ABSTRACT
In 2015 the English Newborn Screening programme expanded to include Isovaleric Acidaemia (IVA). Screening is performed by flow injection analysis tandem mass spectrometry of isovalerylcarnitine. Isovalerylcarnitine is isobaric with pivaloylcarnitine which can be present in blood due to the use of pivalic ester pro-drugs or pivalic acid derivatives used as emollients in some nipple creams; the potential for false positives (FP) is well documented. A pilot study in England screened 438,164 babies, 18 had presumptive positive results but only 4 were confirmed as true positives (TP). We developed a simple test to separate the isobaric compounds and investigate these samples further.We studied newborn screening blood spots from 122 randomised controls and 34 infants with an initial raised C5 result. Dried blood spots were eluted with 30% acetonitrile (150 µL) and injected into a Waters Acquity UPLC coupled to a Waters Premier XE tandem mass spectrometer operating in positive ion mode. Isocratic separation of isovalerylcarnitine, pivaloylcarnitine, valerylcarnitine and 2-methylbutyrylcarnitine was achieved within 8 min. Assay performance characteristics were acceptable and non-parametric reference ranges (n = 122) were determined for each analyte.If this method had been used as a second tier test for the 34 presumptive positive samples, the number of FP's would have reduced from 24 to 8 and the positive predictive value of the screening test would have increased from 29 to 56%. Introduction of this test into the screening protocol has the potential to significantly reduce FP results for IVA and prevent unnecessary anxiety.
ABSTRACT
A programme for proficiency testing of biochemical genetics laboratories undertaking urinary qualitative organic acid analysis and its results for 50 samples examined for factors contributing to poor performance are described. Urine samples from patients in whom inherited metabolic disorders have been confirmed as well as control urines were circulated to participants and the results from 94 laboratories were evaluated. Laboratories showed variability both in terms of their individual performance and on a disease-specific basis. In general, conditions including methylmalonic aciduria, propionic aciduria, isovaleric aciduria, mevalonic aciduria, Canavan disease and 3-methylcrotonyl-CoA carboxylase were readily identified. Detection was poorer for other diseases such as glutaric aciduria type II, glyceric aciduria and, in one sample, 3-methylcrotonyl-CoA carboxylase deficiency. To identify the factors that allow some laboratories to perform well on a consistent basis while others perform badly, we devised a questionnaire and compared the responses with the results for performance in the scheme. A trend towards better performance could be demonstrated for those laboratories that regularly use internal quality control (QC) samples in their sample preparation (p = 0.079) and those that participate in further external quality assurance (EQA) schemes (p = 0,040). Clinicians who depend upon these diagnostic services to identify patients with these defects and the laboratories that provide them should be aware of the potential for missed diagnoses and the factors that may lead to improved performance.
Subject(s)
Carboxylic Acids/urine , Metabolic Diseases/diagnosis , Metabolic Diseases/urine , Chemistry, Clinical/standards , Humans , Laboratories/standards , Quality Assurance, Health Care , Quality Control , Reproducibility of ResultsABSTRACT
Making a diagnosis of transient non-ketotic hyperglycinaemia (tNKH) can be difficult. We report an infant who presented in the neonatal period with symptoms of NKH. Metabolic studies performed on day 2 of life showed raised cerebrospinal fluid (CSF) and plasma glycine, and a CSF:plasma glycine ratio consistent with NKH; however, a liver biopsy performed on day 5 revealed normal liver glycine cleavage system activity. Subsequently, the child's clinical condition improved in the absence of any therapeutic medication. Clinical assessment and developmental follow-up at 5 months, 1 year, and 2 years were age-appropriate. Guidance for the investigation and management of future suspected cases of tNKH is discussed.
Subject(s)
Glycine/metabolism , Hyperglycinemia, Nonketotic/diagnosis , Amino Acids/metabolism , Diagnosis, Differential , Female , Glycine/blood , Glycine/cerebrospinal fluid , Humans , Hyperglycinemia, Nonketotic/metabolism , Infant, Newborn , Liver/metabolism , Time FactorsABSTRACT
Whenever a child presents to hospital with a reduced level of consciousness, admitting clinicians have to decide the underlying cause rapidly so that the correct emergency treatment can be initiated. Unfortunately, the clinical presentations of many of the possible diagnoses are very similar. The diagnosis often results from investigations within the clinical biochemistry laboratory. In the past, clinicians have had limited guidance on which tests to request when presented with a child with a reduced level of consciousness. Guidelines have recently been developed relating to all aspects of management of the child in a coma. Due to a lack of evidence in the literature regarding the most appropriate first line tests for children with a reduced level of consciousness, a formal consensus process ('Delphi consensus') was performed using a large multidisciplinary panel of experts. The recommendations reached by this process include the list of initial ('core') tests to request for all children with a reduced level of consciousness (excluding those immediately after suffering a convulsion and those involved in obvious trauma). Depending upon the results of these 'core' tests and the clinical condition of the child, further tests may be requested later. The key point is that all the samples have been taken at the time of presentation to provide the best chance of reaching a diagnosis and correctly treating the child. The article reviews the recommended core investigations and further tests and discusses how individual laboratories can help to implement the guidelines jointly with their Emergency and Paediatric Departments.
Subject(s)
Clinical Chemistry Tests/methods , Consciousness Disorders/diagnosis , Consciousness Disorders/therapy , Guidelines as Topic , Algorithms , Child , Consciousness Disorders/complications , Consciousness Disorders/epidemiology , Guideline Adherence , Humans , Hyperammonemia/diagnosis , Hyperammonemia/etiology , Hypoglycemia/diagnosis , Hypoglycemia/etiology , Ketosis/diagnosis , Ketosis/etiology , Selection BiasABSTRACT
BACKGROUND: Mitochondrial diseases are an important group of neurometabolic disorders in children with varied clinical presentations and diagnosis that can be difficult to confirm. AIM: To report the significance of reduced respiratory chain enzyme (RCE) activity in muscle biopsy samples from children. METHODS: Retrospective odds ratio was used to compare clinical and biochemical features, DNA studies, neuroimaging, and muscle biopsies in 18 children with and 48 without reduced RCE activity. RESULTS: Children with reduced RCE activity were significantly more likely to have consanguineous parents, to present with acute encephalopathy and lactic acidaemia and/or within the first year of life; to have an axonal neuropathy, CSF lactate >4 mmol/l; and/or to have signal change in the basal ganglia. There were positive associations with a maternal family history of possible mitochondrial cytopathy; a presentation with failure to thrive and lactic acidaemia, ragged red fibres, reduced fibroblast fatty acid oxidation and with an abnormal allopurinol loading test. There was no association with ophthalmic abnormalities, deafness, epilepsy or myopathy. CONCLUSION: The association of these clinical, biochemical and radiological features with reduced RCE activity suggests a possible causative link.
Subject(s)
Electron Transport Chain Complex Proteins/metabolism , Mitochondrial Diseases/complications , Mitochondrial Diseases/diagnosis , Muscles/enzymology , Adolescent , Age Factors , Brain/pathology , Case-Control Studies , Child , Child, Preschool , Consanguinity , Female , Humans , Infant , Lactic Acid/metabolism , Male , Mitochondrial Diseases/enzymologyABSTRACT
General mitochondrial trifunctional protein (TFP) deficiency leads to a wide clinical spectrum of disease ranging from severe neonatal/infantile cardiomyopathy and early death to mild chronic progressive sensorimotor poly-neuropathy with episodic rhabdomyolysis. Isolated long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency resulting from the common Glu510Gln mutation usually gives rise to a moderately severe phenotype with multiorgan involvement with high morbidity and mortality. However, isolated LCHAD deficiency can also be consistent with long-term survival in patients identified and treated from an early age. We present biochemical, clinical and mutation data in 9 patients spanning the full spectrum of disease. Fibroblast acylcarnitine profiling shows good correlation with clinical phenotype using the ratio C18(OH)/(C14(OH)+C12(OH)). This ratio shows a gradation of values, from high in four patients with severe neonatal disease (2.5+/-0.8), to low in two neuromyopathic patients (0.35, 0.2). Fibroblast fatty acid oxidation flux assays also show correlation with the patient phenotype, when expressed either as percentage residual activity with palmitate or as a ratio of percentage activity of myristate/oleate (M/O ratio). Fibroblasts from four patients with severe neonatal disease gave an M/O ratio of 4.0+/-0.6 compared to 1.97 and 1.62 in two neuromyopathic patients. Specific enzyme assay of LCHAD and long-chain 3-ketothiolase activity in patient cells shows lack of correlation with phenotype. These results show that measurements in intact cells, which allow all determinative and modifying cellular factors to be present, better reflect patient phenotype. Mutation analysis reveals a number of alpha- and beta-subunit mutations. Peripheral sensorimotor polyneuropathy, often as the initial major presenting feature but usually later accompanied by episodic rhabdomyolysis, is a manifestation of mild TFP protein deficiency. The mild clinical presentation and relative difficulty in diagnosis suggest that this form of TFP is probably underdiagnosed.
Subject(s)
Acyl-CoA Dehydrogenase, Long-Chain/deficiency , Lipid Metabolism, Inborn Errors/diagnosis , Lipid Metabolism, Inborn Errors/genetics , Mitochondria/pathology , Multienzyme Complexes/deficiency , Cardiomyopathies/diagnosis , Cardiomyopathies/genetics , Carnitine/analogs & derivatives , Carnitine/metabolism , Exons , Fatty Acids/metabolism , Fibroblasts/metabolism , Homozygote , Humans , Male , Mitochondrial Trifunctional Protein , Mutation , Phenotype , Polyneuropathies/diagnosis , Polyneuropathies/genetics , Prognosis , Rhabdomyolysis/diagnosis , Rhabdomyolysis/geneticsABSTRACT
Carnitine palmitoyltransferase type II (CPT II) deficiency has three basic phenotypes, late-onset muscular (mild), infantile/juvenile hepatic (intermediate) and severe neonatal. We have measured fatty acid oxidation and CPT II activity and performed mutation studies in 24 symptomatic patients representing the full clinical spectrum of disease. Severe and intermediate phenotypes show a clear correlation with biochemical indices and genetic analysis revealed causative mutations in most patients. Studies of mild phenotypes suggest a more complex interaction, with higher residual fatty acid oxidation, a wider range of CPT II activity (10-60%) but little evidence of genotype-phenotype correlation. Residual CPT II mutant protein from myopathic patients shows thermal instability at 41 degrees C. The common 'polymorphisms' V3681 and M647V are strikingly overrepresented in the myopathic patients, the implication being that they may significantly influence the manifestation of clinical disease and could therefore potentially be considered as a susceptibility variants. Among myopathic individuals, males comprised 88% of patients, suggesting increased susceptibility to clinical disease. A small number of symptomatic patients appear to have significant residual CPT II activity (42-60%) The synergistic interaction of partial deficiencies of CPT II, muscle adenosine monophosphate deaminase and possibly other enzymes of muscle energy metabolism in the aetiology of episodic myopathy deserves wider consideration.
Subject(s)
Carnitine O-Palmitoyltransferase/deficiency , Carnitine O-Palmitoyltransferase/genetics , Lipid Metabolism, Inborn Errors/enzymology , Lipid Metabolism, Inborn Errors/genetics , AMP Deaminase/metabolism , Adolescent , Adult , Cell Line , Child , Child, Preschool , Female , Fibroblasts/metabolism , Genotype , Humans , Infant , Infant, Newborn , Male , Mutation/genetics , Mutation/physiology , Oxidation-Reduction , Palmitates/metabolism , Polymorphism, Genetic/genetics , TemperatureABSTRACT
Hyperammonemia has been reported rarely in the pediatric age group in systemically ill patients. All cases resulted from infections with urea splitting organisms, which are more common among patients who have undergone surgical procedures on the urinary tract. The authors report for the first time in the pediatric literature, one patient who presented with hyperammonemic encephalopathy that resulted from urinary tract infection with Staphylococcus epidermidis and Corynebacterium sp.
Subject(s)
Brain Diseases, Metabolic/etiology , Corynebacterium Infections/complications , Hyperammonemia/etiology , Postoperative Complications/etiology , Staphylococcal Infections/complications , Staphylococcus epidermidis , Urinary Tract Infections/complications , Bacterial Proteins/metabolism , Brain Damage, Chronic/etiology , Child , Corynebacterium/enzymology , Humans , Hydronephrosis/surgery , Male , Spinal Dysraphism/complications , Staphylococcus epidermidis/enzymology , Stents , Urease/metabolism , Ureterostomy , Urinary Bladder, Neurogenic/etiology , Urinary Tract Infections/metabolismABSTRACT
Lactate, pyruvate, 3-hydroxybutyrate, acetoacetate and non-esterified fatty acids are intermediary metabolites that normally occur in blood and all have a vital role in energy metabolism. Their relative concentrations are an expression of nutritional balance, providing a snapshot of the metabolic disturbances arising in a patient. They are therefore invaluable tools to investigate intermediary metabolism in health and disease, particularly in the fields of diabetes and inherited metabolic disease. Although the analysis of these key metabolites would appear to be straightforward, with apparently simple assays widely available, there are many pitfalls in their measurement. To compound this difficulty there is limited advice available for the optimum pre-analytical and analytical aspects of their measurement and also for the interpretation of results. In this personal view, we aim to highlight a number of these problems, such as sample stability, assay interference and availability of reference ranges, with the aim of producing guidelines for the measurement and interpretation of these metabolites.
Subject(s)
3-Hydroxybutyric Acid/blood , Fatty Acids, Nonesterified/blood , Lactic Acid/blood , Metabolism, Inborn Errors/diagnosis , Pyruvic Acid/blood , Artifacts , Biomarkers/blood , Diagnostic Techniques and Procedures/standards , Humans , Predictive Value of Tests , Sensitivity and SpecificityABSTRACT
OBJECTIVES: We sought to investigate the effects of short- and long-term vitamin C therapy on endothelial dysfunction in patients with homocystinuria. BACKGROUND: Untreated homocystinuria due to cystathionine beta-synthase deficiency is associated with premature atherothrombotic disease; 25% of untreated patients suffer a vascular event by the age of 16 years and 50% by 29 years. Treatment directed at reducing homocysteine accumulation significantly reduces this risk. However, despite 'optimal' treatment and compliance, hyperhomocysteinaemia usually persists and individuals exhibit endothelial dysfunction indicative of an adverse cardiovascular prognosis. Additional intervention is therefore required to further reduce cardiovascular risk. METHODS: We investigated the endothelial effects of acute (2 g single dose) and chronic (1 g/day for 6 months) administration of oral vitamin C in 5 patients with homocystinuria (mean age 26 years, 1 male) and 5 age- and sex-matched controls. Brachial artery endothelium-dependent flow-mediated dilatation (FMD) and endothelium-independent responses to nitroglycerin (NTG) were measured using high-resolution ultrasonic vessel wall-tracking. RESULTS: Baseline: Plasma total homocysteine was 100.8 +/- 61.6 and 9.2 +/- 1.9 micromol/L in the patient and control groups, respectively (p < 0.001). FMD responses were impaired in the patient group (20 +/- 40 microm) compared with the controls (116 +/- 30 microm) (p < 0.001). Vitamin C administration: FMD responses in the patient group improved both acutely, 160 +/- 65 microm at 4 h (p < 0.001), and chronically, 170 +/- 70 microm at 2 weeks (p < 0.001) and 170 +/- 40 microm at 6 months (p < 0.001). FMD responses in the control group were unaltered (p = 0.526). Within both groups, neither the vascular response to NTG nor plasma homocysteine was altered (p > 0.4). CONCLUSIONS: Vitamin C ameliorates endothelial dysfunction in patients with homocystinuria, independent of changes in homocysteine concentration and should therefore be considered as an additional adjunct to therapy to reduce the potential long-term risk of atherothrombotic disease.
Subject(s)
Ascorbic Acid/therapeutic use , Endothelium, Vascular/physiopathology , Homocystinuria/drug therapy , Homocystinuria/physiopathology , Adult , Ascorbic Acid/administration & dosage , Blood Flow Velocity , Blood Pressure , Brachial Artery , Endothelium, Vascular/drug effects , Female , Heart Rate , Homocystine/blood , Humans , Male , Methionine/blood , Nitric Oxide/physiology , Nitroglycerin/pharmacology , Tetrahydrofolates/blood , VasodilationABSTRACT
AIMS: Raised homocysteine (hcy) levels are associated with premature coronary artery disease, but the underlying vascular mechanism and the extent to which hcy affects small vessel vasodilator responses (especially non-nitric oxide mediated pathways) are unclear. METHODS: This double-blind, placebo-controlled crossover study in 14 healthy male subjects evaluated the effects of single-dose oral methionine 15 g (to induce acute hyperhomocysteinaemia) on cutaneous microvascular vasodilator responses to incremental-dose iontophoretic administration of acetylcholine (Ach) and sodium nitroprusside (SNP) using laser Doppler fluximetry (LDF), and the effects on von Willibrand factor (vWF) levels and systemic haemodynamics. RESULTS: Methionine administration produced a three fold rise in plasma hcy levels at 8 h, which was accompanied by a significant increase in pulse pressure (53 vs 49 mmHg, P < 0.05) but no change in heart rate. Acute hyperhomocysteinaemia had no significant effect on incremental microvascular vasodilator dose-response curves to Ach and SNP, or circulating levels of vWF. CONCLUSIONS: The present study shows that acute hyperhomocysteinaemia increases pulse pressure (a marker of large vessel stiffness) but has no effect on endothelial-dependent (non-NO-mediated) microvascular vasodilation.
Subject(s)
Blood Vessels/physiology , Homocysteine/blood , Pulse , Vasodilation/physiology , Acetylcholine/pharmacology , Administration, Oral , Adult , Blood Pressure/drug effects , Blood Vessels/drug effects , Cross-Over Studies , Double-Blind Method , Heart Rate/drug effects , Homocysteine/drug effects , Humans , Laser-Doppler Flowmetry , Male , Methionine/pharmacology , Nitroprusside/pharmacology , Pressure , Skin/blood supply , Vasodilation/drug effects , Vasodilator Agents/pharmacologyABSTRACT
Carnitine palmitoyltransferase type I (CPT I) is unique among long-chain fatty acid oxidation enzymes in that there are two tissue-specific isoforms, 'hepatic' and 'muscle', which are encoded by two separate genes. The 'hepatic' isoform is expressed in liver, kidney and fibroblasts and at low levels in the heart, while the other isoform occurs in skeletal muscle and is the predominant form in heart. Reported patients with CPT I deficiency lack activity of the hepatic isoform and present before 30 months of age with hypoketotic hypoglycaemia, hepatomegaly with raised transaminases, seizures and coma. We discuss four new cases in three families showing, variously, renal tubular acidosis, transient hyperlipidaemia and, paradoxically, myopathy with elevated creatinine kinase or cardiac involvement in the neonatal period as additional features that deserve wider recognition.
Subject(s)
Carnitine O-Palmitoyltransferase/deficiency , Acidosis, Renal Tubular/enzymology , Cardiomyopathies/enzymology , Female , Humans , Hyperlipidemias/enzymology , Infant, Newborn , Male , Muscular Diseases/enzymologyABSTRACT
Although epidemiological studies suggest that people with minor impairment of renal function are at higher risk of stroke and coronary heart disease, the mechanisms underlying this relation are unclear. One explanation may lie with observations that deterioration in renal function is accompanied by elevations in plasma homocysteine concentrations. There is evidence that moderate hyperhomocysteinemia may play a causal role in atherosclerotic disease. We investigated the relations between renal function, plasma homocysteine and atherosclerosis of the carotid arteries in 128 men and women aged 69-74 years. Renal function was assessed by creatinine clearance and serum creatinine. Duplex ultrasonography was used to quantify the degree of stenosis in the extracranial carotid arteries. Severity of carotid atherosclerosis was greatest in men and women with the poorest renal function, whether measured by creatinine clearance or serum creatinine. After adjustment for plasma homocysteine, pulse pressure and other cardiovascular risk factors, the odds ratio for having carotid stenosis >30% was 4.3 (95% CI 1.4-12.9) in those whose creatinine clearance rate was 55 ml/min or less compared with those whose creatinine clearance rate was >73 ml/min. Even small decrements in renal function were associated with increased risk; people whose creatinine clearance rate was between 56 and 73 ml/min had an odds ratio of 3.8 (95% CI 1.2-11.9). Plasma homocysteine concentrations were significantly higher in people with poorer renal function, but they did not explain the associations we found between carotid atherosclerosis and creatinine clearance or serum creatinine.
Subject(s)
Carotid Artery Diseases/physiopathology , Homocysteine/blood , Kidney/physiopathology , Aged , Blood Pressure , Carotid Artery Diseases/blood , Carotid Artery Diseases/etiology , Creatinine/blood , Creatinine/metabolism , Female , Humans , Male , Odds Ratio , Pulse , Risk FactorsABSTRACT
Hyperhomocysteinaemia is considered to be an independent risk factor for vascular disease. Elevated plasma homocysteine may pose an oxidative stress, leading to the development of vascular damage. A component of this effect may be a disturbance of the extracellular aminothiol redox state. The relative contributions of plasma total homocysteine (tHcy) and plasma total cysteine (tCys) to the total antioxidant capacity (TAOC) of plasma was established in subjects with normal and elevated plasma tHcy. A total of 10 subjects with severe hyperhomocysteinaemia (due to inherited metabolic defects), 13 of their heterozygous parents and 72 normal healthy subjects were recruited to the study. The mean plasma tHcy in the patients was 91.8 micromol/l, compared with 13.2 micromol/l in the parents and 14.7 micromol/l in healthy control subjects. Plasma tCys and plasma TAOC were significantly lower in the subjects with severe hyperhomocysteinaemia compared with the parents and healthy control subjects (P<0.05). In blood samples from subjects with a normal tHcy, a positive correlation was observed between tCys and tHcy (P=0.0001). In contrast, in blood samples with tHcy >or=20 micromol/l, plasma tCys was negatively correlated with tHcy (P=0.0001). In samples with tHcy >or=20 micromol/l, tHcy was inversely correlated with TAOC (P=0.0001), whereas tCys was positively associated with TAOC (P=0.0001). Multiple regression analysis revealed that tCys was the most important independent determinant of TAOC in the patient and control groups when the effects of tHcy and several factors known to influence TAOC, such as urate, were taken into account. Thus hyperhomocysteinaemia may pose an oxidative stress not only through the direct cytotoxicity of homocysteine, but also from an associated fall in plasma cysteine.
Subject(s)
Antioxidants/metabolism , Cysteine/physiology , Homocysteine/physiology , Hyperhomocysteinemia/blood , Vascular Diseases/blood , Adolescent , Adult , Aged , Child , Cysteine/blood , Female , Homocysteine/blood , Humans , Hyperhomocysteinemia/complications , Linear Models , Male , Middle Aged , Oxidation-Reduction , Oxidative Stress/physiology , Risk Factors , Vascular Diseases/etiologyABSTRACT
Elevated plasma homocysteine is considered to be a risk factor for cardiovascular disease. The mechanisms for this effect are not fully understood but there is some evidence for a role for reactive oxygen species (ROS). This study was conducted to explore the effects of elevated plasma total homocysteine (tHcy) concentration on activity of antioxidant enzymes in the circulation. The study group consisted of 10 patients with inherited defects of homocysteine metabolism, from whom 41 blood samples were collected over a period of six months. Blood samples were also collected from 13 of their obligate heterozygous parents. For data analysis samples were classified as those with plasma tHcy < 20 microM or > 20 microM. The activity of erythrocyte superoxide dismutase (SOD) and plasma glutathione peroxidase (GSHPx) was elevated in samples with plasma tHcy > 20 microM. Moreover, a significant correlation was demonstrated between plasma GSHPx activity, plasma glutathione peroxidase protein and plasma tHcy. III vitro studies confirmed that this observation was not due to a simple chemical enhancement of enzyme activity. Homocysteine protected GSHPx from loss of activity following incubation at 37 degrees C. A similar effect was seen with another thiol-containing amino acid, cysteine. Results suggest that elevated plasma tHcy represents an oxidative stress, resulting in an adaptive increase in activity of antioxidant enzymes in the circulation.
Subject(s)
Antioxidants/metabolism , Homocysteine/blood , Adolescent , Adult , Aged , Cardiovascular Diseases/blood , Catalase/blood , Child , Cysteine/pharmacology , Erythrocytes/enzymology , Female , Glutathione Peroxidase/blood , Homocysteine/pharmacology , Humans , Male , Middle Aged , Risk Factors , Superoxide Dismutase/bloodABSTRACT
Jaundice persisting beyond the first 2 wk of life is often regarded as an indication for investigation to exclude cholestatic liver disease. Most babies with prolonged jaundice have breast milk-related jaundice, which is a benign condition. Cholestatic liver disease is usually accompanied by pale stools and yellow or orange urine. A community programme was established to ascertain the incidence of prolonged jaundice and determine whether abnormal stool and urine colour could be used to assist primary care staff in referral decisions. Data were collected on normal stool and urine colour and used to devise a colour chart and information sheet for parents. Babies with prolonged jaundice were identified and referred for investigation. In all, 3661 babies were recruited into the study, of which 127 were jaundiced at 28 d of age. Of these, 125 were breastfed. The incidence of jaundice in breastfed babies at 28 d was 9.2% (95% CI 7.8%-11.0%) Abnormal liver function tests (LFTs) were common, but no baby had abnormal stool or urine colour and none was found to have liver disease. Jaundiced breastfed babies who are well are unlikely to have serious disease. Elevated LFTs are compatible with a diagnosis of breast milk-related jaundice. Prolonged jaundice in bottle-fed babies, and persistent pallor of stools or yellow/orange urine, are rare and merit immediate referral. Parents and professionals can be advised to report pale stools without generating a large number of unnecessary referrals. Further work is needed to determine whether a colour chart reduces the mean age of referral and treatment of infants with cholestatic liver disease.
Subject(s)
Breast Feeding , Color , Feces , Jaundice, Neonatal/diagnosis , Urine , Analysis of Variance , Anxiety , Community Health Services , Data Collection , Diagnosis, Differential , Female , Humans , Infant, Newborn , Jaundice, Neonatal/etiology , Liver Diseases/diagnosis , Liver Function Tests , MaleABSTRACT
Several recent studies have indicated that an increased concentration of plasma homocysteine is an independent risk factor for the premature development of vascular disease. These important findings emphasize the need for careful selection of an appropriate analytical approach to diagnose and treat individuals who may be at risk. We compared the results obtained from the measurement of plasma total homocysteine (free + protein-bound fractions) by high-performance liquid chromatography (HPLC) with the measurement of plasma free homocystine (free fraction) by conventional ion-exchange chromatography in 10 patients with inherited defects of homocysteine metabolism and 13 obligate heterozygote individuals. This study can be used to formulate recommendations on the appropriate use of these assays in different clinical circumstances. Our results show that the concentration of total plasma homocysteine must exceed 60 mumol/L before plasma free homocystine becomes detectable by conventional ion-exchange chromatography. Similarly, assessment of the urinary excretion of homocysteine in these patients indicates that it may not become consistently detectable by conventional ion-exchange chromatography or HPLC until plasma total homocysteine exceeds 150 mumol/L. On this basis, while most patients with classical homocystinuria would be detected by analysis of plasma using conventional ion-exchange chromatography or by measurement of of the urinary homocysteine excretion, occasional patients would be missed. When monitoring patients receiving treatment for classical homocystinuria, in whom metabolic control is good, and when investigating individuals with a suspected inherited defect of cobalamin or folate metabolism, a method which measures plasma total homocysteine should be used. The identification of moderate hyperhomocysteinaemia of undefined cause investigated in relation to a history of early vacsular disease can only be identified by this approach.