Fatigue In Primary Biliary Cirrhosis Research Articles

A Randomized, Placebo-Controlled Clinical Trial of Efficacy and Safety: Modafinil in the Treatment of Fatigue in Patients With Primary Biliary Cirrhosis.

Fatigue is a common symptom of primary biliary cirrhosis (PBC), and is associated with an impaired quality of life. No studies have assessed the use of modafinil in fatigue related to PBC in a controlled manner. A randomized, double-blind, placebo-controlled study was conducted to determine the safety and efficacy of modafinil for the treatment of fatigue in PBC. Forty patients were randomized to modafinil (n = 20) or placebo (n = 20) for 12 weeks. A verbal report of fatigue for at least 6 months was required for enrollment. Modafinil was administered at 100 mg by mouth once daily; a change by 50 mg every 2 weeks (maximum: 200 mg once daily) was allowed, depending on the subject's response to treatment. The primary outcome was defined as a ≥50% improvement in fatigue severity [quantified by the Fisk Fatigue Impact Scale (FFIS)] after 12 weeks of treatment, compared with baseline values. Thirty-three PBC patients completed the study. After 12 weeks of therapy, only 5 patients had a ≥50% reduction in FFIS scores: 3 patients (17.6%) in the modafinil arm and 2 (12.5%) in the placebo arm (P = 1.00). Change in median FFIS score was not statistically different between patients in the 2 treatment groups (P = 0.36). Modafinil was associated with minimal adverse events (headaches, diarrhea, and rash). In patients with PBC who have fatigue, treatment with modafinil for 12 weeks was safe and fairly well tolerated; however, it did not result in beneficial effects on fatigue compared with patients treated with placebo (CONSORT Table 1). ClinicalTrials.gov identifier NCT00943176.

RITPBC: B-cell depleting therapy (rituximab) as a treatment for fatigue in primary biliary cirrhosis: study protocol for a randomised controlled trial

IntroductionPrimary biliary cirrhosis (PBC) is an autoimmune liver disease with approximately 50% of patients experiencing fatigue. This can be a particularly debilitating symptom, affecting quality of life and resulting in...

P1328 : RITPBC: B-cell depleting therapy (RITUXIMAB) as a treatment for fatigue in primary biliary cirrhosis: study protocol for a randomised controlled trial

P1328 : RITPBC: B-cell depleting therapy (RITUXIMAB) as a treatment for fatigue in primary biliary cirrhosis: study protocol for a randomised controlled trial

P1207 : Fatigue in primary biliary cirrhosis: similar prevalence to the population from the same geographic area, and association with comorbidities and severity of cholestasis

P1207 : Fatigue in primary biliary cirrhosis: similar prevalence to the population from the same geographic area, and association with comorbidities and severity of cholestasis

Restless leg syndrome is a treatable cause of sleep disturbance and fatigue in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) patients frequently describe sleep problems. The cause remains unclear and treatment is challenging. Restless leg syndrome (RLS) is a common sleep disorder. In this study, we systematically screened PBC patients for the presence of RLS. Participants were recruited from our specialist PBC clinical service. Subjects completed the International Restless Leg Syndrome Study Group rating scale (IRLSS) a validated measure of the presence of RLS and its severity. Those fulfilling diagnostic criteria for RLS underwent foot actigraphy (CamNtech Actiwatch) to objectively assess periodic limb movement index (PLMI) (normal <5/h). Restless leg syndrome was assessed in 42 consecutive early stage PBC patients. Twelve (29%) fulfilled the IRLSS criteria for RLS. Scores were significantly higher in PBC compared to controls (P = 0.005). Twenty-four patients were further assessed with foot actigraphy for 3 nights (12 with subjective RLS symptoms and 12 with no RLS symptoms). Thirteen of twenty-four subjects had PLMI >5/h and four had moderate or severe PLMI >15/h. All moderate or severe PLMI subjects had subjective symptoms of moderate or severe RLS. No patients had PLMI >10 in the absence of RLS symptoms. Eleven PBC patients with symptomatic RLS went on to have treatment. Sixty-three per cent had clear benefit in restless leg symptoms and associated symptoms of fatigue. Restless leg syndrome symptoms are common and underdiagnosed in PBC patients. RLS represents a potential therapy for PBC patients with daytime sleepiness, fatigue and unpleasant lower limb symptoms and this is worthy of further studies in larger cohorts.

Patogeneza zespołu przewlekłego zmęczenia w pierwotnej marskości żółciowej wątroby

ENWEndNote BIBJabRef, Mendeley RISPapers, Reference Manager, RefWorks, Zotero AMA Raszeja-Wyszomirska J, Wunsch E, Koziarska D, Milkiewicz P. The pathogenesis of chronic fatigue in primary biliary cirrhosis. Gastroenterology Review/Przegląd Gastroenterologiczny. 2012;7(4):192-196. doi:10.5114/pg.2012.30501. APA Raszeja-Wyszomirska, J., Wunsch, E., Koziarska, D., & Milkiewicz, P. (2012). The pathogenesis of chronic fatigue in primary biliary cirrhosis. Gastroenterology Review/Przegląd Gastroenterologiczny, 7(4), 192-196. https://doi.org/10.5114/pg.2012.30501 Chicago Raszeja-Wyszomirska, Joanna, Ewa Wunsch, Dorota Koziarska, and Piotr Milkiewicz. 2012. "The pathogenesis of chronic fatigue in primary biliary cirrhosis". Gastroenterology Review/Przegląd Gastroenterologiczny 7 (4): 192-196. doi:10.5114/pg.2012.30501. Harvard Raszeja-Wyszomirska, J., Wunsch, E., Koziarska, D., and Milkiewicz, P. (2012). The pathogenesis of chronic fatigue in primary biliary cirrhosis. Gastroenterology Review/Przegląd Gastroenterologiczny, 7(4), pp.192-196. https://doi.org/10.5114/pg.2012.30501 MLA Raszeja-Wyszomirska, Joanna et al. "The pathogenesis of chronic fatigue in primary biliary cirrhosis." Gastroenterology Review/Przegląd Gastroenterologiczny, vol. 7, no. 4, 2012, pp. 192-196. doi:10.5114/pg.2012.30501. Vancouver Raszeja-Wyszomirska J, Wunsch E, Koziarska D, Milkiewicz P. The pathogenesis of chronic fatigue in primary biliary cirrhosis. Gastroenterology Review/Przegląd Gastroenterologiczny. 2012;7(4):192-196. doi:10.5114/pg.2012.30501.

Research development of pruritus and fatigue in primary biliary cirrhosis

原发性胆汁性肝硬化(primary biliary cirrhosis,PBC)是一种肝脏特异的慢性自身免疫性疾病.该病女性易患,以胆汁淤积、酶系升高为特征表现,病理以肝内小胆管非化脓性进行性破坏为特征,长期持续性肝内胆汁淤积可最终导致肝纤维化及肝硬化。

The complexity of fatigue

We read with interest the article by Al-Harthy et al.1 and believe that it provides important additional insights into the prevalence of fatigue in patients with primary biliary cirrhosis (PBC). The finding in a North American population of PBC-40 fatigue domain scores comparable to those in our previous United Kingdom–based studies2, 3 underlines the importance of this symptom in this patient group. Interestingly, the North American population was 10 years younger than the populations of previous studies, and this may in part explain the slightly lower scores. This study presents further evidence underlining that fatigue is a significant problem in the lives of patients with PBC. However, one of the conclusions of this article—fatigue in PBC is nonspecific and multifactorial—gives rise to a number of important issues. First, the conclusion that fatigue in PBC is associated with comorbidities is unsurprising and underlines the necessity of excluding patients with comorbidities from mechanistic studies (of the kind recently reported by our group4-6) exploring the pathophysiology of fatigue in PBC. Second, although fatigue can arise in PBC in association with comorbidities or because of medications (it occurs with a number of other chronic liver diseases and most, if not all, chronic inflammatory processes), it is no less of a problem to the patients who experience it. Furthermore, it is clear that the fatigue profile for PBC patients is significantly greater than that for age-matched community controls experiencing all the comorbidities identified by Al-Harthy et al.1 in PBC patients.7 Recent studies have also confirmed that fatigue in PBC is associated not only with impaired quality of life but also with reduced length of life.8, 9 Therefore, although fatigue may be a ubiquitous symptom in chronic disease; it is associated with PBC and is perceived by patients as a disease-associated problem. Although fatigue may not always be specific to PBC, it is vital for this fact not to be used as a rationale by clinicians managing PBC patients to avoid addressing this symptom. To do so because fatigue is in some way “not a PBC-specific problem” can contribute to a disappointing patient experience if clinical management is not relevant to the patient's perceived problems. The third issue is the important question of why PBC patients experience, at a seemingly enhanced frequency, the problem set that underpins fatigue; Al-Harthy et al.1 quite correctly stated that this requires study in centers other than our own. The fatigue phenotype seen in PBC is strikingly similar to that seen in other chronic inflammatory conditions, and PBC-associated problems, such as autonomic dysfunction and sleep disturbance, are themselves associated with fatigue in multiple different settings. Each of these can in turn be associated with the comorbid processes identified by Al-Harthy et al. This raises the intriguing question whether PBC is in fact a paradigm for complex fatigue in chronic disease. Because of the advantages that PBC holds for the study of phenomena such as fatigue (e.g., robust diagnostic criteria and validated assessment tools), it might represent an important and exciting context in which to study fatigue in ways that will be highly relevant to other disease settings. We believe that Al-Harthy et al.1 have provided further support for the consensus that fatigue is a problem experienced by a significant proportion of PBC patients. We acknowledge that although fatigue may not be specific to the disease in all patients, it is complex in its origin, expression, and impact. We suggest that now is the time to move away from a sterile debate about whether PBC patients do or do not experience fatigue and to start to address the important question of why this complex symptom occurs in this disease state. Doing this will allow the entire field to move toward improved treatment paradigms of the type successfully implemented in Newcastle.10 David E. J. Jones M.D.*, Julia L. Newton M.D.*, * National Institute for Health Research Biomedical Research Centre in Ageing, Newcastle University, Newcastle, United Kingdom.

Central nervous system dysfunction in primary biliary cirrhosis and its relationship to symptoms

Primary biliary cirrhosis (PBC) is associated with fatigue, memory impairment, and sleep disturbances. These symptoms suggest the possibility of underlying central nervous system (CNS) dysfunction. During exercise, fatigue develops due to muscular processes (peripheral fatigue) and decreased neurological activation of the muscle (central fatigue). In this study we objectively quantify central and peripheral fatigue in PBC and investigate the integrity of cortical inhibitory and excitatory circuits. Finally, we determine the relationship of these indices to the symptoms of PBC. 16 early-stage PBC patients, 8 post-liver transplant PBC patients, and 12 age-matched controls were studied at the Specialist PBC clinic and neuroscience research unit. In these patients, twitch interpolation was used to measure peripheral and central fatigue. Paired-pulse trans-cranial magnetic stimulation was used to assess intra-cortical inhibition (ICI) and facilitation (ICF). PBC patients had a significantly lower central activation before fatiguing exercise (mean 86.6.8% (±12.75) vs. 95.2% (±7.4); p<0.05) and a greater response variability than controls. The decline in central activation during exercise and peripheral fatigue were normal. ICI was significantly reduced in PBC patients and daytime somnolence was greater in patients where net inhibition exceeded facilitation. Transplanted and non-transplanted patients had similar central activation, ICI, and ICF. PBC patients have impaired central activation and abnormal ICI, suggesting CNS abnormalities beyond voluntary control. Transplanted and non-transplanted patients show similar abnormalities raising interesting questions about the mechanisms underpinning these changes and the permanence of neurological dysfunction in PBC. ICI and ICF and the balance between them are related to daytime somnolence (an important symptom in PBC).

A follow-up study of modafinil for the treatment of daytime somnolence and fatigue in primary biliary cirrhosis

A follow-up study of modafinil for the treatment of daytime somnolence and fatigue in primary biliary cirrhosis

Fatigue in primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a chronic, autoimmune, cholestatic liver disease with a slowly progressive course. Without treatment, most patients eventually develop fibrosis of the liver and may need liver transplantation in the late stage of disease. Fatigue and pruritus are the most common symptoms of PBC, but the majority of patients are asymptomatic at first presentation. There is no specific treatment for fatigue in PBC, but modafinil has shown some potential beneficial effects, such as increased energy levels and decreased total sleep time. This Review article discusses the natural history and the measurement of fatigue in patients with PBC. The central and the peripheral mechanisms that have been suggested for the pathogenesis of fatigue in PBC are also discussed and treatment options are reviewed.

Loss of capacity to recover from acidosis in repeat exercise is strongly associated with fatigue in primary biliary cirrhosis

Upon exercise, primary biliary cirrhosis (PBC) is associated with significant acidosis in peripheral muscle with recovery rate from acidosis strongly associating with fatigue. PBC patients describe particular problems with repeat exercise describing subsequent exercise episodes being limited by perceived effects of the first. We modelled this effect by exploring kinetics of pH recovery during 3 linked exercise episodes using magnetic resonance spectroscopy (MRS). Muscle acid handling capacity was studied following 3 x 3 min exercise periods at 35% maximum voluntary capacity in matched fatigued PBC, non-fatigued PBC and healthy controls (n=8 per group). Time to pH recovery following initial exercise was prolonged in PBC compared to controls (160 s [60-390] vs. 25 [0-180], p=0.005) with the longest recovery time seen in fatigued patients (median 210 s). All subjects shortened recovery time between exercise periods 1-2 (controls: mean -28%, non-fatigued PBC patients: -29% and fatigued PBC patients: -30%. Normals showed further recovery shortening between exercise periods 2-3 (-18%, p=ns vs. period 1-2 recovery) however this adaptive response was lost in non-fatigued PBC patients (+3%) and reversed in fatigued patients (+19%, p=0.01 vs. period 1-2). PBC patients retain the physiological capacity to shorten pH recovery time following repeat exercise. Capacity to shorten recovery time after a 2nd exercise period is lost in low-fatigue PBC patients and replaced by recovery prolongation in fatigued patients. Improvement in post-exercise acid recovery through exercise therapy should be possible in PBC patients and could be a novel approach to peripheral fatigue treatment.

The specificity of fatigue in primary biliary cirrhosis: Evaluation of a large clinic practice

Quality of life is an important concern for patients with chronic liver disease. We sought to describe the frequency, severity, and associations of fatigue, in patients with primary biliary cirrhosis (PBC). We performed association testing between PBC-40 multidomain disease-specific quality of life responses and clinical findings. Three hundred twenty-seven patients from a single clinic with PBC (94% female, 92% AMA-positive) were evaluated. The average age was 57 years and average disease duration 7.2 years. Verbally reported fatigue was noted in 48% but present in the overwhelming majority on PBC-40 completion, with 44% having moderate or severe symptoms. Of those not complaining of fatigue clinically, 25% documented moderate or severe fatigue by questionnaire. Age had an inverse relationship with fatigue (P < 0.01), whereas body mass index (BMI) was positively associated (P < 0.01), as was the presence of pruritus (P < 0.001), sicca symptoms (P < 0.001), depression (P < 0.001), fibromyalgia (P < 0.004), and scleroderma (P < 0.05). For those with varices (P < 0.05) or cirrhosis clinically (P < 0.05), higher fatigue scores were noted, although those who initially presented with noncirrhotic disease had higher scores at the time of testing (P < 0.005). Fatigue was associated with greater use of prescription medication (P < 0.01), in particular for antipruritics (cholestyramine: P < 0.001; rifampin: P < 0.001), proton pump inhibitors (P < 0.002), beta-blockers (P < 0.02), and antidepressants (P < 0.001), whereas those taking calcium and vitamin D appeared less fatigued (P < 0.05). In a multivariate model, calcium and vitamin D use, BMI, stage of disease at diagnosis, as well as symptomatic fatigue or pruritus, were significant. Biochemical response to UDCA was not associated with lower fatigue scores. Attempts at defining the biological basis of fatigue in patients with PBC, and improving its treatment, must account for its multifactoral causes.

Variability of perceived fatigue in primary biliary cirrhosis: implications for symptom assessment

Variability of perceived fatigue in primary biliary cirrhosis: implications for symptom assessment

Serum anti‐mitochondrial antibodies and fatigue in primary biliary cirrhosis

Serum anti‐mitochondrial antibodies and fatigue in primary biliary cirrhosis

Modafinil in the Treatment of Debilitating Fatigue in Primary Biliary Cirrhosis: A Clinical Experience

Modafinil may be a potentially effective treatment for primary biliary cirrhosis (PBC)-related fatigue. About 42 patients were given a 3-day trial of 100-200 mg modafinil. Response was defined as increased energy, decreased somnolence and sleep requirements, and improved daily function. Patients with positive responses were continued indefinitely on the medication. During the initial trial period, 31 (73%) patients had complete response and continued to take the medication. Eleven (26%) had no response. In long-term follow-up (average 17.7 months), 25 (81%) patients continued to take 100-200 mg modafinil daily. Some required an increased dosage and some took the medication as needed. Four (12%) patients stopped the medication because of side-effects or reduced efficacy; one patient (3%) stopped due to medication cost and one (3%) due to resolution of fatigue. Side-effects included insomnia, nausea, nervousness, and headaches. Modafinil appears to be a safe, effective treatment for PBC-related fatigue.

Fatigue in primary biliary cirrhosis: a possible role of comorbidities

Fatigue is considered to be a specific manifestation of primary biliary cirrhosis (PBC). Recent reports have, however, questioned these findings. Considering the high rate of comorbidities in PBC patients and the fact that fatigue is a multifactorial symptom, we hypothesized that it might also be due to nonhepatic causes. Our aim was to evaluate fatigue in PBC patients and its relationship with comorbidities and depression. We enroled 49 Italian PBC patients (44 women; mean age: 58.9 years, range: 21-73 years) and 30 matched healthy controls, who completed the Fatigue Impact Scale (FIS), Modified FIS (MFIS), Fatigue Severity Score (FSS) and Rand Medical Outcomes Study Depression Screener. Comorbidities and several clinical and biochemical data were investigated. Linear regression, analysis of variance and post-hoc analysis were applied. Fatigue was higher in patients than in controls (FIS: 33 vs. 24; MFIS: 24 vs. 14; FSS: 3.3 vs. 1.9). Physical domain was significantly different in all the three questionnaires (FIS: P=0.05; MFIS: P=0.002; FSS: P=0.0002). Comorbidities (38% of patients) were independently associated with higher fatigue scores (FIS: 45; MFIS: 32; FSS: 3.3). Depressed patients (30%) were more fatigued, even if not always significantly (FIS: 43; MFIS: 29; FSS: 3.5), than controls and patients with no depression. Patients without comorbidities or depression (51%) did not have higher fatigue than controls (FIS: 20; MFIS: 17; FSS: 2.4). Fatigue in patients with PBC was higher, but not always significantly, than in healthy controls. Comorbidities and depression might have played a role in its pathogenesis. Our data arouse doubts about the specificity of fatigue in PBC and the pathogenetic role of liver impairment.

A Predictive Model for Fatigue and Its Etiologic Associations in Primary Biliary Cirrhosis

Excessive day-time somnolence and autonomic dysfunction are biological processes prevalent in Primary Biliary Cirrhosis (PBC) that associate with fatigue. Here we explore how these biological associates inter-relate, and their cumulative impact upon typical clinical cohorts. A predictive model for daytime hypersomnolence (Epworth Sleepiness Scale (ESS)) and autonomic dysfunction (Orthostatic Grading Scale (OGS)) was developed in a derivation cohort (n=124) and subsequently validated in a second cohort (n=114). Subjects also completed the disease specific quality of life tool, the PBC-40. A composite predictive criterion (presence of either ESS > or =10 or OGS > or =4) for the presence of fatigue in PBC patients had a sensitivity of 0.71 (95% confidence intervals 0.59-0.81) and specificity 0.8 (0.67-0.9) (positive predictive value (PV); 0.84 (0.72-0.92), negative PV; 0.66 (0.53-0.78) for moderate or severe fatigue). Ninety-seven percent of severely fatigued patients (0% of non-fatigued) met the aetiology predictive criterion (chi(2) 49.6, P<.0001). Expression of both significant daytime somnolence and autonomic dysfunction was not associated with more severe fatigue, suggesting that there is a threshold effect for fatigue in PBC. When applied to a second independent cohort, the composite criterion retained strongly significant predictive value for fatigue. A significant proportion of fatigue in PBC associates with one or both of autonomic dysfunction (OGS > or =4) and sleep disturbance (ESS > or =10). Those meeting both ESS and OGS criteria were not more severe fatigued than those meeting the diagnostic criterion for either OGS or ESS alone. A threshold effect for fatigue has implications for potential therapeutic interventions.

Autonomic dysfunction in primary biliary cirrhosis correlates with fatigue severity

Autonomic dysfunction has previously been described in primary biliary cirrhosis patients. In nonhepatic diseases, fatigue is associated with autonomic dysfunction and impaired baroreflex sensitivity. Here, we investigate the prevalence of autonomic dysfunction using highly sensitive detection modalities and its relationship with fatigue in both noncirrhotic and cirrhotic primary biliary cirrhosis patients. Autonomic reflex tests were performed, using continuous blood pressure and electrocardiograph measurement in 47 primary biliary cirrhosis patients and age and sex-matched controls. Fatigue was measured using the primary biliary cirrhosis-40. In all, 100% of precirrhotic and 81% of cirrhotic primary biliary cirrhosis patients exhibited autonomic dysfunction. Valsalva ratio and 30 : 15 ratio (measures of parasympathetic autonomic dysfunction) were significantly lower in primary biliary cirrhosis patients than in controls (valsalva ratio: 1.42 vs. 1.57; P=0.01, 30 : 15: 1.1 vs. 1.2; P=0.01). Blood pressure drop on standing (sympathetic autonomic dysfunction) was greater in the primary biliary cirrhosis group (31+/-22 vs. 23+/-15 mmHg; P=0.03). Valsalva phase IV size was similar between primary biliary cirrhosis patients and controls, however, time to phase IV was significantly longer (P=0.01), suggesting adrenergic failure. Increasing fatigue was associated with impaired baroreflex sensitivity and an earlier, bigger phase IV (sympathetic overactivity). No significant differences were seen, between cirrhotic and noncirrhotic patients. The prevalence of autonomic dysfunction in primary biliary cirrhosis patients is significantly higher than has previously been thought to be the case. Indeed, when sensitive detection modalities are used, it is found to be almost universal at all stages of the disease process. Fatigue in primary biliary cirrhosis is associated with abnormalities of autonomic function.

An open study of modafinil for the treatment of daytime somnolence and fatigue in primary biliary cirrhosis

Fatigue is a debilitating symptom which frequently impairs the quality of life of patients with primary biliary cirrhosis (PBC). Although the mechanisms underpinning fatigue in PBC remain unclear, there is an emerging consensus that CNS mechanisms play a key role. It has recently been shown that there is a strong association between abnormalities in sleep regulation, in particular excessive daytime somnolence, and fatigue severity in PBC. The CNS-acting drug modafinil has an established role in the treatment of excessive daytime somnolence in non-liver disease states. To explore, in an open label study, the responses of PBC patients suffering from significant daytime somnolence and associated fatigue to modafinil therapy. All patients in the series (n = 21) underwent daytime somnolence assessment using the Epworth Sleepiness Scale and PBC symptom assessment using the PBC-40, a multi-domain, disease specific, psychometrically robust quality of life measure. Modafinil was started at a dose of 100 mg/day and was titrated according to tolerability and response. Patients underwent repeat Epworth Sleepiness Scale and PBC-40 assessment after 2 months of treatment. Significant improvement was seen in Epworth Sleepiness Scale scores with modafinil therapy [15 +/- 3 vs. 8 +/- 6, P < 0.0005 (intention-to-treat analysis)]. An equally significant improvement in fatigue severity was also seen [PBC-40 fatigue domain score (46 +/- 6 vs. 34 +/- 12, P < 0.0001) (intention-to-treat analysis)]. Open label modafinil therapy was associated, where tolerated by patients, with improvement in excessive daytime somnolence and associated fatigue in PBC. Further study in placebo-controlled trials is warranted.