No rise in incidence but geographical heterogeneity in the occurrence of primary biliary cirrhosis in North East England.

In this study, we examined temporal changes in the incidence of primary biliary cirrhosis (PBC) and investigated associations between PBC incidence and sociodemographic factors and spatial clustering. We included 982 patients aged ≥40 years from North East England with incident PBC diagnosed during 1987-2003. Age-standardized incidence rates with 95% confidence intervals were calculated. Negative binomial regression was used to analyze incidence and socioeconomic deprivation. Clustering analysis was performed using point process methods, testing the null hypothesis that disease risk does not vary spatially and that PBC cases occur independently. The age-standardized incidence rate was 53.50 per million persons per year (95% confidence interval: 48.65, 58.35) in 1987-1994 and 45.09 per million persons per year (95% confidence interval: 41.10, 49.07) in 1995-2003. Risk of PBC increased in areas with higher levels of socioeconomic deprivation (P = 0.035). More specifically, risk increased in areas with higher levels of overcrowded homes (P = 0.040), higher levels of households without cars (P < 0.001), and higher levels of non-owner-occupied homes (P < 0.001). Overall, there was evidence of spatial clustering (P = 0.001). The findings confirm that overall incidence of PBC did not rise over time, but sociodemographic variations suggest that certain aspects of deprivation are involved in its etiology.

Seasonal variation in the patient diagnosis of primary biliary cirrhosis: further evidence for an environmental component to etiology.

UNLABELLED: The etiology of primary biliary cirrhosis (PBC) is far from clear. Both genetic and environmental factors are likely to be involved. We have previously reported evidence of space-time clustering, suggesting that a transient environmental agent may be involved in etiology. To further examine whether a seasonally varying environmental agent may contribute to the etiology of PBC, we have analyzed seasonal variation with respect to month of diagnosis using population-based data from northeast England over a defined period (1987-2003). Date of diagnosis was defined as the earliest date at which the patient was found to have fulfilled any two of three diagnostic criteria (i.e., antimitochondrial antibody-positive titer ≥1 in 40, cholestatic liver blood tests, diagnostic or compatible liver histology). Monthly expected (E) numbers of cases were calculated under an assumption of a uniform distribution throughout the year. Observed counts (O) were compared with the expected numbers. The chi-squared heterogeneity test was used to test for overall nonuniform variation and also for individual months. Poisson regression analysis was used to fit a sinusoidal (i.e., harmonic) model to the data, using month of diagnosis as a covariate in the model. There was a marked peak for diagnoses in the month of June (O = 115, E = 84.7, O/E = 1.36; P = 0.001). Furthermore, there was evidence of a sinusoidal pattern with a June peak (P = 0.012). CONCLUSION: These highly novel results provide further evidence for the involvement of a seasonally varying environmental agent in the etiology of PBC.

Capability and dependency in the Newcastle 85+ cohort study. Projections of future care needs.

BACKGROUND: Little is known of the capabilities of the oldest old, the fastest growing age group in the population. We aimed to estimate capability and dependency in a cohort of 85 year olds and to project future demand for care. METHODS: Structured interviews at age 85 with 841 people born in 1921 and living in Newcastle and North Tyneside, UK who were permanently registered with participating general practices. Measures of capability included were self-reported activities of daily living (ADL), timed up and go test (TUG), standardised mini-mental state examination (SMMSE), and assessment of urinary continence in order to classify interval-need dependency. To project future demand for care the proportion needing 24-hour care was applied to the 2008 England and Wales population projections of those aged 80 years and over by gender. RESULTS: Of participants, 62% (522/841) were women, 77% (651/841) lived in standard housing, 13% (106/841) in sheltered housing and 10% (84/841) in a care home. Overall, 20% (165/841) reported no difficulty with any of the ADLs. Men were more capable in performing ADLs and more independent than women. TUG validated self-reported ADLs. When classified by 'interval of need' 41% (332/810) were independent, 39% (317/810) required help less often than daily, 12% (94/810) required help at regular times of the day and 8% (67/810) required 24-hour care. Of care-home residents, 94% (77/82) required daily help or 24-hour care. Future need for 24-hour care for people aged 80 years or over in England and Wales is projected to increase by 82% from 2010 to 2030 with a demand for 630,000 care-home places by 2030. CONCLUSIONS: This analysis highlights the diversity of capability and levels of dependency in this cohort. A remarkably high proportion remain independent, particularly men. However a significant proportion of this population require 24-hour care at home or in care homes. Projections for the next 20 years suggest substantial increases in the number requiring 24-hour care due to population ageing and a proportionate increase in demand for care-home places unless innovative health and social care interventions are found.

Are transient environmental agents involved in the cause of primary biliary cirrhosis? Evidence from space-time clustering analysis.

The cause of primary biliary cirrhosis (PBC) is unclear. Both genetic and environmental factors are likely to contribute. Some studies have suggested that one or more infectious agents may be involved. To examine whether infections may contribute to the cause of PBC, we have analyzed for space-time clustering using population-based data from northeast England over a defined period (1987-2003). Space-time clustering is observed when excess cases of a disease are found within limited geographical areas at limited periods of time. If present, it is suggestive of the involvement of one or more environmental components in the cause of a disease and is especially supportive of infections. A second-order procedure based on K-functions was used to test for global space-time clustering using residential addresses at the time of diagnosis. The Knox method determined the spatiotemporal range over which global clustering was strongest. K-function tests were repeated using nearest neighbor thresholds to adjust for variations in population density. Individual space-time clusters were identified using Kulldorff's scan statistic. Analysis of 1015 cases showed highly statistically significant space-time clustering (P < 0.001). Clustering was most marked for cases diagnosed within 1-4 months of one another. A number of specific space-time clusters were identified. In conclusion, these novel results suggest that transient environmental agents may play a role in the cause of PBC.

Does primary biliary cirrhosis cluster in time?

The aetiology of primary biliary cirrhosis (PBC) is not well established. Previously we found evidence of space-time clustering and seasonal variation in the date of diagnosis, suggesting a possible role for a transient or seasonally varying environmental factor. We examined whether a temporally varying environmental agent may be involved by analysing population-based PBC data from northeast England over 1987-2003. Using an adaptation of a method proposed by Potthoff and Whittinghill, we found significant temporal variation by date of diagnosis at the level of aggregation of one year. However, there was no evidence for general irregular (non-seasonal) temporal clustering within periods less than a year. These results provide little support for the involvement of agents occurring in geographically widespread mini-epidemics, but--taken together with studies of spatial and spatio-temporal clustering--do not preclude the role of more localised sporadic mini-epidemics. Future research should seek to elicit putative environmental agents.

Mortality and recovery after stroke in the Gambia.

BACKGROUND AND PURPOSE: There are no previously published studies of the long-term outcome of stroke in sub-Saharan Africa. Our goal was to determine the case fatality, time to and cause of death, and recovery in a hospital cohort of stroke patients in The Gambia. METHODS: For 1 year beginning April 1, 1990, any patient presenting to the Royal Victoria Hospital (Banjul) with a diagnosis of stroke or having a stroke as an inpatient was recruited. After a standardized assessment, patients were followed up at 1 month, 6 months, and 3 to 4 years to assess recovery or, for those who died, record the date and likely cause of death. RESULTS: Mean age of the 106 patients (70 men) was 58 years (range, 20 to 93 years). By 1 and 6 months, 29 (27%) and 47 (44%), respectively, had died, with only 27 (25%) surviving to final follow-up (4 patients not traced). Death occurred in hospital in 43 patients (57%). Cause of death was the initial stroke in 46 (61%), further stroke in 5 (7%), infection in 9 (12%), miscellaneous in 8 (11%) (only 1 vascular), and unknown in 7 (9%). On Cox regression analysis, incontinence in the first 24 hours, sensory inattention, and impaired gag reflex on admission were significant predictors of mortality. Predictors of recovery were similar to those of developed countries. CONCLUSIONS: Despite the young mean age, there was a high case fatality rate. The main cause of death was the stroke itself, and ischemic heart disease was very rare.

The epidemiology of primary biliary cirrhosis.

Over the last 30 years, many studies have reported on the epidemiology of PBC. Substantial increases in prevalence were noted in the majority of studies examining longitudinal data, and several have reported increases in the incidence of PBC. Furthermore, although it is difficult to compare studies directly, as methods of case ascertainment have greatly improved over this period, there has been a definite trend toward increasing prevalence (and also possibly incidence) across studies. Together, these data strongly suggest that in many countries, the frequency with which PBC is diagnosed has increased considerably between 1980 and the present time. The reasons for this change may be complex. There may have been a true increase in the incidence of PBC, reflecting either increased exposure to a currently unknown environmental etiological agent or demographic changes with an increased elderly, at-risk population. The prevalence may have further increased due to increased survival of patients, either due to improved care or earlier diagnosis. Some of the apparent increase in PBC frequency may also be artifactual, however, resulting from increased use of diagnostic tests, particularly autoantibody screens. This may be due to increased availability of testing, increased clinician (or patient) awareness of PBC, increased use of testing in well-person screening, or increased investigation of ill-defined symptoms. Furthermore, there may also have been an improvement in clinicians' ability to recognize PBC on the basis of the clinical picture (in one study, 37% of patients whose clinical results indicated a diagnosis of PBC were not recognized by the clinician caring for the patient at that time). The last factor alone suggests that all studies based only upon cases known to interested clinicians have probably substantially underestimated the prevalence of disease. Whatever the reason, the recognized epidemiology of PBC has dramatically changed over the past 30 years. It is now a frequent cause of liver morbidity, and patients with PBC are significant users of health resources, including liver transplantation. Large geographical variations in disease frequency, both between and within studies, tantalizingly suggest the presence of as-yet-unidentified risk factors. This should be further followed up with new analytical epidemiological studies. Only two case control studies have examined risk factors for PBC, and these have been either relatively small or used poorly defined and potentially biased experimental groups. These need repeating in new settings. We suggest that, as with other diseases, modern epidemiological instruments used in well-designed studies may provide important clues to the cause or causes of this disease.

Health and disease in 85 year olds: baseline findings from the Newcastle 85+ cohort study.

OBJECTIVES: The Newcastle 85+ Study aims to systematically study the clinical, biological, and psychosocial attributes of an unselected cohort of 85 year olds and to examine subsequent health trajectories as the cohort ages; health at baseline is reported. DESIGN: Cross sectional analysis of baseline data from a cohort study. SETTING: Newcastle upon Tyne and North Tyneside primary care trusts, United Kingdom. PARTICIPANTS: 1042 people born in 1921 and registered with the participating general practices. MAIN OUTCOME MEASURES: Detailed health assessment and review of general practice records (disease, medication, and use of general practice services); participants could decline elements of the protocol. RESULTS: Of the 1453 eligible people, 851 (58.6%) were recruited to health assessment plus record review, 188 (12.9%) to record review only, and 3 (0.2%) to health assessment only. Data from record review are reported on a maximum of 1030 and from health assessment on a maximum of 853; individual denominators differ owing to withdrawal and missing values. Of the health assessment sample (n=853), 62.1% (n=530) were women and 10.4% (n=89) were in institutional care. The most prevalent diseases were hypertension (57.5%, 592/1030) and osteoarthritis (51.8%, 534/1030). Moderate or severe cognitive impairment was present in 11.7% (96/824) of participants, severe or profound urinary incontinence in 21.3% (173/813), hearing impairment in 59.6% (505/848), and visual impairment in 37.2% (309/831). Health assessment identified participants with possible disease but without a previous diagnosis in their medical record for hypertension (25.1%, 206/821), ischaemic heart disease (12.6%, 99/788), depression (6.9%, 53/772), dementia (6.7%, 56/840), and atrial fibrillation (3.8%, 30/788). Undiagnosed diabetes mellitus and thyroid disease were rare (1%, 7/717 and 6/762, respectively). A median of 3 (interquartile range 1-8) activities of daily living were undertaken with difficulty. Overall, 77.6% (646/832) of participants rated their health compared with others of the same age as good, very good, or excellent. High contact rates in the previous year with general practitioners (93.8%, 960/1024) were recorded. Women had significantly higher disease counts (medians: women 5, men 4; P=0.033) and disability scores (medians: women 4, men 2; P=0.0006) than men, but were less likely to have attended outpatient clinics in the previous three months (women 29% (150/524), men 37% (118/320), odds ratio 0.7, 95% confidence interval 0.5 to 0.9). CONCLUSIONS: This large cohort of 85 year olds showed good levels of both self rated health and functional ability despite significant levels of disease and impairment. Hypertension, ischaemic heart disease, atrial fibrillation, depression, and dementia may be underdiagnosed. Notable differences were found between the sexes: women outnumbered men and had more disease and disability.

HLA class II alleles, genotypes, haplotypes, and amino acids in primary biliary cirrhosis: a large-scale study.

Twin and family studies suggest there is a significant genetic component to primary biliary cirrhosis (PBC). However, the inability to replicate reported associations has been a recurring problem, with the only consistently reported genetic association that between PBC and HLA-DRB1*0801. However, recently even this has been questioned, and a number of novel associations have also been reported. We reinvestigated HLA class II DRB1, DQA1, and DQB1 alleles and haplotypes in a total of 492 well-characterized PBC patients, 412 from the United Kingdom and an additional 80 patients from northern Italy. There was a clear and significant association with HLA-DRB1*0801 in both groups of patients compared to population-specific healthy controls (12% versus 4% in the UK patients, P=.00087, OR=3.05; and 18% versus 6% in the Italian patients, P=.021, OR=3.15). There were also significant protective associations with DRB1*11 in the Italian patients (28% versus 47%, P=.0071, OR=0.42), but not in the UK patients (8% versus 8%) and a protective association with DRB1*13 in both series (14% versus 20%, P=.042, OR=0.65 in the UK patients; and 10% versus 31%, P=.00092, OR=0.25 in the Italian patients). In conclusion, a complex relationship exists between HLA and PBC, and some genetic associations may be population specific.

Assessing quality of life in primary biliary cirrhosis.

BACKGROUND AND AIMS: Assessment of health-related quality of life (HRQOL) is not routinely reported in the literature on chronic liver disease (CLD). Few studies have examined quality of life (QOL) in patients with primary biliary cirrhosis (PBC) despite its significant functional impact. One of the reasons for the lack of HRQOL measurement in patients with PBC may be the absence of a well-recognized and widely used measure that clinicians can use in ordinary clinical practice. The aim of this study is to evaluate HRQOL measures used in patients with PBC and examine the suitability of the measures for these patients. METHODS: A literature search identified reports that focused on any aspect of QOL in patients with PBC. Key texts were identified containing generic, domain-specific, and condition-specific measures. The identified measures were systematically evaluated for appropriateness, acceptability, reliability, validity, precision, and responsiveness. RESULTS: Twenty measures were identified from 9 key texts. Six of the measures were previously validated generic measures; 10 were domain-specific measures previously used to measure fatigue, depression, and psychological distress in general and psychiatric populations; and 4 measures had been developed in patients with CLD. Reporting of reliability and validity generally was consistent for all measures used. However, reporting of the remaining criteria was variable, particularly in relation to responsiveness over time and acceptability of the measures to patients with PBC. CONCLUSIONS: A clearer and more rigorous approach is needed in reporting the properties of HRQOL measures used in patients with PBC to help clinicians decide which measures are most suitable for these patients.

Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years.

BACKGROUND & AIMS: Although several excellent studies have described the natural history of primary biliary cirrhosis, most were reported from tertiary referral centers. We examined the prognosis of primary biliary cirrhosis in a comprehensive geographically defined cohort. METHODS: We followed up 770 primary biliary cirrhosis patients prevalent between January 1987 and December 1994 until death, transplantation, or censor on January 1, 2000, by interview and review of case notes and death certificates. Analysis of survival data was performed with Kaplan-Meier methods and Cox regression. RESULTS: Median patient survival was 9.3 years from diagnosis. Patient age, alkaline phosphatase, albumin, and bilirubin at diagnosis independently predicted survival in Cox modeling. Prothrombin time and histologic stage did not independently affect survival. Observed survival was predicted well by this model and by the Mayo prognostic score (R2(M) = 0.37 and 0.18, respectively; R2(M) is a likelihood-based measure of the percentage information gain from the model due to covariates). Forty-two percent of deaths were caused by liver disease. Thirty-nine patients had liver transplantations by the censor date. Survival was much poorer than for an age- and sex-matched control population (standardized mortality ratio = 2.87 [1.73 excluding liver deaths]). The most common symptoms at diagnosis were pruritus (18.9%) and fatigue (21.0%). Twenty-six percent of patients developed liver failure by 10 years after diagnosis. CONCLUSIONS: Although primary biliary cirrhosis is often now diagnosed at an early stage, the diagnosis still carries important prognostic implications. A significant proportion of patients develop liver failure, require transplantation, or die prematurely after this diagnosis.

The true impact of fatigue in primary biliary cirrhosis: a population study.

BACKGROUND & AIMS: Patient surveys suggest that fatigue is a common problem in primary biliary cirrhosis (PBC). The actual extent of the problems caused by fatigue in PBC has yet to be determined as previous studies addressing this question have tended to use selected patient subgroups and subjective or non-quantitative fatigue assessment tools. Here, we have attempted to more accurately assess the extent of fatigue in PBC, and the specificity of the symptom for this disease, by the application of an objective measure of fatigue impact (the fatigue impact score [FIS]) to a geographically based patient cohort, age- and sex-matched normal controls, and chronic liver disease controls. METHODS: Postal completion of the FIS and linked symptom assessment tools. RESULTS: Median FIS was significantly higher in patients (n = 136) than community controls (40 [0-138] vs. 28 [0-156]; P < 0.0001) and chronic liver disease controls (n = 38) (20.5 [0-145]; P < 0.05). Fatigue scores in the 11 patients who had undergone liver transplantation (median 3.5 years previously) were the same as those in non-transplanted patients with advanced disease. CONCLUSIONS: Fatigue is a significant and specific problem in PBC. It is not, however, universal and affects fewer patients than has previously been thought to be the case based on data from selected patient cohorts. This definition of the "normal range" for fatigue in PBC will assist in future studies of etiology and therapy.

Pain as a complication of use of opiate antagonists for symptom control in cholestasis.

Controlled trials have suggested that opiate antagonist therapy may be effective for the treatment of the symptoms of cholestasis. The oral opiate antagonist naltrexone in particular has started to enter into routine clinical use for amelioration of cholestatic itch. Attention regarding the side effects of opiate antagonist therapy has, to date, largely focused on an opiate withdrawal-type reaction (which can be controlled effectively by titrated therapy introduction regimens). Here we describe 3 cases of a further clinically important side effect, loss of control of pain resulting from other pathologies, which in each case necessitated the withdrawal of hitherto clinically effective opiate antagonist therapy. Of the 14 patients treated by our unit with opiate antagonist agents for the control of cholestatic symptoms, 13 (93%) showed resolution of, or significant improvement in, symptoms. Of the 13 patients showing a clinical response, 7 (54%) subsequently had to discontinue therapy because of side effects (including the 3 patients with uncontrolled pain). It is our experience that in the routine clinical setting, opiate antagonists are highly effective for the treatment of cholestatic symptoms. In practice, however, their usefulness is limited by their side-effect profile.