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Biomedical subjects

D I Phillips

Publications and source records attributed to D I Phillips.

At least 73 records · Page 4Linked to original sources
PubMed1995

Thyroid peroxidase autoantibody fingerprints in hypothyroid and euthyroid individuals. I. Cross-sectional study in elderly women.

Human monoclonal immunoglobulin G-class autoantibodies to thyroid peroxidase (TPO), expressed as recombinant F(ab), are powerful tools for analyzing the individual components of polyclonal serum TPO autoantibodies. Four TPO-specific F(ab) interact with epitopes in two closely related domains (A and B) in the immunodominant region on TPO. In the present study, these TPO F(ab) were used to compete for serum autoantibody binding to [125I]TPO to determine the "epitopic fingerprints" in two groups of carefully controlled individuals. All individuals (14 hypothyroid and 32 euthyroid) were elderly women (60-71 yr old) with similar genetic and environmental backgrounds as well as comparable levels of serum TPO autoantibodies. Using the pool of four F(ab), serum TPO autoantibody binding was inhibited to the same extent (approximately 90%) in hypothyroid and euthyroid individuals, demonstrating that the majority of TPO autoantibodies in both groups recognize the TPO immunodominant domain. When tested individually, the F(ab) produced a spectrum of inhibition patterns, ranging from sera preferentially inhibited by domain A F(ab) to sera preferential inhibited by domain B F(ab). The ratio of inhibition by domain A F(ab) to inhibition by domain B F(ab) was similar in hypothyroid (0.11-1.39) and euthyroid (0.21-1.79) women. In conclusion, no difference in TPO autoantibody epitopes was observed in this cross-sectional study of hypothyroid and euthyroid individuals. Longitudinal studies are required to address the question of whether TPO autoantibody epitopic fingerprints are stable over time.

Adult↗
PubMed1994

Fetal growth and insulin secretion in adult life.

Recent studies suggest that NIDDM is linked with reduced fetal and infant growth. Observations on malnourished infants and studies of experimental animals exposed to protein energy or protein deficiency in fetal or early neonatal life suggest that the basis of this link could lie in the detrimental effects of poor early nutrition on the development of the beta cells of the islets of Langerhans. To test this hypothesis we have measured insulin secretion following an IVGTT in a sample of 82 normoglycaemic and 23 glucose intolerant subjects who were born in Preston, England, and whose birthweight and body size had been recorded at birth. The subjects with impaired glucose tolerance had lower first phase insulin secretion than the normoglycaemic subjects (mean plasma insulin concentrations 3 min after intravenous glucose 416 vs 564 pmol/l, p = 0.04). Insulin secretion was higher in men than women (601 vs 457 pmol/l, p = 0.02) and correlated with fasting insulin level (p = 0.04). However, there was no relationship between insulin secretion and the measurements of prenatal growth in either the normoglycaemic or glucose intolerant subjects. These results argue against a major role for defective insulin secretion as a cause of glucose intolerance in adults who were growth retarded in prenatal life.

Blood Glucose↗
PubMed1994

Thinness at birth and insulin resistance in adult life.

Type 2 (non-insulin-dependent) diabetes mellitus may originate through impaired development in fetal life. Both insulin deficiency and resistance to the action of insulin are thought to be important in its pathogenesis. Although there is evidence that impaired fetal development may result in insulin deficiency, it is not known whether insulin resistance could also be a consequence of reduced early growth. Insulin resistance was therefore measured in 81 normoglycaemic subjects, and 22 subjects with impaired glucose tolerance, who were born in Preston, UK, between 1935 and 1943. Their birth measurements had been recorded in detail. Insulin resistance was measured by the insulin tolerance test which uses the rate of fall in blood glucose concentrations after intravenous injection of insulin as an index of insulin resistance. Men and women who were thin at birth, as measured by a low ponderal index, were more insulin resistant. The association was statistically significant (p = 0.01) and independent of duration of gestation, adult body mass index and waist to hip ratio and of confounding variables including social class at birth or currently. Thinness at birth and in adult life has opposing effects such that resistance fell with increasing ponderal index at birth but rose with increasing adult body mass index. It is concluded that insulin resistance is associated with impaired development in fetal life.

Adult↗
PubMed1994

Does non-diabetic hyperglycemia predict future IHD? Evidence from the Caerphilly and Speedwell studies.

We have examined the risk of subsequent ischemic heart disease (IHD) in men according to their initial fasting plasma glucose level in a prospective cohort study (Caerphilly Collaborative Study) of 4860 middle aged men from South Wales and Bristol, U.K. Ninety-four men reported themselves to be diabetic at initial screening and fasting venous plasma glucose levels were determined in these men and in a further 4519 non-diabetic men. At follow-up new IHD events occurred twice as commonly in diabetics compared to non-diabetics and overall mortality was increased 4-fold. Among non-diabetics however, increased IHD events only occurred in men with fasting values at the upper end of the distribution of baseline plasma glucose values [at 6.8 mmol/l (122 mg/dl) or more]. This association was reduced, but remained statistically significant, after adjusting for factors associated with plasma glucose levels; body mass index, plasma triglyceride, smoking habit and pre-existing IHD. In conclusion there is no evidence of a consistent, graded increase in risk of IHD by initial fasting plasma glucose level although the risk is significantly increased in men with baseline plasma values at 6.8 mmol/l (122 mg/dl) or more, and also in diabetics. This study suggests that such levels probably represent a pre-diabetic state in many individuals. Appropriate non-pharmacological intervention may be useful in halting the progression to the diabetic state, although this should be tested in experimental studies.

Blood Glucose↗
PubMed1994

Variability of serum thyroglobulin levels is determined by a major gene.

OBJECTIVE: There are large variations in the circulating concentrations of thyroglobulin. The purpose of this study was to explore the possibility of a genetic basis for the variability of serum concentration of thyroglobulin (Tg) in euthyroid individuals. DESIGN: The serum concentration of thyroglobulin (Tg) varies several-fold in euthyroid individuals. Other circulating proteins also show wide normal ranges of concentration and these variations have been shown to have a genetic as well as an environmental basis. To explore the possibility of a genetic basis for variability in serum Tg levels, an analysis was made of serum Tg levels in 44 pairs of identical twins and 66 nuclear families who were euthyroid and thyroid autoantibody negative (thereby eliminating subclinical autoimmune thyroid disease and Tg autoantibody interference with the Tg assay). RESULTS: Each pair of identical twins tended to have a similar Tg level and the overall correlation was highly significant (r = 0.734, P < 0.001). There was no relation between Tg and TSH levels in the twins (r = 0.119; P = 0.366). Segregation analysis of the 66 families showed that where both parents had Tg levels above the overall median for the subjects (males, 19 micrograms/l; females, 33 micrograms/l), 73% of the offspring also had concentrations above these levels, compared with 30% of the offspring when one parent had a high Tg level and only 16% in families where neither parent had a high Tg level. CONCLUSIONS: Complex segregation analysis using the computer program Pointer suggested that variability in Tg levels was the result of a major dominant-like gene effect (accounting for 80% of the variability) combined with a multifactorial component. Thyroglobulin, a template for thyroid hormone production, is also a major thyroid autoantigen and inherited variations in serum Tg levels may have implications for the pathogenesis of autoimmune thyroid disease.

Adolescent↗
PubMed1994

Understanding oral glucose tolerance: comparison of glucose or insulin measurements during the oral glucose tolerance test with specific measurements of insulin resistance and insulin secretion.

The extent to which the oral glucose tolerance test can be used to estimate insulin secretion and insulin resistance has been evaluated by comparing glucose and insulin concentrations during an oral glucose tolerance test with specific measurements of insulin secretion and insulin resistance in 85 normoglycaemic subjects and 23 subjects with impaired glucose tolerance (IGT). Insulin secretion was measured by the first phase insulin response to intravenous glucose and insulin resistance by the insulin tolerance test which measures the decline of plasma glucose after the injection of a bolus of insulin. The best measure of insulin secretion was the ratio of the 30 min increment in insulin concentration to the 30 min increment in glucose concentration following oral glucose loading. This correlated with the first phase insulin release following intravenous glucose (r = 0.61, p < 0.001) but not insulin resistance (r = -0.05, p > 0.05). Insulin resistance could be estimated by the fasting insulin, proinsulin, or split proinsulin concentrations. However, fasting split proinsulin appeared to discriminate best between insulin resistance (r = -0.53, p < 0.001) and insulin secretion (r = 0.07, p > 0.05). Relative insulin resistance estimated by homeostasis model assessment (HOMA) also correlated well with insulin resistance (r = -0.57, p < 0.001) but not insulin secretion (r = 0.01, p > 0.05). We conclude that the oral glucose tolerance test can be used to derive estimates of the relative roles of insulin secretion and insulin resistance in population studies of glucose tolerance.

Blood Glucose↗
PubMed1993

Is TPO detectable in the circulation?

Recent reports have suggested that thyroid peroxidase (TPO) can be detected in the circulation of normal subjects and of patients with Graves' disease and we have attempted to confirm and extend these observations. A TPO radioimmunoassay with a sensitivity of 1 ng/mL was used to measure TPO in the sera from 20 normal subjects and 21 patients with Graves' disease. In addition, TPO was measured in serum samples from six normal subjects before and after oral TRH. We were unable to detect TPO in 46 out of the 47 sera studied (normals and autoimmune thyroid disease). In the one remaining serum (from a normal subject), low levels of TPO were apparently detected, but we demonstrated that this result was due to assay interference from TPO autoantibodies. Overall our studies suggest that (1) thyroid peroxidase is not detectable in normal subjects nor in TPO autoantibody negative patients with Graves' disease; (2) endogenous TPO autoantibodies can interfere in the TPO radioimmunoassay leading to false positive results; and (3) an acute increase of TSH in normal subjects does not result in TPO release into the circulation.

Adult↗
PubMed1993

Reproducibility of the short insulin tolerance test.

The short insulin tolerance test is a simple method of estimating insulin resistance by measuring the rate of fall of blood glucose following the intravenous administration of insulin. To determine its reproducibility, 18 healthy subjects underwent duplicate insulin tolerance tests separated by at least 1 week. Intravenous insulin (0.05 units kg-1) was administered into an antecubital vein and arterialized venous samples were obtained from a retrogradely cannulated vein on the dorsum of the hand on the same side. The test was terminated with an intravenous glucose injection 15 min after the administration of insulin. The mean whole blood glucose concentration fell from 4.6 mmol l-1 to 2.8 mmol l-1 while plasma insulin concentrations rose to supraphysiological levels and declined exponentially. The glucose disappearance rate (Kitt) calculated from the slope of the fall in log transformed blood glucose between 3 and 15 min after insulin injection ranged from 2.1 to 6.5 (mean 4.4) % min-1 during the first visit and 1.7 to 7.4 (mean 4.4) % min-1 during the second. The ratio of the within-subject to between-subject variance of the test was 0.24, the within-subject coefficient of variation was 13% and the between-subject coefficient of variation 26%. The short insulin tolerance test is reproducible and could be used to measure insulin resistance in large-scale epidemiological studies.

Adult↗
PubMed1993

Infant feeding, fetal growth and adult thyroid function.

Prolonged breast-feeding in humans is associated with increased low-density lipoprotein cholesterol and higher death rates from ischaemic heart disease in adult life. The reasons for this link are unclear. A possible explanation is that thyroid hormones present in breast milk and absorbed by the suckling infant could, by the process of hormonal imprinting, permanently down-regulate the set point of thyroid homeostasis. Thyroid hormones influence cholesterol metabolism, and could explain the link between infant feeding and the regulation of cholesterol levels in the adult. We therefore investigated whether infant feeding was related to adult thyroid function in 303 women aged 60-71 years who were born in the county of Hertfordshire, UK, where birthweight, the weight at 1 year and the method of infant feeding had been recorded routinely. Free thyroxine (FT4) concentrations but not free triiodothyronine (FT3) or thyrotrophin (TSH) were increased in the women who, as infants, had been breast-fed beyond 1 year of age (p < 0.01). In women who were bottle-fed, with or without breast-feeding, serum TSH rose and FT4 fell with increasing birthweight (p = 0.01 and p = 0.04, respectively). Although the metabolic significance of these findings is unclear, they suggest that the set point of thyroid function in the adult is determined by fetal growth and infant feeding.

Adult↗
PubMed1993

Genetic linkage analysis of thyroid autoantibodies.

Segregation analysis has suggested that the inheritance of thyroid autoantibodies (to thyroglobulin and to thyroid peroxidase) is a dominant Mendelian trait. In this study we describe an attempt to find the chromosomal location(s) of gene(s) responsible for thyroid autoantibody production. We have examined a number of restriction length polymorphisms (RFLPs) and highly polymorphic markers (mini- and microsatellite) for genetic linkage with thyroid autoantibodies using a panel of 16 families with autoimmune thyroid disease. None of the markers used in this study gave evidence of linkage, however minisatellite markers (MS1, MS31, MS32, MS43a, M851, G3) for TPO antibody, minisatellite markers (MS1, MS32, MS43a, MS51, G3) for Tg antibody, and all microsatellite markers used, provided evidence for exclusion of genetic linkage.

Adolescent↗
PubMed1993

Fetal growth and autoimmune thyroid disease.

To determine whether fetal and infant growth could influence susceptibility to autoimmune disease in adults, the occurrence of thyroid autoantibodies and autoimmune thyroiditis was studied in 305 women, aged 60-71, born in Hertfordshire and for whom details of birthweight, infant growth, and feeding were routinely recorded. Thyroglobulin autoantibody was detected in 37% of the women, thyroid peroxidase autoantibody in 41%, and autoimmune thyroiditis, defined as biochemical or clinical hypothyroidism in association with thyroid autoantibodies, in 5.6%. The proportion of women with thyroglobulin and thyroid peroxidase autoantibodies fell with increasing birthweight but was not related to weight at 1 year of age or the method of infant feeding. The prevalence of both autoantibodies rose with increasing adult body mass index but fell as the waist to hip ratio increased. These results demonstrate the importance of early environment in determining the susceptibility to autoimmune thyroid disease. The contrasting effects of adult body mass index and waist to hip ratio on antibody prevalence could be explained by their associations with different hormonal environments.

Aged↗
PubMed1992

Association between postpartum thyroid dysfunction and thyroid antibodies and depression.

OBJECTIVE: To define the relation between mood and autoimmune thyroid dysfunction during the eight months after delivery. DESIGN: Double blind comparison of the psychiatric status of women positive and negative for thyroid antibodies. Clinical examination and blood sampling for free triiodothyronine and thyroxine, thyroid stimulating hormone, and thyroid antibody concentrations at four weekly intervals. Psychiatric assessment at six, eight, 12, 20, and 28 weeks post partum. SETTING: Outpatient department of district hospital. PATIENTS: 145 antibody positive women and 229 antibody negative women delivering between August 1987 and December 1989. MAIN OUTCOME MEASURES: Thyroid status. Number of cases of mental ill health by the general health questionnaire, research diagnostic criteria, Hamilton 17 item depression scale, hospital anxiety and depression scale, and Edinburgh postnatal depression scale. RESULTS: Six weeks after delivery the general health questionnaire showed 62 (43%) antibody positive women and 65 (28%) antibody negative women had mental ill health (chi 2 = 8.18, p less than 0.005). Follow up of 110 antibody positive and 132 antibody negative women showed significantly greater depression by research diagnostic criteria in antibody positive women (47%) than antibody negative women (32%) regardless of thyroid dysfunction. Antibody positive women showed higher mean scores for depression on the Hamilton (6.01 v 3.89, p = 0.0002), Edinburgh (7.45 v 5.92, p = 0.031), and hospital depression scales (4.95 v 3.79, p = 0.003). CONCLUSION: Depressive symptoms are associated with positive thyroid antibody status in the postpartum period.

Autoantibodies↗
PubMed1992

The sonographic appearances in postpartum thyroiditis.

During the postpartum period about 50% of women with circulating thyroid autoantibodies develop a transient autoimmune thyroiditis. To determine the sonographic appearances in postpartum thyroiditis (PPT), serial ultrasound (US) scans of the thyroid were performed in 135 postpartum women who were divided into three clinical groups: Group 1, 37 antibody positive subjects who developed PPT; Group 2, 28 antibody positive subjects in whom thyroid function remained normal; Group 3, 70 antibody negative controls. Thyroid hypoechogenicity was observed in 14/31 patients (45%) who were scanned between 4 and 8 weeks postpartum and who subsequently developed PPT (Group 1) compared with 4/24 patients (17%) in Group 2 (P less than 0.05) and 1/65 patients (1.5%) in Group 3 (P less than 0.001). In antibody positive patients, the positive predictive value of an abnormal scan during this period was 78%. Between 15 and 25 weeks postpartum thyroid hypoechogenicity was present in 32/37 patients (86%) in Group 1 compared with 11/28 patients (39%) in Group 2 (P less than 0.001) and 2/70 patients (3%) in Group 3 (P less than 0.001). Sonographic abnormality persisted beyond 32 weeks postpartum in 36/41 antibody positive patients (87%) who had exhibited thyroid hypoechogenicity earlier during the study and who had late scans. The characteristic US appearance in PPT is thyroid hypoechogenicity. The role of sonography in the prediction, diagnosis and follow up of patients with PPT is discussed.

Autoantibodies↗
PubMed1992

Iodine metabolism in postpartum thyroiditis.

To investigate the etiologic role of iodine intake in postpartum thyroiditis (PPT), we have measured postpartum urinary iodine excretion serially in a large prospective study of PPT. A total of 1996 women were screened for thyroid microsomal antibody during the second trimester of pregnancy. One hundred fifty-two of the 235 antibody-positive women and an equal number of age-matched antibody-negative controls were followed postpartum with measurements of urinary iodine and thyroid function at monthly intervals for 12 months. Iodine excretion in the immediate postpartum period did not differ between the 73 women who developed PPT and the antibody-negative controls. In women with PPT with hyperthyroidism, hypothyroidism, or hyperthyroidism followed by hypothyroidism, increased urinary iodine excretion was observed between 8 and 16 weeks postpartum, which preceded the hormonal disturbances among the women with hypothyroidism. The height of the rise in urinary iodine excretion during the first 20 weeks postpartum correlated with the serum free thyroxine levels (r = 0.61, p less than 0.001). Iodine intake is unlikely to affect the prevalence of PPT. However, these data show that the hyperthyroid phase of PPT is associated with a significant release of intrathyroidal iodine due to thyroid destruction and that the same process also occurs to a lesser extent before the hormonal disturbances associated with hypothyroid PPT.

Autoantibodies↗
PubMed1992

Surrogate thyroglobulin receptors and T cell proliferation in Hashimoto's thyroiditis.

Immunoglobulin molecules on the surface of a B lymphocyte are the endogenous "receptors" to which specific antigens bind. Studies in mice have shown that a monoclonal antibody, conjugated with palmitate to provide a lipid tail, can be inserted into the cell membrane to provide a "surrogate" antigen receptor. We have investigated whether a palmitate conjugate of a human monoclonal antibody specific for thyroglobulin (TG) could function as a surrogate TG receptor on blood mononuclear cells separated into fractions enriched for T cells or depleted of T cells (non-T cells). Using flow cytometry, we detected surrogate TG receptors on non-T (but not on T) cells from 11 of 11 individuals studied (5 Hashimoto patients and 6 control donors). In contrast, endogenous TG receptors could only be detected on non-T cells from 1 of 3 Hashimoto patients and from 0 of 4 control donors. Because of the efficient binding of TG by surrogate receptors on non-T cells, we assessed the ability of such cells to present TG to T cells. Proliferation in response to TG was observed in T cells from only 1 of 5 Hashimoto patients. This low frequency of response was no different from that previously detected using cultures of T cells and autologous dendritic cells. Therefore, the successful generation of surrogate receptors on non-T cells is not associated with more efficient TG presentation of T cells. Furthermore, the significance of the present study is that the T cells, not the antigen-presenting cells, are likely to be the limiting element in the T cell proliferative response to TG and other thyroid autoantigens.

Antibodies, Monoclonal↗