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.

Ethnicity and social deprivation contribute to vitamin D deficiency in an urban UK population.

We receive a large number of 25 hydroxyvitamin D (25OHD) assay requests from General Medical Practitioners (GPs) in primary care. We have investigated whether this rate of requesting is related to the ethnicity of the local urban population based in Central Manchester or Trafford areas with very different ethnic populations. Data on assay requesting was collected from January-December 2013. Samples were assayed using an ABSciex 5500 tandem mass spectrophotometer and the Chromsystems 25OHD kit for LC-MS/MS. 11,291 requests for 25OHD measurement received from Central Manchester GPs and 5176 requests from Trafford GPs. Overall 29% of patients were profoundly deficient (<25nmol/L) and a further 32% were insufficient (25-50nmol/L). Using the 2011 Census data we have analysed our data by ethnicity (categorized here as white, Asian, black, Chinese, other) based on patient's home postcode and related this to the Index of Multiple Deprivation (IMD). In areas where >70% of the population were non-white (NW), 69% had 25OHD <50nmol/L. Areas where <5% of patients were NW, 42% of patients were still insufficient. There was a significant correlation between the Index of Social Deprivation (IMD) and the percentage of patients with 25OHD <50nmol/L (p<0.0001). Areas with the highest Index of Social Deprivation (IMD ranking <16,000) showed no association between ethnicity and IMD (p=0.69). We have shown that over 61% of all patients in these urban areas of Manchester and Trafford showed increased risk of bone, and potentially other diseases, based on their 25OHD assay results alone and that social deprivation, as well as ethnicity, contribute to the poor 25OHD levels seen in these patients.

An evaluation of the low-pH enzymatic assay of urinary D-glucaric acid, and its use as a marker of enzyme induction in exocrine pancreatic disease.

We have evaluated a low-pH enzymatic method for measuring urinary D-glucaric acid, and its usefulness as a marker of 'enzyme induction' in patients with exocrine pancreatic disease. The coefficient of variation lay between 7.5 and 10.9% for within-batch precision, and between 7.9 and 19.8% for between-batch precision. The useful range of the method was 20-200 mumol/l, with a lower detection limit of 11 mumol/l. The molar concentration ratio of D-glucaric acid to creatinine in urine correlated with the 8-h output of D-glucaric acid (p less than 0.005): both indices were significantly higher in a group of 29 patients with exocrine pancreatic disease than in controls (median ratios 4.6 and 2.9 X 10(-3), p less than 0.005; median outputs 14.0 and 8.8 mumol/8 h, respectively, p less than 0.005). Comparison with the results of theophylline tests in the same group of patients showed that whereas 72% of patients had theophylline clearances higher than the highest value in controls, 45% of the group had increased D-glucaric acid/creatinine ratios, whilst only 21% had increased outputs of D-glucaric acid. Paradoxically, in patients with established liver disease in whom drug metabolism was impaired urinary D-glucaric acid values were amongst the highest encountered in the study. Thus, the obvious advantages of the method--non-invasive, simple, reproducible, inexpensive, easily applied to out-patients--are offset by an unacceptably low predictive value as an indicator of microsomal 'enzyme induction'.

Evidence of toxic metabolite stress in black South Africans with chronic pancreatitis.

We report the results of a further study to test our hypothesis that toxic metabolite stress is germane to heightened free radical activity and hence to the genesis of chronic pancreatitis. Consecutive black South African patients with clinically quiescent chronic pancreatitis were studied, provided that the diagnosis had been made within the previous 2 years and that they did not have overt liver disease. All of them had been advised to stop drinking alcohol. Analysis of an early morning sample of urine showed a lower ratio of inorganic to ester sulphate (P < 0.001) and a higher ratio of D-glucaric acid to creatinine (P < 0.02) in the group of 14 patients than in 15 local controls, while plasma analysis showed a lower concentration of glutathione (GSH) in the patients (P < 0.001). This evidence of increased utilisation of phase II conjugative pathways of xenobiotic disposal was in keeping with on-going toxic metabolite stress from heightened phase I oxidative metabolism in the group of patients. Parallel studies of theophylline pharmacokinetics showed heightened drug clearance compatible with induced cytochrome P-4501A2 in two patients, whereas increased activity of gamma-glutamyl transferase in serum suggested persisting induction of P-4502E1, as by ethanol, in several others. The contemporaneous increases in free radical activity and utilisation of xenobiotic disposal pathways in Sowetan Africans with chronic pancreatitis is in line with the toxic metabolite concept of disease pathogenesis.

External quality assessment of laboratory performance in analysis of toxicological cases.

A mean of 44 members of the United Kingdom national external quality assessment scheme (UKNEQAS) for toxicology reported analytical findings on 10 toxicological cases circulated between December 1995 and February 2000. Material distributed usually consisted of a 5ml blood and a 20ml urine sample simulated by quantitative addition of drugs and their metabolites to material donated by volunteers and patients. The samples were accompanied by a brief outline of the circumstances surrounding the case. Laboratories were requested to report their analytical findings, list methods of analysis, and provide interpretation of their findings. The mean overall success rate for identification of drugs or their pharmacological group was 76%, failure being largely by laboratories providing an immunoassay-based screening service for a fixed range of drug groups. The latter laboratories indicated that cases would be referred to regional toxicology centres for further investigation or confirmation. The coefficient of variation of measurements was <7% for routine analytes, such as ethanol and paracetamol, but 26-44% for tricyclics and opiates. There were 3% false positive reports. The quantity and content of interpretative comment provided by the laboratories was very variable. A number provide nothing in addition to the analytical result.

A survey of extraction techniques for drugs of abuse in urine.

Sixty nine participants in the United Kingdom national external quality assessment scheme for drugs of abuse in urine reported details of their sample extraction technique by questionnaire. Laboratories were categorised by differences in technique and their analytical test results compared for samples containing D-amfetamine 0.4 (4) and 0.8 (3) mg/l, morphine 0.4 (4) and 0.8 (4)mg/l, and benzoylecgonine 0.15/0.2 (2) and 0.45/0.5 (4) mg/l. Values in parentheses are numbers of samples. For amfetamine, there was no significant difference in the frequency of true positive results between liquid-liquid or solid phase extraction and the Toxi-Lab A system at 0.8 mg/l. Toxi-Lab A gave significantly fewer positives when operating below its specified threshold at 0.4 mg/l. Paradoxically, laboratories using >5 ml urine volume performed less well. Acidification of the extract before volume reduction gave significantly more true positives. For extraction of morphine, solid phase systems significantly outperformed both liquid-liquid and the Toxi-Lab A system at both 0.8 and 0.4 mg/l. No significant differences between extraction techniques were demonstrated for analysis of benzoylecgonine.

Serum creatine kinase activity in the elderly following a stroke.

A serial measurement of serum creatine kinase (CK) activity and its isoenzymes were made in elderly patients following an acute stroke. Seven out of ten patients had elevated CK levels. The maximum concentration was observed between 12-24 h and the level returned to normal within 84 h after a stroke. They all had positive skeletal (MM) muscle isoenzyme, and in only one patient heart (MB) isoenzyme was detected. None of them had positive brain (BB) isoenzyme. Measurement of serum CK activity will possibly provide guidance in the management of patients having recently suffered a stroke.

Enhanced large intestinal potassium permeability in end-stage renal disease.

The capacity of the colon for potassium (K+) secretion increases in end-stage renal disease (ESRD), to the extent that it makes a substantial contribution to K+ homeostasis. This colonic K+ adaptive response may reflect enhanced active K+ secretion, and be associated with an increase in apical membrane K+ permeability. In this study, this hypothesis was tested in patients with normal renal function or ESRD, by evaluating the effect of barium ions (a K+ channel inhibitor) on rectal K+ secretion using a rectal dialysis technique, and the expression of high conductance (BK) K+ channel protein in colonic mucosa by immunohistochemistry. Under basal conditions, rectal K+ secretion was almost threefold greater (p < 0.02) in ESRD patients (n = 8) than in patients with normal renal function (n = 10). Intraluminal barium (5 mmol/l) decreased K+ secretion in the ESRD patients by 45% (p < 0.05), but had no effect on K+ transport in patients with normal renal function. Immunostaining using a specific antibody to the BK channel alpha-subunit revealed greater (p < 0.001) levels of BK channel protein expression in surface colonocytes and crypt cells in ESRD patients (n = 9) than in patients with normal renal function (n = 9), in whom low levels of expression were mainly restricted to surface colonocytes. In conclusion, these results suggest that enhanced colonic K+ secretion in ESRD involves an increase in the apical K+ permeability of the large intestinal epithelium, which most likely reflects increased expression of apical BK channels.

Measurement of bicarbonate output from the intact human oesophagus.

Injury of the oesophageal mucosa can result from exposure to refluxed gastric acid and pepsin. Competence of the lower oesophageal sphincter and peristaltic activity serve to reduce contract time between luminal acid and oesophageal mucosa, but intraluminal neutralisation of residual acid by bicarbonate may also be important in preventing oesophageal mucosal injury. Whereas swallowed saliva contains bicarbonate, recent experiments have also demonstrated alkali secretion from the mammalian oesophagus. Bicarbonate secretion from the human oesophagus was therefore examined with an intubation technique and perfusion of the oesophagus with a non-absorbable marker. Saliva, gastric, and oesophageal aspirates were collected and bicarbonate concentrations determined by measurements of pH and pCO2 or by back titration. In 32 normal subjects (17 women, 15 men) median basal oesophageal bicarbonate secretion determined by a pH/pCO2 method was 416 (range 139-1050) mumol/hour/10 cm. In a subgroup of 15 experiments median oesophageal bicarbonate output was 489 (range 157-1033) mumol/hour/10 cm (pH/pCO2 method) compared with a median alkali output of 563 (range 135-799) mumol/hour/10 cm as determined by back titration. The difference was not significant. Salivary contamination of the oesophagus accounted for 25% of all bicarbonate measured within the oesophagus and refluxed gastric bicarbonate accounted for 2.5%. Bicarbonate secretion from the normal human oesophagus may, in combination with swallowed salivary bicarbonate, play a part in preventing oesophageal mucosal damage due to refluxed gastric acid and pepsin.

Evidence for induction of cytochrome P-450I in patients with tropical chronic pancreatitis.

Theophylline kinetics, as an in vivo probe for the potentially toxic cytochrome P-450I pathway of drug metabolism, were studied in 11 healthy volunteers and 11 patients with calcific chronic pancreatitis at Madras, South India. Theophylline clearance was faster in the patients than controls [median 69 (range 39-114) vs 45 (33-56) ml h-1 kg-1, p = 0.003]. In keeping with this finding, detailed social histories identified a higher exposure level in the patients to xenobiotics that are inducers of cytochrome P-450I and/or yield reactive metabolites upon processing thereby (score 7, 4-11 vs 3, 2-9, p = 0.002). However, the concentration of D-glucaric acid in urine, as a marker of phase II conjugating pathways of drug metabolism, was similar in patients and controls. This pattern of drug metabolism could predispose to oxidant stress: hence micronutrient antioxidant supplements may have therapeutic (or even prophylactic) value in tropical chronic pancreatitis.

Effect of topical oesophageal acidification on human salivary and oesophageal alkali secretion.

Recent human studies suggest that oesophageal HCO3- secretion, in conjunction with salivary HCO3- secretion and secondary oesophageal peristalsis, is important for the protection of oesophageal mucosa from refluxed gastric contents. This study evaluated simultaneously the responsiveness of oesophageal and salivary HCO3- secretion to oesophageal acidification in eight healthy subjects. A 10 cm segment of oesophagus was perfused at a constant rate of 5 ml/min with a specially designed tube assembly. Saline was used initially, and then 10 mM and 100 mM HCl. The perfusates contained 3H-polyethylene glycol (PEG) as a concentration marker to determine volumes. Corrections were applied for a small degree of contamination by swallowed saliva and refluxed gastric alkali. Oesophageal perfusion with 10 mM HCl did not cause symptoms (nausea and heartburn), but tripled the oesophageal HCO3- output from a baseline of 51 mumol/10 cm/10 min (p = 0.021), while doubling the rate of salivary HCO3- secretion from a median basal value of 140 mumol/10 min (p = 0.021). Oesophageal perfusion with 100 mM HCl was associated with symptoms of nausea and heartburn in all subjects. The median oesophageal HCO3- output increased 32 fold to 1659 mumol/10 cm/10 min (interquartile range 569 to 3373; p = 0.036), and salivary HCO3- secretion approximately tripled from basal values (p = 0.036). In conclusion, oesophageal acidification stimulates both salivary and oesophageal HCO3- secretion, responses which may be protective to the oesophageal epithelium.

Neural influences on human esophageal and salivary alkali secretion.

Esophageal secretion HCO3- ions occurs in opossum and man and may contribute to mucosal defense. Using a perfusion technique, neuroregulatory influences on esophageal and salivary HCO3- secretion were investigated in 24 healthy human subjects. The sight and smell of food increased median salivary HCO3- output from 424 to 573 mumol/15 min (P = 0.014), without significantly altering esophageal HCO3- secretion (74-105 mumol/15 min, P = 0.24). Atropine reduced both salivary (610 to 68, 17, 10, and 3 mumol/15 min in successive periods; P < 0.028) and esophageal HCO3- output (108 to 78, 35, 18, and 7 mumol/10 cm/15 min; P < 0.028, respectively. Following atropinization, cholinergic stimulation failed to increase salivary secretion but did "unmask" a small rise in esophageal alkali output (7 to 27 mumol/10 cm/15 min, P = 0.036), implicating a noncholinergic mechanism. Cold-induced pain activated sympathetic reflexes and reduced esophageal HCO3- output (91 to 64 mumol/10 cm/15 min, P = 0.041) without influencing salivary secretion. These observations support a role for the autonomic nervous system in modulating human esophageal and salivary HCO3- secretion.