Understanding fatigue and pruritus in primary biliary cholangitis
Asma Faisal
Abstract
INTRODUCTION AND EPIDEMIOLOGY Primary biliary cholangitis (PBC) is a chronic progressive autoimmune disease of the hepatobiliary system. It is characterized by a cycle of immune-mediated epithelial injury of the small and intermediate intrahepatic bile ducts, resulting in periportal inflammation, cholestasis, fibrosis, and potentially end-stage biliary cirrhosis.1,2 Predominantly affecting women, with a female-to-male ratio of 10:1,3 PBC is typically diagnosed in the fifth or sixth decade of life.4 Although pediatric onset has been reported, it is not classically encountered.5 Liver-associated chemistries demonstrate a cholestatic pattern with elevations in alkaline phosphatase, mild elevations in aminotransferase, and a potential rise in serum bilirubin as a marker of late progression of the disease.6 Without noteworthy correlation to the stage of liver disease, PBC is associated with a complex and significant symptom burden that results in a substantial deficit in perceived quality of life, much more so than in age-matched and sex-matched community control groups.7,8 Major symptoms of PBC, most associated with impaired health status and social dysfunction, include significant fatigue and chronic cholestatic pruritus.7,9 As the most prevalent symptom, fatigue is reported in up to 80% of patients, with approximately 40% experiencing severe fatigue.10–12 This severity has the greatest impact on quality of life in patients with PBC and serves as a predictor of liver-related mortality and transplant outcomes.10–12 Pruritus, the second most common symptom in PBC, is prevalent in 20%–70% of patients and is a major determinant of health-related quality of life. Intense nighttime itch can lead to sleep deprivation, worsening fatigue, depression, and even suicidal ideation.13,14 An earlier onset is not only associated with a more aggressive disease and/or the ductopenic variant but also with poorer survival outcomes.3,15 This review aims to provide a summary of the clinical presentation, current understanding of pathophysiology, evaluation, management, and a brief insight into potential future treatment perspectives of these debilitating symptoms. FATIGUE IN PBC Pathophysiology of fatigue in PBC While the pathophysiology of fatigue in PBC remains uncertain, it is thought to be composed of central (lack of intention) and peripheral (lack of ability) components (Figure 1).11,12 Central fatigue manifests as motivational fatigue and cognitive symptoms, such as concentration and memory deficits, and is strongly associated with sleep disturbance and depression. It is often described as “the failure to initiate and/or sustain attentional tasks and physical activities requiring self-motivation.”16 Cholestasis in PBC is theorized to lead to the accumulation of toxic bile acids, which, through toll-like receptor-mediated mechanisms, trigger inflammatory cytokines.12,16 Moreover, chronic hepatic inflammation characteristic of PBC, stemming from its autoimmune nature, may also contribute to the increased cytokine pool.17 This cascade of events activates cerebral microglia, which subsequently recruit monocytes into the brain, triggering changes in central neural activity and ultimately causing central fatigue.12,17 Animal models have illustrated such changes in brain function leading to diminished social interest and other behavioral irregularities analogous to the central fatigue observed in PBC.12,17 These alterations notably had an inflammatory aspect as mice lacking essential inflammatory mediators, such as cytokines, TNF receptor 1, and adhesion molecules crucial for leukocyte recruitment into the brain, did not exhibit central nervous system symptoms in the setting of cholestasis.12,16,17 Additionally, a study demonstrated an overall disturbance in the resting-state functional connectivity (rsFC) of deep gray matter brain structures in patients without cirrhosis and with PBC compared to matched controls.18 This altered connectivity was observed in association with both fatigue (exhibited by decreased rsFC of the putamen with the motor cortex)18,19 and impaired cognitive performance, including deficits in concentration and verbal working memory (demonstrated by decreased rsFC of the putamen and amygdala with regions involved in cognitive processing such as the superior and inferior frontal and parietal gyri)18,20,21 Moreover, patients with PBC showed a contrasting increase in rsFC in other regions, suggesting a potential compensatory homeostatic response to the chronic immune-mediated liver-to-brain signaling.17,18 White matter brain lesions are also seen in patients with PBC with cognitive deficits and are associated with autonomic dysfunction and impaired cerebral autoregulation.12,22 Such structural brain lesions have been identified in patients with early-stage PBC and are therefore likelier attributed to cholestasis than advanced liver disease or HE.12,22 The theory suggesting that cholestasis early in disease progression leads to permanent alterations in the brain (subsequently resulting in central fatigue) is supported by an absence of fatigue improvement after liver transplantation.12,23 This is further reinforced by neurophysiological testing in patients with fatigue and PBC, using paired-pulse transcranial magnetic stimulation, which demonstrated impaired central activation and distinct abnormalities correlating with sleep disturbance, that importantly showed no resolution post-transplant.12,24FIGURE 1: Pathophysiology of fatigue in PBC. Abbreviation: PBC, Primary biliary cholangitis.Altered central neurotransmission, specifically in the serotonergic and noradrenaline pathways, is also hypothesized to contribute to central fatigue in PBC.11,25 However, treatments like ondansetron (serotonin receptor agonist) and selective serotonin reuptake inhibitors (SSRI), like fluoxetine, have not shown conclusive efficacy.6,11 Peripheral fatigue includes neuromuscular dysfunction, such as reduced activity levels and an inability to sustain repetitive exercise.12,26 It is often described by patients as “energy depletion” and “batteries running down.”12 In patients with PBC, postexercise 31P magnetic resonance spectroscopy demonstrated increased muscle acidosis and a prolonged recovery time correlating with fatigue severity.27 This muscle bioenergetic abnormality suggests an autonomic (where the autonomic nervous system plays a dual role in regulating proton transport and controlling vascular runoff from the muscle) and mitochondrial dysfunction. This leads to an excessive deviation from aerobic to anerobic metabolism, delayed recovery, and an ultimate decline in muscle function.11 High titers of the characteristic antimitochondrial antibodies of PBC, targeting the pyruvate dehydrogenase complex, are linked to impaired mitochondrial function and are also suggested to be involved in the pathogenesis of peripheral fatigue.12 Contributing and exacerbating factors of fatigue in PBC Many comorbid conditions and therapeutic agents may individually or collectively contribute to an increased fatigue burden in patients with PBC. These concurrent processes make it challenging to address fatigue adequately. Some of these conditions include cholestatic nocturnal pruritus, autoimmune conditions associated with PBC such as hypothyroidism, celiac disease, and anemia, certain age-related comorbidities like type II diabetes, renal failure, and heart failure, and medications including antibiotics and anti-hypertensives.11,12 Anxiety and depressive symptoms are also more prevalent in patients with fatigue and PBC than in their nonfatigued counterparts and community controls.12,28 It remains unclear whether depression precedes fatigue or emerges as a result of living with a chronic debilitating disease.12,28 Where structured psychiatric evaluation, assessing depressive ideation, has been conducted in patients scoring highly on depression screening tools (such as the Beck Depression Inventory), only a low level of formal depressive disorders is seen.28 Depressive symptoms are therefore likelier to be reactive consequences of the impact of fatigue. Sleep disorders are also often comorbid with fatigue in PBC. Patients with fatigue and PBC report various sleep-related issues, including poor sleep quality, delayed sleep timing, heightened sleep-wake disturbances, and notably, excessive daytime somnolence.11,12 Like depressive symptoms, the causal connection between sleep disruption and fatigue is ambiguous, given that each can exacerbate the other.29 Additionally, autonomic dysfunction, most typically in the form of vasomotor abnormalities such as low heart rate variability, paradoxical tachycardia with flushing, and postural hypotension (resulting in dizziness and a greater fall frequency), is strongly associated with fatigue in PBC.12 Although somnolence (attributed to HE) and autonomic abnormalities are common in late-stage cirrhosis, the fatigue associations of PBC can be distinguished, as they may manifest at all stages of liver disease.12 Evaluation of fatigue in PBC Fatigue is widely considered a subjective patient-reported outcome. Thus, having reliable and valid tools to measure this health outcome from the patient’s perspective is essential for accurately evaluating the effects of interventions. Multiple scales may be used as assessment tools to clinically monitor fatigue in PBC.30 One such standardized measure of fatigue is the National Institute of Health’s (NIH) Patient-Reported Outcomes Measurements Information System (PROMIS)–Fatigue Short Form.31 The PROMIS Fatigue Short Form comprises 7 items designed to assess both the experience of fatigue and its interference with daily activities over the past week.32 Responses to items such as “How often did you feel tired,” “How often were you too tired to take a bath/shower,” and “How often did you have enough energy to exercise strenuously” are measured on a 5-point Likert scale and a summative score is obtained, indicating fatigue severity.12,32 Although it has not yet been validated in PBC, the PROMIS Fatigue Short Form is an efficient and precise unidimensional scale and can be useful as a screening tool or for assessing fatigue severity.11 Conversely, multidimensional scales like the PBC-validated Fatigue Impact Scale provide more comprehensive information by assessing the impact of fatigue on psycho-social, cognitive, and physical activities.11 However, the PBC-40 is an health-related quality of life measure specific to PBC. The 40-question survey encompasses 6 domains: fatigue, pruritus, emotional, social, cognitive function, and general symptoms.33 With a validated fatigue domain, it is therefore ideal for quantifying PBC-related fatigue. Moreover, cognitive dysfunction may also be assessed using the PBC-40 cognitive symptom domain.22,33 In addition to patient-reported outcomes, fatigue can also be evaluated through objective measures such as brain imaging, serological tests, and physical performance assessments.11 Fatigue in PBC may also be difficult to address because of comorbid disease processes that may be contributing to and/or exacerbating fatigue symptoms. Hence, it’s crucial to conduct a complete assessment to screen for such conditions. A comprehensive approach involving detailed history-taking, thorough physical examination, biochemical and serological testing, and diagnostic imaging, if necessary, may be required to rule out or diagnose PBC-associated autoimmune disease and age-related conditions. Depressive symptoms may be screened and assessed using various tools, depending on clinician preference, such as the Beck Depression Inventory, the Patient Health Questionnaire-2 and Patient Health Questionnaire-9, and the Hamilton Depression Rating Scale, and may require appropriate specialist referrals.28 Sleep disturbance may be assessed using the Epworth Sleepiness Scale or the PROMIS Sleep Disturbance and Impairment Short-Forms.22,29,34 A formal assessment of autonomic dysfunction may include initial autonomic testing using deep breathing and Valsalva maneuver testing, 24-hour blood pressure monitoring, and heart rate variability monitoring using electrocardiograph measurements.1,35 Tilt table testing may be considered if the initial evaluation does not yield a definitive or highly probable diagnosis despite the presence of signs and symptoms of autonomic instability, such as postural hypotension.1,36 Management of fatigue in PBC Currently, there is no recommended approved therapy for treating fatigue in PBC.6 While a first-line agent for treating PBC, ursodeoxycholic acid has not been proven to improve fatigue.11 Fatigue is also unresponsive to obeticholic acid therapy and may be worsened by obeticholic acid’s dose-dependent increase in nocturnal pruritus.37 Among the disease-modifying agents, off-label fibrates have reported a subjective improvement in fatigue in the BEZURSO trial; however, further studies are required to confirm these findings.38 Liver transplantation is also not recommended for patients with severe fatigue due to post-transplant persistence.6 An effective structured management approach to fatigue in PBC involves evaluating and quantifying fatigue and its impacts (as discussed above), addressing contributing and exacerbating factors, and providing support to help patients cope with its impact (Figure 2).1,11,12 Disease processes directly or indirectly contributing to fatigue, including other autoimmune conditions such as autoimmune anemias or hypothyroidism and demographic-associated conditions such as type II diabetes, can be effectively managed through therapeutic interventions and therefore must be adequately treated to improve the overall fatigue burden.FIGURE 2: A structured approach to managing fatigue in PBC. Abbreviations: AIH, autoimmune hepatitis; BP, blood pressure; PBC, primary biliary cholangitis; PPAR, peroxisome proliferator-activated receptor.Once these contributing factors and comorbidities have been addressed, other fatigue-exacerbating processes—depression, sleep disturbance, and autonomic dysfunction must be formally addressed.1 With the help of specialists, the right antidepressant regimen can improve overall function. Modafinil, while approved for the treatment of daytime somnolence, has not shown any significant improvements in PBC and must therefore be used with caution.39 However, morning bright light therapy has shown some promise in improving sleep quality in patients with PBC and should be investigated further.40 The underdiagnosed restless leg syndrome also represents a potential therapeutic option for patients with PBC with sleep disturbance and fatigue.41 Volume repletion and 24-hour blood pressure monitoring can help mitigate the effects of autonomic dysfunction.1 Additionally, contrary to avoiding activity to conserve energy, patients may experience improvement in peripheral muscle function through structured exercise.1,42 Finally, empathy, education, and counseling are of utmost importance in empowering patients to take ownership of disease and implement lifestyle adjustments for better fatigue management in PBC.6 Patients must be supported to develop coping mechanisms, such as timing (arranging key tasks earlier in the day as fatigue is typically worse later in the day) and pacing strategies (using available energy to its best advantage).1 Psychological approaches such as cognitive behavioral therapy have also been found to be effective in supporting patients.5 Regarding future treatment options, seledelpar, a selective peroxisome proliferator-activated receptor delta agonist, and S-adenosyl-L-methionine, when combined with ursodeoxycholic acid, have demonstrated improved sleep quality and reduced fatigue in open-label trials among patients with PBC. Nevertheless, is required to these in has demonstrated a significant in the PBC-40 fatigue by dehydrogenase complex Conversely, has been proven to be effective in this IN PBC of in PBC in PBC is of cholestatic severity or and may at any stage of the It may as the symptom of PBC or after an initial and has even been reported to diagnosis for to The clinical often between of and with in advanced liver disease.6 A of primary lesions the cholestatic itch from other However, may result in lesions such as and described as a itch deep the in PBC is not by and is often by a or in and with in the late and at as by in patients with at the more specifically the is also often is often by with such as and of changes in women, such as and Pathophysiology of in PBC The pathogenesis of in PBC is only It is hypothesized that in cholestasis, which hepatobiliary into the and from the to the primary that the itch to the and the a motor response of Animal clinical and to therapeutic interventions have identified potential including bile acids, acid and (Figure bile components have been to contribute to levels of bilirubin and bile acid are found in and receptor in primary have as potential of cholestatic These are notably by bile and potentially the of biliary and inhibitors of the bile acid or through interventions such as therapeutic or results in a noteworthy in of serum a and a itch have been reported in patients with PBC with compared to matched Patients with PBC also demonstrate increased activity of the for activity with the of itch and to therapeutic a receptor agonist, a of Additionally, treatment of with system or therapeutic also with a in levels and results in a improvement in itch levels and of in liver have been observed in both models and patients with cholestatic While such as as a exhibit an in patients with Additionally, have also been identified as potential of hepatic like have been shown to improve the of itch Pathophysiology of cholestatic in PBC. Abbreviations: bile acid acid receptor obeticholic receptor IN PBC The initial assessment of in PBC must include a evaluation and or management of other and renal hypothyroidism, and autoimmune of its significant impact on health-related quality of life, must be and assessed at the time of diagnosis and through for and clinical must on the of such as time and exacerbating to and itch may be in clinical evaluation tools, such as the itch and itch of the PBC-40 for an approach to scales and from to are clinically effective tools for progression between and treatment Conversely, the PBC-40 itch and itch a more comprehensive assessment of the symptom and its impact on quality of IN PBC to current by the for the of Liver Disease and the for the of Liver disease, in PBC is managed to an therapeutic response for improved health (Figure interventions are often disease-modifying Patients must be to that exacerbate or such as with of and measures should be including and agents with brief with Psychological such as may help cope with the A brief of management of cholestatic Abbreviations: liver bile acid receptor ursodeoxycholic acid is the first-line treatment for PBC, it has not been shown to improve and bile acid and are first-line medications for in PBC but are not because of their and effects In addition to bile acids, they also various other potential in the impaired of other the disease-modifying agents, patients should be a between the of and other improvement in after a treatment approved therapy for in PBC low of bile and other as potential in the and receptor of leading to increased and of of on of reuptake effects and and with with of other disease-modifying agents like to liver failure, renal of hepatic altered of other blood and Sleep in between of other to other if no response after a at and and in or in of symptom control is or effects patients can be on at a low or increase by of management of severe if and subsequently to liver at a low up to therapeutic and for a of monitoring of and other may be used as Abbreviations: ursodeoxycholic to bile acid is treated with a agent with the for improvement of cholestatic It is reported to be effective in approximately of As an of hepatic it potentially changes the and of It can also serum a by through its receptor Although is a severe that monitoring of liver and in patients with bilirubin levels greater than also with such as when to the the but has a reduced and may fatigue as a receptor and increased levels in patients with cholestatic and are the recommended agents for improving in patients with PBC.6 must be to an may exacerbate chronic Additionally, has been reported with which of liver are the recommended agents with reported improvements in of cholestatic of their including sleep disturbances, and may increase fatigue and should be may be to for or therapy such as biliary or and These have proven to have an from cholestatic in but are not without their cholangitis after biliary to all therapy is an for liver even in the absence of liver Liver transplantation is highly effective in often the initial However, in some may in of liver transplant is often attributed to cholestasis to or biliary or chronic ductopenic potentially on the pathophysiology of cholestatic has for bile acid such as are investigated in a after in itch severity in II potentially disruption of the and increased of potential proliferator-activated receptor such as have also been in the BEZURSO and with in itch Additionally, inhibitors and and receptor provide the for and further Fatigue and cholestatic the perceived quality of life of patients with PBC, yet they are often resulting in Although much of the pathophysiology is fatigue is to immune-mediated liver dysfunction, and cognitive and neuromuscular symptoms. the absence of approved specifically targeting fatigue in PBC, a structured approach to management involves assessing fatigue and its impacts through patient-reported outcomes, addressing contributing factors, and providing support to Multiple have been in the of cholestatic including bile and of its on quality of life, cholestatic evaluation typically involves lifestyle and in managing these debilitating symptoms. at better understanding pathophysiology and interventions are to the burden of fatigue and pruritus, ultimately and for living with PBC.