Outcomes of CSF spectrophotometry in cases of suspected subarachnoid haemorrhage with negative CT: two years retrospective review in a Birmingham hospital.

AIM: The aim of this study was to evaluate the adherence to current guidelines for the investigation of suspected subarachnoid haemorrhage and the prevalence and outcome of computed tomography (CT)-negative aneurysmal subarachnoid haemorrhage. DESIGN: A retrospective review in a single large tertiary referral centre. SUBJECTS: A total of 796 patients, aged 16-90 years, who underwent lumbar puncture (LP) for suspected subarachnoid haemorrhage (SAH) following a negative or equivocal CT scan between January 2012 and November 2013 (23 months). METHODS: Xanthochromia reports were obtained using the hospital's department of biochemistry database and clinical data for these patients were reviewed using patient notes. RESULTS: Of 796 CSF reports reviewed, 728 (91%) were negative for xanthochromia, 31 (4%) were positive and 37 (5%) were equivocal. Only 2 out of the 31 patients with positive spectrophotometry results were subsequently found to have an underlying aneurysm on CT angiography. A further 9 out of these 31 patients underwent digital subtraction angiography, with no cerebral aneurysms being detected. Amongst the 37 patients with equivocal xanthochromia reports, 13 underwent CT angiography and only 1 cerebral aneurysm was detected. CONCLUSIONS: In patients with clinically suspected SAH but who have negative or questionable CT findings, CSF analysis is likely to be negative in the vast majority of cases, which was 91% in our series. In patients yielding positive or equivocal CSF results the likelihood of an aneurysm being detected is low, amounting to three out of 68 or approximately one in 23 (approximately 4%). Overall in suspected SAH cases where CT scan has been negative, the rate for the detection of cerebral aneurysm is three out of 796 cases (0.4%).

Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS): a prospective cohort study.

OBJECTIVE: To evaluate mildly abnormal liver function test (LFT) results in general practice among patients who do not have known liver disease. DESIGN: Prospective cohort study of people with abnormal LFT results identified in primary care. Participants were intensively investigated using a common protocol and followed up for 2 years. Substudies investigated the psychological sequelae of abnormal test results, clinicians' reasons for testing, decision options when LFT results were abnormal and early detection of liver fibrosis. SETTING: Eleven primary-care practices: eight in Birmingham and three in Lambeth. PARTICIPANTS: Adults with abnormal LFT results who did not have pre-existing or obvious liver disease. Eight analytes were included in the panel of LFTs. MAIN OUTCOME MEASURES: Statistical tests were used to identify the interactions between clinical features, the initial pattern of abnormal LFT results and (1) specific viral, genetic and autoimmune diseases, such as viral hepatitis, haemochromatosis and primary biliary cirrhosis; (2) a range of other serious diseases, such as metastatic cancer and hypothyroidism; (3) 'fatty liver' not associated with the above; and (4) the absence of detectable disease. RESULTS: Fewer than 5% of people with abnormal LFT results had a specific disease of the liver, and many of these were unlikely to need treatment. The diagnostic potential of the LFT panel is largely subsumed into just two analytes: alanine aminotransferase (ALT) and alkaline phosphatase (ALP). Gamma-glutamyltransferase (GGT) offers a small increase in sensitivity at the margin at the cost of a large loss of specificity. Eighty-four per cent of abnormal LFT results remain abnormal on retesting 1 month later. In many cases, carrying out a definitive or specific test will be more efficient than repeating LFTs, with a view to specific testing only if the test remains abnormal. An ultrasound diagnosis of 'fatty liver' was present in nearly 40% of patients with abnormal LFTs and a small amount of weight loss over 2 years was associated with a reduced incidence of liver fat. There was a J-shaped relationship between alcohol intake and fatty liver in men. An abnormal LFT result causes temporary anxiety, which does not appear to promote sustained behaviour change. CONCLUSIONS: Liver disease is rare among people with abnormal LFT results in primary care. Only two analytes (ALT and ALP) are helpful in identifying the majority of liver disease. GGT adds little information in return for a high false-positive rate but it is sensitive to alcohol intake. LFT results seldom revert from abnormal to normal over a 1-month period, and modelling shows that repeating an abnormal LFT panel, as recommended in the current guidelines, is inefficient. LFTs are often undertaken to meet perceived patient need for a blood test, but as they are neither specific nor indicative of any particular disease they are among the least suitable tests for this purpose. Obesity and raised ALT provide strong evidence for a presumptive diagnosis of 'fatty' liver. Abnormal LFTs and 'fatty' liver provoke only short-term anxiety and neither is associated with sustained weight loss. Even a small amount of weight loss reduces liver fat. FUTURE WORK RECOMMENDATIONS: (1) the cases of 'fatty liver' and controls should be followed up in the long term to identify features that predict development of hepatosteatosis and then cirrhosis; (2) the acceptability of replacing the traditional six- to eight-analyte LFT panel with a drop down menu including the ALT/ALP combination should be evaluated. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Prevalence of hepatitis in early syphilis among an HIV cohort.

To investigate the prevalence of syphilitic hepatitis among a group of HIV-infected patients we performed a cross-sectional observational study of consecutive HIV-infected patients with early syphilis attending University Hospital Birmingham between 1 January 2005 and 31 August 2008. The AIDS Clinical Trials Group grading for abnormal liver enzymes was used to identify hepatitis. A total of 62 HIV-infected patients were diagnosed with early syphilis during the study period. Twelve (19.3%) of them demonstrated abnormal liver enzymes consistent with syphilitic hepatitis involving raised levels of alanine aminotransferase, aspartate transaminase, alkaline phosphatase or gamma-glutamyl transferase (GGT). Grade 3 hepatotoxicity was observed among five patients. None of the patients with syphilitic hepatitis had grade IV hepatitis or abnormal bilirubin levels. Liver biopsy was not carried out in any of the patients, and following completion of treatment of syphilis all abnormal liver enzymes returned to normal levels after a median of 16 weeks. Exclusion of syphilis must be considered when investigating hepatic disease in HIV-infected patients.

Family tracing to identify patients with familial hypercholesterolaemia: the second audit of the Department of Health Familial Hypercholesterolaemia Cascade Testing Project.

BACKGROUND: Family tracing is a method recognized to find new patients with familial hypercholesterolaemia (FH). We have implemented family tracing led by FH Nurses and have determined acceptability to patients, feasibility and costs. METHODS: Nurses were located at five National Health Service (NHS) Trusts; they identified FH patients and offered them family tracing. Responses and test results were recorded on a database and summarized on a family pedigree. RESULTS: The majority ( approximately 70%) of index cases participated; the proportion was lower when patients had been discharged from the clinics and in metropolitan areas. On average, 34% (range 13-50%) of relatives lived outside the catchment area of the clinics and could not attend the nurse-led FH clinics. Of the previously untested relatives, 76% who lived in the catchment area of the clinic came forward to be tested. One-third of the relatives who came forward for testing were children

Are patients with familial hypercholesterolaemia well managed in lipid clinics? An audit of eleven clinics from the Department of Health Familial Hypercholesterolaemia Cascade Testing project.

BACKGROUND: Familial hypercholesterolaemia (FH) is an autosomal co-dominant disorder which is relatively common, leads to high levels of LDL-cholesterol and if untreated to early coronary heart disease. An audit of current practice at National Health Service Trusts in England was undertaken to determine whether FH patients meet the diagnostic criteria for FH; are being offered appropriate advice and treatment; and to what extent their families are contacted and offered testing for the disorder. METHODS: Medical records of known FH patients (over 18 years of age and diagnosed before 31 December 2003) were accessed to obtain information on diagnosis, treatment and family tracing. RESULTS: The records of 733 FH patients were examined, 79% met the UK 'Simon Broome' register criteria for the diagnosis of definite or possible FH. Analyses showed that patients were usually offered appropriate advice and treatment, with 89% being on a statin. However, the audit indicated a high variability in family tracing between the sites, with significant differences in the frequency of inclusion of a family pedigree in the notes (range 1-71%, mean 35%); the general practitioner (GP) being advised that first-degree relatives should be tested (range 4-52%, mean 27%); and the proportion of relatives contacted and tested (range 6-50%, mean 32%). CONCLUSION: FH patients are well cared for in lipid clinics in England, are being given appropriate lifestyle advice and medication, but an increase in recording of LDL-cholesterol levels may lead to improvements in their management. Practice in family tracing appears to vary widely between clinics.

Serum lipid and lipoprotein profile of patients with glycogen storage disease types I, III and IX.

With current dietary therapy, life expectancy in glycogen storage disease (GSD) has improved considerably and more children reach adulthood. Notwithstanding intensive dietary therapy, moderate to severe hyperlipidaemia is still observed frequently. There is limited information about the type and extent of hyperlipidaemia. We studied the lipid profile in 20 patients, aged 8-54 years, of the three (types I, III and IX) most common forms of adult GSD. Hyperlipidaemia was shown to be type-specific, affecting predominantly patients with GSD type Ia, who showed marked combined hypercholesterolaemia and hypertriglyceridaemia. By contrast, a heterogeneous distribution of HDL was found in patients with GSD I and III. There was no significant difference in Apo Al and Apo B concentrations between groups. In addition, mass measurements of the fractions of VLDL1, VLDL2 and IDL were raised in all patients with GSD Ia by comparison with all other patients with GSD. Patients with GSD type Ia have lipid concentrations and individual mass measurements that are consistent with ranges found in patients who have a significant risk of atherosclerosis. Accumulated evidence, however, suggest GSD type Ia patients do not have an increased risk of atherosclerotic cardiovascular disease (CVD) but the reason remains unknown. Intervention to reduce their lipid levels could therefore be on the basis of seeking to prevent the risk of pancreatitis rather than that of CVD.

Acquired copper deficiency following prolonged jejunostomy feeds.

A 19-year-old man who developed extensive oesophageal lye (Alkali) stricture and received long-term enteral nutrition (eight months) with a jejunostomy tube developed macrocytic anaemia (Hb: 41 g/L) with leucopenia (white blood cell [WBC]: 3.0 x 10(9)/L). The patient's serum vitamin B12, folate, iron and liver function tests were normal. Bone marrow examination revealed gross erythroid hyperplasia and cytoplasmic vacuolization of erythroid and myeloid elements. Further investigations revealed low serum copper (0.3 micromol/L) and ceruloplasmin concentrations (<30 mg/L) with marginally low normal serum concentration of red cell peroxidase (13 U/gHb), establishing the diagnosis of copper deficiency anaemia. The anaemia and leucopenia responded intermittently to intravenous copper therapy, but the serum copper concentration dropped when intravenous copper therapy was withdrawn. Enteral jejunostomy copper supplementation failed to maintain adequate serum copper concentrations. After stabilizing the general condition of the patient, a pharyngo-gastric anastamosis was performed and normal oral diet commenced, which restored normal serum copper concentration. This case report suggests that copper supplements in the form of copper sulphate are not adequately absorbed when administered through a jejunostomy tube.

Bone mineral density and markers of bone turnover in patients with glycogen storage disease types I, III and IX.

Patients with glycogen storage disease (GSD) types I, III and IX show reduced bone mineral content, but there is scarce data on new serum and urine markers of bone turnover or their relationship to bone densitometry. Six GSD I, four GSD III and four GSD IX patients underwent bone mineral density (BMD) measurement by dual-energy X-ray absorptiometry. Free pyridinoline (fPYD):creatinine and free deoxypyridinoline (fDPD):creatinine ratios were analysed on random urines. Procollagen type I C-terminal propeptide, procollagen type I N-terminal propeptide (PINP), carboxyterminal telopeptide of type I collagen and bone-specific alkaline phosphatase were analysed in serum. Some GSD I and GSD III patients had low or very low BMD. There was no difference in total body BMD z-score between the GSD types after adjusting for height (p=0.110). Bone marker analysis showed no consistent pattern. Urine fPYD:creatinine ratio was raised in four GSD I and two GSD III patients, while serum PINP was inappropriately low in some of these patients. There was no clear correlation between any markers of bone destruction and total body z-score, but the patient with the lowest total body z-score showed the highest concentrations of both urinary fPYD:creatinine and fDPD:creatinine ratios. We conclude that some GSD I and GSD III patients have very low bone mineral density. There is no correlation between mineral density and bone markers in GSD patients. The inappropriately low concentration of PINP in association with the raised urinary fPYD:creatinine and fDPD:creatinine ratios seen in two GSD I patients reflect uncoupling of bone turnover. All these findings taken together suggest that some GSD I and GSD III patients may be at an increased risk of osteoporosis.

Statin-fibrate combination: therapy for hyperlipidemia: a review.

Statins and fibrates are well-established treatments for hyperlipidaemias and the prevention of vascular events. However, fibrate + statin therapy has been restricted following early reports of rhabdomyolysis that mainly involved gemfibrozil, originally with bovastatin, and recently, with cerivastatin. Despite this limitation, several reports describing combination therapy have been published. This review considers these studies and the relevant indications and contraindications. Statin + fibrate therapy should be considered if monotherapy or adding other drugs (e.g. cholesterol absorption inhibitors, omega-3 fatty acids ornicotinic acid) did not achieve lipid targets or is impractical. Combination therapy should be hospital-based and reserved for high-risk patients with a mixed hyperlipidaemia characterised by low density lipoprotein cholesterol (LDL) >2.6 mmol/l(100 mg/dl, high density lipoprotein cholesterol (HDL) <1.0 mmol/l (40 mg/dl) and/or triglycerides> 5.6 mmol/l (500 mg/dl. These three 'goals' are individually mentioned in guidelines. Patients should have normal renal, liver and thyroid function tests and should not be receiving therapy with cyclosporine, protease inhibitors or drugs metabolised through cytochrome P450 (especially 3A4). Combination therapy is probably best conducted using drugs with short plasma half-lives; fibrates should be prescribed in the morning and statins at night to minimise peak dose interactions. Both drug classes should be progressively titated from low doses. Regular (3-monthly) monitoring of liver function and creatine kinase is required. In conclusion, fibrate + statin therapy remains an option in high-risk patents. However, long-term studies involving safety monitoring and vascular endpoints are required to demonstrate the efficacy of this regimen.

Cyclosporin: revisions in monitoring guidelines and review of current analytical methods.

This article summarizes the main changes that have occurred in cyclosporin (ciclosporin) monitoring and measurement since the previous review in this journal. Cyclosporin has been reformulated to reduce variability in its absorption, leading to fewer post-transplant rejection episodes. Monitoring has mostly utilized the measurement of pre-dose blood levels of the drug, but more recently the potential benefit of using samples collected during the first few hours post-dose has been evaluated. Calculating the area under the cyclosporin concentration-time curve may be the ideal, but is not viable in the routine clinical situation and 2-h post-dose sampling seems likely to offer a practical clinical solution. Analytical methods based on high-performance liquid chromatography (HPLC) and immunoassay are available for the determination of whole blood cyclosporin concentrations. HPLC is specific but rarely used for routine monitoring, although HPLC-tandem mass spectrometry is making the technique more viable. New immunoassays have been introduced, but none are completely specific for the parent drug and all exhibit cross-reactivity towards cyclosporin metabolites. Immunoassays were originally designed for the lower cyclosporin concentrations seen in pre-dose samples, but are being evaluated and modified for determination of the higher concentrations seen 2 h post-dose.

Protease inhibitor related type III hyperlipoproteinaemia is common and not associated with apolipoprotein-E E2/E2 phenotype.

OBJECTIVE: To determine the prevalence of type III hyperlipoproteinaemia in a cohort of HIV infected patients taking protease inhibitors and its correlation with the apolipoprotein-E2 isoform. DESIGN: Cross sectional study of 57 consecutive HIV infected subjects taking protease inhibitor therapy for a median of 12.5 (1-29) months, seen in an outpatient HIV clinic. Controls were 17 patients on non-nucleoside reverse transcriptor inhibitor therapy (NNRTI) for 9 (1-19) months and 50 antiviral naive patients. METHODS: Fasting cholesterol, triglyceride, HDL cholesterol, lipoprotein (a), and glucose were measured. Lipoprotein electrophoresis was performed on patients with a cholesterol >6.5 mmol/l and a triglyceride concentration of >4.5 mmol/l. Apolipoprotein-E phenotype was determined in serum. RESULTS: Dyslipidaemia was found in 43 (75%) PI treated patients-37 with triglyceride >2.3 mmol/l, 30 with cholesterol >6.5 mmol/l, and nine with HDL cholesterol <0.9 mmol/l. 38% had a lipoprotein (a) >300 mg/l. 11 patients (19.3%) had a type III hyperlipoproteinaemia pattern. Only one was homozygous for the E2 phenotype and none had clinical diabetes. An additional patient had a serum lipid profile compatible with type III hyperlipoproteinaemia and an E3/E2 phenotype in whom electrophoresis was not carried out before treatment. Six (35%) of the NNRTI and 16 (32%) of the antiviral naive patients had dyslipidaemia. 18 (31.6%) of the PI and none of the control patients had a cholesterol and/or triglyceride >8 mmol/l. CONCLUSION: Type III hyperlipoproteinaemia is common in this group of patients and need not be associated with the apolipoprotein-E2/E2 isoform. HIV protease inhibitors may interfere with lipoprotein receptor related protein.

Worsening lipid profile is associated with progression of carotid artery stenosis.

BACKGROUND: To determine if uncontrolled hypercholesterolaemia predisposes to progression of carotid artery stenosis. METHODS: Fasting blood samples were collected from 76 patients referred for carotid duplex ultrasound for investigation of transient ischaemic attacks or recent stroke. Patients were grouped depending on the severity of the stenosis found. Patients on lipid lowering agents were excluded. The data were analysed using one way analysis of variance and the c2 test as appropriate. RESULTS: There were more men in the 70-99% group (15 vs 6, c2 = 10.6, p < 0.001, Table I). The total cholesterol was raised in all three groups. Patients with carotid stenosis of 70-99% had significantly elevated triglycerides (2.4 mmol vs 1.47 mmol and 1.37 mmol, p < 0.003), low HDL (1.14 mmol vs 1.45 mmol and 1.18 mmol, p < 0.003) and a higher cholesterol/HDL ratio (5.56 vs 4.29 and 4.71, p < 0.014) compared with the other two groups. There was no difference in lipoprotein(a) in the three groups. CONCLUSIONS: Increased triglycerides and low HDL cholesterol seen in the 70-99% group suggest that a worsening lipid profile is associated with progression of carotid artery stenosis.

Adverse change in low-density lipoprotein subfractions profile with oestrogen-only hormone replacement therapy.

In a prospective longitudinal study in 17 women, we investigated the effects of surgical menopause and subsequent oestrogen-only hormone replacement therapy (HRT) on plasma concentrations of total cholesterol, HDL cholesterol, LDL cholesterol, triglyceride and LDL subfractions profile. Plasma LDL is a heterogeneous population of particles of varying size, density and chemical composition. The predominance of small LDL particles is a newly-recognized risk factor for coronary artery disease. The LDL score is used to describe LDL subfractions profile and the greater the score, the higher the proportion of small LDL particles. Six weeks after hysterectomy and bilateral oopherectomy, total cholesterol and triglyceride concentrations were significantly increased (p < 0.01) as well as the LDL score (p < 0.05). After 6 weeks of oestrogen-only HRT, total cholesterol concentration was significantly lower and HDL cholesterol concentration significantly higher than before the treatment (p < 0.05). At the same time, mean LDL score significantly increased and in none of the women did LDL subfractions profile change favourably.

Investigation of low density lipoprotein subfractions as a coronary risk factor in normotriglyceridaemic men.

There is an increasing interest in low density lipoprotein (LDL) subfractions since some of them are associated with a higher risk for coronary artery disease (CAD). Small LDL particles are particularly atherogenic and more of those are produced in hypertriglyceridaemia. However, high triglyceride concentrations are not the only explanation for the predominance of small LDL particles and other influences, including genetic factors, are also responsible for LDL particle size. We investigated LDL subfraction profiles in two groups: 46 men with and 21 men without CAD proven angiographically. For the separation of LDL subfractions, we used continuous disc polyacrylamide gel electrophoresis (PAGE) that is rapid and easier to perform than the other methods usually used which, although more precise in terms of measuring particle diameter, are much more demanding of time and equipment. The described method is suitable for routine use in assessing large numbers of patients. All studied men had triglyceride concentrations below 2.3 mmol/l. LDL scores were calculated on the basis of all LDL subfractions present in a particular profile; the higher the score, the greater the proportion of small LDL particles. LDL cholesterol (P < 0.05) and LDL score (P < 0.001) were the only significant discriminators between two groups. LDL score was significantly correlated with CAD, even after adjusting for triglyceride and HDL cholesterol concentrations and it was the best discriminant factor for the presence of CAD.