Laboratory-Confirmed Metformin-Associated Lactic Acidosis

Introduction Metformin is considered the first line oral hypoglycaemic agent for the treatment of type 2 diabetes. We report three cases of prospectively identified laboratory confirmed metformin-associated lactic acidosis admitted to our intensive care unit. Case 1 72-year-old female presented with lactic acidosis; pH 6.7, lactate 22.6mmol/L with elevated Metformin levels of 4.9mg/L. Case 2 56-year-old female presented with lactic acidosis; pH 7.2 and lactate 14.8mmol/L. Metformin levels elevated at 3.9mg/L. Case 3 72-year-old female presented with lactic acidosis, pH 6.95 and lactate of 27.6mmol/L with elevated Metformin levels of 48.7mg/L. Results All three cases were admitted to the intensive care unit to receive supportive care. Despite CVVHD, two patients died. Discussion Metformin is considered the first line oral hypoglycaemic agent. Confirmation of this diagnosis often proves difficult due to the scarcity of laboratory testing. Our case series highlights the issues of inappropriate prescription in specific patient populations.

Review article: the economic impact of the irritable bowel syndrome.

BACKGROUND: Irritable bowel syndrome (IBS) is a chronic functional disorder of the gastrointestinal system affecting a large number of people worldwide. Whilst it has no attributable mortality, it has substantial impact on patients' quality of life (QoL) and is associated with considerable healthcare resource use. AIM: To review the economic impact of IBS, firstly on the individual, secondly on healthcare systems internationally and thirdly to society. METHODS: Appropriate databases were searched for relevant papers using the terms: Irritable Bowel Syndrome; IBS; irritable colon; functional bowel/colonic disease; economics; health care/service costs; health expenditure/resources; health care/service utilisation; productivity. RESULTS: Irritable bowel syndrome impacts most substantially on patients' work and social life. Reduction in QoL is such that on average patients would sacrifice between 10 and 15 years of their remaining life expectancy for an immediate cure. Between 15% and 43% of patients pay for remedies. No studies quantify loss of earnings related to IBS. Direct care costs are substantial; 48% of patients incur some costs in any year with annual international estimates per patient of: USA $742-$7547, UK £90-£316, France €567-€862, Canada $259, Germany €791, Norway NOK 2098 (€262) and Iran $92. Minimising extensive diagnostic investigations could generate savings and has been shown as not detrimental to patients. Cost to industry internationally through absenteeism and presenteeism related to IBS is estimated between £400 and £900 per patient annually. CONCLUSIONS: Irritable bowel syndrome is associated with substantial costs to patients, healthcare systems and society. Considerable benefit could be obtained from effective interventions.

Ultrasound elastography for fibrosis surveillance is cost effective in patients with chronic hepatitis C virus in the UK.

BACKGROUND: Chronic hepatitis C (HCV) is a significant risk factor for cirrhosis and subsequently hepatocellular carcinoma (HCC). HCV patients with cirrhosis are screened for HCC every 6 months. Surveillance for progression to cirrhosis and consequently access to HCC screening is not standardized. Liver biopsy, the usual test to determine cirrhosis, carries a significant risk of morbidity and associated mortality. Transient ultrasound elastography (fibroscan) is a non-invasive test for cirrhosis. PURPOSE: This study assesses the cost effectiveness of annual surveillance for cirrhosis in patients with chronic HCV and the effect of replacing biopsy with fibroscan to diagnose cirrhosis. METHOD: A Markov decision analytic model simulated a hypothetical cohort of 10,000 patients with chronic HCV initially without fibrosis over their lifetime. The cirrhosis surveillance strategies assessed were: no surveillance; current practice; fibroscan in current practice with biopsy to confirm cirrhosis; fibroscan completely replacing biopsy in current practice (definitive); annual biopsy; annual fibroscan with biopsy to confirm cirrhosis; annual definitive fibroscan. RESULTS: Our results demonstrate that annual definitive fibroscan is the optimal strategy to diagnose cirrhosis. In our study, it diagnosed 20 % more cirrhosis cases than the current strategy, with 549 extra patients per 10,000 accessing screening over a lifetime and, consequently, 76 additional HCC cases diagnosed. The lifetime cost is £98.78 extra per patient compared to the current strategy for 1.72 additional unadjusted life years. Annual fibroscan surveillance of 132 patients results in the diagnosis one additional HCC case over a lifetime. The incremental cost-effectiveness ratio for an annual definitive fibroscan is £6,557.06/quality-adjusted life years gained. CONCLUSION: Annual definitive fibroscan may be a cost-effective surveillance strategy to identify cirrhosis in patients with chronic HCV, thereby allowing access of these patients to HCC screening.

No difference in mortality in undetected coeliac disease compared with the general population: a UK cohort study.

BACKGROUND: Studies of mortality in undetected coeliac disease compared with the general population give contradictory findings, suggesting it is either increased fourfold compared with the general population or not at all. AIM: To establish all-cause and cause-specific mortality in undiagnosed coeliac disease, identified by anti-endomysial antibody (EMA) positivity, in the Cambridge GP Health Survey cohort. METHOD: This cohort was recruited in 1990 from the general population aged 45-76 years. All deaths were ascertained from the Office for National Statistics. Mortality rates were calculated per 1000 person years and adjusted for age, gender, smoking and socioeconomic group using multivariate Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: There were 117,914 patient years of follow-up (median 16.8 years) from 7527 participants. Eighty-seven had undetected coeliac disease, their all-cause mortality rate was 9.4 per 1000 person years (95% CI 5.4-16.1) compared with 12.7 (95% CI 12.1-13.4) in EMA-negative participants. The adjusted all-cause mortality HR was 0.98 (95% CI 0.57-1.69). Death due to cancer and circulatory diseases was not increased, adjusted HR were 1.27 (95% CI 0.57-2.85) and 1.39 (95% CI 0.66-2.92) respectively. CONCLUSIONS: We observed no excess overall mortality in people aged over 45 years with undetected coeliac disease compared with the general population, nor any increase in deaths related to circulatory disease or cancer. Our findings do not support screening the general population aged over 45 years, for coeliac disease for the purpose of improving life expectancy.

Meta-analysis: mortality in Crohn's disease.

AIM: To perform a meta-analysis is of published literature reporting standardized mortality ratios (SMR) for Crohn's patients from 1970 to date. METHODS: Medline search identified relevant papers. Exploding references identified additional papers. When two papers reviewed mortality of one patient group at different times, the later publication was used. RESULTS: Of 13 papers identified, three studies reported SMR below 1.0, two others had confidence intervals including 1.0. All other studies reported mortality higher than the general population. Meta-analysis using a random effects model shows the pooled estimate for SMR in Crohn's disease is 1.52 (95% CI: 1.32 to 1.74 [P < 0.0001]). Meta-regression shows the SMR for these patients has decreased slightly over the past 30 years, but this decrease is not statistically significant (P = 0.08). CONCLUSION: Assessing evidence from original studies and conducting a meta-analysis shows age-adjusted mortality risk from Crohn's disease is over 50% greater than the general population. Whilst mortality has improved since the condition was first recognized, further evaluation of the patients studied in the cohorts included here is necessary to assess more recent changes in clinical practice.

Long-term prognosis in Crohn's disease: An epidemiological study of patients diagnosed more than 20 years ago in Cardiff.

AIM: To investigate the incidence of death in patients diagnosed with Crohn's disease in Cardiff over 20 years ago. METHODS: The Cardiff database of patients with Crohn's disease contains data on all patients diagnosed there since 1934. Patients (394) diagnosed before 1 January 1985 were traced and their mortality status on 31 December 2004 was established. RESULTS: The overall standardized mortality ratio (SMR) was 1.29 (95% CI 1.12-1.45) and it has not significantly changed since the 1970s. SMR decreases with age, from 16.95 (95% CI 14.99-18.91) for patients aged 10-19 years (although only one death) to 0.92 (95% CI 0.65-1.19) in those over 75 years. Kaplan-Meier analysis of age at death shows that patients diagnosed aged 10-26 years have median age at death of 58 years, those aged 27-52 years of 66 years, those aged 53-58 years of 74 years, and those over 59 years of 79 years. CONCLUSIONS: It shows a significantly raised SMR, not statistically changed since the 1970s and similar to other chronic conditions. Patients diagnosed younger have worse prognosis than those diagnosed later in life and a reduced life expectancy compared with the general population.

Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn's disease.

BACKGROUND: Crohn's disease is associated with small bowel cancer whilst risk of colorectal cancer is less clear. AIM: To ascertain the combined estimates of relative risk of these cancers in Crohn's disease. METHODS: MEDLINE was searched to identify relevant papers. Exploding references identified additional publications. When two papers reviewed the same cohort, the later study was used. RESULTS: Meta-analysis showed overall colorectal cancer relative risk in Crohn's disease as 2.5 (1.3-4.7), 4.5 (1.3-14.9) for patients with colonic disease and 1.1 (0.8-1.5) in ileal disease. Meta-regression showed reduction in relative risk over the past 30 years. Subgroup analysis showed Scandinavia had significantly lower colorectal cancer relative risk than the UK and North America. Cumulative risk analysis showed 10 years following diagnosis of Crohn's disease relative risk of colorectal cancer is 2.9% (1.5%-5.3%). Meta-analysis showed small bowel cancer relative risk in Crohn's disease is 33.2 (15.9-60.9). Small bowel cancer relative risk has not significantly reduced over the last 30 years. CONCLUSION: Relative risk of colorectal and small bowel cancers are significantly raised in Crohn's disease. Cumulative risk of colorectal cancer of 2.9% at 10 years suggests a potential benefit from routine screening. However, the value of screening requires rigorous appraisal.

Long-term prognosis in Crohn's disease: factors that affect quality of life.

BACKGROUND: There are many studies investigating quality of life in recently diagnosed patients and following surgery for Crohn's disease, but there are none investigating quality of life changes with disease duration. The response shift model suggests quality of life improves with time following diagnosis. AIM: To assess how well the model applies to patients with Crohn's disease. METHODS: The Cardiff Crohn's disease database contains data on all patients diagnosed there since 1934. Three hundred and ninety four patients diagnosed before 1 January 1985 were traced and the mortality status on 31 December 2004 established. Two hundred and eleven still living were sent quality of life questionnaires. Two hundred and eighty five questionnaires were sent to patients with varying disease duration attending out-patient clinics in Leicester. RESULTS: Eighty-nine valid replies were received from Cardiff, 63 from Leicester patients diagnosed over 20 years, 69 from Leicester patients diagnosed <10 years. There was no difference in quality of life between newly diagnosed and established patients. Of greatest concern was possible need for ostomy, uncertain nature of disease, and lack of energy. Stepwise regression showed that increased disease severity, older age and smoking adversely affect quality of life. DISCUSSION: Quality of life is equally poor in patients with established disease as in those newly diagnosed, and directly correlates with disease severity. The response shift model may not be applicable in Crohn's disease.

Potential effects of forest fire and storm flow on total mercury and methylmercury in sediments of an arid-lands reservoir.

A study was conducted from July 1995 to June 1996 to examine the spatial and temporal changes of mercury concentrations in sediments of an arid-lands reservoir. Prior to the first sample collection in July, a forest fire burned 2930 ha of mixed conifer and ponderosa pine in the watershed of Caballo Reservoir in south-central New Mexico. The fire was eventually extinguished by summer rains and storm runoff resulting in the mobilization and transport of charred vegetative material into an intermittent tributary (Palomas Creek) that drains the watershed into Caballo Reservoir. Concentrations of total mercury (THg), monomethlymercury (MMHg), and total organic carbon (TOC) in surficial sediments revealed fire, followed by storm runoff, enhanced the transport of mercury and organic matter to the reservoir. Concentrations of THg in sediments increased from 7.5 etag/g in July to 46.1 etag/g by November 1995 at one site (Palomas) nearest the outflow of Palomas Creek. No other spatial or temporal trends were observed for THg at other sites throughout the remainder of the study. Concentrations of MMHg in sediments at the Palomas site increased from 0.428 etag/g in July to 12.46 etag/g by October 1995 compared to concentrations in sediments at the remaining sites which ranged from 0.11 to 1.50 etag/g throughout the study. The ratio of MMHg to THg (a gross index of methylation activity) was greatest in sediments from the Palomas site (5.4-33.8%) compared to the remaining sites (0.01-3.60%). The ratio was mirrored by elevated TOC in sediments at the Palomas site (2.5-11.8%) that remained elevated throughout the study. Fire and subsequent late-summer rains may have had a twofold effect on mercury concentrations in Caballo Reservoir. The storm-driven runoff following the forest fire carried mercury complexed to organic matter which resulted in elevated levels of mercury as well as providing a carbon source for microbial methylation processes in sediment.

Discharge of methylmercury-enriched hypolimnetic water from a stratified reservoir.

A study conducted from July 1995 to June 1996 examining spatial and temporal distribution of mercury (Hg) at the Caballo Reservoir, New Mexico, revealed that the highest levels of methylmercury (MMHg) occurred in both the inlet and the Rio Grande upstream of the reservoir. As a result, a second study was designed to identify possible sources of the elevated levels of MMHg, and to determine if water discharged from the Elephant Butte Reservoir upstream could be a primary source. In July 1996, as anoxia began to develop in the hypolimnion of the Elephant Butte Reservoir, surface water MMHg concentrations were below the MDL of 0.018 ng/l while water discharged into the tailrace was 0.149 ng/l MMHg. By September 1996, when the anoxic hypolimnion spanned 60% of the total reservoir depth, surface water MMHg was still below the MDL, while discharge water had increased to 1.144 ng/l MMHg. Following reservoir turnover in November 1996, surface water increased to 0.264 ng/l MMHg while discharge water decreased to 0.420 ng/l MMHg. By January 1997, MMHg in the tailrace decreased to pre-stratification levels, and both surface water and discharge water reached similar MMHg levels until the onset of summer stratification in July 1997. This trend was repeated the following year when MMHg concentrations in the tailrace increased from 0.190 ng/l in August 1997 to 1.240 ng/l in September 1997. In addition, vertical profile sampling of the reservoir from August 1997 to September 1997 showed a buildup of MMHg in the anoxic hypolimnion which coincided with increasing levels of MMHg discharged into the tailrace. During the course of this study the single largest contribution of MMHg to the river below the reservoir was from water released through the dam during the fall months of the year.

Treatment of angina pectoris in the community: is medical therapy given a chance?

OBJECTIVE: To describe the routine management of patients with chronic stable angina by GPs in Northern Ireland and the factors which they perceived affected the success of medical therapy. DESIGN: A questionnaire survey of all general practitioners in Northern Ireland (n = 962). SETTING: A survey conducted collaboratively by the Departments of Public Health Medicine in each of the four Health Boards in the province. Total population served, 1.5 million. MAIN OUTCOME MEASURES: The relationship between the perceived reasons for medical treatment failure and the stated referral and prescribing practice of the GPs. RESULTS: A total of 541 GPs replied; the response rate was 56%. The two most important reasons given for the perceived failure of medical therapy were (i) underlying disease progression and (ii) an adverse patient lifestyle such as smoking or obesity (cited as of primary importance by (i) 264 and (ii) 225 doctors respectively). The ranking differed significantly according to the doctor's propensity to prescribe triple therapy, with those doctors in the highest tertile of this distribution being less likely to cite the patient's lifestyle as a primary reason for treatment failure (chi-squared = 6.7, d.f. = 2, P = 0.035) and more likely to cite underlying disease progression as a primary reason (chi-square = 7.0, d.f. = 2, p = 0.031). The overall ranking of the primary reasons for referral differed significantly according to the proportion of patients given a trial of triple therapy and to the doctor's propensity to refer. Doctors who had given a greater proportion of their patients at least a trial of triple therapy (in the highest tertile of the distribution) were more likely to cite the need for revascularisation assessment as the primary reason (chi-square = 12.5, d.f. = 2, P = 0.0019). On the other hand, the need for further advice on medical therapy was generally ranked higher by those doctors who had given fewer of their patients at least a trial of triple therapy (chi-square = 7.3, d.f. = 2, P = 0.027). GPs who had referred fewer of their new patients to hospital were more likely to be those doctors with fewer patients given at least a trial of triple therapy. Doctors with a greater percentage of their patients managed primarily by a hospital specialist tended to have more who had had a trial of triple therapy for their symptoms. CONCLUSIONS: The results suggest the need for clearer definition for GPs of the place of revascularisation and of medical therapy for patients with stable angina.

Expanding access to coronary artery bypass surgery: who stands to gain?

OBJECTIVE: To determine the perceptions of general practitioners (GPs) about the benefits of coronary artery bypass surgery, in terms of gains in life expectancy, for different groups of patients. DESIGN: A questionnaire survey of all GPs in Northern Ireland. SETTING: A survey conducted collaboratively by the departments of public health medicine in each of the four health boards in the province, serving a total population of 1.5 million. MAIN OUTCOME MEASURES: The median and mean gain in life expectancy perceived by groups of doctors for smoking and non-smoking male and female 55 year old patients. The percentage of 50 year old and 70 year old non-smoking patients considered likely to have their lives extended with bypass surgery. Differences were assessed using the Mann-Whitney U test for unpaired samples and the Wilcoxon signed rank tests for paired. RESULTS: 541 GPs replied (response rate 56%). The median (and mean) perceived gain in life expectancy after cardiac surgery for non-smoking 55 year old subjects was 120 (104) months for men and 120 (112) months for women (z = 6.42; P < 0.0001; Wilcoxon signed rank test). For male and female smokers of the same age, the perceived gains were 48 (47) and 60 (52) months respectively (z = 6.72; P < 0.0001; Wilcoxon signed ranks test), both figures being significantly different than for non-smokers. The median (and mean) percentage of patients that the doctors considered would have their lives extended by bypass surgery was 70 (64) of every 100 "young" patients and 40 (42) of every 100 "old" patients, (z = 16.2; P < 0.0001). CONCLUSIONS: These results point to a significant overestimation of the benefits of coronary artery bypass surgery by GPs in Northern Ireland and to a need to develop guidelines for referral.

Is choice of general practitioner important for patients having coronary artery investigations?

OBJECTIVE: To determine whether particular sociodemographic characteristics of patients with stable angina affected their general practitioners' (GPs') decisions to refer them for revascularisation assessment. DESIGN: Postal questionnaire survey. SETTING: Collaborative survey by the departments of public health medicine in each of the four health boards in Northern Ireland, serving a total population of 1.5 million. SUBJECTS: All (962) GPs. MAIN MEASURES: The relation between GPs' referral decisions and patients' age, sex, employment status, home circumstances, smoking habits, and obesity. RESULTS: 541 GPs replied (response rate 56%). Most were "neutral" towards a patient's sex (428, 79%), weight (331, 61%), smoking habit (302, 56%), employment status (431, 80%), and home circumstances (408, 75%) in making decisions about referral. In assigning priority for surgery most were neutral towards the patient's sex (459, 85%), employment status (378, 70%), and home circumstances (295, 55%). However, most GPs (518, 95%) said that younger patients were more likely to be referred, and a significant minority were less likely to refer patients who smoked (202, 37%) and obese patients (175, 32%) and more likely to refer employed patients (97, 18%) and those with dependents (117, 22%) (compared with patients with otherwise comparable clinical characteristics); these views paralleled the priority which GPs assigned these groups. The stated likelihood of referral of young patients was independent of the GPs' belief in ability to benefit from revascularisation, but propensity to refer and perception of benefit were significantly associated for all other patient characteristics. CONCLUSION: GPs' weighting of certain characteristics in reaching decisions about referral for angiography is not uniform and may contribute to unequal access to revascularisation services for certain patient groups.

Leukotriene C4 action and metabolism in the isolated perfused bullfrog heart.

The effects of leukotrienes (LTs) have been widely studied in the isolated perfused mammalian heart; however, little is known about the effect or metabolism of LTs in the isolated bullfrog heart. Isolated perfused bullfrog hearts were administered randomized doses of LTC4, LTD4, or LTE4. The cardiac parameters of heart rate, developed tension, and its first derivative (dT/dt) were recorded. LTC4 was the most potent of the leukotrienes tested in eliciting positive inotropic effects. LTD4 and LTE4 were equally effective but about one order of magnitude less potent than LTC4. None of the LTs showed any chronotropic effects in this preparation. A series of [3H]LTC4 metabolism experiments were carried out using whole perfused hearts and minced bullfrog heart tissue. Isolated perfused bullfrog hearts administered [3H]LTC4 converted significant amounts to [3H]LTD4, and to a lesser degree, [3H]LTE4, during the 6-min course of collection. Both minced atrial and ventricular tissue converted [3H]LTC4 to radioactive metabolites that co-migrated with authentic LTD4 and LTE4 standards. In both tissues, the major product was [3H]LTD4, with smaller amounts of [3H]LTE4 produced. The atrium converted significantly more [3H]LTC4 to its metabolites than did the ventricle. The metabolism of [3H]LTC4 to [3H]LTD4 by both tissues was virtually abolished in the presence of serine borate. Cysteine had no effect on [3H]LTE4 production. The data in this study demonstrate that leukotrienes have the opposite inotropic effect on the heart when compared with mammals. Also in contrast to mammals, frogs metabolize LTC4 to a less potent compound and may use the LTC4 to LTD4 conversion as a mechanism of LTC4 inactivation.

Bioconversion of leukotriene C4 by the bullfrog heart.

Isolated perfused bullfrog hearts were administered randomized doses of LTC4, LTD4 or LTE4. The cardiac parameters of heart rate, developed tension and its first derivative (dT/dt) were recorded. LTC4 was the most potent of the leukotrienes tested in eliciting positive inotropic effects. LTD4 and LTE4 were equally effective but about one order of magnitude less potent than LTC4. None of the LTs showed any chronotropic effects in this preparation. LTC4 was significantly more potent in the presence of L-serine borate, an inhibitor of gamma-glutamyl transpeptidase, than in its absence, raising the possibility of significant bioconversion of LTC4 by the bullfrog heart. 3H-LTC4 metabolism experiments were carried out using whole perfused hearts or minced bullfrog heart tissue. During the six minute course of collection, the isolated perfused heart converted significant amounts of LTC4 to LTD4 and to a lesser degree LTE4. This conversion was attenuated in the presence of L-serine borate. Both minced atrial and ventricular tissue converted 3H-LTC4 to radioactive metabolites which co-migrated with authentic LTD4 and LTE4 standards. In both tissues, the major product was LTD4, with smaller amounts of LTE4 produced. The atrium converted significantly more LTC4 to its metabolites than did the ventricle. The metabolism of LTC4 to LTD4 by both tissues was virtually abolished in the presence of serine borate. It is interesting that LTC4 metabolism pattern and rate is comparable in mammals and frogs in spite of the fact that the inotropic effects of leukotrienes are opposite in the two taxa and, in frogs, metabolism results in a less potent agent.