Katharine Wilton

Fatigue in primary biliary cirrhosis is associated with excessive daytime somnolence

A significant proportion of patients with primary biliary cirrhosis (PBC) suffer from severe fatigue. The aim of this study was to characterize patterns of daytime sleep in patients with PBC (using both objective and subjective assessment approaches) and to study the association between sleep abnormality and fatigue severity. Fatigue severity was assessed in 48 female subjects with PBC (using a disease‐specific quality of life instrument (the PBC‐40) and a generic fatigue measure (Fatigue Impact Scale [FIS]) as well as 48 case‐matched normal controls. All participants also completed the Pittsburgh Sleep Quality Index (PSQI) and the Epworth Sleepiness Scale (ESS, which assesses daytime hypersomnolence). Objective sleep assessment was performed using accelerometry over 7 days. Global sleep quality assessed by the PSQI was significantly lower in the PBC group compared to controls (P < .0001). ESS scores were significantly higher in patients with PBC than controls (P = .0001), suggesting significantly greater daytime somnolence in the patients with PBC. Objective sleep assessment confirmed that subjects with PBC were sleeping on average almost twice as long as controls during the daytime. Both degree of daytime somnolence (ESS) and actual daytime sleep activity (accelerometry) correlated strongly with fatigue severity in the patient group (r2 = 0.5, P < .0001 and r2 = 0.2, P < .01, respectively). In conclusion, Sleep abnormality, in the form of excessive daytime somnolence, is present in a significant proportion of patients with PBC, with the degree of daytime somnolence correlating strongly with the degree of fatigue. Existing agents effective at reducing daytime somnolence (such as modafinil) hold potential for the treatment of fatigue in PBC. (HEPATOLOGY 2006;44:91–98.)

Fatigue in Non-Alcoholic Fatty Liver Disease (NAFLD) is significant and associates with inactivity and excessive daytime sleepiness but not with liver disease severity or insulin resistance.

Objective: To quantify fatigue in non-alcoholic fatty liver disease (NAFLD), to determine whether perceived fatigue reflects impairment of physical function and to explore potential causes. Patients and methods: A cohort study was carried out on 156 consecutive patients with histologically proven NAFLD studied in two cohorts. Phase 1 determined the perceived fatigue experienced by NAFLD patients (assessed using the Fatigue Impact Scale (FIS)) in comparison with normal and liver disease controls, and the relationship to physical function (actigraphy). In phase 2, biological associations of fatigue in NAFLD were explored. Results: Fatigue was markedly higher in NAFLD patients than in controls (mean (SD) FIS 51 (38) vs 8 (12), p<0.001). NAFLD patients showed significantly lower physical activity over 6 days (7089 (2909) mean steps/day vs 8676 (2894), p = 0.02). A significant inverse correlation was seen between FIS and physical activity (r2 = 0.1, p = 0.02). Fatigue experienced by NAFLD patients was similar to that in primary biliary cirrhosis (n = 36) (FIS 64 (9) vs 61 (2), p = NS). No association was seen between FIS and biochemical and histological markers of liver disease severity or insulin resistance (homeostasis model assessment (HOMA)) (r2<0.005). Significant association was seen between fatigue severity and daytime somnolence (Epworth Sleepiness Scale) (r2 = 0.2, p<0.001). Conclusion: Fatigue is a significant problem in NAFLD, is similar in degree to that in primary biliary cirrhosis patients and is associated with impairment in physical function. Fatigue in NAFLD appears to be unrelated to either severity of underlying liver disease or insulin resistance, but is associated with significant daytime somnolence.

An integrated care pathway improves quality of life in Primary Biliary Cirrhosis

BACKGROUND Clinical management of the chronic autoimmune liver disease, Primary Biliary Cirrhosis (PBC) involves addressing the underlying liver disease and a range of symptoms independent of liver disease severity. We have formally explored how these two perspectives of chronic disease management can be combined into a clinic consultation and impact upon quality of life (QOL) in PBC. AIMS To develop and implement the first Integrated Care Pathway (ICP) for the management of liver disease progression and symptom management in PBC. METHODS Process mapping of current practice by a multidisciplinary group developed a flowchart of care from which the clinical record evolved. Symptom assessment is incorporated into the PBC ICP (QOL; PBC-40, autonomic symptoms; Orthostatic Grading Scale, daytime sleepiness; Epworth Sleepiness Scale). All patients were considered who attended clinic between July 2005 and June 2006. Symptom assessment was repeated after 1 year in those participating in the initial clinic cohort. RESULTS The PBC ICP was successfully introduced into our clinical environment with high levels of patient satisfaction. A total of 225 PBC patients attended over 12 months. Initial QOL assessments were in 195 (87%). Five patients died (3%). Repeat assessment 1 year later occurred in 149 subjects (149/190; 78%). All symptom domains improved after ICP implementation with significant improvements in those with moderate and severe symptoms in all PBC-40 symptom domains (P < 0.02). In those with severe fatigue (n = 38) symptom improvement was even more dramatic (P = 0.002). CONCLUSION ICP implementation delivers evidence-based care, leads to improvements in QOL coupled with high levels of patient satisfaction.

Lower ambulatory blood pressure in chronic fatigue syndrome.

Objective: To examine blood pressure circadian rhythm in subjects with chronic fatigue syndrome (CFS) and appropriate normal and fatigued controls to correlate parameters of blood pressure regulation with perception of fatigue in an observational cohort study. The cause of CFS remains unknown and there are no effective treatments. Methods: To address whether inactivity was a confounder, we performed a 24-hour ambulatory blood pressure monitoring in the following three subject groups: 1) CFS patients (Fukuda Diagnostic criteria) (n = 38); 2) normal controls (n = 120); and 3) a fatigue comparison group (n = 47) with the autoimmune liver disease primary biliary cirrhosis (PBC). All patients completed a measure of fatigue severity (Fatigue Impact Scale). In view of the different demographics between the patient groups, patients were age- and sex-matched on a case-by-case basis to normal controls and blood pressure parameters were compared. Results: Compared with the control population, the CFS group had significantly lower systolic blood pressure (p < .0001) and mean arterial blood pressure (p = .0002) and exaggerated diurnal variation (p = .009). There was a significant inverse relationship between increasing fatigue and diurnal variation of blood pressure in both the CFS and PBC groups (p < .05). Conclusion: Lower blood pressure and abnormal diurnal blood pressure regulation occur in patients with CFS. We would suggest the need for a randomized, placebo-controlled trial of agents to increase blood pressure such as midodrine in CFS patients with an autonomic phenotype. CFS = chronic fatigue syndrome; SBP = systolic blood pressure; MAP = mean arterial pressure; HR = heart rate; DBP = diastolic blood pressure; PBC = primary biliary cirrhosis; FIS = Fatigue Impact Scale.

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

BACKGROUND & AIMS 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Home orthostatic training in chronic fatigue syndrome – a randomized, placebo-controlled feasibility study

Eur J Clin Invest 2010; 40 (1): 18–24

Impedance cardiography: a role in vasovagal syncope diagnosis?

BACKGROUND vasovagal syncope is the most common cause of syncope in all age groups, with diagnosis usually based on history, examination and basic investigations to exclude alternative causes of syncope. Where doubt exists, the head-up tilt (HUT) test is used for diagnosis but is time consuming and lacks a gold standard to accurately assess sensitivity and specificity. Alternative methods of diagnosing vasovagal syncope would thus be useful. OBJECTIVE to investigate the potential for impedance cardiography (ICG)-derived haemodynamic measures to predict HUT test outcome in unexplained syncope. DESIGN prospective controlled study. SUBJECTS eighty-six patients with unexplained syncope and 43 non-syncopal controls. METHODS all subjects underwent continuous heart rate, blood pressure and ICG measurements during 10 min supine rest and during HUT. Vasovagal syncope was diagnosed when patients experienced symptom reproduction with concomitant haemodynamic derangements. RESULTS during rest prior to HUT, the syncopal group had higher mean heart rate (P = 0.0008) and lower baroreceptor effectiveness index (P < 0.0001) compared to non-syncopal controls. On comparing patients who presented with unexplained syncope who subsequently had a positive HUT (therefore a diagnosis of vasovagal syncope 55 [64%]; mean age 47 years, range 17-85) to those having a negative tilt test (n = 31; mean age 47 years, range 17-88), there were no significant differences found in cardiovascular or autonomic parameters prior to HUT. A predictive ROC curve model at a 85% threshold allowed using cardiac index (CI), end-diastolic index (EDI) and left ventricular work index (LVWI) would identify those who would have a positive HUT from baseline cardiovascular measurements (CI >3.5, EDI > 77, LVWI >4.7) with 93% sensitivity and 17% specificity. CONCLUSION supine haemodynamic measures derived from transthoracic ICG can simply, non-invasively and sensitively differentiate HUT-positive patients from those with negative tilt tests. Further work is needed, particularly in older patients, before this technique can be used in clinical practice.

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.

Primary Sjögrens syndrome is associated with impaired autonomic response to orthostasis and sympathetic failure

BACKGROUND Symptoms in keeping with autonomic dysfunction are commonly described by primary Sjögrens syndrome patients (pSS); whether objective abnormalities of autonomic function occur is unclear. This study set out to explore dynamic cardiovascular autonomic responses in pSS and their relationship with symptoms and quality of life. METHODS Twenty-one people from the UK pSS registry, 21 community controls and 21 patients with the autoimmune liver disease primary biliary cirrhosis (PBC) (matched case-wise for age and sex) attended for assessment of autonomic responses to orthostasis and Valsalva manoeuvre (VM). pSS patients also completed EULAR Sjögrens Syndrome patient-reported index (ESSPRI), EULAR Sjögrens syndrome disease activity index (ESSDAI), fatigue impact scale and EURO-QOL 5-dimension (EQ-5D). RESULTS Compared with controls, pSS patients had significantly lower baseline systolic blood pressure (SBP) (114 ± 13 vs. 127 ± 20; P = 0.02), which dropped to a significantly lower value (98 ± 22 vs. 119 ± 24, P = 0.009). When area under the curve (AUC) was calculated for when the SBP was below baseline this was significantly greater in pSS compared to both control groups (pSS vs. control vs. PBC: 153 ± 236 vs. 92 ± 85 vs. 1.2 ± 0.3, P = 0.005). Peak phase IV SBP during the VM was significantly lower in pSS (P = 0.007) indicating early sympathetic failure. Increased heart rate associated with fatigue (P = 0.02; r(2) = 0.2) and EQ-5D. A shift in sympathetic-vagal balance associated with overall symptom burden (ESSPRI) (P = 0.04, r(2) = 0.3) and EULAR sicca score (P = 0.016; r(2) = 0.3), the latter also correlated with baroreceptor effectiveness (P = 0.03; r(2) = 0.2) and diastolic blood pressure variability (P = 0.003; r(2) = 0.4). CONCLUSION pSS patients have impaired blood pressure response to standing. Dysautonomia correlates with PSS-associated symptoms and quality of life.

Cognitive impairment in non-cirrhotic chronic liver disease is unrelated to liver disease severity but associated with ineffective baroreflex function

We read with interest the commentary by Bercik1 emphasising the influence that gut intestinal microflora may have on cognitive function—a model with clear therapeutic implications. We would like to propose, however, that a third party—the presence of autonomic nervous system dysfunction—complicates the relationship between cognitive impairment and gut microflora. In a number of diseases, autonomic dysfunction has been associated with cognitive impairment,2 3 and its presence is associated with impaired gastrointestinal motility, a risk factor for changes in bacterial colonisation. Autonomic dysfunction is a common problem in patients with chronic liver disease (CLD)4—the group of patients highlighted in the commentary as having obvious cognitive problems, as benefiting from treatment aimed at modifying the …