitis C-infected patients are a direct
©2006 Pulsus Group Inc. All rights reserved
Swain.qxd 2/24/2006 10:51 AM Page 181
result of the hepatitis C virus within the brain, are related to
the complex behavioural, social and mental sequelae associated
with carrying a diagnosis of chronic hepatitis C infection or are
related to the mode of acquisition of their hepatitis C (eg,
intravenous drug abuse).
Therefore, any discussion of the pathophysiology and man-
agement of fatigue in the context of liver disease must take
these observations into account.
In any discussion of fatigue, it is imperative to differentiate
central from peripheral fatigue. Peripheral fatigue relates to
neuromuscular dysfunction and occurs with muscle overutiliza-
tion and associated metabolic changes, and is classically mani-
fested clinically by weakness (20,21). This type of fatigue does
not appear to be important in patients with liver disease in the
absence of decompensated cirrhosis or liver failure. In contrast,
central fatigue arises within the central nervous system (CNS)
and is characterized by a difficulty in performing physical (and
often mental) activities, which require self-motivation and
responses to internal cues. Furthermore, central fatigue is often
associated with a higher perceived effort when undertaking
tasks (20). Therefore, by definition, central fatigue directly
results from altered neurotransmission within the brain.
Typically, the complaint of central fatigue in the setting of
any chronic disease, including liver diseases, does not correlate
with traditional markers of disease activity or severity (20,21).
Moreover, central fatigue is often associated with other neu-
ropsychiatric complaints also thought to be secondary to
altered neurotransmission within the CNS; namely depression
and anxiety (20,21). This association of fatigue with depres-
sion and anxiety is commonly encountered in patients with
cholestatic and hepatitic liver diseases (6-8,22).
Given that central fatigue arises from changes in neuro-
transmitter systems within the brain, it is readily apparent that
objective measurements of fatigue are problematic. Therefore,
fatigue assessments in patients with liver disease have tradi-
tionally been performed using either general or specifically
designed questionnaires (eg, Short Form-36 [12,15] versus
Fatigue Impact Scale [23] or Fatigue Severity Scale [24]). By
scoring a patient’s answers to a given set of questions concern-
ing fatigue, these questionnaires allow for an objective quan-
tification or score of fatigue to be made. Changes in these
scores have been used to determine worsening or improving in
fatigue with therapeutic interventions in patients with liver
The pathogenesis of fatigue in general is poorly understood and
this holds true for fatigue in the setting of liver disease
(20,21,25). However, given that altered neurotransmission
within the CNS drives central fatigue, and that central fatigue
is the predominant issue in the setting of liver disease, any dis-
cussion of the possible etiology of fatigue in the context of liver
disease must relate to these potential changes in neurotrans-
mission within the brain (21,25,26). Therefore, the discussion
of the pathophysiology of fatigue in liver disease must incorpo-
rate two main concepts:
1. How does the diseased or damaged liver ‘communicate’
with the brain to cause changes in neurotransmission?
2. What specific changes in neurotransmission occur within
the brain as a result of this ‘communication’, and how do
these changes give rise to the genesis of central fatigue?
Moreover, this discussion must also be placed in the context
that fatigue in patients with liver disease is manifest in the set-
ting of a diagnosis often holding an uncertain outcome and
often associated with societal taboos. Therefore, the diagnosis
of chronic liver disease encompasses complex interactions
among biological, psychosocial and behavioural processes,
which can all significantly affect the clinical expression of
fatigue in a given patient.
As outlined previously, the ultimate cause of central fatigue
in patients with liver disease must entail alterations in neuro-
transmitter pathways within the brain. The specific neuro-
transmitter pathways that have received the greatest clinical
and experimental attention as potentially causing central
fatigue include pathways that are important in behavioural
activation, arousal and locomotor activity (25-28). Brain areas
important in this regard include the basal ganglia, brainstem,
reticular and limbic systems and higher cortical centres
(20,25,26). The neurotransmitter systems that have been
directly implicated in the genesis of central fatigue include the
corticotropin-releasing hormone (CRH), serotonin, noradren-
aline and other neurotransmitter systems.
CRH was initially identified as the factor released from the
hypothalamus, which is the most potent activator of the
hypothalamic-pituitary-adrenal axis. However, over the past
three decades, it has become increasingly clear that CRH-
containing nerve fibres are widely distributed throughout the
CNS and are intimately involved in arousal and behavioural
activation (27,29-31; Figure 1). These observations have led to
Can J Gastroenterol Vol 20 No 3 March 2006182
Figure 1) Corticotropin-releasing hormone (CRH) acts in its tradi-
tional role to stimulate adrenocorticotropic hormone (ACTH) release
from the anterior pituitary gland. However, CRH release from nerve
fibres projecting to areas within the brain stimulates behavioural activa-
tion and arousal
Swain.qxd 2/24/2006 10:51 AM Page 182
the hypothesis that defective release of CRH within the brain
may be important in the development of central fatigue (31-
33). In an animal model of cholestatic liver disease, behaviours
and physiological responses consistent with defective central
CRH release have been documented (34-36). In addition, rats
with experimental cholestasis demonstrate reduced hypothala-
mic CRH levels and increased CRH type 1 receptor expres-
sion, as well as enhanced sensitivity to the behavioural
activating effects of centrally infused CRH (36); these findings
are consistent with defective central CRH release playing an
important role in cholestasis-associated fatigue. Moreover,
clinical observations in patients with PBC also support this
suggestion. Specifically, PBC patients demonstrate augmented
adrenocorticotropic hormone release after intravenous CRH
infusion, consistent with an upregulation of pituitary CRH
receptors in these patients, possibly secondary to defective
endogenenous CRH stimulation of their anterior pituitary
glands (37). Of interest, defective central CRH release has also
been implicated in central fatigue in patients with atypical
depression and the chronic fatigue syndrome (26,32).
Abnormal serotonergic neurotransmission has been commonly
implicated in the development of altered behaviours including
depression, anxiety and central fatigue (28). Serotonergic
nerve fibres arise mainly within the dorsal raphe nucleus in the
midbrain and project widely throughout the CNS (28,38,39).
Of interest, the serotonin and CRH neurotransmitter systems
are known to be intimately interrelated (38,40). Serotonin
mediates its biological effects by activating a large number of
receptor subtypes (41). However, the precise role played by
serotonin in the generation of central fatigue remains unclear.
It appears that serotonin released within the brain has a differ-
ential effect on the development of fatigue depending on
whether exercise-induced fatigue or more classically defined
central fatigue is being examined. Specifically, in rodents or
athletes exercised to exhaustion, increased central serotonin
levels appear to decrease exercise capacity (42,43). These
observations suggest that increased central serotonin levels
may contribute to central fatigue. However, the applicability of
findings regarding serotonin in the setting of exercise to
exhaustion appears to be less relevant to fatigue in the setting
of liver disease. Patients with chronic fatigue syndrome exhibit
findings on pharmacological challenge that are consistent with
increased central serotonin sensitivity due to decreased sero-
tonin release (44). These observations provided the impetus to
use serotonin reuptake inhibitors to treat patients with chronic
fatigue syndrome, albeit with mixed results (45).
The serotonin neurotransmitter system has been studied in
an animal model of cholestatic liver disease and the findings
are consistent with a possible role of serotonin in liver disease-
associated fatigue (46,47). The 5-hydroxytryptamine 1A
(5HT)1A receptor subtype has been commonly linked to
altered behaviours in humans and animals (48,49). The
5HT1A receptor exists as an autoreceptor situated on cell bod-
ies of serotonergic nerves originating in the midbrain dorsal
raphe nucleus (50; Figure 2). Activation of these cell body
serotonin autoreceptors in the midbrain results in decreased
serotonin release from the distal nerve terminals that project
throughout the CNS (48-50). However, 5HT1A receptors also
exist postsynaptically within the brain. Activation of postsynaptic
5HT1A receptors typically exerts an inhibiting influence on
neurons where they are located (48). Therefore, systemic
administrations of a 5HT1A receptor agonist results in a net
decrease in serotonin neurotransmission at all postsynaptic
serotonin receptors except those of the 5HT1A subtype (48).
Experimental results in cholestatic rats are consistent with
increased sensitivity and the number of 5HT1A midbrain
autoreceptors coupled with normal 5HT1A postsynaptic recep-
tors elsewhere within the CNS (46,47); these findings that
would be expected to give rise to decreased central serotonin
release as a potential contributor to central fatigue in cholesta-
tic liver disease. In fact, this suggestion is supported by findings
that the repeated administration of a 5HT1A receptor agonist,
which desensitizes 5HT1A autoreceptors and increases central
serotonin release into synapses where postsynaptic 5HT1A
receptors are active, ameliorated fatigue-like behaviours in
cholestatic rats (51). These observations suggest that the
5HT1A receptor may play an important role in the genesis of
central fatigue in patients with liver disease.
More recently, 5HT3receptor antagonists have been
reported to improve fatigue in patients with the chronic
fatigue syndrome (52), as well as in a patient with hepatitis C-
induced fatigue (53). Similar findings have been reported in
preliminary experiments in cholestatic rats (54). Of note, in a
recent clinical trial, the 5HT3receptor antagonist
ondansetron appeared to have a limited effect on fatigue in
PBC patients, although the results of this study are difficult to
interpret due to possible patient unblinding and a significant
placebo effect (55). Therefore, the role played by serotonin-
activating central 5HT3receptors in the genesis of liver dis-
ease-associated fatigue remains unclear.
Noradrenaline is a classical neurotransmitter important in
behavioural activation, especially in the context of acute stress
(56). More important, hypofunctioning of noradrenaline-
containing nerve pathways within the brain has been implicated
in the development of central fatigue (57). Specifically, reser-
pine, which depletes central calecholamine stores, is commonly
associated with the development of fatigue and depression (58).
Moreover, beta-blockers and alpha-2 agonists frequently cause
fatigue (58). Unfortunately, the role of altered noradrenaline
Fatigue in liver disease
Can J Gastroenterol Vol 20 No 3 March 2006 183
Figure 2) Serotonin-secreting nerves originate in the dorsal raphe
nucleus within the midbrain and their axons project throughout the cen-
tral nervous system. Activation of 5-hydroxytryptamine 1A (5HT1A)
autoreceptors located on serotonin nerve cell bodies within the raphe
nucleus results in a decrease in serotonin release from nerve terminals
at the distal projection sites of these serotonergic nerves. Decrease
Swain.qxd 3/1/2006 4:00 PM Page 183
neurotransmission in liver disease-associated fatigue remains
completely unknown. However, an obvious patient population
that could be studied includes cirrhotic patients taking beta-
blockers as variceal bleed prophylaxis (59).
Other neurotransmitters
Numerous other neurotransmitter systems have also been
implicated in the control of locomotor activity and behavioural
activation, including the dopaminergic and cannabinoid sys-
tems (60,61). However, no studies of the role of these neuro-
transmitter systems in liver disease-associated fatigue have
been performed.
The obvious question that arises is, how do these alterations
in central neurotransmission, which lead to fatigue, come
about in the setting of liver disease? Although the answer to
this question is still unclear, it likely involves specific commu-
nication pathways from the diseased liver to the brain, as well
as nonspecific effects of liver disease acting in the context of a
chronic stress for an individual (62).
Chronic stress can have profound behavioural effects (63).
These changes in behaviour can include depression, anxiety
and fatigue (63,64). Moreover, this effect can be caused by
physical, psychological or a combination of stressors, and these
stressors have been implicated in changes in central neuro-
transmitter systems (63,65,66). Of note, chronic stress in
rodents can induce marked changes in neurotransmitter sys-
tems within the brain, which have been discussed earlier with
regards to the genesis of central fatigue (65,66). Furthermore,
chronic liver disease can be viewed as both a physical and a
psychological stressor. Although the physical stress of chronic
liver disease is often relatively mild in the absence of cirrhosis
or liver failure, the psychological impact of carrying a diagno-
sis of liver disease can be substantial because it directly
involves social and professional interactions, and feelings of
self-worth and fear. Certainly this ‘indirect’ pathway that
relates to disease-labelling may contribute significantly to the
development of central fatigue in patients who are aware of
their diagnosis (14,67-69). However, this does not account for
the observation that a significant proportion of patients with
liver disease presents to doctors specifically complaining of
fatigue before a diagnosis of liver disease is made. Therefore, a
‘direct’ communication pathway between the liver and the
brain appears to play an important role in fatigue genesis in the
context of liver disease.
Traditionally, communication between the periphery (ie,
outside the CNS) and the brain has been considered to
involve two potential pathways: neural (ie, nerve projections;
Figure 3) and/or humoral (ie, substances contained within the
circulation; Figure 4) (70). In the setting of liver disease, either
or both pathways may be activated.
The liver and peritoneum are richly innervated with affer-
ent signals being carried to the brain in vagal and spinal nerve
projections (71,72). Activation of these nerves during inflam-
mation in rodents stimulates areas of the brain important in
regulating behavioural arousal and results in the development
of fatigue-like behaviours (73-75). Moreover, these effects can
be abolished by subdiaphragmatic vagotomy (76). However,
patients who have recurrent liver inflammation following liver
transplantation and therefore after complete hepatic denerva-
tion (eg, hepatitic C, PBC) often continue to experience
fatigue (77,78). These observations suggest that neural projec-
tions from the liver to the brain are less likely to contribute sig-
nificantly to changes in CNS neurotransmitter systems that
give rise to central fatigue in the setting of liver disease.
Communication between the diseased liver and the brain
may also occur via mediators released into the circulation as a
result of hepatic injury. In this regard, cytokines present within
the circulation have received the greatest attention (79,80).
Specifically, the liver contains the largest population of fixed
macrophages in the body, which represents an important
source of cytokines found in the circulation (79,80). Moreover,
elevated circulating cytokine levels have commonly been doc-
umented in the setting of both cholestatic and hepatitic liver
diseases (81-85). Furthermore, elevations in circulating
Can J Gastroenterol Vol 20 No 3 March 2006184
Figure 3) Neural transmission pathway for liver to brain signalling.
Kupffer cells within the liver secrete proinflammatory mediators (eg,
cytokines, prostaglandins) that activate vagal afferent nerves, which
innervate the liver. Nerve impulses are then carried to the nucleus trac-
tus solitarius (NTS) within the brainstem, which acts as a relay centre
for the transmission of these impulses to areas throughout the brain.
Stimulation of vagal afferent nerves can thereby result in alterations in
neurotransmitter systems within the brain, which may give rise to cen-
tral fatigue
Figure 4) Humoral transmission pathway for liver to brain signalling.
Substances released within the circulation in the setting of liver disease
(eg, cytokines, including tumour necrosis factor-alpha [TNF
]) acti-
vate the cerebral endothelial cells that make up the blood-brain barrier.
Activated cerebral endothelial cells then secrete secondary messengers
(eg, nitric oxide, prostaglandin E2) into the brain parenchyma, which
induce changes in central neurotransmitter systems, which give rise to
central fatigue
Swain.qxd 3/1/2006 4:00 PM Page 184
cytokine levels, including interleukin-6, tumour necrosis factor-
alpha and interferons, commonly induce fatigue and lethargy
(86-90). In addition, elevated plasma endotoxin levels have
been documented in patients with liver disease (91-93), and
endotoxin administration to humans and animals results in
elevated circulating cytokine levels as well as the generation of
malaise and lethargy (94). In support of inflammatory media-
tors in the circulation causing changes in central neurotrans-
mission and inducing fatigue, the intravenous administration
of cytokines or endotoxin in rodents results in altered central
neurotransmitter levels, including those implicated in the gen-
esis of central fatigue (eg, CRH, serotonin; [95-97]).
Furthermore, in support of the hypothesis that endotoxin can
alter central neurotransmission to change behaviour, a recent
report (98) suggested that gut-derived endotoxin can precipi-
tate hepatic encephalopathy in cirrhotic patients.
An obvious question that arises concerns how cytokines,
which are large proteins, gain access to the CNS. Two poten-
tial theories have been put forward to explain this observation.
First, there are areas of the brain that are devoid of an intact
blood-brain barrier, which represent potential areas where
large molecules such as cytokines could gain access to the CNS
(99). Second, the cerebral endothelial cells, which form the
basis of the blood-brain barrier, express a number of cytokine
receptors and can be stimulated by cytokines within the circu-
lation to produce a variety of secondary messengers (eg, nitric
oxide, prostaglandin E2), which can then be secreted into
brain parenchynal structures (100-102). Moreover, both
prostaglandin E2and nitric oxide are capable of inducing
changes in central neurotransmitter systems (79,80). In addi-
tion, circulating cytokines (via either of these mechanisms)
can induce de novo synthesis and release of cytokines within
the brain (from astroglia for example) (79,80). In support of
the hypothesis that liver disease is associated with altered
central cytokine responses, rats with experimental cholestat-
ic liver disease exhibit increased sensitivity to the generation
of fatigue-like behaviours compared with controls when
interleukin-1-beta is administered centrally (103). These find-
ings suggest that cytokines entering, or being produced within,
the brain, in the setting of liver disease can induce fatigue when
present at levels that are without effect in healthy patients.
General approach
Management of central fatigue associated with liver disease is
complicated and hampered by a general lack of understanding
of fatigue in general. Therefore, specific therapies are currently
not available. However, many patients can benefit from a sys-
tematic approach. An important first step in this process is to
rule out causes of fatigue that may be separate from the
patient’s liver disease. While meeting with a patient, specific
questions should be asked with regard to symptoms of hypothy-
roidism, sleep patterns/behaviours, exercise, caffeine and alco-
hol ingestion, and life stresses. Moreover, a loss of motivation
and pleasure in things that a patient would normally enjoy (ie,
anhedonia), loss of interest in social activities, early morning
awakenings, feelings of guilt and thoughts of suicide are impor-
tant clues to the presence of depression and need to be directly
addressed, and therapy instituted or psychiatric referral con-
sidered (20). In addition, a complete review of a patient’s
prescription medications (eg, beta-blockers, benzodiazepines,
etc) as well as over-the-counter medications and health sup-
plements should be undertaken. Finally, simple laboratory tests
should be performed to exclude other possible causes of fatigue
(eg, thyroid-stimulating hormone, calcium, creatinine, blood
urea nitrogen, electrolytes, fasting blood sugar and magne-
Modifying behavioural components to fatigue
Significant central fatigue warrants lifestyle changes, which
may include rest periods and reduced workloads (104,105).
However, the maintenance of physical activity is of paramount
importance. The natural inclination of patients with central
fatigue is to decrease physical activity. However, decreased
physical activity over time will lead to cardiovascular and mus-
cular deconditioning, which then makes physical activity even
more difficult (104,105). Therefore, all patients need to be
counselled with regard to maintaining an appropriate level of
activity. In addition, an increase in activity should be attempted
through the institution of a graded exercise program (106).
In many patients with liver disease and central fatigue, the
degree and perpetuation of fatigue may be directly related to
and influenced by a complex interaction of physiological, emo-
tional, cognitive, behavioural and social factors (107). A
patient’s thoughts and beliefs (ie, cognitions) may contribute
significantly to the maintenance of certain illness behaviours,
including fatigue (107,108). This concept has received the
greatest attention in the setting of central fatigue related to
chronic fatigue syndrome (107,108). The idea is that psycho-
logical processes not only drive deleterious behavioural pat-
terns, but also directly increase the perception of fatigue (108).
Moreover, cognitive behavioural therapy is the only therapy of
proven efficacy for patients with chronic fatigue syndrome
(109). Therefore, cognitive behaviour therapy needs to be
examined as a potential therapeutic modality for fatigue in
patients with liver disease. Subjective sleep disturbance is
commonly associated with fatigue in patients with liver disease
(8,110). Therefore, all fatigued liver disease patients need to be
counselled with regard to proper sleep habits. However, any
historical clues as to the presence of a specific sleep disorder
(eg, sleep apnea) mandate the pursuit of formal sleep studies.
In this vein, alcohol and caffeine should be limited. Moreover,
any medications that may be contributing to fatigue should be
discontinued if possible.
Pharmacological interventions
Specific pharmacological therapies directed at the physiologi-
cal abnormalities that may underlie central fatigue in patients
with liver disease are currently not available. Nonspecific CNS
stimulants, including modafinil, have been used to treat cen-
tral fatigue (111,112); however, their use in patients with liver
disease and fatigue has not been reported but may warrant fur-
ther investigation, especially for patients with severe fatigue.
Some patients respond to nocturnal therapy with low-dose
amitriptyline, especially if poor sleep patterns are possibly con-
Fatigue is the most common symptom reported by patients
with liver disease. Although the underlying pathogenesis of
fatigue in liver disease is still poorly defined, it appears to
involve changes in central neurotransmission, which result
from signalling between the diseased liver and the brain. A
Fatigue in liver disease
Can J Gastroenterol Vol 20 No 3 March 2006 185
Swain.qxd 2/24/2006 10:51 AM Page 185
better understanding of the pathways and the neurotransmitter
systems involved may provide directed specific therapies for
liver disease-associated fatigue.
ACKNOWLEDGEMENTS: Mark G Swain is an Alberta
Heritage Foundation for Medical Research Senior Scholar and a
Canadian Institutes of Health Research Investigator.
Can J Gastroenterol Vol 20 No 3 March 2006186
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... Now, however, it is being increasingly recognised that CLD can impair quality of life (QoL). Related changes include increased fatigue, non-encephalopathic cognitive impairment, autonomic dysfunction, a loss of appetite, or mood alternation (anxiety, depression) [4,5]. These symptoms can occur at any stage of liver disease and may not be alleviated with treatment of the underlying process. ...
... These symptoms can occur at any stage of liver disease and may not be alleviated with treatment of the underlying process. The most common symptom reported by patients with CLD is fatigue [4][5][6]. Fatigue is common and is experienced by everyone during their lives, but it is a complex symptom that includes lethargy, exhaustion, and malaise. It can present as a specific clinical problem or as an occult problem not linked to liver disease; this makes it easy to miss in clinical assessment. ...
... Most studies on fatigue in CLD patients separate it into 2 types: peripheral and central. Peripheral fatigue is manifested by muscle weakness and is associated with neuromuscular dysfunction at the peripheral nervous system and muscular levels [5,9]. Recent studies [10] have described muscle metabolism changes in patients with CLD, but, in general, peripheral fatigue is not a major problem in the early stages of CLD. ...
Full-text available
Fatigue is the most commonly encountered symptom in patients with chronic liver disease (CLD). The resulting decrease in quality of life contributes markedly to the societal costs of fatigue. Moreover, fatigue is associated with social dysfunction, increased daytime somnolence, impaired working ability, and increased risk of mortality. Fatigue is not related to the severity of the underlying liver fibrosis or dysfunction. In CLD patients, fatigue manifests with both central symptoms, characterised by cognitive impairment, sleep disturbance, apathy, and autonomic dysfunction, and peripheral symptoms, characterised by decreased exercise tolerance and reduced physical activity levels. The pathogenesis of fatigue in CLD is multifactorial and involves changes in the brain-liver axis resulting from changes in inflammatory cytokines or the gut microbiome. Numerous interventions have attempted to alleviate fatigue in CLD by improving its central and peripheral manifestations or the underlying liver disease. Currently, however, there are no widely accepted or effective treatments for fatigue in CLD patients. In this review, we highlight the problem of fatigue in CLD, the current theories regarding its pathogenesis, and current approaches to its treatment.
... Central fatigue is characterized by a lack of self-motivation, while peripheral fatigue typically manifests itself in neuromuscular dysfunction and muscle weakness [34]. Some studies suggested that both types of fatigue were present in patients with chronic liver disease [35,36]. Therefore, fatigue can manifest itself as a lack of intention and inability to exercise, which may be the cornerstone of treatment for overweight/obese patients with NAFLD. ...
Full-text available
Non-alcoholic fatty liver disease (NAFLD) is often thought of as clinically asymptomatic. However, many NAFLD patients complain of fatigue and low mood, which may affect their quality of life (QoL). This may create a barrier to weight loss and hinder the achievement of NAFLD therapy goals. Our study aimed to evaluate the QoL in NAFLD patients vs. healthy volunteers, and to analyze likely influencing factors. From March 2021 through December 2021, we enrolled 140 consecutive adult subjects (100 NAFLD patients and 40 controls). Overall, 95 patients with NAFLD and 37 controls were included in the final analysis. Fatty liver was diagnosed based on ultrasonographic findings. We employed 36-Item Short Form Health Survey (SF-36) to evaluate QoL, Hospital Anxiety and Depression Scale (HADS) to identify anxiety and/or depression, and Fatigue Assessment Scale (FAS) to measure fatigue. NAFLD patients had significantly lower physical component summary scores, as well as significantly higher HADS-D scores, compared with the control group (Mann-Whitney U criterion = 1140.0, p = 0.001 and U = 1294.5, p = 0.022, respectively). Likewise, fatigue was more common in NAFLD patients (χ2 = 4.008, p = 0.045). Impaired QoL was significantly associated with fatigue (FAS score ≥ 22, p < 0.001) and depression (HADS-D ≥ 8, p < 0.001). In conclusion, NAFLD patients had significantly poorer QoL vs. controls, in particular with respect to the physical component of health. Impaired QoL may be associated with fatigue and depression, and together they may interfere with increased physical activity and lifestyle modifications in patients with NAFLD.
... Fatigue is a common symptom presented by patients with chronic liver disease, where iron overload can lead to liver fibrosis and even cirrhosis. The pathophysiology of fatigue in liver disease is not clearly understood; it appears to involve changes in central neurotransmission, which result from signaling between the diseased liver and the brain, and changes in extracerebral neurotransmission affecting fatigue sensing behavior [120,121]. Free radicals also damage pancreatic tissue, which can lead to the development of diabetes [110]. Disrupted blood glucose metabolism may result in hyperglycemic episodes, hypoglycemia, or blood glucose fluctuations, which can lead to fatigue. ...
Full-text available
Fatigue is a common, non-specific symptom that often impairs patients’ quality of life. Even though fatigue may be the first symptom of many serious diseases, it is often underestimated due to its non-specific nature. Iron metabolism disorders are a prominent example of conditions where fatigue is a leading symptom. Whether it is an iron deficiency or overload, tiredness is one of the most common features. Despite significant progress in diagnosing and treating iron pathologies, the approach to chronic fatigue syndrome in such patients is not precisely determined. Our study aims to present the current state of knowledge on fatigue in patients with deteriorated iron metabolism.
... Fatigue is the most common symptom not only in patients with chronic liver disease (Swain, 2006), but also in LT recipients . Fatigue often causes great physical and mental distress to LT recipients (Chen et al., 2019). ...
Full-text available
Objective The objective of the study was to explore the relationship between social support and fatigue as well as the mediating role of social functioning on that relationship.Background Psychosocial factors such as social support and social functioning may influence patients’ fatigue symptoms. There is limited evidence on the relationship between social support, social functioning, and fatigue in liver transplant recipients.MethodsA total of 210 patients with liver transplants from two tertiary hospitals were enrolled in the current study. Questionnaires used include one for general demographic data, the Perceived Social Support Scale (PSSS), Social Disability Screening Schedule (SDSS), and Fatigue Symptom Inventory (FSI).ResultsA total of 126 (60%) recipients reported fatigue. Gender, residence, BMI, and liver function were the primary factors affecting fatigue. Social support was positively correlated with social functioning and was negatively correlated with fatigue. The effect of social support on fatigue was partially mediated by social functioning (35.74%).Conclusion The fatigue of liver transplant recipients should be attended to. The higher the social support, the lower the fatigue of liver transplant recipients. Social support may also reduce fatigue through social functioning. The liver transplant team should help the liver transplant recipient establish a social support system, restore social functioning, and reduce fatigue symptoms.
... Furthermore, a reduction in sedentary-related behaviour (i.e., sitting, reclining or lying posture) is associated with a less liver fat (Bowden Davies et al., 2019) and a decrease in insulin resistance (Sabinicz et al., 2016) among people living with liver disease. However, given reduced muscle mass and fatigue in people living with liver disease (Swain, 2006), meeting the guidelines can be difficult. Specifically, people living with NAFLD are more physically inactive than their healthy counterparts and those diagnosed with cirrhosis spend 76% of their waking hours sedentary (Dunn et al., 2016;Hallsworth et al., 2015). ...
The importance of integrated movement behaviours (MB, i.e., physical activity [PA], sedentary behaviour, and sleep) and their interdependence for health has been recently discussed in the literature. The proposition that the amount of time spent in any one of these behaviours may impact the amount of time spent in another is supported by the ActivityStat hypothesis. The aim of this review is to (1) to assess whether individuals with liver disease display MB and/or energy (i.e., total energy expenditure [EE], basal EE, resting EE, and activity EE) compensation throughout the day and/or days; and (2) to examine whether a prescribed PA intervention triggers compensatory responses. Documents were included if they focused on people living with liver disease; analysed MB and/or EE components; were data-based; and were published in English. Fifteen documents were included in the final synthesis. The one finding that addressed research question 1 showed no compensatory response. As for research question 2, most of the findings suggest no compensation effects in response to a PA intervention. There is insufficient evidence to support the ActivityStat hypothesis in people living with liver disease. Further research should be conducted to test this hypothesis using standardized methodological procedures.
Background Nonalcoholic fatty liver disease (NAFLD) is a silent disease, yet patients might report nonspecific symptoms. The objectives of this study were to examine the effect of polypharmacy on patient-reported symptoms in NAFLD adult patients and to examine the impact of patient-reported symptoms on quality of life (QoL).MethodsA retrospective observational study was conducted to evaluate NAFLD patient-reported symptoms, QoL, and polypharmacy in the US. QoL was measured using the 36-Item Short Form Survey (SF-36) questionnaire. Patients were classified as having polypharmacy if they used five medications or more. The comparisons of patient-reported symptoms between patients with and without polypharmacy were done using the Wilcoxon Rank Sum Test. To examine each symptom and its effect on QoL, multivariable linear models were performed on QoL scores.ResultsThe study included 1032 patients. The average percentage of reporting “none at all” in patients with polypharmacy was 50%, while it was 66% in the non-polypharmacy group (p < 0.01). In multivariable linear models, the symptoms that had a negative impact on QoL in terms of physical health were muscle weakness, fatigue, and swelling of ankles (B = − 13.7, − 9.7, and − 7.914, respectively; all p < 0.01). For mental health, depression/sadness, fatigue, and muscle weakness were the most common symptoms that negatively affected QoL (B = − 20.3, − 11.2 and − 7.1, respectively; all p < 0.01)ConclusionNAFLD patients with polypharmacy reported more symptoms than NAFLD patients with non-polypharmacy. Fatigue and muscle weakness were the most common symptoms that negatively affected physical health QoL, while depression/sadness and fatigue had a negative impact on mental health QoL.
Background: Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by non-suppurative destructive cholangitis of the small intrahepatic bile ducts and female preponderance. Chronic fatigue, a condition marked by extreme tiredness and inability to function because of a lack of energy, is the most common symptom in PBC, affecting up to 80% of patients. However, the pathogenesis of PBC-associated fatigue is unknown, and treatment outcomes are poor. Purpose: We aim to provide an updated summary of pathogenesis and emerging treatments for fatigued PBC patients. Methods: We conducted a structured literature survey and compiled a narrative review. Results: Fatigue is often the most bothersome symptom in PBC patients and is frequently accompanied by cognitive impairment, depressive symptoms, and anxiety. Fatigue is an independent predictor of mortality in PBC. The pathophysiology of these phenomena is complex and poorly understood; therefore, a causal treatment is lacking. Multiple lines of evidence point towards biological, psychological, and social factors that are underlying and modulating the disease burden in fatigued PBC patients. Animal models suggest that an inflammatory liver-brain axis is implicated in the pathogenesis of cholestatic fatigue. The currently available management options for fatigue and cognitive symptoms are mainly supportive. However, specific medical treatment options for relieving fatigue symptoms emerge, including anti-inflammatory treatments. Conclusion: Emerging pathophysiological concepts and experimental therapies may improve outcomes of fatigued PBC patients in the near future.
The objective of this study is to elucidate how the OM-X made from many kinds of plants fermented using lactic acid bacteria (LAB) and bifidobacteria contributes to anti-fatigue. A randomized, placebo-controlled, double-blind, comparative study design was adopted. We investigated the effects of 12-week ingestion of the test food or placebo. Visual analogue scale (VAS) and Chalder fatigue scale (CFS) were examined to evaluate the feeling of fatigue, and diacron-reactive oxygen metabolites (d-ROMs) and Biological Antioxidant Potential (BAP) were measured to appraise comprehensive antioxidative ability. We also evaluated the safety of the food. As a result, significant differences between the two groups were detected in VAS and CFS. No safety-related matter occurred. It turned out that the ingestion of OM-X improved feelings of fatigue for healthy people with temporary fatigue. Additionally, there was no adverse effect by the ingestion of the food.
Background: Long working hours causes several health risks, but little is known about its effects on the liver. This study aimed to examine the correlation between working hours and abnormal liver enzyme levels. Methods: We used data from the Korea National Health and Nutrition Examination Survey IV-VII. For the final 15,316 study participant, the information on working hours was obtained through questionnaires, and liver enzyme levels, consisting of serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), through blood tests. The relationship between weekly working hours and abnormal levels of liver enzymes was analyzed using multiple logistic regression, and a trend test was also conducted. Results: In male, working ≥ 61 hours per week was significantly associated with elevated AST and ALT levels compared with working 35-52 hours per week. Even after adjusting for covariates, the odds ratios (ORs) of abnormal AST and ALT increased by 1.51 (95% confidence interval: 1.20-2.05) and 1.25 (1.03-1.52), respectively, and a dose-response relationship was observed. This association was more prominent among the high-risk group, such as those aged > 40 years, obese individuals, worker on non-standard work schedule, pink-collar workers, or temporary worker. No correlation was observed in female. Conclusions: Long working hours are associated with abnormal liver function test results in male. Strict adherence to statutory working hours is necessary to protect workers' liver health.
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Background The Joint Working Group of the Royal Colleges of Physicians, Psychiatrists and General Practitioners (1996) recommended graded exercise and antidepressants for patients with chronic fatigue syndrome. We assessed efficacy and acceptability of these treatments. Method Six-month prospective randomised placebo and therapist contact time controlled trial with allocation to one of four treatment cells: exercise and 20 mg fluoxetine, exercise and placebo drug, appointments only and 20 mg fluoxetine, appointments and placebo drug. Drug treatment was double blind and patients were blind to assignment to exercise or appointments. Results Ninety-six (71%) of 136 patients completed the trial. Patients were more likely to drop out of exercise than non-exercise treatment ( P =0.05). In an intention to treat analysis, exercise resulted in fewer patients with case level fatigue than appointments only at 26 weeks (12 (18%) v . 4 (6%) respectively P =0.025) and improvement in functional work capacity at 12( P =0.005) and 26 weeks ( P =0.03). Fluoxetine had a significant effect on depression at week 12 only ( P =0.04). Exercise significantly improved health perception ( P =0.012) and fatigue ( P =0.028) at 28 weeks. Conclusions Graded exercise produced improvements in functional work capacity and fatigue, while fluoxetine improved depression only.
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Interleukin-6 (IL-6) is a pleiotropic cytokine believed to play key roles in the neuroimmune interactions. This molecule may act on the nervous system by interacting with its specific receptor subunit (IL-6R) and the signal transducer gp130. The purposes of the present study were to describe the central distribution of IL-6, IL-6R, and gp130 mRNAs under basal conditions and to verify the influence of the immune activator lipopolysaccharide (LPS) and the proinflammatory cytokine interleukin-1beta (IL-1beta) on the expression of IL-6 and its related genes throughout the rat brain. Rats were killed at multiple times after intraperitoneal injection of the bacterial endotoxin and intravenous administration of the recombinant rat IL-1beta (rrIL-1beta), and their brains were cut into 30-microm coronal sections from the olfactory bulb to the end of the medulla. Each transcript was localized by in situ hybridization histochemistry using 35S-labeled rat riboprobes. The results show that IL-6 mRNA was undetectable in the brain under basal conditions and following the injection of rrIL-1beta. Injection of LPS rapidly stimulated transcription of this gene in the choroid plexus and the sensorial circumventricular organs (CVOs), including the organum vasculosum laminae terminalis (OVLT), subfornical organ, median eminence, and area postrema. Conversely, IL-6R and gp130 mRNAs were heterogeneously distributed throughout the brain under basal conditions. The injection of LPS stimulated the biosynthesis of IL-6R in the CVOs, medial preoptic area, bed nucleus stria terminalis, central nucleus of the amygdala, hippocampus, hypothalamic paraventricular nucleus, cerebral cortex, and blood vessels. Increased levels of IL-6R mRNA were also observed in the microvasculature following rrIL-1beta injection. Finally, gp130 mRNA expression was increased in the OVLT and throughout the endothelium of brain capillaries of LPS-treated rats but remained unchanged after administration of rrIL-1beta. These results demonstrate that expression of the genes encoding IL-6, IL-6R, and gp130 can be up-regulated in selective regions of the brain in response to the bacterial endotoxin LPS and the proinflammatory cytokine IL-1beta (only for IL-6R expression). This fine genetic regulation might be of great importance in the neuroimmune interplay and provides the evidence that sensorial CVOs and microvasculature are in a privileged position to mediate the action of IL-6 of central and/or systemic origin in the brain of immune-challenged animals.
It is now well established that an inflammatory challenge as evoked by bacterial endotoxin (LPS) induces autonomic, endocrine, and behavioral responses that are controlled by the brain. However, detailed information on the neuronal pathways and neurotransmitters involved is scarce. We used in vivo microdialysis and biotelemetry in rats to monitor hippocampal and preoptic serotonergic and noradrenergic neurotransmission, body temperature, and heart rate after an i.p. LPS injection. Moreover, free corticosterone levels were measured in the dialysates, and behavioral activity was scored by visual observation. Apart from a biphasic fever response, tachycardia, elevated free corticosterone levels, and sickness behavior, peripheral injection of LPS caused a dramatic increase in preoptic extracellular concentrations of noradrenaline, but no effect on serotonin in this structure. The increase in preoptic noradrenaline levels appears to underlie the first fever phase and may participate in hypothalamic-pituitary-drenocorticul axis activation. In contrast, whereas LPS had only a moderate effect on hippocampal noradrenaline, a marked increase in hippocampal extracellular serotonin levels was found. Use of the interleukin (IL)-1 receptor antagonist and the cyclooxygenase inhibitor indomethacine learned that IL-1 and prostaglandins are mediators in this response. Our data show that an endotoxin challenge results in highly differentiated changes in brain neurotransmission, probably subserving the coordinate processing of immune information in circuits involved in autonomic, neuroendocrine, and behavioral regulation.
Objective: To study the effect of fluoxetine (FL) and amitriptyline (AM), alone and in combination, in patients with fibromyalgia (FM). Methods: Nineteen patients with FM completed a randomized, double-blind crossover study, which consisted of 4 6-week trials of FL (20 mg), AM (25 mg), a combination of FL and AM, or placebo. Patients were evaluated on the first and last day of each trial period. Outcome measures included a tender point score, the Fibromyalgia Impact Questionnaire (FIQ), the Beck Depression Inventory (BDI) scale, and visual analog scales (VAS) for global well-being (1 completed by the physician and 1 by the patient), pain, sleep trouble, fatigue, and feeling refreshed upon awakening. Results: Both FL and AM were associated with significantly improved scores on the FIQ and on the VAS for pain, global well-being, and sleep disturbances. When combined, the 2 treatments worked better than either medication alone. Similar, but nonsignificant, improvement occurred in the BDI scale, the physician global VAS, and the VAS for fatigue and feeling refreshed upon awakening. Trends were less clear for the tender point score. Conclusion: Both FL and AM are effective treatments for FM, and they work better in combination than either medication alone.
Quality of life is an important factor to consider when assessing the value of liver transplantation. Using a large, prospective database of liver transplantation recipients from three clinical centers in the United States, we examined the quality of life of 346 adults before and 1 year after surgery. Five quality of life domains were evaluated (measures of disease, psychological distress and well-being, personal function, social/role function, and general health perception) with standardized questionnaires completed according to established protocol. The largest numbers of patients were distressed by fatigue and muscle weakness, both before transplantation and 1 year after surgery. Compared to baseline, recipients at follow-up noted fewer disease-related symptoms (P < .001) and lower levels of distress overall (P < .001). However, levels of distress due to excess appetite (P < .001), headaches (P = .02), and poor/blurred vision (P = .05) were more likely to increase than decrease. Although 57% to 64% of the recipients were distressed by each of the psychological conditions examined at follow-up, distress was more likely to decrease than increase (P < .001), and well-being was comparable to the general population. All measures of personal functioning improved significantly (P < .05). Fifty-eight percent of the patients prevented by their disease from going to work or school before transplantation were no longer so limited at follow-up. With the exception of marriage (P = .23), all facets of social/role functioning improved more often than worsened (P < .01). Perception of health improved remarkably, with 13.4 times as many recipients reporting improved health as reporting worse health (P < .001). We conclude that liver transplantation markedly improves the quality of life of patients with end-stage liver disease.
Cytokines act on the brain to induce fever and behavioural depression after infection. Although several mechanisms of cytokine-to-brain communication have been proposed, their physiological significance is unclear. We propose that behavioural depression is mediated by the vagus nerve activating limbic structures, while fever would primarily be due to humoral mechanisms affecting the preoptic area, including interleukin-6 (IL-6) action on the organum vasculosum of the laminae terminalis (OVLT) and induction of prostaglandins. This study assessed the effects of subdiaphragmatic vagotomy in rats on fever, behavioural depression, as measured by the social interaction test, and Fos expression in the brain. These responses were compared with induction of the prostaglandin-producing enzyme cyclooxygenase-2 and the transcription factor Stat3 that translocates after binding of IL-6. Vagotomy blocked behavioural depression after intraperitoneal injection of recombinant rat IL-1β (25 µg/kg) or lipopolysaccharide (250 µg/kg; LPS) and prevented Fos expression in limbic structures and ventromedial preoptic area, but not in the OVLT. Fever was not affected by vagotomy, but associated with translocation of Stat3 in the OVLT and cyclooxygenase-2 induction around blood vessels. These results indicate that the recently proposed vagal link between the immune system and the brain activates limbic structures to induce behavioural depression after abdominal inflammation. Although the vagus might play a role in fever in response to low doses of LPS by activating the ventromedial preoptic area, it is likely to be overridden during more severe infection by action of circulating IL-6 on the OVLT or prostaglandins induced along blood vessels of the preoptic area.
Corticotropin-releasing factor (CRF), when administered directly into the CNS, can have activating properties on behaviour and can enhance behavioural responses to stress. CRF injected intraventricularly produces a dose-dependent increase in locomotor activity and increased responsiveness to an acoustic startle stimulus. However, this profile of activation changes to enhanced suppression of behaviour in stressful situations and includes increased freezing, increased conditioned suppression, increased conflict, decreased feeding and decreased behaviour in a novel open field. These effects of CRF are independent of the pituitary–adrenal axis and can be reversed by the CRF antagonist α-helical CRF(9–41). More importantly, the CRF antagonist can also reverse many behavioural responses to stressors. α-Helical CRF(9–41) reverses stress-induced fighting behaviour, stress-induced freezing, stress-induced suppression of feeding, stress-induced decreases in exploration of an elevated plus maze, fear-potentiated startle and the development of conditioned suppression. Intracerebral microinjections suggest that the amygdala may be an important site for the anti-stress effects of α-helical CRF(9–41). These results suggest that endogenous CRF systems in the CNS may have a role in mediating behavioural responses to stress and further suggest that CRF in the brain may function as a fundamental behavioural activating system. This CRF system may be particularly important in situations where an organism must mobilize not only the pituitary–adrenal system but also the CNS in response to environmental challenge.