Grip strength and subjective fatigue in patients with primary biliary cirrhosis.
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Fatigue↗
Biomedical subjects
O F James
Publications and source records attributed to O F James.
Differences between human and mouse alpha-fetoprotein expression during early development.
Alpha-fetoprotein (AFP) is the major serum protein during development. AFP is one of the earliest proteins to be synthesised by the embryonic liver. The synthesis of AFP decreases dramatically after birth and only trace amounts are expressed in the adult liver. The tissue distribution of AFP in early human embryogenesis has not been defined. We have studied the expression pattern of AFP mRNA in human and mouse embryos by in situ hybridisation. In humans, AFP is expressed in the hepatic diverticulum at 26 d postovulation as it differentiates from the foregut endoderm (i.e. in the most primitive hepatocytes). It is also expressed in the endoderm of the gastrointestinal tract and in the yolk sac at this age. AFP is subsequently expressed in the mesonephros and transiently in the developing pancreas. In the mouse, no expression of AFP was observed in the mesonephros but other sites of expression were similar. Thus AFP has a distinct temporospatial expression pattern during the embryonic period and this differs between human and mouse species. It is interesting that AFP is expressed by tumours such as primitive gastrointestinal, renal cell and pancreatic tumours as well as those of hepatocyte origin. This distribution reflects the sites of AFP expression during development.
Animals↗
The geographical distribution of primary biliary cirrhosis in a well-defined cohort.
The incidence of primary biliary cirrhosis (PBC) varies widely between regions. However, little is known about variation within regions and the degree to which this may reflect environmental risk factors. The aim of this study was to describe the spatial distribution of cases of PBC in a defined region of Northeast England over a defined period, and to assess the magnitude of any departure from random spatial distribution. Seven hundred seventy patients with established PBC were identified in a previous comprehensive case finding study. A total of 3,044 control locations were randomly selected from postcode (zip code) data weighted for number of drop off points per postcode. Geographical analysis was performed by testing both for spatial variation in risk and local clustering by using previously described point process methods. Both tests used the same null hypothesis that risk of disease does not vary spatially and cases occur independently of each other. Statistically significant spatial variations in risk were found in the whole study region (P <.001) and in the major urban area within the region (P <.004). Risk was higher in the urban area of Tyneside than in the surrounding rural area. Within the rural area, spatial variation in risk was equivocal (P =.012), but there was significant (P =.001) clustering of cases (estimated average cluster effect approximately 10 excess cases within a 7-km radius). PBC occurred to a density of 10.7 cases/km(2) in the highest risk areas. In conclusion, PBC is unevenly distributed in Northeast England. This may reflect one or more environmental risk factors in its etiology.
Cluster Analysis↗
Reduction in incidence of severe paracetamol poisoning.
We report substantial reductions in the frequency of severe paracetamol hepatotoxicity locally and nationally after legislative limitations on its sale. These reductions were not explained by changes in referral patterns or use of N-acetylcysteine.
Acetaminophen↗
CTLA-4 gene polymorphism confers susceptibility to primary biliary cirrhosis.
BACKGROUND/AIM: Primary biliary cirrhosis (PBC) is an autoimmune cholestatic liver disease thought to develop through a complex interaction of genetic and environmental factors. It is characterised by T-cell-mediated non-suppurative destructive cholangitis. We have studied the polymorphic cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene, which encodes a molecule that is a vital negative regulator of T-cell activation, as a candidate susceptibility locus for PBC. This gene on chromosome 2q33 (designated IDDM12) is associated with susceptibility to both type 1 diabetes and autoimmune thyroid disease. METHODS: The CTLA-4 exon 1 polymorphism (A/G encoding for threonine or alanine, respectively) was genotyped via polymerase chain reaction in 200 Caucasoid PBC patients and 200 non-related geographically matched Caucasoid controls. RESULTS: There was significant overrepresentation of the G/A and G/G genotypes in PBC patients compared to controls (G/A 53% vs 40%; G/G 18.5% vs 10.5%, Odds Ratio (OR)=2.45 [95% CI 1.6-3.7], p=0.00006, chi2=19.4). Likewise, there was a significant difference in allele frequencies (G encoding alanine at codon 17, PBC 0.45 vs controls 0.305: OR=1.9 [1.4-2.5], p<0.0002). This association remained significant (p=0.00027) when patients with autoimmune thyroid disease were excluded from the analysis. CONCLUSIONS: The CTLA-4 exon 1 polymorphism is the first non-major histocompatibility complex gene to be identified as a susceptibility locus for PBC. Our data support the hypothesis that clinically distinct autoimmune disease may be controlled by a common set of susceptibility genes.
Abatacept↗
Validation of a fatigue impact score in primary biliary cirrhosis: towards a standard for clinical and trial use.
BACKGROUND/AIMS: Fatigue is the commonest symptom of the chronic liver disease primary biliary cirrhosis (PBC). PBC is increasingly being diagnosed earlier in its natural history at a stage when concerns about progression to liver failure may be less prominent than current symptoms. The importance of symptomatic treatment is therefore increasingly being recognised. Research into the aetiology and treatment of fatigue in PBC has been hampered by the lack of relevant, reproducible measures of fatigue severity. The aim of this study was to validate the Fisk Fatigue Severity Score (FFSS), a measure of the impact of fatigue on daily living, for use in PBC and to use the FFSS to study the severity and correlates of fatigue in this condition. METHODS: Fifty-eight patients with PBC and 31 matched control patients attending hospital for nonhepatic disease were studied. The reproducibility of FFSS was assessed over periods from 1 hour to 1 month. Fatigue, as measured by FFSS, was compared in PBC patients and controls. The severity of fatigue in the patients with PBC was correlated with other symptoms and with established biochemical and histological markers of severity. RESULTS: The FFSS questionnaire was acceptable to patients and had reasonable intra-observer variation (coefficient of reproducibility 13% of mean value at 1 hour). The FFSS was more reproducible than a visual analogue scale. FFSSs varied over 4 weeks by up to 36%. Median FFSS's were 2.3 times higher in PBC patients than controls (p<0.005). There were no associations between FFSS and patient age, disease duration, or histological or biochemical markers of severity. CONCLUSIONS: The FFSS is a highly acceptable, internally consistent and reproducible measure of fatigue severity in PBC. We advocate its use in clinical assessment of patients, in studies of the aetiology of fatigue in PBC and, most importantly, in therapeutic trials of symptomatic treatment.
Clinical Trials as Topic↗
An exploratory population-based case-control study of primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is a disease of unknown etiology, with unexplained geographical variation. Various exposures have been suggested as triggers for disease development-possibly in susceptible individuals, but the evidence was not always well founded. We therefore conducted a population-based case-control study in Northeast England to investigate these and other exposures. All cases incident during 1993 to 1995 in a defined area of Northeast England were identified, and age- and sex-matched population controls were identified from primary care population registers. Cases and controls were sent postal self-completion questionnaires covering medical history and lifestyle. Information was received from 100 cases and 223 controls. The familial tendency of PBC was found to be less marked than has been claimed: Only weak associations were found with other autoimmune diseases. Among factors considered previously, no significant associations were found with surgical procedures, events in pregnancy, past infections, vaccinations, and medications. No significant associations were found for previously unconsidered lifestyle factors (drinking alcohol, previous pets, or stressful events), but there was an unexpected association with past smoking (ever smoked: 76% in cases vs. 57% in controls, odds ratio 2.4; smoked for 20 years or more: 64% vs. 35%, odds ratio 3.5). There were also unexpected significant associations with psoriasis (13% in cases vs. 3% in controls, odds ratio 4.6) and eczema (3% in cases vs. 11% in controls, odds ratio 0. 13). These findings merit further investigation.
Adult↗
Presentation and mortality of primary biliary cirrhosis in older patients.
OBJECTIVES: many patients with primary biliary cirrhosis present for the first time aged over 65, but it is unclear whether the disease is different in older patients. We have examined presentation and mortality in relation to age at which primary biliary cirrhosis was first suspected clinically. DESIGN: we identified 1023 patients from our regional primary biliary cirrhosis database with definite or probable primary biliary cirrhosis (689 definite); 397 (39%) presented aged > or =65. Definite primary biliary cirrhosis was defined as a positive antimitochondrial antibody titre > or =1/40, abnormal liver enzymes and compatible/diagnostic histology; probable as the presence of two of these indications. RESULTS: there was no difference in presenting clinical features between the older and younger groups. Older patients were significantly less likely than younger to have had liver biopsy (50% vs 78%; P < 0.001). The 1023 patients had been followed for 8561 patient years. Follow-up was shorter (5.9+/-4 vs 9.8+/-5.5 years; P < 0.001) in the older group because of higher cumulative mortality (59% vs 33%; P < 0.001). Liver-related deaths were significantly commoner in the older group (18% vs 13%; P < 0.05). The mortality ratio for liver deaths (liver deaths per year of follow-up) was 2.4 times higher in the older group (0.031 vs 0.013). CONCLUSIONS: patients with primary biliary cirrhosis who are over and under 65 have similar features on presentation. The annual risk of liver death is 2.4 times higher in those presenting over 65, reaffirming the importance of age as an independent prognostic factor in an unselected primary biliary cirrhosis population.
Adult↗
Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: a double-blind, randomized, dose-finding multi-centre study.
OBJECTIVE: To determine the efficacy, tolerability and safety of oral rifaximin given at three dose levels in patients with cirrhosis and mild to moderate hepatic encephalopathy (HE). DESIGN: Prospective, double-blind, randomized, parallel-group study. SETTING: Multi-centre trial in four university teaching hospitals. PARTICIPANTS: Fifty-four patients with cirrhosis and mild to moderate HE. INTERVENTION: Seven days treatment with rifaximin, 600, 1200 or 2400 mg/day in three divided doses. MAIN OUTCOME MEASURE: Change in the portal-systemic encephalopathy (PSE) index between baseline and day 7, calculated on the basis of mental state, asterixis, number connection test time, EEG mean cycle frequency and blood ammonia concentrations. RESULTS: Treatment with rifaximin was associated with an improvement in the PSE index. There was a trend towards a greater treatment effect of rifaximin with the highest dose of 2400 mg/day. Rifaximin was well tolerated; the few treatment-related adverse events showed no consistent pattern or dose relationship. CONCLUSION: Rifaximin may be useful as alternative or adjuvant therapy for grade I-III hepatic encephalopathy in patients with cirrhosis at a dose of 1200 mg/day.
Administration, Oral↗
Study on COgnition and Prognosis in the Elderly (SCOPE): baseline characteristics.
The Study on COgnition and Prognosis in the Elderly (SCOPE) is a multi-centre, prospective, randomized, double-blind, parallel-group study. The primary objective of SCOPE is to assess the effect of the angiotensin II type 1 (AT1) receptor blocker, candesartan cilexetil 8-16 mg once daily, on major cardiovascular events in elderly patients (70-89 years of age) with mild hypertension (DBP 90-99 and/or SBP 160-179 mmHg). The secondary objectives of the study are to test the hypothesis that antihypertensive therapy can prevent cognitive decline (as measured by the Mini Mental State Examination, MMSE) and dementia, and to assess the effect of therapy on total mortality, myocardial infarction (MI), stroke, renal function, and hospitalization. A total of 4964 patients from 15 participating countries were recruited during the randomization phase of SCOPE, exceeding the target population of 4000. The mean age of the patients at enrolment was 76 years, the ratio of male to female patients was approximately 1:2, and 52% of patients were already being treated with an antihypertensive agent at enrolment. The majority of patients (88%) were educated to at least primary school level. At randomization, mean sitting blood pressure values were SBP 166 mmHg and DBP 90 mmHg, and the mean MMSE score was 28. Previous cardiovascular disease in the study population included myocardial infarction (4%), stroke (4%) and atrial fibrillation (4%). Men, more often than women, had a history of previous MI, stroke and atrial fibrillation. A greater percentage of men were smokers (13% vs 6% in women) and had attended university (11% vs 3% of women). Of the randomized patients, 21% were 80 years of age. In this age group smoking was less common (4% vs 10% for 70-79-year-olds) and fewer had attended university (4% vs 7% for 70-79-year-olds). The incidence of MI was similar in both age groups. However, stroke and atrial fibrillation had occurred approximately twice as frequently in the older patients. The patients' mean age at baseline was similar in the participating countries, and most countries showed the approximate 1:2 ratio for male to female patients. There was also little inter-country variation in terms of mean SBP, DBP or MMSE score. However, there was considerable regional variation in the percentage of patients on therapy prior to enrolment.
Aged↗
Development of autoimmune hepatitis following liver transplantation for primary biliary cirrhosis.
Two patients undergoing liver transplantation for classical end-stage primary biliary cirrhosis (PBC) are described, who went on to develop de novo autoimmune hepatitis (AIH) in the transplanted liver. The presentation, in both instances, was with malaise and lethargy. Markedly elevated serum transaminases were found, together with a raised serum IgG and/or globulin fraction and histological features on liver biopsy typical of AIH. Both cases had had changes in their immunosuppressive therapy before the onset of AIH episodes, and both rapidly responded to reinstitution of steroid therapy. The finding, in each case, of a coincidental multiple HLA class I allele match between the recipient and their liver donor suggests that HLA class I-restricted mechanisms may play an important role in the pathogenesis of AIH.
Female↗
Primary biliary cirrhosis once rare, now common in the United Kingdom?
There is a widespread impression that the number of patients with the autoimmune liver disease primary biliary cirrhosis (PBC) is increasing, although its incidence and prevalence vary widely. Using thorough case-finding methods and rigorous definitions to assess changes in incidence and prevalence with time and to explore the symptomatology and mortality of the disease in a large group of unselected patients, we performed a descriptive epidemiological study of PBC in a well defined population over a fixed period of time using established diagnostic criteria and with clinical follow-up of all cases. In a population of 2.05 million in northern England 770 definite or probable PBC cases were identified. Prevalence rose from 201.9 per 10(6) in the adult population and 541. 4 per 10(6) women over 40 in 1987 to 334.6 per 10(6) adults and 939. 8 per 10(6) women over 40 in 1994. Incidence was 23 per 10(6) in 1987 and 32.2 per 10(6) in 1994. Three hundred patients died in median follow-up of 6.27 years (141 liver deaths); the standardized mortality ratio was 2.85. At presumed diagnosis, 60.9% had no symptoms of liver disease. By June 1994 62% of prevalent patients had liver symptoms. PBC is apparently increasing. It is still unclear whether this is because of a true increase, case finding, or increased disease awareness. The study draws attention to (1) high mortality from liver disease and non-liver-related causes even in patients initially with no liver symptoms and (2) apparently poor diagnostic awareness of the disease.
Adult↗
Tumour necrosis factor-alpha promoter polymorphisms in primary biliary cirrhosis.
BACKGROUND/AIMS: The incidence of primary biliary cirrhosis (PBC) is increased in the close relatives of patients, suggesting that genetic factors play a role in disease susceptibility. Decreased in vitro production of tumour necrosis factor (TNF)-alpha has been reported in PBC patients, suggesting a potential aetiological role for this cytokine. The aim of this study was to examine two biallelic polymorphisms in the promoter region of the TNF-alpha gene, which may play a role in the control of TNF-alpha secretion, as candidate susceptibility loci in PBC. METHODS: The polymorphisms at positions -238 and -308 in the TNF-alpha promoter region were analysed by polymerase chain reaction in 168 unrelated PBC patients and 145 local unrelated, geographically matched normal individuals. All PBC subjects were also genotyped for HLA DR8, a previously identified susceptibility locus in PBC. RESULTS: The -308 TNF1/TNF1 genotype was seen in a similar proportion of PBC patients (66%) and controls (60%). However, this genotype was found significantly more frequently in the 95 PBC patients with more advanced disease (histological stage III/IV) (77%) than in either controls (p<0.01, OR = 2.2 [1.2-4.0]) or the PBC patients with earlier disease (38/73 (52%), p = 0.001 OR 3.1 [1.6-5.9]). Linkage between TNF -308 and HLA DR8 was not seen. No association was found between PBC and the biallelic -238 TNF-alpha polymorphism, either in the whole PBC population or the histological Stage III/IV subgroup. CONCLUSIONS: Our study provides no evidence for involvement of the TNF-alpha -308 or -238 promoter polymorphisms in genetic predisposition to PBC. However, the significantly increased frequency of the -308 TNF1/TNF1 genotype seen in 95 patients with more advanced disease raises the possibility that this allele may be linked to disease progression rather than susceptibility. The finding of different allele frequencies in PBC patients in different disease subgroups emphasises the importance of clinical phenotype/casemix in the design of disease association studies.
Aged↗
Familial primary biliary cirrhosis reassessed: a geographically-based population study.
BACKGROUND/AIMS: Development of primary biliary cirrhosis in the close relatives of patients with the disease has been reported in several series, suggesting a genetic component to disease susceptibility. In this study we set out to calculate, as accurately as possible, the prevalence of familial primary biliary cirrhosis in a geographically-based population. Using local population prevalence data, we have also calculated the first-degree relative, sibling and offspring relative risks of overt primary biliary cirrhosis development. METHODS: All patients with definite or probable primary biliary cirrhosis in the city of Newcastle-upon-Tyne, England, were identified by an exhaustive case-finding search and were prospectively interviewed by a single investigator. Full details of family pedigree and familial primary biliary cirrhosis history were obtained. RESULTS: One hundred and seventy-three patients were identified, with 160 participating in the study. Thirteen reported a family history of primary biliary cirrhosis. In three cases, both relative pairs were within the study group. The prevalence of a positive family history of primary biliary cirrhosis was therefore 10/157 (6.4% [95% Confidence Interval 2.6-10.2%]), 8/10 cases occurring in first-degree relatives. The patients had a total of 1118 first-degree relatives (live or dead) and 468 siblings. The first-degree relative prevalence of primary biliary cirrhosis was 0.72% [0.2-1.2%] (siblings 0.41% [-0.2-1.0%]). The offspring prevalence was 1.2% [0.04-2.4%], (2.3% [0.1-4.5%] for daughters). The sibling relative risk (lambda(s)) was 10.5. CONCLUSIONS: The overall prevalence of definite or probable primary biliary cirrhosis in the first-degree relatives of existing patients is <1%. The risk of disease is not, however, uniform, the highest prevalence being seen in the daughters of patients. Suspicion of disease should therefore be highest in this relative group. The calculated lambda(s) for primary biliary cirrhosis in this geographically-based study is significantly lower than previous estimates from case-note-derived case series, but similar to values seen in other autoimmune diseases.
Adult↗
Case report: oral antioxidant therapy for the treatment of primary biliary cirrhosis: a pilot study.
BACKGROUND: The symptoms of the chronic cholestatic liver disease primary biliary cirrhosis (PBC), in particular fatigue and chronic pruritus, adversely affect quality of life and respond only poorly to treatment. Recent studies have suggested that oxidative stress may play a role in tissue damage in cholestatic liver disease and may contribute to symptoms, such as fatigue. We have, therefore, examined, in an open-label pilot study, the therapeutic effects of antioxidant medication on the biochemistry and symptomatology of PBC. METHODS: Patients were randomized to 3 months treatment with a compound antioxidant vitamin preparation (Bio-Antox), four tablets daily (n = 11, group 1), or the combination of Bio-Quinone Q10 (100 mg) with Bio-Antox (n = 13, group 2). Biochemical and symptomatic responses were assessed at 3 months. RESULTS: Significant improvement in both pruritus and fatigue was seen in the patients in group 2. Mean itch visual analogue score improved from 2.4 +/- 3.0 to 0.4 +/- 0.7 post therapy (P < 0.05) while mean night itch severity score improved from 2.6 +/- 1.9 to 1.3 +/- 0.7 (P < 0.05). Nine of 13 of these patients reported less fatigue, while 10/13 showed an improvement in at least one domain of their Fisk Fatigue Severity Score. No significant improvement in itch and only limited improvement in fatigue were seen in the patients in group 1. No change in biochemical parameters was seen in either group. CONCLUSIONS: Antioxidant therapy, as a combination of Bio-Antox and Bio-Quinone Q10, may improve the pruritus and fatigue of PBC. This combination of therapy should be investigated further in a double-blind, placebo-controlled trial.
Antioxidants↗
Study on COgnition and Prognosis in the Elderly (SCOPE).
The Study on COgnition and Prognosis in the Elderly (SCOPE) is a multicentre, prospective, randomized, double-blind, parallel-group study designed to compare the effects of candesartan cilexetil and placebo in elderly patients with mild hypertension. The primary objective of the study is to assess the effect of candesartan cilexetil on major cardiovascular events. The secondary objectives of the study are to assess the effect of candesartan cilexetil on cognitive function and on total mortality, cardiovascular mortality, myocardial infarction, stroke, renal function, hospitalization, quality of life and health economics. Male and female patients aged between 70 and 89 years, with a sitting systolic blood pressure (SBP) of 160-179 mmHg and/or diastolic blood pressure (DBP) of 90-99 mmHg, and a Mini-Mental State Examination (MMSE) score of 24 or above, are eligible for the study. The overall target study population is 4000 patients, at least 1000 of whom are also to be assessed for quality of life and health economics data. After an open run-in period lasting 1-3 months, during which patients are assessed for eligibility and those who are already on antihypertensive therapy at enrolment are switched to hydrochlorothiazide 12.5 mg o.d., patients are randomized to receive either candesartan cilexetil 8 mg once daily (o.d.) or matching placebo o.d. At subsequent study visits, if SBP remains >160 mmHg, or has decreased by <10 mmHg since the randomization visit, or DBP is >85 mmHg, study treatment is doubled to candesartan cilexetil 16 mg o.d. or two placebo tablets o.d. Recruitment was completed in January 1999. At that time 4964 patients had been randomized. All randomized patients will be followed for an additional 2 years. If the event rate is lower than anticipated, the follow-up will be prolonged.
Aged↗
The prevalence of stroke and associated disability.
BACKGROUND: There are limited data available on the prevalence of stroke in the United Kingdom. Such data are important for the assessment of the health needs of the population. This study aimed to determine the prevalence of stroke and the prevalence of associated dependence in a district of northern England. METHODS: This was a two-stage point prevalence study. A valid screening questionnaire was used to identify stroke survivors from an age- and sex-stratified sample of the population aged 45 years and over in a family health services authority district. This was followed by assessment of stroke patients with scales of disability and handicap. RESULTS: The overall prevalence of stroke was found to be 17.5/1000 (95 per cent confidence interval (CI) 17.0, 18.0). The prevalence of stroke-associated dependence was 11.7/1000 (95 per cent CI 11.3, 12.1). Self-reported comorbidity was most commonly due to circulatory and musculoskeletal disorders. CONCLUSIONS: The prevalence of stroke in this district is considerably higher than current guidelines and previous results suggest. Nevertheless, the result from this study combined with that from a previous study in another district in the United Kingdom should allow those interested in epidemiologically based health needs assessment to make reasonable estimates of the burden of stroke in their area.
Activities of Daily Living↗
Portal hypertension secondary to arterio-portal fistulae: two unusual cases.
A 62-year-old male presented with variceal haemorrhage. Investigation demonstrated a fistula between the left gastric artery and portal vein with a porto-systemic gradient of 35 mm Hg. Variceal bleeding was controlled by a transcatheter embolisation of the fistula, but the patient died of septicaemia three weeks later. The second patient, a 42-year-old male who presented with variceal bleeding was shown to have diffuse arterio-venous fistulae involving the right lobe of the liver with a portosystemic gradient of 25 mm Hg. In this case the variceal bleeding was successfully controlled by insertion of a transjugular intrahepatic portosystemic shunt (TIPS). The pathogenesis of portal hypertension in arterioportal fistulae and the role of interventional radiological techniques in the management of variceal bleeding in these patients is discussed.
Adult↗