Jessie Pairman

Population prevalence and symptom associations of autonomic dysfunction in primary biliary cirrhosis

Patients with primary biliary cirrhosis (PBC) frequently experience significant fatigue thought to result from as‐yet‐unidentified central nervous system (CNS)‐mediated processes. Pilot studies have suggested that autonomic dysfunction is a frequent occurrence in PBC and may contribute to the pathogenesis of this fatigue. The degree to which autonomic dysfunction affects the PBC population as a whole, and its interrelationship with other symptoms experienced by PBC patients remains unstudied. In this study, we used a geographically defined, fully representative PBC patient cohort to study the prevalence of symptoms of autonomic dysfunction and its relationship with other symptoms of PBC. Symptoms of cardiovascular autonomic dysfunction (as assessed using the Orthostatic Grading Scale [OGS]) were significantly more frequently reported and significantly more severe in PBC patients than in both matched normal controls (40% versus 6% with moderate or worse orthostasis (P < .0001), mean OGS score 3.2 ± 3.4 versus 1.3 ± 1.9, P < .005) and in patients with primary sclerosing cholangitis and in severity were independently associated with severity of fatigue and cognitive symptoms (both r 2 = 0.3, P < .0001). Thirteen of 20 patients with an OGS value > 4 (moderate severity and worse) had significant abnormality in autonomic regulation of blood pressure, which was identified on dynamic testing. Conclusion: Symptoms suggestive of autonomic dysfunction frequently occur in PBC patients and reflect dysregulation of actual blood pressure. Autonomic dysfunction is independently associated with both fatigue and, importantly, symptoms of cognitive dysfunction, suggesting the potential for significant organic sequelae. (HEPATOLOGY 2007;45:1496–1505.)

Clinical characteristics of a novel subgroup of chronic fatigue syndrome patients with postural orthostatic tachycardia syndrome

A significant proportion of patients with chronic fatigue syndrome (CFS) also have postural orthostatic tachycardia syndrome (POTS). We aimed to characterize these patients and differentiate them from CFS patients without POTS in terms of clinical and autonomic features.

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.

Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome: a case-control study.

Eur J Clin Invest 2011

Familial neurocardiogenic (vasovagal) syncope

Vasovagal syncope (VSS) is an exaggerated tendency towards the common faint caused by a sudden and profound hypotension with or without bradycardia. The etiology of VVS is unknown though several lines of evidence indicate central and peripheral abnormalities of sympathetic function. Studies however indicate a strong heritable component to the etiology of VVS in over 20% of cases. Here, we report the findings from a family that shows apparently autosomal dominant VVS in at least three generations. Clinical findings included an absence of any discernible cardiac or autonomic abnormalities and reproducible hypotension on tilt table testing in affected family members.

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.

Reduction in functional ability is significant postliver transplantation compared with matched liver disease and community dwelling controls

We compared functional ability and symptom severity in liver transplant recipients and matched chronic liver disease (CLD) and community controls. A total of 103/140 consecutive liver transplant recipients from a single centre (73%) and matched controls completed the patient‐reported functional outcome measure: Patient‐Reported Outcomes Measurement Information System, Health Assessment Questionnaire (PROMIS HAQ). Symptoms frequently seen in CLD were quantified by (i) Fatigue Impact Scale (FIS), (ii) Orthostatic Grading Scale (OGS: autonomic dysfunction), (iii) Cognitive Failures Questionnaire (CFQ) and (iv) Epworth Sleepiness Scale (ESS: Daytime somnolence). Liver transplant recipients exhibited significant reduction in function (P < 0.0001) across all domains of the PROMIS HAQ suggesting that functional impairment is broad‐based. Seventy‐seven per cent of all postliver transplants identified some difficulty with activities of daily living. There was no relationship between PROMIS HAQ and liver biochemistry (r2 = 0.04, P = NS) or time since transplant (r2 = 0.1, P = NS). Elevation in PROMIS HAQ (and therefore functional impairment) strongly associated with symptoms, particularly fatigue, cognitive impairment and daytime somnolence. Fatigue severity was independently associated with functional impairment (FIS) (Beta 0.727, P < 0.0001). Symptoms or functional ability was not different between liver transplant recipients and matched chronic liver disease controls. Although survival postliver transplantation is improving, our cross‐sectional study suggests that functional ability may not improve postliver transplantation. Further study is warranted to address the mechanisms responsible for post‐transplant functional impairment and to develop effective rehabilitation regimes to maximize function following liver transplantation.

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

Eur J Clin Invest 2010; 40 (1): 18–24

Functional capacity is significantly impaired in primary biliary cirrhosis and is related to orthostatic symptoms.

Objective To assess patient-reported functional ability and its relationship with symptoms in primary biliary cirrhosis (PBC). Methods Functional status was assessed in a representative cohort of 75 patients with PBC using the Patient-Reported Outcome Measure Information System Health-Assessment Questionnaire (PROMIS-HAQ) functional assessment tool and was related to both symptom severity at the point of assessment (assessed using the PBC-40 and Orthostatic Grading Scale) and symptom severity change over the previous 4 years. Functional status in the PBC group was compared with primary sclerosing cholangitis (cholestatic liver disease) and community controls. Results Functional impairment at follow-up (PROMIS-HAQ) was substantial in PBC significantly higher than that in both primary sclerosing cholangitis and community controls. PROMIS-HAQ domain scores confirmed that patients with PBC had significant impairment in arising, eating, walking, reach and grip and activity, but not dressing or hygiene. Functional impairment correlated positively with greater PBC-40 Fatigue, Cognitive and Social and Emotional domains and higher orthostatic symptoms. Over 4 years, total symptom burden increased significantly (P=0.03). The predominant factor was rise in Cognitive domain scores indicating worsening cognitive symptoms (P<0.0001). Change in PBC-40 Cognitive, Social and Emotional scores (2005–2009) strongly predicted functional ability in 2009. Multivariate analysis confirmed that PROMIS-HAQ scores were predicted independently by PBC-40 Social and Emotional scores (P=0.02; &bgr;=0.3) and orthostatic symptoms (P=0.04; &bgr;=0.3). Conclusion PBC associates with substantial functional impairment. PBC symptom distribution evolves over time, with cognitive symptoms making ever-greater contribution to overall symptom burden. The major potentially modifiable determinant responsible for the functional impairment appears to be orthostatic symptoms.