- Email: [email protected]
Fatigue in Primary Biliary Cirrhosis
Clin Liver Dis 12 (2008) 367–383
Fatigue in Primary Biliary Cirrhosis Julia L. Newton, MBBS, FRCP, PhD Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle, United Kingdom, NE2 4HH
Over the past 20 years the clinical spectrum of primary biliary cirrhosis (PBC) has changed. Recognition of the antimitochondrial antibody, the characteristic autoantibody of PBC [1–3], as a sensitive diagnostic tool able to identify PBC in even early stages of the disease [4] has led to the majority of patients seen in clinical practice being those who have milder forms of the disease rather than those who have end-stage PBC [2,5]. For the majority of patients who have PBC, therefore, the risk for development of endstage disease is low and therapy aimed solely at reducing risk for progression accordingly less relevant [5].This large group of patients, however, who has mild or slowly progressive disease, remains at high risk for developing a range of seemingly stage-independent symptoms of the disease, such as fatigue [6]. Initial descriptions of lethargy in some patients who had PBC emerged in the early 1980s [7,8]. Since then, there has been a progressive increase in reporting the degree, impact, and, latterly, effects on health-related quality of life (HRQOL) of fatigue in PBC [9–13]. With the recognition that debilitating symptoms, in particular fatigue, have a profound impact on those who have PBC has come improved techniques to quantify fatigue [14], recognition of its association with impaired physical activity [15], delineation of its biologic associates [16–18], and its consideration as an endpoint in clinical trials and in the management of patients. Understanding the mechanisms responsible for fatigue and the identification and validation of treatments able to ameliorate it are among the important current issues in PBC and repeatedly are identified as key outstanding issues in surveys of patient groups. Prevalence of fatigue in primary biliary cirrhosis Estimates from Canadian and Northern United Kingdom series confirm that between 40% and 80% of patients who have PBC suffer from E-mail address: [email protected] 1089-3261/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cld.2008.02.010 liver.theclinics.com
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significant fatigue [10,12], with more than half of those who have fatigue considering it the worst symptom of the disease [19]. Other European studies controversially have suggested that although present, fatigue may not be a symptom specific to PBC [20]. These apparent variations in the prevalence of fatigue in PBC reflect the origin of the patient cohort studied, with prevalence higher for all symptoms in clinic-based cohorts compared with geographically based community cohorts; the origin of the control cohorts (which probably accounts for the Scandinavian study [20] as the control group in that study seemingly disproportionately fatigued compared with levels of perceived fatigue measured in other population-derived control populations [12]); and, to some extent, the different assessment approaches used.
Quantifying fatigue in primary biliary cirrhosis To date, the majority of assessment of fatigue in PBC has been performed through the application of questionnaire-based fatigue impact and related HRQOL assessment tools. One study has shown a close relationship between perceived fatigue and actual impairment in physical activity measured using the objective assessment tool of accelerometry [15]. Compared to historical series, the prevalence of fatigue reported in recent studies seems higher. This reflects an increasing appreciation among physicians of the importance of this symptom, and the move toward the use of patient-completed (as opposed to physician-completed) fatigue impact assessment tools, with the first reported studies exploring fatigue prevalence in PBC involving simple assessment of the presence or absence of fatigue. Some of the variability seen in fatigue prevalence studies in PBC reflects the fact that they have used fatigue and HRQOL assessment tools not derived or even, in some cases, validated for use in PBC. The tools used historically in PBC research (generic HRQOL measures, such as Short Form-36 Health Survey or generic fatigue impact measures, such as the fatigue impact score [FIS]) potentially lack relevance, sensitivity, and specificity. This has led to an appreciation of the need for the development of a PBC-derived and PBC-specific patient-oriented HRQOL measure that can be used in impact, etiology, and therapy studies [21]. The PBC-40 is such a PBC-specific HRQOL measure and was developed and validated in the Northeast of England [14]. The availability of this psychometrically robust assessment tool has allowed accurate identification of high- and low-fatigued patient groups and will be an important outcome measure in future intervention trials for fatigue and other symptomatology in PBC. The PBC-40 (available at no charge from the author) contains 40 questions in five domains (fatigue, itch, cognitive, social and emotional, and other symptoms [a domain relating to PBC-related symptoms that do not
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map to the other domains]). Participants rate individual items on a 5-point scale (1 ¼ ‘‘never,’’ 2 ¼ ‘‘rarely,’’ 3 ¼ ‘‘sometimes,’’ 4 ¼ ‘‘most of the time,’’ and 5 ¼ ‘‘always’’). Recent studies have demonstrated clinically meaningful bands for symptom severity (none, mild, moderate, or severe) in each of the symptom domains of the PBC-40 [22]. Using these symptom severity thresholds in the author’s clinic cohort, the overall symptom burden in those who have PBC is high, with more than two thirds of patients having moderate or severe symptoms (Fig. 1) and the most frequently seen status in patients who had PBC was none for ‘‘itch’’; mild for ‘‘other symptoms,’’ ‘‘cognitive,’’ and ‘‘social and emotional’’; and moderate for ‘‘fatigue,’’ confirming previous observations that fatigue is the symptom with the greatest apparent impact on quality of life in patients who have PBC. In addition, the value of the PBC-40 can be seen in its ability to delineate symptoms across a range of domains and explore their overlap. Symptomatic patients who have PBC most frequently have a median of three PBC-40 domain scores in the moderate or severe range (Fig. 2). Studies performed during the validation of the PBC-40 also demonstrated strong correlations between individual fatigue domain and other-symptom, cognitive, and social and emotional domain scores (which, in turn, all correlated with each other) but no correlation with itch scores. This suggests that fatigue in PBC is not a symptom in isolation but forms part of a PBC symptom
Percentage of Total Population
40
30
20
10
0 Asymptomatic
Minimal
Intermediate
High
Overall PBC Symptom Impact Fig. 1. Overall symptom impact in a large PBC patient cohort (n ¼ 197). Minimal, moderate in one PBC-40 domain; Intermediate, moderate in two or three PBC-40 domains or severe in 1; High, moderate in four or five PBC-40 domains, severe in two or more or moderate in three domains, and severe in one.
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30
Percentage of Total Population
25
20
15
10
5
0 0
1
2
3
4
5
Number of PBC-40 Domains With Moderate of Severe Scores Fig. 2. Distribution of moderate or worse symptoms in a PBC cohort (n ¼ 197).
complex [15] and points toward a common pathogenetic mechanism for symptomatology in PBC. The potential for use of the PBC-40 in clinical studies has been underlined in recent publications confirming the relationship between symptom domains in those who have PBC, how they change after transplantation, and that patients’ experience of fatigue translates directly into an impaired ability to function [15,23–25].
Fatigue-associated increase in mortality in primary biliary cirrhosis Recent work performed by the author’s group has suggested that the impact on patients associated with the presence of fatigue may go beyond simple impairment of HRQOL. In a study revisiting the author’s group’s original geographically defined PBC fatigue study cohort [12], the followup mortality rate was significantly higher in patients who had above-median fatigue scores (FIS O 40) in the original study than in patients who had below-median FIS. Although only 4 of the 28 deaths in the original 136-patient cohort were liver disease related, 13 were principally cardiovascular (9.6% of patients and 46% of deaths). Moreover, only one of eight (12.5%) of patients in the low-fatigue group who died had a cardiac death, whereas 12 of 20 (60%, P!.05) of the high-fatigue group had a cardiac death. These differences could not be accounted for by overrepresentation of pre-existing cardiac morbidity or risk factors, patient
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age, or other confounding factors in the fatigued group [26]. Re-evaluation of this cohort has confirmed that the excess mortality has its major impact particularly in those patients who have PBC and are middle aged [27]. These observations require replication but do build on the findings of an earlier study, involving a different patient cohort, which demonstrated a significantly increased standardized mortality ratio for PBC (2.7) [28] with half the increased mortality resulting from non–liver-related processes.
Current understanding of the pathogenesis of fatigue in primary biliary cirrhosis Current, understanding of PBC fatigue pathogenesis is outlined in Fig. 3 and comes from a combination of studies performed in patients who have
MEMORY PROBLEMS
DISTURBED SLEEP PATTERN
BRAIN
Accumulation of a substance due to inability of the liver to remove
Abnormality of liver ability to act as a reservoir (composition or flow)
AUTONOMIC NERVOUS SYSTEM
LIVER
BLOOD PRESSURE
Risk of cardia c death
HEART RATE
FATIGUE MUSCLE DYSFUNCTION
Fig. 3. Hypothesis: fatigue in PBC is a consequence of the central nervous system sequelae of cholestasis, resulting from the localized accumulation of factors (the clearance of which is reduced in the setting of cholestasis) and mediated in part through HPA axis dysfunction and associated primary autonomic dysfunction failure of the brainstem to generate appropriate autonomic signals. The net result of these central processes is a cumulative effect on functional control of blood pressure and peripheral tissue oxygen delivery, which leads to the expression of fatigue through secondary dysfunction of peripheral muscle. The parallel dysfunction of cardiac muscle resulting from functional impairment of perfusion and oxygen delivery that is a predisposing factor for the increased incidence of sudden cardiac death seen in fatigued patients who have PBC.
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PBC and studies performed in animal models of cholestasis, typically the bile duct–resected (BDR) rat. Animal studies of the bile duct–resected rodent BDR rats show significant behavior changes (over and above those seen in sham-operated controls), including anhedonia, loss of social interest [29], and reduced locomotor activity [30], changes that have been interpreted as representing ‘‘fatigue’’ in the laboratory animal setting. Notwithstanding, the issues associated with the different disease kinetic and the conceptual problem regarding interpretation of the symptom of fatigue in laboratory animals this model has yielded important findings that have informed, and will continue to inform, human studies. The BDR studies have shed light particularly on potential signaling pathways, which may be responsible for these behavioral changes. Cholestatic rats have an increase in midbrain 5HT-1A receptors and exhibit enhanced 5HT-1A autoreceptor-mediated responses (hypothermia and hyperphagia) after administration of a highly specific 5HT-1A receptor agonist [31]. This agonist also is effective at reducing ‘‘fatigue-like’’ behavior in cholestatic rats [32]. Furthermore, the impairment in locomotor activity seen in BDR rats is partially reversed after intraventricular administration of a corticotropin-releasing hormone (CRH) type-1 receptor antagonist [30]. These observations are interpreted as suggesting defective central CRH neurotransmission with secondary locomotor activity decrease. One factor potentially contributing to defective CRH neurotransmission may be an increased central sensitivity to interleukin (IL)-1b seen in cholestasis [33]. A recent animal study [34] has hinted at the potential role for inflammatory mechanisms in the pathogenesis of fatigue in cholestasis. To date, studies in humans exploring the association between fatigue severity and degree of cholestasis, assessed, for example, through serum bile acid levels and inflammation are limited. Factors not associated with fatigue in primary biliary cirrhosis There is a broad consensus, from multiple patient cohort studies, that the degree of fatigue experienced by patients who have PBC is not associated with histologic stage of disease, degree of hepatocellular dysfunction, or autoantibody levels [10,11,12,19]. Whether or not fatigue in PBC is a manifestation of depression is an area of contention in PBC. Several studies have suggested variable associations between the presence of fatigue and features of depressive illness (assessed using diverse depression screeners) in PBC [10,12,19]. One problem with the use of such depression screening tools is that they are weighted toward physical manifestations of depression and thus can be significantly skewed in patients who have physical disease, giving rise to a largely spurious elevation in the apparent prevalence of depression in such chronic disease patient
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groups. This view is supported by a Dutch study of 73 patients who had PBC, 41% of whom had depressive symptoms as determined by the Beck Depression Inventory but only 4.9% of whom had a depressive syndrome according to structured psychiatric interview [35,36]. Established biologic associates of fatigue in primary biliary cirrhosis Structural cerebral abnormalities that may lead to fatigue in primary biliary cirrhosis Preliminary studies in a limited number of patients using cerebral magnetization contrast imaging and proton magnetic resonance spectroscopy (MRS) have demonstrated a significant reduction in globus pallidus magnetization transfer ratio (MTR) in precirrhotic patients who have PBC compared with healthy controls, with a significant correlation between the degree of abnormality and fatigue severity experienced by patients [37]. There were no differences in MRS measurements between the groups, suggesting that the abnormal MTR was not related to hepatic encephalopathy. In this study, abnormality in MTR measurements correlated with levels of manganese in the blood, which in turn correlated with degree of fatigue. These early studies have raised the possibility that impairment in liver function in cholestatic conditions may adversely affect the brain long before the development of cirrhosis and hepatic encephalopathy. Confirmation of these findings is required; however, these studies would, if replicated, concur with the rat cholestasis model data in implicating central mechanisms in the pathogenesis of PBC. The importance of central mechanisms in the pathogenesis of fatigue in PBC is supported further by studies from the authors’ group using validated neurophysiologic techniques. When assessed using transcranial magnetic stimulation, patients who have early-stage PBC seem to have a global cerebral abnormality, which remains in a cohort of post-transplant patients who have PBC [38]. In addition, more recent magnetic resonance studies have shown the presence of structural brain lesions (deep white matter hyperintensities) even in early stages of PBC [39], which associate with objective measures of cognitive impairment (seen at higher prevalence in PBC) and, as seen in non–liver disease settings, degree of autonomic nervous system dysfunction [40]. This raises the possibility that those who have PBC are at risk for irreversible, potentially progressive brain lesions that are unrelated to the characteristic delirium of end-stage liver disease, hepatic encephalopathy [39]. Excessive daytime sleepiness One of the earliest studies to describe fatigue in PBC identified an association between fatigue severity and poor sleep hygiene (assessed using the Pittsburgh Sleep Quality Index) [10]. This relationship has been explored further using subjective (Epworth Sleepiness Scale [ESS]) and objective
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(actigraphy) assessment modalities, which confirmed a strong relationship between fatigue and excessive daytime sleepiness in PBC [18]. This was not the result of an increased prevalence of obstructive sleep apnoea in those patients who had PBC who underwent formal sleep studies. Recognition of this association has been a major step toward offering effective fatigue-ameliorating treatments to those who have PBC. In 2005, Kaplan and Bonis [41] described the potential benefits of symptom management with the use of the wake-inducing medication, modafinil, in PBC. In a further open-label series of patients treated with modafinil, significant improvements in daytime sleepiness were seen, coupled with dramatic improvements in fatigue severity and interestingly cognitive symptoms [24]. Further studies are needed to determine the long-term benefits of modafinil and to explore the biologic processes that lead to excessive sleepiness in PBC. Autonomic dysfunction and fatigue in primary biliary cirrhosis Recently, the authors’ group also identified a link between abnormalities of the autonomic nervous system, in particular, blood pressure homeostasis, and degree of fatigue in patients who had PBC [16,17,22,23,42]. Associations between fatigue and autonomic dysfunction are noted in several other fatigue-associated chronic conditions, including primary autonomic failure, multisystem atrophy, chronic fatigue syndrome, Parkinson’s disease, and multiple sclerosis [42–45]. Studies using novel beat-to-beat methodology with increased sensitivity compared with classical autonomic function tests have examined the integrity of the autonomic nervous system in patients who have PBC (through examination of dynamic cardiovascular reflexes, heart rate variability [HRV], and baroreflex sensitivity). Fatigued patients who have PBC have significantly lower HRV than nonfatigued patients who have PBC or normal controls (no such association being seen for the other, non–fatiguerelated domains of the PBC-40), with the HRV reduction occurring predominantly in the very low frequency domain, an observation again implicating central mechanisms [17]. A 24-hour ambulatory blood pressure assessment performed in the same cohort of patients shows significant inverse relationships between fatigue and both mean systolic blood pressure (r ¼ 0.35) and pulse pressure (r ¼ 0.34), with this relationship particularly strong for night-time blood pressure [23]. Dynamic testing of cardiovascular reflexes, including the Valsalva maneuver and head-up tilt testing, confirms the presence of neurally mediated hypotension in 65% of a series of patients who had PBC and strongly implicates sympathetic overactivity and impaired baroreflex sensitivity as having a role in the fatigue experienced by those who have PBC [22]. Autonomic dysfunction previously has been reported in advanced stages of PBC although no attempt was made to link it with fatigue [46,47]. This led to the assumption that autonomic dysfunction was related to the presence of cirrhotic disease. The author’s work has shown that autonomic
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dysfunction is present, at comparable frequency, in cirrhotic and precirrhotic patients, with an equal association with fatigue severity seen in both groups (a finding that concurs with the lack of a stage association for fatigue in PBC) [16]. The link between fatigue and autonomic function in PBC is potentially highly significant given the author’s observation of increased mortality associated with fatigue in PBC, with a particular increase in cardiac deaths and an over-representation of sudden cardiac death. Autonomic dysfunction has been demonstrated, in settings outside PBC, as associated with an increased risk for (principally sudden) cardiac death [48–51], and in liver disease its presence conveys a fivefold increase in mortality. This, coupled with the observation of a prolonged QTc in PBC, points toward an increased tendency to arrhythmic-associated deaths in PBC [46].
Reduced physical activity and abnormalities in peripheral muscle function in primay biliary cirrhosis Perceived fatigue (assessed using subjective assessment modalities) has been shown to associate with reduced physical activity (measured using actigraphy over 7 days) [15]. The direction of this association is uncleardDoes fatigue lead to reduced physical activity or, conversely, does impaired physical function result in fatigue? Either way, physical activity monitoring has potential as an important endpoint in clinical trails in PBC and may prove to be a fatigue-ameliorating intervention. In addition to the evidence supporting a central mechanism for fatigue development in PBC, studies suggest that there are peripheral mechanisms, in particular muscle dysfunction, that contribute to fatigue in PBC [52]. Fatigued patients who have PBC are shown to have accelerated reduction in muscle function on repeated sustained activity compared with normals and nonfatigued subjects, with the rate of reduction in muscle function correlating with the severity of fatigue. This points to a contribution of peripheral muscle fatigability to the fatigue experienced by patients. The mechanisms underlying this dysfunction currently are unknown but early MRS studies confirm that there are abnormalities in muscle bioenergetics in those who have PBC. During exercise, patients who have PBC showed excess muscle acidosis after exercise compared with controls. The degree of this acidosis correlated closely with elevation of the phosphocreatine/ ADP recovery ratio, indicating that postexercise acidosis in patients who have PBC is related to mitochondrial dysfunction. Patients who have PBC also showed significant prolongation of the muscle pH recovery time after exercise with a significant association between the degree of clinical fatigue experienced by patients who have PBC and prolonged pH recovery after exercise. This preliminary data has demonstrated that patients who have PBC exhibit a variable degree of muscle mitochondrial dysfunction, which manifests itself as excess acidosis after exercise. The extent to which patients
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can recover rapidly from this acidosis seems to determine whether or not they are clinically fatigued [53]. Other putative mechanisms for fatigue pathogenesis in primary biliary cirrhosis Inflammatory cytokines Administration of IL-6 in humans is associated with daytime somnolence and fatigue [54], and elevations of IL-6, tumor necrosis factor a, and IL-1 occur in a range of clinical conditions in which daytime somnolence and fatigue are prominent [55]. This has led to the concept that IL-6 (levels of which have a circadian rhythm) plays a key role in the sleep/ wake cycle [56]. mRNA levels for IL-6 are elevated in the liver in patients who have PBC [57,58] and peripheral blood mononuclear cells from patients who have PBC show enhanced spontaneous and evoked IL-6 release [59]. Elevated IL-6 seems to occur, in part, as a direct consequence of cholestasis, as hydrophobic bile acids of the type retained in PBC induce cultured biliary epithelial cells to release IL-6 [60]. This is of relevance to understanding fatigue pathogenesis given that circulating IL-6 levels and muscle IL-6 mRNA are elevated acutely in exercise with a postulated energy homeostasis role [61], whereas elevation of IL-6 in hospitalized older patients is associated with impairment of muscle function and fatigue [62]. Adipokines A key factor stimulating release of IL-6 is leptin, an adipokine that conveys information on energy homeostasis [63]. IL-6, in turn, has a role in regulating leptin release [64]. Leptin levels are significantly elevated (and ghrelin levels significantly decreased) in patients who have PBC when corrected for fat mass [65]. Pilot data confirm that in patients who have PBC, fat mass in general (assessed using bioelectrical impedance) and visceral fat in particular (a specific source of leptin) are specifically increased [17]. More than 70% of patients who have PBC have waist/hip ratios over 0.8. Furthermore, lipid metabolism is deranged in patients who have PBC and cholesterol levels high [66]. Strikingly, the degree of leptin elevation in patients who have PBC correlates directly with severity of fatigue [67]. In addition to a profatigue effect through induction of IL-6 release, leptin potentially could have a fatigue-inducing effect via its central actions, including its suppression of the hypothalamic-pituitary-adrenal (HPA) axis [68] or its effects on neuropeptide function [69]. A potential mechanism for the elevation of leptin seen in PBC is suggested by the observation that leptin promotes biliary cholesterol elimination during weight loss in the ob/ob leptin-deficient mouse [70]. In light of the prevalence of autonomic dysfunction in fatigued patients who have PBC and the apparent links between autonomic function, leptin, fatigue, and omega-3 fatty acids [71],
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the autonomic nervous system, lipid metabolism, and leptin release seem highly interdependent [72]. The brain-liver axis It is intriguing to speculate how a disease characterized by an autoimmune process that affects the largest organ of the body results in such profound symptoms that are partly or entirely central in their origin. It is plausible that the pathogenic processes that characterize PBC also lead to the central (or peripheral) abnormality that results in the symptom of fatigue. Such PBC-specific features that could lead to such a phenomenon would include inflammation, cholestasis, or presence of the antimitochondrial antibody that characterizes the disease. Further signaling mechanisms between the liver and the brain require better delineation and will form the basis of exciting future research. The classical assumption that PBC is purely a liver disease may not be true; the abnormalities found in those who have PBC are not restricted to the liver and PBC may, in fact, be a systemic disease. Clinical management of fatigue in those who have primary biliary cirrhosis Although reducing morbidity and mortality related to the underlying disease is of fundamental importance as a goal in the treatment of any disease, it is just as critical that clinicians treat patients’ symptoms and improve their quality of life (surely fatigue is a cause of morbidity). This is particularly vital in a chronic disease, such as PBC, where significant impairment of HRQOL is recognized. Improvement in quality of life as a goal of therapy in its own right is made more pertinent by the observation that outcomes in terms of survival are very good, almost regardless of therapy in young patients who have PBC with early disease (although the outcome in terms of survival may be less rosy in older patient groups) [28]. In patients in whom the disease is only slowly progressive, the symptoms of the disease can have a major impact on HRQOL. Ameliorating symptoms and as a result improving QOL in such patients would be of major practical benefit to many patients. Fatigue is a critical factor in determining quality of life in those who have PBC and there is, therefore, the real opportunity to make a difference in this patient group if appropriate and effective strategies can be developed to reduce or reverse this debilitating symptom. Fig. 4 describes the clinical management strategy for fatigue and associated symptoms in patients attending the author’s dedicated PBC clinic. Getting such strategies right can be immensely clinically rewarding and early suggestions are that it is not nearly as daunting as it seems at first. In the author’s experience, however, to achieve consistent benefit for patients, the clinical approach must be structured. The recent introduction of a PBCspecific, integrated care pathway, which combines a range of management algorithms into a dedicated PBC service, has confirmed that such an approach can lead to significant improvements in quality of life [73].
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PBC patient with Fatigue Exclude other causes of fatigue: Hypothyroid/anaemia/celiac/uncontrolled diabetes Review necessity for all drugs : Sedatives/sleeping meds etc.
Does patient complain of daytime sleepiness ?
Yes – do Epworth Sleepiness Score (ESS)
ESS >10
No Patient taking any meds that might lead to blood pressure dysregulation ? e.g antihypertensives/antianginals/amitryptiline/ alphablockers etc.
ESS <10
No
Yes
Consider trial of modafinil Consider Sleep Apnoea
Review ESS and PBC-40 after trial Improvement ?
Yes continue
Review need for this medication Patient complains of postural dizziness ? OGS >4
No – supportive treatment No
Consider stopping Consider 24 hour BP Consider longer acting meds/meds at night
Yes – consider autonomic dysfunction Review strategies to increase intravascular volume – fluid intake etc.
Refer for formal autonomic assessment including testing for vasovagal syncope and orthostatic hypotension
Fig. 4. Suggested clinical management protocol for fatigue in PBC.
Managing biologic features that associate with fatigue in clinical practice The two main biologic associates of fatigue in PBC, namely excessive daytime sleepiness and autonomic dysfunction, can be assessed easily in clinical practice. The relative contributions of each of these biologic fatigue associates have been considered using the Orthostatic Grading Scale (OGS) [74] as a subjective assessment of autonomic nervous system symptoms and the ESS [75] as a measure of daytime somnolence
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[25]. Using these two clinical assessment modalities, the author has evaluated a clinical diagnostic criterion for use in clinical practice. A significant proportion of fatigue in PBC was associated with the presence of either or both autonomic dysfunction (OGS R 4) and sleep disturbance (ESS R10). The relative distributions of these contributions and their overlap are shown in Fig. 5. For clinical management of patients who have fatigue, those meeting ESS and OGS criteria did not have more severe fatigue than those patients meeting the diagnostic criterion for OGS or ESS alone (all three groups showed substantially greater fatigue severity than the group of patients who met neither of the criteria). The finding of such a threshold effect for fatigue in PBC will have implications for potential therapeutic interventions directed toward reducing fatigue [25]. Approach to fatigue management in primary biliary cirrhosis A supportive positive approach to the management of symptoms in PBC, in particular fatigue, is vital and in itself can lead to improvements in quality of life (Box 1). Managing patients who have fatigue in any chronic disease requires empathy. The chronic fatigue syndrome literature indicates that doctors’ belief whether or not fatigue constitutes a biologic symptom determines whether or not they offer supportive treatment and whether or not patients have a positive outcome. In focus group discussions with the author’s patient group, the same is true of fatigue and its management in PBC, with the outcome of consultations involving clinicians who have a positive attitude to symptom management proving beneficial for patients. Fatigue in PBC is associated with high levels of frustration [76] and recognizing this as a direct consequence of fatigue and delivering directed interventions
Neither (10%)
Autonomic Dysfunction (28%)
AD EDS AD+EDS Both (38%)
NEITHER
Excessive daytime sleepiness (24%) Fig. 5. Biologic associates in the 29% of the author’s PBC clinic cohort who complain of severe fatigue.
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Box 1. Key strategies for the successful management of fatigue in primary biliary cirrhosis 1. Fatigue usually is ‘‘real’’ in chronic disease: Treat it as such. 2. It is normally multifactorial, with different patients who have the same symptom having different causes (and different responses to treatment). 3. Treat the treatable, ameliorate the ameliorable, and always support and understand (do not fail before you start). 4. Take a structured approach 5. Quantification is key. 6. Treat the underlying cause. 7. Ameliorate the effects of the fatigue. 8. Cope with the effects fatigue has on life. 9. Empathize and understand.
that address the psychologic distress that arises in patients who have PBC as a consequence of fatigue should be considered supportive treatment.
Summary The autoimmune liver disease PBC is associated with debilitating fatigue in a significant proportion of patients. In addition to having an impact on quality-of-life fatigue in PBC, it may influence length of life. The pathogenesis of fatigue in PBC is unclear, but preliminary studies suggest it has central mechanisms and may have peripheral manifestations. Studies of fatigue in nonhepatic diseases show that autonomic dysfunction plays a role, and early data strongly suggest the same is true in PBC. Comprehensive studies investigating the pathogenesis of fatigue in PBC are urgently needed as are large-scale prospective outcome studies.
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[7] Christensen E, Crowe J, Doniach D, et al. Clinical pattern and course of disease in primary biliary cirrhosis based on an analysis of 236 patients. Gastroenterology 1980;78:236–46. [8] James OFW, Macklon AF, Watson AJ. Primary biliary cirrhosis: a revised clinical spectrum. Lancet 1981;1:1278–81. [9] Witt-Sullivan H, Heathcote J, Cauch K, et al. The demography of primary biliary cirrhosis in Ontario, Canada. Hepatology 1990;12:98–105. [10] Cauch-Dudek K, Abbey S, Stewart DE, et al. Fatigue in primary biliary cirrhosis. Gut 1998; 43:705–10. [11] Prince MI, James OFW, Holland NP, et al. Validation of a fatigue impact score in primary biliary cirrhosis: towards a standard for clinical and trial use. J Hepatol 2000;32:368–73. [12] Goldblatt J, Taylor PJS, Lipman T, et al. The true impact of fatigue in primary biliary cirrhosis: a population study. Gastroenterology 2002;122:1235–41. [13] Poupon RE, Chretien Y, Chazouilleres O, et al. Quality of life in patients with primary biliary cirrhosis. Hepatology 2004;40:489–94. [14] Jacoby A, Rannard A, Buck D, et al. Development, validation and evaluation of the PBC-40, a disease specific health related quality of life measure for primary biliary cirrhosis. Gut 2005; 54:1622–9. [15] Newton JL, Bhala N, Burt J, et al. Characterisation of the associations and impact of symptoms in primary biliary cirrhosis using a disease specific quality of life measure. J Hepatol 2006;44:776–82. [16] Newton JL, Davidson A, Kerr S, et al. Autonomic dysfunction in primary biliary cirrhosis correlates with fatigue severity. Eur J Gastroenterol Hepatol 2007;19:125–32. [17] Newton JL, Allen J, Kerr S, et al. Reduced heart rate variability and baroreflex sensitivity in primary biliary cirrhosis. Liver Int 2006;26:197–202. [18] Newton JL, Gibson JG, Tomlinson M, et al. Fatigue in primary biliary cirrhosis is associated with excessive daytime somnolence. Hepatology 2006;44:91–8. [19] Huet PM, Deslauriers J, Tran A, et al. Impact of fatigue on the quality of life in patients with primary biliary cirrhosis. Am J Gastroenterol 2000;95:760–7. [20] Bjornsson E, Simren M, Olsson R, et al. Fatigue is not a specific symptom in patients with primary biliary cirrhosis. Eur J Gastroenterol Hepatol 2005;17:351–7. [21] Rannard AC, Buck D, Jones DEJ, et al. Assessing quality of life in primary biliary cirrhosis. Clin Gastroenterol Hepatol 2004;2:164–74. [22] Newton JL, Jones DEJ, Newton JL, et al. The population prevalence of autonomic dysfunction and daytime somnolence in Primary Biliary Cirrhosis. Hepatology 2007;47:1496–505. [23] Newton JL, Bhala N, Jones DEJ. Fatigue in primary biliary cirrhosis is associated with nocturnal hypotension. Hepatology 2004;40:461A. [24] Jones DEJ, Newton JL. An open study of Modafinil for the treatment of daytime somnolence and fatigue in Primary Biliary Cirrhosis. Aliment Pharmacol Ther 2007;25:471–6. [25] Newton JL, Jones DEJ. A predictive model for fatigue and its aetiological associations in primary biliary cirrhosis. Clin Gastroenterol Hepatol 2008;6:228–33. [26] Jones DE, Bhala N, Burt JA, et al. Four year follow up of fatigue in a geographically defined primary biliary cirrhosis patient cohort. Gut 2006;55:536–41. [27] Jones DEJ, Newton JL. Fatigue-associated mortality in primary biliary cirrhosis is principally a problem of the over 65’s. Gut 2007;56:1166. [28] Prince M, Chetwynd A, Newman WL, et al. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology 2002;123:1044–51. [29] Swain MG, Le T. Chronic cholestasis in rats induces anhedonia and loss of social interest. Hepatology 1998;28:6–10. [30] Burak KW, Le T, Swain MG. Increased sensitivity to the locomotor-activating effects of corticotrophin-releasing hormone in cholestatic rats. Gastroenterology 2002;122:681–8. [31] Burak KW, Le T, Swain MG. Increased midbrain 5-HT1A receptor number and resposiveness in cholestatic rats. Brain Res 2001;892:376–9.
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[32] Swain MG, Maric M. Improvement in cholestasis-associated fatigue with a serotonin receptor agonist using a novel rat model of fatigue assessment. Hepatology 1997;25:492–4. [33] Swain MG, Beck P, Rioux K, et al. Augmented interleukin-1 beta-induced depression of locomotor activity in cholestatic rats. Hepatology 1998;28:1561–5. [34] Kerfoot SM, D’Mello C, Nuyen H, et al. TNF-a-secreting monocytes are recruited into the brain of cholestatic mice. Hepatology 2006;43:154–62. [35] Van Os E, van den Broek WW, Mulder PGH, et al. Depression in patients with primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol 2007;46:1099–103. [36] Jones DEJ. Fatigue in cholestatic liver disease: is it all in the mind? J Hepatol 2007;46:992–4. [37] Forton D, Patel N, Prince M, et al. Fatigue and primary biliary cirrhosis: association of globus pallidus magnetization transfer ratio measurements with fatigue seveirty and blood manganese levels. Gut 2004;53:587–92. [38] McDonald C, Baker S, Lai M, et al. Central cerebral activation is reduced in primary biliary cirrhosis and associated with excessive daytime sleepiness [abstract]. Hepatology 2007;46:S1 A695. Presented as an abstract at the American Association for the Study of the Liver and the British Association for the Study of the Liver 2007. [39] Hollingsworth KG, Blamire AM, El-Sharkawy A, et al. Autonomic dysfunction in primary biliary cirrhosis is associated with structural brain abnormalities, particularly in the globus pallidus [abstract]. Hepatology 2007;46:S1 A696. Presented as an abstract at the American Association for the Study of the Liver 2007. [40] Garde E, Lykke Mortensen E, Rostrup E, et al. Decline in intelligence is associated with progression in white matter hyperintensity volume. J Neurol Neurosurg Psychiatry 2005;76: 1289–91. [41] Kaplan MM, Bonis PAL. Modafinil for the treatment of fatigue in primary biliary cirrhosis. Ann Intern Med 2005;143:546. [42] Newton JLO, Sutcliffe O, Seth K, et al. Symptoms of autonomic dysfunction in chronic fatigue syndrome. QJM 2007;100:519–26. [43] Flackenecker P, Rufer A, Bihler I, et al. Fatigue in MS is related to sympathetic vasomotor dysfunction. Neurology 2003;61:851–3. [44] Freeman R, Komaroff AL. Does the chronic fatigue syndrome involve the autonomic nervous system? Am J Med 1997;102:357–64. [45] Keselbrener L, Akselrod S, Ahiron A, et al. Is fatigue in patients with multiple sclerosis related to autonomic dysfunction? Clin Auton Res 2000;10:169–75. [46] Kempler P, Varadi A, Kadar E, et al. Autonomic and peripheral neuropathy in primary biliary cirrhosis: evidence of small sensory fibre damage and prolongation of the QT interval. J Hepatol 1994;21:1150–1. [47] Keresztes K, Istenes I, Folhoffer A, et al. Autonomic and sensory nerve dysfunction in primary biliary cirrhosis. World J Gastroenterol 2004;10:3030–43. [48] Parati G, Di Renzo M, Mancia G. Dynamic modulation of baroreflex sensitivity in health and disease. Ann N Y Acad Sci 2001;940:469–87. [49] Schwarz PJ. The autonomic nervous system and sudden death. Eur Heart J 1998;19:F72–80. [50] Kleiger RE. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol 1987;59:256–62. [51] Vanoli E, Cerati D, Pedretti RF. Autonomic control of heart rate: pharmacological and nonpharmacological modulation. Basic Res Cardiol 1998;93:133–42. [52] Goldblatt J, James OFW, Jones DEJ. Grip strength and subjective fatigue in patients with primary biliary cirrhosis. JAMA 2001;285:2196–7. [53] Hollingsworth KG, Blamire AM, Taylor R, et al. Primary biliary cirrhosis (PBC) is characterised by abnormalities in pH handling by peripheral muscle on 31P magnetic resonance spectroscopy: implications for the pathogenesis of fatigue. Presented at the British Association for the Study of the Liver 2007. September 2007. [54] Mastorakos G, Chrousos GP, Weber JS. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J Clin Endocrinol Metab 1993;77:1690–4.
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[55] Vgontzas AN, Papanicolau DA, Bixler EO, et al. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab 1997;82:1313–6. [56] Bauer J, Hohagen T, Ebert J, et al. Interleukin-6 serum levels in healthy persons correspond to the sleep-wake cycle. Clin Investig 1994;72:315. [57] Martinez OM, Villanueva JC, Gershwin ME, et al. Cytokine patterns and cytotoxic mediators in primary biliary cirrhosis. Hepatology 1995;21:113–9. [58] Nagano T, Yamamoto K, Matsumoto S, et al. Cytokine profile in the liver of primary biliary cirrhosis. J Clin Immunol 1999;19:422–7. [59] Kakumu S, Shinagawa T, Ishikawa T, et al. Interleukin 6 production by peripheral blood mononuclear cells in patients with chronic hepatitis B virus infection and primary biliary cirrhosis. Gastroenterol Jpn 1993;28:18–24. [60] Lamireau T, Zoltowska M, Levy E, et al. Effects of bile acids on biliary epithelial cells: proliferation, cytotoxicity and cytokine secretion. Life Sci 2002;72:1401–11. [61] Febbraio MA, Pedersen BK. Muscle-dered interleukin-6: mechanisms for activation and possible biological roles. FASEB J 2002;16:1335–47. [62] Bautmans I, Njemini R, Lambert M, et al. Circulating acute phase mediators and skeletal muscel pperformance in hospitalized geriatric patients. J Gerontol A Biol Sci Med Sci 2005;60:361–7. [63] Loffreda S, Yang SQ, Lin HZ, et al. Leptin regulates pro-inflammatory immune responses. FASEB J 1998;12:57–63. [64] Faggioni R, Feingold KR, Grunfeld C. Leptin regulation of the immune response and the immuno-deficiancy of malnutrition. FASEB J 2001;14:2565–71. [65] Breidert M, Zimmermann TF, Schneider R, et al. Ghrelin/leptin-imbalance in patients with primary biliary cirrhosis. Exp Clin Endrocrinol Diabetes 2004;112:123–6. [66] Longo M, Crosignani A, Battezzati PM, et al. Hyperlipidaemic state and cardiovascular risk in primary biliary cirrhosis. Gut 2002;51:265–9. [67] Piche T, Gelsi E, Schneider SM, et al. Fatigue is associated with high circulating leptin levels in chronic hepatitis C. Gut 2002;51:434–9. [68] Hosoi T, Kawagishi T, Okuma Y, et al. Brain stem is a direct target for leptin’s action in the central nervous system. Endocrinology 2002;143:3498–504. [69] Sakurai T. Roles of orexin/hypocretin in regulation of sleep/wakefulness and energy homeostasis. Sleep Med Rev 2005;9:231–41. [70] Hyogo H, Roy S, Paigen B, et al. Leptin promotes biliary cholesterol elimination during weight loss in ob/ob mice by regulating the enterohepatic circulation of bile salts. J Biol Chem 2002;277:34117–24. [71] Christensen JH. n-3 fatty acids and the risk of sudden cardaic death: emphasis on heart rate variability. Dan Med Bull 2003;50:347–67. [72] Evans BA, Agar L, Summers RJ. The role of the sympathetic nervous system in the regulation of leptin synthesis in C57Bl/6 mice. FEBS Lett 1999;444:149–54. [73] National Library for Health. Primary biliary cirrhosis. Available at: http://www.library.nhs. uk/Pathways/viewResource.aspx?resID¼270519. Accessed March 2008. [74] Schrezenmaier C, Gehrking JA, Hines SM, et al. Evaluation of orthostatic hypotension: relationship of a new self-report instrument to laboratroy-based measures. Mayo Clin Proc 2005;80:330–4. [75] Johns M. Sleepiness in different situations measured by the Epworth Sleepiness Scale. Sleep 1994;17:703–10. [76] Blackburn P, Freeston M, Baker C, et al. The role of psychological factors in the fatigue of Primary Biliary Cirrhosis. Liver Int 2007;27:654–61.
Fatigue in Primary Biliary Cirrhosis Julia L. Newton, MBBS, FRCP, PhD Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle, United Kingdom, NE2 4HH
Over the past 20 years the clinical spectrum of primary biliary cirrhosis (PBC) has changed. Recognition of the antimitochondrial antibody, the characteristic autoantibody of PBC [1–3], as a sensitive diagnostic tool able to identify PBC in even early stages of the disease [4] has led to the majority of patients seen in clinical practice being those who have milder forms of the disease rather than those who have end-stage PBC [2,5]. For the majority of patients who have PBC, therefore, the risk for development of endstage disease is low and therapy aimed solely at reducing risk for progression accordingly less relevant [5].This large group of patients, however, who has mild or slowly progressive disease, remains at high risk for developing a range of seemingly stage-independent symptoms of the disease, such as fatigue [6]. Initial descriptions of lethargy in some patients who had PBC emerged in the early 1980s [7,8]. Since then, there has been a progressive increase in reporting the degree, impact, and, latterly, effects on health-related quality of life (HRQOL) of fatigue in PBC [9–13]. With the recognition that debilitating symptoms, in particular fatigue, have a profound impact on those who have PBC has come improved techniques to quantify fatigue [14], recognition of its association with impaired physical activity [15], delineation of its biologic associates [16–18], and its consideration as an endpoint in clinical trials and in the management of patients. Understanding the mechanisms responsible for fatigue and the identification and validation of treatments able to ameliorate it are among the important current issues in PBC and repeatedly are identified as key outstanding issues in surveys of patient groups. Prevalence of fatigue in primary biliary cirrhosis Estimates from Canadian and Northern United Kingdom series confirm that between 40% and 80% of patients who have PBC suffer from E-mail address: [email protected] 1089-3261/08/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.cld.2008.02.010 liver.theclinics.com
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significant fatigue [10,12], with more than half of those who have fatigue considering it the worst symptom of the disease [19]. Other European studies controversially have suggested that although present, fatigue may not be a symptom specific to PBC [20]. These apparent variations in the prevalence of fatigue in PBC reflect the origin of the patient cohort studied, with prevalence higher for all symptoms in clinic-based cohorts compared with geographically based community cohorts; the origin of the control cohorts (which probably accounts for the Scandinavian study [20] as the control group in that study seemingly disproportionately fatigued compared with levels of perceived fatigue measured in other population-derived control populations [12]); and, to some extent, the different assessment approaches used.
Quantifying fatigue in primary biliary cirrhosis To date, the majority of assessment of fatigue in PBC has been performed through the application of questionnaire-based fatigue impact and related HRQOL assessment tools. One study has shown a close relationship between perceived fatigue and actual impairment in physical activity measured using the objective assessment tool of accelerometry [15]. Compared to historical series, the prevalence of fatigue reported in recent studies seems higher. This reflects an increasing appreciation among physicians of the importance of this symptom, and the move toward the use of patient-completed (as opposed to physician-completed) fatigue impact assessment tools, with the first reported studies exploring fatigue prevalence in PBC involving simple assessment of the presence or absence of fatigue. Some of the variability seen in fatigue prevalence studies in PBC reflects the fact that they have used fatigue and HRQOL assessment tools not derived or even, in some cases, validated for use in PBC. The tools used historically in PBC research (generic HRQOL measures, such as Short Form-36 Health Survey or generic fatigue impact measures, such as the fatigue impact score [FIS]) potentially lack relevance, sensitivity, and specificity. This has led to an appreciation of the need for the development of a PBC-derived and PBC-specific patient-oriented HRQOL measure that can be used in impact, etiology, and therapy studies [21]. The PBC-40 is such a PBC-specific HRQOL measure and was developed and validated in the Northeast of England [14]. The availability of this psychometrically robust assessment tool has allowed accurate identification of high- and low-fatigued patient groups and will be an important outcome measure in future intervention trials for fatigue and other symptomatology in PBC. The PBC-40 (available at no charge from the author) contains 40 questions in five domains (fatigue, itch, cognitive, social and emotional, and other symptoms [a domain relating to PBC-related symptoms that do not
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map to the other domains]). Participants rate individual items on a 5-point scale (1 ¼ ‘‘never,’’ 2 ¼ ‘‘rarely,’’ 3 ¼ ‘‘sometimes,’’ 4 ¼ ‘‘most of the time,’’ and 5 ¼ ‘‘always’’). Recent studies have demonstrated clinically meaningful bands for symptom severity (none, mild, moderate, or severe) in each of the symptom domains of the PBC-40 [22]. Using these symptom severity thresholds in the author’s clinic cohort, the overall symptom burden in those who have PBC is high, with more than two thirds of patients having moderate or severe symptoms (Fig. 1) and the most frequently seen status in patients who had PBC was none for ‘‘itch’’; mild for ‘‘other symptoms,’’ ‘‘cognitive,’’ and ‘‘social and emotional’’; and moderate for ‘‘fatigue,’’ confirming previous observations that fatigue is the symptom with the greatest apparent impact on quality of life in patients who have PBC. In addition, the value of the PBC-40 can be seen in its ability to delineate symptoms across a range of domains and explore their overlap. Symptomatic patients who have PBC most frequently have a median of three PBC-40 domain scores in the moderate or severe range (Fig. 2). Studies performed during the validation of the PBC-40 also demonstrated strong correlations between individual fatigue domain and other-symptom, cognitive, and social and emotional domain scores (which, in turn, all correlated with each other) but no correlation with itch scores. This suggests that fatigue in PBC is not a symptom in isolation but forms part of a PBC symptom
Percentage of Total Population
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Overall PBC Symptom Impact Fig. 1. Overall symptom impact in a large PBC patient cohort (n ¼ 197). Minimal, moderate in one PBC-40 domain; Intermediate, moderate in two or three PBC-40 domains or severe in 1; High, moderate in four or five PBC-40 domains, severe in two or more or moderate in three domains, and severe in one.
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Number of PBC-40 Domains With Moderate of Severe Scores Fig. 2. Distribution of moderate or worse symptoms in a PBC cohort (n ¼ 197).
complex [15] and points toward a common pathogenetic mechanism for symptomatology in PBC. The potential for use of the PBC-40 in clinical studies has been underlined in recent publications confirming the relationship between symptom domains in those who have PBC, how they change after transplantation, and that patients’ experience of fatigue translates directly into an impaired ability to function [15,23–25].
Fatigue-associated increase in mortality in primary biliary cirrhosis Recent work performed by the author’s group has suggested that the impact on patients associated with the presence of fatigue may go beyond simple impairment of HRQOL. In a study revisiting the author’s group’s original geographically defined PBC fatigue study cohort [12], the followup mortality rate was significantly higher in patients who had above-median fatigue scores (FIS O 40) in the original study than in patients who had below-median FIS. Although only 4 of the 28 deaths in the original 136-patient cohort were liver disease related, 13 were principally cardiovascular (9.6% of patients and 46% of deaths). Moreover, only one of eight (12.5%) of patients in the low-fatigue group who died had a cardiac death, whereas 12 of 20 (60%, P!.05) of the high-fatigue group had a cardiac death. These differences could not be accounted for by overrepresentation of pre-existing cardiac morbidity or risk factors, patient
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age, or other confounding factors in the fatigued group [26]. Re-evaluation of this cohort has confirmed that the excess mortality has its major impact particularly in those patients who have PBC and are middle aged [27]. These observations require replication but do build on the findings of an earlier study, involving a different patient cohort, which demonstrated a significantly increased standardized mortality ratio for PBC (2.7) [28] with half the increased mortality resulting from non–liver-related processes.
Current understanding of the pathogenesis of fatigue in primary biliary cirrhosis Current, understanding of PBC fatigue pathogenesis is outlined in Fig. 3 and comes from a combination of studies performed in patients who have
MEMORY PROBLEMS
DISTURBED SLEEP PATTERN
BRAIN
Accumulation of a substance due to inability of the liver to remove
Abnormality of liver ability to act as a reservoir (composition or flow)
AUTONOMIC NERVOUS SYSTEM
LIVER
BLOOD PRESSURE
Risk of cardia c death
HEART RATE
FATIGUE MUSCLE DYSFUNCTION
Fig. 3. Hypothesis: fatigue in PBC is a consequence of the central nervous system sequelae of cholestasis, resulting from the localized accumulation of factors (the clearance of which is reduced in the setting of cholestasis) and mediated in part through HPA axis dysfunction and associated primary autonomic dysfunction failure of the brainstem to generate appropriate autonomic signals. The net result of these central processes is a cumulative effect on functional control of blood pressure and peripheral tissue oxygen delivery, which leads to the expression of fatigue through secondary dysfunction of peripheral muscle. The parallel dysfunction of cardiac muscle resulting from functional impairment of perfusion and oxygen delivery that is a predisposing factor for the increased incidence of sudden cardiac death seen in fatigued patients who have PBC.
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PBC and studies performed in animal models of cholestasis, typically the bile duct–resected (BDR) rat. Animal studies of the bile duct–resected rodent BDR rats show significant behavior changes (over and above those seen in sham-operated controls), including anhedonia, loss of social interest [29], and reduced locomotor activity [30], changes that have been interpreted as representing ‘‘fatigue’’ in the laboratory animal setting. Notwithstanding, the issues associated with the different disease kinetic and the conceptual problem regarding interpretation of the symptom of fatigue in laboratory animals this model has yielded important findings that have informed, and will continue to inform, human studies. The BDR studies have shed light particularly on potential signaling pathways, which may be responsible for these behavioral changes. Cholestatic rats have an increase in midbrain 5HT-1A receptors and exhibit enhanced 5HT-1A autoreceptor-mediated responses (hypothermia and hyperphagia) after administration of a highly specific 5HT-1A receptor agonist [31]. This agonist also is effective at reducing ‘‘fatigue-like’’ behavior in cholestatic rats [32]. Furthermore, the impairment in locomotor activity seen in BDR rats is partially reversed after intraventricular administration of a corticotropin-releasing hormone (CRH) type-1 receptor antagonist [30]. These observations are interpreted as suggesting defective central CRH neurotransmission with secondary locomotor activity decrease. One factor potentially contributing to defective CRH neurotransmission may be an increased central sensitivity to interleukin (IL)-1b seen in cholestasis [33]. A recent animal study [34] has hinted at the potential role for inflammatory mechanisms in the pathogenesis of fatigue in cholestasis. To date, studies in humans exploring the association between fatigue severity and degree of cholestasis, assessed, for example, through serum bile acid levels and inflammation are limited. Factors not associated with fatigue in primary biliary cirrhosis There is a broad consensus, from multiple patient cohort studies, that the degree of fatigue experienced by patients who have PBC is not associated with histologic stage of disease, degree of hepatocellular dysfunction, or autoantibody levels [10,11,12,19]. Whether or not fatigue in PBC is a manifestation of depression is an area of contention in PBC. Several studies have suggested variable associations between the presence of fatigue and features of depressive illness (assessed using diverse depression screeners) in PBC [10,12,19]. One problem with the use of such depression screening tools is that they are weighted toward physical manifestations of depression and thus can be significantly skewed in patients who have physical disease, giving rise to a largely spurious elevation in the apparent prevalence of depression in such chronic disease patient
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groups. This view is supported by a Dutch study of 73 patients who had PBC, 41% of whom had depressive symptoms as determined by the Beck Depression Inventory but only 4.9% of whom had a depressive syndrome according to structured psychiatric interview [35,36]. Established biologic associates of fatigue in primary biliary cirrhosis Structural cerebral abnormalities that may lead to fatigue in primary biliary cirrhosis Preliminary studies in a limited number of patients using cerebral magnetization contrast imaging and proton magnetic resonance spectroscopy (MRS) have demonstrated a significant reduction in globus pallidus magnetization transfer ratio (MTR) in precirrhotic patients who have PBC compared with healthy controls, with a significant correlation between the degree of abnormality and fatigue severity experienced by patients [37]. There were no differences in MRS measurements between the groups, suggesting that the abnormal MTR was not related to hepatic encephalopathy. In this study, abnormality in MTR measurements correlated with levels of manganese in the blood, which in turn correlated with degree of fatigue. These early studies have raised the possibility that impairment in liver function in cholestatic conditions may adversely affect the brain long before the development of cirrhosis and hepatic encephalopathy. Confirmation of these findings is required; however, these studies would, if replicated, concur with the rat cholestasis model data in implicating central mechanisms in the pathogenesis of PBC. The importance of central mechanisms in the pathogenesis of fatigue in PBC is supported further by studies from the authors’ group using validated neurophysiologic techniques. When assessed using transcranial magnetic stimulation, patients who have early-stage PBC seem to have a global cerebral abnormality, which remains in a cohort of post-transplant patients who have PBC [38]. In addition, more recent magnetic resonance studies have shown the presence of structural brain lesions (deep white matter hyperintensities) even in early stages of PBC [39], which associate with objective measures of cognitive impairment (seen at higher prevalence in PBC) and, as seen in non–liver disease settings, degree of autonomic nervous system dysfunction [40]. This raises the possibility that those who have PBC are at risk for irreversible, potentially progressive brain lesions that are unrelated to the characteristic delirium of end-stage liver disease, hepatic encephalopathy [39]. Excessive daytime sleepiness One of the earliest studies to describe fatigue in PBC identified an association between fatigue severity and poor sleep hygiene (assessed using the Pittsburgh Sleep Quality Index) [10]. This relationship has been explored further using subjective (Epworth Sleepiness Scale [ESS]) and objective
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(actigraphy) assessment modalities, which confirmed a strong relationship between fatigue and excessive daytime sleepiness in PBC [18]. This was not the result of an increased prevalence of obstructive sleep apnoea in those patients who had PBC who underwent formal sleep studies. Recognition of this association has been a major step toward offering effective fatigue-ameliorating treatments to those who have PBC. In 2005, Kaplan and Bonis [41] described the potential benefits of symptom management with the use of the wake-inducing medication, modafinil, in PBC. In a further open-label series of patients treated with modafinil, significant improvements in daytime sleepiness were seen, coupled with dramatic improvements in fatigue severity and interestingly cognitive symptoms [24]. Further studies are needed to determine the long-term benefits of modafinil and to explore the biologic processes that lead to excessive sleepiness in PBC. Autonomic dysfunction and fatigue in primary biliary cirrhosis Recently, the authors’ group also identified a link between abnormalities of the autonomic nervous system, in particular, blood pressure homeostasis, and degree of fatigue in patients who had PBC [16,17,22,23,42]. Associations between fatigue and autonomic dysfunction are noted in several other fatigue-associated chronic conditions, including primary autonomic failure, multisystem atrophy, chronic fatigue syndrome, Parkinson’s disease, and multiple sclerosis [42–45]. Studies using novel beat-to-beat methodology with increased sensitivity compared with classical autonomic function tests have examined the integrity of the autonomic nervous system in patients who have PBC (through examination of dynamic cardiovascular reflexes, heart rate variability [HRV], and baroreflex sensitivity). Fatigued patients who have PBC have significantly lower HRV than nonfatigued patients who have PBC or normal controls (no such association being seen for the other, non–fatiguerelated domains of the PBC-40), with the HRV reduction occurring predominantly in the very low frequency domain, an observation again implicating central mechanisms [17]. A 24-hour ambulatory blood pressure assessment performed in the same cohort of patients shows significant inverse relationships between fatigue and both mean systolic blood pressure (r ¼ 0.35) and pulse pressure (r ¼ 0.34), with this relationship particularly strong for night-time blood pressure [23]. Dynamic testing of cardiovascular reflexes, including the Valsalva maneuver and head-up tilt testing, confirms the presence of neurally mediated hypotension in 65% of a series of patients who had PBC and strongly implicates sympathetic overactivity and impaired baroreflex sensitivity as having a role in the fatigue experienced by those who have PBC [22]. Autonomic dysfunction previously has been reported in advanced stages of PBC although no attempt was made to link it with fatigue [46,47]. This led to the assumption that autonomic dysfunction was related to the presence of cirrhotic disease. The author’s work has shown that autonomic
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dysfunction is present, at comparable frequency, in cirrhotic and precirrhotic patients, with an equal association with fatigue severity seen in both groups (a finding that concurs with the lack of a stage association for fatigue in PBC) [16]. The link between fatigue and autonomic function in PBC is potentially highly significant given the author’s observation of increased mortality associated with fatigue in PBC, with a particular increase in cardiac deaths and an over-representation of sudden cardiac death. Autonomic dysfunction has been demonstrated, in settings outside PBC, as associated with an increased risk for (principally sudden) cardiac death [48–51], and in liver disease its presence conveys a fivefold increase in mortality. This, coupled with the observation of a prolonged QTc in PBC, points toward an increased tendency to arrhythmic-associated deaths in PBC [46].
Reduced physical activity and abnormalities in peripheral muscle function in primay biliary cirrhosis Perceived fatigue (assessed using subjective assessment modalities) has been shown to associate with reduced physical activity (measured using actigraphy over 7 days) [15]. The direction of this association is uncleardDoes fatigue lead to reduced physical activity or, conversely, does impaired physical function result in fatigue? Either way, physical activity monitoring has potential as an important endpoint in clinical trails in PBC and may prove to be a fatigue-ameliorating intervention. In addition to the evidence supporting a central mechanism for fatigue development in PBC, studies suggest that there are peripheral mechanisms, in particular muscle dysfunction, that contribute to fatigue in PBC [52]. Fatigued patients who have PBC are shown to have accelerated reduction in muscle function on repeated sustained activity compared with normals and nonfatigued subjects, with the rate of reduction in muscle function correlating with the severity of fatigue. This points to a contribution of peripheral muscle fatigability to the fatigue experienced by patients. The mechanisms underlying this dysfunction currently are unknown but early MRS studies confirm that there are abnormalities in muscle bioenergetics in those who have PBC. During exercise, patients who have PBC showed excess muscle acidosis after exercise compared with controls. The degree of this acidosis correlated closely with elevation of the phosphocreatine/ ADP recovery ratio, indicating that postexercise acidosis in patients who have PBC is related to mitochondrial dysfunction. Patients who have PBC also showed significant prolongation of the muscle pH recovery time after exercise with a significant association between the degree of clinical fatigue experienced by patients who have PBC and prolonged pH recovery after exercise. This preliminary data has demonstrated that patients who have PBC exhibit a variable degree of muscle mitochondrial dysfunction, which manifests itself as excess acidosis after exercise. The extent to which patients
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can recover rapidly from this acidosis seems to determine whether or not they are clinically fatigued [53]. Other putative mechanisms for fatigue pathogenesis in primary biliary cirrhosis Inflammatory cytokines Administration of IL-6 in humans is associated with daytime somnolence and fatigue [54], and elevations of IL-6, tumor necrosis factor a, and IL-1 occur in a range of clinical conditions in which daytime somnolence and fatigue are prominent [55]. This has led to the concept that IL-6 (levels of which have a circadian rhythm) plays a key role in the sleep/ wake cycle [56]. mRNA levels for IL-6 are elevated in the liver in patients who have PBC [57,58] and peripheral blood mononuclear cells from patients who have PBC show enhanced spontaneous and evoked IL-6 release [59]. Elevated IL-6 seems to occur, in part, as a direct consequence of cholestasis, as hydrophobic bile acids of the type retained in PBC induce cultured biliary epithelial cells to release IL-6 [60]. This is of relevance to understanding fatigue pathogenesis given that circulating IL-6 levels and muscle IL-6 mRNA are elevated acutely in exercise with a postulated energy homeostasis role [61], whereas elevation of IL-6 in hospitalized older patients is associated with impairment of muscle function and fatigue [62]. Adipokines A key factor stimulating release of IL-6 is leptin, an adipokine that conveys information on energy homeostasis [63]. IL-6, in turn, has a role in regulating leptin release [64]. Leptin levels are significantly elevated (and ghrelin levels significantly decreased) in patients who have PBC when corrected for fat mass [65]. Pilot data confirm that in patients who have PBC, fat mass in general (assessed using bioelectrical impedance) and visceral fat in particular (a specific source of leptin) are specifically increased [17]. More than 70% of patients who have PBC have waist/hip ratios over 0.8. Furthermore, lipid metabolism is deranged in patients who have PBC and cholesterol levels high [66]. Strikingly, the degree of leptin elevation in patients who have PBC correlates directly with severity of fatigue [67]. In addition to a profatigue effect through induction of IL-6 release, leptin potentially could have a fatigue-inducing effect via its central actions, including its suppression of the hypothalamic-pituitary-adrenal (HPA) axis [68] or its effects on neuropeptide function [69]. A potential mechanism for the elevation of leptin seen in PBC is suggested by the observation that leptin promotes biliary cholesterol elimination during weight loss in the ob/ob leptin-deficient mouse [70]. In light of the prevalence of autonomic dysfunction in fatigued patients who have PBC and the apparent links between autonomic function, leptin, fatigue, and omega-3 fatty acids [71],
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the autonomic nervous system, lipid metabolism, and leptin release seem highly interdependent [72]. The brain-liver axis It is intriguing to speculate how a disease characterized by an autoimmune process that affects the largest organ of the body results in such profound symptoms that are partly or entirely central in their origin. It is plausible that the pathogenic processes that characterize PBC also lead to the central (or peripheral) abnormality that results in the symptom of fatigue. Such PBC-specific features that could lead to such a phenomenon would include inflammation, cholestasis, or presence of the antimitochondrial antibody that characterizes the disease. Further signaling mechanisms between the liver and the brain require better delineation and will form the basis of exciting future research. The classical assumption that PBC is purely a liver disease may not be true; the abnormalities found in those who have PBC are not restricted to the liver and PBC may, in fact, be a systemic disease. Clinical management of fatigue in those who have primary biliary cirrhosis Although reducing morbidity and mortality related to the underlying disease is of fundamental importance as a goal in the treatment of any disease, it is just as critical that clinicians treat patients’ symptoms and improve their quality of life (surely fatigue is a cause of morbidity). This is particularly vital in a chronic disease, such as PBC, where significant impairment of HRQOL is recognized. Improvement in quality of life as a goal of therapy in its own right is made more pertinent by the observation that outcomes in terms of survival are very good, almost regardless of therapy in young patients who have PBC with early disease (although the outcome in terms of survival may be less rosy in older patient groups) [28]. In patients in whom the disease is only slowly progressive, the symptoms of the disease can have a major impact on HRQOL. Ameliorating symptoms and as a result improving QOL in such patients would be of major practical benefit to many patients. Fatigue is a critical factor in determining quality of life in those who have PBC and there is, therefore, the real opportunity to make a difference in this patient group if appropriate and effective strategies can be developed to reduce or reverse this debilitating symptom. Fig. 4 describes the clinical management strategy for fatigue and associated symptoms in patients attending the author’s dedicated PBC clinic. Getting such strategies right can be immensely clinically rewarding and early suggestions are that it is not nearly as daunting as it seems at first. In the author’s experience, however, to achieve consistent benefit for patients, the clinical approach must be structured. The recent introduction of a PBCspecific, integrated care pathway, which combines a range of management algorithms into a dedicated PBC service, has confirmed that such an approach can lead to significant improvements in quality of life [73].
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PBC patient with Fatigue Exclude other causes of fatigue: Hypothyroid/anaemia/celiac/uncontrolled diabetes Review necessity for all drugs : Sedatives/sleeping meds etc.
Does patient complain of daytime sleepiness ?
Yes – do Epworth Sleepiness Score (ESS)
ESS >10
No Patient taking any meds that might lead to blood pressure dysregulation ? e.g antihypertensives/antianginals/amitryptiline/ alphablockers etc.
ESS <10
No
Yes
Consider trial of modafinil Consider Sleep Apnoea
Review ESS and PBC-40 after trial Improvement ?
Yes continue
Review need for this medication Patient complains of postural dizziness ? OGS >4
No – supportive treatment No
Consider stopping Consider 24 hour BP Consider longer acting meds/meds at night
Yes – consider autonomic dysfunction Review strategies to increase intravascular volume – fluid intake etc.
Refer for formal autonomic assessment including testing for vasovagal syncope and orthostatic hypotension
Fig. 4. Suggested clinical management protocol for fatigue in PBC.
Managing biologic features that associate with fatigue in clinical practice The two main biologic associates of fatigue in PBC, namely excessive daytime sleepiness and autonomic dysfunction, can be assessed easily in clinical practice. The relative contributions of each of these biologic fatigue associates have been considered using the Orthostatic Grading Scale (OGS) [74] as a subjective assessment of autonomic nervous system symptoms and the ESS [75] as a measure of daytime somnolence
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[25]. Using these two clinical assessment modalities, the author has evaluated a clinical diagnostic criterion for use in clinical practice. A significant proportion of fatigue in PBC was associated with the presence of either or both autonomic dysfunction (OGS R 4) and sleep disturbance (ESS R10). The relative distributions of these contributions and their overlap are shown in Fig. 5. For clinical management of patients who have fatigue, those meeting ESS and OGS criteria did not have more severe fatigue than those patients meeting the diagnostic criterion for OGS or ESS alone (all three groups showed substantially greater fatigue severity than the group of patients who met neither of the criteria). The finding of such a threshold effect for fatigue in PBC will have implications for potential therapeutic interventions directed toward reducing fatigue [25]. Approach to fatigue management in primary biliary cirrhosis A supportive positive approach to the management of symptoms in PBC, in particular fatigue, is vital and in itself can lead to improvements in quality of life (Box 1). Managing patients who have fatigue in any chronic disease requires empathy. The chronic fatigue syndrome literature indicates that doctors’ belief whether or not fatigue constitutes a biologic symptom determines whether or not they offer supportive treatment and whether or not patients have a positive outcome. In focus group discussions with the author’s patient group, the same is true of fatigue and its management in PBC, with the outcome of consultations involving clinicians who have a positive attitude to symptom management proving beneficial for patients. Fatigue in PBC is associated with high levels of frustration [76] and recognizing this as a direct consequence of fatigue and delivering directed interventions
Neither (10%)
Autonomic Dysfunction (28%)
AD EDS AD+EDS Both (38%)
NEITHER
Excessive daytime sleepiness (24%) Fig. 5. Biologic associates in the 29% of the author’s PBC clinic cohort who complain of severe fatigue.
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Box 1. Key strategies for the successful management of fatigue in primary biliary cirrhosis 1. Fatigue usually is ‘‘real’’ in chronic disease: Treat it as such. 2. It is normally multifactorial, with different patients who have the same symptom having different causes (and different responses to treatment). 3. Treat the treatable, ameliorate the ameliorable, and always support and understand (do not fail before you start). 4. Take a structured approach 5. Quantification is key. 6. Treat the underlying cause. 7. Ameliorate the effects of the fatigue. 8. Cope with the effects fatigue has on life. 9. Empathize and understand.
that address the psychologic distress that arises in patients who have PBC as a consequence of fatigue should be considered supportive treatment.
Summary The autoimmune liver disease PBC is associated with debilitating fatigue in a significant proportion of patients. In addition to having an impact on quality-of-life fatigue in PBC, it may influence length of life. The pathogenesis of fatigue in PBC is unclear, but preliminary studies suggest it has central mechanisms and may have peripheral manifestations. Studies of fatigue in nonhepatic diseases show that autonomic dysfunction plays a role, and early data strongly suggest the same is true in PBC. Comprehensive studies investigating the pathogenesis of fatigue in PBC are urgently needed as are large-scale prospective outcome studies.
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