ABSTRACT
BACKGROUND: Age at presentation with primary biliary cholangitis (PBC) is associated with differential response to ursodeoxycholic acid (UDCA) therapy. Younger-presenting patients are less likely to respond to treatment and more likely to need transplant or die from the disease. PBC has a complex impact on quality of life (QoL), with systemic symptoms often having significant impact. AIM: To explain the impact of age at presentation on perceived QoL and the inter-related symptoms which impact upon it. METHODS: Using the UK-PBC cohort, symptoms were assessed using the PBC-40 and other validated tools. Data were available on 2055 patients. RESULTS: Of the 1990 patients reporting a global PBC-QoL score, 66% reported good/neutral scores and 34% reported poor scores. Each 10-year increase in age at presentation was associated with a 14% decrease in risk of poor perceived QoL (OR = 0.86, 95% CI: 0.75-0.98, P < 0.05). All symptom domains were similarly age-associated (P < 0.01). Social dysfunction was the symptom factor with the greatest impact on QoL. Median (interquartile range) PBC-40 social scores for patients with good perceived QoL were 18 (14-23) compared with 34 (29-39) for those with poor QoL. CONCLUSION: The majority of patients with primary biliary cholangitis do not feel their QoL is impaired, although impairment is reported by a sizeable minority. Age at presentation is associated with impact on perceived QoL and the symptoms impairing it, with younger patients being more affected. Social dysfunction makes the greatest contribution to QoL impairment, and it should be targeted in trials aimed at improving life quality.
Subject(s)
Liver Cirrhosis, Biliary , Quality of Life , Adolescent , Adult , Aged , Aged, 80 and over , Cholagogues and Choleretics/therapeutic use , Female , Humans , Liver Cirrhosis, Biliary/drug therapy , Male , Middle Aged , Severity of Illness Index , Ursodeoxycholic Acid/therapeutic use , Young AdultABSTRACT
BACKGROUND: Brain change can occur in primary biliary cholangitis (PBC), potentially as a result of cholestatic and/or inflammatory processes. This change is linked to systemic symptoms of fatigue and cognitive impairment. AIM: To identify whether brain change occurs early in PBC. If the change develops early and is progressive, it may explain the difficulty in treating these symptoms. METHODS: Early disease brain change was explored in 13 patients with newly diagnosed biopsy-proven precirrhotic PBC using magnetisation transfer, diffusion-weighted imaging and 1 H magnetic resonance spectroscopy. Results were compared to 17 healthy volunteers. RESULTS: Cerebral magnetisation transfer ratios were reduced in early PBC, compared to healthy volunteers, in the thalamus, putamen and head of caudate with no greater reduction in patients with greater symptom severity. Mean apparent diffusion coefficients were increased in the thalamus only. No 1 H magnetic resonance spectroscopy abnormalities were seen. Serum manganese levels were elevated in all PBC patients, but no relationship was seen with imaging or symptom parameters. There were no correlations between neuroimaging data, laboratory data, symptom severity scores or age. CONCLUSIONS: This is the first study to be performed in this precirrhotic patient population, and we have highlighted that neuroimaging changes are present at a much earlier stage than previously demonstrated. The neuroimaging abnormalities suggest that the brain changes seen in PBC occur early in the pathological process, even before significant liver damage has occurred. If such changes are linked to symptom pathogenesis, this could have important implications for the timing of second-line-therapy use.
Subject(s)
Brain/abnormalities , Brain/diagnostic imaging , Cholangitis/diagnostic imaging , Diffusion Magnetic Resonance Imaging/methods , Adult , Aged , Early Diagnosis , Female , Humans , Liver Cirrhosis, Biliary/diagnostic imaging , Magnetic Resonance Imaging/methods , Magnetic Resonance Spectroscopy/methods , Male , Middle AgedABSTRACT
BACKGROUND: Pruritus is a common symptom associated with cholestatic liver diseases. To date only small single centre case series have suggested efficacy of nasobiliary drainage in relieving cholestatic pruritus. AIM: To perform a multicentre study to evaluate the safety and efficacy of nasobiliary drainage in cholestatic pruritus. METHODS: This was a retrospective study of all patients treated with nasobiliary drainage for refractory cholestatic pruritus between 2006 and 2015 at five European centres. Pruritus was quantified using a visual analogue scale (VAS) and liver enzymes, serum bilirubin and total serum bile salts (TBS) were measured before (pre-NBD) and after nasobiliary drainage (post-NBD). We analysed the duration of treatment response and associated complications. RESULTS: In total, 27 patients (59% females) underwent 29 nasobiliary drainage procedures. The median duration of NBD was 7 days. NBD decreased pruritus in 89.6% of cases (VAS from 10.0 to 0.3, P < 0.0001). The median percentage decline in pruritus VAS was 94% and 33% of patients were free of pruritus within 24 h of starting drainage. The duration of treatment response was independent of duration of drainage (P = 0.12) and bile output. Significant improvements were seen in the median levels of serum alkaline phosphatase (P = 0.001) and serum bilirubin (P = 0.03) but not in serum TBS (P = 0.07). Mild post-endoscopic retrograde cholangiopancreatography pancreatitis (31%) was the most frequent complication. CONCLUSIONS: Nasobiliary drainage is effective in relieving cholestatic pruritus in most patients and has favourable effect on biomarkers of cholestasis. Nasobiliary drainage may be associated with high risk of adverse events, especially pancreatitis. Prospective studies are needed to confirm our findings.
Subject(s)
Cholestasis/complications , Drainage/methods , Pruritus/therapy , Adult , Bile/metabolism , Cholangiopancreatography, Endoscopic Retrograde/adverse effects , Female , Humans , Male , Middle Aged , Pancreatitis/etiology , Pruritus/etiology , Retrospective StudiesABSTRACT
Biliary epithelial cells (BEC) are important targets in some liver diseases, including acute allograft rejection. Although some injured BEC die, many can survive in function compromised states of senescence or phenotypic de-differentiation. This study was performed to examine changes in the phenotype of BEC during acute liver allograft rejection and the mechanism driving these changes. Liver allograft sections showed a positive correlation (p < 0.0013) between increasing T cell mediated acute rejection and the number of BEC expressing the senescence marker p21(WAF1/Cip) or the mesenchymal marker S100A4. This was modeled in vitro by examination of primary or immortalized BEC after acute oxidative stress. During the first 48 h, the expression of p21(WAF1/Cip) was increased transiently before returning to baseline. After this time BEC showed increased expression of mesenchymal proteins with a decrease in epithelial markers. Analysis of TGF-ß expression at mRNA and protein levels also showed a rapid increase in TGF-ß2 (p < 0.006) following oxidative stress. The epithelial de-differentiation observed in vitro was abrogated by pharmacological blockade of the ALK-5 component of the TGF-ß receptor. These data suggest that stress induced production of TGF-ß2 by BEC can modify liver allograft function by enhancing the de-differentiation of local epithelial cells.
Subject(s)
Bile Ducts, Intrahepatic/pathology , Cellular Senescence , Epithelial Cells/pathology , Graft Rejection/pathology , Liver Transplantation/pathology , Acute Disease , Bile Ducts, Intrahepatic/metabolism , Biopsy , Blotting, Western , Cells, Cultured , Densitometry , Enzyme-Linked Immunosorbent Assay , Epithelial Cells/metabolism , Gene Expression Regulation , Graft Rejection/genetics , Graft Rejection/metabolism , Humans , Immunohistochemistry , Oxidative Stress/genetics , RNA/genetics , Real-Time Polymerase Chain Reaction , Transforming Growth Factor beta2/biosynthesis , Transforming Growth Factor beta2/genetics , Transplantation, HomologousABSTRACT
OBJECTIVES: to examine fatigue variability over time in chronic fatigue syndrome (CFS) and the effect of other symptoms on its predictability. DESIGN: longitudinal cohort study of patients with CFS (Fukuda criteria). SETTING: specialist CFS clinical service. SUBJECTS: phase 1: 100 patients who participated in a study of CFS symptoms in 2005 were revisited in 2009. Phase 2: 25 patients completed fatigue diaries to address intra- and inter-day variability in perceived fatigue. MAIN OUTCOME MEASURES: phase 1: subjects completed fatigue impact scale (FIS), Epworth sleepiness scale (ESS), orthostatic grading scale (OGS) and hospital anxiety and depression scale (HADS). Changes in variables represented the differences between 2005 and 2009. Phase 2: subjects rated fatigue on a scale of 0 (no fatigue) to 10 (severe fatigue) four times a day for 5 weeks. RESULTS: symptom assessment tools were available in both 2005 and 2009 for 74% of patients. FIS and HADS depression (HAD-D) and anxiety (HAD-A) scores significantly improved during follow-up whereas ESS and OGS remained stable. FIS improved in 29/74 (39%) subjects, and by ≥ 10 points in 19 (26%). FIS worsened by ≥ 10 points in 33/74 (45%) subjects. On multivariate analysis, independent predictors of current fatigue (FIS in 2009) were FIS in 2005, HAD-D in 2009, OGS in 2009 and change in HAD-A. Reported fatigue was stable from week to week and from day to day. Patients reported higher fatigue in the morning (mean ± SD; 6.4 ± 2), becoming significantly lower at lunchtime (6.2 ± 2; P < 0.05) and increasing again to 7 ± 2 at bedtime. CONCLUSIONS: current fatigue is independently associated with current autonomic symptom burden, current depression and change in anxiety during follow-up. These findings have implications for targeted symptom management in CFS.
Subject(s)
Fatigue Syndrome, Chronic/complications , Orthostatic Intolerance/etiology , Adult , Aged , Anxiety Disorders/etiology , Depressive Disorder/etiology , Epidemiologic Methods , Fatigue Syndrome, Chronic/psychology , Humans , Middle Aged , PrognosisABSTRACT
OBJECTIVES: To examine muscle acid handling following exercise in chronic fatigue syndrome (CFS/ME) and the relationship with autonomic dysfunction. DESIGN: Observational study. SETTING: Regional fatigue service. SUBJECTS & INTERVENTIONS: Chronic fatigue syndrome (n = 16) and age and sex matched normal controls (n = 8) underwent phosphorus magnetic resonance spectroscopy (MRS) to evaluate pH handling during exercise. Subjects performed plantar flexion at fixed 35% load maximum voluntary contraction. Heart rate variability was performed during 10 min supine rest using digital photophlethysmography as a measure of autonomic function. RESULTS: Compared to normal controls, the CFS/ME group had significant suppression of proton efflux both immediately postexercise (CFS: 1.1 +/- 0.5 mmol L(-1) min(-1) vs. normal: 3.6 +/- 1.5 mmol L(-1) min(-1), P < 0.001) and maximally (CFS: 2.7 +/- 3.4 mmol L(-1) min(-1) vs. control: 3.8 +/- 1.6 mmol L(-1) min(-1), P < 0.05). Furthermore, the time taken to reach maximum proton efflux was significantly prolonged in patients (CFS: 25.6 +/- 36.1 s vs. normal: 3.8 +/- 5.2 s, P < 0.05). In controls the rate of maximum proton efflux showed a strong inverse correlation with nadir muscle pH following exercise (r(2) = 0.6; P < 0.01). In CFS patients, in contrast, this significant normal relationship was lost (r(2) = 0.003; P = ns). In normal individuals, the maximum proton efflux following exercise were closely correlated with total heart rate variability (r(2) = 0.7; P = 0.007) this relationship was lost in CFS/ME patients (r(2) < 0.001; P = ns). CONCLUSION: Patients with CFS/ME have abnormalities in recovery of intramuscular pH following standardised exercise degree of which is related to autonomic dysfunction. This study identifies a novel biological abnormality in patients with CFS/ME which is potentially open to modification.
Subject(s)
Fatigue Syndrome, Chronic/metabolism , Muscle, Skeletal/metabolism , Blood Pressure/physiology , Case-Control Studies , Energy Metabolism , Fatigue Syndrome, Chronic/physiopathology , Heart Rate/physiology , Humans , Hydrogen-Ion Concentration , Magnetic Resonance Spectroscopy/methods , Muscle Contraction/physiology , Phosphorus , Physical Exertion/physiology , Time FactorsABSTRACT
BACKGROUND: Osteoporosis and autonomic dysfunction are prevalent in the autoimmune liver disease primary biliary cirrhosis (PBC). Postural hypotension is one consequence of autonomic dysfunction and is a recognized risk factor for falls, which, alongside osteoporosis could lead to significant injury and fractures. AIM: To determine the prevalence and sequelae of falls in PBC and to identify modifiable risk factors. DESIGN: Cross-sectional, geographical, population census of PBC and two control groups: primary sclerosing cholangitis and a community dwelling population. Multidisciplinary falls assessment of a representative group of PBC. METHODS: Symptom assessment tools, completed by the three cohorts, determined the prevalence of falls, injuries and associated symptoms. Multidisciplinary assessments, adhering to NICE guidelines, identified modifiable fall associations. RESULTS: Significantly more of the PBC population had fallen (72% P < 0.001) than both control groups. Fifty-five percent had fallen in the last year (P < 0.001), and 22% more than once in the last year (P < 0.01). Seventy percent of PBC fallers were injured, 27% fractured a bone and 19% were admitted to hospital, all significantly more common than controls. Postural dizziness was significantly worse in fallers (P < 0.001), as were balance (P < 0.001) and lower limb strength (P = 0.002). Lower limb strength was independently associated with number of falls in previous year (beta = 0.184, P < 0.001). CONCLUSION: Falls and resultant injury are prevalent in PBC and more common than previously recognized. Addressing postural dizziness, poor balance and lower limb weakness using a multidisciplinary approach has the potential to reduce falls, morbidity and mortality and as a result improve quality of life.
Subject(s)
Accidental Falls , Liver Cirrhosis, Biliary/physiopathology , Aged , Aged, 80 and over , Dizziness/epidemiology , Dizziness/etiology , Epidemiologic Studies , Female , Health Status , Humans , Liver Cirrhosis, Biliary/complications , Liver Cirrhosis, Biliary/epidemiology , Male , Middle Aged , Prevalence , Risk Factors , United Kingdom/epidemiology , Wounds and Injuries/epidemiology , Wounds and Injuries/etiologyABSTRACT
BACKGROUND: Studies have established that levels of fatigue vary between different patient groups. It is less clear whether the nature, as opposed to severity of fatigue differs between groups. OBJECTIVE: To examine descriptions of fatigue by patients with a range of chronic diseases and determine the relationship between symptom domains. DESIGN: Retrospective review of Fatigue Impact Scale (FIS) data. SETTING: Fatigue Research Group. PARTICIPANTS: Six hundred subjects in five chronic disease groups and one (n = 45) normal control group. MAIN OUTCOME MEASURES: Statistical analysis was performed to assess the effect of increasing fatigue and the overlap of FIS domain scores between disease groups by calculation of geometric means as proportions summed to 1 in each FIS domains, whilst controlling for total score. RESULTS: Those with lower scores exhibit relatively higher physical scores than patients with higher total scores. In contrast, as total score increases, so does the proportion accounted for by the cognitive and psychosocial scores. This was not related to a threshold effect as the maximum total score of 40 in the physical domain was only achieved in three patients (<1%). Average domain proportions between patient groups did not vary to any degree among physical (0.30-0.39), cognitive (0.15-0.23) and psychosocial (0.42-0.47) domain proportions of the patient groups. CONCLUSION: Perceived fatigue is similar between patient groups. Increasing scores were not related to simply reaching the maximum threshold in the physical domain. Studies have confirmed a positive-structured approach to symptom management in one fatigue-associated chronic disease, primary biliary cirrhosis, leads to significant improvements in quality of life. We suggest that, with a similar approach, the same might be true in other chronic diseases where moderate fatigue is a significant problem.
Subject(s)
Fatigue Syndrome, Chronic/complications , Fatigue/etiology , Liver Diseases/complications , Syncope, Vasovagal/complications , Case-Control Studies , Female , Humans , Male , Retrospective Studies , Severity of Illness Index , Surveys and QuestionnairesABSTRACT
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 (r = 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)) (r < 0.005). Significant association was seen between fatigue severity and daytime somnolence (Epworth Sleepiness Scale) (r = 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.
Subject(s)
Disorders of Excessive Somnolence/complications , Fatigue/etiology , Fatty Liver/complications , Insulin Resistance , Motor Activity , Adult , Aged , Cohort Studies , Fatigue/physiopathology , Fatty Liver/physiopathology , Female , Humans , Male , Middle Aged , Physical Exertion , Severity of Illness IndexABSTRACT
BACKGROUND: Chronic fatigue syndrome (CFS) is common and its cause is unknown. AIM: To study the prevalence of autonomic dysfunction in CFS, and to develop diagnostic criteria. DESIGN: Cross-sectional study with independent derivation and validation phases. METHODS: Symptoms of autonomic dysfunction were assessed using the Composite Autonomic Symptom Scale (COMPASS). Fatigue was assessed using the Fatigue Impact Scale (FIS). Subjects were studied in two groups: phase 1 (derivation phase), 40 CFS patients and 40 age- and sex-matched controls; phase 2 (validation phase), 30 CFS patients, 37 normal controls and 60 patients with primary biliary cirrhosis. RESULTS: Symptoms of autonomic dysfunction were strongly and reproducibly associated with the presence of CFS or primary biliary cirrhosis (PBC), and correlated with severity of fatigue. Total COMPASS score >32.5 was identified in phase 1 as a diagnostic criterion for autonomic dysfunction in CFS patients, and was shown in phase 2 to have a positive predictive value of 0.96 (95%CI 0.86-0.99) and a negative predictive value of 0.84 (0.70-0.93) for the diagnosis of CFS. DISCUSSION: Autonomic dysfunction is strongly associated with fatigue in some, but not all, CFS and PBC patients. We postulate the existence of a 'cross-cutting' aetiological process of dysautonomia-associated fatigue (DAF). COMPASS >32.5 is a valid diagnostic criterion for autonomic dysfunction in CFS and PBC, and can be used to identify patients for targeted intervention studies.
Subject(s)
Autonomic Nervous System Diseases/diagnosis , Fatigue Syndrome, Chronic/complications , Adult , Autonomic Nervous System Diseases/epidemiology , Cross-Sectional Studies , Female , Heart Rate , Humans , Male , Middle Aged , Prevalence , Reproducibility of Results , Severity of Illness IndexABSTRACT
BACKGROUND: 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. AIM: To explore, in an open label study, the responses of PBC patients suffering from significant daytime somnolence and associated fatigue to modafinil therapy. METHODS: 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. RESULTS: 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)]. CONCLUSIONS: 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.
Subject(s)
Benzhydryl Compounds/therapeutic use , Central Nervous System Stimulants/therapeutic use , Disorders of Excessive Somnolence/drug therapy , Fatigue/etiology , Liver Cirrhosis, Biliary/complications , Adult , Aged , Female , Humans , Middle Aged , Modafinil , Sleep/physiologyABSTRACT
BACKGROUND: Annually, 35-40% of those aged >65 years fall; up to 5% of such falls result in fracture. Fracture is determined both by propensity to fall and by bone fragility. AIM: To determine osteoporosis prevalence and predictors in patients who have fallen. DESIGN: Observational cross-sectional study. METHODS: We measured calcaneal BMD in 408 consecutive patients aged >50 years attending after falling. Fall number, fracture history, weight, height, and risk factors for falls and osteoporosis were recorded. T scores (SD above or below the mean for young adults) were derived in both sexes, and Z scores (SD above or below age-related normal score) in females. RESULTS: In females (n = 300, 74%), mean (SD) T score was -1.1(1.6), and mean Z score was 0(1.4); 127 (42%) had osteoporosis (T score < - 1.6). ROC curves confirmed significant relationships between osteoporosis and age, weight and height (all p < 0.0001). Incorporating fracture history, our model (fracture aged >50 years, age >83 years, weight <57 kg, height <153 cm as dichotomous variables) predicted osteoporosis with 91% sensitivity, 34% specificity. Of 108 male fallers, 36 (33%) had osteoporosis. Age, height and weight all predicted osteoporosis (p < 0.02). The resulting model (fracture aged >50 years, age > or =80 years, weight < or =68 kg, height < or =167 cm as dichotomous variables) predicted osteoporosis with 92% sensitivity, 30% specificity. DISCUSSION: Osteoporosis prevalence is not increased in female fallers compared to age-related norms; empirical use of osteoporosis treatment solely on the basis of falls thus appears inappropriate. In both sexes, the factors predicting osteoporosis were age, height and weight. Where BMD is not practical, possible or economical, our model may be a sensitive means of predicting fallers with osteoporosis.
Subject(s)
Accidental Falls , Bone Density/physiology , Calcaneus/diagnostic imaging , Fractures, Bone/epidemiology , Osteoporosis/physiopathology , Absorptiometry, Photon/standards , Aged , Calcaneus/physiology , Cross-Sectional Studies , England/epidemiology , Female , Humans , Male , Osteoporosis/epidemiology , Prevalence , Risk Factors , Sensitivity and SpecificityABSTRACT
BACKGROUND AND AIMS: Fatigue is the commonest symptom described by patients in most populations with the autoimmune liver disease primary biliary cirrhosis (PBC), and appears to be unrelated to liver disease severity. At present, it is unclear how the fatigue experienced by patients (only characterised to date in cross sectional studies) evolves over time. In this study, we set out to address how fatigue had changed over four years of follow up in a geographically defined cohort of PBC patients who participated in an earlier cross sectional study of fatigue impact. METHODS: Participants in the original 2000 study who were still alive in 2004 were asked to complete the same fatigue assessment tool (fatigue impact score, FIS). In those who had died between 2000 and 2004, medical notes, death certificates, and primary care records were reviewed. RESULTS: A total of 108 of the original cohort of 136 patients were alive at the time of the follow up study, 99 of whom (92%) participated in the follow up study. With the exception of four patients who underwent transplantation between 2000 and 2004, all of whom showed significant improvement in fatigue severity as assessed by FIS, fatigue severity was unchanged over four years of follow up. Among the 28 patients who died during the follow up period, survival was significantly lower in patients who were fatigued at the 2000 baseline (FIS above the median for the whole PBC population (40/160); log rank test, p = 0.006 v non-fatigued patients at baseline). Increased fatigue severity was independently associated with decreased survival on multivariate analysis. Fatigued PBC subjects were significantly more likely to have suffered a cardiac death than non-fatigued patients. CONCLUSIONS: The fatigue phenotype appears to be highly stable in PBC. The presence of fatigue in PBC is independently associated with a significantly increased risk of death in general, and cardiac death in particular. Factors underpinning fatigue in PBC, and the mechanisms whereby fatigue is associated with increased mortality, warrant further study.
Subject(s)
Fatigue/complications , Liver Cirrhosis, Biliary/complications , Adult , Aged , Aged, 80 and over , Cause of Death , Cholagogues and Choleretics/therapeutic use , Female , Follow-Up Studies , Humans , Liver Cirrhosis, Biliary/drug therapy , Liver Cirrhosis, Biliary/mortality , Liver Transplantation , Male , Middle Aged , Phenotype , Severity of Illness Index , Survival Analysis , Ursodeoxycholic Acid/therapeutic useABSTRACT
BACKGROUND AND AIMS: Study of health related quality of life (HRQOL) and the factors responsible for its impairment in primary biliary cirrhosis (PBC) has, to date, been limited. There is increasing need for a HRQOL questionnaire which is specific to PBC. The aim of this study was to develop, validate, and evaluate a patient based PBC specific HRQOL measure. SUBJECTS AND METHODS: A pool of potential questions was derived from thematic analysis of indepth interviews carried out with 30 PBC patients selected to represent demographically the PBC patient population as a whole. This pool was systematically reduced, pretested, and cross validated with other HRQOL measures in national surveys involving a total of 900 PBC patients, to produce a quality of life profile measure, the PBC-40, consisting of 40 questions distributed across six domains. The PBC-40 was then evaluated in a blinded comparison with other HRQOL measures in a further cohort of 40 PBC patients. RESULTS: The six domains of PBC-40 relate to fatigue, emotional, social, and cognitive function, general symptoms, and itch. The highest mean domain score was seen for fatigue and the lowest for itch. The measure has been fully validated for use in PBC and shown to be scientifically sound. PBC patient satisfaction, measured in terms of the extent to which a questionnaire addresses the problems that they experience, was significantly higher for the PBC-40 than for other HRQOL measures. CONCLUSION: The PBC-40 is a short easy to complete measure which is acceptable to PBC patients and has significantly greater relevance to their problems than other frequently used HRQOL measures. Its scientific soundness, shown in extensive testing, makes it a valuable instrument for future use in clinical and research settings.
Subject(s)
Health Status Indicators , Liver Cirrhosis, Biliary/rehabilitation , Quality of Life , Adult , Aged , Female , Humans , Liver Cirrhosis, Biliary/psychology , Male , Middle Aged , Psychometrics , Reproducibility of Results , Surveys and QuestionnairesABSTRACT
Renal, hepatic, and lung allografts are compromised by aggressively deteriorating function. This chronic process is produced by an overall burden of organ damage, but the pathophysiology remains poorly understood. Rates of chronic rejection in the lung, for example, have not substantially improved over the last decade, despite new immunosuppressive drugs and improvements in surgical procedure. We present a hypothesis that epithelial-to-mesenchymal transition is a common cause of chronic allograft failure. Research in this area may provide insights into chronic rejection of kidney, liver, and lung allografts that impact on future therapeutic strategies.
Subject(s)
Epithelial Cells/pathology , Heart Transplantation/pathology , Kidney Transplantation/pathology , Lung Transplantation/pathology , Mesoderm/pathology , Cell Differentiation , Humans , Transplantation, Homologous/pathology , Treatment FailureABSTRACT
BACKGROUND: Chemokines and their receptors are important mediators of leucocyte trafficking and are suggested to be critical for establishment of inflammatory autoimmune processes. CC chemokine receptor 5 (CCR5) is expressed preferentially by CD4+ T cells. We hypothesised that the CCR5delta(Delta)32 genotype, which impairs surface expression of CCR5 in heterozygotes and is linked to a functional polymorphism of CD45RA expressed on suppressor-inducer-like 'naive' CD4+ T cells, may modulate the inflammatory process in primary biliary cirrhosis (PBC). METHODS: CCR5Delta32 polymorphism was determined by PCR in 226 Caucasian PBC patients and 197 racially matched controls from two geographical areas, Newcastle, UK and Padua, Italy. (UK: 144 PBC, 105 controls, Italy: 82 PBC, 92 controls). RESULTS: When the two series were analysed separately, there were no significant differences in the genotype distribution comparing patients and controls (UK: wt/wt 72% vs 76%; wt/Delta32 28% vs 22%; Delta32/Delta32 0% vs 2%, P=0.24; Italy: wt/wt 72% vs 82%; wt/Delta32 27% vs 17%; Delta32/Delta32 0% vs 1%, P=0.14). However, when the data for the two series were pooled and reanalysed, we found an increase in the CCR5Delta32 mutation in PBC patients vs controls (28% vs 21%, OR=1.43, P=0.03), but there was no evidence that this Delta32 polymorphism is associated with less severe disease. CONCLUSIONS: Although this two-centre genetic association study is large compared with others performed in PBC, taken separately, each geographically based cohort of patients and controls is underpowered to detect a small effect of this functional polymorphism. This emphasises the need for far larger case-control collections to address which polymorphic markers or haplotypes might modify the pathogenesis and clinical course of PBC. We propose that multi-centre collaboration on an international scale in 'orphan' complex liver diseases such as (PBC) is supported by the International Association for the Study of the Liver and promoted via their journal with development of a brief format for web-based publication of studies.
Subject(s)
Genetic Predisposition to Disease , Liver Cirrhosis, Biliary/genetics , Polymorphism, Genetic , Receptors, CCR5/genetics , Base Sequence , Case-Control Studies , Cohort Studies , Disease Progression , Female , Genetics, Population , Genotype , Humans , Italy , Liver Cirrhosis, Biliary/physiopathology , Male , Molecular Sequence Data , Odds Ratio , Polymerase Chain Reaction , Probability , Receptors, CCR5/metabolism , Reference Values , Sensitivity and Specificity , United KingdomABSTRACT
BACKGROUND: Primary biliary cirrhosis (PBC) is a chronic liver disease with autoimmune features but uncertain aetiology. Increased risk of PBC among relatives of patients may reflect common environmental factors, or inherited immunogenetic susceptibility. Associations between PBC and other autoimmune diseases have been reported, but their true extent and pattern is unknown. AIM: To examine the prevalence and association patterns of autoimmune disease in a representative group of PBC patients. DESIGN: Clinical cohort study. METHODS: We clinically assessed members of a geographically-based PBC patient cohort (n = 160) for the presence of additional autoimmune disease, using established specific diagnostic criteria. RESULTS: Some 53% of patients had at least one additional autoimmune condition, and 63% had serum autoantibodies other than AMA or ANA. AMA+ patients had a significantly lower prevalence of additional autoimmunity than AMA- patients (49% vs. 79%; p < 0.01). The greatest relative increase in disease prevalence was for scleroderma (8% of patients). Autoimmune disease was present in 14% of first-degree relatives. DISCUSSION: PBC patients and their families have a wide susceptibility to autoimmunity. This observation supports an autoimmune aetiology and suggests that the genetic basis of PBC is likely to be expressed, at least in part, through factors controlling immune tolerance in general.